Classifications

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  • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
  • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
  • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
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  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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  • A61K31/4245—Oxadiazoles
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  • A61K31/425—Thiazoles
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • 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
  • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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  • 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
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D215/14—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/18—Halogen atoms or nitro radicals
• • C—CHEMISTRY; METALLURGY
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  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
  • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
  • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
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  • 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
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  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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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  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
• • C—CHEMISTRY; METALLURGY
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  • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
  • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
  • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present disclosure generally relates to compounds useful as inhibitors of the PD-1/PD-L1 protein protein and CD80/PD-L1 protein protein interactions.
• compounds, compositions comprising such compounds, and methods of their use are compounds, compositions comprising such compounds, and methods of their use.
• the disclosure further pertains to pharmaceutical compositions comprising at least one compound according to the disclosure that are useful for the treatment of various diseases, including cancer and infectious diseases.
• Programmed death- 1 is a receptor on T cells that has been shown to suppress activating signals from the T cell receptor when bound by either of its ligands, Programmed death-ligand 1 (PD-L1, CD274, B7-H1) or PD-L2 (CD273, B7-DC) (Sharpe et al., Nat. Imm. 2007).
• PD-1 expressing T cells contact cells expressing its ligands, functional activities in response to antigenic stimuli, including proliferation, cytokine secretion, and cytolytic activity are reduced.
• T cells that express elevated levels of PD- 1 and are dysfunctional with respect to activity towards the chronic antigen (reviewed in Kim and Ahmed, Curr Opin Imm, 2010). This is termed "T cell exhaustion”. B cells also display PD-l/PD-ligand suppression and "exhaustion”.
• PD-L1 has also been shown to interact with CD80 (Butte MJ et al, Immunity ;27: 1 11-122 (2007)).
• the interaction of PD-L1/CD80 on expressing immune cells has been shown to be an inhibitory one. Blockade of this interaction has been shown to abrogate this inhibitory interaction (Paterson AM, et al., J Immunol., 187: 1097-1105 (2011); Yang J, et al. J Immunol. Aug 1 ; 187(3): 1113-9 (2011)).
• Blockade of the PD-1/PD-L1 interaction using antibodies to PD-L1 has been shown to restore and augment T cell activation in many systems.
• Chronic lymphocytic chorio meningitis virus infection of mice also exhibits improved virus clearance and restored immunity with blockade of PD-L1 (Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006; 439(7077):682- 687).
• Humanized mice infected with HIV-1 show enhanced protection against viremia and reduced viral depletion of CD4+ T cells (Palmer et al., J. Immunol 2013).
• Blockade of PD-1/PD-L1 through monoclonal antibodies to PD-L1 can restore in vitro antigen- specific functionality to T cells from HIV patients (Day, Nature 2006; Petrovas, J. Exp. Med. 2006; Trautman, Nature Med. 2006; D'Souza, J.Immunol. 2007; Zhang, Blood 2007; Kaufmann, Nature Imm. 2007; Kasu, J. Immunol. 2010; Porichis, Blood 2011), HCV patients [Golden-Mason, J. Virol. 2007; Jeung, J. Leuk. Biol. 2007; Urbani, J. Hepatol. 2008; Nakamoto, PLoS Path. 2009; Nakamoto, Gastroenterology 2008] or HBV patients (Boni, J. Virol. 2007; Fisicaro, Gastro. 2010; Fisicaro et al.,
• Gastroenterology 2012; Boni et al., Gastro., 2012; Penna et al., JHep, 2012;
• Blockade of the PD-L1/CD80 interaction has also been shown to stimulate immunity (Yang J., et al., J Immunol. Aug 1 ; 187(3): 1 113-9 (2011)).
• the immune stimulation resulting from blockade of the PD-L1/CD80 interaction has been shown to be enhanced through combination with blockade of further PD-1/PD-L1 or PD-1/PD-L2 interactions.
• Alterations in immune cell phenotypes are hypothesized to be an important factor in septic shock (Hotchkiss, et al., Nat Rev Immunol (2013)). These include increased levels of PD-1 and PD-L1 and T ceoll apoptosis (Guignant, et al, Crit. Care (2011)).
• Antibodies directed to PD-L1 can reduce the level of Immune cell apoptosis (Zhang et al, Crit. Care (2011)). Furthermore, mice lacking PD-1 expression are more resistant to septic shock symptoms than wildtype mice (Yang J., et al.. J Immunol. Aug
• blockade of the PD-1/PD-L1 pathway has also been shown to enhance responses to vaccination, including therapeutic vaccination in the context of chronic infection (S. J. Ha, S. N. Mueller, E. J. Wherry et al., "Enhancing therapeutic vaccination by blocking PD-1- mediated inhibitory signals during chronic infection," The Journal of Experimental Medicine, vol. 205, no. 3, pp. 543-555, 2008.; A. C. Finnefrock, A. Tang, F. Li et al., "PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination," The Journal of Immunology, vol. 182, no. 2, pp.980-987, 2009; M.
• the PD-1 pathway is a key inhibitory molecule in T cell exhaustion that arises from chronic antigen stimulation during chronic infections and tumor disease. Blockade of the PD-1/PD-L1 interaction through targeting the PD-L1 protein has been shown to restore antigen-specific T cell immune functions in vitro and in vivo, including enhanced responses to vaccination in the setting of tumor or chronic infection.
• agents that block the interaction of PD-L1 with either PD-1 or CD80 are desired.
• potent compounds that have activity as inhibitors of the interaction of PD-L1 with PD-1 and CD80, and thus may be useful for therapeutic administration to enhance immunity in cancer or infections, including therapeutic vaccine. These compounds are provided to be useful as pharmaceuticals with desirable stability, bioavailability, therapeutic index, and toxicity values that are important to their drugability.
• compositions comprising a compound of formula (I) and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
• the present disclosure also provides a method of treating a disease or disorder associated with the activity of PD-Ll including its interaction with other proteins such as PD-1 and B7-1(CD80), the method comprising administering to a patient in need thereof a compound of formula (I) and/or a pharmaceutically acceptable salt thereof.
• the present disclosure also provides processes and intermediates for making the compounds of formula (I) and/or salts thereof.
• the present disclosure also provides a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, for use in therapy.
• the present disclosure also provides the use of the compounds of formula (I) and/or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment or prophylaxis of PD-Ll related conditions, such as cancer and infectious diseases.
• compositions comprising the compounds of formula (I) may be used in treating, preventing, or curing various infectious diseases and cancer.
• Pharmaceutical compositions comprising these compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as cancer and infectious diseases.
• harmaceutically acceptable salt thereof wherein: m is 0, 1, or 2;
• R 1 is selected from hydrogen, -(CH 2 ) n X and -(CH 2 ) n Ar; wherein
• n 1, 2, 3, or 4;
• X is selected from -CH 3 , -CF 3 , CN, -C0 2 R 4 , -C(0)NH 2 , OR 4 , and pyrrolidonyl;
• R 4 is H or Ci-C 3 alkyl
• Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, and quinolinyl; wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci- C 4 alkoxy, Ci-C 4 alkoxycarbonyl, Ci-C 4 alkoxycarbonylamino, Ci-C 4 alkyl, (Ci-
• R 2 is selecte from
• Y is selected from cyano, chloro, and methyl
• R q is selected from hydrogen, Ci-C 3 alkyl, and benzyl
• R 3 is selected from
• R z is selected from Ci-C 3 alkyl, Ci-C 3 alkylsulfonylCi-C 3 alkyl, C ⁇ - C 3 alkylsulfoxylCi-C 3 alkyl, amidoCi-C 3 alkyl, aminoCi-C 4 alkyl, carboxyCi-C 3 alkyl, cyanoCi-C 3 alkyl, dimethylamidoCi-C 3 alkyl, dimethylaminoCi-C 4 alkyl, haloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-C 3 alkylsulfanylCi-C 3 alkyl, pyridinylCi-C 3 alkyl, tetrazolylCi- C 3 alkyl, imidazolylCi-C 3 alkyl wherein the imidazole is optionally substituted with methyl or a benzyl group, phenylCi-C 3 al
• R 6 is selected from hydrogen, benzyl, and methyl
• each R 6 is independently selected from hydrogen and methyl
• R 7 is selected from hydrogen, Ci-C 3 alkyl, and benzyl
• o 1 or 2;
• X is CH or ;
• p is 0 or 1 ;
• R a is hydroxy
• R b is selected from hydrogen, benzyl, and methyl
• R 3 and R q together with the nitrogen atom to which they are attached, form a ring selected from
• s is 0 or 1 ;
• z is 1, 2, or 3;
• R 8 is selected from hydroxy and -NHS0 2 R n ;
• R 9 is selected from hydrogen and -C0 2 H
• R 10 is selected from halo and hydroxy
• R 11 is selected from trifluoromethyl, cyclopropyl, Ci-C 3 alkyl, dimethylamino, and imidazolyl substituted with a methyl group;
• Q is selected from CH 2 , S, O, and NCH 3 ;
• R 5 is selected from C 2 -C 4 alkenyl, Ci-C 4 alkyl, cyano, methoxy, halo, and trifluoromethyl.
• R 2 is
• n 0, 1, or 2;
• R 1 is selected from hydrogen, -(CH 2 ) n X and -(CH 2 ) n Ar; wherein
• n 1, 2, 3, or 4;
• X is selected from -CH 3 , -CF 3 , CN, -C0 2 R 4 , -C(0)NH 2 , OR 4 , and pyrrolidonyl;
• R 4 is H or Ci-C 3 alkyl
• Ar is selected from benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, pyridinyl, pyrimidinyl, and quinolinyl; wherein each ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Ci- C 4 alkoxy, Ci-C 4 alkoxycarbonylamino, Ci-C 4 alkyl, (Ci-C 4 alkyl)carbonyl, (Ci- C 4 alkyl)sulfonyl, amido, aminocarbonyl, aminocarbonyl(Ci-C 3 alkyl), -(CH 2 ) q C0 2 Ci- C 4 alkyl, -(CH 2 ) q OH, carboxy, cyano, formyl, halo, haloCi-C 4 alkyl, haloCi-C 4 alkoxy, nitro, phen
• R is selecte from
• Y is selected from cyano, chloro, and methyl
• R q is selected from hydrogen, Ci-C 3 alkyl, and benzyl
• R 3 is selected from
• R z is selected from Ci-C 3 alkyl, Ci-C 3 alkylsulfonylCi-C 3 alkyl, C ⁇ - C 3 alkylsulfoxylCi-C 3 alkyl, amidoCi-C 3 alkyl, aminoCi-C 3 alkyl, carboxyCi-C 3 alkyl, cyanoCi-C 3 alkyl, dimethylamidoCi-C 3 alkyl, dimethylaminoCi-C 3 alkyl, haloCi-C 3 alkyl, hydroxyCi-C 3 alkyl, Ci-C 3 alkylsulfanylCi-C 3 alkyl, pyridinylCi-C 3 alkyl tetrazolylCi- C 3 alkyl, imidazolylCi-C 3 alkyl wherein the imidazole is optionally substituted with methyl or a benzyl group, phenylCi-C 3 alky
• R 6 is selected from hydrogen, benzyl, and methyl
• each R 6 is independently selected from hydrogen and methyl
• R 7 is selected from hydrogen, Ci-C 3 alkyl, and benzyl
• o 1 or 2;
• X is CH or ;
• p is 0 or 1 ;
• R a is hydroxy
• R b is selected from hydrogen , benzyl, and methyl
• R 3 and R q together with the nitrogen atom to which they are attached, form a ring selected from
• s is 0 or 1 ;
• z is 1 or 2;
• R 8 is selected from hydroxy and -NHS0 2 R n ;
• R 9 is selected from hydrogen and -C0 2 H
• R 10 is selected from halo and hydroxy
• R 11 is selected from trifluoromethyl, cyclopropyl, Ci-C 3 alkyl, dimethylamino, and imidazolyl substituted with a methyl group;
• Q is selected from CH 2 , S, O, and NCH 3 ;
• R 5 is selected from C 2 -C 4 alkenyl, Ci-C 4 alkyl, cyano, methoxy, halo, and
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present disclosure provides a method of enhancing, stimulating, modulating and/or increasing the immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
• the method further comprises administering an additional agent prior to, after, or simultaneously with the compound of formula (I), or the pharmaceutically acceptable salt thereof.
• the additional agent is an antimicrobial agent, an antiviral agent, an agent that modifies gene expression, a cytotoxic agent, and/or an immune response modifier.
• the present disclosure provides a method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt.
• the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and a hematological malignancy.
• NSCLC non-small cell lung cancer
• colorectal cancer castration-resistant prostate cancer
• ovarian cancer gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and a hematological malignancy.
• the present disclosure provides a method of treating an infectious disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
• the infectious disease is caused by a virus.
• the virus is selected from HIV, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, herpes viruses, papillomaviruses and influenza.
• the present disclosure provides a method of treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a method blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
• references made in the singular may also include the plural.
• references made in the singular may also include the plural.
• “a” and “an” may refer to either one, or one or more.
• the phase "compound(s) or pharmaceutically acceptable salts thereof refers to at least one compound, at least one salt of the compounds, or a combination thereof.
• compounds of formula (I) or pharmaceutically acceptable salts thereof includes a compound of formula (I); two compounds of formula (I); a salt of a compound of formula (I); a compound of formula (I) and one or more salts of the compound of formula (I); and two or more salts of a compound of formula (I).
• any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.
• Ci-C 4 alkoxy refers to a Ci-C 4 alkyl group attached to the parent molecular moiety through an oxygen atom.
• Ci-C 4 alkoxycarbonyl refers to a Ci-C 4 alkoxy group attached to the parent molecular moiety through a carbonyl group.
• Ci-C 4 alkoxycarbonylamino refers to a Ci- C 4 alkoxycarbonyl group attached to the parent molecular moiety through an -NH group.
• Ci-C 3 alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to three carbon atoms.
• Ci-C 4 alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to four carbon atoms.
• Ci-C 4 alkylcarbonyl refers to a Ci-C 4 alkyl group attached to the parent molecular moiety through a carbonyl group.
• Ci-C 3 alkylsulfanyl refers to a Ci-C 3 alkyl group attached to the parent molecular moiety through a sulfur atom.
• Ci-C 3 alkylsulfanylCi-C 3 alkyl refers to a Ci- C 3 alkylsulfanyl attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• Ci-C 3 alkylsulfonyl refers to a Ci-C 4 alkyl group attached to the parent molecular moiety through a sulfonyl group.
• Ci-C 4 alkylsulfonyl refers to a Ci-C 4 alkyl group attached to the parent molecular moiety through a sulfonyl group.
• Ci-C 3 alkylsulfonylCi-C 3 alkyl refers to a Ci-
• Ci-C 3 alkyl group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• Ci-C3alkylsulfoxyl refers to a Ci-C3alkyl group attached to the parent molecular moiety through a sulfoxyl group.
• Ci-C 3 alkylsulfoxylCi-C 3 alkyl refers to a Ci-
• amidoCi-C3alkyl refers to an amido group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• aminoCi-C3alkyl refers to an amino group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• aminocarbonyl refers to an amino group attached to the parent molecular moiety through a carbonyl group.
• aminocarbonyl(Ci-C 3 alkyl) refers to an aminocarbonyl(Ci-C 3 alkyl)
• carbonyl refers to -C(O)-.
• carboxyCi-C3alkyl refers to a carboxy group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• cyano refers to -CN.
• cyanoCi-C3alkyl refers to a cyano group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• dimethylamido refers to -C(0)N(CH 3 ) 2 .
• dimethylamidoCi-C 3 alkyl refers to a dimethylamido group attached to the parent molecular moiey through a Ci-C 3 alkyl group.
• dimethylamino refers to -N(CH 3 ) 2 .
• dimethylaminoCi-C 3 alkyl refers to a dimethylamino group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• halo and halogen, as used herein, refer to F, CI, Br, or I.
• haloCi-C 3 alkyl refers to a Ci-C 3 alkyl group substituted with one, two, or three halogen atoms.
• haloCi-C 4 alkyl refers to a Ci-C 4 alkyl group substituted with one, two, or three halogen atoms.
• haloCi-C 4 alkoxy refers to a haloCi-C 4 alkyl group attached to the parent molecular moiety through an oxygen atom.
• hydroxy refers to -OH.
• hydroxyCi-C 3 alkyl refers to a hydroxy group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• imidazolylCi-C 3 alkyl refers to an imidazolyl group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• nitro refers to -N0 2 .
• phenylCi-C 3 alkyl refers to a phenyl group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• phenylcarbonyl refers to a phenyl group attached to the parent molecular moiety through a carbonyl group.
• phenyloxy refers to a phenyl group attached to the parent molecular moiety through an oxygen atom.
• pyridinylCi-C 3 alkyl refers to a pyridinyl ring attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• sulfonyl refers to -S0 2 -.
• sulfoxyl refers to -SO-.
• tetrazolylCi-C 3 alkyl refers to a tetrazolyl ring attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• thiazolylCi-Csalkyl refers to a thiazolyl group attached to the parent molecular moiety through a Ci-C 3 alkyl group.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
• the compounds of formula (I) can form salts which are also within the scope of this disclosure. Unless otherwise indicated, reference to an inventive compound is understood to include reference to one or more salts thereof.
• the term “salt(s)” denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases.
• the term “salt(s) may include zwitterions (inner salts), e.g., when a compound of formula (I) contains both a basic moiety, such as an amine or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid.
• Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of the formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
• Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, maleates (formed with maleic acid), 2-hydroxyethanesulfonates, lactates, methanesulfonates (formed with methanesulf
• Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc, and aluminum salts; salts with organic bases (for example, organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, ⁇ , ⁇ '-dibenzylethylene-diamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceutically acceptable amines and salts with amino acids such as arginine, lysine and the like.
• organic bases for example, organic amines
• trialkylamines such as triethylamine, procaine, dibenzylamine, N-benzyl- ⁇ -phenethylamine, 1-ephenamine, ⁇
• Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
• Preferred salts include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate salts.
• compounds of formula (I), subsequent to their preparation, can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of formula (I) ("substantially pure"), which is then used or formulated as described herein.
• substantially pure compounds of formula (I) are also contemplated herein as part of the present disclosure.
• “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present disclosure is intended to embody stable compounds.
• “Therapeutically effective amount” is intended to include an amount of a compound of the present disclosure alone or an amount of the combination of compounds claimed or an amount of a compound of the present disclosure in combination with other active ingredients effective to inhibit PD-1/PD-L1 protein/protein and/or CD80/PD-L1 protein/protein interactions, or effective to treat or prevent cancer or infectious disease, such as HIV or hepatitis B, hepatitis C, and hepatitis D.
• treating cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease- state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting its development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
• the compounds of the present disclosure are intended to include all isotopes of atoms occurring in the present compounds.
• Isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium (D) and tritium (T).
• Isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
• methyl (-CH 3 ) also includes deuterated methyl groups such as -CD 3 .
• compositions comprising a compound of formula (I) and/or
• the compounds of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
• the compounds and compositions of the present disclosure may, for example, be administered orally, mucosally, rectally, or parentally including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally in dosage unit formulations containing conventional pharmaceutically acceptable carriers, adjuvants, and vehicles.
• the pharmaceutical carrier may contain a mixture of mannitol or lactose and microcrystalline cellulose.
• the mixture may contain additional components such as a lubricating agent, e.g. magnesium stearate and a disintegrating agent such as crospovidone.
• the carrier mixture may be filled into a gelatin capsule or compressed as a tablet.
• the pharmaceutical composition may be administered as an oral dosage form or an infusion, for example.
• the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid.
• the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
• the pharmaceutical composition may be provided as a tablet or capsule comprising an amount of active ingredient in the range of from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, and more preferably from about 0.5 to 100 mg.
• a suitable daily dose for a human or other mammal may vary widely depending on the condition of the patient and other factors, but, can be determined using routine methods.
• any pharmaceutical composition contemplated herein can, for example, be delivered orally via any acceptable and suitable oral preparations.
• Exemplary oral preparations include, but are not limited to, for example, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs.
• Pharmaceutical compositions intended for oral administration can be prepared according to any methods known in the art for manufacturing pharmaceutical compositions intended for oral administration.
• a pharmaceutical composition in accordance with the disclosure can contain at least one agent selected from sweetening agents, flavoring agents, coloring agents, demulcents, antioxidants, and preserving agents.
• a tablet can, for example, be prepared by admixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets.
• excipients include, but are not limited to, for example, inert diluents, such as, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate; granulating and disintegrating agents, such as, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, and alginic acid; binding agents, such as, for example, starch, gelatin, polyvinyl-pyrrolidone, and acacia; and lubricating agents, such as, for example, magnesium stearate, stearic acid, and talc.
• a tablet can either be uncoated, or coated by known techniques to either mask the bad taste of an unpleasant tasting drug, or delay disintegration and absorption of the active ingredient in the gastrointestinal tract thereby sustaining the effects of the active ingredient for a longer period.
• exemplary water soluble taste masking materials include, but are not limited to, hydroxypropyl-methylcellulose and hydroxypropyl- cellulose.
• Exemplary time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.
• Hard gelatin capsules can, for example, be prepared by mixing at least one compound of formula (I) and/or at least one salt thereof with at least one inert solid diluent, such as, for example, calcium carbonate; calcium phosphate; and kaolin.
• at least one inert solid diluent such as, for example, calcium carbonate; calcium phosphate; and kaolin.
• Soft gelatin capsules can, for example, be prepared by mixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one water soluble carrier, such as, for example, polyethylene glycol; and at least one oil medium, such as, for example, peanut oil, liquid paraffin, and olive oil.
• at least one water soluble carrier such as, for example, polyethylene glycol
• at least one oil medium such as, for example, peanut oil, liquid paraffin, and olive oil.
• An aqueous suspension can be prepared, for example, by admixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one excipient suitable for the manufacture of an aqueous suspension.
• excipients suitable for the manufacture of an aqueous suspension include, but are not limited to, for example, suspending agents, such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, alginic acid, polyvinyl-pyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents, such as, for example, a naturally-occurring phosphatide, e.g., lecithin; condensation products of alkylene oxide with fatty acids, such as, for example, polyoxy ethylene stearate; condensation products of ethylene oxide with long chain aliphatic alcohols, such as, for example heptadecaethylene-oxycetanol; condensation products of ethylene oxide
• An aqueous suspension can also contain at least one preservative, such as, for example, ethyl and n-propyl p- hydroxybenzoate; at least one coloring agent; at least one flavoring agent; and/or at least one sweetening agent, including but not limited to, for example, sucrose, saccharin, and aspartame.
• Oily suspensions can, for example, be prepared by suspending at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof in either a vegetable oil, such as, for example, arachis oil; olive oil; sesame oil; and coconut oil; or in mineral oil, such as, for example, liquid paraffin.
• An oily suspension can also contain at least one thickening agent, such as, for example, beeswax; hard paraffin; and cetyl alcohol.
• at least one of the sweetening agents already described hereinabove, and/or at least one flavoring agent can be added to the oily suspension.
• An oily suspension can further contain at least one preservative, including, but not limited to, for example, an anti-oxidant, such as, for example, butylated hydroxyanisol, and alpha-tocopherol.
• Dispersible powders and granules can, for example, be prepared by admixing at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof with at least one dispersing and/or wetting agent; at least one suspending agent; and/or at least one preservative.
• Suitable dispersing agents, wetting agents, and suspending agents are as already described above.
• Exemplary preservatives include, but are not limited to, for example, anti-oxidants, e.g., ascorbic acid.
• dispersible powders and granules can also contain at least one excipient, including, but not limited to, for example, sweetening agents; flavoring agents; and coloring agents.
• An emulsion of at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof can, for example, be prepared as an oil-in-water emulsion.
• the oily phase of the emulsions comprising compounds of formula (I) may be constituted from known ingredients in a known manner.
• the oil phase can be provided by, but is not limited to, for example, a vegetable oil, such as, for example, olive oil and arachis oil; a mineral oil, such as, for example, liquid paraffin; and mixtures thereof. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
• Suitable emulsifying agents include, but are not limited to, for example, naturally-occurring phosphatides, e.g., soy bean lecithin; esters or partial esters derived from fatty acids and hexitol anhydrides, such as, for example, sorbitan monooleate; and condensation products of partial esters with ethylene oxide, such as, for example, polyoxy ethylene sorbitan monooleate.
• naturally-occurring phosphatides e.g., soy bean lecithin
• esters or partial esters derived from fatty acids and hexitol anhydrides such as, for example, sorbitan monooleate
• condensation products of partial esters with ethylene oxide such as, for example, polyoxy ethylene sorbitan monooleate.
• a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
• An emulsion can also contain a sweetening agent, a flavoring agent, a preservative, and/or an antioxidant.
• Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present disclosure include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate alone or with a wax, or other materials well known in the art.
• the compounds of formula (I) and/or at least one pharmaceutically acceptable salt thereof can, for example, also be delivered intravenously, subcutaneously, and/or intramuscularly via any pharmaceutically acceptable and suitable injectable form.
• Exemplary injectable forms include, but are not limited to, for example, sterile aqueous solutions comprising acceptable vehicles and solvents, such as, for example, water, Ringer's solution, and isotonic sodium chloride solution; sterile oil-in-water
• Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents.
• the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and/or various buffers.
• the active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).
• suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol) or micellar solubilization (i.e. Tween 80).
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
• a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed, including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• a sterile injectable oil-in-water microemulsion can, for example, be prepared by 1) dissolving at least one compound of formula (I) in an oily phase, such as, for example, a mixture of soybean oil and lecithin; 2) combining the formula (I) containing oil phase with a water and glycerol mixture; and 3) processing the combination to form a microemulsion.
• an oily phase such as, for example, a mixture of soybean oil and lecithin
• combining the formula (I) containing oil phase with a water and glycerol mixture and 3) processing the combination to form a microemulsion.
• a sterile aqueous or oleaginous suspension can be prepared in accordance with methods already known in the art.
• a sterile aqueous solution or suspension can be prepared with a non-toxic parenterally-acceptable diluent or solvent, such as, for example, 1,3-butane diol; and a sterile oleaginous suspension can be prepared with a sterile non-toxic acceptable solvent or suspending medium, such as, for example, sterile fixed oils, e.g., synthetic mono- or diglycerides; and fatty acids, such as, for example, oleic acid.
• Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethyleneglycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, polyethoxylated castor oil such as CREMOPHOR surfactant (BASF), or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose
• Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3 -hydroxypropyl- cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.
• the pharmaceutically active compounds of this disclosure can be processed in accordance with conventional methods of pharmacy to produce medicinal agents for administration to patients, including humans and other mammals.
• the pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and/or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Tablets and pills can additionally be prepared with enteric coatings.
• Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.
• the amounts of compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this disclosure depends on a variety of factors, including the age, weight, sex, the medical condition of the subject, the type of disease, the severity of the disease, the route and frequency of administration, and the particular compound employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods.
• the daily dose can be administered in one to four doses per day. Other dosing schedules include one dose per week and one dose per two day cycle.
• the active compounds of this disclosure are ordinarily combined with one or more adjuvants appropriate to the indicated route of
• the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,
• Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in
• compositions of this disclosure comprise at least one compound of formula (I) and/or at least one pharmaceutically acceptable salt thereof, and optionally an additional agent selected from any pharmaceutically acceptable carrier, adjuvant, and vehicle.
• Alternate compositions of this disclosure comprise a compound of the formula (I) described herein, or a prodrug thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
• the compounds of the disclosure inhibit the PD-1/PD-L1 protein/protein resulting in a PD-L1 blockade.
• the blockade of PD-L1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans.
• the present disclosure relates to treatment of a subject in vivo using a compound of formula (I) or a salt thereof such that growth of cancerous tumors is inhibited.
• a compound of formula (I) or a salt thereof may be used alone to inhibit the growth of cancerous tumors.
• a compound of formula (I) or a salt thereof may be used in conjunction with other immunogenic agents or standard cancer treatments, as described below.
• the disclosure provides a method of inhibiting growth of tumor cells in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a salt thereof.
• a method for treating cancer comprising administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I) or a salt thereof.
• cancers include those whose growth may be inhibited using compounds of the disclosure include cancers typically responsive to immunotherapy.
• Non-limiting examples of preferred cancers for treatment include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer).
• the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
• cancers examples include bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid
• the compounds of formula (I) or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines (He et al (2004) J. Immunol.
• tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gplOO, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
• some tumors have been shown to be immunogenic such as melanomas. It is anticipated that by raising the threshold of T cell activation by PD-L1 blockade, tumor responses are expected to be activated in the host.
• the PD-L1 blockade can be combined with a vaccination protocol.
• Many experimental strategies for vaccination against tumors have been devised (see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCO Educational Book Spring: 60-62; Logothetis, C, 2000, ASCO Educational Book Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring: 414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see also Restifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp.
• a vaccine is prepared using autologous or allogenenic tumor cells. These cellular vaccines have been shown to be most effective when the tumor cells are transduced to express GM-CSF. GM-CSF has been shown to be a potent activator of antigen presentation for tumor vaccination (Dranoff et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).
• tumor specific antigens are differentiation antigens expressed in the tumors and in the cell from which the tumor arose, for example melanocyte antigens gplOO, MAGE antigens, and Trp-2. More importantly, many of these antigens can be shown to be the targets of tumor specific T cells found in the host.
• PD-L1 blockade may be used in conjunction with a collection of recombinant proteins and/or peptides expressed in a tumor in order to generate an immune response to these proteins.
• the tumor antigen may also include the protein telomerase, which is required for the synthesis of telomeres of chromosomes and which is expressed in more than 85% of human cancers and in only a limited number of somatic tissues (Kim, N et al. (1994) Science 266: 201 1-2013).
• Tumor antigen may also be "neo-antigens" expressed in cancer cells because of somatic mutations that alter protein sequence or create fusion proteins between two unrelated sequences (ie. bcr-abl in the Philadelphia chromosome), or idiotype from B cell tumors.
• tumor vaccines may include the proteins from viruses implicated in human cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV, HDV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
• HPV Human Papilloma Viruses
• HBV Hepatitis Viruses
• HDV High Papilloma Viruses
• KHSV Kaposi's Herpes Sarcoma Virus
• Another form of tumor specific antigen which may be used in conjunction with PD-L1 blockade is purified heat shock proteins (HSP) isolated from the tumor tissue itself. These heat shock proteins contain fragments of proteins from the tumor cells and these HSPs are highly efficient at delivery to antigen presenting cells for eliciting tumor immunity (Suot, R & Srivastava, P (1995) Science 269: 1585-1588; Tamura, Y. et al. (1997) Science 278: 1 17-120).
• DC Dendritic cells
• DCs are potent antigen presenting cells that can be used to prime antigen-specific responses.
• DCs can be produced ex vivo and loaded with various protein and peptide antigens as well as tumor cell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332).
• DCs may also be transduced by genetic means to express these tumor antigens as well.
• DCs have also been fused directly to tumor cells for the purposes of immunization (Kugler, A. et al. (2000) Nature Medicine 6:332-336).
• DC immunization may be effectively combined with PD-L1 blockade to activate more potent anti-tumor responses.
• PD-L1 blockade may also be combined with standard cancer treatments. PD-L1 blockade may be effectively combined with chemotherapeutic regimes. In these instances, it may be possible to reduce the dose of chemotherapeutic reagent administered (Mokyr, M. et al. (1998) Cancer Research 58: 5301-5304).
• An example of such a combination is a compound of this disclosure in combination with dacarbazine for the treatment of melanoma.
• Another example of such a combination is a compound of this disclosure in combination with interleukin-2 (IL-2) for the treatment of melanoma.
• IL-2 interleukin-2
• PD-Ll blockade The scientific rationale behind the combined use of PD-Ll blockade and chemotherapy is that cell death, that is a consequence of the cytotoxic action of most chemotherapeutic compounds, should result in increased levels of tumor antigen in the antigen presentation pathway.
• Other combination therapies that may result in synergy with PD-Ll blockade through cell death are radiation, surgery, and hormone deprivation. Each of these protocols creates a source of tumor antigen in the host.
• Angiogenesis inhibitors may also be combined with PD-Ll blockade. Inhibition of angiogenesis leads to tumor cell death which may feed tumor antigen into host antigen presentation pathways.
• the compounds of this disclosure can also be used in combination with bispecific compounds that target Fc alpha or Fc gamma receptor-expressing effectors cells to tumor cells (see, e.g., U.S. Pat. Nos. 5,922,845 and 5,837,243).
• Bispecific compounds can be used to target two separate antigens.
• anti-Fc receptor/anti tumor antigen e.g., Her-2/neu
• bispecific compounds have been used to target macrophages to sites of tumor. This targeting may more effectively activate tumor specific responses.
• the T cell arm of these responses would be augmented by the use of PD-Ll blockade.
• antigen may be delivered directly to DCs by the use of bispecific compounds which bind to tumor antigen and a dendritic cell specific cell surface marker.
• Tumors evade host immune surveillance by a large variety of mechanisms. Many of these mechanisms may be overcome by the inactivation of proteins which are expressed by the tumors and which are immunosuppressive. These include among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163: 1037-1050), IL- 10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13: 198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274: 1363-1365). Inhibitors that bind to and block each of these entities may be used in combination with the compounds of this disclosure to counteract the effects of the immunosuppressive agent and favor tumor immune responses by the host.
• PD-Ll blockade Compounds that activate host immune responsiveness can be used in combination with PD-Ll blockade. These include molecules on the surface of dendritic cells which activate DC function and antigen presentation. Anti-CD40 compounds are able to substitute effectively for T cell helper activity (Ridge, J. et al. (1998) Nature 393: 474- 478) and can be used in conjunction with PD-L1 blockade (Ito, N. et al. (2000)
• T cell costimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No. 5,811,097), OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB (Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS (Hutloff, A. et al. (1999) Nature 397: 262-266) may also provide for increased levels of T cell activation.
• Bone marrow transplantation is currently being used to treat a variety of tumors of hematopoietic origin. While graft versus host disease is a consequence of this treatment, therapeutic benefit may be obtained from graft vs. tumor responses.
• PD-L1 blockade can be used to increase the effectiveness of the donor engrafted tumor specific T cells.
• Another aspect of the disclosure provides a method of treating an infectious disease in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or salts thereof.
• the compound of formula (I) or salts thereof can be used alone, or as an adjuvant, in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self-antigens.
• pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to HIV, Hepatitis (A, B, C or D), Influenza, Herpes, Giardia, Malaria,
• PD-L1 blockade is particularly useful against established infections by agents such as HIV that present altered antigens over the course of the infections. These novel epitopes are recognized as foreign at the time of administration, thus provoking a strong T cell response that is not dampened by negative signals through PD-1.
• pathogenic viruses causing infections treatable by methods of the disclosure include HIV, hepatitis (A, B, C, or D), herpes viruses (e.g., VZV, HSV-1 , HAV-6, HHv-7, HHV-8, HSV-2, CMV, and Epstein Barr virus), adenovirus, influenza virus, fiaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial viras, mumps viras, rotaviras, measles viras, rabella viras, parvovirus, vaccinia virus, HTLV viras, dengue viras, papillomavirus, molluscum viras, poliovirus, rabies viras, JC viras and arboviral encephalitis viras.
• herpes viruses e.g., VZV, HSV-1 , HAV-6, HH
• pathogenic bacteria causing infections treatable by methods of the disclosure include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, lebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lymes disease bacteria.
• pathogenic fungi causing infections treatable by methods of the disclosure include Candida (albicans, krasei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
• pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii,
• PD-L1 blockade can be combined with other forms of immunotherapy such as cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), or bispecific antibody therapy, which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2: 1121-1 123), vaccines, or agents that modify gene expression.
• cytokine treatment e.g., interferons, GM-CSF, G-CSF, IL-2
• bispecific antibody therapy which provides for enhanced presentation of tumor antigens (see, e.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak (1994) Structure 2: 1121-1 123), vaccines, or agents that modify gene expression.
• the compounds of this disclosure may provoke and amplify autoimmune responses. Indeed, induction of anti-tumor responses using tumor cell and peptide vaccines reveals that many anti-tumor responses involve anti-self reactivities
• Alzheimer's disease involves inappropriate accumulation of A.beta. peptide in amyloid deposits in the brain; antibody responses against amyloid are able to clear these amyloid deposits (Schenk et al, (1999) Nature 400: 173-177).
• Analogous methods as described above for the use of anti-PD-Ll antibody can be used for induction of therapeutic autoimmune responses to treat patients having an inappropriate accumulation of other self-antigens, such as amyloid deposits, including A.beta. in Alzheimer's disease, cytokines such as TNF alpha, and IgE.
• the compounds of this disclosure may be used to stimulate antigen-specific immune responses by co-administration of a compound of formula (I) or salts thereof with an antigen of interest (e.g., a vaccine).
• an antigen of interest e.g., a vaccine
• the disclosure provides a method of enhancing an immune response to an antigen in a subject, comprising administering to the subject: (i) the antigen; and (ii) a compound of formula (I) or salts thereof, such that an immune response to the antigen in the subject is enhanced.
• the antigen can be, for example, a tumor antigen, a viral antigen, a bacterial antigen or an antigen from a pathogen.
• Non-limiting examples of such antigens include those discussed in the sections above, such as the tumor antigens (or tumor vaccines) discussed above, or antigens from the viruses, bacteria or other pathogens described above.
• the compounds of the disclosure can be co-administered with one or more other therapeutic agents, e.g., a cytotoxic agent, a radiotoxic agent or an immunosuppressive agent.
• the compounds of the disclosure can be administered before, after or concurrently with the other therapeutic agent or can be co-administered with other known therapies, e.g., an anti-cancer therapy, e.g., radiation.
• Such therapeutic agents include, among others, anti-neoplastic agents such as doxorubicin (adriamycin), cisplatin bleomycin sulfate, carmustine, chlorambucil, decarbazine and
• cyclophosphamide hydroxyurea which, by themselves, are only effective at levels which are toxic or subtoxic to a patient.
• Cisplatin is intravenously administered as a 100 mg/dose once every four weeks and adriamycin is intravenously administered as a 60-75 mg/ mL dose once every 21 days.
• Co-administration of a compound of formula (I) or salts thereof, with chemotherapeutic agents provides two anti-cancer agents which operate via different mechanisms which yield a cytotoxic effect to human tumor cells. Such co-administration can solve problems due to development of resistance to drugs or a change in the antigenicity of the tumor cells which would render them unreactive with the antibody.
• kits comprising a compound of formula (I) or salts thereof and instructions for use.
• the kit can further contain at least one additional reagent.
• Kits typically include a label indicating the intended use of the contents of the kit.
• the term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit.
• therapeutic agents when employed in combination with the compounds of the present disclosure, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
• PDR Physicians' Desk Reference
• such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the
• the compounds of formula (I) inhibit the PD-1/PD-L1 interaction with IC 50 values of 20 ⁇ or less, for example, from 0.006 to 20 ⁇ , as measured by the PD-1/PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) binding assay.
• the compounds of formula (I) inhibit the PD-1/PD-L1 interaction with IC 50 values from 0.006 to 100 nM.
• TFA trifluoroacetic acid
• ACN for acetonitrile
• min for minutes RT for room temperature or retention time (context will dictate)
• DMAP 4-N,N- dimethylaminopyridine
• EDC for l-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DMF for ⁇ , ⁇ -dimethylformamide, h or hr for hrs
• EtOAc for ethyl acetate
• THF for tetrahydroiuran
• EtOH for ethanol
• Me for methyl
• DMSO for dimethylsulfoxide
• AcOH for acetic acid
• HATU for (l-[bis(dimethylamino)methylene]-lH-l ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate).
• Analytical LCMS injections were typically chosen from among the following methods to determine the final purity of intermediates and examples.
• Methanol conditions Column: Waters BEH CI 8, 2.0 x 50 mm, 1.7- ⁇ particles; Mobile Phase A: 5:95 methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5 methanol: water with 10 mM ammonium acetate; Temperature: 50 °C; Gradient: 0%B, 0- 100% B over 3 minutes, then a 0.5-minute hold at 100% B; Flow: 0.5 mL/min; Detection: UV at 220 nm.
• Solvent B 95 % ACN: 5% Water : lOmM Ammonium Actetate.
• Tetrahydrofuran solvent and aqueous 0.5M potassium tribasic phosphate solutions were sparged with nitrogen for 15 minutes prior to dispensing for use.
• 2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)boronic acid (5.201 g, 28.9 mmol)
• (3- bromo-2-methylphenyl)methanol 5.00 g, 24.87 mmol
• chloro(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , 1 '-biphenyl-2-yl) palladium(II) also known as second generation XPhos precatalyst, CAS number
• the organic extract was washed again (lx) with brine and dried over magnesium sulfate, filtered and solvent removed in vacuo using a rotary evaporator.
• the crude reaction product (7.84g dark oil) was purified by silica gel chromatography eluting with a step gradient of 25% ethyl acetate in hexanes and 30% ethyl acetate in hexanes.
• the purified product (6.19g, 95% yield) was obtained as a brown oil.
• the reaction was diluted with ethyl acetate ( 100 mL ) and filtered through a celite bed and the bed was washed with ethyl acetate ( 2 x 50 mL ).
• the aqueous layer was extracted with ethyl acetate (lx 100 mL ).
• the combined organic portions were washed with water ( 1 x 25 mL ), brine solution (lx 25 mL ) and dried over sodium sulfate.
• the solvent was removed under vacuum to give a brown solid.
• the crude material was purified on a 24 g silica gel column using petroleum ether: ethyl acetate as eluent. The product eluted at 10% ethyl acetate.
• Lithium hydroxide hydrate (0.925 g, 22.04 mmol) was added to a suspension of ethyl 3-chloro-2-cyanobenzoate (3.85g, 18.37 mmol) in 1 ,4-Dioxane (40 mL) and water (40 mL). A clear solution was obtained. Stirred for 5 hours. TLC with 6:4 petroleum ether: ethyl acetate showed no remaining starting material. The solvent was evaporated under vacuum and the residue was dissolved in 50 mL of water. The pH of the aqueous layer was adjusted to 1 using 1.5N hydrochloric acid. A white solid precipitated. Stirred for 15 minutes, collected the white solid by filtration and washed with 25 mL water.
• Example 1000 N-(2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)- 2-methylbenzylox -6-methylbenzylamino)ethyl)acetamide
• Example 1001 (R)-2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)-2-methylbenzylo -6-methylbenzylamino)-3-hydroxy-2-methylpropanoic acid
• Example 1002 (R)-2-(2-(3-cyanobenzyloxy)-4-(3-(2,3-dihydrobenzo[b][l ,4]dioxin-6- yl)-2-methylbenzylox -6-methylbenzylamino)-3-hydroxypropanoic acid
• Example 1005 N-(2-(2-((5-cyanopyridin-3-yl)methoxy)-4-(3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyloxy)-6- methylbenzylamin thyl)acetamide
• Example 101 1 (S)-4-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[l,r-biphenyl]-3- yl)methoxy)benzyl)amino)-3-hydroxybutanoic acid
• the crude material was purified via preparative LCMS with the following conditions: Column: XBridge C18, 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/minutes Fractions containing the desired product were combined and dried via centrifugal evaporation.
• Example 1014 2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino)-3-hydroxy-2-methylpropanoic acid
• Example 1017 2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amin -3-hydroxypropanoic acid
• Example 1020 2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)ami -2-(hydroxymethyl)-3-methylbutanoic acid
• Example 1017 2-((2-((3- cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-
• Example 1020 2-((2-((3- cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-
• Example 1335 N-(2-((2-methoxy-4-((2-methyl-[l, -biphenyl]-3- yl)methoxy)benzyl)amino)ethyl) acetamide
• Methyl iodide (65 mg) was dissolved in 3 mL of DMF.
• Examples 1024 through 1 120 were prepared utilizing the two-step procedure described for Example 1335: N-(2-((2-methoxy-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide.
• the appropriate alkyl bromide was utilized in place of methyl iodide to alkylate the phenolic oxygen and N-(2-aminoethyl)acetamide was utilized for reductive amination to provide the desired example. Characterization data is provided in the table following the examples.
• Example 1028 N-(2-((2-((3-cyanobenzyl)oxy)-4-((2-methyl-[l, -biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1030 N-(2-((2-(2-hydroxyethoxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl) acetamide
• Example 1031 2-(2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)phenoxy) acetamide
• Example 1032 methyl 5-(2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l,l'- biphenyl]-3-yl)methoxy) phenoxy) pentanoate
• Example 1034 methyl 3-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l ,l'- biphenyl]-3-yl)methoxy) phenoxy) methyl) benzoate
• Example 1035 N-(2-((2-(3-hydroxypropoxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl) acetamide
• Example 1036 methyl 4-(2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[ 1 , 1 '- biphenyl]-3-yl)methoxy) phenoxy )butanoate
• Example 1039 4-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l,r-biphenyl]-3- yl)methoxy)phenoxy)methyl) benzamide
• Examplel041 N-(2-((4-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-((2- (methylsulfonyl)benzyl)oxy) benzyl) amino)ethyl)acetamide
• Example 1042 N-(2-((2-(3-methoxypropoxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl) acetamide
• Example 1043 4-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)phenoxy) methyl)benzoic acid
• Example 1045 N-(2-((4-((2-methyl-[ 1 , 1 '-biphenyl]-3-yl)methoxy)-2-((2- methylbenzyl)oxy)benzyl) amino) ethyl) acetamide
• Example 1048 N-(2-((2-((2-fluorobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1050 N-(2-((2-((3-fluorobenzyl)oxy)-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1051 N-(2-((4-((2-methyl-[ 1 , 1 '-biphenyl]-3-yl)methoxy)-2-((3- (trifluoromethyl)benzyl)oxy)benzyl) amino)ethyl)acetamide
• Example 1053 N-(2-((2-((2-chlorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1054 N-(2-((2-((3-chlorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1055 N-(2-((2-((2-cyanobenzyl)oxy)-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1056 N-(2-((4-((2-methyl-[ 1 , 1 '-biphenyl]-3-yl)methoxy)-2-(naphthalen-2- ylmethoxy)benzyl)amino) ethyl)acetamide
• Example 1058 N-(2-((4-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-((4- nitrobenzyl)oxy)benzyl)amino)ethyl) acetamide
• Example 1060 N-(2-((2-((2,5-difluorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1061 N-(2-((2-((3,5-bis(trifluoromethyl)benzyl)oxy)-4-((2-methyl-[l, - biphenyl]-3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1062 N-(2-((2-((3,5-difluorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1067 methyl 4-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l,r- biphenyl]-3-yl)methoxy) phenoxy)methyl)benzoate
• Example 1068 N-(2-((2-((4-chlorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1069 N-(2-((2-((3,4-dichlorobenzyl)oxy)-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1070 N-(2-((2-((2-fluoro-3-methylbenzyl)oxy)-4-((2-methyl-[l, -biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1071 N-(2-((2-((2,3-difluorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1072 N-(2-((2-((3-chloro-2-fluorobenzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1074 N-(2-((4-((2-methyl-[l, -biphenyl]-3-yl)methoxy)-2-(quinolin-8- ylmethoxy)benzyl)amino) ethyl)acetamide
• Example 1075 N-(2-((2-((4-fluorobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1076 N-(2-((4-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-((3- nitrobenzyl)oxy)benzyl)amino)ethyl) acetamide
• Example 1077 N-(2-((2-((3-(2-fluorophenoxy)benzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]- 3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1078 N-(2-((2-((3-(4-fluorophenoxy)benzyl)oxy)-4-((2-methyl-[l , -biphenyl]- 3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1079 N-(2-((2-((2-fluoro-3-(trifluoromethyl)benzyl)oxy)-4-((2-methyl-[l , ⁇ - biphenyl]-3-yl) methoxy)benzyl)amino)ethyl)acetamide
• Example 1080 N-(2-((2-((2-fluoro-5-(trifluoromethyl)benzyl)oxy)-4-((2-methyl-[l ,1'- biphenyl]-3-yl) methoxy)benzyl)amino)ethyl)acetamide
• Example 1081 N-(2-((2-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3-yl) methoxy)benzyl)amino)ethyl)acetamide
• Example 1082 N-(2-((4-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-((3- (trifluoromethoxy)benzyl)oxy) benzyl)amino)ethyl)acetamide
• Example 1083 N-(2-((2-((4-chloro-2-(trifluoromethyl)quinolin-6-yl)methoxy)-4-((2- methyl-[ 1 , 1 '-biphen -3-yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1086 N-(2-((2-((3-methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1088 N-(2-((2-((4-(difluoromethoxy)benzyl)oxy)-4-((2-methyl-[l , ⁇ -biphenyl]- 3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1090 N-(2-((2-((4-methoxybenzyl)oxy)-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1096 N-(2-((2-((3-fluoro-5-methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]- 3-yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1100 N-(2-((4-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2-(pyrimidin-4- ylmethoxy)benzyl)amino) ethyl)acetamide
• Example 1101 methyl 2-(3-((2-((((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[ 1 , 1 '- biphenyl]-3-yl) methoxy)phenoxy)methyl)phenyl)acetate
• Example 1102 N-(2-((2-((lH-indazol-6-yl)methoxy)-4-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1103 methyl 3-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l ,l'- biphenyl]-3-yl) methoxy)phenoxy)methyl)-4-fluorobenzoate
• Example 1104 N-(2-((2-((5-methyl-l,2,4-oxadiazol-3-yl)methoxy)-4-((2-methyl-[l,l'- biphenyl]-3-yl) methoxy)benzyl)amino)ethyl)acetamide
• Example 1105 tert-butyl 3-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[ 1 , 1 '- biphenyl]-3-yl) methoxy)phenoxy)methyl)benzoate
• Example 1106 N-(2-((2-((3-fluoro-5-(trifluoromethoxy)benzyl)oxy)-4-((2-methyl-[l,r- biphenyl]-3-yl) methoxy)benzyl)amino)ethyl)acetamide
• Example 1108 N-(2-((2-((4-fluoro-3-methylbenzyl)oxy)-4-((2-methyl-[l, -biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1109 N-(2-((2-((5-chloro-2-fluorobenzyl)oxy)-4-((2-methyl-[l,r-biphenyl]-3- yl)methoxy benzyl) amino)ethyl)acetamide
• Example 1110 N-(2-((2-((3-chloro-4-fluorobenzyl)oxy)-4-((2-methyl-[l,r-biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 111 1 N-(2-((4-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2-(pyridin-4- ylmethoxy)benzyl)amino) ethyl)acetamide
• Example 1112 N-(2-((2-((3-(lH-pyrrol-l-yl)benzyl)oxy)-4-((2-methyl-[l ,l'-biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1114 N-(2-((2-((3-cyano-4-fluorobenzyl)oxy)-4-((2-methyl-[l,r-biphenyl]-3- yl)methoxy)benzyl) amino)ethyl)acetamide
• Example 1115 N-(2-((4-((2-methyl-[l, -biphenyl]-3-yl)methoxy)-2-((5-methylisoxazol- 3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1116 N-(2-((2-((3-(difluoromethoxy)benzyl)oxy)-4-((2-methyl-[l,r-biphenyl]- 3-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1117 N-(2-((4-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2-(pyridin-3- ylmethoxy)benzyl)amino) ethyl)acetamide
• Example 1118 N-(2-((2-(isoquinolin-l-ylmethoxy)-4-((2-methyl-[l, -biphenyl]-3- yl)methoxy)benzyl)amino) ethyl)acetamide
• Example 1119 tert-butyl (3-((2-(((2-acetamidoethyl)amino)methyl)-5-((2-methyl-[l, - biphenyl] -3 -yl) methoxy)phenoxy)methyl)phenyl)carbamate
• Example 1120 (S)-N-(2-((4-((2-methyl-[l,l'-biphenyl]-3-yl)methoxy)-2-((5- oxopyrrolidin-2-yl)methoxy) benzyl)amino)ethyl)acetamide
• Example 1028 N-(2-((2-((3- A 1.98 520.3 cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1029 N-(2-((2-((4- M 3.13 520.2 cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1030 N-(2-((2-(2-hydroxyethoxy)- A 1.64 449.4 4-((2-methyl- [1,1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1031 2-(2-(((2- M 2.55 462.4 acetamidoethyl)amino)methyl)-5-((2-methyl- [l,l'-biphenyl]-3- yl)methoxy)phenoxy)acetamide
• Example 1032 methyl 5-(2-(((2- A 2.14 519.4 acetamidoethyl)amino)methyl)-5-((2-methyl- [l,l'-biphenyl]-3- yl)methoxy)phenoxy)pentanoate
• Example 1033 N-(2-((4-((2-methyl-[l ,l'- M 3.12 509.4 biphenyl] -3 -yl)methoxy)-2- phenethoxybenzyl)amino)ethyl)acetamide
• Example 1034 methyl 3-((2-(((2- M 3.06 553.6 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1035 N-(2-((2-(3-hydroxypropoxy)- M 2.82 463.4 4-((2-methyl- [1,1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1036 methyl 4-(2-(((2- M 2.97 505.4 acetamidoethyl)amino)methyl)-5-((2-methyl- [l,l'-biphenyl]-3- yl)methoxy)phenoxy)butanoate
• Example 1039 4-((2-(((2- M 2.83 538.4 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1040 N-(2-((2-((4- A 2.09 537.4 acetylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1042 N-(2-((2-(3- A 2.04 477.4 methoxypropoxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1043 4-((2-(((2- A 1.71 539.4 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1045 N-(2-((4-((2-methyl-[l ,l'- M 3.16 509.3 biphenyl] -3 -yl)methoxy)-2-((2- methylbenzyl)oxy)benzyl)amino)ethyl)acetam
• Example 1046 N-(2-((2-((4-(tert- M 3.35 551.1 butyl)benzyl)oxy)-4-((2 -methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1048 N-(2-((2-((2- M 3.09 513.4 fluorobenzyl)oxy)-4-((2 -methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1049 N-(2-((2-((2,6- M 3.08 531.2 difluorobenzyl)oxy)-4-((2 -methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1050 N-(2-((2-((3- M 3.08 513.4 fluorobenzyl)oxy)-4-((2 -methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1053 N-(2-((2-((2- M 3.4 529.2 chlorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1054 N-(2-((2-((3- A 2.16 529.2 chlorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1055 N-(2-((2-((2- A 1.98 520.3 cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1056 N-(2-((4-((2-methyl-[l ,l'- A 2.24 545.3 biphenyl]-3-yl)methoxy)-2-(naphthalen-2- ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1057 N-(2-((4-((2-methyl-[l ,l'- A 2.06 540.2 biphenyl]-3-yl)methoxy)-2-((2- nitrobenzyl)oxy)benzyl)amino)ethyl)acetamid
• Example 1058 N-(2-((4-((2-methyl-[l ,l'- A 2.05 540.3 biphenyl]-3-yl)methoxy)-2-((4- nitrobenzyl)oxy)benzyl)amino)ethyl)acetamid
• Example 1059 N-(2-((2-((3,4- M 3.28 531.2 difluorobenzyl)oxy)-4-((2-methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1060 N-(2-((2-((2,5- A 2.09 531.2 difluorobenzyl)oxy)-4-((2-methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1061 N-(2-((2-((3,5- A 2.37 631.2 bis(trifluoromethyl)benzyl)oxy)-4-((2-methyl-
• Example 1062 N-(2-((2-((3,5- A 2.26 531.4 difluorobenzyl)oxy)-4-((2-methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1063 N-(2-((4-((2-methyl-[l ,l'- M 3.24 545.4 biphenyl]-3-yl)methoxy)-2-(naphthalen- 1 - ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1064 N-(2-((2-((2,4- M 3.12 531.4 difluorobenzyl)oxy)-4-((2-methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1067 methyl 4-((2-(((2- M 3.04 553.4 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1068 N-(2-((2-((4- A 2.23 529.4 chlorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1069 N-(2-((2-((3,4- M 3.24 563.6 dichlorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1070 N-(2-((2-((2-fluoro-3- M 3.2 549.6 methylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1071 N-(2-((2-((2,3- A 2.25 531.4 difluorobenzyl)oxy)-4-((2-methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1072 N-(2-((2-((3-chloro-2- M 3.2 547.4 fluorobenzyl)oxy)-4-((2-methyl- [1,1'- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1073 N-(2-((2-((3- M 3.15 599.4 benzoylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1074 N-(2-((4-((2-methyl-[l ,l'- M 3.07 546.4 biphenyl]-3-yl)methoxy)-2-(quinolin-8- ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1075 N-(2-((2-((4- M 3.07 513.4 fluorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1076 N-(2-((4-((2-methyl-[l ,l'- M 3.23 540.2 biphenyl] -3 -yl)methoxy)-2-((3 - nitrobenzyl)oxy)benzyl)amino)ethyl)acetamid
• Example 1080 N-(2-((2-((2-fluoro-5- M 3.18 581.6
• Example 1081 N-(2-((2-((3-fluoro-5- M 3.2 581.6 (trifluoromethyl)benzyl)oxy)-4-((2-methyl- [l,l'-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1082 N-(2-((4-((2-methyl-[l ,l'- M 3.21 579.4 biphenyl] -3 -yl)methoxy)-2-((3 - (trifluoromethoxy)benzyl)oxy)benzyl)amino)e
• Example 1083 N-(2-((2-((4-chloro-2- A 2.42 648.4 (trifluoromethyl)quinolin-6-yl)methoxy)-4- ((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1086 N-(2-((2-((3- A 2.07 525.3 methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1090 N-(2-((2-((4- A 2.16 525.3 methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1091 N-(2-((2-((3-chloro-5- M 3.21 547.3 fluorobenzyl)oxy)-4-((2 -methyl- [ 1 , - biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1092 N-(2-((2-((2,6-difluoro-3- A 2.16 561.3 methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1093 N-(2-((2-((4-fluoro-3- A 2.17 543.3 methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1094 N-(2-((2-((2-fluoro-5- M 3.15 527.3 methylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1096 N-(2-((2-((3-fluoro-5- M 3.11 543.4 methoxybenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1097 N-(2-((2-((4-bromo-2- A 2.15 600.3 cyanobenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1099 N-(2-((4-((2-methyl-[l ,l'- M 3.09 619.4 biphenyl]-3-yl)methoxy)-2-((l-(tetrahydro- 2H-pyran-2-yl)-lH-indazol-5- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1100 N-(2-((4-((2-methyl-[l ,l'- A 1.81 497.3 biphenyl]-3-yl)methoxy)-2-(pyrimidin-4- ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1101 methyl 2-(3-((2-(((2- M 2.98 567.3 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1102 N-(2-((2-((lH-indazol-6- M 2.93 535.3 yl)methoxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1103 methyl 3-((2-(((2- M 3.1 571.4 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1104 N-(2-((2-((5-methyl- 1,2,4- M 2.81 501.5 oxadiazol-3-yl)methoxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1105 tert-butyl 3-((2-(((2- M 3.27 595.4 acetamidoethyl)amino)methyl)-5-((2-methyl-
• Example 1108 N-(2-((2-((4-fluoro-3- A 2.15 527.6 methylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1109 N-(2-((2-((5-chloro-2- A 2.14 547.6 fluorobenzyl)oxy)-4-((2-methyl- [1,1'- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1110 N-(2-((2-((3-chloro-4- A 2.15 547.6 fluorobenzyl)oxy)-4-((2-methyl- [1,1'- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 111 1 N-(2-((4-((2-methyl-[l ,l'- A 1.68 496.5 biphenyl] -3 -yl)methoxy)-2-(pyridin-4- ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1112 N-(2-((2-((3-(lH-pyrrol-l- M 3.18 560.6 yl)benzyl)oxy)-4-((2-methyl- [1,1 '-biphenyl]- 3-yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1113 N-(2-((2-((3-fluoro-5- A 2.14 527.6 methylbenzyl)oxy)-4-((2-methyl-[ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1114 N-(2-((2-((3-cyano-4- A 1.99 538.5 fluorobenzyl)oxy)-4-((2-methyl- [ 1 , 1 '- biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1115 N-(2-((4-((2-methyl-[l ,l'- A 1.82 500.5 biphenyl] -3 -yl)methoxy)-2-((5 - methylisoxazol-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1117 N-(2-((4-((2-methyl-[l ,l'- M 2.8 496.3 biphenyl]-3-yl)methoxy)-2-(pyridin-3- ylmethoxy)benzyl)amino)ethyl)acetamide
• Example 1118 N-(2-((2-(isoquinolin-l- M 3 546.6 ylmethoxy)-4-((2-methyl-[ 1 , 1 '-biphenyl]-3- yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1120 (S)-N-(2-((4-((2-methyl-[l,l'- A 1.61 502.5 biphenyl] -3 -yl)methoxy)-2-((5 -oxopyrrolidin- 2-yl)methoxy)benzyl)amino)ethyl)acetamide
• Example 1124 2-((2-((3- cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2- A 1.75 595.3 593.4 methylbenzyl)oxy)benzyl)amino)-3- hydroxy-2-methylpropanoic acid
• Example 1128 (S)-2-((2-((3- cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2- A 1.79 595.3 593.4 methylbenzyl)oxy)benzyl)amino)-3- hydroxy-2-methylpropanoic acid
• 6-yl)-2-methylbenzyl)oxy)-2-hydroxy-6-methylbenzaldehyde 100 mg, 0.256 mmol
• 3-(bromomethyl)benzonitrile 80 mg, 0.531 mmol
• the mixture was diluted with ethyl acetate, neutralized with dilute hydrochloric acid (0.1 N) and washed with water and brine. Dried over sodium sulfate. Filtered and removed the solvent by rotary evaporation. The residue was purified with 2:3 hexanes:ethyl acetate on a 24 g silica gel column. Collected fractions to afford a white solid (18 mg , 13.8 % yield).
• Example 1130 N-(2-(2-((4-cyanopyridin-2-yl)methoxy)-4-(3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyloxy)benzylamino)ethyl)acetamide
• Example 1131 (R)-2-(2-((4-cyanopyridin-2-yl)methoxy)-4-(3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyloxy)benzylamino)-3-hydroxy-2- methylpropanoic aci
• the crude material was purified via preparative LC/MS 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: 40-80% B over 15 minutes, then a 7- minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 12.3 mg, and its estimated purity by LCMS analysis was 100%.
• Example 1134 (R)-2-((2-((3-cyanobenzyl)oxy)-6-methoxy-4-((2-methyl-[l ,l'-biphenyl]- 3 -y l)methoxy)benzyl) amino) -3 -hydro xypropano ic acid
• Example 1137 2-((2-((3-cyanobenzyl)oxy)-6-methoxy-4-((2-methyl-[l,r-biphenyl]-3- yl)methoxy)benzyl)ami -3-hydroxy-2-methylpropanoic acid
• Example 1136 (2S,3S)-2-((2-((3- cyanobenzyl)oxy)-6-methoxy-4-((2- methyl-[ 1 , 1 '-biphenyl]-3- A 2.08 567.4 565.5 yl)methoxy)benzyl)amino)-3- hydroxybutanoic acid
• Example 1137 2-((2-((3- cyanobenzyl)oxy)-6-methoxy-4-((2- methyl-[ 1 , 1 '-biphenyl]-3- A 1.96 567.3 565.3 yl)methoxy)benzyl)amino)-3-hydroxy- 2-methylpropanoic acid
• Example 1138 (2R,3R)-2-((2-((3- cyanobenzyl)oxy)-6-methoxy-4-((2- methyl-[ 1 , 1 '-biphenyl]-3- A 1.93 567.4 565.4 yl)methoxy)benzyl)amino)-3- hydroxybutanoic acid
• Example 1142 (S)-2-((2-((3-cyanobenzyl)oxy)-4-((3-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)-2-methylbenzyl)o -6-methoxybenzyl)amino)-3-hydroxy-2-methylpropanoic acid
• the crude material was purified via preparative LCMS 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: 35-75% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/minutes Fractions containing the desired product were combined and dried via centrifugal evaporation. The yield of the product was 9.5 mg, and its estimated purity by LCMS analysis was 100%. Two analytical LCMS injections were used to determine the final purity.
• Example 1150 N-(2-(4-(2-chloro-3-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)benzyloxy)-2- (3-cyanobenzyloxy) benzylamino)ethyl)acetamide
• Example 1148 (R)-2-(4-(2-chloro-3- M 2.8 615.3 613.3 (2,3 -dihydrobenzo [b] [ 1 ,4] dioxin-6- yl)benzyloxy)-2-(3- cyanobenzyloxy)benzylamino)-3- hydroxy-2-methylpropanoic acid
• Example 1150 N-(2-(4-(2-chloro-3- A 1.9 598.3 656.3 (2,3 -dihydrobenzo [b] [ 1 ,4] dioxin-6- (+ yl)benzyloxy)-2-(3- AcOH) cyanobenzyloxy)benzylamino)ethyl)
• Examplel 151 5-((5-(2-chloro-3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)benzyloxy)-2-((2- hydroxyethylamino)m thyl)-4-methylphenoxy)methyl)nicotinonitrile
• Example 1 156 (R)-2-(4-(2-chloro-3-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)benzyloxy)-2-
• 5-Chloro-2,4-dihydroxybenzaldehyde was prepared using the literature procedure: Vogel,H; Goeldner,M. et.al. Angew. Chem. Int. Ed. 2007, 46, 3505 -3508,
• reaction was diluted to approxately 2 mL using tetrahydrofuran and 2 drops of water added to help solublize salts.
• the reaction was filtered through a 0.45 um syringe filter and product was purified by reverse phase HPLC using the following conditions:
• Example 1158 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)succinic acid
• Example 1159 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(3- hydroxyphenyl)propanoic acid
• Example 1160 (R)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3- (methylthio)propanoi acid
• Example 1161 (R)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-2-(4- hydroxyphenyl)acetic acid
• Example 1162 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)- trifluoropropanoic a id
• Example 1164 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(lH-imidazol-4- yl)propanoic acid
• Example 1165 l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)pyrrolidine-2-carboxylic acid
• Example 1166 (2R,4R)-l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-4-hydroxypyrrolidine-2- carboxylic acid
• Example 1168 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(l -methyl- 1H- indol-3-yl)propanoic acid
• Example 1170 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- methylbenzyl)oxy)-2- 2-hydroxyethyl)amino)methyl)phenoxy)methyl)benzonitrile
• Example 1172 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)- (dimethylamino)propanoic acid
• Example 1174 (2S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-4- (methylsulfinyl)butanoic acid
• Example 1176 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(l -methyl- 1H- imidazol-4-yl)propanoic acid
• Example 1177 l-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2- methylbenzyl)oxy)benzyl)amino)cyclopropanecarboxylic acid
• Example 1178 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(thiazol-2- yl)propanoic acid
• Example 1179 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-methoxy-3- methylbutanoic acid
• Examplel 180 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-cyanopropanoic acid
• Examplel 181 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(2- hydroxyphenyl)propanoic acid
• Example 1182 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-4- (methylsulfonyl)butanoic acid
• Examplel 183 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl) hydroxypropanoic acid
• Example 1184 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)- methoxypropanoic a id
• Example 1186 (S)-3-(l-benzyl-lH-imidazol-4-yl)-2-((5-chloro-2-((3-cyanobenzyl)oxy)- 4-((3-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)-2- methylbenzyl)oxy)benzyl)amino)propanoic acid
• Example 1187 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(4- hydroxyphenyl)propanoic acid
• Example 1188 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl)amino)propanoic acid
• Example 1191 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(lH-imidazol-4- yl)-2-methylpropanoic acid
• Example 1192 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(lH-indol-3- yl)propanoic acid
• Example 1200 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-4- (methylsulfonyl)butanoic acid
• Examplel201 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)butanoic acid
• Example 1202 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-4- (methylthio)butan ic acid
• Examplel203 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)(methyl)amino)succinic acid
• Example 1204 (2S,3R)-l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-3-hydroxypyrrolidine-2- carboxylic acid
• Example 1205 (R)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-4-hydroxybutanoic acid
• Example 1206 (R)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(thiazol-4- yl)propanoic acid
• Example 1208 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(thiazol-4- yl)propanoic acid
• Example 1209 l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)azetidine-2-carboxylic acid
• Example 1210 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-hydroxy-3- methylbutanoic acid
• Example 121 1 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b][l,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-2-(lH-indol-3- yl)acetic acid
• Example 1212 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][l ,4]dioxin methylbenzyl)oxy)-2-(((2-hydroxy-3- morpholinopropyl)amino)methyl)phenoxy)methyl)benzonitrile
• Example 1213 4-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)morpholine-3-carboxylic acid
• Example 1214 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-2- (hy droxymethyl)- 3 -methy lbutano ic acid
• Example 1215 (2S,4R)-l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-4-fluoropyrrolidine-2- carboxylic acid
• Example 1216 2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)- trifluorobutanoic aci
• Example 1217 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(3- cyanophenyl)propan ic acid
• Example 1218 2-benzyl-2-((5-cmoro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3- hydroxypropanoic ac
• Example 1220 4-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)- 1 - methylpiperidine-4- arboxylic acid
• Example 1221 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(pyridin-2- yl)propanoic acid
• Example 1223 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- methylbenzyl)oxy)-2-(((2 -methyl- 1 -(4-methylpiperazin- 1 -yl)propan-2- yl)amino)methyl)phen xy)methyl)benzonitrile
• Example 1224 l-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-4-methylpiperazine-2- carboxylic acid
• Example 1225 3-((4-chloro-5-((3-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2- methylbenzyl)oxy)-2-(((2-hydroxy-3-(2-oxopyrrolidin- 1 - yl)propyl)amino)methyl)phenoxy)methyl)benzonitrile
• Example 1226 5-(5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)-4,5,6,7-tetrahydro imidazo[4,5-c]pyridi -4-carboxylic acid
• Example 1227 (S)-2-((5-chloro-2-((3-cyanobenzyl)oxy)-4-((3-(2,3- dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-2-methylbenzyl)oxy)benzyl)amino)-3-(2H-tetrazol-2- yl)propanoic acid
• Example 1228 (R)-3-(l -benzyl- lH-imidazo l-4-yl)-2-((5-chloro-2-((3-cyanobenzyl)oxy)- 4-((3-(2,3-dihydrobenzo[b][l ,4]dioxin-6-yl)-2- methylbenzyl)oxy)benzyl)amino)propanoic acid
• Example 1229 3-((2-(((((lH-tetrazol-5-yl)methyl)amino)methyl)-4-chloro-5-((3-(2,3- dihydrobenzo[b][l ,4]dioxin-6-yl)-2-methylbenzyl)oxy)phenoxy)methyl)benzonitrile

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