WO2018047143A1

WO2018047143A1 - Vista signaling pathway inhibitory compounds useful as immunomodulators

Info

Publication number: WO2018047143A1
Application number: PCT/IB2017/055488
Authority: WO
Inventors: Pottayil Govindan Nair Sasikumar; Muralidhara Ramachandra; Seetharamaiah Setty Sudarshan Naremaddepalli
Original assignee: Aurigene Discovery Technologies Limited
Priority date: 2016-09-12
Filing date: 2017-09-12
Publication date: 2018-03-15

Abstract

The present invention relates to VISTA signaling pathway inhibitory compounds of formula (I) which are useful as immune modulators for the treatment of various disease conditions including various types of cancer. The invention also encompasses the use of the compound of formula (I) and pharmaceutically acceptable salts thereof for the treatment of diseases or disorders mediated by VISTA.

Description

VISTA SIGNALING PATHWAY INHIBITORY COMPOUNDS USEFUL AS

IMMUNOMODULATORS

This application claims the benefit of Indian provisional application number 201641031129, filed on September 12, 2016; the specifications of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to VISTA signaling pathway inhibitory compounds of formula (I) which are useful as immune modulators for the treatment of various disease conditions including various types of cancer.

The invention also relates to the process for preparation thereof, pharmaceutical compositions comprising them, and their use for the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder associated with modulation of VISTA signaling pathway.

BACKGROUND OF THE INVENTION

Immune cells and certain human cancers express a ligand on their cell surface referred to as Programmed Cell Death Ligand- 1 (PD-L1) which binds to its cognate receptor, Programmed Cell Death Protein- 1 (PD-1) present on the surface of the immune system's T cells. Cell surface interactions between tumor cells and T cells through PD-Ll/PD-1 molecules result in T cell inactivation and hence the inability to mount an effective immune response against the tumor. It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PDl antibodies or anti-PD-Ll antibodies can lead to T cell activation that result in the observed anti-tumor effects in the tumor tissues. Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the USFDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.

In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint regulators that are involved in the modulation of immune responses to tumor cells (Front Immunol. 2015; 6:418-433). One such regulator is V-domain Ig suppressor of T-cell activation or VISTA or PD-1H that shares structural similarity with PD-L1. VISTA is a -60 kDa typel Ig membrane protein with an unusual distribution of cysteine residues and is a member of the CD28 family of proteins. VISTA is a negative checkpoint regulator that directly suppresses T-cell activation. VISTA protein's structure comprises an extracellular IgV domain followed by a stalk region, a trans-membrane region, and an intracellular tail. The intracellular tail contains tyrosine residues that may bind protein kinase C. VISTA is predominantly expressed in hematopoietic tissues (e.g., spleen, lymph nodes, and peripheral blood) or tissues that contain a significant number of infiltrating leukocytes. VISTA acts as both a ligand for a T cell receptor on antigen presenting cells and as a co-inhibitory receptor during T-cell activation. Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors (PNAS. 2015; 112:6682- 6687).

VISTA when produced as an Ig fusion protein or over expressed on artificial antigen- presenting cells (APCs), inhibits both CD4 and CD8+T cell proliferation and cytokine production, VISTA expression on myeloid APCs is inhibitory for T cell responses in vitro, over expression on tumor cells impairs protective antitumor immunity in vaccinated mice, and antibody mediated VISTA blockade exacerbates the development of a T cell-mediated autoimmune disease (J. Exp. Med., 2011, 208(3) 577-592).

VISTA as a therapeutic target tends to be expressed on hematopoietic cells rather than non-hematopoietic cells. In mouse tumors, infiltrating leukocytes such as myeloid-derived suppressor cells, tumor-associated macrophages and dendritic cells, consistently express unusually high levels of VISTA, whereas non-hematopoietic tumor cells are negative. In contrast, PD-L1 is expressed in peripheral tissues and on tumor cells in areas of tumors with T- cell infiltration and expression of IFN-γ. Therefore, although the efficacy of PD-1 blockade seems to correlate somewhat with the expression of PD-L1 on the tumor, the consistent expression of VISTA on leukocytes within the tumors may allow VISTA blockade to be more effective across a broad range of solid cancers. It could therefore be envisioned that blockade of different inhibitory molecules may be tailored to the individual. In this context, VISTA will be among the most relevant targets for immune intervention (Cancer Res; 2014, 74(7); 1933-44). The present invention relates to compounds and therapeutic methods that modulate the VISTA signaling pathway. The present invention in particular relates to the use of peptides / peptidomimetics / new chemical entities specific to modulate an immune response mediated by VISTA signaling pathway to treat various cancers.

SUMMARY OF THE INVENTION

The present invention relates to VISTA signaling pathway inhibitory compounds of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compounds of the present invention are capable of modulating the VISTA signaling pathway.

In one aspect, the present invention provides compound of formula (I):

(I)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent or an amino acid residue Thr.

In another aspect, the present invention relates to a process for preparation of compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof. In a further aspect of the present invention, it relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof and processes for preparing such compositions.

In yet another aspect of the present invention, it provides a method of modulating the VISTA signaling pathway comprising administering to the subject, a therapeutically effective amount of a compound of formula (I).

In yet another aspect of the present invention, it provides use of compounds and derivatives of formula (I), pharmaceutically acceptable salts and stereoisomers thereof, which are capable of modulating VISTA signaling pathway. For example, these compounds can be used to treat one or more diseases characterized by aberrant or undesired activity of the VISTA signaling pathway.

BRIEF DESCRIPTION OF THE DRAWING

Figure-1 contains the graphs showing in vivo antitumor activity of compound-3 in CT26 metastasis model in male Balb/c mice. DETAILED DESCRIPTION OF THE INVENTION

The present invention provides VISTA signaling pathway inhibitory compounds of formula (I) and their derivatives as therapeutic agents useful for treatment of disorders via immunopotentiation comprising inhibition of immunosuppressive signals induced due to VISTA and therapies using them.

Each embodiment is provided by way of explanation of the invention, and not by way of limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. For instance, features illustrated or described as part of one embodiment can be used on another embodiment to yield a still further embodiment. Thus it is intended that the present invention covers such modifications and variations within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present invention are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only, and is not to be construed as limiting the broader aspects of the present invention.

In certain embodiments, the present invention provides compound of formula (I):

(I)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl;

Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent or an amino acid residue Thr;

with the proviso that the compound of formula (I) is not

In certain embodiments, the present invention provides compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂; R₂ is -CONH2;

R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl;

In certain embodiments of formula (I), Xi is O and X₂ is N. In certain such embodiments, the ring containing Xi and X₂ is 1,3,4-oxadiazole ring.

In certain embodiments of formula (I), Xi is N and X₂ is O. In certain such embodiments, the ring containing Xi and X₂ is 1,2,4-oxadiazole ring.

In certain embodiments, the present invention provides compound of formula (IA):

(IA) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is -aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

In certain embodiments of formula (IA), R₂ is-CONH₂.

In certain embodiments, the present invention provides compound of formula (IA), wherein, R₂ is -CONH₂; and R₃, R_3a, R4 and R4_a are hydrogen. In certain embodiments of formula (IA), R₃ is -CO-Aaai- Aaa₂.

In certain embodiments of formula (IA), Aaa₂ is absent or an amino acid residue Thr.

In certain embodiments, the present invention provides compound of formula (IA), wherein,

Ri is phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂;

R₃ is hydrogen, -CO-Aaai- Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are hydrogen; and

In certain embodiments, the present invention provides compound of formula (IB):

(IB) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai- Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides compound of formula (IB) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser, Glu and Leu.

In certain embodiments of formula (IB), R₂ is -CONH₂.

In certain embodiments, the present invention provides compound of formula (IB), wherein, R₂ is -CONH₂ and R_3a, R4 and R4_a are hydrogen.

In certain embodiments, the present invention provides compound of formula (IB), wherein,

Ri is phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂;

R₃ is hydrogen, -CO-Aaai or -Fmoc;

R_3a, R₄ and R_4a are hydrogen; and

Aaa is an amino acid residue Ser.

In certain embodiments, the present invention provides compound of formula (IC):

(IC) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein, is an optional bond;

one of Xi and X₂ is O or S and the other is N;

R₃ is hydrogen, alkyl, -CO-Aaai- Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent or an amino acid residue Thr; wherein the C-terminus is either free or amidated.

In certain embodiments, the present invention provides compound of formula (IC), wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

R₃ is hydrogen, alkyl, -CO-Aaai or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser and Glu; wherein the C-terminus is either free or amidated.

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

R is -CO-Aaai;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments of formula (IC), R₃ is -CO- Aaai.

In certain embodiments of formula (IC), R₃ is hydrogen, alkyl or -Fmoc;

In certain embodiments, the present invention provides compound of formula (ID):

(ID) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein, R₃, R_3a, R4 and R4_a are as defined in formula (IC).

In certain embodiments, the present invention provides compound of formula (ID), wherein,

R₃ is hydrogen or -CO-Aaai ;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides compound of formula (IE):

(IE) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein, R₃, R_3a, R4 and R4_a are as defined in formula (IC). In certain embodiments, the present invention provides compound of formula (IE), wherein,

R₃ is hydrogen, -CO-Aaai or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Aaai is Ser; wherein the C-terminus is free.

In certain embodiments, the present invention provides compound of formula (IF):

(IF) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

R₃ is -CO-Aaai- Aaa₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain preceding embodiments,— represents a bond.

In certain preceding embodiments, Ri is phenyl, phenyl-OH or -CH₂CH₂NHC(=NH)NH₂.

In certain preceding embodiments,

or CH₂CH₂NHC(=NH)NH₂. In certain preceding embodiments, R₂ is -CONH₂.

In certain preceding embodiments, R₃ is hydrogen or -CO-Aaai- Aaa₂.

In certain preceding embodiments, R₃ is hydrogen, -CO-Aaai- Aaa₂ or -Fmoc; wherein R_3a, R₄ and R_4a are hydrogen.

In certain preceding embodiments, R₃ is hydrogen.

In certain preceding embodiments, R₃ is -CO-Aaai-Aaa₂.

In certain preceding embodiments, R₃ is -Fmoc.

In certain preceding embodiments, R_3a is hydrogen.

In certain preceding embodiments, R₃ and R_3a are hydrogen.

In certain preceding embodiments, R4 and R4_a are hydrogen.

In certain preceding embodiments, R₃, R_3a, R4 and R4_a are hydrogen.

In certain preceding embodiments, Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent or an amino acid residue Thr.

In certain preceding embodiments, Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent.

In certain preceding embodiments, Aaai is an amino acid residue selected from Ser, Glu and Leu; wherein the amino acid Aaai has either free, amidated or esterified C-terminus.

In certain preceding embodiments, Aaai is an amino acid residue selected from Ser and

Leu.

In certain preceding embodiments, the Aaai has a free C-terminus.

In certain preceding embodiments, the Aaai has an amidated C-terminus.

In certain embodiments, Aaa₂ is absent or an amino acid residue Thr.

In certain embodiments, Aaa₂ is absent.

In certain embodiments, Aaa₂ is an amino acid residue Thr.

In certain preceding embodiments, the Aaa₂ has a free C-terminus. In certain other embodiments, the present invention provides compound of formula (Γ):

( )

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xiand X₂ is O or S and the other is N;

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl,-CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu.

In certain embodiments of formula (Γ), Xi is O and X₂ is N. In certain such embodiments, the ring containing Xi and X₂ is 1,3,4-oxadiazole ring.

In certain embodiments of formula (Γ), Xi is N and X₂ is O. In certain such embodiments, the ring containing Xi and X₂ is 1,2,4-oxadiazole ring.

In certain embodiments,— represents a bond;

In certain embodiments, Ri is phenyl, phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

In certain embodiments, R_3a, R₄ and R_4a are hydrogen.

In certain embodiments, one or more of R_3a, R4 and R_4a are alkyl;

In certain preceding embodiments, alkyl is methyl. In certain embodiments, R₂ is -CONH₂.

In certain embodiments, R₃ is hydrogen.

In certain embodiments, R₃ is -CO-(Aaa)i_₂, wherein Aaa is same as defined in compound of formula (Γ).

In certain embodiments, the present invention provides compound of formula (ΙΑ'):

(ΙΑ') or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu.

In certain embodiments, the present invention provides compound of formula (ΙΑ'), wherein, R₂ is -CONH₂; and R₃, R_3a, R₄ and R_4a are hydrogen.

In certain embodiments, the present invention provides compound of formula (ΙΑ'), wherein,

Ri is phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen,-CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R_4a are hydrogen; and Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu.

In certain embodiments, the present invention provides compound of formula (IB'):

(IB')

or a pharmaceutically acceptable salt or stereoisomer thereof; wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu.

In certain embodiments, the present invention provides compound of formula (IB'), wherein, R₂ is -CONH₂ and R4 is hydrogen.

In certain embodiments, Aaa is an amino acid residue selected from Ser, Thr, Glu or Leu.

In certain embodiments, the present invention provides compound of formula (IB'), wherein,

Ri is phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂;

R₃ is hydrogen,-CO-Aaa or -Fmoc;

R_3a, R₄ and R_4a are hydrogen; and Aaa is an amino acid residue selected from Ser or Thr.

In certain embodiments, the present invention provides a compound of formula (I) selected from:

rmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, the compound of formula (Γ) is not selected from,

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present invention.

The singular forms "a", "an" and "the" encompass plural references unless the context clearly indicates otherwise.

As used herein, the term "or" refers to "and/or", unless stated otherwise.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, "optionally substituted alkyl" refers to when the alkyl may be substituted as well as the event or circumstance where the alkyl is not substituted.

The term "substituted" refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone. Thus, a moiety that is optionally substituted may have one or more hydrogens of the indicated moiety be replaced by a substituent, each of which may be the same or different. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, and an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as "unsubstituted," references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

As used herein, the term "optionally substituted" refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, halogen, alkyl, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, cycloalkyl, cycloalkoxy, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, amino, aminoalkyl, alkylamino, dialkylamino, acyl, - C(0)₂H, -O(acyl), -NH(acyl), -N(alkyl)(acyl), cyano, phosphinate, phosphate, phosphonate, sulfonate, sulfonamido, sulfate, haloalkyl or haloalkoxy. Preferably, "optionally substituted" refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

As used herein, the term "alkyl" refers to saturated aliphatic groups, including, but not limited to, Ci-Cio straight-chain alkyl groups or C₃-C₁₀ branched-chain alkyl groups. Preferably, the "alkyl" group refers to Ci-C₆ straight-chain alkyl groups or C₃-C6 branched-chain alkyl groups. Most preferably, the "alkyl" group refers to C1-C₄ straight-chain alkyl groups or C3-C₄ branched-chain alkyl groups. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, sec -butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1- hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The "alkyl" group may be optionally substituted.

The term "aryl" as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term "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. Optionally substituted aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

In certain embodiments, 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. In a further embodiment, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

In certain embodiments, 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. For example, 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 ²H ("D"), ³H, ⁿC, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵0, ¹⁷0, ¹⁸0, ³⁵S, ¹⁸F, ³⁶C1, ¹²³I and ¹²⁵I. 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-isotopically labeled reagent.

Pharmaceutical Compositions

In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound as disclosed herein, optionally admixed with a pharmaceutically acceptable carrier or excipient (eg. diluent).

In other words, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and at least one compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof

The present invention also provides methods for formulating the disclosed compounds for pharmaceutical administration.

The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human or a non-human mammal. When administered to an animal, such as a human, 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 are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent 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. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein 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. Some examples of 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) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. 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 (preparation) 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). The compound may also be formulated for inhalation. In certain embodiments, 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 invention, with the carrier and, optionally, one or more accessory ingredients. In general, 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.

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), 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, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical 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, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, 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. They 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. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated 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. In addition to the active ingredient, 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.

Besides inert diluents, the oral compositions can also include 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, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, 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.

Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash or an oral spray or an oral ointment.

Alternatively or additionally, 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, 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, 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. Such dosage forms can be made by dissolving or dispersing the active compound 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. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

The phrases "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.

Pharmaceutical 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.

Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions of the invention 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. 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. 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 aluminum monostearate and gelatin.

In some cases, 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(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

For use in the methods of this invention, 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. For example, 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. By "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).

In general, 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. If desired, 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. In certain embodiments of the present invention, 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, emulsifiers and lubricants, 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.

Examples of pharmaceutically acceptable antioxidants 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, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Methods of Treatment

V-domain immunoglobulin suppressor of T-cell activation (VISTA) functions as an immune checkpoint protein that suppresses T-cell activation. VISTA is primarily expressed on hematopoietic cells.

In certain embodiments, the present invention provides a method of treatment of diseases or disorder by modulating the VISTA signaling pathway, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain embodiments, the present invention provides a method of treatment of diseases or disorder by modulating an immune response mediated by VISTA signaling pathway, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof. In certain embodiments, the disease or disorder mediated by VISTA signaling pathway is cancer.

In certain embodiments, the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

In certain embodiments, 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.

In certain embodiments, the hematologic malignancies 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 granular lymphocytic leukemia, aggressive NK cell leukemia, nasal-type extranodal NK/T-cell lymphoma, hepatosplenic .gamma.-.delta. 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), myelodysplasia syndrome (MDS), indolent Non-Hodgkin's Lymphoma (iNHL) and aggressive Non-Hodgkin's Lymphoma (aNHL).

In certain embodiments, the disease or disorder mediated by VISTA is an infectious disease.

In certain embodiments, the infectious disease mediated by VISTA is a bacterial, viral or a fungal infection.

In certain embodiments, the infectious diseases include but are not limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, the pathogenic infection by the virus Hepatitis (A, B, & C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, E. coli, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.

In certain other embodiments, the present invention provides a method of using at least one compound of formula (I) to inhibit the VISTA signaling pathway.

In certain other embodiments, the present invention provides a method of using at least one compound of formula (I) to inhibit VISTA signaling pathway associated suppression of T cell activation or proliferation.

Still yet other embodiments of the present invention provide a method of treatment of cancer by modulation of the VISTA signaling pathway, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

Still yet other embodiments of the present invention provide a method of treatment of infection by modulation of the VISTA signaling pathway, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (II),

(II)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N; Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu; wherein Aaa has either a free, an amidated or an esterified C-terminus.

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, is an optional bond; one of Xi and X₂ is O or S and the other is N; Ri is -CONH₂, phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂; R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu; wherein Aaa has either a free, an amidated or an esterified C-terminus. In certain embodiments, the present invention provides a method of modulating the

VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, is an optional bond; one of Xi and X₂ is O or S and the other is N; Ri is -CONH2, phenyl or -phenyl-OH; R₂ is -CONH2 or -CH2CONH2;

R₃ is -CO-(Aaa);

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr and Glu; wherein Aaa has either a free, an amidated or an esterified C-terminus.

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (IIA),

(IIA) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH2 or -CH2CONH2;

R₃ is hydrogen, alkyl, -CO-(Aaa)i_2 or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Aaa is an amino acid residue selected from Ser, Thr, Glu and Leu; wherein Aaa has either a free, an amidated or an esterified C-terminus.

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is -CONH2, phenyl, -phenyl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (IIA), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, Ri is -CONH₂, phenyl or -phenyl-OH;

R₂ is -CONH₂ or -CH₂CONH₂; R₃ is hydrogen, -CO-(Aaa) or -Fmoc; R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Ri is -CONH₂, phenyl or -phenyl-OH; R₂ is -CONH2 or -CH2CONH2;

R₃ is -CO-(Aaa);

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (IIB),

(IIB) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

Ri is -CONH₂, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (IIB), or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, -CO-(Aaa) or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the compound of formula (IIA) is a compound of formula (II).

In certain embodiments, the compound of formula (IIB) is a compound of formula (II).

In certain embodiments, the present invention provides the method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject a compound of formula (II) selected from:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

In certain embodiments, the present invention provides use of compound in the manufacture of medicament for treating diseases or disorder mediated by VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (II).

In certain embodiments, the present invention provides a compound of formula (II) for use as a medicament for treating diseases or disorder mediated by VISTA signaling pathway.

In certain embodiments, the present invention provides a compound for use in the treatment of diseases or disorders mediated by VISTA in a subject, wherein the compound is represented by compound of formula (II),

(Π) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, is an optional bond; one of Xi and X₂ is O or S and the other is N;

Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides use of compound in the manufacture of a medicament for treating diseases or disorders mediated by VISTA signaling pathway in a subject, wherein the com ound is represented by compound of formula (II),

(II) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, is an optional bond; one of Xi and X₂ is O or S and the other is N;

Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides a method of modulating an immune response mediated by VISTA activity in a cell, comprising contacting the cell with a compound of formula (II).

In certain other embodiments, the present invention provides a method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (I),

(I)

or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, is an optional bond; one of Xi and X₂ is O or S and the other is N;

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

-CONH₂ or -CH₂CONH₂ R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

In certain embodiments, the present invention provides a method of modulating an immune response mediated by VISTA activity in a cell, comprising contacting the cell with a compound of formula (I).

In certain embodiments, the present invention provides a method of treating diseases or disorders mediated by the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (I).

V-Set and Immunoglobulin domain containing 8 (VSIG-8) is identified as a receptor of B7 family member VISTA (PD-1H). VSIG-8 receptor has been used in identifying the antagonists which may suppress VISTA's suppressive effects on T cell immunity, and more particularly used in the treatment of cancer or infectious disease (WO2016090347).

In certain embodiments, the present invention provides a method of modulating an immune response by inhibiting the interaction of VISTA and its receptor VSIG8.

In certain other embodiments, the present invention provides a method of treatment of diseases or disorder by modulating the effects of interaction of VISTA and VSIG8, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain other embodiments, the present invention provides a method of modulating an immune response mediated by the interaction of VISTA and VSIG8, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain other embodiments, the present invention provides a method of using at least one compound of formula (I) to inhibit the interaction of VISTA and VSIG8. In certain other embodiments, the present invention provides a method of using at least one compound of formula (I) to inhibit VISTA and VSIG8 complex associated suppression of T cell activation or proliferation.

In certain preceding embodiments, the present invention provides a method of treating cancer comprising modulating an immune response mediated by the interaction of VISTA and VSIG8, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain preceding embodiments, the present invention provides a method of treating an infectious disease comprising modulating an immune response mediated by the interaction of VISTA and VSIG8, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

V-Set and Immunoglobulin domain containing 3 (VSIG-3 or IGSF11) is a ligand of B7 family member VISTA (or PD-1H) and inhibits human T cell functions through a novel VSIG- 3/VISTA pathway ( . Immunol, May 1, 2017, 198 (1 Supplement) 154.1).

In certain embodiments, the present invention provides a method of modulating the co- inhibitory pathway of VISTA and its ligand VSIG3.

In certain other embodiments, the present invention provides a method of modulating an immune response mediated by the interaction of VISTA and its ligand VSIG3, wherein the method comprises administration of a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

In certain other embodiments, the present invention provides a method of using at least one compound of formula (I) to inhibit the interaction of VISTA and its ligand VSIG3.

VISTA functions as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of cells including apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells (Science 31 July 2015: Vol. 349, Issue 6247, 1261669).

In certain embodiments, the invention provides compounds of formula (I), for use in the manufacture of a medicament for modulating the VISTA signaling pathway. In certain embodiments, the invention provides compounds of formula (I), for use in modulating the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (I) in the manufacture of a medicament for inhibiting the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (I) in inhibiting the VISTA signaling pathway.

In certain embodiments, the invention provides a compound of formula (I) for use in modulating the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (I) in the manufacture of a medicament for the treatment of cancer.

In certain embodiments, the invention provides use of a compound of formula (I), in the manufacture of a medicament for the treatment of cancer mediated by VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (I) in the manufacture of a medicament for the treatment of an infectious disease.

In certain embodiments, the invention provides use of a compound of formula (I), in the manufacture of a medicament for the treatment of an infectious disease mediated by VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (I) in the manufacture of a medicament for the treatment of a bacterial, a viral or a fungal infection.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) for treating cancer.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) for treating a bacterial, a viral or a fungal infection.

In certain embodiments, the invention provides compounds of formula (II), for use in the manufacture of a medicament for modulating the VISTA signaling pathway. In certain embodiments, the invention provides compounds of formula (II), for use in modulating the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (II) in the manufacture of a medicament for inhibiting the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (II) in inhibiting the VISTA signaling pathway.

In certain embodiments, the invention provides a compound of formula (II) for use in modulating the VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (II) in the manufacture of a medicament for the treatment of cancer.

In certain embodiments, the invention provides use of a compound of formula (II), in the manufacture of a medicament for the treatment of cancer mediated by VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (II) in the manufacture of a medicament for the treatment of an infectious disease.

In certain embodiments, the invention provides use of a compound of formula (II), in the manufacture of a medicament for the treatment of an infectious disease mediated by VISTA signaling pathway.

In certain embodiments, the invention provides use of a compound of formula (II) in the manufacture of a medicament for the treatment of a bacterial, a viral or a fungal infection.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (II) for treating cancer.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (II) for treating a bacterial, a viral or a fungal infection.

In certain embodiments, the present invention provides use of a compound of the present invention for the preparation of a medicament, e.g., for the treatment of cancer. In certain embodiments, 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.

In certain embodiments, the present invention provides methods for inhibiting growth of tumour cells and/or metastasis by administering a therapeutically effective amount of a compound of the present invention to the subject in need thereof.

Representative tumour cells include cells of a cancer such as but not limited to melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) and/or (II), for use in treating cancer.

In certain embodiments, the invention provides a method comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) and/or (II), for treating cancer wherein the subject is a mammal, e.g., a human. In certain preceding embodiments, the invention provides a method, further comprising conjointly administering to the subject a second chemotherapeutic agent.

Conjoint therapy can be employed to treat any diseases discussed herein. For example, in the methods of the invention directed to the treatment of cancer, the compound of the present invention can be used with an existing chemotherapeutic conjointly using a single pharmaceutical composition or a combination of different pharmaceutical compositions. Examples of 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. Further, 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. 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, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ironotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine. In certain embodiments, a compound of the invention may be conjointly administered with non-chemical methods of cancer treatment. In a further embodiment, a compound of the invention may be conjointly administered with radiation therapy. In a further embodiment, 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.

In certain embodiments, different compounds of the invention may be conjointly administered with one or more other compounds of the invention. Moreover, 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. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect. In certain embodiments, conjointly administering one or more additional chemotherapeutics agents provides an additive effect.

Exemplary agents that can be conjointly administered with compounds disclosed herein include a therapeutic cancer vaccine or adoptive T cell therapy. In certain embodiments, the therapeutic cancer vaccine is a dendritic cell vaccine. The dendritic cell vaccine can be composed of autologous dendritic cells and/or allogeneic dendritic cells. In certain embodiments, the autologous or allogeneic dendritic cells are loaded with cancer antigens prior to administration to the subject. In certain embodiments, the autologous or allogeneic dendritic cells are loaded with cancer antigens through direct administration to the tumor. In certain embodiments, the adoptive T cell therapy comprises autologous and/or allogenic T -cells. In certain embodiments, the autologous and/or allogenic T -cells are targeted against tumor antigens.

In certain embodments, non-limiting examples of cancer vaccines include tumor cell vaccines, antigen vaccines, dendritic cell vaccines, DNA vaccines, and vector based vaccines. Antigen vaccines boost the immune system by using one or more antigens, such as peptides. Antigen vaccines may be specific for a certain type of cancer because each tumor type may be identified by specific antigen profiles. Dendritic cell vaccines are often autologous vaccines, and must often be made individually for each subject. Non-limiting examples of dendritic vaccines are Sipuleucel-T and DCvax. For preparing DNA vaccines, vectors can be engineered to contain specific DNAs that can be injected into a subject which leads to the DNA being taken up by cells. Once the cells take up the DNA, the DNA will program the cells to make specific antigens, which can then provoke the desired immune response.

Pancreatic cancer

Exemplary agents that that can be used conjointly with compounds disclosed herein for the treatment of pancreatic cancer include, but are not limited to, TAXOL, an albumin-stabilized nanoparticle paclitaxel formulation (e.g., ABRAXANE) or a liposomal paclitaxel formulation); gemcitabine (e.g., gemcitabine alone or in combination with AXP107-11); other chemotherapeutic agents such as oxaliplatin, 5-fluorouracil, capecitabine, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin, docetaxel (e.g., TAXOTERE), mitomycin C, ifosfamide; interferon; tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, panitumumab, cetuximab, nimotuzumab); HER2/neu receptor inhibitor (e.g., trastuzumab); dual kinase inhibitor (e.g., bosutinib, saracatinib, lapatinib, vandetanib); multikinase inhibitor (e.g., sorafenib, sunitinib, XL184, pazopanib); VEGF inhibitor (e.g., bevacizumab, AV-951, brivanib); radioimmunotherapy (e.g., XR303); cancer vaccine (e.g., GVAX, survivin peptide); COX-2 inhibitor (e.g., celecoxib); IGF-1 receptor inhibitor (e.g., AMG 479, MK-0646); mTOR inhibitor (e.g., everolimus, temsirolimus); IL-6 inhibitor (e.g., CNTO 328); cyclin-dependent kinase inhibitor (e.g., P276-00, UCN-01); Altered Energy Metabolism-Directed (AEMD) compound (e.g., CPI-613); HDAC inhibitor (e.g., vorinostat); TRAIL receptor 2 (TR-2) agonist (e.g., conatumumab); MEK inhibitor (e.g., AS703026, selumetinib, GSK1120212); Raf/MEK dual kinase inhibitor (e.g., R05126766); Notch signaling inhibitor (e.g., MK0752); monoclonal antibody- antibody fusion protein (e.g., L19IL2); curcumin; HSP90 inhibitor (e.g., tanespimycin, STA-9090); riL-2; denileukin diftitox; topoisomerase 1 inhibitor (e.g., irinotecan, PEP02); statin (e.g., simvastatin); Factor Vila inhibitor (e.g., PCI-27483); AKT inhibitor (e.g., RX-0201); hypoxia-activated prodrug (e.g., TH-302); metformin hydrochloride, gamma-secretase inhibitor (e.g., R04929097); ribonucleotide reductase inhibitor (e.g., 3-AP); immunotoxin (e.g., HuC242- DM4); PARP inhibitor (e.g., KU-0059436, veliparib); CTLA-4 inhbitor (e.g., CP-675,206, ipilimumab); AdVtk therapy; proteasome inhibitor (e.g., bortezomib (Velcade), NPI-0052); thiazolidinedione (e.g., pioglitazone); NPC-1C; Aurora kinase inhibitor (e.g., R763/AS703569), CTGF inhibitor (e.g., FG-3019); siG 12D LODER; and radiation therapy (e.g., tomotherapy, stereotactic radiation, proton therapy), surgery, and a combination thereof.

Small cell lung cancer

Exemplary agents that that can be used conjointly with compounds disclosed herein to treat small cell lung cancer include, but are not limited to, etoposide, carboplatin, cisplatin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012, FR901228, flavopiridol); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (e.g., sorafenib, sunitinib); VEGF inhibitor (e.g., bevacizumab, vandetanib); cancer vaccine (e.g., GVAX); Bcl-2 inhibitor (e.g., oblimersen sodium, ABT-263); proteasome inhibitor (e.g., bortezomib (Velcade), NPI-0052), paclitaxel or a paclitaxel agent; docetaxel; IGF-1 receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (e.g., MLN8237); radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g., tanespimycin, STA-9090); mTOR inhibitor (e.g., everolimus); Ep-CAM-/CD3-bispecific antibody (e.g., MT110); CK-2 inhibitor (e.g., CX-4945); HDAC inhibitor (e.g., belinostat); SMO antagonist (e.g., BMS833923); peptide cancer vaccine, and radiation therapy (e.g., intensity-modulated radiation therapy (IMRT), hypofractionated radiotherapy, hypoxia-guided radiotherapy), surgery, and combinations thereof.

Non-small cell lung cancer

Exemplary agents that that can be used conjointly with compounds disclosed herein to treat non-small cell lung cancer include, but are not limited to, vinorelbine, cisplatin, docetaxel, pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafurgimeracil- oteracil potassium, sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804, nimotuzumab, R05083945), MET inhibitor (e.g., PF-02341066, ARQ 197), PI3K kinase inhibitor (e.g., XL147, GDC-0941), Raf/MEK dual kinase inhibitor (e.g., R05126766), PDK/mTOR dual kinase inhibitor (e.g., XL765), SRC inhibitor (e.g., dasatinib), dual inhibitor (e.g., BIBW 2992, GSK1363089, ZD6474, AZD0530, AG-013736, lapatinib, MEHD7945A, linifanib), multikinase inhibitor (e.g., sorafenib, sunitinib, pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor (e.g., endostar, endostatin, bevacizumab, cediranib, BIBF 1120, axitinib, tivozanib, AZD2171), cancer vaccine (e.g., BLP25 liposome vaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein), Bcl-2 inhibitor (e.g., oblimersen, sodium), proteasome inhibitor (e.g., bortezomib, carfilzomib, NPI-0052, ixazomid), paclitaxel or a paclitaxel agent, docetaxel, IGF-1 receptor inhibitor (e.g., cixutumumab, MK-0646, OSI906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor (e.g., tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (e.g., everolimus, temsirolimus, ridaforolimus), Ep-CAM-/CD3- bispecific antibody (e.g., MT110), CK-2 inhibitor (e.g., CX-4945), HDAC inhibitor (e.g., MS 275, LBH589, vorinostat, valproic acid, FR901228), DHFR inhibitor (e.g., pralatrexate), retinoid (e.g., bexarotene, tretinoin), antibody-drug conjugate (e.g., SGN-15), bisphosphonate (e.g., zoledronic acid), cancer vaccine (e.g., belagenpumatucel-L), low molecular weight heparin (LMWH) (e.g., tinzaparin, enoxaparin), GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase inhibitor (e.g., amrubicin, etoposide, karenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (e.g., MM-121, U3-1287), survivin inhibitor (e.g., YM155, LY2181308), eribulin mesylate, COX-2 inhibitor (e.g., celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist (e.g., CS-1008), CNGRC peptide-TNF alpha conjugate, dichloroacetate (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550, PPAR-gamma agonist (e.g., CS-7017), gamma-secretase inhibitor (e.g., R04929097), epigenetic therapy (e.g., 5- azacitidine), nitroglycerin, MEK inhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g., UCN-01), cholesterol-Fus 1 , antitubulin agent (e.g., E7389), farnesyl-OHtransferase inhibitor (e.g., lonafarnib), immunotoxin (e.g., BB-10901, SSI (dsFv) PE38), fondaparinux, vascular-disrupting agent (e.g., A VE8062), PD-L1 inhibitor (e.g., MDX-1105, MDX-1106), beta-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (e.g., GSKl 120212), epothilone analog (e.g., ixabepilone), kinesin-spindle inhibitor (e.g., 4SC-205), telomere targeting agent (e.g., KML-001), P70 pathway inhibitor (e.g., LY2584702), AKT inhibitor (e.g., MK-2206), angiogenesis inhibitor (e.g., lenalidomide), Notch signaling inhibitor (e.g., OMP- 21M18), radiation therapy, surgery, and combinations thereof.

Ovarian cancer

Exemplary agents that that can be used conjointly with compounds disclosed herein to treat ovarian cancer include, but are not limited to, a chemotherapeutic agent (e.g., paclitaxel or a paclitaxel agent; docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin; irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan, pemetrexed disodium, SJG- 136, cyclophosphamide, etoposide, decitabine); ghrelin antagonist (e.g., AEZS-130), immunotherapy (e.g., APC8024, oregovomab, OPT-821), tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib), dual inhibitor (e.g., E7080), multikinase inhibitor (e.g., AZD0530, JI- 101, sorafenib, sunitinib, pazopanib), ON 01910.Na), VEGF inhibitor (e.g., bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFR inhibitor (e.g., IMC-303), paclitaxel, topoisomerase inhibitor (e.g., karenitecin, Irinotecan), HDAC inhibitor (e.g., valproate, vorinostat), folate receptor inhibitor (e.g., farletuzumab), angiopoietin inhibitor (e.g., AMG 386), epothilone analog (e.g., ixabepilone ), proteasome inhibitor (e.g., carfilzomib ), IGF-1 receptor inhibitor (e.g., OSI 906, AMG 479), PARP inhibitor (e.g., veliparib, AGO 14699, iniparib, MK-4827), Aurora kinase inhibitor (e.g., MLN8237, ENMD-2076), angiogenesis inhibitor (e.g., lenalidomide), DHFR inhibitor (e.g., pralatrexate ), radioimmunotherapeutic agnet (e.g., Hu3S 193 ), statin (e.g., lovastatin), topoisomerase 1 inhibitor (e.g., NKTR -1 02), cancer vaccine (e.g., p53 synthetic long peptides vaccine, autologous OC-DC vaccine), mTOR inhibitor (e.g., temsirolimus, everolimus), BCR/ABL inhibitor (e.g., imatinib), ET-A receptor antagonist (e.g., ZD4054), TRAIL receptor 2 (TR-2) agonist (e.g., CS-1008), HGF/SF inhibitor (e.g., AMG 102), EGEN- 001, Polo-like kinase 1 inhibitor (e.g., BI 6727), gamma-secretase inhibitor (e.g., R04929097), Wee-1 inhibitor (e.g., MK-1775), antitubulin agent (e.g., vinorelbine, E7389), immunotoxin (e.g., denileukin diftitox), SB-485232, vascular-disrupting agent (e.g., A VE8062), integrin inhibitor (e.g., EMD 525797), kinesin-spindle inhibitor (e.g., 4SC-205), revlimid, HER2 inhibitor (e.g., MGAH22), ErrB3 inhibitor (e.g., MM- 121), radiation therapy; and combinations thereof.

Myeloma

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat myeloma include, but are not limited to, thalidomide analogs, (e.g., lenalidomide), HSCT (Cook, R. (2008) J Manag Care Pharm. 14(7 Suppl): 19-25), an anti-TIM-3 antibody (Hallett, WHD et al. (2011) J of American Society for Blood and Marrow Transplantation 17 (8): 1133-145), tumor antigen-pulsed dendritic cells, fusions (e.g., electrofusions) of tumor cells and dendritic cells, or vaccination with immunoglobulin idiotype produced by malignant plasma cells (reviewed in Yi, Q. (2009) Cancer J. 15(6):502-10). Renal cell carcinoma

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat renal cell carcinoma include, but are not limited to, interleukin-2 or interferon-a, a targeted agent (e.g., a VEGF inhibitor such as a monoclonal antibody to VEGF, e.g., bevacizumab (Rini, B.I. et al. (2010) J. Clin. Oncol. 28(13):2137-2143)); a VEGF tyrosine kinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib (reviewed in Pal S.K. et al. (2014) Clin. Advances in Hematology & Oncology 12(2):90-99)); an RNAi inhibitor), or an inhibitor of a downstream mediator of VEGF signaling, e.g., an inhibitor of the mammalian target of rapamycin (mTOR), e.g., everolimus and temsirolimus (Hudes, G. et al. (2007) N. Engl. J. Med. 356(22):2271-2281, Motzer, RJ. et al. (2008) Lancet 372: 449-456).

Chronic myelogenous leukemia

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat chronic myelogenous leukemia (CML) include, but are not limited to, a chemotherapeutic (e.g., cytarabine, hydroxyurea, clofarabine, melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin, pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine, topotecan), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), a dual inhibitor (e.g., dasatinib, bosutinib), multikinase inhibitor (e.g., DCC-2036, ponatinib, sorafenib, sunitinib, RGB-286638)), interferon alfa, steroids, apoptotic agent (e.g., omacetaxine mepesuccinat), immunotherapy (e.g., allogeneic CD4+ memory Thl-like T cells/microparticle -bound anti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK), AHN-12), CD52 targeting agent (e.g., alemtuzumab), HSP90 inhibitor (e.g., tanespimycin, STA- 9090, AUY922, XL888), mTOR inhibitor (e.g., everolimus), SMO antagonist (e.g., BMS 833923), ribonucleotide reductase inhibitor (e.g., 3-AP), JAK-2 inhibitor (e.g., INCB018424), hydroxychloroquine, retinoid (e.g., fenretinide), cyclin-dependent kinase inhibitor (e.g., UCN- 01), HDAC inhibitor (e.g., belinostat, vorinostat, JNJ-26481585), PARP inhibitor (e.g., veliparib), MDM2 antagonist (e.g., R05045337), Aurora B kinase inhibitor (e.g., TAK-901), radioimmunotherapy (e.g., actinium-225-labeled anti-CD33 antibody HuM195), Hedgehog inhibitor (e.g., PF-04449913), STAT3 inhibitor (e.g., OPB-31121), KB004, cancer vaccine (e.g., AG858), bone marrow transplantation, stem cell transplantation, radiation therapy, and combinations thereof. Chronic lymphocyic leukemia

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat chronic lymphocyic leukemia (CLL) include, but are not limited to, a chemotherapeutic agent (e.g., fludarabine, cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine, chlorambucil, busulfan, gemcitabine, melphalan, pentostatin, mitoxantrone, 5-azacytidine, pemetrexed disodium), tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib), BTK inhibitor (e.g., PCI-32765), multikinase inhibitor (e.g., MGCD265, RGB-286638), CD-20 targeting agent (e.g., rituximab, ofatumumab, R05072759, LFB-R603), CD52 targeting agent (e.g., alemtuzumab), prednisolone, darbepoetin alfa, lenalidomide, Bcl-2 inhibitor (e.g., ABT-263), immunotherapy (e.g., allogeneic CD4+ memory Thl-like T cells/microparticle -bound anti- CD3/anti-CD28, autologous cytokine induced killer cells (CIK)), HDAC inhibitor (e.g., vorinostat, valproic acid, LBH589, JNJ-26481585, AR-42), XIAP inhibitor (e.g., AEG35156), CD-74 targeting agent (e.g., milatuzumab), mTOR inhibitor (e.g., everolimus), AT-101, immunotoxin (e.g., CAT-8015, anti-Tac(Fv)-PE38 (LMB-2)), CD37 targeting agent (e.g., TRU-5016), radioimmunotherapy (e.g., 131-tositumomab), hydroxychloroquine, perifosine, SRC inhibitor (e.g., dasatinib), thalidomide, PI3K delta inhibitor (e.g., CAL-101), retinoid (e.g., fenretinide), MDM2 antagonist (e.g., R05045337), plerixafor, Aurora kinase inhibitor (e.g., MLN8237, TAK-901), proteasome inhibitor (e.g., bortezomib), CD-19 targeting agent (e.g., MEDI-551, MOR208), MEK inhibitor (e.g., ABT-348), JAK-2 inhibitor (e.g., INCB018424), hypoxia-activated prodrug (e.g., TH-302), paclitaxel or a paclitaxel agent, HSP90 inhibitor, AKT inhibitor (e.g., MK2206), HMG-CoA inhibitor (e.g., simvastatin), GNKG 186, radiation therapy, bone marrow transplantation, stem cell transplantation, and combinations thereof.

Acute lymphocyic leukemia

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat acute lymphocyic leukemia (ALL) include, but are not limited to, a chemotherapeutic agent (e.g., prednisolone, dexamethasone, vincristine, asparaginase, daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine, mercaptopurine, clofarabine, liposomal annamycin, busulfan, etoposide, capecitabine, decitabine, azacitidine, topotecan, temozolomide ), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g., sorafenib)), CD-20 targeting agent (e.g., rituximab), CD52 targeting agent (e.g., alemtuzumab), HSP90 inhibitor (e.g., STA-9090), mTOR inhibitor (e.g., everolimus, rapamycin), JAK-2 inhibitor (e.g., INCB018424), HER2/neu receptor inhibitor (e.g., trastuzumab), proteasome inhibitor (e.g., bortezomib), methotrexate, asparaginase, CD-22 targeting agent (e.g., epratuzumab, inotuzumab), immunotherapy (e.g., autologous cytokine induced killer cells (CIK), AHN-12), blinatumomab, cyclin-dependent kinase inhibitor (e.g., UCN-01), CD45 targeting agent (e.g., BC8), MDM2 antagonist (e.g., R05045337), immunotoxin (e.g., CAT-8015, DT2219ARL), HDAC inhibitor (e.g., JNJ-26481585), JVRS- 100, paclitaxel or a paclitaxel agent, STAT3 inhibitor (e.g., OPB-31121), PARP inhibitor (e.g.,veliparib), EZN-2285, bone marrow transplantation, stem cell transplantation, radiation therapy, and combinations thereof.

Acute myeloid leukemia

Exemplary agents that that can be conjointly administered with compounds disclosed herein to treat acute myeloid leukemia (AML) include, but are not limited to, a chemotherapeutic agent (e.g., cytarabine, daunorubicin, idarubicin, clofarabine, decitabine, vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan, elacytarabine, azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib, nilotinib), ON 01910.Na, multikinase inhibitor (e.g., midostaurin, SU 11248, quizartinib, sorafinib)), immunotoxin (e.g., gemtuzumab ozogamicin), DT388IL3 fusion protein, HDAC inhibitor (e.g., vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g., everolimus), SRC inhibitor (e.g., dasatinib), HSP90 inhbitor (e.g., STA-9090), retinoid (e.g., bexarotene, Aurora kinase inhibitor (e.g., BI 811283), JAK-2 inhibitor (e.g., INCBO 18424), Polo-like kinase inhibitor (e.g., BI 6727), cenersen, CD45 targeting agent (e.g., BC8), cyclin-dependent kinase inhibitor (e.g., UCN-01), MDM2 antagonist (e.g., R05045337), mTOR inhibitor (e.g., everolimus), LY573636-sodium, ZRx-101, MLN4924, lenalidomide, immunotherapy (e.g., AHN-12), histamine dihydrochloride, bone marrow transplantation, stem cell transplantation, radiation therapy, and combinations thereof.

Multiple myeloma

Exemplary agents that can be conjointly administered with compounds disclosed herein to treat multiple myeloma include, but are not limited to, a chemotherapeutic agent (e.g., melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine, bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide, lenalidomide, dexamethasone, prednisone, pomalidomide, proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomid), cancer vaccine (e.g., GVAX), CD-40 targeting agent (e.g., SGN-40, CHIR-12.12), perifosine, zoledronic acid, immunotherapy (e.g., MAGE- A3, NY-ESO-1, HuMax-CD38), HDAC inhibitor (e.g., vorinostat, LBH589, AR-42), aplidin, cycline-dependent kinase inhibitor (e.g., PD-0332991, dinaciclib), arsenic trioxide, CB3304, HSP90 inhibitor (e.g., KW-2478), tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., cetuximab), multikinase inhibitor (e.g., AT9283)), VEGF inhibitor (e.g., bevacizumab), plerixafor, MEK inhibitor (e.g., AZD6244), IPH2101, atorvastatin, immunotoxin (e.g., BB- 10901), NPI-0052, radioimmunotherapeutic (e.g., yttrium Y 90 ibritumomab tiuxetan), STAT3 inhibitor (e.g., OPB-31121), MLN4924, Aurora kinase inhibitor (e.g., ENMD-2076), IMGN901, ACE-041, CK-2 inhibitor (e.g., CX-4945), bone marrow transplantation, stem cell transplantation, radiation therapy, and combinations thereof.

Prostrate cancer

Exemplary agents that can be conjointly administered with compounds disclosed herein to treat prostrate cancer include, but are not limited to, a chemotherapeutic agent (e.g., docetaxel, carboplatin, fludarabine), abiraterone, hormonal therapy (e.g., flutamide, bicalutamide, nilutamide, cyproterone acetate, ketoconazole, aminoglutethimide, abarelix, degarelix, leuprolide, goserelin, triptorelin, buserelin), tyrosine kinase inhibitor (e.g., dual kinase inhibitor (e.g., lapatanib ), multikinase inhibitor (e.g., sorafenib, sunitinib)), VEGF inhibitor (e.g., bevacizumab), TAK-700, cancer vaccine (e.g., BPX-101, PEP223), lenalidomide, TOK-001, IGF-1 receptor inhibitor (e.g., cixutumumab), TRC105, Aurora A kinase inhibitor (e.g., MLN8237), proteasome inhibitor (e.g., bortezomib), OGX-011, radioimmunotherapy (e.g., F 591-GS), HDAC inhibitor (e.g., valproic acid, SB939, LBH589), hydroxychloroquine, mTOR inhibitor (e.g., everolimus), dovitinib lactate, diindolylmethane, efavirenz, OGX-427, genistein, IMC-303, bafetinib, CP-675,206, radiation therapy, surgery, or a combination thereof.

Hodgkin's Lymphomas

Exemplary agents that that can be used conjointly with compounds disclosed herein for the treatment of Hodgkin's lymphomas include, but are not limited to, chemotherapeutics such as Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), dacarbazine, etoposide (Toposar, VePesid), cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), prednisone, Ifosfamide (Ifex), carboplatin (Paraplatin), Mechlorethamine, Chlorambucil, methylprenisolone (Solu-Medrol), cytarabine (Cytosar-U), cisplatin (Platinol), Gemcitabine (Gemzar), vinorelbine (Navelbine), oxaliplatin (Eloxatin), Lomustine, Mitoxantrone, carmustine, melphalan, Bendamustine, Lenalidomide, and vinorelbine; either alone or in combinations; Brentuximab vedotin (Adcetris - a CD30 anti-body drug conjugate); Iodine 131-CHT25 antibody conjugate; HDAC inhibitors (e.g., vorinostat); m- TOR inhibitors (e.g., everolimus, temsirolimus); PI3K inhibitors (e.g., CAL-101, BAY80-6946, TGR-1202, BKM-120, AMG-319); JAK/STAT pathway inhibitors; Bcl-2 inhibitors (e.g., venetoclax); Mcl-l inhibitors; multikinase inhibitors such as BAY 43-9006 (sorafenib); proteasome inhibitors (e.g., bortezomib (Velcade), NPI-0052); dual PI3K/HDAC targeted inhibitors (e.g., CUDC-907); NF-kB inhibitors; anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab); anti-CTLA-4 antibodies (e.g., ipilimumab); anti-CD-20 antibodies (e.g., rituximab); anti-CD40 antibodies; anti-CD80 antibodies; and radiation therapy (e.g., tomotherapy, stereotactic radiation, proton therapy), surgery, and a combination thereof.

Non-Hodgkin's Lymphomas

Exemplary agents that that can be used conjointly with compounds disclosed herein for the treatment of Hodgkin's lymphomas include, but are not limited to, chemotherapeutics such as Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), dacarbazine, etoposide (Toposar, VePesid), cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), prednisone, Ifosfamide (Ifex), carboplatin (Paraplatin), Mechlorethamine, Chlorambucil, methylprenisolone (Solu-Medrol), cytarabine (Cytosar-U), cisplatin (Platinol), Gemcitabine (Gemzar), vinorelbine (Navelbine), oxaliplatin (Eloxatin), Lomustine, Mitoxantrone, methotrexate, carmustine, melphalan, Bendamustine, Lenalidomide, and vinorelbine; either alone or in combinations; tyrosine kinase inhibitors (e.g., EGFR inhibitor (e.g., erlotinib, panitumumab, cetuximab, nimotuzumab); HDAC inhibitors (e.g., vorinostat); IRAK-4 inhibitors; HSP90 inhibitors (e.g., tanespimycin, STA-9090, CUDC-305); m-TOR inhibitors (e.g., everolimus, temsirolimus); PI3K inhibitors (e.g., CAL-101, BAY80-6946, TGR- 1202, BKM-120, AMG-319); JAK/STAT pathway inhibitors; AKT inhibitors (e.g., RX-0201); Bcl-2 inhibitors (e.g., venetoclax); Mcl-l inhibitors; multikinase inhibitors such as BAY 43-9006 (sorafenib); proteasome inhibitors (e.g., bortezomib (Velcade), NPI-0052); dual PI3K/HDAC targeted inhibitors (e.g., CUDC-907); NF-kB inhibitors; BTK inhibitors (e.g., ibrutinib); BET bromodomain inhibitors; anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab); anti-CTLA-4 antibodies (e.g., ipilimumab); anti-CD-20 antibodies (e.g., rituximab); anti-CD40 antibodies; anti-CD80 antibodies; and radiation therapy (e.g., tomotherapy, stereotactic radiation, proton therapy), surgery, and a combination thereof.

In certain preceding embodiments, the invention provides a method, further comprising conjointly administering to the subject one or more non-chemical cancer treatments, e.g., radiation therapy, surgery, thermoablation, focused ultrasound therapy or cryotherapy.

In certain preceding embodiments, the invention provides a method, further comprising inhibiting the growth of tumour cells and/or metastasis by administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) and/or (II).

In certain embodiments, the present invention provides methods for treating an infectious disease in a subject comprising administering a therapeutically effective amount of a compound of the present invention.

In certain preceding embodiments, the invention provides a method, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) for treating a bacterial, viral or a fungal infection.

In certain embodiments, the present invention provides uses of a compound of the present invention for the preparation of a medicament for the treatment of a bacterial, viral and/or a fungal infection, as well as methods of administering a therapeutically effective amount of a compound of the present invention for the treatment of a bacterial, viral or a fungal infection.

Representative infectious diseases include but are not limited to HIV, Influenza, Herpes, Giardia, Malaria, Leishmania, the pathogenic infection by the virus Hepatitis (A, B, & C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, pathogenic infection by the bacteria chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, E. coli, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria, pathogenic infection by the fungi Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infection by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.

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.

The pharmaceutical composition may be administered by oral or inhalation routes, or by parenteral administration route. For example, compositions can be administered orally, by intravenous infusion, topically, intraperitoneally, intravesically or intrathecally. Examples of 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. Generally, 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. In alternative embodiments, in certain adults the compound 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. As used herein, 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). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, 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. Thus, 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. For example, 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 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, β or γ, IL-1, IL-2, IL-3, IL-12, Poly(LC), and C_PG.

In certain embodiments, the potentiating agents includes cyclophosphamide and analogs of cyclophosphamide, anti-TGFP 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.

As used herein, a therapeutic agent 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.

The term "treating" includes prophylactic and/or therapeutic treatments. The term "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 term "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. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain embodiments, 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.

As used herein, 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.

As used herein, the term "including" as well as other forms, such as "include",

"includes," and "included," is not limiting.

As used herein, the term "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. In some embodiments, the amino acids are α-, β- , γ-, or δ-amino acids, including their stereoisomers and racemates. As used herein, the term "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. The term "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, (heteroaryl)alkyl or acyl.

For example, 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 NH₂ group (e.g., wherein the amino group of the lysine sidechain is taken together with its substituents to form a heterocyclic ring such as piperidine or pyrrolidine). In another example, 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. In another example, the alkyl portion of the lysine side chain can be incorporated into a carbocyclic ring structure to form a semirigid analog, such as, e.g., cyclohexyl or cyclopentyl.

In certain embodiments, the unnatural amino acid can be a derivative of a natural amino acid having one or more double bonds.

In other embodiments, in threonine, the beta-methyl group can be replaced with an ethyl, phenyl or other higher alkyl group. In histidine, the imidazole moiety can be substituted, or alternatively, the alkylene backbone of the side chain can be substituted.

Further examples of unnatural amino acids include homoserine, and homologs of natural amino acids.

In further example embodiments, an unnatural amino acid can be alkylated (e.g., methylated) at the alpha position.

Further examples of unnatural amino acids include alpha,beta- and beta,gamma dehydroamino amino acid analogs.

Further exemplary amino acids include penicillamine and betamethoxyvaline.

Further examples of 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.

Modification of the N-terminal amino group is preferably with the general formula - NR_xR_y; wherein R_x is hydrogen or alkyl and R_y is alkyl, alkenyl, -C(=NH)NH₂, alkynyl or acyl.

Examples of N-terminal modifications include, but are not limited to, acetylated, formylated or guanylated N-termini.

Modification of the C-terminal carboxyl group is preferably with the general formula - COR' (R' replaces the hydroxyl group of the last amino acid); wherein R' is alkoxy, amino or an imide. For example, the C-terminus may be esterified or amidated.

This disclosure includes pharmaceutically acceptable salts of compounds of the invention and their use in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra- alkyl ammonium salts. In certain embodiments, 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. In certain embodiments, 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.

The term "stereoisomers" refers to any enantiomers, diastereomers or geometrical isomers, such as of the 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. Examples of 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. Also advantageous is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatised methacrylate polymers immobilised on silica gel).

In certain embodiments, 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.

The term "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).

Naturally-occurring amino acids (L-form) are identified throughout the description and claims by the conventional three-letter abbreviations indicated in the below table.

Table -I: List of Amino acid codes

The abbreviations used in the entire specification may be summarized herein below with their particular meaning.

°C (degree Celsius); % (percentage); brine (NaCl solution); CH₂C1₂/DCM (Dichlorome thane); Boc (Tert-butyloxycarbonyl); DIC (Ν,Ν'-Diisopropylcarbodiimide); DMF (Dimethyl formamide); EtOH (Ethanol); Et₂NH (Diethylamine); Fmoc (9- Fluorenylmethyloxycarbonyl); g or gr (gram); HOBt (1 -Hydroxy benzotriazole); h or hr (Hours); HPLC (High-performance liquid chromatography); K₂C0₃ (Potassium carbonate); LCMS (Liquid chromatography mass spectroscopy); Aqueous NH₃ (Liquor ammonia); mmol (Millimoles); M (Molar); μΐ (Microlitre); mL (Millilitre); mg (Milligram); MS (ES) (Mass spectroscopy-electro spray); min (Minutes); Na (Sodium); sat.NaHC0₃ (saturated Sodium bicarbonate); NH₂NH₂.H₂0 (Hydrazine hydrate); NMM (N-Methylmorpholine); Na₂S0₄ (Sodium sulphate); NH₂OH.HCl (Hydroxylamine hydrochloride); PDl/PD-1 (Programmed cell death 1); PD-L1 (Programmed death-ligand 1); PD-L2 (Programmed cell death 1 ligand 2); prep- HPLC/preparative HPLC (Preparative High-performance liquid chromatography); TEA/Et₃N (Triethylamine); TFAA: Trifluoroacetic anhydride; TLC (Thin Layer Chromatography); THF (Tetrahydrofuran); TIPS (Triisopropylsilane); TFA (Trifluoroacetic acid); t_R (Retention time); Trt (Trityl or Triphenylmethyl), etc.

EXPERIMENTAL

The present invention provides methods for the preparation of compounds of formula (I) according to the procedures of the following examples, using appropriate materials. Those skilled in the art will understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present invention.

The intermediates or starting materials required for the synthesis are commercially available (commercial sources such as Sigma-Aldrich, USA or Germany; Chem-Impex USA; G.L. Biochem, China and Spectrochem, India) or alternatively, these intermediates or starting materials can be prepared using known literature methods. The invention is described in greater detail by way of specific examples. Purification and characterization of compounds

Analytical HPLC method:

Analytical HPLC was performed on ZIC HILIC 200 A° column (4.6 mm x 250 mm, 5 μιη), Flow rate: 1.0 mL / min. The elution conditions used are: Buffer A: 5 mmol ammonium acetate, Buffer B: Acetonitrile, Equilibration of the column with 90 % buffer B and elution by a gradient of 90 % to 40 % buffer B during 30 min.

Preparative HPLC method:

Preparative HPLC was performed on SeQuant ZIC HILIC 200 A° column (10 mm x 250 mm, 5 μπι), Flow rate: 5.0 mL/min. 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.

Synthesis of Intermediates:

Synthesis of compound lg (N0₂-C₆H₄-OCO-Ser(tBu)-O^tBu):

To a stirred solution of 4-N0₂Ph-OCOCl (3.9 g, 19.7 mmol) in DCM, Pyridine (2.4 mL,

29.6 mmol) was added at 0 °C and stirred for 10 min. Further a solution of H-Ser(tBu)-OtBu ( 5.0 g, 23 mmol) in CH₂C1₂ was added slowly to the above reaction mass at 0 °C and stirred for one more hour. Progress of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure and residue was partitioned between diethyl ether (2 x 200 mL) and water. Organic layer was washed withl0% citric acid, brine solution, dried over Na₂S0₄ and evaporated under reduced pressure to give crude compound lg. The crude compound was suspended in n-hexane (200 mL) and stirred for 2 h. The precipitated solid was filtered through sintered funnel and dried under reduced pressure to yield 5.5 g of compound lg.

Synthesis of compound 2i (N0₂-C₆H₄-OCO-Leu-O^tBu):

The above compound 2i was synthesized as per the procedure given for the synthesis of compound lg.

Example 1: Synthesis of compound 3

Step la:

Potassium carbonate (2.3 g, 16.9 mmol) and methyl iodide (0.8 ml, 13.6 mmol) were added to a solution of compound la (3.0 g, 11.3 mmol) in DMF (30 mL) and stirred at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na₂S0₄ and evaporated under reduced pressure to get 3.0 g of compound lb. LCMS: 280.1 (M+H)⁺.

Step lb:

Hydrazine hydrate (4.3 mL, 85.7 mmol) was added to a solution of compound lb (3.0 g, 10.7 mmol) in methanol (30 mL) and stirred at room temperature for 3 h. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, the residue obtained was partitioned between water and ethyl acetate. Organic layer was washed with water, brine, dried over Na₂S0₄ and evaporated under reduced pressure to get 3.0 g of compound lc. LCMS: 280.2 (M+H)⁺.

Step lc:

NMM (2.3 mL, 21.4 mmol), HATU (4.8 g, 12.8 mmol) and compound lc (3.0 g, 10.7 mmol) were added to a solution of Fmoc-Asn(Trt)-OH (6.4 g, 10.7 mmol) in DMF (30 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice and the solid precipitated out was filtered and dried under vacuum to obtain 8.6 g of pure product Id. LCMS: 858.3 (M+H)⁺. Step Id:

To a stirred solution of Id (3.0 g, 3.5 mmol) in dry THF (25 mL) and DMF (5 mL), triphenylphosphine (1.83 g, 7.0 mmol) and iodine (1.8 g, 7.0 mmol) were added at 0 °C. After the iodine was completely dissolved, Et₃N (1.9 mL, 13.9 mmol) was added to this reaction mixture at ice cold temperature. Reaction mixture was allowed to attain room temperature and stirred for 1 h. The completeness of the reaction was confirmed by TLC analysis. The reaction was quenched with ice water and extracted with ethyl acetate. Organic layer was washed with saturated sodium thiosulphate and brine solution. The separated organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to get 4.0 g of compound le.

Step le:

Fmoc group was deprotected by the addition of 20% Piperidine in DCM (20.0 mL) to a compound le (4.0 g, 4.8 mmol) at 0°C. The reaction was stirred at room temperature for 1 h. The resulting solution was concentrated in vacuum to get a thick gummy residue which was washed with n-Hexane to remove Fmoc impurity. Then solid was partitioned between water and EtOAc (2 x 100ml). The organic layer was washed with NaHC0₃ solution and brine solution, dried over Na₂S0₄ and evaporated under reduced pressure to get solid. Finally solid was washed with n- hexane and dried under high vacuum to get pure product 2.9 g of compound If. LCMS: 618.1(M+H)⁺.

Step If:

"If

Compound If (2.0 g, 3.2 mmol) and compound lg (1.6 g, 4.2 mmol) dissolved in EtOH at room temperature. The reaction was stirred at 85 °C for 2 h. The completeness of the reaction was confirmed by TLC analysis. The resulting solution was concentrated in vacuum to get 2.0 g of product lh. LCMS: 861.2(M+H)⁺.

Step lg:

1 h Compound 3

To a solution of compound lh (2.0 g, 2.3 mmol) in cocktail mixture [TFA (18 mL), TIPS (2 mL)], at room temperature for 2 h to remove the acid sensitive protecting groups. The reaction mixture was evaporated under nitrogen atmosphere to give crude. The crude compound washed with diethyl ether (3 x 20 mL) and to get crude compound. Further the crude compound was purified by preparative HPLC to get 40 mg of pure compound 3. LCMS: 407.4 (M+H)⁺.

The below compounds were prepared by a procedure similar to the one described in Example 1 (Compound 3) with appropriate variations in the number and order of steps involved, reactants or amino acids, solvents, quantities of reagents and reaction conditions.

Example 2: Synthesis of compound 8

Step 2a: H

Ethylchloroformate (1.53 g, 14.2 mmol) and NMM (1.44 g, 14.2 mmol) were added to a solution of compound 2a (5.0 g, 9.5 mmol) in THF (50 mL) and stirred at -20 °C for 20 min. After 20 min 25% of aqueous ammonia (20 mL, 132.0 mmol) was added to the active mixed anhydride and stirred at 0 °C for 30 min. 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 NaHC0₃ solution followed by citric acid solution and brine solution. The separated organic layer was dried over Na₂S0₄, filtered and evaporated under reduced pressure to yield 5.0 g of compound 2b. LCMS: 526.4 (M+H)⁺. Step 2b:

2b 2c

Trifluroacetic anhydride (3.1 g, 14.8 mmol) was added to a solution of compound 2b (5 g, 9.9 mmol) in DCM and pyridine (5.1g, 64.1 mmol) and stirred at room temperature for lh. The completion of the reaction was confirmed by TLC analysis. The reaction mixture was diluted with DCM then washed with citric acid solution, NaHC0₃ solution, water and brine solution. The separated organic layer was dried over Na₂S0₄, filtered and evaporated under reduced pressure to yield 4.5 g of compound 2c, which was used for next step directly. LCMS: 508.1 (M+H)⁺.

Step 2c:

Hydroxylamine hydrochloride (1.2 g, 17.8 mmol), water (10 mL) and potassium carbonate (2.4 g, 17.8 mmol) were added to a solution of compound 2c (4.5 g, 8.8 mmol) in EtOH (30 mL) and stirred at reflux for 3 h. The completeness 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 brine solution, dried over Na₂S0₄ then filtered and evaporated under reduced pressure to yield 4.5 g of compound 2d. LCMS: 541.0 (M+H)⁺.

Step 2d:

To a solution of Fmoc-L-Asn(Trt)-OH (3.1 g, 5.2 mmol) in DMF (30 mL) were added HOBt (1.3 g, 9.7 mmol) and DIC (1.2 g, 9.7 mmol) at 0 °C and stirred for 30 min. Then compound 2d (3.5 g, 6.5 mmol) was added at the same temperature and continued the stirring for 2 h and then at room temperature for 2 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water, the precipitated white solid was filtered, washed with water (1 L) and dried under high under reduced pressure. The solid was stirred with diethyl ether (500 mL) for 15 min, filtered and dried to yield 6 g of compound 2e. LCMS: 1119.5 (M+H)⁺.

Step 2e:

To a solution of compound 2e (4 g, 3.6 mmol) in acetonitrile (40 mL) was added acetic acid (4.0 mL) at room temperature and refluxed at 85 °C for 12 h. The completion of the reaction was confirmed by TLC analysis. The volatiles were evaporated under reduced pressure to obtain crude semi solid which was diluted with water and ethyl acetate. The organic layer was washed with NaHC0₃ solution followed by citric acid solution and brine solution. The organic layer was dried over Na₂S0₄, filtered and evaporated under reduced pressure to get crude solid and dried to yield 3.5 g of compound 2f. LCMS: 1101.6 (M+H)⁺.

Step 2f:

2g

To a solution of 20% piperidine in DCM (30 mL) was added compound 2f (3gm) at 0 °C and stirred for 1 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was concentrated under reduced pressure and diluted with hexane, stirred and filtered. The filtered solid was dissolved in EtOAc and washed with sat. NaHC0₃ solution, brine solution, dried over Na₂S0₄, filtered and concentrated to get 1.5 g of white compound 2f. LCMS: 879.6 (M+H)⁺.

Step 2g:

A solution of compound 2i (0.2 g, 0.6 mmol) and compound 2g (0.5 g, 0.6 mmol) in ethanol (10 mL) at room temperature stirred for 4 h under reflux condition. The completeness of the reaction was confirmed by TLC analysis. The volatiles from the reaction mass were evaporated and the crude compound was purified by column chromatography to get 0.7 g of compound 2h. LCMS: 1092.5 (M+H)⁺.

Step 2h:

Compound 8

To a solution of compound 2h (0.7 g, 0.64 mmol) in CH₂C1₂ (5 mL) were added trifluoroacetic acid (5 mL) and catalytic amount of triisopropylsilane and stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure to yield 0.65 g of crude compound 8. The crude solid material was purified as preparative HPLC method described under experimental conditions to get 0.1 g of pure compound 8. LCMS: 442.2 (M+H)⁺.

The below compounds were prepared by a procedure similar to the one described in

Example 2 (Compound 8) with appropriate variations in the number and order of steps involved, reactants or amino acids, solvents, quantities of reagents and reaction conditions.

The below compound was prepared by following a similar procedure as described above with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present application:

Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Example 3: Human PBMC IFN-γ release assay

Requirement:

Vehicle : Milli Q water; RPMI 1640 (GIBCO, Cat # 11875); Fetal Bovine Serum [Hyclone, Cat # SH30071.03]; Penicilin (10000 unit/ml)-Streptomycin( 10,000 μ^ιηΐ) liquid (GIBCO, Cat # 15140-122); MEM Sodium Pyruvate solution 100 mM (lOOx), Liquid (GIBCO, Cat # 11360); Nonessential amino acid (GIBCO, Cat # 11140); L-Glutamine (GIBCO, Cat # 25030); Recombinant human VISTA (rhGi24 VISTA/B7-H5 Fc chimera (R&D systems, cat no: 7126-B7); Anti-h/m Gi24/VISTA/B7-H5 purified mouse monoclonal IgG2B (R&D systems, cat no: MAB7126); Mouse IgG2B isotype control (R&D Systems cat no: MAB 004); Anti human- CD3 antibody (eBiosciences - 16-0039); Anti human-CD28 antibody (eBiosciences - 16- 0289); Histopaque (density- 1.077 gm/ml) (SIGMA 1077); Trypan Blue solution (SIGMA- T8154); Hemacytometer (Bright line-SIGMA Z359629); FACS Buffer containing Phosphate Buffered Saline (PBS) pH 7.2; (HiMedia TS1006) with 0.1% Bovine Serum Albumin (BSA) (SIGMA A7050) and sodium azide (SIGMA 08591); 96-well format ELISA plates (Corning 3599) ; 96-well format ELISA plates (Corning 3361); BD FACS caliber (E6016); Centrifuge (Eppendorf 5810 R); Human IFN-γ Duo set ELISA kit (R&D Systems; cat no: DY-285).

Procedure:

96-well cell culture plates were pre-coated with recombinant human VISTA (2.5 μg/ml) and anti-human CD3 (2.5 μg/ml), and stored at 4 °C overnight. Anti-human VISTA and isotype control antibodies were either coated along with the VISTA or incubated for 30 min next day before addition of cells. On the next day, plates were washed with lx PBS and then incubated with test compounds for 30 min. Isolated PBMC (0.1 x 10⁶ cells/well) and anti- human CD28 antibodies (^g/ml) were added to the wells. The culture was further incubated for 72 h at 37 °C with 5% C0₂. After 72 h of incubation the cell culture supernatants were collected after brief centrifugation at 200 g x 5 min at 4 °C and processed for human IFN- γ measurement by ELISA following manufacturer's protocol (R&D Systems; DY-285).

In brief, 96-well ELISA plates were coated with 100 μΐ/well of capture antibody in coating buffer and incubated overnight at 4°C. Plates were washed five times with wash buffer and further blocked with 200 μΐ of lx assay diluents for 1 hr at RT. Following wash step, 100 μΐ of cell culture supernatants were added to wells and further incubated for 2 hr at RT. Appropriate standards were also included. After wash step, plate was incubated for one hour with 100 μΐ/well of detection antibody. The wash step was repeated and the plate was incubated for 30 min with 100 μΐ/well of Avidin-HRP. The plate was washed four times with wash buffer and incubated for 15 min with 100 μΐ/well of substrate solution. 50 μΐ of stop solution was added to each well and the plate was read at 450 nm using Gen5 ver 2.05. Delta OD values were used for calculating the concentrations. The absorbance values were plotted against the standards and the concentration of IFN-γ was determined using GraphPad Prism software. Each experimental condition was carried out in triplicates. The selected compounds of the invention were found to have % rescue of IFN-γ release in a human PBMC assay as in the table-II below.

Table II: Percent rescue of IFN-γ release in a human PBMC assay

Example 4: In vivo efficacy of compound-3 on tumor growth inhibition in CT26 metastasis model

1X10⁶ CT26 cells were injected subcutaneously to male Balb/c mice. The test compound was formulated in 1% Tween80+10% Capmul+89% of 5% HPCD+0.1 M Citric acid+0.1% EDTA and dosed orally at 30mg/kg dose, once daily. Vehicle control group of mice received just the formulation. Each group consisted of ten animals. Body weight and clinical signs were recorded daily and tumor volumes were recorded thrice a week. Results are shown in Figure- 1.

Claims

A compound of formula (I),

(I)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl;

with the proviso that the compound of formula (I) is not

2. The compound of claim 1, wherein the compound is of formula (IA),

(IA) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R is hydrogen, alkyl, -CO-Aaai-Aaa₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent or amino acid residue Thr.

3. The compound of claim 1 , wherein the compound is of formula (IB),

(IB) or a pharmaceutically acceptable salt or stereoisomer thereof;

wherein,

Ri is aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, alkyl, -CO-Aaai or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and Aaai is an amino acid residue selected from Ser, Glu and Leu.

4. The compound of claim 1, wherein the compound is of formula (IC),

(IC) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

R₃ is hydrogen, alkyl, -CO-Aaai or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

Aaai is an amino acid residue selected from Ser and Glu; wherein the C-terminus free or amidated.

5. The compound of claim 4, wherein the compound is of formula (ID),

(ID) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein, R₃, R_3a, R₄ and R_4a are as defined in claim 4.

The compound of claim 4, wherein the compound is of formula

(IE) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein, R₃, R_3a, R₄ and R_4a are as defined in claim 4.

7. The compound of any one of claims 1 to 3, wherein Ri is phenyl, phenyl-OH or - CH₂CH₂NHC(=NH)NH₂.

8. The compound of any one of claims 1 to 3, wherein R₂ is -CONH₂.

9. The compound of any one of claims 1 to 6, wherein R₃ is hydrogen or -CO-Aaai- Aaa₂.

10. The compound of any one of claims 1 to 6, wherein R₃ is -Fmoc.

11. The compound of any one of claims 1 to 6, wherein R_3a, R₄ and R_4a are hydrogen.

12. The compound of any one of claims 1 to 3; wherein Aaai is an amino acid residue selected from Ser, Glu and Leu; and Aaa₂ is absent.

13. The compound of 12; wherein the amino acid residue Aaai has either a free, an amidated or an esterified C-terminus.

14. The compound of any one of claims 1 to 6, wherein the Aaai has a free C-terminus.

15. The compound of any one of claims 1 to 6, wherein Aaai has an amidated C-terminus.

16. The compound of any one of claims 1 to 15 selected from:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and at least one compound of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof.

18. A compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.

19. A compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in inhibiting the VISTA signaling pathway.

20. A compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating cancer.

21. The compound of claim 20, wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

22. A compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in treating a bacterial, viral or a fungal infection.

23. A method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof.

24. A method of treating diseases or disorders mediated by the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof.

25. The method of claim 23 or 24, wherein the disease or disorder mediated by VISTA signaling pathway is cancer.

26. The method of claim 25, wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

27. The method of any one of claims 23 to 25, wherein the subject is a mammal, e.g., a human.

28. The method of any one of claims 23 to 25, further comprising conjointly administering to the subject a second chemotherapeutic agent.

29. The method of any one of claims 23 to 27, further comprising conjointly administering to the subject one or more non-chemical cancer treatments, e.g., radiation therapy, surgery, thermoablation, focused ultrasound therapy or cryotherapy.

30. The method of any one of claims 23 to 27, further comprising inhibiting the growth of tumour cells and/or metastasis by administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I).

31. The method of any one of claims 23 to 24, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (I) for treating a bacterial, a viral or a fungal infection.

32. A method of modulating the VISTA signaling pathway in a subject, comprising administering to the subject, a therapeutically effective amount of a compound of formula (II),

(Π)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

Ri is -CONH2, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

33. The method of claim 32, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (IIA),

(IIA) or a pharmaceutically acceptable salt or a stereoisomer thereof; wherein,

Ri is -CONH₂, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

34. The method of any one of claims 32 to 33, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (IIA), wherein,

Ri is -CONH₂, phenyl or -phenyl-OH;

R₂ is -CONH₂ or -CH₂CONH₂;

R₃ is hydrogen, -CO-(Aaa) or -Fmoc;

R_3a, R₄ and R_4a are independently hydrogen or alkyl; and

35. The method of any one of claims 32 to 34, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound selected from:

or a pharmaceutically acceptable salt or a stereoisomer thereof.

36. The method of any one of claims 32 to 35, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (II) for treating cancer.

37. The method of any one of claims 32 to 36, wherein the subject is a mammal, e.g., a human.

38. The method of any one of claims 32 to 36, further comprising conjointly administering to the subject a second chemotherapeutic agent.

39. The method of any one of claims 32 to 38, further comprising conjointly administering to the subject one or more non-chemical cancer treatments, e.g., radiation therapy, surgery, thermoablation, focused ultrasound therapy or cryotherapy.

40. The method of any one of claims 32 to 38, further comprising inhibiting the growth of tumour cells and/or metastasis by administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (II).

41. The method of any one of claims 32 to 35, comprising administering to the subject in need thereof, a therapeutically effective amount of a compound of formula (II) for treating a bacterial, a viral or a fungal infection.

42. A compound for use in the treatment of diseases or disorders mediated by VISTA in a subject, wherein the compound is re resented by compound of formula (II),

(Π) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

Ri is -CONH₂, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

43. The compound of claim 42, wherein the compound is represented by the compound of formula (IIA), R_4a O R_3a

(IIA) or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

Ri is -CONH₂, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂;

R₂ is -CONH₂ or -CH₂CONH₂;

R3 is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

44. The compound of any one of claims 42 to 43, for use as a medicament.

45. The compound of any one of claims 42 to 43, wherein the disease or disorder mediated by VISTA is cancer.

46. The compound of claim 45, wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

47. The compound of any one of claims 42 to 43, wherein the disease or disorder mediated by VISTA is an infectious disease.

48. A use of a compound of any one of claims 1 to 16, in the manufacture of a medicament for treating diseases or disorders mediated by VISTA signaling pathway.

49. The use of a compound of claim 48 in the manufacture of a medicament for the treatment of cancer.

50. The use of a compound of claim 48 in the manufacture of a medicament for the treatment of a bacterial, a viral or a fungal infection.

51. Use of compound in the manufacture of a medicament for treating diseases or disorders mediated by VISTA signaling pathway in a subject, wherein the compound is represented by compound of formula (II),

(II)

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

is an optional bond;

one of Xi and X₂ is O or S and the other is N;

-CONH₂, aryl, -aryl-OH or -CH₂CH₂NHC(=NH)NH₂

-CONH₂ or -CH₂CONH₂ R₃ is hydrogen, alkyl, -CO-(Aaa)i_₂ or -Fmoc;

R_3a, R₄ and R4_a are independently hydrogen or alkyl; and

52. The use of a compound of claim 51, wherein the disease or disorder mediated by VISTA is cancer.

53. The use of a compound of claim 49 or 51, wherein wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer and lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumours of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, mycosis fungoides, merkel cell cancer, and other hematologic malignancies, environmentally induced cancers including those induced by asbestos, and combinations of said cancers.

54. The use of a compound of claim 51, wherein the disease or disorder mediated by VISTA is an infectious disease.