[go: up one dir, main page]

WO2019008156A1 - Inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1 - Google Patents

Inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1 Download PDF

Info

Publication number
WO2019008156A1
WO2019008156A1 PCT/EP2018/068419 EP2018068419W WO2019008156A1 WO 2019008156 A1 WO2019008156 A1 WO 2019008156A1 EP 2018068419 W EP2018068419 W EP 2018068419W WO 2019008156 A1 WO2019008156 A1 WO 2019008156A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
group containing
ring atoms
ring
groups
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/068419
Other languages
English (en)
Inventor
Alexander Dömling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Rijksuniversiteit Groningen
Original Assignee
Rijksuniversiteit Groningen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rijksuniversiteit Groningen filed Critical Rijksuniversiteit Groningen
Publication of WO2019008156A1 publication Critical patent/WO2019008156A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/34—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/76—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings

Definitions

  • 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.
  • 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.
  • a similar mechanism is used by viruses and bacteria to undermine the effective immune recognitions and answer.
  • the present invention provides compounds of formula (I) :
  • R 1 and R 2 are independently from each other a hydrogen atom, a Ci-6 alkyl group or a group of formula - CH 2 -Ar or - CH 2 - CH 2 - R 3 R 4 ; 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 R 3 and R 4 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 R 3 and R 4 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.
  • R 1 and R 2 are identical.
  • R 1 and R 2 are independently from each other a group of formula -C3 ⁇ 4-Ar or -CH 2 -CH2-NR 3 R 4 .
  • both R 1 and R 2 are independently from each other a group of formula -C3 ⁇ 4-Ar.
  • R 1 is a hydrogen atom and R 2 is a group of formula -CHb-Ar.
  • R 1 and R 2 are not both hydrogen atoms.
  • R 1 and R 2 are not both methyl groups .
  • Ar is an optionally substituted phenyl group .
  • Ar is substituted by a CN group or a O2 group .
  • Ar is substituted by a group of formula - (CH 2 )n-NR 5 R 6 wherein the groups R 5 and R 6 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 R 5 and R 6 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 .
  • n is 0 or 1.
  • R 5 and R 6 are both hydrogen atoms.
  • R 5 is a hydrogen atom or a methyl group (especially a hydrogen atom) and R 6 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 ring
  • R 1 and R 2 are independently from each other a group of formula -CH 2 -CH 2 -NR 3 R 4 .
  • R 3 and R 4 are both hydrogen atoms.
  • R 3 is a hydrogen atom or a methyl group (especially a hydrogen atom) and R 4 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 C 1 - 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 ring
  • R 7 and R 8 are independently from each other are a group of formula - ⁇ C3 ⁇ 4) n -NR 5 R 6 wherein the groups R s and R 6 and n are as defined above, or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof . Moreover preferably, R 7 and R 8 are identical.
  • R 7 and R 8 are both a group of formula -CH2-NH-R 6 .
  • R 7 is a group of formula - (C3 ⁇ 4) n -NR 5 R 6 wherein the groups R 5 and R 6 and n are as defined above, or a pharmaceutically acceptable salt, ester, solvate or hydrate or a pharmaceutically acceptable formulation thereof.
  • 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.
  • 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.
  • halogen atom preferably F or Cl
  • 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.
  • alkenyl groups have one or two (especially preferably one) double bond(s)
  • alkynyl groups have one or two (especially preferably one) triple bond(s)
  • alkenyl and alkynyl refer to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl) .
  • 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.
  • 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) .
  • 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) .
  • Ci-C 4 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) .
  • heteroalkyl refers to groups in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or CI) .
  • heteroalkyl groups are groups of formulae: R a -0-Y a -, R a -S-Y a -, R a -SO-Y a -, R a -S0 2 -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 ) -CO-Y a - , R a -0-CO-N(R b ) -Y a - , R a -N(R b
  • 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-0-Y a - , R a -N (R b ) -CS-N (R c ) -Y a - , R a -N (R b
  • heteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy, isopropyloxy, butoxy, tert-butyloxy, methoxymethyl, ethoxymethyl, -CH 2 CH 2 OH, -CH 2 OH, 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 e,
  • 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.
  • 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 .
  • 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) .
  • 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.
  • 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 .
  • 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) .
  • alkylheterocycloalkyl examples include alkylheterocycloalkyl , alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, hetero- alkylcycloalkyl, heteroalkylheterocycloalkyl and hetero- alkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
  • 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 .
  • 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, NH 2 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 , pyrrol
  • 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.
  • 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.
  • 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 , heteroarylalkyl- cycloalkyl, heteroarylalkylheterocycloalkenyl , heteroarylalkyl
  • halogen or halogen atom refers to F, CI, Br or I.
  • 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, C 2 -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.
  • optionally substituted further preferably refers to a group which may be substituted by a group of formula - (C3 ⁇ 4) n -NR 5 R s wherein R 5 , R 6 and n are as defined above.
  • 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.
  • Especially preferred substituents are F, CI, Br, OH, N3 ⁇ 4, CH2NH2, N0 2 , Me, Ethyl, NMe 2
  • all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl , alkylcycloalkyl , heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may optionally be substituted.
  • 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.
  • 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,
  • SCA1 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.
  • 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.
  • 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.
  • 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.
  • 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) .
  • 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.
  • esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates .
  • 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.
  • 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 .
  • 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
  • TDS transdermal delivery system
  • 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.
  • 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.
  • excipients e.g.
  • excipients e.g. water, alcohols, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal or synthetic oils.
  • 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).
  • excipients as are e.g.
  • 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 .
  • 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 .
  • 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.
  • NSCLC 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.
  • 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 .
  • the infectious disease is caused by a virus .
  • the virus is selected from HIV, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, herpes viruses, papillomaviruses and influenza.
  • a method 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.
  • 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) .
  • the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the present invention.
  • cancers examples 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
  • 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.
  • herpes viruses e.g., VZV, HSV-1 , HAV-6
  • 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.
  • 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.
  • Candida albicans, krasei, glabrata, tropicalis, etc.
  • Cryptococcus neoformans Aspergillus (fumigatus, niger, etc.)
  • Genus Mucorales micor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Paracoccidioides brasiliensis Coccidioides immit
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 .
  • DSF Differential scanning fluorimetry
  • Uniform 15 N labeling was obtained by expressing the protein in the M9 minimal medium containing 15 NH 4 C1 as the sole nitrogen source. Unlabeled proteins were prepared as for crystallization.
  • 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 D 2 0 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 15 N- 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) .
  • MST Microscale Thermophoresis
  • Monolith NT.115 NanoTemper technologies, Munchen
  • MST Microscale Thermophoresis
  • Munchen Monolith NT.115
  • 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%.
  • 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.
  • MST 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 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés de formule (I) qui sont utiles en tant qu'inhibiteurs de l'interaction protéine/protéine PD-1/PD-L1. Les composés peuvent être utilisés dans le traitement du cancer, de maladies infectieuses et de maladies neurodégénératives telles que la schizophrénie, la maladie d'Alzheimer, la sclérose en plaques ou la maladie de Parkinson.
PCT/EP2018/068419 2017-07-07 2018-07-06 Inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1 Ceased WO2019008156A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17180369 2017-07-07
EP17180369.5 2017-07-07

Publications (1)

Publication Number Publication Date
WO2019008156A1 true WO2019008156A1 (fr) 2019-01-10

Family

ID=59298406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2018/068419 Ceased WO2019008156A1 (fr) 2017-07-07 2018-07-06 Inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1

Country Status (1)

Country Link
WO (1) WO2019008156A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN113461668A (zh) * 2021-04-30 2021-10-01 西安新通药物研究股份有限公司 一种新型联苯类衍生物及其制备方法与医药用途
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US20230044941A1 (en) * 2019-05-15 2023-02-09 Chemocentryx, Inc. Triaryl compounds for treatment of pd-l1 diseases
CN116987046A (zh) * 2023-06-25 2023-11-03 南方医科大学 一种联苯噁二唑醚类衍生物作为pd-1/pd-l1小分子抑制剂及其合成方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2842930A1 (fr) * 2012-04-24 2015-03-04 Sumitomo Chemical Company Limited Procédé de fabrication de composé d'hydroxyphénylcyclohexanol
WO2015034820A1 (fr) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Composés utiles comme immunomodulateurs
WO2015160641A2 (fr) 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Composés utiles comme immunomodulateurs
WO2017066227A1 (fr) * 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Composés utiles en tant qu'immunomodulateurs
WO2018044963A1 (fr) * 2016-09-01 2018-03-08 Bristol-Myers Squibb Company Composés biaryles utiles en tant qu'immunomodulateurs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2842930A1 (fr) * 2012-04-24 2015-03-04 Sumitomo Chemical Company Limited Procédé de fabrication de composé d'hydroxyphénylcyclohexanol
WO2015034820A1 (fr) 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Composés utiles comme immunomodulateurs
WO2015160641A2 (fr) 2014-04-14 2015-10-22 Bristol-Myers Squibb Company Composés utiles comme immunomodulateurs
WO2017066227A1 (fr) * 2015-10-15 2017-04-20 Bristol-Myers Squibb Company Composés utiles en tant qu'immunomodulateurs
WO2018044963A1 (fr) * 2016-09-01 2018-03-08 Bristol-Myers Squibb Company Composés biaryles utiles en tant qu'immunomodulateurs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MAURI LOUNASMAA: "Sur la préparation du diméthoxy-3,3' diméthyl-2,2' biphényle par la réaction d'Ullmann", ACTA CHEMICA SCANDINAVICA, vol. 22, no. 7, 1968, pages 2388 - 2390, XP055400501, DOI: 10.3891/acta.chem.scand.22-2388 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US20230044941A1 (en) * 2019-05-15 2023-02-09 Chemocentryx, Inc. Triaryl compounds for treatment of pd-l1 diseases
CN113461668A (zh) * 2021-04-30 2021-10-01 西安新通药物研究股份有限公司 一种新型联苯类衍生物及其制备方法与医药用途
CN113461668B (zh) * 2021-04-30 2022-12-09 西安新通药物研究股份有限公司 一种新型联苯类衍生物及其制备方法与医药用途
CN116987046A (zh) * 2023-06-25 2023-11-03 南方医科大学 一种联苯噁二唑醚类衍生物作为pd-1/pd-l1小分子抑制剂及其合成方法和用途

Similar Documents

Publication Publication Date Title
AU2017205707A1 (en) Inhibitors of the PD-1/PD-L1 protein/protein interaction
WO2019008156A1 (fr) Inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1
WO2019008154A1 (fr) Dérivés de 3- (azolylméthoxy)biphényle utilisés en tant qu'inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1
CA2885969C (fr) Derives de pyridine substitues et leurs compositions utiles comme inhibiteurs d'histone demethylases
CA2691987C (fr) Agents antibacteriens
CN100402523C (zh) 杂环化合物及以其为有效成分的抗肿瘤药
CA3041840A1 (fr) Compositions et procedes pour le traitement du cancer a mediation par l'ezh2
JP2006523693A (ja) ヒドロキサム酸化合物およびその使用方法
CN105315321B (zh) 具有抗肿瘤作用的化合物及其制备方法和应用
US11142535B2 (en) Heterocyclic compound as Syk inhibitor and/or Syk-HDAC dual inhibitor
WO2019008152A1 (fr) Dérivés de 3-cyanothiophène utilisés en tant qu'inhibiteurs de l'interaction protéine/protéine pd-1/pd-l1
CA3135921C (fr) Compose contenant du quinolyle, composition pharmaceutique et utilisation associee
CN115894439B (zh) 一种靶向降解gpx4的protac嵌合体及其制备方法和应用
KR101055236B1 (ko) 알파-케토아미드 유도체, 및 이의 제조 방법 및 용도
RU2697519C1 (ru) Средство пептидной природы, включающее псма-связывающий лиганд на основе производного мочевины, способ его получения и применение для получения конъюгата с лекарственным и диагностическим агентом
JP2016504272A (ja) 官能化９−ブロモ−カンプトテシン誘導体
WO1997046551A1 (fr) Analogues de quinolylmethylen-oxindole substitues en tant qu'inhibiteurs des tyrosines kinases
EP3628664A1 (fr) Inhibiteurs irréversibles de kras g12c mutantes
AU741867B2 (en) Matrix metalloproteinase inhibitors
US8084471B2 (en) Proteomimetic compounds as inhibitors of the interaction of nuclear receptor with coactivator peptides
WO2007045962A2 (fr) Nouveaux inhibiteurs hdac
CN115368306B (zh) 含四氢异喹啉类结构的hdac抑制剂、组合物及其用途
EP2086950A2 (fr) Inhibiteurs de l'histone desacetylase
US6172256B1 (en) Chiral-β-amino acid compounds and derivatives thereof
US11655269B2 (en) Prodrug-type anticancer agent using cancer-specific enzymatic activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18742733

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18742733

Country of ref document: EP

Kind code of ref document: A1