WO2018047139A1 - Composés modulateurs de la voie de signalisation de tigit - Google Patents

Composés modulateurs de la voie de signalisation de tigit Download PDF

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WO2018047139A1
WO2018047139A1 PCT/IB2017/055484 IB2017055484W WO2018047139A1 WO 2018047139 A1 WO2018047139 A1 WO 2018047139A1 IB 2017055484 W IB2017055484 W IB 2017055484W WO 2018047139 A1 WO2018047139 A1 WO 2018047139A1
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cancer
compound
aryl
cooh
cell
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PCT/IB2017/055484
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Pottayil Govindan Nair Sasikumar
Muralidhara Ramachandra
Seetharamaiah Setty Sudarshan Naremaddepalli
Chennakrishnareddy GUNDALA
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Aurigene Discovery Technologies Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the present invention relates to modulators of TIGIT signalling pathway comprising 1,2,4- and/or 1,3,4-oxadiazole compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to methods for treating or delaying progression of diseases or disorders mediated by TIGIT in an individual comprising administering the said compounds.
  • the aim of immunotherapy is to treat diseases by controlling the immune response to a "foreign agent", for example a pathogen or a tumour cell.
  • a "foreign agent” for example a pathogen or a tumour cell.
  • This may include methods to induce or enhance specific immune responses or to inhibit or reduce specific immune responses.
  • the immune system is a highly complex system made up of a great number of cell types, including, T-cells, B-cells, natural killer cells, antigen-presenting cells, dendritic cells, monocytes and macrophages.
  • Many immune related diseases are known and such diseases include immune-mediated inflammatory diseases, non-immune-mediated inflammatory diseases, infectious diseases and immunodeficiency diseases.
  • cancers are also interconnected with the immune system, as various immune cells are able to mount an anti-cancer cell response, but cancer cells also possess mechanisms to suppress or evade these responses.
  • genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect.
  • Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.
  • tumours may utilize receptors or ligands that normally would trigger inhibitory pathways in effector T cells.
  • receptors and/or ligands such as PDL1, PD-1, CTLA-4, CD155 and TIGIT, have been identified as important regulatory molecules.
  • TIGIT T-cell Ig and ITIM domain
  • CD155 T-cell Ig and ITIM domain
  • TIGIT T cell immunoreceptor with Ig and ITIM domains
  • WUCAM WUCAM
  • Vstm3 Vsig9.
  • TIGIT has an immunoglobulin variable domain, a transmembrane domain, and an immunoreceptor tyrosine-based inhibitory motif (ITIM), and contains signature sequence elements of the PVR protein family. It is known to interact with poliovirus receptor (PVR; CD155) and with nectin2 (CD112) (Stengel et al. (2012) Proc. Natl Acad. Sci. (USA) 19:5399).
  • PVR poliovirus receptor
  • CD112 nectin2
  • TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells.
  • TIGIT and other such co-inhibitory molecules may play a role in evasion of immunosurveillance by tumour cells.
  • PVR/CD 155 is over- expressed on melanoma cells (Inozume et al. (2014) J. Invest. Dermatol. 134:S121— Abstract 693) and various other tumours. It is possible that the TIGIT/PVR interaction can shield such tumour cells from immune-mediated eradication by inhibiting anti-tumour responses of T and NK cells (Stanietsky et al. (2009) Proc. Natl Acad. Sci.
  • TIGIT may act to 'turn off the immune response similarly to other co-inhibitory receptors such as CTLA-4, PD-1 and BTLA.
  • CTLA-4 ipilimumab
  • PD-1 nivolumab, pembrolizumab
  • Antibodies targeting CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have been approved for the treatment of human cancers, validating this therapeutic approach.
  • Antibodies that bind to human TIGIT might also find use in treatment of cancers.
  • antibody blockade of both PD-L1 and TIGIT leads to a synergistic enhancement of CD8 ⁇ +> T cell mediated tumour rejection (Grogan et al. (2014) J. Immunol. 192(1) Suppl. 203.15; Johnston et al.
  • TIGIT blockade is effective to enhance anti-tumour CD8 ⁇ +> T cell response only in the presence of the co- activating receptor DNAM-1/CD226, which competes with TIGIT for binding to PVR/CD 155 (Johnston et al. (2014) Cancer Cell 26: 1-15).
  • 1,2,4- and 1,3,4-oxadiazole compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof that are capable of modulating T cell Immunoreceptor with Ig and ITIM domains (TIGIT) signalling pathway. These compounds are useful for treatment of diseases or disorders mediated by TIGIT.
  • Ri represents hydrogen, -CH 2 -aryl, -(CH 2 )2-CONH 2 or -CH 2 -SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH 2 -SH, -CH 2 -COOH, or - (CH 2 ) 2 -COOH;
  • Aaa is amino acid residue selected from Ser, Tyr, He, or Gly;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, -(CH 2 ) 2 - COOH, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 (CH)(CH 3 ) 2 , or -CH(CH 3 ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 - heteroaryl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, His, or Gin; in formula (IC), one of Xi and X 2 is O and the other is N;
  • Ri represents hydrogen, -CH 2 -aryl-OH, -CH(CH3)OH, -CH2-heteroaryl, - (CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CHa-aryl, or -CH2-COOH;
  • R 2 represents hydrogen, -CH 2 -aryl, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 - COOH, -CH 2 -SH, or -CH 2 -heteroaryl;
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -aryl-OH, or -OH
  • R 2 represents -aryl or -aryl-OH
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring; in formula (IE),
  • Ri represents -(CH 2 ) 2 -COOH, -CH 2 -aryl-OH, -CH(CH 3 )CH 2 CH 3 , or -CH 2 - heteroaryl;
  • R 2 represents -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -heteroaryl, or -CH(CH 3 )OH;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH 2 -aryl-OH, -CH 2 -aryl, or -CH(CH 3 )OH;
  • R 2 represents -SH, -aryl, or -COOH
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH(CH 3 )OH, or -CH2-COOH
  • R2 represents hydrogen or -Ctb-aryl-OH
  • Aaa is amino acid residue selected from Thr, or Pro.
  • composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof and processes for preparing such compositions.
  • the present invention provides 1 ,2,4- and 1 ,3,4-oxadiazole compounds as therapeutic agents useful for treatment of diseases or disorders mediated by TIGIT.
  • the present invention provides a compound of formula (I),
  • Ri represents hydrogen, -CH 2 -aryl, -(CH 2 ) 2 -CONH 2 or -CH 2 -SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH 2 -SH, -CH 2 -COOH, or (CH 2 ) 2 -COOH;
  • Aaa is amino acid residue selected from Ser, Tyr, He, or Gly;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH2-COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, -(CH 2 ) 2 - COOH, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 (CH)(CH3) 2 , or -CH(CH 3 ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 - heteroaryl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, His, or Gin; in formula (IC), one of Xi and X 2 is O and the other is N;
  • Ri represents hydrogen, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 -heteroaryl, - (CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -aryl, or -CH 2 -COOH;
  • R 2 represents hydrogen, -CH 2 -aryl, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 - COOH, -CH 2 -SH, or -CH 2 -heteroaryl;
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -aryl-OH, or -OH
  • R 2 represents -aryl or -aryl-OH
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring; in formula (IE),
  • Ri represents -(CH 2 ) 2 -COOH, -CH 2 -aryl-OH, -CH(CH 3 )CH 2 CH 3 , or -CH 2 - heteroaryl;
  • R 2 represents -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -heteroaryl, or -CH(CH 3 )OH;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH 2 -aryl-OH, -CH 2 -aryl, or -CH(CH 3 )OH;
  • R 2 represents -SH, -aryl, or -COOH
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R3a is hydrogen; or R 2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH(CH 3 )OH, or -CH 2 -COOH
  • R 2 represents hydrogen or -CH 2 -aryl-OH
  • Aaa is amino acid residue selected from Thr, or Pro.
  • compound of general formula (I) comprises,
  • the present invention provides compound of formula (I) selected from formulae (IA), (IB, and (ID), wherein, in formula (IA), Ri represents hydrogen, -CH 2 -aryl, -(CH 2 ) 2 -CONH 2 or -CH 2 -SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH 2 -SH, -CH 2 -COOH, or -(CH 2 ) 2 - COOH;
  • Aaa is an amino acid residue selected from Ser, Tyr, He, or Gly;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring; in formula (IB),
  • Ri represents -CH 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, -(CH 2 ) 2 - COOH, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 (CH)(CH3) 2 , or -CH(CH 3 ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 - heteroaryl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, His, or Gin;
  • Ri represents -aryl-OH, or -OH
  • R 2 represents -aryl or -aryl-OH
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • Aaa is amino acid residue selected from Asp, Pro, or Ser.
  • the present invention provides compounds of formula (I) represented by formula (IA), wherein
  • Ri represents hydrogen, -CH 2 -aryl, -(CH 2 ) 2 -CONH 2 or -CH 2 -SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH 2 -SH, -CH 2 -COOH, or - (CH 2 ) 2 -COOH;
  • Aaa is an amino acid residue selected from Ser, Tyr, He, or Gly; and R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • Ri in formula (IA), represents hydrogen, -Cth-phenyl, - (CH 2 ) 2 -CONH 2 or -CH2-SH.
  • R2 in formula (IA) represents hydrogen, -CH(CH3)CH2CH3, -CH2-SH, or -(CH 2 ) 2 -COOH.
  • Aaa in formula (IA), is an amino acid residue selected from Ser, Tyr, or He.
  • R4, in formula (IA), is hydrogen
  • the present invention provides compounds of formula (I), represented by formula (IA), wherein
  • Ri represents hydrogen, -CH2-phenyl, -(CH2)2-CONH2 or -CH2-SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH2-SH, or -(CH 2 ) 2 -COOH;
  • Aaa is an amino acid residue selected from Ser, Tyr, or He;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the present invention provides compounds of formula (I), represented by formula (IA), wherein
  • Ri is hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 )OH, -CH 2 -SH, -CH2-COOH, -(CH 2 ) 2 - COOH, -CH 2 -heteroaryl, -CH 2 -aryl or -CH 2 -aryl-OH;
  • R 2 is hydrogen, -CH 2 -aryl-OH, -CH 2 -aryl, -CH(CH 3 )OH, -CH 2 -COOH, - CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, or -CH 2 -SH;
  • Aaa is an amino acid residue selected from Phe, Gly, He, Asp, Tyr, His or Thr;
  • R4 is hydrogen or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the present invention provides compound of formula (I) represented by formula (IB), wherein
  • Ri represents -CH 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, -(CH 2 ) 2 - COOH, -CH 2 -aryl-OH, -CH(CH )OH, -CH 2 (CH)(CH3) 2 , or -CH(CH ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 - heteroaryl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, His, or Gin;
  • Ri in formula (IB), represents -CH 2 -COOH, -CH 2 - imadazolyl, -(CH 2 ) 2 -COOH, -CH 2 -(p-OH)phenyl, -CH(CH 3 )OH, -CH 2 (CH)(CH 3 ) 2 , or -
  • Ri in formula (IB), represents -CH 2 -COOH, -CH 2 - imadazolyl, -(CH 2 ) 2 -COOH, -CH(CH )OH, -CH 2 (CH)(CH ) 2 , or -CH(CH ) 2 .
  • Ri in formula (IB), represents -CH2-COOH, -CH 2 - imadazolyl, -(CH 2 ) 2 -COOH, -CH 2 (CH)(CH 3 ) 2 , or -CH(CH 3 ) 2 .
  • Ri in formula (IB), represents -CH 2 -COOH, or -CH 2 - imadazolyl.
  • R 2 in formula (IB), represents hydrogen, -CH(CH3)OH, - CH 2 -(/?-OH)phenyl, -CH 2 -phenyl -CH 2 -imidazolyl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or - CH(CH 3 ) 2 .
  • R 2 in formula (IB), represents hydrogen, -CH(CH3)OH, - CH 2 -OH)phenyl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 .
  • R 2 in formula (IB), represents hydrogen, -CH(CH3)OH, - CH 2 -OH)phenyl, -CH 2 -OH, or -CH(CH 3 ) 2 .
  • R 2 in formula (IB), represents hydrogen, or -CH(CH3)OH.
  • Aaa in formula (IB), is an amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, or Gin.
  • Aaa in formula (IB), is an amino acid residue selected from Tyr, Thr, Phe, Gly, or Gin.
  • Aaa in formula (IB), is an amino acid residue selected from Tyr, or Thr.
  • the present invention provides compound of formula (I), represented by formula (IB), wherein
  • Ri represents -CH 2 -COOH, -CH 2 -imadazolyl, -(CH 2 ) 2 -COOH, -CH 2 -(p- OH)phenyl, -CH(CH 3 )OH, or -CH 2 (CH)(CH 3 ) 2 or -CH(CH 3 ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -( -OH)phenyl, -CH 2 -phenyl, - CH 2 -imidazolyl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, or Gin.
  • the present invention provides compound of formula (I), represented by formula (IB), wherein
  • Ri represents -CH 2 -COOH, or -CH 2 -imadazolyl
  • R 2 represents hydrogen, or -CH(CH 3 )OH,; and Aaa is amino acid residue selected from Tyr or Thr.
  • the present invention provides compound of formula (I) represented by formula (ID), wherein
  • Ri represents -aryl-OH, or -OH
  • R2 represents -aryl or -aryl-OH
  • R3a is hydrogen; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • Aaa is amino acid residue selected from Asp, Pro, or Ser.
  • Ri in formula (ID), represents -aryl-OH.
  • Ri in formula (ID) represents -(/?-OH)phenyl or -OH; and R2, in formula (ID), represents -phenyl or -(p-OH)phenyl.
  • R3a, in formula (ID) represents hydrogen.
  • R2 and R3 a taken together with the atoms to which they are attached form a pyrrolidine ring.
  • Aaa in formula (ID), is amino acid residue selected from Asp, and Pro.
  • Aaa in formula (ID), is amino acid residue of Asp.
  • the present invention provides compound of formula (I) represented by formula (ID), wherein
  • Ri represents -(p-OH)phenyl, or -OH;
  • R2 represents -phenyl or -(p-OH)phenyl
  • R3a is hydrogen; or R2 and R3 a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • Aaa is amino acid residue selected from Asp, Pro, or Ser.
  • the compounds represented by formula (ID) selected from or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the present invention provides compound of formula (I) represented by formula (IC), wherein
  • one of Xi and X2 is O and the other is N;
  • Ri represents hydrogen, -CH 2 -aryl-OH, -CH(CH3)OH, -CH 2 -heteroaryl, - (CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CHa-aryl, or -CH2-COOH;
  • R 2 represents hydrogen, -CH 2 -aryl, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 -
  • R 3 a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • TM represents point of attachment.
  • Ri represents -CH 2 -aryl- OH, -CH(CH 3 )OH, -CH 2 -heteroaryl, -(CH 2 ) 2 -COOH, -CH(CH )CH 2 CH , -CH 2 -aryl, or - CH2-COOH; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • Ri represents -CH 2 -(p- OH)phenyl, -CH(CH 3 )OH, -CH 2 -imadazolyl, -(CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 - phenyl, or -CH 2 -COOH.
  • Ri represents -CH 2 -(p- OH)phenyl, -CH(CH 3 )OH, -CH 2 -imadazolyl, -(CH 2 ) 2 -COOH, -CH 2 -phenyl, or -CH 2 -COOH.
  • R4 is hydrogen
  • Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • R 2 represents -CH 2 -aryl, - CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 -COOH, -CH 2 -SH, or -CH 2 -heteroaryl; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring.
  • R 2 represents -CH 2 -phenyl, -CH 2 -(p-OH)phenyl, -CH(CH 3 )OH, -CH 2 -COOH, -CH 2 -SH, or -CH 2 -imidazolyl.
  • R 3a is hydrogen
  • R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring.
  • the present invention provides compound of formula (I) represented by formula (IC), wherein
  • ⁇ represents point of attachment
  • Ri represents -CH 2 -(p-OH)phenyl, -CH(CH 3 )OH, -CH 2 -imadazolyl, -(CH 2 ) 2 - COOH, -CH(CH )CH 2 CH , -CHa-phenyl, or -CH 2 -COOH; and R 2 represents -CH 2 -phenyl, -CH 2 -(p-OH)phenyl, -CH(CH 3 )OH, -CH2-COOH, - CH2-SH, or -CH 2 -imidazolyl.
  • formula (IC) represents point of attachment.
  • Ri represents hydrogen, - CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 -heteroaryl, -(CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 - aryl, or -CH 2 -COOH; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • Ri represents hydrogen, - CH 2 -OH)phenyl, -CH(CH 3 )OH, -CH 2 -imidazolyl, -(CH 2 ) 2 -COOH, -CH(CH 3 )CH 2 CH 3 , - CH 2 -phenyl, or -CH 2 -COOH.
  • R 2 represents hydrogen, - CHa-phenyl, -CH 2 -SH, -CH 2 -(p-OH)phenylêt -CH(CH )OH, or -CH 2 -COOH.
  • Ri represents hydrogen, -CH 2 -(p-OH)phenyl, -CH(CH 3 )OH, -CH 2 -imidazolyl, - (CH 2 ) 2 -COOH, -CH(CH )CH 2 CH , -CHa-phenyl, or -CH 2 -COOH;
  • R 2 represents hydrogen, -CH 2 -phenyl, -CH 2 -SH, -CH 2 -(p-OH)phenyllibrary - CH(CH 3 )OH, or -CH 2 -COOH;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the compound of formula (I) selected from compounds represented by formulae (IA), (IB), (IC), and (ID). In certain embodiments, the compounds of formula (I) selected from
  • the present invention provides a compound of formula (I),
  • Ri is hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 )OH, -CH 2 -SH, -CH2-COOH, -(CH 2 ) 2 - COOH, -CH 2 -heteroaryl, -CH 2 -aryl or -CH 2 -aryl-OH;
  • R 2 is hydrogen, -CH 2 -aryl-OH, -CH 2 -aryl, -CH(CH 3 )OH, -CH 2 -COOH, - CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, or -CH 2 -SH;
  • R 3 is hydrogen or -CO- Aaa
  • Aaa is an amino acid residue selected from Phe, Gly, He, Asp,Tyr, His or Thr;
  • R 3a represents hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring; R4IS hydrogen or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • the present invention provides compound of formula (I) selected from formulae (IE), (IF), (IG), wherein,
  • Ri represents -(CH 2 ) 2 -COOH, -CH 2 -aryl-OH, -CH(CH 3 )CH 2 CH 3 , or -CH 2 - heteroaryl;
  • R 2 represents -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -heteroaryl, or -CH(CH 3 )OH;
  • R4 is hydrogen;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr; in formula (IF) Ri represents -CH 2 -aryl-OH, -CH 2 -aryl, or -CH(CH 3 )OH; R2 represents -SH, -aryl, or -COOH;
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R3a is hydrogen; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH(CH 3 )OH, or -CH2-COOH
  • R2 represents hydrogen or -Ctk-aryl-OH
  • Aaa is amino acid residue selected from Thr, or Pro.
  • the present invention provides compound of formula (I) represented by formula (IE), wherein
  • Ri represents -(CH 2 ) 2 -COOH, -CH 2 -aryl-OH, -CH(CH 3 )CH 2 CH 3 , or -CH 2 - heteroaryl;
  • R 2 represents -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -heteroaryl, or -CH(CH 3 )OH;
  • R4 is hydrogen;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr.
  • Ri in formula (IE), represents -(CH2)2-COOH, -Ctb-aryl-OH, or -CH2-heteroaryl. In another embodiment, Ri, in formula (IE), represents -(CH2)2-COOH, - CH2-(p-OH)phenyl, or -Ctk-imidazolyl.
  • Ri in formula (IE), represents -(CH2)2-COOH, or -CH2- imidazolyl.
  • R2, in formula (IE), represents -CH2-(p-OH)phenyl, -CH2- phenyl, -CH 2 -imidazolyl, or -CH(CH 3 )OH. In certain embodiments, R2, in formula (IE), represents -CH2-(p-OH)phenyl, -CH2- imidazolyl, or -CH(CH 3 )OH.
  • R2 in formula (IE) represents -CH2-(p-OH)phenyl, or - CH(CH 3 )OH.
  • Aaa in formula (IE), is amino acid residue selected from Phe, Thr or Tyr.
  • the present invention provides compound of formula (I) represented by formula (IE), wherein
  • Ri represents -(CH 2 )2-COOH, -CH 2 -(p-OH)phenyl, or -CH 2 -imidazolyl;
  • R2 represents -CH2-(p-OH)phenyl, -Ctb-phenyl, -Ctb-imidazolyl, or - CH(CH 3 )OH;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr.
  • the present invention provides compound of formula (I) represented by formula (IE), wherein
  • Ri is hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH(CH 3 )OH, -CH2-COOH, -(CH 2 ) 2 -COOH, - CH2-heteroaryl, -CH2-aryl or -CH2-aryl-OH;
  • R 2 is hydrogen, -CH 2 -aryl-OH, -CH 2 -aryl, -CH(CH 3 )OH, -CH2-COOH, - CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, or -CH2-SH;
  • Aaa is an amino acid residue selected from Phe, Gly, He, Tyr, Asp, Cys, Pro, His or Thr;
  • R4 is hydrogen or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • IE formula (IE)
  • the present invention provides compound of formula (I) represented by formula (IF), wherein
  • Ri represents -CH 2 -aryl-OH, -CH 2 -aryl, or -CH(CH 3 )OH;
  • R2 represents -SH, -aryl, or -COOH;
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R3a is hydrogen; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • Ri in formula (IF), represents -CH2-(p-OH)phenyl, -CH2- phenyl, or -CH(CH 3 )OH.
  • Ri in formula (IF), represents -CH2-(p-OH)phenyl, or -
  • R2 in formula (IF) represents -SH, -phenyl, or -COOH; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring.
  • R2 in formula (IF) represents -phenyl, or -COOH.
  • R3a in formula (IF), is hydrogen.
  • R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring.
  • R4 in formula (IF) is hydrogen
  • Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the present invention provides compound of formula (I) represented by formula (IF), wherein
  • Ri represents -CH 2 -(p-OH)phenyl, -CH 2 -phenyl, or -CH(CH 3 )OH;
  • R2 represents -SH, -phenyl, or -COOH
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R3a is hydrogen; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the present invention provides compound of formula (I) represented by formula (IF), wherein
  • Ri represents -CH 2 -(p-OH)phenyl, or -CH(CH 3 )OH;
  • R2 represents -phenyl, or -COOH
  • Aaa is amino acid residue selected from Pro, Asp, or Gly;
  • R3a is hydrogen; or R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring.
  • the present invention provides compound of formula (I) represented by formula (IG), wherein
  • Ri represents -CH(CH 3 )OH, or -CH2-COOH
  • R2 represents hydrogen or -CFb-aryl-OH
  • Aaa is amino acid residue selected from Thr, or Pro.
  • Ri in formula (IG), represents -CH(CH3)OH.
  • R2 in formula (IG) represents hydrogen or -CH 2 -(p- OH)phenyl.
  • R2 in formula (IG) represents -CH2-(p-OH)phenyl.
  • Aaa in formula (IG), is amino acid residue Pro.
  • the present invention provides compound of formula (I) represented by formula (IG), wherein
  • Ri represents -CH(CH 3 )OH, or -CH2-COOH
  • R2 represents hydrogen or -CH2-(p-OH)phenyl
  • Aaa is amino acid residue selected from Thr, or Pro.
  • the compound of formula (I) comprises compounds represented by formulae (IE), (IF), (IC), and (IG).
  • the present invention provides compound of formula (I)
  • Ri is hydrogen, -CH(CH 3 )OH, -CH2-COOH, -CH 2 -aryl-OH, -(CH 2 ) 2 -COOH, -CH 2 - aryl, -CH 2 -heteroaryl, or -CH(CH 3 )CH 2 CH 3 ;
  • R 2 is hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -COOH, - CH(CH )CH 2 CH , -CH 2 -heteroaryl, or -CH 2 -SH;
  • R 3 is hydrogen or -CO- Aaa
  • Aaa is an amino acid residue selected from Phe, Gly, He, Tyr, Asp, Cys, Pro, His or
  • R 3a represents hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is selected from:
  • the present invention provides a method for treating or delaying progression of diseases or disorders mediated by TIGIT in an individual comprising administering to the said individual a TIGIT modulator, wherein the said TIGIT modulator is compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • diseases or disorders mediated by TIGIT is cancer.
  • diseases or disorders mediated by TIGIT is small cell lung cancer, non-small cell lung cancer, breast cancer, gastric carcinoma, renal cell cancer, mesothelioma, melanoma, esophageal cancer, head and neck cancer, colorectal cancer, thyroid cancer, sarcoma, pancreatic cancer, prostate cancer, ovarian cancer.
  • diseases or disorders mediated by TIGIT is glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphomas, myelomas, bladder cancer, mycoses fungoids, merkel cell cancer, and other hematologic malignancies.
  • one, more than one or all amino acid residues are D amino acid residues.
  • compounds of the invention may be prodrugs of the compounds of formula (I), e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H ("D"), 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopicallyl abeled reagent.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or diluent.
  • the present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol and oils such as olive oil or injectable organic esters.
  • the aqueous solution is pyrogen-free or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of compound of present invention or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as an eye drop.
  • 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.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15
  • a pharmaceutically acceptable carrier including a physiologically acceptable agent
  • the preparation of pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system.
  • the pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin or as an eye drop).
  • routes of administration including, for example orally (for example, drenches as in aqueous or non-a
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the present invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules or as a solution or a suspension in an aqueous or non-aqueous liquid or as an oil-in-water or water-in-oil liquid emulsion or as an elixir or syrup or as pastilles (using an inert base, such as gelatin and glycerin or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • inert diluents commonly used in the art, such as
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth and mixtures thereof.
  • Formulations of the pharmaceutical compositions for rectal, vaginal or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash or an oral spray or an oral ointment.
  • compositions can be formulated for delivery via a catheter, stent, wire or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum or intestine.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound, i.e., compound described herein, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof.
  • Powders and sprays can contain, in addition to an active compound, i.e., compound described herein, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound, i.e., compound described herein, in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
  • Exemplary ophthalmic formulations are described in U.S. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Pat. No. 6,583,124, the contents of which are incorporated herein by reference.
  • liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids.
  • a preferred route of administration is local administration (e.g., topical administration, such as eye drops or administration via an implant).
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils, such as olive oil and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminummonostearate and gelatin.
  • antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid and the like.
  • isotonic agents such as sugars, sodium chloride and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminummonostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(ortho-esters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal-chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin
  • the TIGIT pathway has been implicated in a number of diseases and conditions and the pathway is known to regulate various immune responses. The studies have sought to activate immune response by targeting the TIGIT pathway, thereby providing a therapy for certain conditions, including cancers.
  • the present invention provides uses of a compound of the present invention for the preparation of a medicament, e.g., for the treatment of cancer.
  • the present invention provides methods for treating cancer, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compounds of the present invention to the subject in need thereof. In certain embodiments, the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (I) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (I A) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (IB) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (IC) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (ID) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (IE) to the subject in need thereof.
  • IE compound of formula
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (IF) to the subject in need thereof.
  • the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of compound of formula (IG) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (I) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IA) to the subject in need thereof. In certain embodiments, the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IB) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IC) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (ID) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IE) to the subject in need thereof.
  • IE compound of formula
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IF) to the subject in need thereof.
  • the present invention provides methods for treating cancer, wherein the method comprises administering a therapeutically effective amount of compound of formula (IG) to the subject in need thereof.
  • tumour cells include cells of a cancer such as, but are not limited to, melanoma, renal cancer, colorectal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, gastric carcinoma, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, thymic carcinoma, ovarian cancer, rectal cancer, cancer of the anal region, glioblastoma, stomach cancer, thyroid cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, cervical cancer, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, esophageal cancer, mesothelioma, 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, sar
  • the cancer is selected from non-small cell lung cancer, small cell lung cancer, renal cancer, colorectal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, melanoma, cancer of the head or neck, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphomas, myelomas, mycosis fungoides, and merkel cell cancer.
  • hematologic malignancy is selected from the group consisting of multiple myeloma, acute lymphocytic leukemia, mantle cell lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, precursor B -lymphoblastic leukemia/lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma (with or without villous lymphocytes), hairy cell leukemia, plasma cell myeloma/plasmacytoma, extranodal marginal zone B-cell lymphoma of the MALT type, nodal marginal zone B-cell lymphoma (with or without monocytoid B cells), Burkitt's lymphoma; precursor T-lymphoblastic lymphoma/leukemia, T-cell prolymphocytic leukemia, T-cell gran
  • T-cell lymphoma mycosis fungoides/Sezary syndrome, anaplastic large cell lymphoma (T/null cell, primary cutaneous type), anaplastic large cell lymphoma (T-/null-cell, primary systemic type), peripheral T-cell lymphoma not otherwise characterized, angioimmunoblastic, polycythemia vera (PV), myelodysplastic syndrome (MDS), indolent Non-Hodgkin's Lymphoma (iNHL) and aggressive Non-Hodgkin's Lymphoma (aNHL).
  • PV polycythemia vera
  • MDS myelodysplastic syndrome
  • iNHL indolent Non-Hodgkin's Lymphoma
  • aNHL aggressive Non-Hodgkin's Lymphoma
  • the present invention provides methods for treating cancer, wherein the cancer is selected from lung cancer, breast cancer, colon cancer, renal cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma and Hodgkin's lymphoma.
  • the invention provides uses of a compound of the present invention in inhibiting TIGIT pathway.
  • the compounds of present invention comprises compounds represented by formulae (I), (IA), (IB), (IC), (ID), (IE), (IF), and (IG).
  • the present invention provides a method for treating or delaying progression of diseases or disorders mediated by TIGIT in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof,
  • Ri represents hydrogen, -CH 2 -aryl, -(CH 2 ) 2 -CONH 2 or -CH 2 -SH;
  • R 2 represents hydrogen, -CH(CH 3 )CH 2 CH 3 , -CH 2 -SH, -CH 2 -COOH, or - (CH 2 ) 2 -COOH;
  • Aaa is amino acid residue selected from Ser, Tyr, He, or Gly;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH 2 -COOH, -CH(CH 3 )CH 2 CH 3 , -CH 2 -heteroaryl, -(CH 2 ) 2 - COOH, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 (CH)(CH 3 ) 2 , or -CH(CH 3 ) 2 ;
  • R 2 represents hydrogen, -CH(CH 3 )OH, -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 - heteroaryl, -(CH 2 ) 2 -CONH 2 , -CH 2 -OH, or -CH(CH 3 ) 2 ;
  • Aaa is amino acid residue selected from Tyr, Thr, Phe, Cys, Gly, His, or Gin; in formula (IC), one of Xi and X 2 is O and the other is N;
  • Ri represents hydrogen, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 -heteroaryl, - (CH 2 ) 2 -COOH, -CH(CH )CH 2 CH , -CH 2 -aryl, or -CH 2 -COOH;
  • R 2 represents hydrogen, -CH 2 -aryl, -CH 2 -aryl-OH, -CH(CH 3 )OH, -CH 2 - COOH, -CH 2 -SH, or -CH 2 -heteroaryl;
  • R 3a is hydrogen; or R 2 and R 3a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -aryl-OH, or -OH
  • R2 represents -aryl or -aryl-OH
  • R3a is hydrogen; R2 and R3a taken together with the atoms to which they are attached form a pyrrolidine ring; and
  • Aaa is amino acid residue selected from Asp, Pro, or Ser; in formula (IE),
  • Ri represents -(CH 2 ) 2 -COOH, -CH 2 -aryl-OH, -CH(CH 3 )CH 2 CH3, or -CH 2 - heteroaryl;
  • R 2 represents -CH 2 -aryl-OH, -CH 2 -aryl, -CH 2 -heteroaryl, or -CH(CH 3 )OH;
  • Aaa is amino acid residue selected from Phe, Cys, His, Thr or Tyr;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH 2 -aryl-OH, -CH 2 -aryl, or -CH(CH 3 )OH;
  • R2 represents -SH, -aryl, or -COOH
  • Aaa is amino acid residue selected from He, Pro, Asp, or Gly;
  • R3a is hydrogen; or R2 and R3 a taken together with the atoms to which they are attached form a pyrrolidine ring;
  • R4 is hydrogen; or Ri and R4 taken together with the atoms to which they are attached form pyrrolidine ring;
  • Ri represents -CH(CH 3 )OH, or -CH2-COOH
  • R2 represents hydrogen or -Ctb-aryl-OH
  • Aaa is amino acid residue selected from Thr, or Pro.
  • the present invention provides compound of formula (I) or a pharmaceutically acceptable salt thereof and a stereoisomer thereof for use as a medicament.
  • the present invention provides compound of formula (I) or a pharmaceutically acceptable salt thereof and a stereoisomer thereof for use in the treatment of cancer.
  • the present invention provides methods for treating or delaying progression of an immune -related disease in an individual, the method comprising administering to the individual an effective amount of the compound of formula (I).
  • the immune-related disease is associated with a T cell dysfunctional disorder.
  • T cell dysfunctional disorder is characterized by T cell exhaustion.
  • the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumour immunity.
  • the invention provides methods of modulating the immune response of a subject.
  • the method of modulating the immune response comprises a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject.
  • a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject comprises administering a therapeutically effective amount of a compound described herein.
  • a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject comprises administering a therapeutically effective amount of a compound that specifically binds TIGIT described herein.
  • a method of inducing an immune response in a subject comprises administering a compound described herein.
  • a method of activating an immune response in a subject comprises administering a compound described herein.
  • a method of promoting an immune response in a subject comprises administering a compound described herein.
  • a method of increasing an immune response in a subject comprises administering a compound described herein.
  • a method of enhancing an immune response in a subject comprises administering a compound described herein.
  • a method of prolonging an immune response in a subject comprises administering a compound described herein.
  • the immune response is to an antigenic stimulation.
  • the antigenic stimulation is a tumour or a tumour cell. In some embodiments, the antigenic stimulation is a pathogen. In some embodiments, the antigenic stimulation is a virus. In some embodiments, the antigenic stimulation is a virally-infected cell. In some embodiments, the immune response is against a tumour or cancer.
  • the invention provides methods of increasing the activity of immune cells.
  • a method of increasing the activity of immune cells comprises contacting the cells with an effective amount of a compound described herein.
  • the immune cells are T-cells, NK cells, monocytes, macrophages, myeloid-derived cells, antigen-presenting cells (APCs), and/or B-cells.
  • a method of increasing the activity of NK cells in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of increasing the activity of T-cells in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of increasing the activation of T-cells and/or NK cells in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, a method of increasing the T-cell response in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, a method of increasing the activity of Cytotoxic T Lymphocytes (CTLs) in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein. In some embodiments, a method of inhibiting the activity of Tregs in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • CTLs Cytotoxic T Lymphocytes
  • a method of inhibiting the suppressive activity of Tregs in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of inhibiting the activity of myeloid-derived suppressor cells (MDSCs) in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of inhibiting the suppressive activity of MDSCs in a subject comprises administering to the subject a therapeutically effective amount of a compound described herein.
  • the invention provides methods of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a compound that binds human TIGIT.
  • a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject comprises administering to the subject a therapeutically effective amount of a compound that inhibits or reduces TIGIT activity.
  • a method of inducing, activating, promoting, increasing, enhancing, or prolonging an immune response in a subject comprises administering to the subject a therapeutically effective amount of a compound that inhibits or reduces TIGIT signaling.
  • the immune response is against a tumour cell, a tumour, or cancer.
  • the immune response is against a viral infection, a viral antigen, or a virally-infected cell.
  • the invention provides methods of inhibiting growth of tumour cells or a tumour comprising contacting the tumour or tumour cell with an effective amount of a compound described herein.
  • a method of inhibiting growth of a tumour comprises contacting a tumour or tumour cell with an effective amount of a compound that binds human TIGIT.
  • the tumour is selected from the group consisting of colorectal tumour, colon tumour, ovarian tumour, pancreatic tumour, lung tumour, liver tumour, breast tumour, kidney tumour, prostate tumour, gastrointestinal tumour, melanoma, cervical tumour, bladder tumour, glioblastoma, and head and neck tumour.
  • the invention provides methods of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein.
  • a method of treating cancer in a subject comprises administering to the subject a therapeutically effective amount of an agent that binds TIGIT.
  • a method of treating cancer in a subject comprises administering to the subject a therapeutically effective amount of a compound that binds human TIGIT.
  • the cancer is selected from the group consisting of colorectal cancer, ovarian cancer, pancreatic cancer, lung cancer, liver cancer, breast cancer, kidney cancer, prostate cancer, gastrointestinal cancer, melanoma, cervical cancer, bladder cancer, glioblastoma, and head and neck cancer.
  • the invention provides methods of stimulating and/or inducing long-term anti-tumour immunity in a subject comprising administering to the subject a therapeutically effective amount of a compound described herein.
  • the compounds of the present invention may be used as single drugs (monotherapy) or conjointly with one or more other agents (conjoint therapy).
  • the compounds may be used by themselves or, preferably, in a pharmaceutical composition in which the compound is mixed with one or more pharmaceutically acceptable materials.
  • compositions may be administered by oral or inhalation routes or by parenteral administration route.
  • compositions can be administered orally, by intravenous infusion, topically, intraperitoneally, intravesically or intrathecally.
  • parenteral administration includes but not limited to intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes.
  • Suitable liquid compositions may be aqueous or non-aqueous, isotonic sterile injection solutions and may contain antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the intended recipient and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers and preservatives.
  • Oral administration, parenteral administration, subcutaneous administration and intravenous administration are preferred methods of administration.
  • the dosage of the compounds of the present invention varies depending on a patient's age, weight or symptoms, as well as the compound's potency or therapeutic efficacy, the dosing regimen and/or treatment time.
  • suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections.
  • the compounds of the invention may be administered in an amount of 0.5 mg or 1 mg up to 500 mg, 1 g or 2 g per dosage regimen.
  • the dosage may be administered once per week, once per three days, once per two days, once per day, twice per day, three times per day or more often.
  • the compound in certain adults can be continuously administered by intravenous administration for a period of time designated by a physician. Since the dosage is affected by various conditions, an amount less than or greater than the dosage ranges contemplated about may be implemented in certain cases. A physician can readily determine the appropriate dosage for a patient undergoing therapeutic treatment.
  • the compounds of the present invention may be administered in combination with one or more other drugs (1) to complement and/or enhance effect of the compound of the present invention, (2) to modulate pharmacodynamics, improve absorption or reduce dosage of the compound of the present invention and/or (3) to reduce or ameliorate the side effects of the compound of the present invention.
  • the phrase "conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds).
  • the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially.
  • the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours or a week of one another.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.
  • the respective compounds may be administered by the same or different route and the same or different method.
  • the dosage of the other drug can be a dosage that has been clinically used or may be a reduced dosage that is effective when administered in combination with a compound of the present invention.
  • the ratio of the compound of the present invention and the other drug can vary according to age and weight of a subject to be administered, administration method, administration time, disorder to be treated, symptom and combination thereof.
  • the other drug may be used in an amount of 0.01 to 100 parts by mass, based on 1 part by mass of the compound of the present invention.
  • the method comprises administering to the individual an effective amount of a compound that decreases or inhibits TIGIT expression and/or activity, an anti-cancer agent, and an anti-cancer therapy.
  • the anti-cancer therapy is selected from the group consisting of radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, adjuvant therapy, neoadjuvant therapy, and combinations thereof.
  • the anti-cancer agent is selected from the group consisting of a chemotherapeutic or growth inhibitory agent, a targeted therapeutic agent, a T cell expressing a chimeric antigen receptor, an antibody or antigen-binding fragment thereof, an antibody-drug conjugate, an angiogenesis inhibitor, an antineoplastic agent, a cancer vaccine, an adjuvant, and combinations thereof.
  • the chemotherapeutic or growth inhibitory agent is selected from the group consisting of an alkylating agent, an anthracycline, an anti-hormonal agent, an aromatase inhibitor, an anti-androgen, a protein kinase inhibitor, a lipid kinase inhibitor, an antisense oligonucleotide, a ribozyme, an antimetabolite, a topoisomerase inhibitor, a cytotoxic agent or antitumour antibiotic, a proteasome inhibitor, an anti-microtubule agent, an EGFR antagonist, a retinoid, a tyrosine kinase inhibitor, a histone deacetylase inhibitor, and combinations thereof.
  • the targeted therapeutic agent is selected from 5 the group consisting of a B-raf inhibitor, a MEK inhibitor, a K-ras inhibitor, a c-Met inhibitor, an Alk inhibitor, a phosphatidylinositol 3 -kinase inhibitor, an Akt inhibitor, an mTOR inhibitor, a dual phosphatidylinositol 3-kinase/mTOR inhibitor, and combinations thereof.
  • the T cell expressing a chimeric antigen receptor comprises a dominant-negative TGF beta receptor.
  • the antibody or antigenic) binding fragment thereof is selected from the group consisting of alemtuzumab, bevacizumab, cetuximab, panitumumab, rituximab, pertuzumab, trastuzumab, tositumomab, apolizumab, aselizumab, atlizumab, bapineuzumab, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, clivatuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, labetuzumab, lintuzumab, matuzumab, 15 mepolizumab, motavizumab, motovizumab, natalizumab, nimot
  • the compound that decreases or inhibits TIGIT expression and/or activity is administered intermittently.
  • the anti-cancer agent or anti-cancer therapy is administered continuously.
  • the anti-cancer agent or anti-cancer therapy is administered intermittently.
  • the compound that decreases or inhibits TIGIT expression and/or activity is administered before the anti-cancer agent or anti-cancer therapy. In certain embodiments, the compound that decreases or inhibits TIGIT expression and/or activity is administered simultaneous with the anti-cancer agent or anti-cancer therapy. In certain embodiments, the compound that decreases or inhibits TIGIT expression and/or activity is administered after the anti-cancer
  • the compound of the present invention in methods of the invention directed to the treatment of cancer, can be used with an existing chemotherapeutic conjointly using a single pharmaceutical composition or a combination of different pharmaceutical compositions.
  • the chemotherapeutic include an alkylation agent, nitrosourea agent, antimetabolite, anticancer antibiotics, vegetable-origin alkaloid, topoisomerase inhibitor, hormone drug, hormone antagonist, aromatase inhibitor, P- glycoprotein inhibitor, platinum complex derivative, other immunotherapeutic drugs and other anticancer drugs.
  • a compound of the invention can be administered conjointly with a cancer treatment adjunct, such as a leucopenia (neutropenia) treatment drug, thrombocytopenia treatment drug, antiemetic and cancer pain intervention drug, concomitantly or in a mixture form.
  • a cancer treatment adjunct such as a leucopenia (neutropenia) treatment drug, thrombocytopenia treatment drug, antiemetic and cancer pain intervention drug, concomitantly or in a mixture form.
  • Chemotherapeutic agents that may be conjointly administered with compounds of the invention include: aminoglutethimide, amsacrine, anastrozole, asparaginase, beg, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exeme
  • a compound of the invention may be conjointly administered with non-chemical methods of cancer treatment.
  • a compound of the invention may be conjointly administered with radiation therapy.
  • a compound of the invention may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy or with any combination of these.
  • different compounds of the invention may be conjointly administered with one or more other compounds of the invention.
  • such combinations may be conjointly administered with other therapeutic agents, such as other agents suitable for the treatment of cancer, immunological or neurological diseases, such as the agents identified above.
  • conjointly administering one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect.
  • conjointly administering one or more additional chemotherapeutics agents provides an additive effect.
  • the compound of the present invention can be used with one or more other immunomodulators and/or potentiating agents conjointly using a single pharmaceutical composition or a combination of different pharmaceutical compositions.
  • Suitable immunomodulators include various cytokines, vaccines and adjuvants. Examples of cytokines, vaccines and adjuvants that stimulate immune responses include GM-CSF, M- CSF, G-CSF, interferon-a, ⁇ or ⁇ , IL-1, IL-2, IL-3, IL-12, Poly(I:C) and C P G.
  • the potentiating agents includes cyclophosphamide and analogs of cyclophosphamide, anti-TGF and Imatinib (Gleevec), a mitosis inhibitor, such as paclitaxel, Sunitinib (Sutent) or other antiangiogenic agents, an aromatase inhibitor, such as letrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesis inhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists and IL-18 antagonists.
  • a mitosis inhibitor such as paclitaxel, Sunitinib (Sutent) or other antiangiogenic agents
  • an aromatase inhibitor such as letrozole
  • A2a adenosine receptor (A2AR) antagonist an angiogenesis inhibitor
  • anthracyclines oxaliplatin
  • doxorubicin TLR4 antagonists
  • alkyl refers to “alkyl” as well as the “alkyl” portions of “hydroxy alkyl,” “haloalkyl,” “-O-alkyl,” etc.
  • compound(s) of the present invention comprises compounds of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), or a pharmaceutical acceptable salt thereof and stereoisomers thereof.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline and the like.
  • the term 'aryl' includes phenyl.
  • heteroaryl includes substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, indole, 1,2,4-oxadiazole, 1,3,4- oxadiazole, 1,3,4-thiadiazole, benzimidazole, pyrimidine and the like.
  • a heteroaryl group may be substituted at one or more positions, as permitted by valence, with any optional substituents described herein.
  • the term 'heteroaryl' includes imidazolyl, and indolyl.
  • a therapeutic that "prevents" a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • treating includes prophylactic and/or therapeutic treatments.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • the phrase "delaying progression” refers to the procedures or applications that are intended to delay in time the development of a disease or symptoms of a disease (including delaying in time the appearance or occurrence of atleast one symptom of the particular disease).
  • prodrug is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formula (I)).
  • a common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal.
  • esters or carbonates e.g., esters or carbonates of alcohols or carboxylic acids
  • some or all of the compounds of formula (I) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester.
  • the term “comprise” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more additional (unspecified) features or components.
  • target activity refers to a target activity capable of being modulated by a selective modulator.
  • Certain exemplary target activities include, but are not limited to, binding affinity, signal transduction, enzymatic activity, tumor growth, inflammation or inflammation-related processes, and amelioration of one or more symptoms associated with a disease or condition.
  • Tumor immunity refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.
  • disease refers to a pathological condition in an organism resulting from cause or condition including, but not limited to, infections, acquired conditions, genetic conditions, and characterized by identifiable symptoms. Diseases and disorders also include those that are caused by the absence of a compound, such as TIGIT modulators.
  • patient or “subject” or “individual” to be treated includes humans and or non-human animals, including mammals.
  • Mammals include primates, such as humans, chimpanzees, gorillas and monkeys; domesticated animals, such as dogs, horses, cats, pigs, goats, cows; and rodents such as mice, rats, hamsters and gerbils.
  • kits refers to a packaged combination, optionally including reagents and other products and/or components for practicing methods using the elements of the combination.
  • kits containing a compounds provided herein and another item for a purpose including, but not limited to, administration, diagnosis, and assessment of a biological activity or property are provided. Kits optionally include instructions for use.
  • amino acid means a molecule containing both an amino group and a carboxyl group and includes its salts, esters, combinations of its various salts, as well as tautomeric forms. In solution, at neutral pH, amino and acid groups of an amino acid can exchange a proton to form a doubly ionized, through overall neutral, entity identified as a zwitterion.
  • the amino acids are ⁇ -, ⁇ -, ⁇ - or ⁇ -amino acids, including their stereoisomers and racemates.
  • L-amino acid denotes an a- amino acid having the levorotatory configuration around the a-carbon, that is, a carboxylic acid of general formula -CH(COOH)(NH2)-(side chain), having the L-configuration.
  • D-amino acid similarly denotes a carboxylic acid of general formula CH(COOH)(NH2)-(side chain), having the dextrorotatory-configuration around the a-carbon.
  • Side chains of L-amino acids can include naturally occurring and non-naturally occurring moieties.
  • Non-naturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains in, for example, amino acid analogs.
  • An "amino acid residue” as used herein, means a moiety sharing structural similarity to the parent amino acid.
  • An amino acid residue may be covalently bonded to another chemical moiety via the amino group of the residue or the carboxylate group of the residue (i.e., a hydrogen atom of -NH2 or -OH is replaced by a bond to another chemical moiety).
  • Amino acids include the twenty standard amino acids used by most biological organisms in protein synthesis.
  • Unnatural amino acid residues may be selected from, but are not limited to, alpha and alpha-disubstituted amino acids, N-alkyl amino acids and natural amino acids substituted with lower alkyl, aralkyl, hydroxyl, aryl, aryloxy, heteroarylalkyl or acyl.
  • lysine can be substituted to form an unnatural amino acid, e.g., at a carbon atom of its side chain or alternatively by mono- or dialkylation of its terminal N3 ⁇ 4 group (e.g., wherein the amino group of the lysine side chain is taken together with its substituents to form a heterocyclic ring such as piperidine or pyrrolidine).
  • the terminal amino group of the lysine sidechain can form a ring with the amino acid backbone, as in capreomycidine.
  • Further unnatural derivatives of lysine include homolysine and norlysine.
  • the sidechain of lysine can alternatively be substituted by a second amino group.
  • the alkyl portion of the lysine side chain can be incorporated into a carbocyclic ring structure to form a semirigidanalog, such as, e.g., cyclohexyl or cyclopentyl.
  • the unnatural amino acid can be a derivative of a natural amino acid having one or more double bonds.
  • the beta-methyl group in threonine, can be replaced with an ethyl, phenyl or other higher alkyl group.
  • the imidazole moiety in histidine, can be substituted.
  • the pyrrolidine moiety in proline, the pyrrolidine moiety can be substituted.
  • unnatural amino acids include homoserine and homologs of natural amino acids.
  • an unnatural amino acid can be alkylated (e.g., methylated) at the alpha position.
  • unnatural amino acids include alpha, beta- and beta,gamma- dehydroamino amino acid analogs.
  • amino acids include penicillamine and betamethoxyvaline.
  • unnatural amino acids include the amino acids wherein the side chain comprises amino, alkylamino, acylamino, -COO-alkyl, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl.
  • Modified N-terminal amino group and “modified C-terminal carboxyl group” mean that the amino group or carboxyl group is altered.
  • N-terminal modifications include, but are not limited to, are acetylated, formylated or guanylated N-termini.
  • Modification of the C-terminal carboxyl group is preferably with the general formula CORz (Rz replaces the hydroxyl group of the last amino acid); wherein R z is -NRbRc, alkoxy, amino or an imide; wherein Rb and R c are independently are hydrogen, (Ci-Ce)alkyl, aryl or heterocyclyl; wherein (Ci-Ce)alkyl, aryl and heterocyclyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, aryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl.
  • CORz Rz replaces the hydroxyl group of the last amino acid
  • R z is -NRbRc, alkoxy, amino or an imide
  • salts include, but are not limited to, amine salts, such as but not limited to chloroprocaine, choline, ⁇ , ⁇ '- dibenzyl-ethylenediamine, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzyl-phenethylamine, 1-para-chloro- benzyl-2-pyrrolidin-l'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxy-methyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to
  • Exemplary pharmaceutically acceptable salts include acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, bromide, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulf
  • this invention includes pharmaceutically acceptable salts of compounds of the invention and their use in the compositions and methods of the present invention.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, lH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization or adventitious to such solvent.
  • stereoisomers refers to any enantiomers, diastereoisomers or geometrical isomers, such as of the compounds of the invention.
  • compounds of the invention When compounds of the invention are chiral, they can exist in racemic or in optically active form. Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use compounds that are enriched in one of the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis. In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent.
  • suitable resolving agents are optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N- protected amino acids (for example N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids.
  • optically active resolving agent for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel.
  • compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee or even 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de or even 95% or greater de.
  • subject includes mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • HC1 Fmoc (9- Fluorenylmethyloxycarbonyl); g or gr (gram); HOBt (1 -Hydroxy benzotriazole); h or hr (Hours); HPLC (High-performance liquid chromatography); K2CO3 (Potassium carbonate); LCMS (Liquid chromatography mass spectroscopy); Liq.N3 ⁇ 4 (Liquid ammonia); mmol (Millimoles); M (Molar); ⁇ (Microlitre); mL (Millilitre); mg (Milligram); MS (ES) (Mass spectroscopy-electro spray); min (Minutes); Na (Sodium); NaHC(3 ⁇ 4 (Sodium bicarbonate); NH2NH2.H2O (Hydrazine hydrate); NMM (N-Methylmorpholine); Na2S04 (Sodium sulphate); NH2OH.HCI (Hydroxylamine hydrochloride); prep-HPLC
  • the elution conditions used are: Buffer A: 5 mmol ammonium acetate (adjust to pH-4 with Acetic Acid), Buffer B: Acetonitrile, Equilibration of the column with 90 % buffer B and elution by a gradient of 90 % to 40 % buffer B during 20 min.
  • LCMS was performed on API 2000 LC/MS/MS triple quad (Applied biosystems) with Agilent 1100 series HPLC with G1315 B DAD, using Mercury MS column or using Agilent LC/MSD VL single quad with Agilent 1100 series HPLC with G1315 B DAD, using Mercury MS column or using Shimadzu LCMS 2020 single quad with Prominence UFLC system with SPD-20 A DAD.
  • Step lb Synthesis of compound lc
  • Trifluroacetic anhydride (14.2 g, 67.77 mmol) was added to a solution of compound lb (7.6 g, 22.59 mmol) in pyridine (9.92 mL, 112.96 mmol) and stirred at room temperature for 2 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCCb solution followed by citric acid and brine solution. The separated organic layer was dried over Na2S04, filtered and evaporated under reduced pressure to yield 5.5 g of compound lc, which was used for next step directly.
  • the Compound 2a was synthesized as per the similar procedure described in steps la to lc of Example 1 (Compound 1) by using Boc-Tyr('Bu)-OH.
  • N,N'-Diisopropylcarbodiimide (1.89 g, 15.0 mmol) was slowly added to a stirred solution of compound 4c (2.8 g, 10.0 mmol), compound 4d (4.69 g, 8.0 mmol), HOBt (2.03 g, 15.0 mmol) in DMF (30 mL) at 0 °C.
  • the resulting reaction mixture was stirred at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The reaction was quenched with ice and the precipitate was filtered and dried under vacuum to obtain 7.6 g of Compound 4e.
  • Fmoc protecting group was deprotected by the addition of 20% piperidine in DCM (20.0 mL) to compound 4f (2.0 g, 2.4 mmol) at 0 °C.
  • the reaction was stirred at room temperature for 2 h.
  • the resulting solution was concentrated in vacuum to get a thick gummy residue.
  • the residue was washed with n-Hexane to remove Fmoc impurity.
  • the solid was partitioned between water/EtOAC (2 x 500 mL).
  • the organic layer was washed with NaHC03 and brine solution, dried over Na2SC1 ⁇ 4 and evaporated under reduced pressure to get solid. Finally the solid was washed with n-hexane and dried under high vacuum to yield 1.0 g of compound 4g.
  • LCMS 607.23 [M+H] + .
  • the acid sensitive protecting groups was removed by the addition of trifluoroacetic acid (5.0 mL) and catalytic amount of triisopropylsilane and 3,6-dioxa-18-octane-dithiol (DODt) to the compound 4g (0.45 g, 0.7 mmol) .
  • the reaction mixture was stirred at room temperature for 3 h.
  • the resulting solution was concentrated under nitrogen atmosphere and purified by preparative HPLC method to obtain compound 34 (Crude: 0.35 g).
  • LCMS: 265.1 [M+H] + ; HPLC: t R 10.92 min.
  • Example - 5 Rescue of the mouse CD8 + T-cell proliferation in the presence of recombinant mPVR
  • Spleen was collected from C57BL/6 male mice with 6-8 weeks of age. Splenocytes were isolated by slowly crushing the spleen between the sterile glass slides in RPMI + 10% FBSand passing it through the 70 ⁇ strainer. Cell suspension was centrifuged at 912xg for 10 minutes at room temperature and discarded the supernatant. Splenocytes were resuspended in RPMI + 10% FBS (Complete RPMI). Resuspendedsplenocytes were overlaid on Ficoll Histopaque-1083 in a 50ml Tarson tubes. Overlaid cells were centrifuged at 584xg for 30 minutes at room temperature without break. A clear buffy coat was carefully aspirated into sterile PBS.
  • Mouse CD8 + T cell were isolated by using EasySep Mouse CD8 + T Cell Isolation kit, as per manufacturers instruction.
  • 96-well cell culture plate was coated with Purified anti-mouse CD3, 1 ⁇ g/mL (50 ⁇ ) and Recombinant Mouse PVR Fc Chimera, O ⁇ g/mL (50ul/well) for 4 hours at 37° C. After 4 hours, the coated plate was washed with sterile PBS.
  • Mouse CD8 + T cells isolated from spleen were added at 0.2 million / well (180 ⁇ ) concentration into a 96-well cell culture plate. Test compound at various concentrations prepared in water or DMSO was added in respective wells (20 ⁇ ⁇ 11) so as to make the total volume 200 ⁇ 11. The plates were incubated in 37°C CO2 incubator for 3 days.
  • cytokine levels IL-2 or IFN- ⁇
  • ELISA cytokine levels
  • the extent of CD8 + T cell proliferation in presence or absence of test compound was measured by analysing the amount of IL-2 or IFN- ⁇ in the culture supernatants using mouse IL-2 or IFN- ⁇ ELISA kits as per manufacture instructions.
  • Recombinant mouse anti-TIGIT antibody was used as positive control to determine the increased proliferation of CD8 + T cells.
  • Percent CD8 + T cell proliferation was analysed by measuring IL-2 levels using IL-2 ELISA kit and percent rescue of CD8 + T cell by test compound was estimated after deduction of % background proliferation value and normalising to % stimulated CD8 + T cell proliferation by anti-TIGIT antibody (positive control) as 100% .
  • the results are given in below Table I.

Abstract

La présente invention concerne un composé de formule (I) utilisé en tant qu'agents thérapeutiques pour moduler la voie de signalisation de TIGIT. L'invention concerne également l'utilisation du composé de formule (I) ou d'un stéréoisomère de celui-ci ou d'un sel pharmaceutiquement acceptable de celui-ci pour le traitement de maladies ou de troubles médiés par TIGIT.
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WO2020095256A1 (fr) * 2018-11-08 2020-05-14 Aurigene Discovery Technologies Limited Association d'inhibiteurs de cd-47 à petites molécules avec d'autres agents anticancéreux
US20200405629A1 (en) * 2018-03-09 2020-12-31 Arcus Biosciences, Inc. Parenterally administered immune enhancing drugs
WO2021257124A1 (fr) 2020-06-18 2021-12-23 Genentech, Inc. Traitement avec des anticorps anti-tigit et des antagonistes de liaison à l'axe pd-1
EP3768259A4 (fr) * 2018-03-14 2022-04-06 Aurigene Discovery Technologies Limited Procédé de modulation de voies de signalisation de tigit et pd-1 à l'aide de composés 1,2,4-oxadiazole
WO2023010094A2 (fr) 2021-07-28 2023-02-02 Genentech, Inc. Méthodes et compositions pour le traitement du cancer
WO2023056403A1 (fr) 2021-09-30 2023-04-06 Genentech, Inc. Méthodes de traitement de cancers hématologiques au moyen d'anticorps anti-tigit, d'anticorps anti-cd38 et d'antagonistes de liaison à l'axe pd-1
WO2023240058A2 (fr) 2022-06-07 2023-12-14 Genentech, Inc. Méthodes pronostiques et thérapeutiques pour le cancer

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US20200405629A1 (en) * 2018-03-09 2020-12-31 Arcus Biosciences, Inc. Parenterally administered immune enhancing drugs
EP3768259A4 (fr) * 2018-03-14 2022-04-06 Aurigene Discovery Technologies Limited Procédé de modulation de voies de signalisation de tigit et pd-1 à l'aide de composés 1,2,4-oxadiazole
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WO2023240058A2 (fr) 2022-06-07 2023-12-14 Genentech, Inc. Méthodes pronostiques et thérapeutiques pour le cancer

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