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  • 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
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  • 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
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  • 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
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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.

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