WO2018026971A1 - Symmetric or semi-symmetric compounds useful as immunomodulators - Google Patents

Symmetric or semi-symmetric compounds useful as immunomodulators Download PDF

Info

Publication number
WO2018026971A1
WO2018026971A1 PCT/US2017/045185 US2017045185W WO2018026971A1 WO 2018026971 A1 WO2018026971 A1 WO 2018026971A1 US 2017045185 W US2017045185 W US 2017045185W WO 2018026971 A1 WO2018026971 A1 WO 2018026971A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
biphenyl
methoxy
hydroxyethyl
Prior art date
Application number
PCT/US2017/045185
Other languages
French (fr)
Inventor
Minghua Wang
Original Assignee
Arising International, Llc
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 Arising International, Llc filed Critical Arising International, Llc
Priority to AU2017305399A priority Critical patent/AU2017305399A1/en
Priority to CA3030773A priority patent/CA3030773A1/en
Priority to JP2019527771A priority patent/JP2019530732A/en
Priority to EP17837640.6A priority patent/EP3493804A1/en
Priority to CN201780024052.4A priority patent/CN109195602B/en
Publication of WO2018026971A1 publication Critical patent/WO2018026971A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • 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
    • C07D213/60—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 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C07D277/66—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2 with aromatic rings or ring systems directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention generally relates to compounds useful as inhibitors of the PD- 1/PD-Ll protein/protein and CD80/PD-L1 protein/protein interactions.
  • Programmed cell death- 1 (PD-1, CD279) protein is a member of the CD28 superfamily that can suppress activation signals upon interaction with either of its natural ligands, program cell death-ligand 1 (PD-Ll, CD274, B7-H1) and PD-L2 (CD273, B7-DC).
  • PD-1 and its ligands are broadly expressed in immune systems and play critical roles in immune modulation including T cell activation and tolerance (Sharpe et. al., Nat. Imm. 2007).
  • T cells When PD-Ll expressing cells contact T cells that express PD-1, it results in attenuation of T cell activities in cytokine secretion, cytolytic activity and proliferation, in response to antigenic stimulation.
  • T cell exhaustion a biological significance of PD-1/PD-L1 interaction in attenuating infectious immunity, tumor immunity and in facilitating chronic infection and tumor progression.
  • PD-Ll has also been shown to interact with CD80.
  • the interaction between PD-Ll and CD80 on immune cells has also been shown to inhibit immune response (Deng et. al., J Immunol. 2015).
  • Monoclonal antibodies that block the PD-1 -mediated immune checkpoint pathway can prevent T cell down regulation and promote immune responses against cancer and infectious diseases (Harvey et. al., Clin Pharmacol Ther 2014). Ample clinical and preclinical evidence has demonstrated that inhibition of PD-1/PD-L1 interaction with PD-l-or PD-L1- specific antibodies can restore immune response to diverse forms of cancer and infectious diseases (Dong et. al., Nat. Med. 2002; Dong et. al., J Mol. Med. 2003).
  • PD- 1/PD-Ll -targeting antibodies including pembrolizumab, nivolumab and atezolizumab
  • IO immuno-oncology
  • studies have demonstrated that interference with PD-l/PD- Ll interaction can also enhance T cell activity in chronic infection systems, thus expected to function against viral infections, like HIV (Attanasio et. al., Immunity. 2016; Porichis et. al., Curr HIV/ AIDS Rep. 2012).
  • blockage of the PD-l/PD-Ll pathway can also enhance responses to vaccination, including therapeutic vaccination in the context of viral infection (Ha et. al., J. Exp. Med. 2008). More recent discoveries also suggested therapeutic value of disrupting PD1/PD-L1 interaction for patients with certain inflammation and neurodegenerative diseases like Alzheimer's disease (Bodhankar et. al., Stroke 2015; Baruch et. al., Nat Med. 2016).
  • agents that block the interaction of PD-Ll with either PD-1 or CD80 are considered beneficial for diverse therapeutic areas, including but not limited to cancer, viral infection and vaccination.
  • PD-l/PD-Ll -targeting antibodies there is still great demand for more potent, better selective and more easily administered therapeutics against PD-l/PD-Ll and/or CD80/PD-L1 protein-protein interactions.
  • the elucidation of structural details of the human PD-l/PD-Ll complex has provided unique insights into the molecular mechanism of PD-l/PD-Ll protein-protein interaction (Zak et. al., Oncotarget 2016; Zak et. al., Structure 2015). Such has afforded an opportunity for structural- based design of small molecule inhibitors to target PD-l/PD-Ll and/or CD80/PD-L1 interaction.
  • potent small molecules that can have activity as inhibitors of the interaction of PD-Ll with PD-1 and/or CD80, and thus may be useful for therapeutic administration to enhance immunity against cancer and/or infectious diseases.
  • These small molecules are expected to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are crucial to become efficient medicines to promote human health.
  • inhibitors of the PD-l/PD-Ll protein/protein and CD80/PD-L1 protein/protein are the inhibitors of the PD-l/PD-Ll protein/protein and CD80/PD-L1 protein/protein
  • A is a bivalent arene or a bivalent heteroarene
  • Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a 6-membered heterocyclic ring, a 9- to 10-membered aromatic hydrocarbon ring, or a 9- to 10-membered heterocyclic ring
  • Y and Y' are independently, null (direct bond), -CHRi-, -CH2-CH2-, - Ri-, -0-, -OCH2-, -CH2O-, -SCH2-, -CH 2 S-, -SOCH2-, -CH2SO- or -S0 2 CH 2 -
  • Ri is H, C 1-6 alkyl, or C3-6 cycloalkyl
  • R 3 and R' 3 are independently H, SO 2 H 2 ,
  • R 5 and Rg are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or heteroaryl or R 5 and 5 form a C 3 - 8 cycloalkyl, heterocyclyl, or heteroaryl ring
  • R 7 is H, aryl, heteroaryl, acetyl, CH 2 CH 2 OH, CH 2 CH 2 HCOCH 3 , C 3 -C 8 alkyl carboxylic acid, C 3 -C 8 alkyl amide, C 3 -C 8 alkyl alcohol, - CH 2 -Ar, or -CH 2 -heterocyclyl
  • R 4 , R' 4 , Z, and Z' are independently H, halogen, CHF 2 , CF 3 , CN, Ci-6 alkyl, C 1-6 alkoxy, aryl, or heteroaryl.
  • Formula (I) is represented by following Formula (II):
  • Ring B and Ring B' are independently a 6- membered aromatic hydrocarbon ring or a 6-membered heterocyclic ring;
  • X 3 , and X' 3 are
  • Y and Y' are independently -CHRi-, -CH 2 -CH 2 -, -NRi-, -0-, -OCH 2 -, -CH 2 O-, -SCH 2 -, -CH 2 S-, -SOCH 2 -, -CH 2 SO- or -SO 2 CH 2 -, and Ri is H, Ci -6 alkyl, or C 3-6 cycloalkyl;
  • Formula (I) is represented by following Formula (III):
  • Ring B and Ring B' are independently a 9- to 10-membered aromatic hydrocarbon ring or a 9- to 10-membered heterocyclic ring;
  • X 2 , X' 2, X 3 , and X' 3 are independently C or N;
  • U and U' are independently C and N;
  • Y and Y' are independently, null (direct bond), -CHRi- , -CH 2 -CH 2 -, - Ri-, -0-, -OCH 2 -, -CH 2
  • R a ' are independently COR', OMe, halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 cycloalkyl, CN, CF 3; CH 2 CF 3 ;
  • R' is C 1-6 alkyl;
  • R and R b ' are independently C 1-6 alkyl, C 2 - 6 alkynyl, C 1-6 cycloalkyl or alkyl halogen, and
  • R 3 and R' 3 are the same, R4 and R' 4 are the same, Y and Y' are the same, Z and Z' are the same, or Ring B and Ring B' are the same.
  • R 3 and R' 3 are the same, R4 and R' 4 are the same, Y and Y' are the same, Z and Z' are the same, and Ring B and Ring B' are the same.
  • the inhibitors of the PD-l/PD-Ll protein/protein and CD80/PD-L1 protein/protein interactions are 2-( ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl ⁇ methoxy)-3 - methylphenyl]methyl ⁇ amino)ethan-l-ol, 2- ⁇ [(4- ⁇ [3-( ⁇ 4-[(azetidin-l-yl)methyl]-2- methylphenoxy ⁇ methyl)-2-chlorophenyl]methoxy ⁇ -3 -methylphenyl)m ethyl] amino ⁇ ethan- 1 - ol, l-[(4- ⁇ [3-( ⁇ 4-[(azetidin-l-yl)methyl]-2-methylphenoxy ⁇ methyl)-2-
  • described herein is a method of treating a disease associated with the modulation of PD-1/PD-L1 or CD80/PD-L1 interaction comprising administering to a patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease is an infection, inflammation cancer, or neurodegenerative disorders like Alzheimer's disease.
  • Figure 1 shows the docking pose of compound 1-1 in PD-L1 dimer.
  • Figure 2 shows the docking pose of compound I- 10 in PD-L1 dimer.
  • Prodrugs mean any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound.
  • Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Tautomers mean compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. One of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • Isomers mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers, and those that are non- superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. A chiral compound can exist as either individual enantiomer or as a mixture thereof. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • Solvates refer to a complex formed by combination of solvent molecules with the compound of Formula (I).
  • the solvent can be an organic compound, an inorganic compound, or a mixture thereof.
  • Pharmaceutically acceptable salts represent those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like.
  • the acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • Therapeutically effective amount means an amount of compound or a composition of the present invention effective in inhibiting the PD-1/PD-L1 protein/protein and CD80/PD- Ll protein/protein interactions, and thus producing the desired therapeutic effect.
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • C 1-6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl.
  • Alkyl also includes saturated aliphatic hydrocarbon radicals wherein one or more hydrogen atoms are replaced with deuterium, for example, CD 3 .
  • branched alkyl refers to an alkyl group as defined above except that straight chain alkyl groups in the specified range are excluded.
  • branched alkyl includes alkyl groups in which the alkyl is attached to the rest of the compound via a secondary or tertiary carbon.
  • isopropyl is a branched alkyl group.
  • cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C 3 - 6 cycloalkyl refers to cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br and/or I).
  • a halogen i.e., F, CI, Br and/or I.
  • Ci-6 haloalkyl refers to a Ci to C 6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH 2 ) 0- 4 CF 3 .
  • C(O) or CO refers to carbonyl.
  • S(0) 2 or S0 2 refers to sulfonyl.
  • S(O) or SO refers to sulfinyl.
  • aromatic hydrocarbons refers to hydrocarbons with sigma bonds and delocalized pi electrons between carbon atoms forming rings.
  • aryl refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl, dihydroindenyl and the like.
  • An aryl of particular interest is phenyl.
  • heterocyclic refers to heteroaryl, saturated heterocyclic, and unsaturated heterocyclic with a double bond.
  • heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a heterobicyclic ring selected from quinolinyl, isoquinolinyl, and quinoxalinyl.
  • Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl.
  • a class of heteroaryls of interest consists of (i) 5- and 6-membered heteroaromatic rings containing from 1 to 3 heteroatoms independently selected from N, O and S, and (ii) heterobicyclic rings selected from quinolinyl, isoquinolinyl, and quinoxalinyl.
  • Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.
  • Examples of 4- to 7-membered, saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl.
  • Examples of 4- to 7-membered, unsaturated heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).
  • A is a bivalent bi-aryl or bi-heteroaryl core
  • a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Suzuki palladium catalyzed cross-coupling of aryl/heteroaryl halide (II) and aryl/heteroaryl boronic acid/ester (III) as shown in Scheme 1-3.
  • A is Xi-3, ⁇ -3 , Y, Y', Z and Z' are defined as in Formula (I).
  • A is , R 3 -R4, R 3 '-R 4 ', X1-3, X' 1 -3 , Y, Y', Z and Z' are defined as in Formula (I).
  • a semi-symmetric compound of Formula (I) can be synthesized via Chan-Lam copper catalyzed C-N coupling reaction of aryl/heteroaryl boronic acid (III) with N-H containing aryl/heteroaryl (V) as shown in Scheme 3.
  • A is R3-R4, R3 -R4' , X1-3, X' 1-3, Y, Y', Z and Z' are defined as in Formula (I).
  • A is a bivalent aryl or heteroaryl core
  • a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Mitsunobu reaction of aryl/heteroaryl alcohol (VI) and aryl/heteroaryl phenol (VII).
  • a compound of formula (I) can also be prepared by O-alkylation or N-alkylation of aryl/heteroaryl (VII or IX) with aryl/heteroaryl halides (VIII) under basic condition (Scheme 4 to Scheme6).
  • A is -R4 R3 -R4', X1-3, X' 1-3, Y, Y', Z and Z' are defined as in Formula (I).
  • IP A isopropyl alcohol
  • Example 1 2-( ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -2-methylphenoxy) methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl ⁇ methoxy)-3-methylphenyl]methyl ⁇ amino)ethan- l-ol (1-1).
  • Example 1-1 The compound of Example 1 was synthesized via the route shown in the scheme below.
  • Step-2 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzoate ( ⁇ -1)
  • Step-3 dimethyl 2,2'-dimethyl-[l, r-biphenyl]-3,3'-dicarboxylate (IV-1)
  • 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzoate III-l 1.5 g, 5.4 mmol
  • methyl-3-bromo-2-methylbenzoate II-2 1.1 g, 4.9 mmol
  • CsF 2.2 g, 14.7 mmol
  • Pd(dppf)Cl 2 250 mg, 0.07 mmol
  • Step-4 (2,2'-dimethyl-[l, r-biphenyl]-3,3'-diyl)dimethanol (IV-2)
  • Step-6 4,4'-(((2,2'-dimethyl-[l,r-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(3- methyl benzaldehyde), IV-4
  • Step-7 2-( ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -2-methylphenoxy)methyl]- 2,2'-dimethyl-[l, l'-biphenyl]-3-yl ⁇ methoxy)-3-methylphenyl]methyl ⁇ amino)ethan-l-ol, 1-1.
  • Example 2 2- ⁇ [(4- ⁇ [3-( ⁇ 4-[(azetidin-l-yl)methyl]-2-methylphenoxy ⁇ methyl)-2- chlorophenyl]methoxy ⁇ -3-m hylphenyl)methyl]amino ⁇ ethan-l-ol (1-2).
  • Example 2 The compound of Example 2 was synthesized via the route shown in the scheme below.
  • Step-1 synthesis of l,3-bis(bromomethyl)-2-chlorobenzene
  • Step-2 synthesis of 4,4'-(2-chloro-l,3-phenylene)bis(methylene)bis(oxy)bis(3-methyl benzaldehyde) (IV-5)
  • Step-3 synthesis of 4-(3-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-2- chlorobenzyloxy)-3-methylbenzaldehyde (IV-6) and l-[(4- ⁇ [3-( ⁇ 4-[(azetidin-l-yl)methyl]-2- methylphenoxy ⁇ methyl)-2-chlorophenyl]methoxy ⁇ -3-methylphenyl)methyl]azetidine (1-3)
  • Step-4 synthesis of 2- ⁇ [(4- ⁇ [3-( ⁇ 4-[(azetidin-l-yl)methyl]-2- methylphenoxy ⁇ methyl)-2-chlorophenyl] methoxy ⁇ -3 -methylphenyl)methyl] amino ⁇ ethan- 1 - ol (1-2)
  • Example 3 The compound of Example 3 was synthesized via the route shown in the scheme below.
  • Step-1 4,4'-(2,2'-dimethylbiphenyl-3,3'-diyl)bis(methylene)bis(oxy)bis(2,6- dimethoxybenzaldehyde) (IV-7)
  • Step-2 (S)-l-(4-((3'-((4-formyl-3,5-dimethoxyphenoxy)methyl)-2,2'- dimethylbiphenyl-3-yl)methoxy)-2,6-dimethoxybenzyl)piperidine-2-carboxylic acid (IV-8) & (2S)-l- ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2S)-2-carboxypiperidin-l-yl]methyl ⁇ -3,5-dimethoxyphenoxy)methyl]- 2,2'-dimethyl-[l, -biphenyl]-3-yl ⁇ methoxy)-2,6-dimethoxyphenyl]methyl ⁇ piperidine-2- carboxylic acid (1-4)
  • Example 4 (2 S)- 1 - ⁇ [4-( ⁇ 3 ' -[(4- ⁇ [(2-hy droxy ethyl)amino]methyl ⁇ -3 , 5 - dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl ⁇ methoxy)-2,6- dimethoxyphenyl]methyl ⁇ piperidine-2-carboxylic acid (1-5).
  • Example 6 l- ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -2-methyl phenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl ⁇ methoxy)-2- methoxyphenyl]methyl ⁇ azetidin-3-ol (1-7).
  • Step-1 4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde ( ⁇ -4)
  • Step-2 l-(4-((3-bro -2-methylbenzyl)oxy)-2-methoxybenzyl)azetidin-3-ol(II-5)
  • Step-1 4-((3'-((4-((3-hydroxyazetidin-l-yl)methyl)-3-methoxy phenoxy)methyl)-2,2' dimethyl-[ 1 , 1 '-biphenyl]-3 -yl)methoxy)benzaldehyde
  • Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use.
  • reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
  • Step-2 l- ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ phenoxy)methyl]-2,2'- dimethyl-[l,r-biphenyl]-3-yl ⁇ methoxy)-2-methoxyphenyl]methyl ⁇ azetidin-3-ol (1-7)
  • Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use.
  • a round-bottom flask charge (2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)methanol III-2 (1.2 mmol), (4-bromo-3-methylthiophen-2-yl)methanol ( ⁇ -6) (1.0 mmol) and 2G palladium Xphos precatalyst (0.03 mmol)(CAS number 1310584- 14-5), add previously deoxygenated tetrahydrofuran (5 mL) and 0.5 M aq potassium phosphate, tribasic solution (5 mL, 2.5 mmol), place under nitrogen and sparged with additional nitrogen for 10 minutes.
  • reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
  • Step-2 6- ⁇ [3-(5- ⁇ [(5-formyl-6-methoxypyridin-2-yl)oxy]methyl ⁇ -4- methylthiophen-3-yl)-2-methylphenyl]methoxy ⁇ -2-methoxypyridine-3-carbaldehyde
  • Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (4-(3-(hydroxymethyl)-2- methylphenyl)-3-methylthiophen-2-yl)methanol (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar.
  • Step-3 2- ⁇ [(6- ⁇ [3-(5- ⁇ [(5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -6-methoxypyridin- 2-yl)oxy ] methyl ⁇ -4-methylthiophen-3 -yl)-2-methylphenyl]methoxy ⁇ -2- methoxypyridin-3-yl)methyl]amino ⁇ ethan-l-ol (1-8)
  • Example 8 2-( ⁇ [4-( ⁇ 4-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3-methoxy phenoxy) methyl]-3-methylthiophen-2-yl ⁇ methoxy)-2-methoxyphenyl]methyl ⁇ amino)ethan-l-ol (1-9)
  • Step-2 4-( ⁇ 4-[(4-formyl-3-methoxyphenoxy)methyl]-3-methylthiophen-2- yl ⁇ methoxy)-2-methoxybenzaldehyde
  • Step-3 2-( ⁇ [4-( ⁇ 4-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3-methoxyphenoxy) methyl]-3-methylthiophen-2-yl ⁇ methoxy)-2-methoxyphenyl]methyl ⁇ amino)ethan-l-ol (1-9)
  • Step-l methyl 2-cyano-3- -formyl-2-methylphenoxy)methyl)benzoate
  • Step-2 methyl 3-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-2- cyanobenzoate
  • Step-3 2-((4-(azetidin- 1 -ylmethyl)-2-methylphenoxy)methyl)-6-
  • saturated aqueous ammonium chloride is charged to a multineck round- bottom flask and cooled to - 5 °C (inner temperature) to which is added the crude reaction mixture slowly over 15 minutes. After addition is complete the temperature is maintained at - 5 °C for 20 minutes.
  • the reaction is diluted with dichloromethane (15 ml ) and the layers are separated.
  • the aqueous layer is extracted with dichloromethane (1 x 15 ml) and the combined organic portions are washed with 1.5 N aqueous hydrochloric acid (1 x 1.3 ml ), saturated aqueous sodium chloride ( 1 x 1.3 ml ) and dried over sodium sulfate.
  • Step-4 2-((4-(azetidin- 1 -ylmethyl)-2-methylphenoxy)methyl)-6-((4- formylphenoxy) methyl nzonitrile ( ⁇ -5)
  • Step-5 2-( ⁇ 4-[(azetidin-l-yl)methyl]-2-methylphenoxy ⁇ methyl)-6- ⁇ [4-( ⁇ [(4- oxoazetidin-2-yl)methyl ]amino ⁇ methyl)phenoxy]methyl ⁇ benzonitrile (1-10)
  • Product was purified via preparative HPLC with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5- ⁇ particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
  • Compound 1-11 is prepared in the same manner as the general procedure described above using aldehyde ( ⁇ -5) and N-(2-aminoethyl)acetamide.
  • Compound 1-12 is prepared in the same manner as the general procedure described above using aldehyde ( ⁇ -5) and 2-aminoethan-l-ol.
  • Compound 1-13 is prepared in the same manner as the general procedure described above using aldehyde ( ⁇ -5) and azetidine hydrochloride salt.
  • Step-1 4-((lH-indol-4-yl)methoxy)-2,6-dimethoxybenzaldehyde
  • Step-2 4-((l-(4-formylbenzyl)-lH-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde
  • Step-3 2-( ⁇ [4-( ⁇ 4-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3,5- dimethoxy phenoxy )methy 1] - 1 H-indol- 1 -y 1 ⁇ methy l)pheny ljmethy 1 ⁇ amino)ethan- 1 -ol (I- 14)
  • Example-14 2-( ⁇ [4-( ⁇ l-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ phenyl)methyl]- lH-indazol-4- l methox -2 6-dimethox hen l meth l amino ethan-l-ol (1-15)
  • Compound 1-15 is prepared in the same manner as the procedure described for I- 14 except using ( lH-indazol-4-yl)methanol (III-6) and azetidine hydrochloride salt.
  • step 1-3 The detailed procedures for step 1-3 are described in Example 9.
  • Example-16 preparation of compound 1-17, 1-18, 1-19, 1-20 and 1-21.
  • Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (2,2'-dimethyl-[l, - biphenyl]-3,3'-diyi)dimethanol IV-2 (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar.
  • Example-18 2-( ⁇ [4-( ⁇ 3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3,5- dimethoxyphenoxy) methyl]-2'-methyl-[l, -biphenyl]-3-yl ⁇ methoxy)-2,6- dimethoxyphenyl]methyl ⁇ amino) ethan-l-ol, 1-26.
  • Step-1 dimethyl 2-methyl-[l, -biphenyl]-3,3'-dicarboxylate (IV-10)
  • Step-2 (2-methyl-[l, -biphenyl]-3,3'-diyl)dimethanol (IV-11)
  • Step-3 3,3'-bis(bromomethyl)-2-methyl-l, 1 '-biphenyl, IV-12
  • Example-19 3,3'-bis( ⁇ [(5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -6- methoxypyridin-2-yl)oxy]methyl ⁇ )-[l, -biphenyl]-2-carbonitrile, 1-30.
  • Step-1 dimethyl 2-cyano-[l, -biphenyl]-3,3 ! -dicarboxyiate (IV-14)
  • Step-3 3,3 ! -bis(((5-formyl-6-methoxypyridin-2-yi)oxy)methyl)-[l, -biphenyi]-2- carbonitrile, IV-16
  • Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and 3,3'-bis(hydroxymethyl)- [l, -biphenyl]-2-carbonitrile IV-15 (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar.
  • Step-4 follow the standard reductive amination procedures described for Example- 16 to yield the title compound 1-30.
  • Example-20 3,3'-bis[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3,5- dimethoxyphenoxy)methyl] -[l,l '-biphenyl]-2-carbonitrile, 1-31.
  • Step-1 3,3 ! -bis(bromomethyl)-[l, -biphenyi]-2-carboiiitrile, IV-17
  • Step-2 3,3'-bis((4-formyl-3,5-dimethoxyphenoxy)methyl)-[l, -biphenyl]-2- carbonitrile, IV-18
  • Step-3 3,3'-bis[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -3,5- dimethoxyphenoxy)methyl] -[l,l '-biphenyl]-2-carbonitrile, 1-31.
  • Step-1 4,4'-(((2,2'-dimethyl-[l, -biphenyl]-3,3 , -diyl)bis(methylene))bis(oxy))bis(2- hydroxy-5 -methyl benzaldehyde), I V- 1 .
  • Step-2 5,5 , -((((((((2,2'-dimethyi-[l ,r )iphenyi]-3,3 , -diyi) ⁇
  • Step-3 5-[(5- ⁇ [3'-( ⁇ 5-[(5-cyanopyridin-3-yl)methoxy]-4- ⁇ [(2-hydroxyethyl)amino]- methyl ⁇ -2-methylphenoxy ⁇ methyl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl]methoxy ⁇ -2- ⁇ [(2- hydroxy ethyl) amino]methyl ⁇ -4-methylphenoxy)methyl]pyridine-3-carbonitrile, 1-50.
  • Example-22 5-[(5- ⁇ [3'-( ⁇ 5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2- methylphenoxy ⁇ methyl)-2,2'-dimethyl-[l, l'-biphenyl]-3-yl]methoxy ⁇ -2-(hydroxymethyl)-4- methylphenoxy)methyl]pyridine-3-carbonitrile, 1-54.
  • the ethanol is removed by evaporation, the aqueous phase is extracted with ethyl acetate three times and the combined organic phase was washed with NaOH (1.0 M, 15 mL), water (15 mL) and brine (15 mL) and dried over anhydrous Na 2 S0 4 , filtered and concentrated.
  • the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/petroleum ether) to yield the title molecule 1-54.
  • Example-23 5- ⁇ [4-chloro-5-( ⁇ 2-cyano-3'-[(4- ⁇ [(2-hydroxyethyl)amino] methyl ⁇ - 2-methylphenoxy)methyl]-[l, l'-biphenyl]-3-yl ⁇ methoxy)-2- ⁇ [(2-hydroxy ethyl)
  • Step- J 3'-(((tert-butyldimethylsilyl)oxy)methyl)-3-(hydroxymethyi)-[l,r- biphenyl]-2-carbonitriie, 11-10.
  • Step-2 3'-(((tert-butyldimethylsilyl)oxy)methyl)-3-((2-chloro-4-formyl-5- hydroxyphenoxy) rnethyl)-[ 1 , 1 ! -biphenyl]-2-carbonitrile, IV-22.
  • Step-3 5-((5-((3'-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-[l, l '-biphenyl]-3- yl) methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile, IV-23.
  • Step-4 5-((4-chloro-5-((2-cyano-3'-(hydroxymethyl)-[l, -biphenyl]-3- yl)methoxy)-2-formyl phenoxy)methyl)nicotinonitrile, IV-24.
  • Step-5 5-((4-chloro-5-((2-cyano-3'-((4-formyl-2-methylphenoxy)methyl)-[l,r- biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-25.
  • Example 24 5-[(4-chloro-2- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -5-( ⁇ 3'-[(4- ⁇ [(2- hydroxy ethyl) amino]methyl ⁇ -3,5-dimethoxyphenoxy)methyl]-2-methyl-[l, l'-biphenyl]-3- yl ⁇ methoxy) phenoxy)methyl]pyridine-3-carbonitrile, 1-69.
  • the compound 1-69 can be synthesized by Method A shown below: :
  • Step- 1-6 in Method A follow the stardard procedures described for Example-23 to yield the tiltle compound 1-69.
  • the compound 1-69 can be synthesized by Method B shown below:
  • the compounds listed in Table 2 are prepared using methods similar to those described for the preparation of 1-50, 1-54, 1-59 and 1-69.
  • Example 25 2-[( ⁇ 2-[3'-(6- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -[l,2,4]triazolo[l,5- a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6- yl ⁇ methyl)amino]ethan- 1 -ol, 1-73.
  • the compound 1-73 can be synthesized via the route shown in the scheme below.
  • Example 26 2-[( ⁇ 2-[3'-(6- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ imidazo[l,2-a]pyridin- 2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]imidazo[ 1 ,2-a]pyridin-6-yl ⁇ methyl) amino]ethan- 1 - ol 1-74.
  • the compound 1-74 can be synthesized via the route shown in the scheme below.
  • Example 27 2-[( ⁇ 2-[3'-(6- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -l,3-benzoxazol-2-yl)- 2,2'-dimethyl-[l, l'-biphenyl]-3-yl]-l,3-benzoxazol-6-yl ⁇ methyl)amino]ethan-l-ol, 1-75.
  • the compound 1-75 can be synthesized via the route shown in the scheme below.
  • Example 28 3-(5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -l,3-benzoxazol-2-yl)-3'-[(4- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-2-carbonitrile, 1-87
  • the compound 1-87 can be synthesized via the route shown in the scheme below:
  • FIG. 1 shows docking pose of compound I-l in PD-Ll dimer (Panel A).
  • Figure 2 shows docking pose of compound 1-10 in PD-Ll dimer (Panel B)
  • compounds 1-1 and 1-5 dock well with PD-L1 dimer. In both cases, hydrophobic channel accommodates the designed novel core scaffold in the center; two pseudo symmetrical side chains attached to the core are extended to either side of the dimer interface. It is believed that such designed inhibitors can effectively induce/stabilize PD-L1 dimer formation, therefore potently disrupting PD-1/PD-L1 protein- protein and CD80/PD-L1 protein-protein interaction. Other compounds disclosed herein are believed to exhibit the same properties in docking experiments. Thus, these compounds can also be potent and selective inhibitors of the PD-1/PD-L1 protein/protein and CD80/PD-L1 protein/protein interactions.
  • the activity of the compounds of Formula (I) to inhibit PD-1/PD-L1 protein-protein interaction can be readily investigated using biochemical and cellular assays well accepted in the field.
  • HTRF Homogenous time-resolved fluorescence
  • HTRF binding assay The ability of the designed compounds to physically disrupt PD-1/PD-L1 interaction was measured by HTRF binding assay.
  • the tag is the Fc portion of immunoglobulin (PD-l-Ig).
  • PD-L1 it is the 6 histidine motif (PD-Ll-His). All required fusion proteins with desired tags were obtained from commercial sources.
  • HTRF assay buffer consists of lxPBS supplemented with 0.1% (w/v) bovine serum albumin and 0.05% (v/v) Tween-20.
  • PD-Ll-His (30 nM final) and PD- l-Ig (10 nM final) in HTRF assay buffer were pre-incubated at RT for 30 min, followed by addition of inhibitors and incubated for another 30 min.
  • HTRF detection was achieved using Tb cryptate-labeled anti-Ig antibody (1 nM final) and d2-labeled anti-His antibody (20 nM final).
  • Antibodies were diluted in HTRF assay buffer and dispensed on top of the binding reaction. The reaction mixture was allowed to equilibrate for 60 min at RT before the resulting signal (665nm/620nm ratio) was obtained using an En Vision fluorometer.
  • DMSO concentration in the solution is 0.2%.
  • Additional binding assays can be established between PD- 1-Ig and PD-L2-His or CD80-His/PD-Ll -Ig, in a similar format.
  • the IC 50 of the designed compounds in disrupting PD-1/PD-L1 interaction will be expected to fall in the range of 0.01 nM to 100 uM, depending on the corresponding structure-activity relationship.
  • IC 50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
  • T-cell activation assay Human peripheral blood mononuclear cells (PBMC) can be isolated from blood buffy coats by commercial kits available.
  • PBMC peripheral blood mononuclear cells
  • CD4+ T cells can be isolated with CD4 enrichment kit as per the manufacturer's instructions.
  • Mouse Ig capture beads can be coated with anti-CD3, anti-CD28 and PD-Ll Fc fusion by incubation under rotation at 4°C.
  • CD4+ T cells can be cultured in 96-well plates together with coated beads, with or without designed compounds at varying concentrations for 3 days at 37°C in RPMI1640 Glutamax I supplemented with 4% human AB serum.
  • Culture supernatant can be removed to measure cytokine expression (e.g. IFNs, IL-2) by ELISA, DELFIA or Luminex technology.
  • the amount of cytokine can be determined by comparing with a standard curve of known amounts of human cytokines.
  • the remaining T cells can be quantified by standard cell proliferation/survival assays (e.g. Thymidine incorporation, CellTiter-Glo) according to manufacturer's instructions. Potent inhibitor compounds will disrupt PD-Ll protein binding to PD-1 on the T cell surface, thus resulting in enhanced cytokine expression and promotion of T cell proliferation/activity.
  • the ability of the designed compounds to functionally inhibit endogenous PD-l/PD- Ll interaction and promote T cell activity can be measured by mixed lymphocyte reaction assay.
  • Human PBMCs can be isolated from leukapheresis packs using Ficoll-Paque Plus as per the manufacturer's instructions. Cells can be cultured in serum-free RPMI 1640 for short period at 37°C. After removal of nonadherent cells, remaining monocytes can be cultured in RPMI 1640 supplemented with 5% human AB serum, 2 ng/mL GM-CSF, and 10 ng/mL IL4. Fresh media with cytokine supplements can be added every 2 to 3 days.
  • Mature dendritic cells can be induced by addition of TNFa on day 6 and culture for 24 hours.
  • CD4+ T cells can be isolated from PBMCs using magnetic beads as per the manufacturer's instructions.
  • CD4+ T cells can be cultured in 96 well-flat bottom plates together with allogeneic dendritic cells at an optimal ratio (e.g. 1 :2.5), using RPMI 1640 supplemented with 10% human AB serum.
  • Dendritic cells can be treated with 100 mg/mL of mitomycin C before addition. Designed compounds or DMSO can be added as desired. Cytokine expression and T cell proliferation/activity can be measured as indicated above according to manufacturer's instructions. Potent inhibitor compound is expected to promote cytokine expression and T cell proliferation/activity.
  • the compounds of Formula (I) possess activity as inhibitors of the PD-l/PD-Ll interaction, and therefore, may be used in the treatment of diseases dependent on or associated with the PD-l/PD-Ll interaction.
  • the compounds of the present disclosure may be utilized to treat infectious diseases such as Hepatitis C, as well as multiple forms of cancer.

Abstract

A compound having Formula I:(I), or a pharmaceutical acceptable salt thereof. A is a bivalent arene or a bivalent heteroarene; Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a 6-membered heterocyclic ring, a 8- to 10-membered aromatic hydrocarbon ring, or a 8- to 10-membered heterocyclic ring; Y and Y' are independently, null (direct bond), -CHR1-, -CH2-CH2-, -NR1-, -0-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO-, or -SO2CH2-, and R1 is H, C1-6 alkyl, or C3-6 cycloalkyl.

Description

SYMMETRIC OR SEMI-SYMMETRIC COMPOUNDS USEFUL AS
IMMUNOMODULATORS
This application claims priority to US Provisional Application No. 62/370,679, filed August 3, 2016, which is incorporated by reference for all purposes as if fully set forth herein.
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention generally relates to compounds useful as inhibitors of the PD- 1/PD-Ll protein/protein and CD80/PD-L1 protein/protein interactions.
Discussion of the Related Art
Programmed cell death- 1 (PD-1, CD279) protein is a member of the CD28 superfamily that can suppress activation signals upon interaction with either of its natural ligands, program cell death-ligand 1 (PD-Ll, CD274, B7-H1) and PD-L2 (CD273, B7-DC). PD-1 and its ligands are broadly expressed in immune systems and play critical roles in immune modulation including T cell activation and tolerance (Sharpe et. al., Nat. Imm. 2007). When PD-Ll expressing cells contact T cells that express PD-1, it results in attenuation of T cell activities in cytokine secretion, cytolytic activity and proliferation, in response to antigenic stimulation. Conditions of tumor progression or chronic infections could lead to chronic antigen stimulation, that results in induction of PD-1 expression and eventually reduced T cell activity (so called "T cell exhaustion"). Such suggests a biological significance of PD-1/PD-L1 interaction in attenuating infectious immunity, tumor immunity and in facilitating chronic infection and tumor progression (Keir et. al., Annu Rev Immunol. 2008). PD-Ll has also been shown to interact with CD80. The interaction between PD-Ll and CD80 on immune cells has also been shown to inhibit immune response (Deng et. al., J Immunol. 2015).
Monoclonal antibodies that block the PD-1 -mediated immune checkpoint pathway can prevent T cell down regulation and promote immune responses against cancer and infectious diseases (Harvey et. al., Clin Pharmacol Ther 2014). Ample clinical and preclinical evidence has demonstrated that inhibition of PD-1/PD-L1 interaction with PD-l-or PD-L1- specific antibodies can restore immune response to diverse forms of cancer and infectious diseases (Dong et. al., Nat. Med. 2002; Dong et. al., J Mol. Med. 2003). To date, several PD- 1/PD-Ll -targeting antibodies (including pembrolizumab, nivolumab and atezolizumab) have already been approved as immuno-oncology (IO) therapeutics to treat different forms of cancer, including melanoma, non-small cell lung cancer, kidney cancer, Hodgkin lymphoma and bladder cancer, etc. Further, studies have demonstrated that interference with PD-l/PD- Ll interaction can also enhance T cell activity in chronic infection systems, thus expected to function against viral infections, like HIV (Attanasio et. al., Immunity. 2016; Porichis et. al., Curr HIV/ AIDS Rep. 2012). In addition, blockage of the PD-l/PD-Ll pathway can also enhance responses to vaccination, including therapeutic vaccination in the context of viral infection (Ha et. al., J. Exp. Med. 2008). More recent discoveries also suggested therapeutic value of disrupting PD1/PD-L1 interaction for patients with certain inflammation and neurodegenerative diseases like Alzheimer's disease (Bodhankar et. al., Stroke 2015; Baruch et. al., Nat Med. 2016).
Therefore, agents that block the interaction of PD-Ll with either PD-1 or CD80 are considered beneficial for diverse therapeutic areas, including but not limited to cancer, viral infection and vaccination. Despite recent approval of PD-l/PD-Ll -targeting antibodies, there is still great demand for more potent, better selective and more easily administered therapeutics against PD-l/PD-Ll and/or CD80/PD-L1 protein-protein interactions. Recently, the elucidation of structural details of the human PD-l/PD-Ll complex has provided unique insights into the molecular mechanism of PD-l/PD-Ll protein-protein interaction (Zak et. al., Oncotarget 2016; Zak et. al., Structure 2015). Such has afforded an opportunity for structural- based design of small molecule inhibitors to target PD-l/PD-Ll and/or CD80/PD-L1 interaction.
In this invention, applicant discovered potent small molecules that can have activity as inhibitors of the interaction of PD-Ll with PD-1 and/or CD80, and thus may be useful for therapeutic administration to enhance immunity against cancer and/or infectious diseases. These small molecules are expected to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are crucial to become efficient medicines to promote human health.
SUMMARY OF THE INVENTION
The inhibitors of the PD-l/PD-Ll protein/protein and CD80/PD-L1 protein/protein
Figure imgf000003_0001
interactions are a compound having Formula I:
(I), or a pharmaceutical acceptable salt thereof. A is a bivalent arene or a bivalent heteroarene; Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a 6-membered heterocyclic ring, a 9- to 10-membered aromatic hydrocarbon ring, or a 9- to 10-membered heterocyclic ring; Y and Y' are independently, null (direct bond), -CHRi-, -CH2-CH2-, - Ri-, -0-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO- or -S02CH2-, and Ri is H, C1-6 alkyl, or C3-6 cycloalkyl; R3 and R'3 are independently H, SO2 H2,
SO2 R5R6, SO2 HR7,
Figure imgf000004_0001
, CH2 R5R5, or CH2 HR7, wherein R5 and Rg are independently H, C1-6 alkyl, C3-8 cycloalkyl, or heteroaryl or R5 and 5 form a C3-8 cycloalkyl, heterocyclyl, or heteroaryl ring, and R7 is H, aryl, heteroaryl, acetyl, CH2CH2OH, CH2CH2 HCOCH3, C3-C8 alkyl carboxylic acid, C3-C8 alkyl amide, C3-C8 alkyl alcohol, - CH2-Ar, or -CH2-heterocyclyl; and R4, R'4, Z, and Z' are independently H, halogen, CHF2, CF3, CN, Ci-6 alkyl, C1-6 alkoxy, aryl, or heteroaryl.
Further described is an isomer or tautomer thereof, a pharmaceutical acceptable solvate thereof, or a pharmaceutical acceptable prodrug thereof.
In one aspect, the Formula (I) is represented by following Formula (II):
Figure imgf000004_0002
(II). Ring B and Ring B' are independently a 6- membered aromatic hydrocarbon ring or a 6-membered heterocyclic ring; Xi, ΧΊ, X2, and X'2 are independently CR2, C=0 or NR2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, Ci-6 alkoxyl, C3-7 cycloalkyl, C3-7 heterocyclyl, or OCH2Ar; and X3, and X'3 are
independently C or N. Y and Y' are independently -CHRi-, -CH2-CH2-, -NRi-, -0-, -OCH2-, -CH2O-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO- or -SO2CH2-, and Ri is H, Ci-6 alkyl, or C3-6 cycloalkyl;
In one aspect, the Formula (I) is represented by following Formula (III):
Figure imgf000004_0003
(III). Ring B and Ring B' are independently a 9- to 10-membered aromatic hydrocarbon ring or a 9- to 10-membered heterocyclic ring;Xi, and ΧΊ are independently CR2, C=0 or NR2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, C1-6 alkoxyl, C3-7 cycloalkyl, C3-7 heterocyclyl, or OCH2Ar; X2, X'2, X3, and X'3 are independently C or N; U and U' are independently C and N; V and V are O, S, -(CH2)2-, -CR'-, or -N=; and Y and Y' are independently, null (direct bond), -CHRi- , -CH2-CH2-, - Ri-, -0-, -OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO- or -S02CH2- and Ri is H, C1-6 alkyl, or C3-6 cycloalkyl;
Figure imgf000005_0001
and Ra' are independently COR', OMe, halogen, C1-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl, CN, CF3; CH2CF3; R' is C1-6 alkyl; R and Rb' are independently C1-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl or alkyl halogen, and V is -(CH2)2-, -CR'-, or -N=,wherein Y and Y' are independently in each occurrence -NRi-, -0-, -OCH2-, -SCH2-, -SOCH2-, or -S02CH2-, provided that the nitrogen of ring A cannot be the connecting atom with Y and Y' .
Figure imgf000006_0001
Figure imgf000007_0001
 (direct bond), - R , -0-, -CH20-, or -CH2S, provided that U in ring B and IT in ring B' cannot be nitrogen.
In one aspect, in Formula (I), R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, or Ring B and Ring B' are the same.
In one aspect, in Formula (I), R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, and Ring B and Ring B' are the same.
In one aspect, the inhibitors of the PD-l/PD-Ll protein/protein and CD80/PD-L1 protein/protein interactions are 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 - methylphenyl]methyl}amino)ethan-l-ol, 2-{[(4-{[3-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy } methyl)-2-chlorophenyl]methoxy } -3 -methylphenyl)m ethyl] amino } ethan- 1 - ol, l-[(4-{[3-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy}methyl)-2- chlorophenyl]methoxy}-3-methylphenyl)methyl]azetidine, (2S)-l-{[4-({3'-[(4-{[(2S)-2- carboxypiperidin-l-yl]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, - biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2-carboxylic acid, (2S)-1- {[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'- dimethyl-[l, -biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2- carboxylic acid, 2-( { [4-( { 3 '- [(4- { [(2-hy droxy ethyl)amino]methyl } -3 , 5 - dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2,6- dimethoxyphenyl]methyl}amino)ethan-l-ol, l-{[4-({3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3- yl}methoxy)-2-methoxyphenyl]methyl}azetidin-3-ol, 2-{[(6-{[3-(5-{[(5-{[(2- hy droxy ethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-4-methylthiophen-3-yl)-2- methylphenyl]methoxy}-2-methoxypyridin-3-yl)methyl]amino}ethan-l-ol, 2-({[4-({4-[(4-
{[(2-hydroxyethyl)amino]methyl}-3-methoxyphenoxy) methyl]-3-methylthiophen-2- yl }methoxy)-2-methoxyphenyl]methyl } amino)ethan- 1 -ol, 2-({4-[(azetidin- 1 -yl)methyl]-2- methylphenoxy }methyl)-6-{ [4-({ [(4-oxoazetidin-2- yl)methyl]amino}methyl)phenoxy]methyl}benzonitrile, N-(2-{[(4-{[3-({4-[(azetidin-l- yl)methyl]-2-methylphenoxy}methyl)-2-cyanophenyl]methoxy}
phenyl)methyl]amino}ethyl)acetamide, 2-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy}methyl)-6-[(4-{[(2- hy droxy ethyl)amino]methyl}phenoxy)methyl]benzonitrile, 2-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy} methyl)-6-({4-[(azetidin-l-yl)methyl]phenoxy} methyl)benzonitrile, 2-({[4- ({4-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-lH-indol-l- yl }methyl)phenyl]methyl } amino)ethan- 1 -ol, 2-({ [4-({ 1 -[(4- { [(2- hydroxyethyl)amino]methyl }phenyl)methyl]- lH-indazol-4-yl }methoxy)-2,6- dimethoxyphenyl]methyl}amino)ethan-l-ol, 2,6-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3- methoxyphenoxy)methyl]benzonitrile, N-[(4-{[3'-({4-[(cyclopropylamino)methyl]-3,5- dimethoxyphenoxy}methyl)-2,2'-dimethyl-[l, -biphenyl]-3-yl]methoxy}-2,6- dimethoxyphenyl)methyl]cyclopropanamine, 4-{[({4-[(3'-{[3,5-dimethoxy-4-({[(4- oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]m
yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]methyl}azetidin-2-one, 2-[({6-[(3'-{[(5- {[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[l, l'-biphenyl]-3- yl)methoxy]pyridin-3-yl}methyl)amino]ethan-l-ol, 2-[({6-[(3'-{[(5-{[(2- hydroxyethyl)amino]methyl } -6-methoxypyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '- biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)amino]ethan-l-ol, N-{2-[({6-[(3'- {[(5-{[(2-acetamidoethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethy [1,1 '-biphenyl]-3 -yl)methoxy]-2-methoxypyridin-3 -yl }methyl)amino] ethyl } acetamide, (2R,4R)-l-({6-[(3'-{[(5-{[(2R,4R)-2-carboxy-4-hydroxypyrrolidin-l-yl]methyl}-6- methoxypyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl)methoxy]-2- methoxypyridin-3-yl}methyl)-4-hydroxypyrrolidine-2-carboxylic acid, (2R,4R)-4-hydroxy-l- ({6-[(3'-{[(5-{ [(2 -hydroxy ethyl)amino]methyl}-6-methoxypyridin-2 -yl)oxy]methyl}-2,2'- dimethyl-[l, -biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)pyrrolidine-2- carboxylic acid, (3R)-l-{[4-({3'-[(4-{[(3R)-3-hydroxypyrrolidin-l-yl]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 - methylphenyl]methyl}pyrrolidin-3-ol, (2R,4R)-l-{[4-({3'-[(4-{[(2R,4R)-2-carboxy-4- hydroxypyrrolidin- 1 -yljmethyl } -2-methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl}methoxy)-3-methylphenyl]methyl}-4-hydroxypyrrolidine-2-carboxylic acid, 2-({[4-({3'- [(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2'-methyl-[l, - biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-l-ol, 2-[({4-[(2-{3-[(4- {[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin- 4-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol, 2-[({4-[(6-{3-[(4-{[(2- hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin-2- yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol, 2-({[4-({2'-chloro-3'-[(4-{[(2- hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 - methylphenyl]methyl}amino)ethan-l-ol, 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-[l, -biphenyl]-2-carbonitrile, 3,3'-bis({[(5-{[(2- hydroxyethyl)amino]methyl }-6-methoxypyridin-2-yl)oxy]methyl })-[ 1 , 1 '-biphenyl]-2- carbonitrile, 3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[l, - biphenyl]-2-carbonitrile, 3,3'-bis({4-[(azetidin-l-yl)methyl]-3,5-dimethoxyphenoxy}methyl)- [l,l'-biphenyl]-2-carbonitrile, 3,3'-bis({4-[(3-hydroxyazetidin-l-yl)methyl]-3,5- dimethoxyphenoxy}methyl)-[l, -biphenyl]-2-carbonitrile, 3,3'-bis({[3,5-dimethoxy-4-({[(4- oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl})-[l,l'-biphenyl]-2-carbonitrile, 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, l'-biphenyl]-2- carbonitrile, N-{2-[({6-[(2'-cyano-3'-{[(5-{[(2-acetamidoethyl)amino]methyl}-6- methoxypyridin-2-yl)oxy]methyl}-[l, -biphenyl]-3-yl)methoxy]-2-methoxypyridin-3- yl}methyl)amino]ethyl}acetamide, 2-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-6-{4-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]pyridin-2-yl}benzonitrile, 2-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-6-{4-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]pyridin-2-yl}benzonitrile, 2-{[(5- {[(2-hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-6-(4-{[(5-{[(2- hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}pyridin-2-yl)benzonitrile, 2 ({4-[(2-{3-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2- methylphenyl}pyridin-4-yl)methoxy]-3-methylphenyl}methyl)amino]ethan-l-ol, 3,3'- bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[l, l'-biphenyl]-2,2'- dicarbonitrile, 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, - biphenyl]-2,2'-dicarbonitrile, 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]- [l, -biphenyl]-2,2'-dicarbonitrile, 5,5'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-[3,3'-bipyridine]-4,4'-dicarbonitrile, 2-[({4-[(4-{3-[(4-{[(2- hy droxy ethyl)amino]methyl } -3 , 5 -dimethoxyphenoxy)m ethyl] -2-methylphenyl } -3 - methylthiophen-2-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol, 2-[({4-[(4- { 3 - [(4- { [(2-hy droxy ethyl)amino]methyl } -2-methylphenoxy)m ethyl] -2-methylphenyl } -3 - methylthiophen-2-yl)methoxy]-3-methylphenyl}methyl)amino]ethan-l-ol, 2-({[4-({5'-[(4- { [(2-hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-4,4'-dimethyl-[3, 3'- bithiophene]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol, 2-({[4-({5'-[(4-{[(2- hy droxy ethyl)amino]methyl } -2-methylphenoxy)methyl]- 1 , 1 '-dimethyl- 1H, 1 Ή-[2,2'- bipyrrole]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol, 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-4-{ [(2-hy droxy ethyl)amino]methyl }-2-methylphenoxy }methyl)- 2,2'-dimethyl-[l, l'-biphenyl]-3-yl]methoxy}-2-{ [(2-hy droxy ethyl)amino]methyl}-4- methylphenoxy)methyl]pyridine-3-carbonitrile, 2-({[4-({3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'- dimethyl-[ 1 , 1 '-biphenyl]-3-yl }methoxy)-5-methyl-2-[(pyridin-3- yl)methoxy]phenyl]methyl}amino)ethan-l-ol, 5-[(4-chloro-5-{[3'-({2-chloro-5-[(5- cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl}phenoxy}methyl)-2,2'- dimethyl-[l,r-biphenyl]-3-yl]methoxy}-2-{[(2- hydroxyethyl)amino]methyl}phenoxy)methyl]pyridine-3-carbonitrile, 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-2-methyl-4-[(methylamino)methyl]phenoxy}methyl)-2,2'- dimethyl-[l, -biphenyl]-3-yl]methoxy}-4-methyl-2-
[(methylamino)methyl]phenoxy)methyl]pyridine-3-carbonitrile, 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2,2'-dimethyl-
[l, -biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3- carbonitrile, 5-[(3-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2,2'- dimethyl-[l, l'-biphenyl]-3-yl]methoxy}-4-m 5-
[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-
2-methyl-[l, -biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4- methylphenoxy)methyl]pyridine-3-carbonitrile, 3,3'-bis({5-[(5-cyanopyridin-3-yl)methoxy]- 4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy}methyl)-[l, -biphenyl]-2,2'- dicarbonitrile, 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2- yl)oxy ]methyl } - [ 1 , 1 '-biphenyl] -3 -yl)methoxy ] -2- { [(2- hydroxyethyl)amino]methyl}phenoxy}methyl)pyridine-3-carbonitrile, 5-{[5-({2-cyano-3'- [(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, -biphenyl]-3- yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile, 5- {[4-chloro-5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]- [1,1 '-biphenyl]-3 -yl }methoxy)-2- { [(2- hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile, 3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-[(4-{[(2- hydroxyethyl)amino]methyl}-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-[l, -biphenyl]-2- carbonitrile, 5-{[5-({2'-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3-yl }methoxy)-2-{ [(2 -hydroxy ethyl)amino]methyl }- 4-methylphenoxy]methyl}pyridine-3-carbonitrile, 5-{[5-({2-cyano-3'-[(4-{[(2- hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-2- {[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3-carbonitri 5-[(4- chloro-2- { [(2-hy droxy ethyl)amino]methyl } -5 - [(3 '- { [(5 - { [(2- hydroxyethyl)amino]methyl }pyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy]phenoxy)methyl]pyridine-3-carbonitrile, 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2- hydroxy ethyl)amino]methyl }pyridin-2-yl)oxy]methyl } -[ 1 , 1 '-biphenyl]-3 -yl)methoxy]-2- [(cyclopropylamino)methyl]phenoxy}methyl)pyridine-3-carbonitrile, 5-{[5-({2-cyano-3'-[(4- {[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2'-methyl-[l, l'-biphenyl]- 3-yl}methoxy)-2-{ [(2 -hydroxy ethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3- carbonitrile, 5-[(5-{[2-cyano-3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2- hydroxyethyl)amino]methyl } -2-methylphenoxy }methyl)-[ 1 , 1 '-biphenyl]-3 -yljmethoxy } -2- {[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 2-({[4- ({3'-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'- dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 -methylphenyljmethyl } amino)ethan- 1 -ol, 5-[(4- chloro-2-{[(2-hydroxyethyl)amino]methyl}-5-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-2-methyl-[l,l'-biphenyl]-3- yl}methoxy)phenoxy)methyl]pyridine-3-carbonitrile, 5-[(2-{[(2- hydroxyethyl)amino]methyl}-5-({3'-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-4- methylphenoxy)methyl]pyridine-3-carbonitrile, 5-[(2-{ [(2 -hydroxy ethyl)amino]methyl }-5- ({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl- [l, -biphenyl]-3-yl}methoxy)-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 2-({[4-({3'- [(4-{[(2-hydroxyethyl)amino]methyl}-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]- 2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-2,6-dimethoxyphenyl]methyl } amino)ethan- 1 -ol, 5 - { [(3 - { [(2-hy droxy ethyl)amino]methyl } -6- [(3 '- { [(5 - { [(2-hydroxy ethyl)amino]methyl } -6- methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[l, -biphenyl]-3-yl)methoxy]pyridin-2- yl)oxy]methyl}pyridine-3-carbonitrile, 2-({[4-({3'-[(2-chloro-4-{[(2- hy droxy ethyl)amino]methyl}-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[ 1,1'- biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol, 5-[(5-{[2-cyano-3'-({5- [(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2'-methyl- [l,l'-biphenyl]-3 -yljmethoxy }-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3- carbonitnle, 5-({2-[(azetidin-l-yl)methyl]-5-{[3'-({4-[(azetidin-l-yl)methyl]-5-[(5- cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2-cyano-[l, -biphenyl]-3- yl]methoxy}-4-methylphenoxy}methyl)pyridine-3-carbonitrile, 5-({2-[(azetidin-l- yl)methyl]-5-{[3'-({4-[(azetidin-l-yl)methyl]-5-[(5-cyanopyridin-3-yl)methoxy]-2- methylphenoxy}methyl)-2,2'-dimethyl-[l, -biphenyl]-3-yl]methoxy}-4- methylphenoxy}methyl)pyridine-3-carbonitrile, 2-[({2-[3'-(6-{[(2- hy droxy ethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '- biphenyl]-3-yl]-[l,2,4]triazolo[l,5-a]pyridin-6-yl}methyl)amino]ethan-l-ol, 2-[({2-[3'-(6- { [(2-hydroxyethyl)amino]methyl }imidazo[ 1 ,2-a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]- 3-yl]imidazo[l,2-a]pyridin-6-yl}methyl)amino]ethan-l-ol, 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-2,2'-dimethyl-[l,l'-biphenyl]-3-yl]-l,3- benzoxazol-6-yl}methyl)amino]ethan-l-ol, 2-({2-[3'-(5-{ [(2-hy droxy ethyl)amino]methyl}- 1 ,3 -benzoxazol-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]- 1 ,3 -benzoxazol-5-yl } amino)ethan-
1- ol, 2 ({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-l,3-benzothiazol-2-yl)-2,2'-dimethyl- [l,r-biphenyl]-3-yl]-l,3-benzothiazol-5-yl}methyl)amino]ethan-l-ol, 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl}-l,3-benzothiazol-2-yl)-2,2'-dimethyl-[l,l'-biphenyl]-3-yl]- benzothiazol-6-yl}methyl)amino]ethan-l-ol, 3, 3'-bis(6-{ [(2-hy droxy ethyl)amino]methyl}- [l,2,4]triazolo[l,5-a]pyridin-2-yl)-[l,r-biphenyl]-2,2'-dicarbonitrile, 3,3'-bis(6-{[(2- hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-[l, l'-biphenyl]-2,2'-dicarbonitrile, 2-[({2- [3 H7" { [(2-hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)-2,2'-dimethyl- [l,r-biphenyl]-3-yl]-[l,2,4]triazolo[l,5-a]pyridin-7-yl}methyl)amino]ethan-l-ol, 2-{[(8- chloro-2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimeth^ [1,1 '-biphenyl]-3 -yl } -[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6-yl)methyl]amino} ethan- 1 -ol, 3 -(8- chloro-6-{[(2-hydroxyethyl)amino]methyl} 1,2,4]triazolo[l,5-a]pyridin-2-yl)-3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l,l'-biphenyl]-2-carbonitrile, 3'- [(4- { [(2-hy droxy ethyl)amino]methyl } -3 , 5 -dimethoxyphenoxy)methyl] -3 -(6- { [(2- hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-[ 1 , 1 '-biphenyl]-2- carbonitrile, 3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2- hy droxy ethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-[ 1 , 1 '-biphenyl]-2- carbonitrile, 2-{[(2-{3'-[(4-{ [(2-hy droxy ethyl)amino]methyl }-2-methylphenoxy )methyl]-2,2'- dimethyl-[l, -biphenyl]-3-yl}-l,3-benzoxazol-6-yl)methyl]amino}ethan-l-ol, 3-(5-{[(2- hy droxy ethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4-{ [(2-hy droxy ethyl)amino]methyl}-
2- methylphenoxy)methyl]-[l,r-biphenyl]-2-carbonitrile, 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- l,3-benzoxazol-5-yl)methyl]amino}ethan-l-ol, 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- l,3-benzothiazol-5-yl)methyl]amino}ethan-l-ol, 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- l,3-benzothiazol-6-yl)methyl]amino}ethan-l-ol, 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- [l,2,4]triazolo[l,5-a]pyridin-6-yl)methyl]amino}ethan-l-ol, 3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2- hydroxy ethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-2'-methyl-[ 1 , 1 '-biphenyl]-2- carbonitrile, 2-{[(4-chloro-2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl } - 1 ,3 -benzoxazol-6- yl)methyl] amino } ethan- 1 -ol, 3 -(4-chloro-6- { [(2-hy droxy ethyl)amino]methyl } - 1 ,3 - benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, - biphenyl]-2-carbonitrile, 3-(5-{[(2-hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4- { [(2-hy droxy ethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-[l, -biphenyl]-2- carbonitrile, 3-(4-chloro-6-{[(2-hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4- { [(2-hy droxy ethyl)amino]methyl }-2-methylphenoxy)methyl]-2'-methyl-[ 1 , 1 '-biphenyl]-2- carbonitrile, 2-[({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-2H-indazol-2-yl)-2,2'-dimethyl- [1,1 '-biphenyl]-3 -yl]-2H-indazol-5-yl }methyl)amino]ethan- 1 -ol, 2-[({2-[3 '-(6- { [(2- hydroxyethyl)amino]methyl}-2H-indazol-2-yl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl]-2H- indazol-6-yl}methyl)amino]ethan-l-ol, 2-[({2-[3'-(6-{[(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-b]pyridazin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl]imidazo[l,2-b]pyridazin-6-yl}methyl)amino]ethan-l-ol, 2-[({6-[3'-(2-{[(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]- 3 -yl]imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-2-yl }methyl)amino] ethan- 1 -ol, 2-[({2-[3 '-(6- { [(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-a]pyrazin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl]imidazo[l,2-a]pyrazin-6-yl}methyl)amino]ethan-l-ol, 2-({[4-({3-[2-(4-{[(2- hy droxy ethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-yl]-2- methylphenyl } methoxy)-3 -methylphenyl]methyl } amino)ethan- 1 -ol, 2-( { [4-( { 3 -[2-(3 - { [(2- hydroxyethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-y^
methylphenyl } methoxy)-3 -methylphenyl]methyl } amino)ethan- l-ol, 2-{[(4-{6-[2-(4-{[(2- hy droxy ethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-yl]-7-methyl- 1,3- benzoxazol-2-yl } phenyl)methyl] amino } ethan- 1 -ol, 2- { [(3 - { 6- [2-(3 - { [(2- hy droxy ethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-yl]-7-methyl- 1,3- benzoxazol-2-yl}phenyl)methyl]amino}ethan-l-ol, 2-[({2-[3'-(5-{[(2- hydroxyethyl)amino]methyl}-2,3-dihydro-lH-isoindol-2-yl)-2,2'-dimethyl-[l, l'-biphenyl]-3- yl]-2,3-dihydro-lH-isoindol-5-yl}methyl)amino]ethan-l-ol, or 2-[({6-[3'-(3-{[(2- hy droxy ethyl)amino]methyl }-2-methoxy-5H, 6H,7H-pyrrolo[3, 4-b]pyri din-6-yl)-2,2'- dimethyl-[l, -biphenyl]-3-yl]-2-methoxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-3- yl}methyl)amino] ethan- l-ol. In another aspect, described herein is a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In another aspect, described herein is a method of treating a disease associated with the modulation of PD-1/PD-L1 or CD80/PD-L1 interaction comprising administering to a patient the compound of Formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, in the method, the disease is an infection, inflammation cancer, or neurodegenerative disorders like Alzheimer's disease.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.
In the drawings:
Figure 1 shows the docking pose of compound 1-1 in PD-L1 dimer.
Figure 2 shows the docking pose of compound I- 10 in PD-L1 dimer.
DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS
Reference will now be made in detail to embodiments of the present invention, example of which is illustrated in the accompanying drawings.
Prodrugs mean any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
Tautomers mean compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. Tautomers also refer to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. One of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.
Isomers mean compounds having identical molecular formulae but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. Stereoisomers that are not mirror images of one another are termed diastereomers, and those that are non- superimposable mirror images of each other are termed enantiomers. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. A chiral compound can exist as either individual enantiomer or as a mixture thereof. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvates refer to a complex formed by combination of solvent molecules with the compound of Formula (I). The solvent can be an organic compound, an inorganic compound, or a mixture thereof.
Pharmaceutically acceptable salts represent those salts which are, within the scope of medical judgement, suitable for use in contact for the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. They may be obtained during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable mineral acid such as hydrochloric acid, phosphoric acid, or sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid, and the like. The acid function can be reacted with an organic or a mineral base, like sodium hydroxide, potassium hydroxide or lithium hydroxide.
Therapeutically effective amount means an amount of compound or a composition of the present invention effective in inhibiting the PD-1/PD-L1 protein/protein and CD80/PD- Ll protein/protein interactions, and thus producing the desired therapeutic effect.
As used herein, the term alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range. For example, C1-6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso-propyl, ethyl and methyl. Alkyl also includes saturated aliphatic hydrocarbon radicals wherein one or more hydrogen atoms are replaced with deuterium, for example, CD3. The term branched alkyl refers to an alkyl group as defined above except that straight chain alkyl groups in the specified range are excluded. As defined herein, branched alkyl includes alkyl groups in which the alkyl is attached to the rest of the compound via a secondary or tertiary carbon. For example, isopropyl is a branched alkyl group.
The term cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range. For example, C3-6cycloalkyl refers to cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.
The term halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
The term haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br and/or I). For example, Ci-6 haloalkyl refers to a Ci to C6 linear or branched alkyl group as defined above with one or more halogen substituents. The term fluoroalkyl has an analogous meaning except that the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0- 4CF3.
The term C(O) or CO refers to carbonyl. The terms S(0)2 or S02 refers to sulfonyl. The term S(O) or SO refers to sulfinyl.
The term aromatic hydrocarbons (sometimes arene or aryl hydrocarbon) refers to hydrocarbons with sigma bonds and delocalized pi electrons between carbon atoms forming rings.
The term aryl (Ar) refers to phenyl, naphthyl, tetrahydronaphthyl, idenyl, dihydroindenyl and the like. An aryl of particular interest is phenyl.
The term heterocyclic refers to heteroaryl, saturated heterocyclic, and unsaturated heterocyclic with a double bond.
The term heteroaryl refers to (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or (ii) is a heterobicyclic ring selected from quinolinyl, isoquinolinyl, and quinoxalinyl. Suitable 5- and 6-membered heteroaromatic rings include, for example, pyridyl (also referred to as pyridinyl), pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, oxatriazolyl, thiazolyl, isothiazolyl, and thiadiazolyl. A class of heteroaryls of interest consists of (i) 5- and 6-membered heteroaromatic rings containing from 1 to 3 heteroatoms independently selected from N, O and S, and (ii) heterobicyclic rings selected from quinolinyl, isoquinolinyl, and quinoxalinyl. Heteroaryls of particular interest are pyrrolyl, imidazolyl, pyridyl, pyrazinyl, quinolinyl (or quinolyl), isoquinolinyl (or isoquinolyl), and quinoxalinyl.
Examples of 4- to 7-membered, saturated heterocyclic rings within the scope of this invention include, for example, azetidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, hexahydropyrimidinyl, thiazinanyl, thiazepanyl, azepanyl, diazepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, and dioxanyl. Examples of 4- to 7-membered, unsaturated heterocyclic rings within the scope of this invention include mono-unsaturated heterocyclic rings corresponding to the saturated heterocyclic rings listed in the preceding sentence in which a single bond is replaced with a double bond (e.g., a carbon-carbon single bond is replaced with a carbon-carbon double bond).
It is understood that the specific rings listed above are not a limitation on the rings which can be used in the present invention. These rings are merely representative.
Synthetic methods for preparing the compounds of the present invention are illustrated in the following Schemes, Methods, and Examples. Starting materials are commercially available or may be prepared according to procedures known in the art or as described herein. The compounds of the invention are illustrated by means of the specific examples shown below. However, these specific examples are not to be construed as forming the only genus that is considered as the invention. These examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations in the conditions and processes can be used to prepare such compounds.
Compounds of the present invention can be synthesized by following the steps outlined in General Schemes 1-7, which comprise different sequences of assembling intermediates II - XII. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.
When A is a bivalent bi-aryl or bi-heteroaryl core, a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Suzuki palladium catalyzed cross-coupling of aryl/heteroaryl halide (II) and aryl/heteroaryl boronic acid/ester (III) as shown in Scheme 1-3.
Scheme 1
Figure imgf000019_0001
2. Reductive amination
Hal = CI, Br or I Y = CH2OH, CH2Br
Y = C02 , CH2OH
In Scheme 1, A is
Figure imgf000019_0002
Z and Z' are defined as in Formula (I).
Scheme 2
Figure imgf000019_0003
Cs2C03 l-a
K2C03
Hal = CI, Br or I R, R' = H, or form a cylic ester
In Scheme 2, A is
Figure imgf000019_0004
Xi-3, ΧΊ-3 , Y, Y', Z and Z' are defined as in Formula (I).
Scheme 3
Figure imgf000019_0005
Hal = CI. R, R' = H, or form a cylic ester
In Scheme 3, A is
Figure imgf000019_0006
, R3-R4, R3'-R4', X1-3, X' 1 -3 , Y, Y', Z and Z' are defined as in Formula (I).
When A is a bi-heteroaryl core, a semi-symmetric compound of Formula (I) can be synthesized via Chan-Lam copper catalyzed C-N coupling reaction of aryl/heteroaryl boronic acid (III) with N-H containing aryl/heteroaryl (V) as shown in Scheme 3.
Scheme 4
Figure imgf000020_0001
In Scheme 4, A is
Figure imgf000020_0002
R3-R4, R3 -R4' , X1-3, X' 1-3, Y, Y', Z and Z' are defined as in Formula (I).
When A is a bivalent aryl or heteroaryl core, a symmetric or semi-symmetric compound of Formula (I) can be synthesized via Mitsunobu reaction of aryl/heteroaryl alcohol (VI) and aryl/heteroaryl phenol (VII). A compound of formula (I) can also be prepared by O-alkylation or N-alkylation of aryl/heteroaryl (VII or IX) with aryl/heteroaryl halides (VIII) under basic condition (Scheme 4 to Scheme6).
Scheme 5
Mitsunobu reaction
or O-alkylation
Figure imgf000020_0003
R=OH, Mitsunobu reaction
VI VII R= Br, O-alkylation of phenol l-d
2 eqv.
R = Br, OH Symmetric compound
In Scheme 5, A is
Figure imgf000020_0004
Z and Z' are defined as in Formula (I).
Scheme 6
NaBH4 or LAH
Figure imgf000020_0005
VIII R=OH, Mitsunobu reaction
R= Br, O-alkylation of phenol IX
R = Br, OH
Figure imgf000020_0006
l-e
Semi-symmetric compound In Scheme 6, A is
Figure imgf000021_0001
-R4 R3 -R4', X1-3, X' 1-3, Y, Y', Z and Z' are defined as in Formula (I).
Scheme 7
Figure imgf000021_0002
XI XII
In Scheme 7, A is
Figure imgf000021_0003
Z and Z' are defined as in Formula (I).
The general ways of preparing target molecules (I) by using intermediates II - XII are outlined in Scheme 1-7. A mixture of enantiomers, diastereomers, cis/trans isomers resulted from the process can be separated into their single components by chiral salt technique, chromatography using normal phase, reverse phase or chiral column, depending on the nature of the separation.
It should be understood that in the description and formulae shown above, the various groups A, B and B', - R3-R4, R3'-R4', X1-3, X' 1-3, Y, Y', Z and Z' and other variables are as defined above, except where otherwise indicated. Furthermore, for synthetic purposes, the compounds of Schemes 1-7 are mere representative with elected radicals to illustrate the general synthetic methodology of the compound of Formula (I) as defined herein.
Abbreviations used in the following examples and elsewhere herein are:
Ac20 acetic anhydride ACN Acetonitrile
BOP ammonium 4-(3-(pyridin-3-ylmethyl)ureido)benzenesulfinate
CDCI3 deuterated chloroform
CS2CO3 cesium carbonate
CuS04 copper sulfate
δ chemical shift
DCM dichloromethane or methylene chloride
DCE 1,2-dichloroethane
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIEA N,N-diisopropylethylamine
DMA N,N-dimethylacetamide
DME dimethoxyethane
DMF N,N-dimethylformamide
DMP Dess-Martin Periodinane
DMSO dimethylsulfoxide
DMSO-<¾ deuterated dimethylsulfoxide
dppf 1 , 1 '-Bis(diphenylphosphino)ferrocene
EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride
EDTA ethylenediaminetetraacetic acid
ee enantiomeric excess
EtOAc ethyl acetate
EtOH ethanol
1H MR proton nuclear magnetic resonance
HO Ac acetic acid
HATU 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yl)-l, 1,3,3- tetramethylisouronium hexafluorophosphate
HC1 hydrochloric acid
HOBT lH-benzo[d][l,2,3]triazol-l-ol hydrate
HPLC high pressure liquid chromatography
Hz hertz
IP A isopropyl alcohol
KOAc potassium acetate K2C03 potassium carbonate
LAH lithium aluminum hydride
LCMS liquid chromatography/mass spectrometry
(M+l) mass + 1
m-CPBA w-chloroperbenzoic acid
MeOH methanol
MeMgBr methyl magnesium bromide
MS mass spectrometry
NaBH4 sodium borohydride
NaBH(OAc)3 sodium triacetoxyborohydride
NaBH3CN sodium cyanoborohydride
Na2S04 sodium sulfate
BS N-bromosuccinimide
Pd(dppf)Cl2 [l,l '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Palladium tetrakis Tetrakis(triphenylphosphine)palladium(0)
Rt retention time
TBAF tetrabutylammonium fluori de
TBDMS-C1 Tert-butyl dimethylsilyl chloride
TEA triethylamine
THF tetrahydrofuran
TLC thin layer chromatography
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
2G Pd Xphos Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, - biphenyl)[2-(2'-amino- 1 , 1 '-biphenyl)]palladium(II)
t-butyl Xphos 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl
Representative Examples
Example 1: 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy) methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan- l-ol (1-1).
Figure imgf000023_0001
1-1 The compound of Example 1 was synthesized via the route shown in the scheme below.
Figure imgf000024_0001
Figure imgf000024_0002
Step-1: methyl 3-bromo-2-methylbenzoate (Π-2)
To a solution of 3-bromo-2-methylbenzoic acid II-l (10 g, 47 mmol) in 150 mL of MeOH was added concentrated H2SO4 (10 mL) dropwise. The mixture was stirred at 70°C overnight. The solvent was evaporated and the remaining mixture was adjusted to pH 9 by adding saturated NaHC0 solution. The mixture was extracted with ethyl acetate. The organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 150 : 1) to give the product as a yellow oil (10.1 g, 94%). 1H NMR (400 MHz, CDC1 ) δ 7.72 (d, J= 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.09 (t, J= 8.0 Hz, 7.6Hz, 1H), 3.90 (s, 3H), 2.63 (s, 3H).
Step-2: 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzoate (ΠΙ-1)
A mixture of methyl 3-bromo-2-methylbenzoate II-2 (3g, 13.1 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane (4 g, 15.7 mmol), Pd(dppf)Cl2 (670 mg, 0.9 mmol), KOAc (2.6 g, 26.2 mmol) in 150 mL of dioxane was stirred at 110°C under N2 overnight. The reaction mixture was filtered and concentrated, then extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The crude was purified by column chromatography (petroleum ether : ethyl acetate = 80 : 1) to give a product as a green oil (2.9 g, 81%). 1H NMR (400 MHz, CDC13) δ 7.86-7.82 (m, 2H), 7.22- 7.21 (m, 1H), 3.88 (s, 3H), 2.74 (s, 3H), 1.36 (s, 12H).
Step-3: dimethyl 2,2'-dimethyl-[l, r-biphenyl]-3,3'-dicarboxylate (IV-1) To a solution of 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) benzoate III-l (1.5 g, 5.4 mmol), methyl-3-bromo-2-methylbenzoate II-2 (1.1 g, 4.9 mmol), CsF (2.2 g, 14.7 mmol), and Pd(dppf)Cl2 (250 mg, 0.07 mmol) in 40 mL of dioxane was added 10 mL of H20. The mixture was stirred at 110°C under N2 overnight. The reaction mixture was filtered and concentrated, then extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The product was purified by column chromatography (petroleum ether : ethyl acetate = 80 : 1) to give a product as a green oil (1.5g, 92%). 1H NMR (400 MHz, CDC13) δ 7.86 (d, J = 1.6 Hz, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.29 (t, J= 7.6 Hz, 7.6 Hz, 2H), 7.24 (d, J= 1.2 Hz, 1H), 7.22 (d, J= 1.2 Hz, 1H), 3.92 (s, 6H), 2.22 (s, 6H).
Step-4: (2,2'-dimethyl-[l, r-biphenyl]-3,3'-diyl)dimethanol (IV-2)
To a solution of ester IV-1 (1.26 g, 4.2 mmol) in 50 ml of THF was added L1AIH4 (638 mg, 16.8 mmol) was added. The mixture was stirred at 0°C for five hours, then quenched with 0.6 mL H20, 0.6 mL 10% NaOH and 1.8 mL H20. The resulting mixture was filtered and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The product was purified by column chromatography (petroleum ether : ethyl acetate = 10 : 1) to give the product as a white solid (831 mg, 82%). 1H NMR (400 MHz, CDCI3) δ 7.39 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 7.2 Hz, 2H), 4.77 (s, 4H), 2.03 (s, 6H).
Step-5 3,3'-bis(bromomethyl)-2,2'-dimethyl-l,r-biphenyl, IV-3
To a solution of (2,2'-dimethyl-[l,r-biphenyl]-3,3'-diyl)dimethanol IV-2 (300 mg, 1.2 mmol) in 50 mL of dichloromethane was added PBr3 (650 mg, 2.4 mmol) dropwise at 0°C. The mixture was stirred at 0°C overnight. It was quenched with water. The mixture was extracted with dichloromethane. The organic layer was dried over Na2S04, filtered and concentrated. The product was purified by column chromatography (petroleum ether : ethyl acetate = 150: 1) to give the desired product IV-3 as a yellow solid (337 mg, 76%). 1H NMR (400 MHz, CDC13) δ 7.35 (d, J = 7.6 Hz, 2H), 7.22 (t, J = 7.6 Hz, 7.2 HZ, 2H), 7.09 (d, J = 7.2 Hz, 2H), 4.59 (s, 4H), 2.09 (s, 6H).
Step-6: 4,4'-(((2,2'-dimethyl-[l,r-biphenyl]-3,3'-diyl)bis(methylene))bis(oxy))bis(3- methyl benzaldehyde), IV-4
A mixture of 3,3'-bis(bromomethyl)-2,2'-dimethyl-l,r-biphenyl, IV-3 (337 mg, 0.92 mmol), 4-hydroxy-3-methylbenzaldehyde (272 mg, 2.0 mmol) and K2C03 (386 mg, 2.8 mmol) in 20 mL of acetonitrile was stirred at room temperature overnight. The mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The product IV-4 was obtained a yellow solid (415 mg, 95%). 1H NMR (400 MHz, CDC13) δ 9.88 (s, 2H), 7.74-7.73 (m, 4H), 7.48 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 7.6 Hz, 2H), 7.18 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 5.21 (s, 4H), 2.33 (s, 6H), 2.07 (s, 6H).
Step-7: 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]- 2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol, 1-1.
A mixture of aldehyde IV-4 (100 mg, 0.21 mmol) and 2-aminoethanol (77 mg, 1.26 mmol) in 15 mL of EtOH was stirred at 85°C for 3 hours. When it cooled down to room temperature, NaBH4 (32 mg, 0.84 mmol) was added at 0°C and stirred for two hours. It was quenched with 2 ml of saturated NaCl. The resulting mixture was concentrated, then diluted with dichloromethane, dried over Na2S04, filtered and concentrated. The crude product was purified by column chromatography (dichloromethane : methanol = 10 : 1 ) to give the title compound 1-1 as a white solid (30 mg, 27%). 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.6 Hz, 7.6 Hz, 2H), 7.10 (d, J = 9.6 Hz, 6H), 7.02 (d, J = 8.0 Hz, 2H), 5.13 (s, 4H), 4.45 (t, J = 5.2 Hz, 4.8 Hz, 2H), 3.60 (s, 4H), 3.45 (dd, J = 5.6 Hz, 5.2 Hz, 4H), 2.54 (d, J= 6.0 Hz, 4H), 2.17 (s, 6H), 2.01 (s, 6H). LCMS: m/z +569.52 [M+H]+.
Example 2: 2-{[(4-{[3-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy}methyl)-2- chlorophenyl]methoxy}-3-m hylphenyl)methyl]amino}ethan-l-ol (1-2).
Figure imgf000026_0001
1-2
The compound of Example 2 was synthesized via the route shown in the scheme below.
Figure imgf000027_0001
1-2
Step-1: synthesis of l,3-bis(bromomethyl)-2-chlorobenzene
To the solution of 2-chloro-l,3-dimethylbenzene (10 g, 71 mmol) in CC14 (200 mL) was added BS (28 g, 157 mmol) and BOP (172 mg, 0.71 mmol). The mixture was heated to reflux for 16 hours. LC-MS indicated that the reaction was completed. The reaction mixture was cooled down, filtered, and concentrated. The residue was crystallized with hexane to give white solid (5 g, 24%).
Step-2: synthesis of 4,4'-(2-chloro-l,3-phenylene)bis(methylene)bis(oxy)bis(3-methyl benzaldehyde) (IV-5)
To the solution of l,3-bis(bromomethyl)-2-chlorobenzene (200 mg, 0.67 mmol) and 4-hydroxy-3-methylbenzaldehyde (192 mg, 1.4 mmol) in acetonitrile (10 mL) was added K2CO3 (195 mg, 138 mmol). The suspended solution was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (50 mL), and the organic layer was washed with brine. Then the organic layer was concentrated and purified by silica gel column (Petroleum ether : ethyl acetate = 2 : 1) to give the title compound as white solid (200 mg, 73%).
Step-3: synthesis of 4-(3-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-2- chlorobenzyloxy)-3-methylbenzaldehyde (IV-6) and l-[(4-{ [3-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3-methylphenyl)methyl]azetidine (1-3)
Figure imgf000027_0002
IV-6 To the solution of 4,4'-(2-chloro-l,3-phenylene)bis(methylene)bis(oxy)bis(3- methylbenzaldehyde) IV-5 (200 mg, 0.49 mmol) in MeOH (5 mL) was added azetidine hydrochloride (46 mg, 0.49 mmol). After stirring for 30 minutes, NaBH3CN (30 mg, 0.49 mmol) was added and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with the water, then extracted with ethyl acetate. The combined organic layer was dried, concentrated and purified by silica gel column (dichloromethane : MeOH = 25 : 1 to 15 : 1) to give IV-6 (60 mg) and 1-3 (50 mg).
l-[(4-{[3-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy}methyl)-2- chlorophenyl]methoxy}-3-methylphenyl)methyl]azetidine (1-3): 1H NMR (400MHz, CDC1 ): δ 7.57 (d, J= 7.6 Hz, 2H), 7.34 (t, J= 7.6 Hz, 1H), 7.12 (s, 2H), 7.07 (d, J= 8.0 Hz, 2H), 6.84 (d, J= 7.2 Hz, 2H), 5.19 (s, 4H), 3.53 (s, 4H), 3.26 (t, J= 7.2 Hz, 8H), 2.31 (s, 6H), 2.11 (m, 4H). LCMS: m/z + 491.3 [M+H]+.
Step-4: synthesis of 2-{[(4-{[3-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy } methyl)-2-chlorophenyl] methoxy } -3 -methylphenyl)methyl] amino } ethan- 1 - ol (1-2)
To the solution of aldehyde IV-6 (60 mg, 0.13 mmol) in MeOH (2 mL) was added 2- aminoethanol (16 mg, 0.27 mmol). After stirring for 30 minutes, NaCNBH (17 mg, 0.27 mmol) was added and the mixture was stirred for 16 hours at room temperature. Quenched the reaction with the water, and extracted with ethyl acetate. The combined organic layer was concentrated and purified by silica gel column (dichloromethane : MeOH = 10 : l)to give 1-2 (30 mg). H NMR (400 MHz, CDC1 ): δ 7.57 (d, J= 7.6 Hz, 2H), 7.34 (t, J= 7.6 Hz, 1H), 7.14-7.05 (m, 4H), 6.84 (t, J = 7.6 Hz, 2H), 5.19 (s, 4H), 3.73 (s, 2H), 3.66 (t, J = 4.2 Hz, 2H), 3.51 (s, 2H), 3.24 (t, J= 4.2 Hz, 4H), 2.78 (m, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 2.12-2.08 (m, 2H). LCMS: m/z + 495.2 [M+H]+.
Example 3: (2S)-l-{[4-({3'-[(4-{[(2S)-2-carboxypiperidin-l-yl]methyl}-3,5- dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2,6- dimethoxyphenyl]methyl}piperidine-2-carboxylic acid (1-4).
H
Figure imgf000028_0001
The compound of Example 3 was synthesized via the route shown in the scheme below.
Step-1: 4,4'-(2,2'-dimethylbiphenyl-3,3'-diyl)bis(methylene)bis(oxy)bis(2,6- dimethoxybenzaldehyde) (IV-7)
To a solution of 3,3'-bis(bromomethyl)-2,2'-dimethyl-l, -biphenyl, IV-3 (500 mg,
1.4 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (497 mg, 2.7 mmol), K2C03 (447 mg, 3.2 mmol) in 10 mL of DMF was stirred at room temperature overnight. The mixture was diluted with water, filtered to give a pale solid (600 mg, 77%). The crude was used for next step without further purification. 1H MR (400 MHz, CDC1 ) δ 10.37 (s, 2H), 7.34-7.17 (m, 6H), 6.20 (s, 4H), 5.18 (s, 4H), 3.89 (s, 12H), 2.10 (s, 6H).
Step-2: (S)-l-(4-((3'-((4-formyl-3,5-dimethoxyphenoxy)methyl)-2,2'- dimethylbiphenyl-3-yl)methoxy)-2,6-dimethoxybenzyl)piperidine-2-carboxylic acid (IV-8) & (2S)-l-{[4-({3'-[(4-{[(2S)-2-carboxypiperidin-l-yl]methyl}-3,5-dimethoxyphenoxy)methyl]- 2,2'-dimethyl-[l, -biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2- carboxylic acid (1-4)
To a solution of aldehyde IV-7 (300 mg, 0.52 mmol) in MeOH (5 mL) was added (S)- piperidine-2-carboxylic acid (68 mg, 0.52 mmol) and Cat. AcOH. After stirring for 30 minutes, NaBH3CN (32 mg, 0.52 mmol) was added and the mixture was stirred for 16 hours at room temperature. Quenched the reaction with the water, and extracted with ethyl acetate. The combined organic layer was concentrated and purified by silica gel column (dichloromethane : MeOH = 25 : 1 to 10 : 1) to give IV-8 (110 mg) and 1-4 (30 mg). 1-4: 1H MR (400MHz, OMSO-d6): 57.50 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.11 (d, J =
7.5 Hz, 2H), 6.42 (s, 4H), 5.20 (s, 4H), 4.10 (s, 4H), 3.79 (s, 13H), 3.12 (s, 2H), 3.04 (s, 2H), 2.63 (s, 2H), 2.02 (s, 6H), 1.81 (s, 4H), 1.55 (s, 4H), 1.39 (s, 4H). LCMS: m/z + 819.43 [M+Na]+.
Example 4 : (2 S)- 1 - { [4-({ 3 ' -[(4- { [(2-hy droxy ethyl)amino]methyl } -3 , 5 - dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2,6- dimethoxyphenyl]methyl}piperidine-2-carboxylic acid (1-5).
Figure imgf000030_0001
To a solution of IV-8 (110 mg, 0.16 mmol) in MeOH (5 mL) was added 2- aminoethanol (20 mg, 0.32 mmol) and catalytical amount of acetic acid. After stirring for 30 minutes, NaBH3CN (20 mg, 0.32 mmol) was added and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with the water, and extracted with AcOEt. The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by silica gel column (dichlorom ethane : MeOH = 25 : 1 to 10 : 1) to give 1-5 (40 mg). 1H NMR (400MHz, OMSO-d6): 7.49 (d, J = 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 2H), 7.10 (s, 2H), 6.41 (s, 2H), 6.35 (s, 2H), 5.19 (s, 2H), 5.16 (s, 2H), 4.10 (s, 2H), 3.78 (s, 6H), 3.75 (s, 6H), 3.61 (s, 2H), 3.22-3.03 (m, 6H), 2.61 (s, 1H), 2.02 (s, 6H), 1.82 (s, 2H), 1.55 (s, 2H), 1.39 (s, 2H). LCMS: m/z + 729.45 [M+H]+.
Example 5: 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxy phenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl] methyl } amino)ethan
Figure imgf000030_0002
To a solution of aldehyde IV-7 (80 mg, 0.14 mmol) in MeOH (5 mL) was added 2- aminoethanol (34 mg, 0.56 mmol) and catalyst AcOH. After stirring for 30 minutes, NaBH3CN (34 mg, 0.56 mmol) was added and the mixture was stirred for 16 hours at room temperature. The combined organic layers were dried over anhydrous Na2S04 and concentrated. The residue was purified by silica gel column (dichloromethane:MeOH = 25 : 1 to 10 : 1) to give 1-6 (40 mg): 1H NMR (400 MHz, CDC1 ) δ 7.45 (d, J= 7.4 Hz, 2H), 7.29 (t, J= 7.6 Hz, 2H), 7.15 (d, J= 7.5 Hz, 2H), 6.24 (s, 4H), 5.09 (s, 4H), 4.43 ( brs, 20H), 3.81 (s, 12H), 3.64-3.63 (m, 4H), 3.49-3.22 (m, 8H), 2.08 (s, 6H). LCMS: m/z + 683.35 [M+Na]+.
Example 6: l-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methyl phenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2- methoxyphenyl]methyl}azetidin-3-ol (1-7).
Figure imgf000031_0001
1-7
The preparation of Intermediate (Π-5): l-(4-((3-bromo-2-methylbenzyl)oxy)-2-
Figure imgf000031_0002
Step-1: 4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzaldehyde (Π-4)
Figure imgf000031_0003
Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (1.5 mL) is added dropwise to a cooled (0 °C) solution of 4-hydroxy-2-methoxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (3-bromo-2-methylphenyl)methanol II-3 (1.0 mmol) in dry tetrahydrofuran (3 mL). The resulting reaction mixture is allowed to slowly warm to room temperature with stirring overnight. The product is filtered from the reaction mixture using a Buchner filter funnel and rinsed with tetrahydrofuran (approx. 3 mL) then dried in vacuo at room temperature to yield the title compound II-4. The crude is used for next step without further purification.
Step-2: l-(4-((3-bro -2-methylbenzyl)oxy)-2-methoxybenzyl)azetidin-3-ol(II-5)
Figure imgf000031_0004
A mixture of 4-((3-bromo-2-methylbenzyl)oxy)-2-methoxy benzaldehyde (1 mmol), azetidin-3-ol (3 mmol) and AcOH (5 mmol) in DMF is stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 mmol) is added and the mixture is stirred at RT until reductive amination is complete (-16 h). Further purification of the crude via reverse phase preparative HPLC or normal phase column chromatography yield the desired product
II-5
The preparation of Intermediate (ΙΠ-3): 3-methyl-4-((2-methyl-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzyl)oxy)benzaldehyde
Figure imgf000032_0001
A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (1.0 mmol) in dry THF (6 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (6 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product (ΙΠ-3).
The preparation of l-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl} phenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2-methoxyphenylmethyl} azetidin-3-ol (1-7)
Figure imgf000032_0002
Step-1: 4-((3'-((4-((3-hydroxyazetidin-l-yl)methyl)-3-methoxy phenoxy)methyl)-2,2' dimethyl-[ 1 , 1 '-biphenyl]-3 -yl)methoxy)benzaldehyde
Figure imgf000032_0003
Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use. In a round-bottom flask charge 4-((3'-((4-((3-hydroxyazetidin-l -yl)methyl)-3-methoxy phenoxy)methyl)-2,2'-dimethyl-[l, -biphenyl]-3-yl)methoxy)-3-methylbenzaldehyde III-3 (1.2 mmol), l-(4-((3-bromo-2-methylbenzyl)oxy)-2-methoxybenzyl)azetidin-3-ol (II-5) (1.0 mmol) and 2G Pd Xphos precatalyst (0.03 mmol)(CAS number 1310584-14- 5), add previously deoxygenated tetrahydrofuran (5 mL) and 0.5 M aq potassium phosphate, tribasic solution (5 mL, 2.5 mmol), place under nitrogen and sparged with additional nitrogen for 10 minutes. The reaction is stirred under nitrogen at room temperature for 2 days. Ethyl acetate (12 mL) is added to the reaction followed by 8 mL of brine then the reaction is partitioned in a separatory funnel. The organic extract is washed ( lx) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator. The crude reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
Step-2: l-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]-2,2'- dimethyl-[l,r-biphenyl]-3-yl}methoxy)-2-methoxyphenyl]methyl}azetidin-3-ol (1-7)
A mixture of 4-((3'-((4-((3-hydroxyazetidin-l-yl)methyl)-3-methoxyphenoxy) methyl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl)methoxy)benzaldehyde (1 mmol), 2-aminoethan-
1- ol (3 mmol) and AcOH (5 mmol) in DMF is stirred at RT for 4-16 h. Then Sodium triacetoxyborohydride (3 mmol) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). Further purification of the crude via reverse phase preparative HPLC yields the desired product 1-7.
Example 7: 2-{[(6-{[3-(5-{[(5-{ [(2-hy droxy ethyl)amino]methyl } -6-methoxypyridin-
2- yl)oxy]methyl}-4-methylthiophen-3-yl)-2-methylphenyl]methoxy}-2-methoxypyridin-3- yl)methyl]amino}etha -l-ol (1-8).
Figure imgf000033_0001
The Preparation f Intermediate (Π-6): (4-bromo-3-methylthiophen-2-yl)methanol
Figure imgf000033_0002
To a solution of 4-bromo-3-methylthiophenecarboxylic acid (2 g; 0.95 mmol) in TFIF (20 mL) was added borane-THF complex (1M, 18.19 mL; 18.19 mmol) dropwise, at 0°C. Subsequently, the reaction mixture was stirred for 1 hour at 60°C. To this reaction mixture was added 1M HC1 (30 mL), at 0°C, and the resulting mixture was stirred at RT for 10 minutes. The resulting mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% aqueous NaHCCVsolution. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo. The product II-6 (2.2 g; 100%) was used without further purification. (Ref: WO 2012004378).
Figure imgf000034_0001
Step-1: (4-(3-(hydroxymethyl)-2-methylphenyl)-3-methylthiophen-2-yl)methanol
Figure imgf000034_0002
Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use. In a round-bottom flask charge (2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)methanol III-2 (1.2 mmol), (4-bromo-3-methylthiophen-2-yl)methanol (Π-6) (1.0 mmol) and 2G palladium Xphos precatalyst (0.03 mmol)(CAS number 1310584- 14-5), add previously deoxygenated tetrahydrofuran (5 mL) and 0.5 M aq potassium phosphate, tribasic solution (5 mL, 2.5 mmol), place under nitrogen and sparged with additional nitrogen for 10 minutes. The reaction is stirred under nitrogen at room temperature for 2 days. Ethyl acetate (12 mL) is added to the reaction followed by 8 mL of brine then the reaction is partitioned in a separatory funnel. The organic extract is washed (lx) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator. The crude reaction product is purified by silica gel chromatography eluting with an appropriate gradient of ethyl acetate/hexanes to yield a pure title compound.
Step-2: 6-{[3-(5-{[(5-formyl-6-methoxypyridin-2-yl)oxy]methyl}-4- methylthiophen-3-yl)-2-methylphenyl]methoxy}-2-methoxypyridine-3-carbaldehyde
Figure imgf000035_0001
Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (4-(3-(hydroxymethyl)-2- methylphenyl)-3-methylthiophen-2-yl)methanol (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture i s purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 °C overnight. The soluble portion of the crude reaction is charged to a 25g silica gel column with dichloromethane and chromatographed with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Step-3: 2-{ [(6-{ [3-(5-{ [(5-{ [(2-hydroxyethyl)amino]methyl}-6-methoxypyridin- 2-yl)oxy ] methyl } -4-methylthiophen-3 -yl)-2-methylphenyl]methoxy } -2- methoxypyridin-3-yl)methyl]amino}ethan-l-ol (1-8)
A mixture of 6-{[3-(5-{[(5-formyl-6-methoxypyridin-2-yl)oxy]methyl}-4-methyl thiophen-3-yl)-2-methylphenyl]methoxy}-2-methoxypyridine-3-carbaldehyde (1 mmol, 2N), 2-aminoethan-l-ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). Further purification of the crude via reverse phase preparative HPLC yields the desired product 1-8.
Example 8: 2-({ [4-({4-[(4-{[(2-hydroxyethyl)amino]methyl}-3-methoxy phenoxy) methyl]-3-methylthiophen-2-yl}methoxy)-2-methoxyphenyl]methyl} amino)ethan-l-ol (1-9)
Figure imgf000036_0001
Figure imgf000036_0002
To a round-bottom flask is charged dimethyl 3-methylthiophene-2,4- dicarboxylate (1.0 mmol, 2N) and tetrahydrofuran (10 mL). The mixture is stirred until a clear solution is obtained. The solution is cooled to - 40°C and lithium borohydride (4 mmol, 2 eqv.) is added portion wise over 15 minutes. After all the lithium borohydride is added, the reaction is slowly brought to room temperature and stirred overnight. When TLC or LCMS analysis showed that the starting material is consumed, saturated aqueous ammonium chloride is charged to a multineck round-bottom flask and cooled to - 5 °C (inner temperature). Added crude reaction slowly over 15 minutes. After addition is complete the temperature is maintained at - 5 °C for 20 minutes. The reaction is diluted with dichloromethane (15 ml) and the layers are separated. The aqueous layer is extracted with dichloromethane (1 x 15 ml) and the combined organic portions are washed with 1.5 N aqueous hydrochloric acid (1 x 1.3 ml), saturated aqueous sodium chloride (1 x 1.3 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude material was dissolved in minimum amount of dichloromethane and cooled in ice bath. Petroleum ether was added until white solid formed. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give the title compound. (Ref: WO 2010125102 Al )
Step-2: 4-({4-[(4-formyl-3-methoxyphenoxy)methyl]-3-methylthiophen-2- yl}methoxy)-2-methoxybenzaldehyde
Figure imgf000037_0001
Diisopropyl azodicarboxylate (2.2 mmol, 1.1 eqv.) in tetrahydrofuran (2.5 mL) is added dropwise to a cooled (0 °C) solution of 4-hydroxy-2-methoxybenzaldehyde (2.2 mmol, 1.1 eqv.), triphenyl phosphine (2.2 mmol, 1.1 eqv.) and (3-methylthiophene-2,4- diyl)dimethanol (1.0 mmol, 2N) in dry tetrahydrofuran (6 mL). The resulting reaction mixture is allowed to slowly warm to room temperature with stirring overnight. The product is filtered from the reaction using a Buchner filter funnel and rinsed with tetrahydrofuran (approx. 5 mL) then dried in vacuo at room temperature to yield the title compound. The crude is used for next step without further purification.
Step-3: 2-({[4-({4-[(4-{[(2-hydroxyethyl)amino]methyl}-3-methoxyphenoxy) methyl]-3-methylthiophen-2-yl}methoxy)-2-methoxyphenyl]methyl}amino)ethan-l-ol (1-9)
Figure imgf000037_0002
A mixture 4-({4-[(4-formyl-3-methoxyphenoxy)methyl]-3-methylthiophen-2- yl}methoxy)-2-methoxybenzaldehyde (1 mmol, 2N), 2-aminoethan-l-ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-9.
Example 9: 2-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy}methyl)-6-{[4-({[(4- oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl}benzonitrile (I- 10)
Figure imgf000038_0001
Step-4 III-5
Figure imgf000038_0002
Step-3 1-10
Step-l: methyl 2-cyano-3- -formyl-2-methylphenoxy)methyl)benzoate
Figure imgf000038_0003
A solution of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and methyl 2-cyano-3-(hydroxymethyl)benzoate (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product.
Step-2: methyl 3-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-2- cyanobenzoate
Figure imgf000038_0004
A solution of tetramethyl ammonium triacetoxyborohydride (2.0 mmol, 2 eqv.) and azetidine hydrochloride salt (2.0 mmol, 2 eqv.) in dichloromethane (12 mL) is added to a solution of methyl 2-cyano-3-((4-formyl-2-methylphenoxy)methyl)benzoate (1.0 mmol, 1 eqv.) in dichloromethane (12 mL). The reaction mixture is stirred at room temperature overnight. The reaction is quenched by the addition of saturated sodium bicarbonate. The organic layer, is washed with saturated, aqueous sodium chloride and dried (Na2S04). The crude residue is then purified by reverse phase preparative HPLC using a methanol-water-TFA buffer system to yield the title compound.
Step-3: 2-((4-(azetidin- 1 -ylmethyl)-2-methylphenoxy)methyl)-6-
(hydroxymethyl) benzonitrile
Figure imgf000039_0001
To a round-bottom flask is charged methyl 3-((4-(azetidin-l-ylmethyl)-2- methylphenoxy)methyl)-2-cyanobenzoate (1.0 mmol) and tetrahydrofuran (5 mL). The mixture is stirred until a clear solution is obtained. The solution is cooled to - 40°C and lithium borohydride (2 mmol, 2 eqv.) is added portion wise over 15 minutes. After all the lithium borohydride is added, the reaction is slowly brought to room temperature and stirred overnight. When TLC or LCMS analysis showed that all starting material is consumed, saturated aqueous ammonium chloride is charged to a multineck round- bottom flask and cooled to - 5 °C (inner temperature) to which is added the crude reaction mixture slowly over 15 minutes. After addition is complete the temperature is maintained at - 5 °C for 20 minutes. The reaction is diluted with dichloromethane (15 ml ) and the layers are separated. The aqueous layer is extracted with dichloromethane (1 x 15 ml) and the combined organic portions are washed with 1.5 N aqueous hydrochloric acid (1 x 1.3 ml ), saturated aqueous sodium chloride ( 1 x 1.3 ml ) and dried over sodium sulfate. The solvent was removed under reduced pressure to give a crude product. The crude material was dissolved in minimum amount of dichloromethane and cooled in ice bath. Petroleum ether was added until white solid formed. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give the title compound. (WO 2010125102 Al )
Step-4: 2-((4-(azetidin- 1 -ylmethyl)-2-methylphenoxy)methyl)-6-((4- formylphenoxy) methyl nzonitrile (ΙΠ-5)
Figure imgf000039_0002
A solution of 4-hydroxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) 2-((4-(azetidin-l-ylmethyl)-2-methylphenoxy)methyl)-6-(hydroxymethyl)benzonitrile (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes:ethyl acetate. Collected fractions to afford the desired product (ΙΠ-5).
Step-5: 2-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy}methyl)-6-{[4-({[(4- oxoazetidin-2-yl)methyl ]amino}methyl)phenoxy]methyl}benzonitrile (1-10)
Figure imgf000040_0001
A mixture 2-((4-(azetidin- 1 -ylmethyl)-2-methylphenoxy)methyl)-6-((4- formylphenoxy) methyl) benzonitrile (1 mmol), 4-(aminomethyl)azetidin-2-one (3 mmol, 3 eqv.) and AcOH (5 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-10.
- 12
Figure imgf000040_0002
1-11, 1-12 & 1-13
General procedure of reductive amination:
A mixture aldehyde (1 equiv), appropriate amine or amino acid (3 equiv) and AcOH (5 equiv) in DMF was stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 equiv) was added and the mixture was stirred at RT until reductive amination is complete (typically overnight). Product was purified via preparative HPLC with the following conditions: Column: XBridge CI 8, 19 x 200 mm, 5-μπι particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 20-60% B over 30 minutes, then a 5- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation.
Example 10: N-(2-{[(4-{[3-({4-[(azetidin-l -yl)methyl]-2-methyl phenoxy}methyl)-2-cyanophenyl]methoxy}phenyl)methyl]amino}ethyl)acetamide (1-11)
Figure imgf000041_0001
Compound 1-11 is prepared in the same manner as the general procedure described above using aldehyde (ΙΠ-5) and N-(2-aminoethyl)acetamide.
Example 11: 2-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy} methyl) -6-[(4- {[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]benzonitrile (1-12)
Figure imgf000041_0002
Compound 1-12 is prepared in the same manner as the general procedure described above using aldehyde (ΙΠ-5) and 2-aminoethan-l-ol.
Example 12: 2-({4-[(azetidin-l-yl)methyl]-2-methylphenoxy} methyl)-6-({4-[(azetidin- l-yl)methyl]phenoxy} methyl)benzonitrile (1-13)
Figure imgf000041_0003
Compound 1-13 is prepared in the same manner as the general procedure described above using aldehyde (ΙΠ-5) and azetidine hydrochloride salt.
Example 13: 2-({[4-({4-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy) methyl]-lH-indol-l-yl}methyl)phenyl]methyl} amino)ethan-l -ol (I- 14)
Figure imgf000041_0004
Step-1: 4-((lH-indol-4-yl)methoxy)-2,6-dimethoxybenzaldehyde
Figure imgf000041_0005
A solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.1 mmol), triphenyl phosphine (1.1 mmol) and (lH-indol-4-yl)methanol (1.0 mmol) in dry THF (5 mL) is cooled in an ice bath. Diisopropyl azodicarboxylate (1.1 mmol) in THF (5 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature while stirring overnight. The solvent is removed and the residue is purified on a silica column with a mixture of hexanes: ethyl acetate. Collected fractions to afford the desired product.
Step-2: 4-((l-(4-formylbenzyl)-lH-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde
Figure imgf000042_0001
NaH (1 mol equiv) is dissolved in anhydrous DMF (5 mL/mmol) under argon and cooled to 0 °C. To this mixture is added 4-((lH-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde (1 mol equiv) dissolved in anhydrous DMF (3 mL/mmol). The reaction is stirred for 15 min at 0 °C followed by the addition of 4-(bromomethyl) benzaldehyde (1 mol equiv) in anhydrous DMF (2 mL/mmol). The reaction is stirred for 2 h at 70 °C and then quenched by the addition of H20 (30 mL). The organic products are extracted with EtOAc (3 x 30 mL), washed with H20 (2 x 30 mL), brine (15 mL), dried over Na2S04, filtered and concentrated in vacuo to yield the title compound.
Step-3 :2-({[4-({4-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxy phenoxy )methy 1] - 1 H-indol- 1 -y 1 }methy l)pheny ljmethy 1 } amino)ethan- 1 -ol (I- 14)
Figure imgf000042_0002
A mixture 4-((l-(4-formylbenzyl)-lH-indol-4-yl)methoxy)-2,6-dimethoxy benzaldehyde (1 mmol), 2-aminoethan- 1 -ol (3 mmol, 3 eqv.) and AcOH (5 mmol, 5 eqv.) in DMF (5 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (3 mmol) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-14. Example-14: 2-({[4-({ l-[(4-{[(2-hydroxyethyl)amino]methyl} phenyl)methyl]- lH-indazol-4- l methox -2 6-dimethox hen l meth l amino ethan-l-ol (1-15)
Figure imgf000043_0001
Compound 1-15 is prepared in the same manner as the procedure described for I- 14 except using ( lH-indazol-4-yl)methanol (III-6) and azetidine hydrochloride salt.
Example-15: 2,6-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3- methoxyphenoxy)methyl] benzonitrile, 1-16
Figure imgf000043_0002
RT
Step-2
Figure imgf000043_0003
The detailed procedures for step 1-3 are described in Example 9.
Example-16: preparation of compound 1-17, 1-18, 1-19, 1-20 and 1-21.
Figure imgf000043_0004
1-17, 1-18, 1-19, I-20 & 1-21
Standard protocol for alkylation:
A mixture of 3,3'-bis(bromomethyl)-2,2'-dimethyl-l, l'-biphenyl, IV-3 (1.0 mmol), an appropriate hydroxy-aryl aldehyde(phenols) (2.17 mmol) and K2C03 (2.5 mmol) in 20 mL of acetonitrile (or DMF) is stirred at room temperature or elevated temperature for 16 h. The mixture was concentrated and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and concentrated. The crude product is subjected purification by normal column chromatography or reversed phase HPLC. Standard protocol for reductive animation.
A mixture of aldehyde (1.0 mmol, 2N) and an appropriate amine (6.0 mmol, 3 eqv) in 60 mL of EtOH was stirred at 85°C for 3 hours. When it cooled down to room temperature, NaBH3CN (6 mmol, 3 eqv) was added at 0°C and stirred for two hours. It is quenched with 2 ml of saturated NaCl. The resulting mixture is concentrated, then diluted with dichloromethane, dried over Na2S04, filtered and concentrated. The crude product is purified by column chromatography (dichloromethane : methanol ) to give the title compound 1-17- -17: preparation of compound 1-22, 1-23, 1-24 and 1-25.
Figure imgf000044_0001
IV-2 t u- os, o uene,
Figure imgf000044_0002
Standard protocol for C-0 coupling reaction:
Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and (2,2'-dimethyl-[l, - biphenyl]-3,3'-diyi)dimethanol IV-2 (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture i s purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 °C overnight. The soluble portion of the crude reaction is charged to a silica gel column with dichloromethane and c h r o m a t o g r a p h e d with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Next step is followed by a standard protocol for reductive amination described for I- 17 to 1-21.
Example-18: 2-({[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy) methyl]-2'-methyl-[l, -biphenyl]-3-yl}methoxy)-2,6- dimethoxyphenyl]methyl}amino) ethan-l-ol, 1-26.
Figure imgf000045_0001
Step-1: dimethyl 2-methyl-[l, -biphenyl]-3,3'-dicarboxylate (IV-10)
To a solution of (3-(methoxycarbonyl) phenyl)boronic acid III-4 (1.10 mmol), methyl-3-bromo-2-methylbenzoate II-2 (1.0 mmol), CsF (3.0 mmol), and Pd(dppf)Cl2 (0.02 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110°C under N2 overnight. The reaction mixture is filtered and concentrated, then extracted with ethyl acetate. The organic layer is dried over Na2S04, filtered and concentrated. The product is purified by column chromatography (petroleum ether : ethyl acetate) to yield title product IV-10.
Step-2: (2-methyl-[l, -biphenyl]-3,3'-diyl)dimethanol (IV-11)
To a solution of dimethyl 2-methyl-[l, -biphenyl]-3,3'-dicarboxylate, IV-10 (1.0 mmol) in 12 ml of THF was added LiAlH4 (4.0 mmol) is added. The mixture is stirred at 0°C for five hours, then quenched with 0.15 mL H20, 0.15 mL 10% NaOH and 0.45 mL H20. The resulting mixture is filtered and extracted with ethyl acetate. The organic layer is dried over Na2S04, filtered and concentrated. The product was purified by column chromatography (petroleum ether/ethyl acetate) to yield the title molecule IV-11.
Step-3: 3,3'-bis(bromomethyl)-2-methyl-l, 1 '-biphenyl, IV-12
To a solution of (2-methyl-[l, -biphenyl]-3,3'-diyl)dimethanol IV-11 (1.0 mmol) in 40 mL of dichloromethane is added PBr3 (2.0 mmol) dropwise at 0 °C. The mixture is stirred at 0°C overnight. It is quenched with water. The mixture was extracted with dichloromethane. The organic layer is dried over Na2S04, filtered and concentrated. The product is purified by column chromatography (petroleum ether : ethyl acetate) to give the desired product IV-12. Step-4&5: follow the standard alkylation and reductive amination procedures described for Example-16 to yield the title compound 1-26.
Example-19: 3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl}-6- methoxypyridin-2-yl)oxy]methyl})-[l, -biphenyl]-2-carbonitrile, 1-30.
Figure imgf000046_0001
Step-3
Step-1: dimethyl 2-cyano-[l, -biphenyl]-3,3!-dicarboxyiate (IV-14)
To a solution of (3-(methoxycarbonyl) phenyi)boronic acid III-4 (1.10 mmol), methyl 3-bromo-2-cyanobenzoate II-9 (1.0 mmol), CsF (3.0 mmol), and Pd(dppf)Cl2 (0.02 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110°C under N2 overnight. The reaction mixture is filtered and concentrated, then extracted with ethyl acetate. The organic layer is dried over Na2S04, filtered and concentrated. The product is purified by column chromatography (petroleum ether : ethyl acetate) to yield title product IV-14.
Step-2: 3,3'-bis(hydroxymethyl)-[l, -biphenyl]-2-carbonitrile (IV-15)
To a solution of LiBH4 (5-10 mmol) in MeOH (6 mL) is added dimethyl 2-eyano- [l,l '-biphenyl]-3,3'-dicarboxylate IV-14 (1.0 mmol). The resulting mixture is stirred at it. A TLC or LCMS analysis is conducted after 1 hour. When TLC/LCMS analyses indicate that the starting material is consumed, the solvent is removed in vacuo. The residue is dissolved in DCM (20 mL) and washed with H20 (10 mL). The organic layer is dried over Na2S04, filtered and concentrated to afford the desired alcohol IV-15.
Step-3: 3,3!-bis(((5-formyl-6-methoxypyridin-2-yi)oxy)methyl)-[l, -biphenyi]-2- carbonitrile, IV-16
Cesium carbonate (4.0 mmol, 2 eqv.), palladium(II) acetate (0.2 mmol, 0.1 eqv.), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (t-butyl Xphos) (0.4 mmol, 0.2 eqv.), 6-chloro-2-methoxynicotinaldehyde (2.6 mmol, 1.3 eqv.), and 3,3'-bis(hydroxymethyl)- [l, -biphenyl]-2-carbonitrile IV-15 (1.0 mmol, 2N) are combined in a 25 mL round bottom flask equipped with a stir bar. Toluene (12 mL) is added and the mixture i s purged with a stream of argon for 5 minutes. The reaction is sealed and heated at 80 °C overnight. The soluble portion of the crude reaction is charged to a silica gel column with dichloromethane and c h r o m a t o g r a p h e d with an appropriate gradient of ethyl acetate in hexanes. A fraction containing a compound tested positive for an aldehyde using 2,4 dinitrophenyl hydrazine stain. This aldehyde-positive fraction is isolated and used for next step reaction.
Step-4 follow the standard reductive amination procedures described for Example- 16 to yield the title compound 1-30.
Example-20: 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl] -[l,l '-biphenyl]-2-carbonitrile, 1-31.
Figure imgf000047_0001
Step-1: 3,3!-bis(bromomethyl)-[l, -biphenyi]-2-carboiiitrile, IV-17
To a solution of 3,3'-bis(hydroxymethyl)-[l,r-biphenyl]-2-carbonitrile IV-15 (1.0 mmol) in 40 mL of dichloromethane is added PBr3 (2.0 mmol) dropwise at 0°C. The mixture is stirred at 0°C overnight. It is quenched with water. The mixture is extracred with dichloromethane. The organic layer is dried over Na2SC"4, filtered and concentrated. The product is purified by column chromatography (petroleum ether/ethyl acetate) to give the desired product IV-17.
Step-2: 3,3'-bis((4-formyl-3,5-dimethoxyphenoxy)methyl)-[l, -biphenyl]-2- carbonitrile, IV-18
A mixture of 3,3'-bis(bromomethyl)-[l, -biphenyl]-2-carbonitrile, IV-17 (1.0 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (2.17 mmol) and K2C03 (2.5 mmol) in 7 mL of DMF is stirred at room temperature (or at 60-80 °C) for 16 h. The mixture is concentrated and extracted with ethyl acetate. The organic layer is dried over Na2S04, filtered and concentrated. The crude product is subjected purification by normal column chromatography or reversed phase HPLC to yield the desired product IV-18. Step-3: 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl] -[l,l '-biphenyl]-2-carbonitrile, 1-31.
Figure imgf000048_0001
To a solution of aldehyde IV-18 (1.0 mmol) in MeOH (30 mL) is added 2- aminoethanol (4.0 mmol) and acetic acid (0.5 mmol). After stirring for 30 minutes, NaBH3CN (4.0 mmol) is added and the mixture is stirred for 16 hours at room temperature. The reaction is quenched with the water, and extracted with AcOEt. The combined organic layers is dried over anhydrious Na2S04 and concentrated. The residue is purified by silica gel column (dichloromethane/ MeOH) to give the title compound 1-31.
The following compounds, I-32--I-49 (in Table 1) are prepared in the same mannar as Example 18-20 from appropriate aldehyde intermediates and amines to provide the title compounds.
The compounds listed in Table 1 are prepared using methods similar to those described for the preparation of I-l to 1-31.
Table 1
Figure imgf000048_0002
Figure imgf000049_0001
1 -yl)methyl]phenoxy } methy l)benzonitrile
Figure imgf000050_0001
Figure imgf000051_0001
carbonitrile
Figure imgf000052_0001
dicarbonitrile N 3,3'-bis[(4-{[(2- hydroxyethyl)amino]methyl}-2--43
metliylphenoxy)m ethyl] -[ 1 , 1 '-biphenyl] - 2 ,2 ' -die arbonitrile
3,3'-bis[(4-{[(2--44 hydroxyethyl)amino]methyl}phenoxy)meth
y 1] - [ 1 , 1 '-biphenyl] -2 ,2 '-die arbonitrile
5,5'-bis[(4-{[(2- hydroxyethyl)amino]methyl}-2--45
methylphenoxy)methyl]-[3,3'-bipyridine]- 4 ,4 ' -die arbonitrile N
2-[({4-[(3-{5-[(4-{[(2- hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-4--46
methy lthiophen-3 -yl } -2 - m ethy lpheny l)m ethoxy ] -2 , 6 - dimethoxyphenyl}methyl)amino]ethan-l-ol
2-[({4-[(4-{3-[(4-{ [(2- hydroxyethyl)amino]methyl}-2--47 methylphenoxy)methyl]-2-methylphenyl}- 3 -methylthiophen-2-yl)methoxy]-3 - methylphenyl }methyl)amino]ethan- 1 -ol
2-({ [4-({5'-[(4-{ [(2- hydroxyethyl)amino]methyl}-2--48 methylphenoxy)methyl]-4,4'-dimethyl- [3,3 '-bithiophene] -5 -yl}methoxy)-3 - H T T ¾_s'
methylphenyl]methyl } amino)ethan- 1 -ol
2-({ [4-({5'-[(4-{ [(2- hydroxyethyl)amino]methyl}-2--49 methylphenoxy)m ethyl] -1,1 ' -dim ethy 1- lH,rH-[2,2'-bipyrrole]-5-yl}methoxy)-3- methylphenyl]methyl } amino)ethan- 1 -ol
Figure imgf000053_0001
Example-21: 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl) amino]methyl}-2-methylphenoxy}methyl)-2,2'-dimethyl-[l, l'-biphenyl]-3-yl]met^
{[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy)methyl]pyridine-3-carbonitri 1-50.
Figure imgf000054_0001
Step-1: 4,4'-(((2,2'-dimethyl-[l, -biphenyl]-3,3,-diyl)bis(methylene))bis(oxy))bis(2- hydroxy-5 -methyl benzaldehyde), I V- 1 .
A mixture of 2,4-dihydroxy-5-methylbenzaldehyde (2.2 mmol), triphenylphosphine (2.2 mmol) and (2,2'-dimethyl-[l,l '-biphenyl]-3,3'-diyl)dimethanol (1.0 mmol) is dissolved in dry tetrahydrofuran (14 mL) and cooled to 0 °C. Diisopropyl azodicarboxylate (2.2 mmol) in tetrahydrofuran (14 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexane s: ethyl acetate) on a silica gel column to afford the desired product, IV-19.
Step-2: 5,5,-((((((2,2'-dimethyi-[l ,r )iphenyi]-3,3,-diyi)^^
bis(0-formyl-4-methyi-3,l-phenyiene))bis(oxy IV-20
Cesium carbonate (3.0 mmol), 4,4"-(((2,2*-dimethyl-[l,l,-biphenyl]-3,3'- diyl)bis(methylene))bis(oxy))bis(2-hydroxy-5-methylbenzaldehyde) (1.0 mmol) and 5- (chloromethyl)nicotinonitrile (4.0 mmol) are stirred at 75 °C for 3 hours in dimethyl formamide(5 mL). The reaction is filtered and concentrated. The residue is purified with a mixture of hexane: ethyl acetate on a silica gel column to afford the desired product IV-20.
Step-3: 5-[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]- methyl}-2-methylphenoxy}methyl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl]methoxy}-2-{[(2- hydroxy ethyl) amino]methyl}-4-methylphenoxy)methyl]pyridine-3-carbonitrile, 1-50.
To a solution of aldehyde IV-20 (1.0 mmol) in MeOH (30 mL) is added 2- aminoethanol (4.0 mmol) and acetic acid (0.5 mmol). After stirring for 30 minutes, NaBH3CN (4.0 mmol) is added and the mixture is stirred for 16 hours at room temperature. The reaction is quenched with the water, and extracted with ethyl acetate. The combined organic layers are dried over anhydrious Na2S04 and concentrated. The residue is purified by silica gel column (eluent: DCM/ MeOH) to give the title compound 1-50.
Example-22: 5-[(5-{ [3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2- methylphenoxy}methyl)-2,2'-dimethyl-[l, l'-biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4- methylphenoxy)methyl]pyridine-3-carbonitrile, 1-54.
Figure imgf000055_0001
5,5'-((((((2,2'-dimethyl-[l,r-biphenyl]-3,3'-diyl)bis(methylene)) bis(oxy))bis(6- formyl-4-methyl-3, l -phenyl ene))bis(oxy))bis(^ IV-20 (1.0 mmo) is dissolved in ethanol (15 mL), and NaBH4 (2.4 mmol) is added in small portions over 30 min to the stirred solution with ice cooling. The resulting solution is then stirred for 4-6 h at room temperature and a NaOH (1 M, 15 mL) solution was added to quench the reaction. The ethanol is removed by evaporation, the aqueous phase is extracted with ethyl acetate three times and the combined organic phase was washed with NaOH (1.0 M, 15 mL), water (15 mL) and brine (15 mL) and dried over anhydrous Na2S04, filtered and concentrated. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate/petroleum ether) to yield the title molecule 1-54.
Example-23: 5-{ [4-chloro-5-({2-cyano-3'-[(4-{ [(2-hydroxyethyl)amino] methyl}- 2-methylphenoxy)methyl]-[l, l'-biphenyl]-3-yl}methoxy)-2-{ [(2-hydroxy ethyl)
amino]methyl}phenoxy] methyl}pyridine-3-carbonitrile, 1-59.
Figure imgf000056_0001
Step- Step-2
Figure imgf000056_0002
Intermediate III-8 is prepared by the literature procedure described in Tetrahedron, 69(16), 3465-3
Figure imgf000056_0003
Step-1 Step-2
Step- J: 3'-(((tert-butyldimethylsilyl)oxy)methyl)-3-(hydroxymethyi)-[l,r- biphenyl]-2-carbonitriie, 11-10.
To a solution of tert-butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzyl)oxy)silane III-8 (1.10 mmol), 2-bromo-6-(hydroxymethyl) benzonitrile (1.1 g, 1.0 mmol), KOAc (2.0 mmol), and Pd(dppf)Cl2 (0.07 mmol) in 8 mL of dioxane is added 2 mL of H20. The mixture is stirred at 110°C under N2 overnight. The reaction mixture is filtered and concentrated, then extracted with ethyl acetate. The organic layer is dried over Na2SC"4, filtered and concentrated. The product is purified by column chromatography (petroleum ether : ethyl acetate) to give a desired product 11-10.
Step-2: 3'-(((tert-butyldimethylsilyl)oxy)methyl)-3-((2-chloro-4-formyl-5- hydroxyphenoxy) rnethyl)-[ 1 , 1 !-biphenyl]-2-carbonitrile, IV-22.
A mixture of 5-chloro-2,4-dihydroxybenzaldehyde (1.1 mmol), triphenylphosphine (1.1 mmol) and 3!-(((tert-butyldimethyisiiyl)oxy)methyl)-3- (hydroxymethyl)-[l, -biphenyl]-2-carbonitrile, 11-10 (1.0 mmol) is dissolved in dry tetrahydrofuran (7 mL) and cooled to 0 °C. Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (7 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes: ethyl acetate) on a silica gel column to afford the desired product, IV-22.
Step-3: 5-((5-((3'-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-[l, l '-biphenyl]-3- yl) methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile, IV-23.
Cesium carbonate (1.5 mmol), 3'-(((tert-butyldimethylsilyl)oxy) methyl)-3-((2- chloro-4-formyl-5-hydroxyphenoxy)methyl)-[l, -biphenyl]-2-carbonitrile, IV-23 (1.0 mmol) and 5-(chloromethyl)nicotinonitrile (2.0 mmol) are stirred at 75 °C for 3 hours in dimethyl formamide(5 mL). The reaction is filtered and concentrated. The residue is purified with a mixture of hexane: ethyl acetate on a silica gel column to afford the desired product IV-23.
Step-4: 5-((4-chloro-5-((2-cyano-3'-(hydroxymethyl)-[l, -biphenyl]-3- yl)methoxy)-2-formyl phenoxy)methyl)nicotinonitrile, IV-24.
To a solution of 5-((5-((3'-(((tert-butyldimethylsilyl)oxy)methyl)-2-cyano-[l, - biphenyl]-3-yl) methoxy)-4-chloro-2-formylphenoxy)methyl)nicotinonitrile, IV-23 (1.0 mmol) in THF (5 mL) is added tetrabutylammonium fluoride in THF (1M solution in THF, 2 mL, 2.0 mmol) drop wise at 0 °C. The reaction mixture is stirred at rt for 1 h and is diluted with H20 (10 mL) and extracted with EtOAc (3 * 20 mL). The combined organic layer is dried over Na2S04 and was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent hexane/EtOAc 30:70) to afford desired product IV-24.
Step-5: 5-((4-chloro-5-((2-cyano-3'-((4-formyl-2-methylphenoxy)methyl)-[l,r- biphenyl]-3-yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-25.
A mixture of 4-hydroxy-3-methylbenzaldehyde (1.1 mmol), triphenylphosphine (1.1 mmol) and 5-((4-chloro-5-((2-cyano-3'-(hydroxymethyl)-[l,r-biphenyl]-3- yl)methoxy)-2-formylphenoxy)methyl)nicotinonitrile, IV-24 (1.0 mmol) is dissolved in dry tetrahydrofuran (7 mL) and cooled to 0 °C. Diisopropyl azodicarboxylate (1.1 mmol) in tetrahydrofuran (7 mL) is added dropwise. The resulting yellow solution is allowed to slowly warm to room temperature overnight. Solvent is removed by rotary evaporator. The crude is purified with an eluent (hexanes: ethyl acetate) on a silica gel column to afford the desired product, IV-25. Step-6% 5-{[4-chloro-5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methyl phenoxy) methyl]-[l,l'-biphenyl]-3-yl}methoxy)-2-{[(2- hydroxyethyl)amino]methyl }phenoxy] methyl }pyridine-3-carbonitrile, 1-59.
A mixture of aldehyde IV-25 (1.0 mmol, 2N), 2-aminoethan-l-ol (6 mmol, 3 eqv.) and AcOH (10 mmol, 5 eqv.) in DMF (10 mL) is stirred at RT for 4-16 h. Then sodium cyanoborohydride (6 mmol, 3 eqv.) is added and the mixture is stirred at RT until reductive amination is complete (typically overnight). The crude is purified via reverse phase preparative HPLC to give the title compound 1-59.
Example 24: 5-[(4-chloro-2-{[(2-hydroxyethyl)amino]methyl}-5-({3'-[(4-{[(2- hydroxy ethyl) amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methyl-[l, l'-biphenyl]-3- yl}methoxy) phenoxy)methyl]pyridine-3-carbonitrile, 1-69.
The compound 1-69 can be synthesized by Method A shown below: :
Figure imgf000058_0001
Step- 1-6 in Method A: follow the stardard procedures described for Example-23 to yield the tiltle compound 1-69.
The compound 1-69 can be synthesized by Method B shown below:
Figure imgf000059_0001
Preparation of intermediate III-9:
Figure imgf000059_0002
11-12
All steps in Method B: follow the stardard procedures described for Example-23 to yield the tiltle compound 1-69.
The compounds listed in Table 2 are prepared using methods similar to those described for the preparation of 1-50, 1-54, 1-59 and 1-69.
Table 2
Figure imgf000059_0003
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
carbonitrile 2-({ [4-({3'-[(4-{ [(2- hy droxy ethy l)amino] me thy 1 } -2 -methy 1-
5-[(pyridin-3- yl)methoxy]phenoxy)methyl]-2,2'- dimethyl-[ 1 , 1 '-bipheny 1] -3 -yl}methoxy )- 2,6- dimethoxyphenyl]methyl}amino)ethan- l-ol
Example 25: 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}-[l,2,4]triazolo[l,5- a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]-[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-6- yl }methyl)amino]ethan- 1 -ol, 1-73.
The compound 1-73 can be synthesized via the route shown in the scheme below.
Figure imgf000063_0001
Example 26: 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}imidazo[l,2-a]pyridin- 2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]imidazo[ 1 ,2-a]pyridin-6-yl }methyl) amino]ethan- 1 - ol 1-74.
The compound 1-74 can be synthesized via the route shown in the scheme below.
Figure imgf000063_0002
Example 27: 2-[({2-[3'-(6-{[(2-hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)- 2,2'-dimethyl-[l, l'-biphenyl]-3-yl]-l,3-benzoxazol-6-yl}methyl)amino]ethan-l-ol, 1-75.
The compound 1-75 can be synthesized via the route shown in the scheme below.
Figure imgf000064_0001
1-75
Example 28: 3-(5-{[(2-hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4- { [(2-hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-2-carbonitrile, 1-87
The compound 1-87 can be synthesized via the route shown in the scheme below:
Figure imgf000064_0002
The compounds listed in Table 3 are prepared using methods similar to those described for the preparation of 1-73, 1-74 and 1-87. Table 3
Figure imgf000065_0001
Figure imgf000066_0001
y l)methyl] amino }ethan- 1 -ol
Figure imgf000067_0001
y l}methy l)amino] ethan- 1 -ol
Figure imgf000068_0001
The compounds disclosed herein, but not listed in Table 1-3 above, can be prepared in a similar manner as Compounds I-l to 1-105.
DOCKING EXPERIMENTS
Compounds I-l and 1-10 are selected as ligands to bind PD-Ll dimer. Figure 1 shows docking pose of compound I-l in PD-Ll dimer (Panel A). Figure 2 shows docking pose of compound 1-10 in PD-Ll dimer (Panel B)
Method of Docking: the protein model was built based on PDB structure of PD-Ll dimer (pdb code: 5j8o) in which Y56 conformation in B chain was rebuilt to allow access to both sides of the ligand core structure. Ligands were docked using rdock and docking poses were selected based on docking score and visual inspection.
Figure legend: the ligand binding site at the dimer interface was displayed in an orientation in which chain A and chain B were located above and below the ligand respectively. Ligands were displayed in ball and stick representation. Surfaces were created surrounding the ligand binding site and were clipped to allow ligand to be better displayed. As shown in Figures 1 and 2, compounds 1-1 and 1-5 dock well with PD-L1 dimer. In both cases, hydrophobic channel accommodates the designed novel core scaffold in the center; two pseudo symmetrical side chains attached to the core are extended to either side of the dimer interface. It is believed that such designed inhibitors can effectively induce/stabilize PD-L1 dimer formation, therefore potently disrupting PD-1/PD-L1 protein- protein and CD80/PD-L1 protein-protein interaction. Other compounds disclosed herein are believed to exhibit the same properties in docking experiments. Thus, these compounds can also be potent and selective inhibitors of the PD-1/PD-L1 protein/protein and CD80/PD-L1 protein/protein interactions.
BIOLOGICAL ASSAY
The activity of the compounds of Formula (I) to inhibit PD-1/PD-L1 protein-protein interaction can be readily investigated using biochemical and cellular assays well accepted in the field.
Homogenous time-resolved fluorescence (HTRF) binding assay:
The ability of the designed compounds to physically disrupt PD-1/PD-L1 interaction was measured by HTRF binding assay. The interaction of PD-1 and PD-L1 was assessed using soluble, purified preparations of the extracellular domains of the two proteins. For PD- 1, the tag is the Fc portion of immunoglobulin (PD-l-Ig). For PD-L1, it is the 6 histidine motif (PD-Ll-His). All required fusion proteins with desired tags were obtained from commercial sources. HTRF assay buffer consists of lxPBS supplemented with 0.1% (w/v) bovine serum albumin and 0.05% (v/v) Tween-20. For the binding assay, PD-Ll-His (30 nM final) and PD- l-Ig (10 nM final) in HTRF assay buffer were pre-incubated at RT for 30 min, followed by addition of inhibitors and incubated for another 30 min. HTRF detection was achieved using Tb cryptate-labeled anti-Ig antibody (1 nM final) and d2-labeled anti-His antibody (20 nM final). Antibodies were diluted in HTRF assay buffer and dispensed on top of the binding reaction. The reaction mixture was allowed to equilibrate for 60 min at RT before the resulting signal (665nm/620nm ratio) was obtained using an En Vision fluorometer. Final DMSO concentration in the solution is 0.2%. Additional binding assays can be established between PD- 1-Ig and PD-L2-His or CD80-His/PD-Ll -Ig, in a similar format. The IC50 of the designed compounds in disrupting PD-1/PD-L1 interaction will be expected to fall in the range of 0.01 nM to 100 uM, depending on the corresponding structure-activity relationship. IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software. Compounds of the present disclosure, as exemplified in Examples 1-6, showed IC50 values in the following ranges: A: IC50 < 0.1 uM; B: 0.1 uM < IC50 <1.0 uM; C: 0.1 uM < IC50 < 25 uM
Data obtained for the representative compounds using the PD-1/PD-L1 homogenous time- resolved fluorescence (HTRF) binding assay described in Example 29 is shown in Table 4.
Table 4
C 'pd I D l 1>I lVi- 1l . A I>'1U¾- 1Ι Λ 1 l 1 l1'I 1'U ΓI.' I Kf 0
I-l A
1-2 c
1-3 c
1-4 B
1-5 A
1-6 A
T-cell activation assay:
The ability of the designed compounds to functionally inhibit PD-1/PD-L1 interaction on a cellular level can be measured by T-cell activation assay. Human peripheral blood mononuclear cells (PBMC) can be isolated from blood buffy coats by commercial kits available. CD4+ T cells can be isolated with CD4 enrichment kit as per the manufacturer's instructions. Mouse Ig capture beads can be coated with anti-CD3, anti-CD28 and PD-Ll Fc fusion by incubation under rotation at 4°C. CD4+ T cells can be cultured in 96-well plates together with coated beads, with or without designed compounds at varying concentrations for 3 days at 37°C in RPMI1640 Glutamax I supplemented with 4% human AB serum. Culture supernatant can be removed to measure cytokine expression (e.g. IFNs, IL-2) by ELISA, DELFIA or Luminex technology. The amount of cytokine can be determined by comparing with a standard curve of known amounts of human cytokines. The remaining T cells can be quantified by standard cell proliferation/survival assays (e.g. Thymidine incorporation, CellTiter-Glo) according to manufacturer's instructions. Potent inhibitor compounds will disrupt PD-Ll protein binding to PD-1 on the T cell surface, thus resulting in enhanced cytokine expression and promotion of T cell proliferation/activity.
Mixed lymphocyte reaction:
The ability of the designed compounds to functionally inhibit endogenous PD-l/PD- Ll interaction and promote T cell activity can be measured by mixed lymphocyte reaction assay. Human PBMCs can be isolated from leukapheresis packs using Ficoll-Paque Plus as per the manufacturer's instructions. Cells can be cultured in serum-free RPMI 1640 for short period at 37°C. After removal of nonadherent cells, remaining monocytes can be cultured in RPMI 1640 supplemented with 5% human AB serum, 2 ng/mL GM-CSF, and 10 ng/mL IL4. Fresh media with cytokine supplements can be added every 2 to 3 days. Mature dendritic cells can be induced by addition of TNFa on day 6 and culture for 24 hours. CD4+ T cells can be isolated from PBMCs using magnetic beads as per the manufacturer's instructions. CD4+ T cells can be cultured in 96 well-flat bottom plates together with allogeneic dendritic cells at an optimal ratio (e.g. 1 :2.5), using RPMI 1640 supplemented with 10% human AB serum. Dendritic cells can be treated with 100 mg/mL of mitomycin C before addition. Designed compounds or DMSO can be added as desired. Cytokine expression and T cell proliferation/activity can be measured as indicated above according to manufacturer's instructions. Potent inhibitor compound is expected to promote cytokine expression and T cell proliferation/activity.
The compounds of Formula (I) possess activity as inhibitors of the PD-l/PD-Ll interaction, and therefore, may be used in the treatment of diseases dependent on or associated with the PD-l/PD-Ll interaction. Through inhibition of the PD-l/PD-Ll interaction, the compounds of the present disclosure may be utilized to treat infectious diseases such as Hepatitis C, as well as multiple forms of cancer.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.

Claims

WHAT IS CLAIMED IS:
1. A compound having Formula I:
Figure imgf000072_0001
(I), or a pharmaceutical acceptable salt thereof, wherein:
A is a bivalent arene or a bivalent heteroarene;
Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring, a 6- membered heterocyclic ring, a 9- to 10-membered aromatic hydrocarbon ring, or a 9- to 10- membered heterocyclic ring;
Y and Y' are independently null (direct bond), -CHRi-, -CH2-CH2-, - R , -0-, - OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO-, or -S02CH2-, and Ri is H, alkyl, or C3-6 cycloalkyl;
R3 and R'3 are independently H, S02 H2, S02 R5R6, S02 HR7,
Figure imgf000072_0002
, ,¾
- OCH3 ^ CH2NR5R6; or CH2 HR7, wherein R5 and R6 are independently H, Ci-6 alkyl, C3- 8 cycloalkyl, or heteroaryl or R5 and R6 form a C3-8 cycloalkyl, heterocyclyl, or heteroaryl ring, and R7 is H, aryl, heteroaryl, acetyl, CH2CH2OH, CH2CH2NHCOCH3, C3-C8 alkyl carboxylic acid, C3-C8 alkyl amide, C3-C8 alkyl alcohol, -CH2-Ar, or -CH2 -heterocyclyl; and
R4, R'4, Z, and Z' are independently H, halogen, CHF2, CF3, CN, C1-6 alkyl, C1-6 alkoxy, aryl, or heteroaryl.
The compound of claim 1, wherein the Formula (I) is represented by following
Formula (II):
Figure imgf000072_0003
(n),
Ring B and Ring B' are independently a 6-membered aromatic hydrocarbon ring or a 6-membered heterocyclic ring; Xi, X' i, X2, and X'2 are independently CR2, C=0 or R2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, C1-6 alkoxyl, C -7 cycloalkyl, C -7 heterocyclyl, or OCH2Ar;
X , and X'3 are independently C or N; and
Y and Y' are independently -CHRi-, -CH2-CH2-, - Ri-, -0-, -OCH2-, -CH20-, - SCH2-, -CH2S-, -SOCH2-, -CH2SO-, or -S02CH2-, and Ri is H, Ci-6 alkyl, or C3-6 cycloalkyl.
3. The com ound of claim 1, wherein the Formula (I) is represented by following
Formula (III):
Figure imgf000073_0001
(ΠΙ),
Ring B and Ring B' are independently a 9- to 10-membered aromatic hydrocarbon ring or a 9- to 10 -membered heterocyclic ring;
Xi, and ΧΊ are independently CR2, C=0 or NR2, and R2 is H, Me, CN, halogen, OMe, CHF2, CF3, Ci-6 alkoxyl, C -7 cycloalkyl, C -7 heterocyclyl, or OCH2Ar;
X2, and X'2; X , and X'3 are independently C or N;
U and U' are independently C and N;
V and V are O, S, -(CH2)2-, -CR'-, or -N=; and
Y and Y' are independently null (direct bond), -CHRi-, -CH2-CH2-, -NR , -0-, - OCH2-, -CH20-, -SCH2-, -CH2S-, -SOCH2-, -CH2SO-, or -S02CH2-, and Ri is H, Ci-6 alkyl, or C -6 cycloalkyl.
4. The compound of claim 1, 2, or 3, wherein A is
Figure imgf000073_0002
Figure imgf000073_0003
Figure imgf000074_0001
and Ra' are independently COR', OMe, halogen, Ci-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl, CN, CF3; CH2CF3; R' is Ci-6 alkyl; Rb and Rb' are independently C1-6 alkyl, C2-6 alkynyl, C1-6 cycloalkyl or alkyl halogen; and V is -(CH2)2-, -CR'-, or -N=. H
The compound of claim 1, 2, 3, or 4, wherein CH2NR5R6 is
Figure imgf000074_0002
Figure imgf000074_0003
Figure imgf000075_0001
Figure imgf000075_0002
74
Figure imgf000076_0001
Figure imgf000076_0002
75
Figure imgf000077_0001
Figure imgf000077_0002
76
Figure imgf000078_0001
10. The compound of claim 1, 2, or 3 wherein R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, or Ring B and Ring B' are the same; or R3 and R'3 are the same, R4 and R'4 are the same, Y and Y' are the same, Z and Z' are the same, and Ring B and Ring B' are the same.
12. The compound of claim 1, 2, or 3, wherein the compound is 2-({[4-({3'-[(4- { [(2-hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]- 3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 2-{[(4-{[3-({4-[(azetidin-l- yl)methyl]-2-methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3- methylphenyl)methyl] amino }ethan-l-ol; l-[(4-{[3-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy}methyl)-2-chlorophenyl]methoxy}-3-methylphenyl)methyl]azetidine; (2S)- l-{[4-({3'-[(4-{[(2S)-2-carboxypiperidin-l-yl]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'- dimethyl-[l, -biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}piperidine-2- carboxylic acid; (2S)-l-{[4-({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3-yl}methoxy)-2,6- dimethoxyphenyl]methyl}piperidine-2-carboxylic acid; 2-({[4-({3'-[(4-{[(2- hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl-[l,l'-biphenyl]- 3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-l-ol; l-{[4-({3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]-3- yl}methoxy)-2-methoxyphenyl]methyl}azetidin-3-ol; 2-{[(6-{[3-(5-{[(5-{[(2- hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-4-methylthiophen-3-yl)-2- methylphenyl]methoxy}-2-methoxypyridin-3-yl)methyl]amino}ethan-l-ol; 2-({[4-({4-[(4- {[(2-hydroxyethyl)amino]methyl}-3-methoxyphenoxy) methyl]-3-methylthiophen-2- yl }methoxy)-2-methoxyphenyl]methyl }amino)ethan- 1 -ol; 2-({4-[(azetidin- 1 -yl)methyl]-2- methylphenoxy }methyl)-6-{ [4-({ [(4-oxoazetidin-2- yl)methyl]amino}methyl)phenoxy]methyl}benzonitrile; N-(2-{[(4-{[3-({4-[(azetidin-l- yl)methyl]-2-methylphenoxy}methyl)-2-cyanophenyl]methoxy}
phenyl)methyl]amino}ethyl)acetamide; 2-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy}methyl)-6-[(4-{[(2- hydroxyethyl)amino]methyl}phenoxy)methyl]benzonitrile; 2-({4-[(azetidin-l-yl)methyl]-2- methylphenoxy} methyl)-6-({4-[(azetidin-l-yl)methyl]phenoxy} methyl)benzonitrile; 2-({[4- ({4-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-lH-indol-l- yl}methyl)phenyl]methyl}amino)ethan-l-ol; 2-({[4-({ l-[(4-{[(2- hydroxyethyl)amino]methyl}phenyl)methyl]-lH-indazol-4-yl}methoxy)-2,6- dimethoxyphenyl]methyl}amino)ethan-l-ol; 2,6-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3- methoxyphenoxy)methyl]benzonitrile; N-[(4-{[3'-({4-[(cyclopropylamino)methyl]-3,5- dimethoxyphenoxy}methyl)-2,2'-dimethyl-[l, -biphenyl]-3-yl]methoxy}-2,6- dimethoxyphenyl)methyl]cyclopropanamine; 4-{[({4-[(3'-{[3,5-dimethoxy-4-({[(4- oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl}-2,2'-dimethyl-[l,l'-bi
yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]methyl}azetidin-2-one; 2-[({6-[(3'-{[(5- { [(2-hydroxyethyl)amino]methyl }pyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy]pyridin-3-yl}methyl)amino]ethan-l-ol; 2-[({6-[(3'-{[(5-{[(2- hydroxyethyl)amino]methyl } -6-methoxypyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '- biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)amino]ethan-l-ol; N-{2-[({6-[(3'- {[(5-{[(2-acetamidoethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'-dim
[1,1 '-biphenyl]-3 -yl)methoxy]-2-methoxypyridin-3 -yl }methyl)amino] ethyl } acetamide;
(2R,4R)-l-({6-[(3'-{[(5-{[(2R,4R)-2-carboxy-4-hydroxypyrrolidin-l-yl]methyl}-6- methoxypyridin-2-yl)oxy]methyl } -2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl)methoxy]-2- methoxypyridin-3-yl}methyl)-4-hydroxypyrrolidine-2-carboxylic acid; (2R,4R)-4-hydroxy-l- ({6-[(3'-{[(5-{ [(2 -hydroxy ethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-2,2'- dimethyl-[l, -biphenyl]-3-yl)methoxy]-2-methoxypyridin-3-yl}methyl)pyrrolidine-2- carboxylic acid; (3R)-l-{[4-({3'-[(4-{[(3R)-3-hydroxypyrrolidin-l-yl]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 - methylphenyl]methyl}pyrrolidin-3-ol; (2R,4R)-l-{[4-({3'-[(4-{[(2R,4R)-2-carboxy-4- hydroxypyrrolidin- 1 -yljmethyl } -2-methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl}methoxy)-3-methylphenyl]methyl}-4-hydroxypyrrolidine-2-carboxylic acid; 2-({[4-({3'- [(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2'-methyl-[l, - biphenyl]-3-yl}methoxy)-2,6-dimethoxyphenyl]methyl}amino)ethan-l-ol; 2-[({4-[(2-{3-[(4- {[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin- 4-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol; 2-[({4-[(6-{3-[(4-{[(2- hydroxy ethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2-methylphenyl}pyridin-2- yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol; 2-({[4-({2'-chloro-3'-[(4-{[(2- hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-3 - methylphenyl]methyl}amino)ethan-l-ol; 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl]-[l, -biphenyl]-2-carbonitrile; 3,3'-bis({[(5-{[(2- hydroxyethyl)amino]methyl }-6-methoxypyridin-2-yl)oxy]methyl })-[ 1 , 1 '-biphenyl]-2- carbonitrile; 3,3'-bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[l, - biphenyl]-2-carbonitrile; 3,3'-bis({4-[(azetidin-l-yl)methyl]-3,5-dimethoxyphenoxy}methyl)- [l,l'-biphenyl]-2-carbonitrile; 3,3'-bis({4-[(3-hydroxyazetidin-l-yl)methyl]-3,5- dimethoxyphenoxy}methyl)-[l, -biphenyl]-2-carbonitrile; 3,3'-bis({[3,5-dimethoxy-4-({[(4- oxoazetidin-2-yl)methyl]amino}methyl)phenoxy]methyl})-[l,l'-biphenyl]-2-carbonitri 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, l'-biph carbonitrile; N-{2-[({6-[(2'-cyano-3'-{[(5-{[(2-acetamidoethyl)amino]methyl}-6- methoxypyridin-2-yl)oxy]methyl}-[l, -biphenyl]-3-yl)methoxy]-2-methoxypyridin-3- yl}methyl)amino]ethyl}acetamide; 2-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5- dimethoxyphenoxy)methyl] -6- { 4-[(4- { [(2-hy droxy ethyl)amino]methyl } -3 , 5 - dimethoxyphenoxy)methyl]pyridin-2-yl}benzonitrile; 2-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-6-{4-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]pyridin-2-yl}benzonitril^ 2-{[(5- { [(2-hy droxy ethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}-6-(4-{[(5-{ [(2- hydroxyethyl)amino]methyl}-6-methoxypyridin-2-yl)oxy]methyl}pyridin-2-yl)benzonitrile; 2-[({4-[(2-{3-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2- methylphenyl}pyridin-4-yl)methoxy]-3-methylphenyl}methyl)amino]ethan-l-ol; 3,3'- bis({[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl})-[l, -biphenyl]-2,2'- dicarbonitrile; 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, - biphenyl]-2,2'-dicarbonitrile; 3,3'-bis[(4-{[(2-hydroxyethyl)amino]methyl}phenoxy)methyl]- [l,l'-biphenyl]-2,2'-dicarbonitrile; 5,5'-bis[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-[3,3'-bipyridine]-4,4'-dicarbonitrile; 2-[({4-[(4-{3-[(4-{[(2- hy droxy ethyl)amino]methyl } -3 , 5 -dimethoxyphenoxy)m ethyl] -2-methylphenyl } -3 - methylthiophen-2-yl)methoxy]-2,6-dimethoxyphenyl}methyl)amino]ethan-l-ol; 2-[({4-[(4- { 3 - [(4- { [(2-hy droxy ethyl)amino]methyl } -2-methylphenoxy)m ethyl] -2-methylphenyl } -3 - methylthiophen-2-yl)methoxy]-3-methylphenyl}methyl)amino]ethan-l-ol; 2-({[4-({5'-[(4- { [(2-hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-4,4'-dimethyl-[3, 3'- bithiophene]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 2-({[4-({5'-[(4-{[(2- hydroxy ethyl)amino]methyl } -2-methylphenoxy)methyl]- 1 , 1 '-dimethyl- 1H, 1 Ή-[2,2'- bipyrrole]-5-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy}methyl)-
2,2'-dimethyl-[l, -biphenyl]-3-yl]methoxy}-2-{[(2-hydroxyethyl)amino]methyl}-4- methylphenoxy)methyl]pyridine-3-carbonitrile; 2-({[4-({3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'- dimethyl-[l, -biphenyl]-3-yl}methoxy)-5-methyl-2-[(pyridin-3- yl)methoxy]phenyl]methyl}amino)ethan-l-ol; 5-[(4-chloro-5-{[3'-({2-chloro-5-[(5- cyanopyridin-3-yl)methoxy]-4-{[(2-hydroxyethyl)amino]methyl}phenoxy}methyl)-2,2'- dimethyl-[l, l'-biphenyl]-3-yl]methoxy}-2-{[(2- hydroxyethyl)amino]methyl}phenoxy)methyl]pyridine-3-carbonitrile; 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-2-methyl-4-[(methylamino)methyl]phenoxy}methyl)-2,2'- dimethyl-[l, l'-biphenyl]-3-yl]methoxy}-4-methyl-2-
[(methylamino)methyl]phenoxy)methyl]pyridine-3-carbonitrile; 5-[(5-{[3'-({5-[(5- cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2,2'-dimethyl-
[l, -biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3- carbonitrile; 5-[(3-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2,2'- dimethyl-[l, -biphenyl]-3-yl]methoxy}-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 5-
[(5-{[3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-
2-methyl-[l,l'-biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4- methylphenoxy)methyl]pyridine-3-carbonitrile; 3,3'-bis({5-[(5-cyanopyridin-3-yl)methoxy]- 4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy}methyl)-[l, -biphenyl]-2,2'- dicarbonitrile; 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2- yl)oxy ]methyl } - [ 1 , 1 '-biphenyl] -3 -yl)methoxy ] -2- { [(2- hydroxyethyl)amino]methyl}phenoxy}methyl)pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'- [(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, l'-biphenyl]-3- yl}methoxy)-2-{[(2-hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile; 5- {[4-chloro-5-({2-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]- [1,1 '-biphenyl]-3 -yl }methoxy)-2- { [(2- hydroxyethyl)amino]methyl}phenoxy]methyl}pyridine-3-carbonitrile; 3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-[(4-{[(2- hydroxyethyl)amino]methyl}-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-[l, -biphenyl]-2- carbonitnle; 5-{[5-({2'-cyano-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3-yl }methoxy)-2-{ [(2 -hydroxy ethyl)amino]methyl }- 4-methylphenoxy]methyl}pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'-[(4-{[(2- hydroxyethyl)amino]methyl } -2-methylphenoxy)methyl]-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-2- {[(2-hydroxyethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3-carbonitrile; 5-[(4- chloro-2- { [(2-hy droxy ethyl)amino]methyl } -5 - [(3 '- { [(5 - { [(2- hydroxyethyl)amino]methyl}pyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[l, -biphenyl]-3- yl)methoxy]phenoxy)methyl]pyridine-3-carbonitrile; 5-({4-chloro-5-[(2-cyano-3'-{[(5-{[(2- hy droxy ethyl)amino]methyl }pyridin-2-yl)oxy]methyl } -[ 1 , 1 '-biphenyl]-3 -yl)methoxy]-2- [(cyclopropylamino)methyl]phenoxy}methyl)pyridine-3-carbonitrile; 5-{[5-({2-cyano-3'-[(4- { [(2-hy droxy ethyl)amino]methyl}-3,5-dimethoxyphen
3 -yl}methoxy)-2-{ [(2-hy droxy ethyl)amino]methyl}-4-methylphenoxy]methyl}pyridine-3- carbonitrile; 5-[(5-{[2-cyano-3'-({5-[(5-cyanopyridin-3-yl)methoxy]-4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy}methyl)-[l, -biphenyl]-3-yl]methoxy}-2- {[(2-hy droxy ethyl)amino]methyl}-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 2-({[4- ({3'-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-3-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'- dimethyl-[ 1 , 1 '-biphenyl]-3-yl }methoxy)-3-methylphenyl]methyl}amino)ethan- 1 -ol; 5-[(4- chloro-2-{ [(2-hy droxy ethyl)amino]methyl}-5-({3'-[(4-{ [(2-hy droxy ethyl)amino]methyl}-3, 5- dimethoxyphenoxy)methyl]-2-methyl-[l, -biphenyl]-3- yl}methoxy)phenoxy)methyl]pyridine-3-carbonitrile; 5-[(2-{[(2- hy droxy ethyl)amino]methyl}-5-({3'-[(4-{ [(2 -hydroxy ethyl)amino]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl }methoxy)-4- methylphenoxy)methyl]pyridine-3-carbonitrile; 5-[(2-{ [(2-hy droxy ethyl)amino]methyl }-5- ({3'-[(4-{[(2-hydroxyethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-2,2'-dimethyl- [l, -biphenyl]-3-yl}methoxy)-4-methylphenoxy)methyl]pyridine-3-carbonitrile; 2-({[4-({3'- [(4-{ [(2-hy droxy ethyl)amino]methyl}-2-methyl-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]- 2,2'-dimethyl-[l , 1 '-biphenyl]-3-yl }methoxy)-2,6-dimethoxyphenyl]methyl }amino)ethan- 1 -ol; 5 - { [(3 - { [(2-hy droxy ethyl)amino]methyl } -6- [(3 '- { [(5 - { [(2-hy droxy ethyl)amino]methyl } -6- methoxypyridin-2-yl)oxy]methyl}-2,2'-dimethyl-[l, -biphenyl]-3-yl)methoxy]pyridin-2- yl)oxy]methyl}pyridine-3-carbonitrile; 2-({[4-({3'-[(2-chloro-4-{[(2- hy droxy ethyl)amino]methyl}-5-[(pyridin-3-yl)methoxy]phenoxy)methyl]-2,2'-dimethyl-[ 1,1'- biphenyl]-3-yl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 5-[(5-{[2-cyano-3'-({5- [(5-cyanopyridin-3-yl)methoxy]-4-(hydroxymethyl)-2-methylphenoxy}methyl)-2'-methyl- [l, -biphenyl]-3-yl]methoxy}-2-(hydroxymethyl)-4-methylphenoxy)methyl]pyridine-3- carbonitnle; 5-({2-[(azetidin-l-yl)methyl]-5-{[3'-({4-[(azetidin-l-yl)methyl]-5-[(5- cyanopyridin-3-yl)methoxy]-2-methylphenoxy}methyl)-2-cyano-[l, -biphenyl]-3- yl]methoxy}-4-methylphenoxy}methyl)pyridine-3-carbonitrile; 5-({2-[(azetidin-l- yl)methyl]-5-{[3'-({4-[(azetidin-l-yl)methyl]-5-[(5-cyanopyridin-3-yl)methoxy]-2- methylphenoxy}methyl)-2,2'-dimethyl-[l, -biphenyl]-3-yl]methoxy}-4- methylphenoxy}methyl)pyridine-3-carbonitrile; 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '- biphenyl]-3-yl]-[l,2,4]triazolo[l,5-a]pyridin-6-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6- { [(2-hydroxyethyl)amino]methyl }imidazo[ 1 ,2-a]pyridin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]- 3-yl]imidazo[l,2-a]pyridin-6-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-2,2'-dimethyl-[l,l'-biphenyl]-3-yl]-l,3- benzoxazol-6-yl}methyl)amino]ethan-l-ol; 2-({2-[3'-(5-{ [(2 -hydroxy ethyl)amino]methyl}- 1 ,3 -benzoxazol-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl]- 1 ,3 -benzoxazol-5-yl } amino)ethan-
1- ol; 2 ({2 3'-(5-{[(2-hydroxyethyl)amino]methyl}-l,3-benzothiazol-2-yl)-2,2'-dimethyl- [l,r-biphenyl]-3-yl]-l,3-benzothiazol-5-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl } - 1 ,3 -benzothiazol-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3-yl]-l,3- benzothiazol-6-yl}methyl)amino]ethan-l-ol; 3,3'-bis(6-{[(2-hydroxyethyl)amino]methyl}- [l,2,4]triazolo[l,5-a]pyridin-2-yl)-[l,r-biphenyl]-2,2'-dicarbonitrile; 3,3'-bis(6-{[(2- hydroxyethyl)amino]methyl}-l,3-benzoxazol-2-yl)-[l, l'-biphenyl]-2,2'-dicarbonitrile; 2-[({2- [3 H7" { [(2-hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 ,5-a]pyridin-2-yl)-2,2'-dimethyl- [l,r-biphenyl]-3-yl] 1,2,4]triazolo[l,5-a]pyridin-7-yl}methyl)amino]ethan-l-ol; 2-{[(8- chloro-2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-d
[l, -biphenyl]-3-yl}-[l,2,4]triazolo[l,5-a]pyridin-6-yl)methyl]amino}ethan-l-ol; 3-(8- chloro-6-{[(2-hydroxyethyl)amino]methyl} 1,2,4]triazolo[l,5-a]pyridin-2-yl)-3' (4-^ hydroxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-[l,l'-biphenyl]-2-carbonitrile; 3'- [(4- { [(2-hy droxy ethyl)amino]methyl } -3 , 5 -dimethoxyphenoxy)methyl] -3 -(6- { [(2- hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-[ 1 , 1 '-biphenyl]-2- carbonitrile; 3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2- hy droxy ethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-[ 1 , 1 '-biphenyl]-2- carbonitrile; 2-{[(2-{3'-[(4-{ [(2-hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'- dimethyl-[l, -biphenyl]-3-yl}-l,3-benzoxazol-6-yl)methyl]amino}ethan-l-ol; 3-(5-{[(2- hy droxy ethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4-{ [(2-hy droxy ethyl)amino]methyl}-
2- methylphenoxy)methyl]-[l,r-biphenyl]-2-carbonitrile; 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- l,3-benzoxazol-5-yl)methyl]amino}ethan-l-ol; 2-{[(2-{3'-[(4-{[(2- hy droxy ethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, -biphenyl]-3-yl}- l,3-benzothiazol-5-yl)methyl]amino}ethan-l-ol; 2-{[(2-{3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, l'-biph
l,3-benzothiazol-6-yl)methyl]amino}ethan-l-ol; 2-{[(2-{3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-2,2'-dimethyl-[l, l'-biphenyl]
[l,2,4]triazolo[l,5-a]pyridin-6-yl)methyl]amino}ethan-l-ol; 3'-[(4-{[(2- hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-3-(6-{[(2- hydroxyethyl)amino]methyl } -[ 1 ,2,4]triazolo[ 1 , 5-a]pyridin-2-yl)-2'-methyl-[ 1 , 1 '-biphenyl]-2- carbonitrile; 2-{[(4-chloro-2-{3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2- methylphenoxy)methyl]-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 -yl } - 1 ,3 -benzoxazol-6- yl)methyl] amino } ethan- 1 -ol ; 3 -(4-chloro-6- { [(2-hy droxy ethyl)amino]methyl } - 1 , 3 - benzoxazol-2-yl)-3'-[(4-{[(2-hydroxyethyl)amino]methyl}-2-methylphenoxy)methyl]-[l, - biphenyl]-2-carbonitrile; 3-(5-{ [(2-hy droxy ethyl)amino]methyl }-l, 3-benzoxazol-2-yl)-3'-[(4- { [(2-hy droxy ethyl)amino]methyl}-3,5-dimethoxyphenoxy)methyl]-[l, -biphenyl]-2- carbonitrile; 3-(4-chl oro-6-{ [(2-hy droxy ethyl)amino]methyl}-l,3-benzoxazol-2-yl)-3'-[(4- { [(2-hy droxy ethyl)amino]methyl }-2-methylphenoxy)methyl]-2'-methyl-[ 1 , 1 '-biphenyl]-2- carbonitrile; 2-[({2-[3'-(5-{[(2-hydroxyethyl)amino]methyl}-2H-indazol-2-yl)-2,2'-dimethyl- [l,r-biphenyl]-3-yl]-2H-indazol-5-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6-{[(2- hydroxyethyl)amino]methyl}-2H-indazol-2-yl)-2,2'-dimethyl-[l,r-biphenyl]-3-yl]-2H- indazol-6-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6-{[(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-b]pyridazin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl]imidazo[l,2-b]pyridazin-6-yl}methyl)amino]ethan-l-ol; 2-[({6-[3'-(2-{[(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-b] [ 1 ,2,4]triazin-6-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-
3-yl]imidazo[l,2-b][l,2,4]triazin-2-yl}methyl)amino]ethan-l-ol; 2-[({2-[3'-(6-{[(2- hy droxy ethyl)amino]methyl }imidazo[ 1 ,2-a]pyrazin-2-yl)-2,2'-dimethyl-[ 1 , 1 '-biphenyl]-3 - yl]imidazo[l,2-a]pyrazin-6-yl}methyl)amino]ethan-l-ol; 2-({[4-({3-[2-(4-{[(2- hy droxy ethyl)amino]methyl }phenyl)-7-methyl-l, 3-benzoxazol-6-yl]-2- methylphenyl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 2-({[4-({3-[2-(3-{[(2- hy droxy ethyl)amino]methyl }phenyl)-7-methyl-l, 3-benzoxazol-6-yl]-2- methylphenyl}methoxy)-3-methylphenyl]methyl}amino)ethan-l-ol; 2-{[(4-{6-[2-(4-{[(2- hy droxy ethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-yl]-7-methyl- 1,3- benzoxazol-2-yl } phenyl)methyl] amino } ethan- 1 -ol ; or 2- { [(3 - { 6-[2-(3 - { [(2- hy droxy ethyl)amino]methyl}phenyl)-7-methyl-l,3-benzoxazol-6-yl]-7-methyl- 1,3- benzoxazol-2-yl}phenyl)methyl]amino}ethan-l-ol, 2-[({2-[3'-(5-{[(2- hydroxyethyl)amino]methyl}-2,3-dihydro-lH-isoindol-2-yl)-2,2'-dimethyl-[l, l'-biphenyl]-3- yl]-2,3-dihydro-lH-isoindol-5-yl}methyl)amino]ethan-l-ol, or 2-[({6-[3'-(3-{[(2- hydroxyethyl)amino]methyl}-2-methoxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl)-2,2'- dimethyl-[l, -biphenyl]-3-yl]-2-methoxy-5H,6H,7H-pyrrolo[3,4-b]pyridin-3- yl }methyl)amino]ethan- 1 -ol
12. A pharmaceutical composition comprising the compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
13. A method of treating a disease associated with the modulation of PD-1/PD-L1 or CD80/PD-L1 interaction comprising administering to a patient the compound of claim 1, 2, or 3 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein the disease is an infection, inflammation, cancer, or neurodegenerative disorder.
15. The method of claim 14, wherein the disease is Alzheimer's disease.
PCT/US2017/045185 2016-08-03 2017-08-02 Symmetric or semi-symmetric compounds useful as immunomodulators WO2018026971A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU2017305399A AU2017305399A1 (en) 2016-08-03 2017-08-02 Symmetric or semi-symmetric compounds useful as immunomodulators
CA3030773A CA3030773A1 (en) 2016-08-03 2017-08-02 Symmetric or semi-symmetric compounds useful as immunomodulators
JP2019527771A JP2019530732A (en) 2016-08-03 2017-08-02 Symmetric or semi-symmetrical compounds useful as immune modulators
EP17837640.6A EP3493804A1 (en) 2016-08-03 2017-08-02 Symmetric or semi-symmetric compounds useful as immunomodulators
CN201780024052.4A CN109195602B (en) 2016-08-03 2017-08-02 Symmetrical or semi-symmetrical compounds useful as immunomodulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662370679P 2016-08-03 2016-08-03
US62/370,679 2016-08-03

Publications (1)

Publication Number Publication Date
WO2018026971A1 true WO2018026971A1 (en) 2018-02-08

Family

ID=61073835

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/045185 WO2018026971A1 (en) 2016-08-03 2017-08-02 Symmetric or semi-symmetric compounds useful as immunomodulators

Country Status (6)

Country Link
EP (1) EP3493804A1 (en)
JP (1) JP2019530732A (en)
CN (1) CN109195602B (en)
AU (1) AU2017305399A1 (en)
CA (1) CA3030773A1 (en)
WO (1) WO2018026971A1 (en)

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018119236A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Triazolo[1,5-a]pyridine derivatives as immunomodulators
WO2018119266A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Benzooxazole derivatives as immunomodulators
WO2018195321A1 (en) 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019034172A1 (en) * 2017-08-18 2019-02-21 上海轶诺药业有限公司 Compound having pd-l1 inhibitory activity, preparation method therefor and use thereof
WO2019160882A1 (en) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019165374A1 (en) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
WO2019175897A1 (en) * 2018-03-13 2019-09-19 Jubilant Biosys Limited Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation
WO2019191707A1 (en) * 2018-03-30 2019-10-03 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
WO2019195181A1 (en) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
WO2019200247A1 (en) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
WO2019204609A1 (en) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
JP2019531274A (en) * 2016-09-01 2019-10-31 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Biaryl compounds useful as immunomodulators
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
WO2019217821A1 (en) * 2018-05-11 2019-11-14 Incyte Corporation Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators
WO2019232319A1 (en) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions and methods for inhibiting cd73
WO2020014643A1 (en) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020011246A1 (en) * 2018-07-13 2020-01-16 广州丹康医药生物有限公司 Benzene ring-containing compound, preparation method therefor and application thereof
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
WO2020024997A1 (en) * 2018-08-01 2020-02-06 上海轶诺药业有限公司 Preparation and application of class of n-containing heterocyclic compounds having immunoregulatory function
WO2020052650A1 (en) * 2018-09-13 2020-03-19 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods there of
WO2020086556A1 (en) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
US10662416B2 (en) 2016-10-14 2020-05-26 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
WO2020123674A1 (en) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Substituted arylmethylureas and heteroarylmethylureas, analogues thereof, and methods using same
WO2020156323A1 (en) * 2019-01-31 2020-08-06 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods thereof
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020192570A1 (en) 2019-03-22 2020-10-01 上海再极医药科技有限公司 Small-molecule inhibitor of pd-1/pd-l1, pharmaceutical composition thereof with pd-l1 antibody, and application of same
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
CN112028870A (en) * 2019-06-04 2020-12-04 中国科学院上海药物研究所 Compound with benzyloxy aromatic ring structure, preparation method and application thereof
WO2020255021A1 (en) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and small molecule pdl1 or pd1 inhibitor
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2021067181A1 (en) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
CN112638899A (en) * 2018-08-01 2021-04-09 上海轶诺药业有限公司 Preparation and application of aromatic compound with immunoregulation function
WO2021113765A1 (en) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
JP2021520342A (en) * 2018-04-03 2021-08-19 ベータ ファーマシューティカルズ カンパニー リミテッド Immunomodulators, compositions and methods thereof
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2021226206A2 (en) 2020-05-05 2021-11-11 Teon Therapeutics, Inc. Cannabinoid receptor type 2 (cb2) modulators and uses thereof
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
WO2022147302A1 (en) * 2020-12-30 2022-07-07 Chulalongkorn University 4-phenyl-indole derivatives and related uses
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2022241134A1 (en) 2021-05-13 2022-11-17 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
WO2022261310A1 (en) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Combination mcl-1 inhibitors with anti-body drug conjugates
WO2022261301A1 (en) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Combination mcl-1 inhibitors with anti-cancer agents
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023034530A1 (en) 2021-09-02 2023-03-09 Teon Therapeutics, Inc. Methods of improving growth and function of immune cells
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
WO2023081730A1 (en) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer
WO2023097211A1 (en) 2021-11-24 2023-06-01 The University Of Southern California Methods for enhancing immune checkpoint inhibitor therapy
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760764B2 (en) 2020-05-22 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2024015372A1 (en) 2022-07-14 2024-01-18 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof
WO2024019957A1 (en) * 2022-07-18 2024-01-25 Celgene Corporation Compounds for the treatment of neurodegenerative diseases
EP4100381A4 (en) * 2020-02-03 2024-04-03 Arbutus Biopharma Corp Substituted 1,1'-biphenyl compounds and methods using same

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11459339B2 (en) * 2018-02-05 2022-10-04 Abbisko Therapeutics Co., Ltd. Biaryl derivative, preparation method thereof and pharmaceutical application thereof
CN109897036B (en) * 2019-03-15 2021-07-30 沈阳药科大学 Triazolopyridine compound and preparation method and application thereof
CN112979641A (en) * 2019-12-17 2021-06-18 上海轶诺药业有限公司 Preparation and application of N-containing heterocyclic compound with immunoregulation function
CN113248492B (en) * 2020-02-10 2022-11-08 上海海雁医药科技有限公司 Heterocycle substituted nitrogen-containing six-membered heterocyclic derivative, preparation method and medical application thereof
EP4313946A1 (en) * 2021-03-26 2024-02-07 Jacobio Pharmaceuticals Co., Ltd. Novel compounds useful as sting agonists and uses thereof
CN113135895A (en) * 2021-04-30 2021-07-20 中国药科大学 Novel biphenyl derivative, preparation method and medical application thereof
CN113321575B (en) * 2021-06-15 2023-05-26 南开大学 Preparation method of benzyl aryl ether and application of benzyl aryl ether in synthesis
WO2024032782A1 (en) * 2022-08-12 2024-02-15 Jacobio Pharmaceuticals Co.Ltd. Vaccine adjuvants and uses thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130022629A1 (en) * 2010-01-04 2013-01-24 Sharpe Arlene H Modulators of Immunoinhibitory Receptor PD-1, and Methods of Use Thereof
US20130217664A1 (en) * 2012-02-10 2013-08-22 Christel Jeanne Marie Menet Novel compounds useful for the treatment of degenerative and inflammatory diseases
WO2015034820A1 (en) * 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
US20150291549A1 (en) * 2014-04-14 2015-10-15 Bristol-Myers Squibb Company Compounds Useful as Immunomodulators
US20150352206A1 (en) * 2012-10-26 2015-12-10 The University Of Chicago Synergistic combination of immunologic inhibitors for the treatment of cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130022629A1 (en) * 2010-01-04 2013-01-24 Sharpe Arlene H Modulators of Immunoinhibitory Receptor PD-1, and Methods of Use Thereof
US20130217664A1 (en) * 2012-02-10 2013-08-22 Christel Jeanne Marie Menet Novel compounds useful for the treatment of degenerative and inflammatory diseases
US20150352206A1 (en) * 2012-10-26 2015-12-10 The University Of Chicago Synergistic combination of immunologic inhibitors for the treatment of cancer
WO2015034820A1 (en) * 2013-09-04 2015-03-12 Bristol-Myers Squibb Company Compounds useful as immunomodulators
US20150291549A1 (en) * 2014-04-14 2015-10-15 Bristol-Myers Squibb Company Compounds Useful as Immunomodulators

Cited By (155)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11866435B2 (en) 2015-12-22 2024-01-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
JP2019531274A (en) * 2016-09-01 2019-10-31 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Biaryl compounds useful as immunomodulators
EP3507284B1 (en) * 2016-09-01 2022-05-25 Bristol-Myers Squibb Company Biaryl compounds useful as immunomodulators
JP7155110B2 (en) 2016-09-01 2022-10-18 ブリストル－マイヤーズ スクイブ カンパニー Biaryl compounds useful as immunomodulators
US10662416B2 (en) 2016-10-14 2020-05-26 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the hepatitis B virus genome
US11274285B2 (en) 2016-10-14 2022-03-15 Precision Biosciences, Inc. Engineered meganucleases specific for recognition sequences in the Hepatitis B virus genome
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
EP4223369A1 (en) * 2016-12-22 2023-08-09 Incyte Corporation Immunomodulator compounds and methods of use
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018119266A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Benzooxazole derivatives as immunomodulators
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US11566026B2 (en) 2016-12-22 2023-01-31 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
WO2018119236A1 (en) * 2016-12-22 2018-06-28 Incyte Corporation Triazolo[1,5-a]pyridine derivatives as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018195321A1 (en) 2017-04-20 2018-10-25 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
KR102522886B1 (en) 2017-04-20 2023-04-19 길리애드 사이언시즈, 인코포레이티드 Pd-1/pd-l1 inhibitors
EP4026835A2 (en) 2017-04-20 2022-07-13 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
KR20220030318A (en) * 2017-04-20 2022-03-10 길리애드 사이언시즈, 인코포레이티드 Pd-1/pd-l1 inhibitors
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2019034172A1 (en) * 2017-08-18 2019-02-21 上海轶诺药业有限公司 Compound having pd-l1 inhibitory activity, preparation method therefor and use thereof
US11787766B2 (en) 2017-08-18 2023-10-17 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Compound having PD-L1 inhibitory activity, preparation method therefor and use thereof
US20200392083A1 (en) * 2017-08-18 2020-12-17 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Compound having pd-l1 inhibitory activity, preparation method therefor and use thereof
US11833156B2 (en) 2017-09-22 2023-12-05 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
US11426412B2 (en) 2017-10-18 2022-08-30 Jubilant Epipad LLC Imidazo-pyridine compounds as PAD inhibitors
US11629135B2 (en) 2017-11-06 2023-04-18 Jubilant Prodell Llc Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation
US11459338B2 (en) 2017-11-24 2022-10-04 Jubilant Episcribe Llc Heterocyclic compounds as PRMT5 inhibitors
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
KR20200121323A (en) * 2018-02-13 2020-10-23 길리애드 사이언시즈, 인코포레이티드 PD-1/PD-L1 inhibitor
CN111712494A (en) * 2018-02-13 2020-09-25 吉利德科学公司 PD-1/PD-L1 inhibitors
EP4227302A1 (en) 2018-02-13 2023-08-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
JP2021513561A (en) * 2018-02-13 2021-05-27 ギリアード サイエンシーズ， インコーポレイテッド PD-1 / PD-L1 inhibitor
AU2019222644B2 (en) * 2018-02-13 2021-04-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
JP7062792B2 (en) 2018-02-13 2022-05-06 ギリアード サイエンシーズ， インコーポレイテッド PD-1 / PD-L1 inhibitor
WO2019160882A1 (en) 2018-02-13 2019-08-22 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
KR102445054B1 (en) 2018-02-13 2022-09-22 길리애드 사이언시즈, 인코포레이티드 PD-1/PD-L1 inhibitors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
AU2021204222B2 (en) * 2018-02-13 2023-02-16 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2019165374A1 (en) 2018-02-26 2019-08-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds as hbv replication inhibitors
WO2019175897A1 (en) * 2018-03-13 2019-09-19 Jubilant Biosys Limited Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation
CN112105610A (en) * 2018-03-13 2020-12-18 朱比连特普罗德尔有限责任公司 Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN112105610B (en) * 2018-03-13 2024-01-26 朱比连特普罗德尔有限责任公司 Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
US11529341B2 (en) 2018-03-13 2022-12-20 Jubilant Prodel LLC Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation
CN112135824A (en) * 2018-03-30 2020-12-25 因赛特公司 Heterocyclic compounds as immunomodulators
AU2019245288B2 (en) * 2018-03-30 2023-10-19 Incyte Corporation Heterocyclic compounds as immunomodulators
US11304949B2 (en) 2018-03-30 2022-04-19 Incyte Corporation Treatment of hidradenitis suppurativa using JAK inhibitors
JP2021519779A (en) * 2018-03-30 2021-08-12 インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
EP4212529A1 (en) * 2018-03-30 2023-07-19 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2019191707A1 (en) * 2018-03-30 2019-10-03 Incyte Corporation Heterocyclic compounds as immunomodulators
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
JP7372255B2 (en) 2018-03-30 2023-10-31 インサイト・コーポレイション Heterocyclic compounds as immunomodulators
JP2021520342A (en) * 2018-04-03 2021-08-19 ベータ ファーマシューティカルズ カンパニー リミテッド Immunomodulators, compositions and methods thereof
WO2019195181A1 (en) 2018-04-05 2019-10-10 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis b virus protein x
US11149052B2 (en) 2018-04-06 2021-10-19 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′-cyclic dinucleotides
US11292812B2 (en) 2018-04-06 2022-04-05 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotides
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
US11142750B2 (en) 2018-04-12 2021-10-12 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
US11788077B2 (en) 2018-04-12 2023-10-17 Precision Biosciences, Inc. Polynucleotides encoding optimized engineered meganucleases having specificity for a recognition sequence in the Hepatitis B virus genome
WO2019200247A1 (en) 2018-04-12 2019-10-17 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
CN112041311A (en) * 2018-04-19 2020-12-04 吉利德科学公司 PD-1/PD-L1 inhibitors
TWI712412B (en) * 2018-04-19 2020-12-11 美商基利科學股份有限公司 Pd-1/pd-l1 inhibitors
KR20200145834A (en) * 2018-04-19 2020-12-30 길리애드 사이언시즈, 인코포레이티드 PD-1/PD-L1 inhibitor
CN112041311B (en) * 2018-04-19 2023-10-03 吉利德科学公司 PD-1/PD-L1 inhibitors
KR102591947B1 (en) * 2018-04-19 2023-10-25 길리애드 사이언시즈, 인코포레이티드 PD-1/PD-L1 inhibitors
JP2021522168A (en) * 2018-04-19 2021-08-30 ギリアード サイエンシーズ， インコーポレイテッド PD-1 / PD-L1 inhibitor
JP7242702B2 (en) 2018-04-19 2023-03-20 ギリアード サイエンシーズ， インコーポレイテッド PD-1/PD-L1 inhibitor
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2019204609A1 (en) 2018-04-19 2019-10-24 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
EP4219492A1 (en) * 2018-05-11 2023-08-02 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2019217821A1 (en) * 2018-05-11 2019-11-14 Incyte Corporation Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
TWI821288B (en) * 2018-05-11 2023-11-11 美商英塞特公司 Heterocyclic compounds as immunomodulators
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
JP7328995B2 (en) 2018-05-11 2023-08-17 インサイト・コーポレイション Tetrahydro-imidazo[4,5-C]pyridine derivatives as PD-L1 immunomodulators
AU2019267824B2 (en) * 2018-05-11 2023-10-05 Incyte Corporation Tetrahydro-imidazo(4,5-C)pyridine derivatives as PD-L1 immunomodulators
CN112752756A (en) * 2018-05-11 2021-05-04 因赛特公司 Tetrahydro-imidazo [4,5-c ] pyridine derivatives as PD-L1 immunomodulators
WO2019232319A1 (en) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions and methods for inhibiting cd73
WO2020011246A1 (en) * 2018-07-13 2020-01-16 广州丹康医药生物有限公司 Benzene ring-containing compound, preparation method therefor and application thereof
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112424185A (en) * 2018-07-13 2021-02-26 广州丹康医药生物有限公司 Compound containing benzene ring, preparation method and application thereof
EP4234030A2 (en) 2018-07-13 2023-08-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
WO2020014643A1 (en) 2018-07-13 2020-01-16 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
CN112638900A (en) * 2018-08-01 2021-04-09 上海轶诺药业有限公司 Preparation and application of N-containing heterocyclic compound with immunoregulation function
CN112638899A (en) * 2018-08-01 2021-04-09 上海轶诺药业有限公司 Preparation and application of aromatic compound with immunoregulation function
US20220056023A1 (en) * 2018-08-01 2022-02-24 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Preparation and application of class of n-containing heterocyclic compounds having immunoregulatory function
CN112638899B (en) * 2018-08-01 2023-09-05 上海轶诺药业有限公司 Preparation and application of aromatic compound with immunoregulation function
WO2020024997A1 (en) * 2018-08-01 2020-02-06 上海轶诺药业有限公司 Preparation and application of class of n-containing heterocyclic compounds having immunoregulatory function
EP3831823A4 (en) * 2018-08-01 2022-04-27 Shanghai Ennovabio Pharmaceuticals Co., Ltd. Preparation and application of aromatic compound having immunoregulatory function
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
WO2020052650A1 (en) * 2018-09-13 2020-03-19 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods there of
CN112654617A (en) * 2018-09-13 2021-04-13 贝达药业股份有限公司 Immunomodulator, composition and preparation method thereof
WO2020086556A1 (en) 2018-10-24 2020-04-30 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112955435A (en) * 2018-10-24 2021-06-11 吉利德科学公司 PD-1/PD-L1 inhibitors
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020123674A1 (en) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Substituted arylmethylureas and heteroarylmethylureas, analogues thereof, and methods using same
WO2020156323A1 (en) * 2019-01-31 2020-08-06 Betta Pharmaceuticals Co., Ltd Immunomodulators, compositions and methods thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020192570A1 (en) 2019-03-22 2020-10-01 上海再极医药科技有限公司 Small-molecule inhibitor of pd-1/pd-l1, pharmaceutical composition thereof with pd-l1 antibody, and application of same
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
CN112028870A (en) * 2019-06-04 2020-12-04 中国科学院上海药物研究所 Compound with benzyloxy aromatic ring structure, preparation method and application thereof
CN112028870B (en) * 2019-06-04 2021-11-05 中国科学院上海药物研究所 Compound with benzyloxy aromatic ring structure, preparation method and application thereof
WO2020255021A1 (en) * 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and small molecule pdl1 or pd1 inhibitor
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
WO2021067181A1 (en) 2019-09-30 2021-04-08 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
WO2021113765A1 (en) 2019-12-06 2021-06-10 Precision Biosciences, Inc. Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
EP4100381A4 (en) * 2020-02-03 2024-04-03 Arbutus Biopharma Corp Substituted 1,1'-biphenyl compounds and methods using same
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021226206A2 (en) 2020-05-05 2021-11-11 Teon Therapeutics, Inc. Cannabinoid receptor type 2 (cb2) modulators and uses thereof
US11760764B2 (en) 2020-05-22 2023-09-19 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
WO2022147302A1 (en) * 2020-12-30 2022-07-07 Chulalongkorn University 4-phenyl-indole derivatives and related uses
WO2022241134A1 (en) 2021-05-13 2022-11-17 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
WO2022261301A1 (en) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Combination mcl-1 inhibitors with anti-cancer agents
WO2022261310A1 (en) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Combination mcl-1 inhibitors with anti-body drug conjugates
US11931424B2 (en) 2021-06-11 2024-03-19 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-body drug conjugates
US11957693B2 (en) 2021-06-11 2024-04-16 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-cancer agents
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2023034530A1 (en) 2021-09-02 2023-03-09 Teon Therapeutics, Inc. Methods of improving growth and function of immune cells
WO2023081730A1 (en) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer
WO2023097211A1 (en) 2021-11-24 2023-06-01 The University Of Southern California Methods for enhancing immune checkpoint inhibitor therapy
WO2024015372A1 (en) 2022-07-14 2024-01-18 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof
WO2024019957A1 (en) * 2022-07-18 2024-01-25 Celgene Corporation Compounds for the treatment of neurodegenerative diseases

Also Published As

Publication number Publication date
EP3493804A1 (en) 2019-06-12
CN109195602A (en) 2019-01-11
CN109195602B (en) 2022-01-07
AU2017305399A1 (en) 2019-01-31
CA3030773A1 (en) 2018-02-08
JP2019530732A (en) 2019-10-24

Similar Documents

Publication Publication Date Title
EP3493804A1 (en) Symmetric or semi-symmetric compounds useful as immunomodulators
JP7005582B2 (en) Multifluoro-substituted compound as Bruton&#39;s tyrosine kinase (BTK) inhibitor
TWI641600B (en) Piperidinyl-indole derivatives complement factor b inhibitors and uses thereof
RU2674701C2 (en) Aminopiridazinove compounds as proteinkinase inhibitors
EP2920162B1 (en) Inhibitors of bruton&#39;s tyrosine kinase
US9586948B2 (en) Inhibitors of IRAK4 activity
KR101358532B1 (en) Novel phenylimidazopyrazines
WO2020114482A1 (en) Isoindoline compound, and preparation method, pharmaceutical composition, and application of isoindoline compound
US11066392B2 (en) Inhibitors of indoleamine 2,3-dioxygenase and methods of their use
US20180208577A1 (en) Compounds and Methods of Use
JP2018508554A (en) Tricyclic heterocyclic compounds useful as TNF inhibitors
US20190040012A1 (en) Ror gamma (rory) modulators
JP2024505732A (en) Pyridopyrimidinone derivatives and their production methods and uses
KR20170129192A (en) A heterocyclic compound useful as an inhibitor of TNF
TWI804266B (en) Tyk2 inhibitors and use thereof
JP6477484B2 (en) Sulfur-containing bicyclic compound
TW202332436A (en) Therapeutic compounds
CN107849044B (en) Triaza-spirodecanones as DDR1 inhibitors
CN117800904A (en) ROR gamma inhibitors containing sulfonyl structures
CA2893637A1 (en) Thiazole derivatives as inhibitors of bruton&#39;s tyrosine kinase
KR20230134500A (en) Imidazo[1,2-A]pyridine derivatives as IRAK4 inhibitors and their use in the treatment of diseases
JP2024516194A (en) Compounds as PD1/PD-L1 inhibitors and methods thereof
AU2022318751A1 (en) Rock2 inhibitors and uses thereof
WO2023250316A1 (en) Compounds for treating spinocerebellar ataxia type 3

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: 17837640

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3030773

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2017305399

Country of ref document: AU

Date of ref document: 20170802

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019527771

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017837640

Country of ref document: EP

Effective date: 20190304