1,2,4-Oxadiazole and thiadiazole compounds as immunomodulatory agents

Abstract

To provide a more potent, better and / or selective immune modulators of the PD-1 pathway.SOLUTION: The present invention relates to 1,2,4-oxadiazole compounds represented by, for example, Compound 1, and their use to inhibit the programmed cell death-1 (PD-1) signaling pathway and / or for treatment of disorders by inhibiting an immunosuppressive signal induced by PD-1,PD-L1 or PD-L2.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims the benefit of Indian Provisional Patent Application No. 1180 / CHE / 2015, filed March 10, 2015, and Indian Provisional Patent Application No. 1178 / CHE / 2015, filed March 10, 2015, the specifications of which are incorporated herein by reference in their entireties.

[0002] Technical Field The present invention relates to 1,2,4-oxadiazole and thiadiazole compounds and derivatives thereof that are therapeutically useful as immunomodulators. The present invention also relates to pharmaceutical compositions comprising 1,2,4-oxadiazole and thiadiazole compounds and derivatives thereof. [Background technology]

[0003] 2. Background of the Invention Programmed cell death-1 (PD-1) is a member of the CD28 superfamily that delivers negative signals through interaction with two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and exert a broader immunoregulatory role in T cell activation and tolerance compared to other CD28 members. PD-1 and its ligands are involved in reducing infection and tumor immunity, and promoting chronic infection and tumor progression. The biological significance of PD-1 and its ligands suggests the therapeutic potential of PD-1 pathway manipulation for various human diseases (Hyun-Tak Jin, et al., Curr Top Microbiol Immunol. (2011); 350: 17-37).

[0004] T cell activation and dysfunction depend on direct and regulated receptors. Based on their functional outcomes, co-signaling molecules can be divided into co-stimulators and co-inhibitors that positively and negatively regulate the priming, growth, differentiation and functional maturation of T cell responses (Li Shi, et al., Journal of Hematology & Oncology 2013,6:74).

[0005] Therapeutic antibodies that block the programmed cell death protein-1 (PD-1) immune checkpoint pathway prevent T cell downregulation and promote immune responses against cancer. Multiple PD-1 pathway inhibitors have shown robust activity in various phases of clinical trials (RD Harvey, Clinical Pharmacology & Therapeutics).

[0006] Programmed cell death-1 (PD-1) is a coreceptor expressed primarily by T cells. Binding of PD-1 to its ligands PD-L1 or PD-L2 is essential for the physiological regulation of the immune system. The primary functional role of the PD-1 signaling pathway is the inhibition of autoreactive T cells that serve to defend against autoimmune diseases. Therefore, abrogation of the PD-1 pathway can result in the destruction of immune tolerance and ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can sometimes co-opt the PD-1 pathway to escape immune surveillance. Therefore, blockade of the PD-1 pathway has become an attractive target for cancer therapy. Current approaches include six agents that are either PD-1 and PD-L1 targeting neutralizing antibodies or fusion proteins. More than 40 clinical trials are ongoing to better define the role of PD-1 blockade in various tumor types (Ariel Pedoeem et al., Clinical Immunology (2014), 153(1), 145-152).

[0007] International patent applications WO2002086083, WO2004004771, WO2004056875, WO2006121168, WO2008156712, WO2010077634, WO2011066389, WO2014055897 and WO2014100079 report PD-1, PD-L1 inhibitory antibodies and / or methods for identifying such antibodies. Additionally, United States patents such as US8735553 and US8168757 report PD-1 or PD-L1 inhibitory antibodies and / or fusion proteins.

[0008] Furthermore, international patent applications WO2011161699, WO2012168944, WO2013144704 and WO2013132317 report peptides or peptidomimetics capable of suppressing and / or inhibiting the programmed cell death 1 (PD1) signaling pathway.

[0009] Nevertheless, there is a need for more potent, better, and / or selective immunomodulators of the PD-1 pathway. Summary of the Invention [Problem to be solved by the invention]

[0010] Summary of the Invention The present invention provides 1,2,4-oxadiazole and thiadiazole compounds, and pharma- ceutically acceptable salts or stereoisomers thereof, which are capable of suppressing and / or inhibiting the programmed cell death 1 (PD1) signaling pathway. [Means for solving the problem]

[0011] In one aspect, the present invention provides a compound of formula (I):

[0012] [ka] (In the formula, ----- is an optional double bond; X is O or S; R1 and R2 are independently the side chain of an amino acid, or hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or cycloalkyl; where (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and cycloalkyl are amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl, heterocyclyl, (heterocyclyl) alkyl, heteroaryl ... optionally substituted by one or more substituents selected from -cycloalkyl, aryl, heterocyclyl and heteroaryl, optionally further substituted by one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; and optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3-7 membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R3 is hydrogen, -CO-[Aaa1] m , [Aaa1] m , [Aaa1] m -CO-[Aaa1] m , -S(O) p -[Aaa1] m , -CONR7R8, -COR c , -SO2R c, (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are selected from the group consisting of amino, alkylamino, acylamino, -COO-alkyl, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, (heteroaryl)alkyl, guanidino, -S optionally substituted by one or more substituents selected from H and -S (alkyl); optionally cycloalkyl, aryl, heterocyclyl and heteroaryl are further substituted by one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; optionally two or three carbon atoms of the (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl form part of a 3-7 membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R4 and R5 are independently hydrogen or absent; R6 is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, acyl, [Aaa2] n , -CO-[Aaa2] n , [Aaa2] n -CO-[Aaa2] n or -S(O) p -[Aaa2] n and; R7 and R8 are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heterocyclyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, aryl and heterocyclyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, aryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); or R7 and R8, together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring containing 0-2 additional heteroatoms independently selected from N, O and S in any stable combination; wherein the optional substituents at each occurrence are selected from hydroxyl, -COOH, -COO-alkyl, amido, halo, amino, nitro and cyano; [Aaa1] and [Aaa2], independently at each occurrence, represent an amino acid residue; where the C-terminal carboxyl group of the amino acid residue is a free C-terminal carboxyl group (-COOH) or a modified C-terminal carboxyl group, and the N-terminal amino group of the amino acid residue is a free N-terminal amino group (-NH2) or a modified N-terminal amino group; R a is hydrogen or alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; R b is hydrogen or alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; or Rb and R2, together with the atom to which it is attached, may form a pyrrolidine or piperidine optionally substituted with one or more groups independently selected from hydroxyl, halo, amino, cyano, and alkyl; R c is (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein said (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from carboxylic acid, hydroxyl, alkyl, alkoxy, amino, alkylamino, acylamino, carboxylate, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl or (heteroaryl)alkyl; m and n are independently integers selected from 1 to 3; p is an integer selected from 1 to 2; with the proviso that R2 is the side chain of Asp, Asn, Glu, or Gln, R3 is hydrogen, -CO-Ser, or -CO-Thr, R6 is hydrogen, alkyl, or acyl, and R a and R b is hydrogen, then R1 is not the side chain of Ser or Thr), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0013] In another aspect, the present invention relates to a process for the preparation of a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0014] In a further aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof, and processes for preparing those compositions.

[0015] Yet another aspect of the present invention provides methods of suppressing and / or inhibiting the programmed cell death 1 (PD1) signaling pathway by administering a compound of formula (I) or a pharma- ceutically acceptable salt or stereoisomer thereof. For example, these compounds may be used to treat one or more diseases characterized by aberrant or unwanted activity of the PD1 signaling pathway. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Detailed Description of the Invention The present invention provides 1,2,4-oxadiazole and thiadiazole compounds, and derivatives thereof, as therapeutic agents useful for the treatment of disorders mediated by immune enhancement, including the inhibition of immunosuppressive signals induced by PD-1, PD-L1 or PD-L2 and treatment therewith.

[0017] Each embodiment is provided as a way of explaining the invention, and is not a limitation of the invention. In fact, it will be apparent to those skilled in the art that various improvements and modifications can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the invention. For example, features illustrated or described as part of one embodiment can be applied to another embodiment to obtain a further embodiment. Therefore, the present invention is intended to encompass such improvements and modifications, and their equivalents. Other objects, features, and aspects of the present invention will be disclosed or become apparent from the following detailed description. It should be understood by those skilled in the art that the present discussion is merely a description of exemplary embodiments, and should not be construed as limiting the broader aspects of the present invention.

[0018] In certain embodiments, the present invention provides a compound of formula (I):

[0019] [ka] (In the formula, ----- is an optional double bond; X is O or S; R1 and R2 are independently the side chain of an amino acid, or hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or cycloalkyl; where (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and cycloalkyl are amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl) alkyl, aryl, arylalkyl, heterocyclyl, (heterocyclyl) alkyl, heteroaryl ... optionally substituted by one or more substituents selected from -cycloalkyl, aryl, heterocyclyl and heteroaryl, optionally further substituted by one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; and optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3-7 membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R3 is hydrogen, -CO-[Aaa1] m , [Aaa1] m , [Aaa1] m -CO-[Aaa1] m , -S(O) p -[Aaa1] m , -CONR7R8, -COR c , -SO2R c, (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are optionally substituted by one or more substituents selected from amino, alkylamino, acylamino, -COO-alkyl, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, (heteroaryl)alkyl, guanidino, -SH and -S(alkyl); optionally substituted by cycloalkyl, aryl, heterocyclic, The heterocyclyl and heteroaryl are further substituted by one or more substituents, such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; optionally, two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3-7 membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R4 and R5 are independently hydrogen or absent; R6 is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, acyl, [Aaa2] n , -CO-[Aaa2] n , [Aaa2] n -CO-[Aaa2] n or -S(O) p -[Aaa2] n and; R7 and R8 are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heterocyclyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, aryl and heterocyclyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, aryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); or R7 and R8, together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring containing 0-2 additional heteroatoms independently selected from N, O and S in any stable combination; wherein the optional substituents at each occurrence are selected from hydroxyl, -COOH, -COO-alkyl, amido, halo, amino, nitro and cyano; [Aaa1] and [Aaa2], independently at each occurrence, represent an amino acid residue; where the C-terminal carboxyl group of the amino acid residue is a free C-terminal carboxyl group (-COOH) or a modified C-terminal carboxyl group, and the N-terminal amino group of the amino acid residue is a free N-terminal amino group (-NH2) or a modified N-terminal amino group; R a is hydrogen or alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; R b is hydrogen or alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; or Rb and R2, together with the atom to which it is attached, may form a pyrrolidine or piperidine optionally substituted with one or more groups independently selected from hydroxyl, halo, amino, cyano, and alkyl; R c is (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein said (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from carboxylic acid, hydroxyl, alkyl, alkoxy, amino, alkylamino, acylamino, carboxylate, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl or (heteroaryl)alkyl; m and n are independently integers selected from 1 to 3; p is an integer selected from 1 to 2; with the proviso that R2 is the side chain of Asp, Asn, Glu, or Gln, R3 is hydrogen, -CO-Ser, or -CO-Thr, R6 is hydrogen, alkyl, or acyl, and R a and R b is hydrogen, R1 is not the side chain of Ser or Thr), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0020] In certain embodiments of the compounds of formula (I), or pharma- ceutically acceptable salts or stereoisomers thereof, ----- is an optional double bond; X is O or S; R1 and R2 are independently the side chain of an amino acid, or hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or cycloalkyl; where (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and cycloalkyl are optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl) alkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH and -S(alkyl); where cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally further substituted with one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; R3 is hydrogen, -CO-[Aaa1] m , [Aaa1] m , [Aaa1] m -CO-[Aaa1] m , -S(O) p -[Aaa1] m , -CONR7R8, -COR c , -SO2R c , (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH and -S(alkyl); optionally cycloalkyl, aryl, heterocyclyl and heteroaryl are further substituted with one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; R4 and R5 are independently hydrogen or absent; R6 is hydrogen, alkyl, acyl, [Aaa2]n , -CO-[Aaa2] n , [Aaa2] n -CO-[Aaa2] n or -S(O) p -[Aaa1] n and; R7 and R8 are independently hydrogen, (C1-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, aryl or heterocyclyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl, aryl and heterocyclyl are optionally substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, aryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); or R7 and R8, together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring containing 0-2 additional heteroatoms independently selected from N, O and S in any stable combination; where the optional substituents at each occurrence are selected from hydroxyl, -COOH, -COO-alkyl, amido, halo, amino, nitro and cyano; Each of [Aaa1] and [Aaa2] is an independently selected amino acid residue; wherein the C-terminal carboxyl group of the amino acid residue is a free C-terminal carboxyl group (-COOH) or a modified C-terminal carboxyl group, and the N-terminal amino group of the amino acid residue is is the free N-terminal amino group (-NH2) or a modified N-terminal amino group; R a is hydrogen or alkyl; R b is hydrogen or alkyl; or R band R2 together with the atom to which it is attached may form a pyrrolidine or piperidine optionally substituted with one or more groups independently selected from hydroxyl, halo, amino, cyano, and alkyl; R c is (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein said (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from carboxylic acid, hydroxyl, alkyl, alkoxy, amino, alkylamino, acylamino, carboxylate, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl or (heteroaryl)alkyl; m and n are independently integers selected from 1 to 3; p is an integer selected from 1 to 2; with the proviso that R2 is the side chain of Asp, Asn, Glu, or Gln, R3 is hydrogen, -CO-Ser, or -CO-Thr, R6 is hydrogen, alkyl, or acyl, and R a and R b is hydrogen, provided that R1 is not the side chain of Ser or Thr.

[0021] In certain embodiments, the compound of the present invention has formula (I):

[0022] [ka] (In the formula, X is O or S; Each dotted line [-----] independently represents an optional double bond; R a and R bare each independently hydrogen or a substituent such as alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl; R1 is (C1-C6)alkyl substituted by one or more substituents selected from amino, alkylamino, acylamino, heterocyclyl, heteroaryl, guanidino, (heterocyclyl)alkyl and (heteroaryl)alkyl, where any heterocyclyl or heteroaryl contains at least one nitrogen atom, and R1 is a substituted or unsubstituted aryl group having a pK of greater than 3, preferably greater than 5, for the conjugate acid. a and optionally two or three carbon atoms of the (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R2 is one or more substituents selected from carboxylate, carboxylic acid, carboxylic ester, thiocarboxylate, thioacid, amide, amino and heterocyclyl; where two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl are optionally part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R3 is hydrogen or -CO-Aaa; Aaa represents an amino acid residue containing a side chain that includes an -OH, -O-acyl, -SH, -NH2, or NH(alkyl) moiety; each of R4 and R5 is hydrogen or absent; R6 represents hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, amino, aminoalkyl, hydroxyalkyl, alkoxyalkyl, or acyl, or a pharma- ceutically acceptable salt thereof.

[0023] Formula (I)

[0024] [ka] In a further embodiment of the compound, or a pharma- ceutical acceptable salt or stereoisomer thereof, ----- is an optional double bond; X is O or S; R1 and R2 are independently the side chain of an amino acid, or (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; where (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl are substituted by one or more substituents selected from amino, alkylamino, acylamino, -COO-alkyl, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl) alkyl, (heterocyclyl) alkyl, and (heteroaryl) alkyl; optionally two or three carbon atoms of the (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R3 is hydrogen, -CO-[Aaa], -CONR7R8, (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are substituted by one or more substituents selected from amino, alkylamino, acylamino, -COO-alkyl, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); R4 and R5 are independently hydrogen or absent; R6 is hydrogen, alkyl, or acyl; R7 and R8 are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl and (C2-C6)alkynyl are substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring); or R7 and R8, together with the nitrogen to which they are attached, form an optionally substituted 3-7 membered ring containing 0-2 additional heteroatoms independently selected from N, O and S in any stable combination; wherein the optional substituents at each occurrence are selected from hydroxyl, -COOH, -COO-alkyl, amido, halo, amino, nitro or cyano; [Aaa1] is an amino acid residue; Ra is hydrogen or alkyl; R b is hydrogen or alkyl; or R b and R2 together with the atom to which it is attached may form a pyrrolidine or piperidine optionally substituted with one or more groups independently selected from hydroxyl, halo, amino, cyano and alkyl; with the proviso that R2 is the side chain of Asp, Asn, Glu, or Gln, R3 is hydrogen, -CO-Ser, or -CO-Thr, and R a and R b is hydrogen, provided that R1 is not the side chain of Ser, Thr, Lys, Arg, or His.

[0025] In certain preferred embodiments of formula (I), X is O. In certain such embodiments, the ring containing X is an oxadiazole ring.

[0026] In certain embodiments, R1 or R2 represents the side chain of an amino acid. Alternatively, R1 or R2 may represent hydrogen.

[0027] In certain embodiments, R1 and R2 may independently represent (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or cycloalkyl, where (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, and cycloalkyl are substituted with carboxylic acid, carboxylate, carboxylic acid ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, and aryl. In certain such embodiments, R1 and R2 may independently represent (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl substituted with carboxylic acid ester, thiocarboxylate, thioacid, or cycloalkyl.

[0028] In certain embodiments, R1 is the side chain of an amino acid, or hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or cycloalkyl; where (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and cycloalkyl are optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, -SH, and -S(alkyl); and where cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally substituted with one or more substituents selected from hydroxy, alkoxy, halo, cycloalkyl ... and optionally, two or three of the carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring).

[0029] In certain embodiments, R1 is (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; where the (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl are optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH, and -S(alkyl).

[0030] In certain embodiments, R1 is a (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl substituted with one or more substituents selected from amino, alkylamino, acylamino, heterocyclyl, heteroaryl, and guanidino, optionally further substituted with one or more substituents such as alkyl, alkoxy, aralkyl, or aryl.

[0031] In certain embodiments, R1 is (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl, substituted by amino, alkylamino, acylamino, heterocyclyl, heteroaryl, guanidino, (heterocyclyl) alkyl, where the (heteroaryl) alkyl, heterocyclyl, or heteroaryl contains at least one basic nitrogen atom. a This refers to nitrogen that is protonated and positively charged at pH levels below the pK value of the conjugate acid of a nitrogen-containing compound. a is >5, preferably >7. In certain such embodiments, R1 is optionally further substituted with one or more substituents, such as alkyl, alkoxy, aralkyl, or aryl.

[0032] In some embodiments, R1 represents a carboxylate, a carboxylic acid, a carboxylic acid ester, a thiocarboxylate, a thioacid, -CONR7R8, a (C1-C6) alkyl, a (C2-C6) alkenyl, or a (C2-C6) alkynyl substituted with one or more substituents selected from a carboxylate, a thiocarboxylate, a thioacid, -CONR7R8, a hydroxy, a cycloalkyl, an aryl, a guanidino, -SH, and -S(alkyl). In some such embodiments, R1 represents a (C1-C6) alkyl, a (C2-C6) alkenyl, or a (C2-C6) alkynyl substituted with one or more substituents selected from a carboxylic acid ester, a thiocarboxylate, a thioacid, or a cycloalkyl.

[0033] According to any of the foregoing embodiments, in certain embodiments, R1 is (C1-C4)alkyl substituted with one or more substituents selected from amino, heteroaryl, or guanidino. In certain embodiments, R1 is -(CH2)imidazolyl, -(CH2)3NHC(=N)-NH2, or -(CH2)4NH2.

[0034] In certain embodiments, R2 is the side chain of an amino acid, or hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, or cycloalkyl; where (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and cycloalkyl are selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylic ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, optionally substituted by one or more substituents selected from guanidino, -SH and -S (alkyl); optionally cycloalkyl, aryl, heterocyclyl and heteroaryl are further substituted by one or more substituents such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; and optionally two or three carbon atoms of the (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring).

[0035] In certain embodiments, R2 is (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; where (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl are optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, aryl, heterocyclyl, (heterocyclyl) alkyl, heteroaryl, (heteroaryl) alkyl, guanidino, -SH, and -S(alkyl). In some such embodiments, R2 represents (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl substituted with one or more substituents selected from alkylamino, acylamino, cycloalkyl, and (heterocyclyl) alkyl.

[0036] In certain embodiments, R2 is (C1-C6)alkyl substituted by one or more substituents selected from carboxylate, carboxylic acid, carboxylic ester, thiocarboxylate, thioacid, amide, amino, and heterocyclyl, and optionally further substituted by one or more substituents, such as alkyl, alkoxy, aralkyl, or aryl. In certain such embodiments, R2 further optionally includes one or more double or triple bonds. In certain embodiments, R2 is (C3-C8)cycloalkyl substituted by one or more substituents selected from carboxylate, carboxylic acid, thiocarboxylate, thioacid, amide, ester, amino, and heterocyclyl, and additionally optionally substituted by one or more further substituents, such as alkyl, alkoxy, aralkyl, or aryl.

[0037] According to any of the foregoing embodiments, in certain embodiments, R2 is (C1-C4) alkyl substituted with one or more substituents selected from carboxylate, carboxylic acid, and amide. In certain embodiments, R2 is -(CH2)COOH, -(CH2)2COOH, -(CH2)CONH2, or -(CH2)2CONH2. In certain such embodiments, R2 is -(CH2)2C(O)NH2, -CH2C(O)NH2, -(CH2)2C(O)NH(alkyl), or -CH2C(O)NH(alkyl).

[0038] In some embodiments, R2 represents amino, alkylamino, acylamino, hydroxy, cycloalkyl, aryl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl substituted with one or more substituents selected from -SH and -S(alkyl). In some such embodiments, R2 represents (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl substituted with one or more substituents selected from alkylamino, acylamino, cycloalkyl, and (heterocyclyl)alkyl.

[0039] In certain embodiments, R3 is hydrogen, -CO-[Aaa1] m , [Aaa1] m , [Aaa1] m -CO-[Aaa1] m or -S(O) p -[Aaa1] m It is.

[0040] In certain embodiments, R3 is -CO-Aaa1, and the side chain of Aaa1 comprises a (C1-C4)alkyl group optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH, and -S(alkyl); the cycloalkyl, aryl, heterocyclyl, and heteroaryl are optionally further substituted with one or more substituents, such as hydroxy, alkoxy, halo, amino, nitro, cyano, or alkyl.

[0041] Or R3 is -CO-[Aaa1] m In another embodiment, R3 may represent [Aaa1] m , [Aaa1] m -CO-[Aaa1] m or -S(O)p-[Aaa1] m (wherein m is an integer from 1 to 3).

[0042] In further embodiments, the side chain of Aaa1 comprises a (C1-C4)alkyl group substituted with one or more substituents selected from amino, acylamino, carboxylic acid, -CONR7R8, hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, -SH and -S(alkyl); where R7 and R8 are independently hydrogen, alkyl, aryl or heterocyclyl.

[0043] In yet another embodiment, R3 may represent carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, (C1-C6) alkyl substituted by hydroxy, -SH and -S(alkyl), (C2-C6) alkenyl, or (C2-C6) alkynyl. In particular, R3 is CONR7R8; where R7 and R8 are independently hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; where (C1-C6) alkyl, (C2-C6) alkenyl, and (C2-C6) alkynyl are substituted by one or more substituents selected from hydrogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl) alkyl, (heterocyclyl) alkyl, and (heteroaryl) alkyl.

[0044] In yet another embodiment, R3 may represent -CONR7R8, where R7 and R8 are independently hydrogen, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; where (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring (such as a cyclobutyl or oxirane ring).

[0045] In certain embodiments, R3 is -COR c or -SO2R c where R cis (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein said (C1-C6)alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from carboxylic acid, hydroxyl, alkyl, alkoxy, amino, alkylamino, acylamino, carboxylate, cycloalkyl, heterocyclyl, heteroaryl, (cycloalkyl)alkyl, (heterocyclyl)alkyl or (heteroaryl)alkyl.

[0046] Or R3 is -COR c or -SO2R c where R c is a (C1-C6) alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, wherein said (C1-C6) alkyl, aryl, heterocyclyl or heteroaryl is optionally substituted by one or more substituents selected from carboxylic acid, hydroxyl, alkyl, amino or acylamino.

[0047] In yet other embodiments, R3 may represent a carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl substituted with hydroxy, -SH, and -S(alkyl).

[0048] In certain embodiments, R6 is hydrogen, alkyl, [Aaa2] n or -CO-[Aaa2] n R6 is -CO-[Aaa2] n Alternatively, R6 can be H.

[0049] In certain embodiments, R6 is -CO-Aaa2, and the side chain of Aaa2 comprises a (C1-C4)alkyl group optionally substituted with one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH, -S(alkyl); the cycloalkyl, heterocyclyl and heteroaryl are optionally further substituted with one or more substituents, such as hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl.

[0050] In further embodiments, the side chain of Aaa2 comprises a (C1-C4)alkyl group substituted with one or more substituents selected from amino, acylamino, carboxylic acid, -CONR7R8, hydroxy, cycloalkyl, aryl, heteroaryl, guanidino, -SH, and -S(alkyl); where R7 and R8 are independently hydrogen or alkyl.

[0051] In certain embodiments, Aaa1 or Aaa2 represents an amino acid residue containing a side chain that includes an -OH, -O-acyl, -SH, -NH2, or NH(alkyl) moiety.

[0052] In certain embodiments, R7 is (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl, and (heteroaryl)alkyl.

[0053] In certain embodiments, R8 is (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl substituted by one or more substituents selected from halogen, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl, and (heteroaryl)alkyl.

[0054] In certain embodiments, R a is alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl.

[0055] In certain embodiments, R1 is the side chain of an amino acid, or hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, or cycloalkyl. wherein the (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and cycloalkyl are optionally substituted by one or more substituents selected from amino, alkylamino, acylamino, carboxylic acid, carboxylate, carboxylate ester, thiocarboxylate, thioacid, -CONR7R8, hydroxy, cycloalkyl, (cycloalkyl)alkyl, aryl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, (heteroaryl)alkyl, guanidino, -SH and -S(alkyl); optionally the cycloalkyl, aryl, heterocyclyl and heteroaryl are further substituted by one or more substituents, for example hydroxy, alkoxy, halo, amino, nitro, cyano or alkyl; and optionally two or three carbon atoms of the (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl form part of a 3- to 7-membered carbocyclic or heterocyclic ring, such as a cyclobutyl or oxirane ring; and R ais hydrogen or alkyl, alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl.

[0056] In certain embodiments, R b is alkenyl, alkynyl, acyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, hydroxyalkyl, or alkoxyalkyl. b and R2 together with the atoms to which they are attached form a pyrrolidine or piperidine ring optionally substituted with one or more groups independently selected from hydroxyl, halo, amino, cyano and alkyl.

[0057] In certain embodiments, the present invention provides a compound of formula (IA):

[0058] [ka] (In the formula, R1, R2, R3, R6, R a and R b is the same as defined in formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0059] In certain embodiments of the compounds of Formula (I) or Formula (IA), R b is H.

[0060] In a further embodiment of the compound of formula (I) or (IA), R3 is -CO-[Aaa1] m It is.

[0061] For example, the compound of the present invention has the formula (IB):

[0062] [ka] (In the formula, R1, R2, R6, R a wherein, [Aaa1] and m are the same as defined in formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0063] In certain embodiments, the present invention provides a compound of formula (IC):

[0064] [ka] wherein R1, R2, [Aaa1] and m are the same as defined in formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0065] In certain embodiments, the present invention provides a compound of formula (ID):

[0066] [ka] (In the formula, R1, R2, R3, R a , R b [Aaa2] and n are the same as defined in formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0067] In certain embodiments, the present invention provides a compound of formula (IE):

[0068] [ka] (In the formula, R1, R2, R a , R b [Aaa2] and n are the same as defined in formula (I), or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0069] It is understood in the art that an amino acid residue refers to a carboxylic acid substituted at the α, β or γ carbon position by an amino (-NH2) group. In the group -CO-Aaa, the amino acid residue Aaa is linked to the carbonyl group CO via a covalent bond between the carbonyl carbon and the amino group of the amino acid residue. In a preferred embodiment, the amino acid is an α-amino acid, and the amino acid residue Aaa is linked to the carbonyl group CO via a covalent bond between the carbonyl carbon and the α-amino group of the amino acid residue.

[0070] According to any of the preceding embodiments, in certain embodiments, X is O.

[0071] According to any of the preceding embodiments, in certain embodiments of formula (I), (IA) or (ID), R3 is hydrogen.

[0072] According to any of the foregoing embodiments, in certain embodiments of formula (I), (IA) or (ID), R3 is -CO-Aaa.

[0073] According to any of the foregoing embodiments, in certain embodiments of formula (I), (IA), (IB), (IC), (ID) or (IE), R1 is alkyl substituted with amino or heteroaryl. Preferably, R1 is -(CH2)4NH2.

[0074] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of an amino acid.

[0075] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of an amino acid.

[0076] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of Lys, Tyr, Gln, Ser, Ala, Glu, Leu, Asp, or His.

[0077] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of Lys, Tyr, or Gln.

[0078] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of Tyr.

[0079] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of Lys. It is.

[0080] According to any of the preceding embodiments, in certain embodiments, R1 is the side chain of Gln.

[0081] In another embodiment, R1 does not represent the side chain of Ser or Thr, i.e., R1 is not -CH2OH or -CH(CH3)OH. In yet another embodiment, R1 is not the side chain of an alkylated or acylated Ser or Thr. For example, in certain embodiments, R1 is not -CH2OCH3, -CHOAc, -CH(CH3)OCH3 or -CH(CH3)OAc. In a further embodiment, R1 does not represent the side chain of an optionally alkylated or acylated Ser or Thr, i.e., R1 is not -CH2OH, -CH(CH3)OH, -CHOCH3, -CHOAc, -CH(CH3)OCH3 or -CH(CH3)OAc.

[0082] According to any one of the above embodiments, in certain embodiments of formula (I), (IA), (IB), (IC), (ID) or (IE), R2 is alkyl substituted with amide. In certain embodiments, R2 is -(CH2)2C(O)NH2 or -CH2C(O)NH2. Preferably, R2 is -CH2C(O)NH2.

[0083] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of Gly, Gln, Glu, Ser, Asn, Asp, Ala, or Ile.

[0084] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of Gln, Glu, Asn, Asp, or Ile.

[0085] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of Ile.

[0086] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of Ala.

[0087] According to any of the preceding embodiments, in certain embodiments, R2 is the side chain of Asn.

[0088] In another embodiment, R2 does not represent the side chain of Asn, Asp, Gln, or Glu, i.e., R2 is not -CH2C(O)NH2, -CH2C(O)OH, -CH2CH2C(O)NH2 or -CH2CH2C(O)OH.

[0089] According to any of the foregoing embodiments, in certain embodiments, R b and R2 together with the atom to which it is attached may form a pyrrolidine optionally substituted with a hydroxyl.

[0090] According to any of the preceding embodiments, in certain embodiments, m is 1.

[0091] According to any of the preceding embodiments, in certain embodiments, [Aaa1] includes a side chain that includes an --OH moiety.

[0092] According to any of the foregoing embodiments, in certain embodiments, [Aaa1] is Ala, Thr, Ile, Glu, Lys, Asp, Tyr, Gln, Ser, or Phe.

[0093] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Ser, Thr, Tyr, Glu, Ala, or Ile.

[0094] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Tyr.

[0095] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Glu.

[0096] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Ala.

[0097] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Thr.

[0098] According to any of the preceding embodiments, in certain embodiments, [Aaa1] is Ile.

[0099] In another embodiment, R3 is -CO-[Aaa1], wherein Aaa1 does not represent the amino acid residues Thr or Ser.

[0100] In yet another embodiment, R3 is not H or -CO-[Aaa1].

[0101] According to any of the preceding embodiments, in certain embodiments, n is 1.

[0102] According to any of the foregoing embodiments, in certain embodiments, [Aaa2] is Ala, Thr, Ile, Glu, Lys, Asp, Tyr, Gln, Ser, or Phe.

[0103] According to any of the preceding embodiments, in certain embodiments, [Aaa2] is Ser, Thr, Tyr, Glu, Ala, or Ile.

[0104] According to any of the preceding embodiments, in certain embodiments, p is 2.

[0105] According to any of the preceding embodiments, in certain embodiments one, more, or all of the amino acid residues are D-amino acid residues.

[0106] According to any of the foregoing embodiments, in certain embodiments one, more than one, or all of the amino acid residues are L-amino acid residues.

[0107] In certain embodiments, the present invention provides a method for producing

[0108] [Table 1] TIFF0007659015000011.tif244170 TIFF0007659015000012.tif251170 TIFF0007659015000013.tif242170 TIFF0007659015000014.tif254170 TIFF0007659015000015.tif252170 TIFF0007659015000016.tif249165 TIFF0007659015000017.tif243170 TIFF0007659015000018.tif232170 TIFF0007659015000019.tif246170 TIFF0007659015000020.tif249170 TIFF0007659015000021.tif249170 TIFF0007659015000022.tif242170 TIFF0007659015000023.tif233170 TIFF0007659015000024.tif229170 The present invention provides a compound selected from the group consisting of: TIFF0007659015000025.tif205170, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0109] In certain embodiments, the compounds of the present invention may be prodrugs of compounds of formula (I), for example, where a hydroxyl in the parent compound is present as an ester or carbonate, or a carboxylic acid present in the parent compound is present as an ester. In further embodiments, the prodrug is metabolized in vivo to the active parent compound (e.g., an ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).

[0110] In certain embodiments, the compounds of the present invention also include any of the atoms constituting such compounds. One or more positions may contain unnatural proportions of atomic isotopes.For example, the present invention also encompasses the isotopically labeled variants of the present invention that are identical to those listed herein, except for the fact that one or more atoms of the compound are replaced by an atom that has a different atomic mass or mass number from the predominant atomic mass or mass number that is usually found in nature for the atom.All isotopes of any individual atom or element specified are contemplated within the scope of the compounds of the present invention and their use.Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, e.g. 2 H("D"), 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 35 S, 18 F, 36 Cl, 123 I and 125Isotopically labeled compounds of the present invention can generally be prepared by procedures similar to those disclosed in the following schemes and / or examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0111] Pharmaceutical Compositions In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound disclosed herein, optionally in admixture with a pharma- ceutically acceptable carrier or diluent.

[0112] The invention also provides methods of formulating the disclosed compounds for pharmaceutical administration.

[0113] The compositions and methods of the present invention can be used to treat an individual in need. 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 compositions or the compounds are preferably administered as a pharmaceutical composition, for example comprising the compound of the present invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers, such as 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, are well known in the art. In a preferred embodiment, if such pharmaceutical compositions are for administration to humans, particularly for invasive routes of administration (i.e., routes such as injection or implantation that avoid transport or diffusion through epithelial barriers), the aqueous solutions are pyrogen-free or substantially pyrogen-free. Excipients can be selected, for example, to effect delayed release of the drug or to selectively target one or more cells, tissues or organs. The pharmaceutical composition may be in unit dosage form such as tablets, capsules (such as sprinkle capsules and gelatin capsules), granules, lyophilisates to be reconstituted, powders, solutions, syrups, suppositories, injections, etc. The composition may also be in a transdermal delivery system, such as a skin patch. The composition may also be in a solution suitable for topical administration, such as eye drops.

[0114] Pharmaceutically acceptable carriers may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility, or increase absorption of compounds such as the compounds of the present invention. Such physiologically acceptable agents include carbohydrates such as glucose, sucrose, or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharma-ceutically acceptable carriers, including physiologically acceptable agents, depends, for example, on the route of administration of the composition. The pharmaceutical composition preparation may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be, for example, a liposome or other polymer matrix that can incorporate the compounds of the present invention therein. Liposomes, for example, including phospholipids or other lipids, are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0115] The phrase "pharmaceutical acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are suitable, within the limits of sound medical judgment, for use in contact with the tissues of humans and animals, without causing excessive toxicity, hypersensitivity, allergic response or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0116] As used herein, the phrase "pharmaceutical acceptable carrier" refers to a pharma- ceutically 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 harmful to the patient. Some examples of materials that can serve as pharma-ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and cellulose derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) soluble oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) oils, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, 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 used in pharmaceutical formulations.

[0117] The pharmaceutical compositions (preparations) can be administered to a subject by any of a number of routes of administration, including, for example, orally (e.g., drenches, such as aqueous or non-aqueous solutions or suspensions, tablets, capsules (such as sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes applied to the tongue, etc.); absorption through the oral mucosa (e.g., sublingually); anally, rectally, or vaginally (e.g., as a pessary, cream, or foam); parenterally (intramuscularly, intravenously, subcutaneously, or intrathecally, e.g., as a sterile solution or suspension); intranasally; intraperitoneally; subcutaneously; transdermally (e.g., as a patch applied to the skin); and topically (e.g., as a cream, ointment, or spray applied to the skin, or as eye drops). The compounds can also be formulated for inhalation. In certain embodiments, the compounds can simply be dissolved or suspended in sterile water. Details of suitable routes of administration and compositions suitable therefor can be found, for example, in 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, and in the patents cited therein.

[0118] The formulation may conveniently be in a unit dosage form and may be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form will vary depending on the host being treated, the individual mode of administration. The amount of active ingredient that can be mixed with the carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally, out of 100%, this amount will be within the range of about 1% to about 99% of the active ingredient, preferably about 5% to about 70%, most preferably about 10% to about 30%.

[0119] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the present invention, with the carrier, and, optionally, one or more accessory ingredients. 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.

[0120] Formulations of the present invention suitable for oral administration may be in the form of capsules (such as sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (containing a flavored base, usually sucrose and acacia or tragacanthus), each containing a predetermined amount of a compound of the present invention as the active ingredient. The composition or compound may be administered in the form of a bolus, electuary, powder, granules, or as a solution or 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 a pastille (with an inert base such as gelatin and glycerin or sucrose and acacia) and / or as a mouthwash, etc. The composition or compound may also be administered as a bolus, electuary, or paste.

[0121] 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 pharma- ceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, 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) dissolution retarders such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as 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 (such as sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also include buffering agents. Similar types of solid compositions may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0122] Tablets can be made by compression or molding, optionally with one or more accessory ingredients.Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents or dispersants.Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0123] Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (such as sprinkle capsules and gelatin capsules), pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical compounding. They can also be formulated to provide slow or controlled release of the active ingredient, for example using hydroxypropylmethylcellulose in various proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example by 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 can also optionally contain opacifying agents, and can be compositions that release the active ingredient(s) only, or preferentially, in a certain part 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 microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0124] Liquid dosage forms useful for oral administration include pharma- ceutically acceptable emulsions, lyophilizates to be reconstituted, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain, in addition to the active ingredient, inert diluents commonly used in the art, such as water or other solvents, cyclodextrins and their derivatives, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0125] 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.

[0126] Suspensions may contain, in addition to the active compound, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0127] Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration can be present as suppositories, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which are solid at room temperature but liquid at body temperature and thereby melt in the rectum or vaginal cavity to release the active compound.

[0128] Formulations of pharmaceutical compositions for administration to the mouth may be present as a mouthwash or an oral spray or an oral ointment.

[0129] Alternatively or additionally, the compositions may be formulated for delivery via a catheter, stent, wire or other intraluminal device, which may be particularly useful for delivery to the bladder, urethra, ureter, rectum or intestine.

[0130] 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.

[0131] Dosage forms for external 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 pharma- ceutical acceptable carrier and any preservatives, buffers or propellants that may be required.

[0132] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, salicylic acid, talc and zinc oxide, or mixtures thereof.

[0133] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.In addition, sprays can contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0134] Transdermal patch has the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing active compound in suitable medium.Absorption enhancers can also be used to increase the permeation of the compound through the skin.The rate of such permeation can be controlled by either providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0135] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated within the scope of the present invention. Exemplary ophthalmic formulations are described in U.S. Patent Application Publication Nos. 2005 / 0080056, 2005 / 0059744, 2005 / 0031697, and 2005 / 004074, the contents of which are incorporated herein by reference, and U.S. Patent No. 6,583,124. If desired, the liquid ophthalmic formulation has properties similar to those of tears, aqueous humor, or vitreous humor, or is compatible with such fluids. The preferred route of administration is topical administration (e.g., external administration such as eye drops or administration via implant).

[0136] As used herein, the phrases "parenteral administration" and "administered parenterally" refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0137] Pharmaceutical compositions suitable for parenteral administration contain one or more active compounds in association with one or more pharma- ceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions immediately before use, and which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0138] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained by using coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by using surfactants.

[0139] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersing agents. Prevention of microbial action may be ensured by the inclusion of various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may be desirable to include isotonic agents such as sugars, sodium chloride, etc. in the composition. In addition, prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0140] 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 can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. In this case, the absorption rate of the drug depends on the dissolution rate, which may also depend on the 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.

[0141] 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 used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. can be.

[0142] When used in the methods of the invention, the active compound may be provided as is or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in association with a pharma- ceutically acceptable carrier.

[0143] The introduction method can also be provided by rechargeable or biodegradable devices.Various delayed release polymeric devices, including proteinaceous biologics, have been developed and tested in vivo in recent years for controlled drug delivery.Various biocompatible polymers, including both biodegradable and non-degradable polymers (such as hydrogels), can be used to form implants for sustained release of compounds at individual target sites.

[0144] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied to obtain an amount of the active ingredient effective to achieve a desired therapeutic response for a particular patient, administration composition and mode without causing toxicity to the patient.

[0145] The selected dosage level will depend on a variety of factors, such as the activity of the particular compound, the combination of compounds or their esters, salts or amides used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) used, the age, sex, weight, illness, general health, past medical history of the patient being treated, and similar factors well known in the medical arts.

[0146] A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can begin the dosage of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. A "therapeutically effective amount" refers to a compound concentration sufficient to induce the desired therapeutic effect. It is generally understood that the effective amount of a compound varies according to the subject's weight, sex, age, and medical history. Other factors that affect the effective amount include, but are not limited to, the severity of the patient's illness, the disorder being treated, the stability of the compound, and other types of therapeutic agents administered together with the compound of the present invention, if desired. A larger total dose can be delivered by repeated administration of the agent. Methods for determining 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, incorporated herein by reference).

[0147] In general, a suitable daily dose of an active compound used in the compositions and methods of the present invention will be that amount of the compound that is the minimum dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0148] If desired, the effective daily dose of the active compound can be administered separately at appropriate intervals throughout the day, as 1, 2, 3, 4, 5, 6 or more divided doses, optionally in unit dosage form.In certain embodiments of the present invention, the active compound can be administered 2 or 3 times a day.In a preferred embodiment, the active compound is administered once a day.

[0149] The patients to be treated are primates, particularly humans, and other mammals, such as horses, cattle, pigs and sheep, and generally any animal in need, such as poultry and pets.

[0150] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

[0151] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, and sodium sulfite; (2) fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0152] Treatment Programmed cell death protein 1 (PD-1) pathway is associated with multiple diseases and illnesses, and is known to regulate various immune responses.Many studies have explored targeting PD-1 pathway to activate immune response, thereby providing treatment for certain diseases, such as cancer.Indeed, studies have shown that blocking PD-1 pathway, for example by inhibiting the immunosuppressive signal induced by PD-1, PD-LI or PD-L2, leads to antitumor activity in various cancers, such as lung cancer, breast cancer, colon cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma and Hodgkin's lymphoma.

[0153] Furthermore, PD-1 activity has also been implicated in autoimmune diseases such as lupus erythematosus, juvenile idiopathic arthritis and allergic encephalomyelitis.

[0154] In certain embodiments, the present invention provides the use of a compound of the present invention for the preparation of a medicament, such as for the treatment of cancer.

[0155] In certain embodiments, the present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0156] In certain embodiments, the present invention provides methods of inhibiting tumor cell growth and / or metastasis by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0157] In certain embodiments, the present invention provides methods of inhibiting tumor cell growth and / or metastasis by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0158] In certain embodiments, the present invention provides a method of treating cancer by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0159] Representative tumor cells include, but are not limited to, melanoma, kidney cancer, prostate cancer, breast cancer, colon cancer, and lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, cancer of the fallopian tubes, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, 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, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic ... and / or cells of cancers such as chronic or acute leukemias, such as chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal pelvis cancer, neoplasms of the central nervous system (CNS), non-small cell lung cancer (NSCLC), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, such as asbestos induced cancers, and combinations of the above cancers.

[0160] In certain embodiments, the present invention provides a method of treating a cancer selected from lung cancer, breast cancer, colon cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma, and Hodgkin's lymphoma.

[0161] In certain embodiments, the present invention provides a method of treating a bacterial, viral or fungal infection, or an immune disease by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt and stereoisomer thereof.

[0162] In certain embodiments, the present invention provides the use of a compound of the present invention for preparing a medicament for the treatment of bacterial, viral and fungal infections, and a method of administering a therapeutically effective amount of a compound of the present invention for the treatment of bacterial, viral or fungal infections.

[0163] In certain embodiments, the present invention provides the use of a compound of formula (I) for preparing a medicament for the treatment of bacterial, viral and fungal infections, and a method of administering a therapeutically effective amount of a compound of formula (I) or a pharma- ceutical acceptable salt and stereoisomer thereof for the treatment of bacterial, viral or fungal infections.

[0164] Yet another embodiment of the invention provides a method for treating an infection by blockade of the PD-1 pathway, e.g., inhibiting immunosuppressive signals induced by PD-1, PD-L1, or PD-L2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

[0165] In certain embodiments, the invention provides for the use of the compounds of the invention in inhibiting the PD-1 pathway (eg, PD-1, PD-L1, or PD-L2).

[0166] In certain embodiments, the present invention provides a method of treating an infectious disease in a subject, comprising administering a therapeutically effective amount of a compound of the present invention for treating the infectious disease.

[0167] In certain embodiments, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt and stereoisomer thereof, for use as a medicament.

[0168] In certain embodiments, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt and stereoisomer thereof, for use in the treatment of cancer.

[0169] In certain embodiments, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt and stereoisomer thereof, for use in the treatment of lung cancer, breast cancer, colon cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma, and Hodgkin's lymphoma.

[0170] In certain embodiments, the present invention provides a compound of formula (I), or a pharma- ceutically acceptable salt and stereoisomer thereof, for use in the treatment of a bacterial, viral or fungal infection, or an immune disorder.

[0171] Representative infectious diseases include HIV, influenza, herpes, giardia, malaria, leishmania, hepatitis viruses (A, B, & C), herpes viruses (e.g., VZV, HSV-I, HAV-6, HSV-II and CMV, Epstein-Barr virus), adenovirus, influenza virus, flavivirus, ecovirus, rhinovirus, coxsackievirus, cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, and rabies virus. Pathogenic infections with vaccinia virus, HTLV virus, dengue virus, papilloma virus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus, chlamydia bacteria, rickettsia bacteria, mycobacteria, staphylococcus, streptococcus, pneumonococcus, meningococcus and gonococci, klebsiella, proteus, serratia, pseudomonas, Escherichia coli, legionella, diphtheria, salmonella, bacillus, cholera, tetanus, botulinum, anthrax, plague, leptospira and lyme burgdorferi, candida fungi (albicans, krusei, glabrata, tropicalis, etc.), cryptococcus neoformans, aspergillus, erythropoietin ... These include, but are not limited to, pathogenic infections by Gills (e.g., Fumigatus, Niger), Mucorales (Mucor, Absidia, Rhizophus), Sporothrix schenckii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Cocchidioides immitis and Histoplasma capsulatum, as well as pathogenic infections by Entamoeba histolytica parasites, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lamblia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii and Ancylostoma braziliensis.

[0172] The compounds of the present invention can be used as a single drug (monotherapy) or in conjunction with one or more other drugs (conjoint therapy).The compounds can be used alone or, preferably, in a pharmaceutical composition in which the compounds are mixed with one or more pharma- ceutically acceptable materials.

[0173] The pharmaceutical composition can be administered by oral or inhalation route, or by parenteral administration route.For example, the composition can be administered orally, intravenous infusion, topically, intraperitoneally, intravesically or intrathecally.Examples of parenteral administration include, but are not limited to, intra-articular (inside a joint), intravenous, intramuscular, intradermal, intraperitoneal and subcutaneous routes.Suitable liquid compositions can be aqueous or non-aqueous isotonic sterile injection solutions, and can include aqueous and non-aqueous sterile suspensions that can contain antioxidants, buffers, bacteriostatic agents, solutes that make the formulation isotonic with the blood of the intended recipient, as well as suspending agents, solubilizers, thickeners, stabilizers and preservatives.Oral, parenteral, subcutaneous and intravenous administration are the preferred methods of administration.

[0174] The dosage of the compound of the present invention varies depending on the age, weight or symptoms of the patient as well as the efficacy or therapeutic effectiveness of the compound, the administration regimen, and / or the duration of treatment. In general, suitable routes of administration can include, for example, oral, ophthalmic, rectal, mucosal, topical or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injection. The compound of the present invention can be administered in an amount of 0.5 mg or 1 mg to 500 mg, 1 g or 2 g per administration regimen. The dosage can be administered once a week, once every three days, once every two days, once a day, twice a day, three times a day, or more frequently. In another embodiment, the compound in a particular adult can be administered continuously by intravenous administration for a period designed by a physician. The dosage can be affected by various conditions, and therefore can be implemented in a smaller or larger amount than the intended dosage range in certain instances. A physician can readily determine the dosage appropriate for a patient undergoing therapeutic treatment.

[0175] The compounds of the present invention may be administered in combination with one or more other drugs to (1) supplement and / or enhance the effects of the compounds of the present invention, (2) adjust the pharmacodynamic action, improve absorption, or reduce the dosage of the compounds of the present invention, and / or (3) reduce or ameliorate the side effects of the compounds of the present invention. As used herein, the phrase "conjoint administration" refers to any of the administration of two or more different therapeutic compounds, in which a second compound is administered while a previously administered therapeutic compound is still effective in the body. It refers to a form in which two compounds are effective in a patient at the same time, and may include a synergistic effect of two compounds. For example, different therapeutic compounds can be administered simultaneously or sequentially, either in the same or separate combinations. In certain embodiments, different therapeutic compounds can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other. Thus, an individual undergoing such treatment can benefit from the combined effect of different therapeutic compounds. Each compound can be administered by the same or different route, and in the same or different manner.

[0176] The dosage of the other drug may be a dosage used in clinical practice, or may be a reduced dosage that is effective when administered in combination with the compound of the present invention. The ratio of the compound of the present invention to the other drug may vary depending on the age and weight of the subject to be administered, the administration method, the administration time, the disorder to be treated, symptoms, and combinations 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.

[0177] Conjoint therapy can be used to treat any disease discussed herein. For example, in the method of the present invention for the treatment of cancer, the compound of the present invention can be used in conjunction with existing chemotherapy drugs using a single pharmaceutical composition or a combination of different pharmaceutical compositions. Examples of chemotherapy drugs include alkylating agents, nitrosoureas, antimetabolites, anticancer antibiotics, plant alkaloids, topoisomerase inhibitors, hormonal drugs, hormone antagonists, aromatase inhibitors, P-glycoprotein inhibitors, platinum complex derivatives, other immunotherapeutic drugs, and other anticancer drugs. In addition, the compound of the present invention can be administered conjointly with cancer treatment adjuncts such as leukopenia (neutropenia) treatment drugs, thrombocytopenia treatment drugs, antiemetic drugs, and cancer pain intervention drugs, simultaneously or in mixed form.Chemotherapeutic agents that may be administered in conjugate with the compounds of the invention include aminoglutethimide, amsacrine, anastrozole, asparaginase, BCG, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, and 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.

[0178] In certain embodiments, the compounds of the present invention may be administered conjointly with non-chemical methods of cancer treatment. In further embodiments, the compounds of the present invention may be administered conjointly with radiation therapy. In further embodiments, the compounds of the present invention may be administered conjointly with surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.

[0179] In certain embodiments, different compounds of the present invention can be conjointly administered with one or more other compounds of the present invention.Moreover, such combinations can be conjointly administered with other therapeutic agents, such as previously identified agents, suitable for treating cancer, immune disease or neurological disease.In certain embodiments, conjointly administering the compounds of the present invention with one or more additional chemotherapeutic agents produces synergistic effects.In certain embodiments, conjointly administering the compounds of the present invention with one or more additional chemotherapeutic agents produces additive effects.

[0180] The compounds of the present invention may be used in conjunction with one or more other immunomodulatory and / or enhancing agents, utilizing a single pharmaceutical composition or a combination of different pharmaceutical compositions. Suitable immunomodulatory agents include various cytokines, vaccines and adjuvants. Examples of cytokines, vaccines and adjuvants that stimulate immune responses include GM-CSF, M-CSF, G-CSF, interferon-α, β or γ, IL-1, IL-2, IL-3, IL-12, Poly(I:C) and C. p Examples include G.

[0181] In certain embodiments, the enhancers include cyclophosphamide and cyclophosphamide analogs, anti-TGFβ and imatinib (Gleevec), mitotic inhibitors such as paclitaxel, sunitinib (Sutent) or other anti-angiogenic agents, aromatase inhibitors such as letrozole, A2a adenosine receptor (A2AR) antagonists, angiogenesis inhibitors, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

[0182] Definitions and Abbreviations: Unless otherwise stated, all technical and scientific terms used herein have the same meaning, and the meaning of such terms is independent at each occurrence and is as commonly understood by those skilled in the art to which the subject matter of this specification belongs. Nevertheless, and unless otherwise stated, the following definitions apply throughout this specification and claims. Chemical names, common names and chemical structures may be used interchangeably to describe the same structure. When a chemical substance is referred to using both a chemical structure and a chemical name, and there is an ambiguity between the structure and the name, the structure takes precedence. These definitions apply regardless of whether the term is used alone or in combination with other terms, unless otherwise stated. Thus, the definition of "alkyl" applies not only to "alkyl" but also to the "alkyl" portion of "hydroxyalkyl", "haloalkyl", "-O-alkyl", etc.

[0183] The term "compounds of the invention" includes compounds according to formula (I), their pharma- ceutically acceptable salts and their stereoisomers.

[0184] The term "acyl" is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0185] The term "acylamino" refers to an amino group substituted with an acyl.

[0186] The term "alkoxy" refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0187] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls," including The latter refers to an alkenyl moiety having a substituent that replaces hydrogen on one or more carbons of the alkenyl group. Such a substituent may be present on one or more carbons that are included or not included in one or more double bonds. Moreover, such a substituent includes all of those contemplated for alkyl groups, as discussed below, except where stability is excessively high. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl or heteroaryl groups is contemplated.

[0188] An "alkyl" group or "alkane" is a straight or branched chain non-aromatic hydrocarbon that is fully saturated. Typically, a straight or branched chain alkyl group has from 1 to about 20, preferably from 1 to about 10, carbon atoms, unless otherwise specified. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl. C1-C6 straight or branched chain alkyl groups are also referred to as "lower alkyl" groups. An alkyl group can be optionally substituted at one or more positions where valence allows. Such optional substituents include, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, and the like.

[0189] The term "alkylamino," as used herein, refers to an amino group substituted with at least one alkyl group.

[0190] The term "alkylthio," as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0191] The term "alkynyl" as used herein refers to an aliphatic group that contains at least one triple bond, and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl", the latter of which refers to an alkynyl moiety that has a substituent replacing hydrogen on one or more carbons of the alkynyl group. Such a substituent may be present on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all of those contemplated for alkyl groups, as discussed above, except where the stability is excessively high. For example, substitution of an alkynyl group with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0192] As used herein, the term "amide" or "amido" refers to a group

[0193] [ka] (In the formula, each R x Any R y independently represent hydrogen or a hydrocarbyl group, or R x Any R y Both of these, together with the N atom to which they are attached, complete a heterocycle having 4 to 8 atoms in the ring structure. Refers to...

[0194] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, as well as their salts, e.g.,

[0195] [ka] (In the formula, each R x independently represent hydrogen or a hydrocarbyl group, or two R x which, together with the N atom to which it is attached, complete a heterocycle having 4 to 8 atoms in the ring structure.

[0196] As used herein, the term "aminoalkyl" refers to an alkyl group substituted with an amino group.

[0197] The terms "aralkyl" or "arylalkyl," as used herein, refer to an alkyl group substituted with an aryl group.

[0198] The term "aryl" as used herein includes substituted or unsubstituted monocyclic 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 rings, in which two or more carbons are common to two adjacent rings, at least one of the rings is aromatic, and the other rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0199] A "cycloalkyl" group is a fully saturated cyclic hydrocarbon. "Cycloalkyl" includes monocyclic and bicyclic compounds. Typically, monocyclic cycloalkyl groups have 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms, unless otherwise specified. The second ring of a bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three, or more atoms are shared between the two rings. The term "fused cycloalkyl" refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring. The second ring of a fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. "Cycloalkenyl" groups are cyclic hydrocarbons containing one or more double bonds. Cycloalkyl groups can be substituted at one or more positions as allowed by valence with any of the optional substituents described herein. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0200] As used herein, the term "cyano" refers to a -CN group.

[0201] The term "carboxy" or "carboxylic acid" as used herein refers to a group represented by the formula -CO2H.

[0202] The term "carboxylate" refers to a compound of the formula -(CO2) - It refers to a group represented by:

[0203] As used herein, the term "ester" refers to an ester selected from the group -C(O)OR x (In the formula, R x represents a hydrocarbyl group).

[0204] The term "guanidino" as used herein refers to the group -NH-C(=NH)-NH.

[0205] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo and iodo.

[0206] As used herein, the term "haloalkyl" refers to an alkyl group substituted with a halogen group.

[0207] The terms "carbocycle", "carbocyclic" or "carbocyclyl" as used herein are intended to mean any stable 3-, 4-, 5-, 6- or 7-membered monocyclic or bicyclic, or 7-, 8-, 9-, 10-, 11-, 12- or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaturated, or aromatic. Examples of carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As indicated above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term "carbocycle" or "carbocyclyl" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms are bonded to two non-adjacent carbon atoms. The preferred bridge is one or two carbon atoms. Note that a bridge always converts a monocyclic compound into a tricyclic compound. When a ring is bridged, the substituents listed for the ring may also be present on the bridge.

[0208] The terms "hetaralkyl" and "heteroaralkyl," as used herein, refer to an alkyl group substituted with a hetaryl group.

[0209] The term "heteroalkyl," as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where no two heteroatoms are adjacent.

[0210] The terms "heteroaryl" and "hetaryl" include substituted or unsubstituted aromatic monocyclic structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, in which the ring structure contains at least one heteroatom, preferably 1-4 heteroatoms, more preferably 1 or 2 heteroatoms. Similarly, the terms "heteroaryl" and "hetaryl" include polycyclic systems having two or more rings, in which two or more carbons are common to two adjacent rings, at least one of the rings is heteroaromatic, and the other rings can be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, indole, 1,3,4-oxadiazole, pyrimidine, and the like. Heteroaryl groups can be substituted at one or more positions, as permitted by valence, with any of the optional substituents described herein.

[0211] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

[0212] The terms "heterocyclyl", "heterocycle" and "heterocyclic" refer to a substituted or unsubstituted non-aromatic ring structure, preferably a 3- to 10-membered ring, more preferably a 3- to 7-membered ring, where the ring structure contains at least one heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. The terms "heterocyclyl" and "heterocyclic" also encompass polycyclic ring systems having two or more rings, where two or more carbons are common to two adjacent rings and at least one of the rings is heterocyclic, e.g., the other rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, 2,3-dihydrobenzo[b][1,4]dioxine, lactones, lactams, and the like. Heterocyclyl groups can be optionally substituted as permitted by valence.

[0213] The terms "heterocyclylalkyl" or "(heterocyclyl)alkyl" as used herein refer to an alkyl group substituted with a heterocycle group.

[0214] As used herein, the term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group.

[0215] The term "hydroxy" or "hydroxyl" as used herein refers to an --OH group.

[0216] As used herein, the term "nitro" refers to the group --NO.sub.2.

[0217] The term "lower", when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms in the substituent, preferably 6 or fewer. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer carbon atoms, preferably 6 or fewer carbon atoms. In certain embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, whether they occur alone or in combination with other substituents, particularly hydroxyalkyl and aralkyl (where, for example, atoms in an aryl group are not counted when counting carbon atoms in an alkyl substituent).

[0218] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbons of the backbone. It is understood that "substituted" or "substituted with" implies the proviso that such substitution is in accordance with the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended 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 nonaromatic 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, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents may include any of the substituents described herein, such as halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Those skilled in the art will appreciate that the substituents themselves may be substituted, if appropriate. It should be understood that references to chemical moieties herein include substituted variants, unless expressly stated as "unsubstituted." For example, references to "aryl" groups or moieties implicitly include both substituted and unsubstituted variants.

[0219] The term "thioalkyl," as used herein, refers to an alkyl group substituted with a thiol group.

[0220] As used herein, the term "thioester" refers to the group -C(O)SR x Or -SC(O)Rx (In the formula, R x represents hydrocarbyl).

[0221] The terms "thioacid," "thiocarboxy," or "thiocarboxylic acid" as used herein refer to a group represented by the formula --C(O)SH.

[0222] The term "thiocarboxylate" refers to a compound of the formula -(C(O)S) - It refers to a group represented by:

[0223] As used herein, a therapeutic agent that "prevents" a disorder or disease refers to a compound that, in a statistical sample, reduces the incidence of the disorder or disease in a treated sample compared to an untreated control sample, or that delays the onset of or reduces the severity of one or more symptoms of the disorder or disease compared to an untreated control sample.

[0224] The term "treating" includes preventative and / or therapeutic treatment. The term "preventative or therapeutic" treatment is art-recognized and includes one or more administrations of the subject compositions to a host. When administered prior to the clinical manifestation of an unwanted condition (e.g., a disease or other undesirable condition of a host animal), the treatment is preventative (i.e., protects the host from developing the unwanted condition), whereas when administered after the manifestation of an unwanted condition, the treatment is therapeutic (i.e., intended to eliminate, ameliorate or stabilize an existing unwanted condition or its side effects).

[0225] The term "prodrug" is intended to include compounds (e.g., compounds of formula (I)) that are converted to the therapeutically active agent of the present invention under physiological conditions. The general method of making a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other examples, the prodrug is converted by the enzyme 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 the above-described formulations can be replaced with the corresponding suitable prodrugs, such as when a hydroxyl in the parent compound exists as an ester or carbonate, or when a carboxylic acid exists in the parent compound exists as an ester.

[0226] As used herein, the terms "comprise" or "comprising" are used generally to mean including, or in other words permitting the presence of, one or more additional (unspecified) features or components.

[0227] As used herein, the term "including" and other forms thereof, such as "include," "includes," and "included," are not limiting.

[0228] The term "amino acid" as used herein refers to a molecule containing both an amino group and a carboxyl group, including salts, esters, various salt combinations, and tautomeric forms thereof. In solution, at neutral pH, the amino and acid groups of an amino acid may exchange protons to form a doubly ionized, but overall neutral, entity identified as a zwitterion. In some embodiments, the amino acid is an α-, β-, γ-, or δ-amino acid, including stereoisomers and racemates. The term "L-amino acid" as used herein refers to an α-amino acid having a left-handed configuration about the α-carbon, i.e., a carboxylic acid of the general formula CH(COOH)(NH2)-(side chain) having an L-configuration. The term "D-amino acid" similarly refers to a carboxylic acid of the general formula CH(COOH)(NH2)-(side chain) having a right-handed configuration about the α-carbon. The side chain of an L-amino acid may include naturally occurring and non-naturally occurring moieties. Non-naturally occurring (ie, unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains, eg, in amino acid analogs.

[0229] As used herein, "amino acid residue" refers to a moiety that shares structural similarity with a parent amino acid. An amino acid residue can be covalently bonded to another chemical moiety through the amino group of the residue or the carboxylic acid group of the residue (i.e., the hydrogen atom of -NH2 or -OH is replaced by a bond to another chemical moiety).

[0230] The phrase "amino acid side chain" as used herein means a moiety that is covalently attached to a D- or L-amino acid structure and can be represented as CH(COOH)(NH2)-R. For example, in the case of alanine CH(COOH)(NH2)(CH3), the amino acid side chain (R) is -CH3. Examples of "amino acid side chain" include, but are not limited to, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl. The amino acid side chain can be substituted by one or more identical or different substituents selected from, but not limited to, amino, amido, alkylamino, acylamino, carboxylic acid, carboxylate, thiocarboxylate, thioacid, -hydroxy, cycloalkyl, (cycloalkyl) alkyl, aryl, heterocyclyl, heteroaryl, guanidino, -SH, -S(alkyl); optionally, the cycloalkyl, aryl, heterocyclyl, and heteroaryl are further substituted by one or more substituents, such as hydroxy, alkoxy, halo, amino, nitro, cyano, or alkyl.

[0231] The amino acids include the 20 standard amino acids used by most organisms in protein synthesis. Non-natural amino acid residues can be selected from, but are not limited to, α- and α-disubstituted amino acids, N-alkyl amino acids, and natural amino acids substituted with lower alkyl, aralkyl, hydroxyl, aryl, aryloxy, haloalkyl, or acyl.

[0232] For example, lysine can be substituted to form unnatural amino acids, for example at the carbon atom of the side chain or by mono- or di-alkylation of the terminal NH2 group (e.g., the amino group of the lysine side chain together with its substituents forms a heterocycle such as piperidine or pyrrolidine). In another example, the terminal amino group of the lysine side chain can form a ring with the amino acid backbone, similar to capreomycidin. Further unnatural derivatives of lysine include homolysine and norlysine. The side chain of lysine can alternatively be substituted by a secondary amino group. In another example, the alkyl portion of the lysine side chain can be incorporated into a carbon ring structure to form a semi-rigid analogue, for example, cyclohexyl or cyclopentyl.

[0233] Throughout this specification and claims, the "L-threonine residue" and / or "L-threonine side chain" mentioned in the compounds of formula (I) and / or their preparation may be represented by any one of the following formulae:

[0234] [ka]

[0235] In certain embodiments, the unnatural amino acids can be derivatives of natural amino acids that have one or more double bonds.

[0236] In other exemplary embodiments, in threonine, the β-methyl group may be replaced with ethyl, phenyl or other higher alkyl groups. In histidine, the imidazole moiety may be substituted or the alkylene backbone of the side chain may be substituted.

[0237] Further examples of unnatural amino acids include homoserine and homologs of natural amino acids.

[0238] In a further exemplary embodiment, the unnatural amino acid can be alkylated (eg, methylated) at the alpha position.

[0239] Further examples of unnatural amino acids include α,β- and β,γ-dehydroamino amino acid analogs.

[0240] Further exemplary amino acids include penicillamine and beta-methoxyvaline.

[0241] Further examples of unnatural amino acids include amino acids whose side chains include amino, alkylamino, acylamino, -COO-alkyl, cycloalkyl, heterocyclyl, heteroaryl, guanidino, (cycloalkyl)alkyl, (heterocyclyl)alkyl and (heteroaryl)alkyl.

[0242] By "modified N-terminal amino group" and "modified C-terminal carboxyl group" is meant that the amino or carboxyl group has been altered.

[0243] The modification of the N-terminal amino group is preferably of the general formula -NR x R y (In the formula, R x is hydrogen or alkyl; R y is alkyl, alkenyl, -C(=NH)NH2, alkynyl, acyl, cycloalkyl, aryl, or heterocyclyl.

[0244] Examples of N-terminal modifications include, but are not limited to, an acetylated, formylated, or guanylated N-terminus.

[0245] The modification of the C-terminal carboxyl group is preferably of the general formula COR z (R z replaces the hydroxyl group of the last amino acid), so in this case R z is -NR7R8, alkoxy, amino or imido. The C-terminal carboxyl group may also be optionally substituted with hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl or cycloalkyl. The heterocyclic compounds may be converted to substituted heterocyclic compounds, such as 1,2,4-oxadiaxole or 1,3,4-oxadiaxole rings.

[0246] The present invention encompasses pharma- ceutically acceptable salts of the compounds of the present invention, and their use in the compositions and methods of the present invention.In certain embodiments, contemplated salts of the present invention include, but are not limited to, alkyl, dialkyl, trialkyl, or tetra-alkyl ammonium salts.In certain embodiments, contemplated salts of the present invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, chlorine, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.In certain embodiments, contemplated salts of the present invention include, but are not limited to, Na, Ca, K, Mg, Zn, or other metal salts.

[0247] Pharmaceutically acceptable acid addition salts may also exist as various solvates with water, methanol, ethanol, dimethylformamide, etc. Mixtures of such solvates may also be prepared. The source of such solvates may be that of the solvent of crystallization, inherent in the solvent of preparation or crystallization, or exogenous to such solvent.

[0248] "Pharmaceutically acceptable" means generally safe, non-toxic and useful in the preparation of pharmaceutical compositions which are not biologically or otherwise harmful, and includes those acceptable for veterinary and human pharmaceutical use.

[0249] The term "stereoisomer" refers to any enantiomer, diastereoisomer or geometric isomer of the compounds of the present invention. When the compounds of the present invention are chiral, they can exist in racemic or optically active form. The pharmaceutical activity of the racemic or stereoisomers of the compounds according to the present invention may differ, so it may be desirable to use compounds enriched in one of the enantiomers. In these cases, the final product or intermediate can be separated into enantiomeric compounds by chemical or physical procedures known to those skilled in the art or used in synthesis or the like. 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 tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the R and S forms of various optically active camphorsulfonic acids. Also advantageous is chromatographic resolution of enantiomers with the aid of optically active resolving agents (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized methacrylate polymers immobilized on silica gel).

[0250] In certain embodiments, the compounds of the present invention may be racemic. In certain embodiments, the compounds of the present invention may be enriched in one enantiomer. For example, the compounds of the present invention may have an ee of more than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee or 95% ee or more. In certain embodiments, the compounds of the present invention may have more than one stereocenter. In certain such embodiments, the compounds of the present invention may be enriched in one or more diastereomers. For example, the compounds of the present invention may have an ee of more than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de or 95% de or more.

[0251] The term "subject" includes mammals, particularly humans, and other animals, such as domestic animals (eg, household pets such as cats and dogs) and non-domestic animals (eg, wild animals).

[0252] Naturally occurring amino acids are identified throughout the specification and claims by their conventional three letter abbreviations as set forth in the table below.

[0253] [Table 2]

[0254] Abbreviations used throughout the specification may be summarized herein below with their respective meanings.

[0255] °C (degrees Celsius);% (percentage);Brine (NaCl solution);CH2Cl2 / DCM (dichloromethane);BOC (tert-butyloxycarbonyl);Bzl (benzyloxycarbonyl);Cs2CO3 (cesium carbonate);DIC: N,N'-diisopropylcarbodiimide;DIPEA (N,N-diisopropylethylamine);DMF (dimethylformamide);EtOH (ethanol);Et2NH (diethylamine);Fmoc (9-fluorenylmethyloxycarbonyl);g or gr (grams);HOBt (1-hydroxybenzotriazole);h or hr (hours);HPLC (high performance liquid chromatography);K2CO3 (potassium carbonate);LCMS (liquid chromatography-mass spectrometry);Liq.NH3 (liquid ammonia);mmol (millimolar);M (molar); μl (microliter); mL (milliliter); mg (milligram); MS(ES) (mass spectrometry-electrospray); min (minute); Na (sodium); NaHCO3 (sodium bicarbonate); NH2NH2.H2O (hydrazine hydrate); NMM (N-methylmorpholine); Na2SO4 (sodium sulfate); NH2OH.HCl (hydroxylamine hydrochloride); PD1 / 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.

[0256] experiment The present invention provides methods for preparing compounds of formula (I) by following the procedures in 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 specifically described, those skilled in the art can prepare additional compounds of the present invention.

[0257] The intermediates or starting materials required for the synthesis are either commercially available (commercial suppliers such as Sigma-Aldrich (USA or Germany); Chem-Impex (USA); GLBiochem (China), and Spectrochem (India)) or these intermediates or starting materials can be prepared using known literature methods. The present invention will now be described in more detail by means of specific examples.

[0258] Compound purification and characterization Analytical HPLC method: Analytical HPLC was performed on a ZIC HILIC 200A° column (4.6 mm×250 mm, 5 μm) at a flow rate of 1.0 mL / min. The elution conditions used were: Buffer A: 5 mmol ammonium acetate, Buffer B: acetonitrile, equilibration of the column with 90% Buffer B, and elution with a gradient of 90% to 40% Buffer B in 30 min.

[0259] Preparative HPLC method: Preparative HPLC was performed on a SeQuant ZIC HILIC 200A° column (10 mm×250 mm, 5 μm) at a flow rate of 5.0 mL / min. The elution conditions used were: Buffer A: 5 mmol ammonium acetate (adjusted to pH 4 with acetic acid), Buffer B: acetonitrile, equilibration of the column with 90% Buffer B, and elution with a gradient of 90% to 40% Buffer B in 20 min.

[0260] LCMS was performed on an AP1 2000 LC / MS / MS triple quadrupole (Applied biosystems) on an Agilent 1100 series HPLC with a G1315B DAD using a Mercury MS column, or utilizing an Agilent LC / MSD VL single quadrupole on an Agilent 1100 series HPLC with a G1315B DAD using a Mercury MS column, or utilizing a Shimadzu LCMS 2020 single quadrupole on a Prominence UFLC system with an SPD-20A DAD.

[0261] Working Example Example 1: Synthesis of Compound 1 Step 1a

[0262] [ka] Ethyl chloroformate (3.4 g, 31.3 mmol) and Et3N (7.0 mL, 52.8 mmol) were added to a solution of compound 1a (5.0 g, 26.4 mmol) in THF (20 mL) and stirred at -20°C for 20 min. After 20 min, 25% aqueous ammonia (10 mL, 132.0 mmol) was added to the activated mixed anhydride and stirred at 0-5°C for 30 min. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 solution, followed by citric acid solution and brine solution. The separated organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give compound 1b 4.0 g. LCMS: 89.3 (M-Boc+H) + .

[0263] Step 1b

[0264] [ka] Trifluoroacetic anhydride (8.4 g, 39.9 mmol) was added to a solution of compound 1b (5 g, 26.6 mmol) in pyridine (21.0 mL, 26.6 mmol) and stirred at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 solution, followed by citric acid solution and brine solution. The separated organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give 3.5 g of compound 1c which was used directly in the next step.

[0265] Step 1c:

[0266] [ka] Hydroxylamine hydrochloride (0.92 g, 13.2 mmol), water (0.5 mL) and potassium carbonate (1.8 g, 13.2 mmol) were added to a solution of compound 1c (1.5 g, 8.8 mmol) in EtOH (20 mL) and stirred at 86 °C for 4 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with brine solution and dried over Na2SO4, then filtered and evaporated under reduced pressure to give compound 1d 0.9 g. LCMS: 104.3 (M-Boc+H). + .

[0267] Step 1d:

[0268] [ka] Deoxo-Fluor (3.7 g, 16.1 mmol) was added to a solution of Fmoc-Ala-OH (5.0 g, 15.0 mmol) in CHCl (50 mL) and stirred at 0° C. for 1 h. Then CHCl was evaporated and triturated with hexane. Sodium acetate (0.2 g, 2.4 mmol) in acetic acid and compound 1d (0.5 g, 2.4 mmol) were taken in a round neck flask and stirred for 30 min. To this mixture, Fmoc-Ala-COF (0.996 g, 3.1 mmol) was added and stirred at room temperature for 30 min. The reaction mixture was stirred at 90° C. for 3 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO solution, followed by citric acid solution and brine solution. The separated organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (eluent: 0-5% ethyl acetate in hexane) to give compound 1e 0.3g. LCMS: 379.0 (M-Boc+H). + , 501.3(M+Na) + .

[0269] Step 1e:

[0270] [ka] Diethylamine (1.0 mL) was added to a solution of compound 1e (0.35 g, 0.73 mmol) in CH2Cl2 (10 mL). The mixture was stirred at room temperature for 3 h, after which the resulting solution was concentrated under nitrogen, washed with diethyl ether, and centrifuged to give 0.18 g of compound 1f, which was used directly in the next step.

[0271] Step 1f:

[0272] [ka] Urea coupling was carried out using coupling of compound 1f (0.18 g, 0.71 mmol) with compound 1h (0.24 g, 0.77 mmol) in DMF (5.0 mL) at room temperature. Coupling was initiated by addition of TEA (0.2 mL, 1.4 mmol) and the resulting mixture was stirred at room temperature. After completion of 3 h, the reaction mass was partitioned between water and ethyl acetate. The organic layer was washed with water followed by brine solution and dried over Na2SO4. The separated organic layer was filtered and evaporated under reduced pressure to give compound 1g 0.2 g. LCMS: 450.1 (M+Na). + .

[0273] Step 1g:

[0274] [ka] To a solution of compound 1g (0.15 g, 0.35 mmol) in CHCl (1 mL), trifluoroacetic acid (0.5 mL) and a catalytic amount of triisopropylsilane were added and stirred at room temperature for 3 h. The resulting solution was concentrated under reduced pressure to give crude compound 0.10 g. The crude solid material was purified similarly to the prep HPLC method described in the experimental conditions. LCMS: 272.2 (M+H). + ; HPLC(t R ):6.2min.

[0275] Synthesis of compound 1h:

[0276] [ka] Pyridine (12.0 g, 25.2 mmol) was added to a solution of H-Ala-OtBu (2.3 g, 12.6 mmol) in CHCl (20 mL) and the resulting solution was stirred at room temperature for 5-10 min. A solution of 4-nitrophenyl chloroformate (2.8 g, 13.8 mmol) in CHCl (20 mL) was added to the above reaction mixture and stirring was continued at room temperature for 1 h. Completion of the reaction was confirmed by TLC analysis. After completion of the reaction, it was diluted with CHCl (50 mL) and washed with 1.0 M sodium hydrogen sulfate solution (50 mL x 2), followed by 1.0 M sodium carbonate solution (50 mL x 2). The organic layer was dried over NaSO, filtered and evaporated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate in hexane) to obtain compound 1h 2.0 g.

[0277] The following compounds were prepared by procedures similar to those described in Example 1 (Compound 1) with moderate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Analytical data for the compounds are summarized in the table below.

[0278] [Table 3] TIFF0007659015000039.tif135170

[0279] Example 2: Synthesis of Compound 7

[0280] [ka]

[0281] Step 2a:

[0282] [ka] Compound 2a was synthesized using a procedure similar to that shown in steps 1a-1c of Example 1 (compound 1) by using Boc-Tyr(tBu)-OH instead of Boc-Ala-OH to give compound 2a 9g.

[0283] Step 2b:

[0284] [ka] HOBt (3.45 g, 30.8 mmol) and DIC (4.5 mL, 30.8 mmol) were added to a solution of Fmoc-Pro-OH (8.6 g, 25.6 mmol) in DMF (250 mL) at 0° C. and stirred for 30 min. Compound 2a (9 g, 25.6 mmol) was further added to the previous reaction mixture at the same temperature and continued to stir at 0° C. for 2 h and then at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with ice water and the precipitated white solid was filtered, washed with water (1 L) and dried under high vacuum. The solid was stirred with diethyl ether (500 mL) for 15 min, filtered and dried to give compound 2b 14 g. LCMS: 671.3 (M+H) + , 693.3(M+Na) + .

[0285] Step 2c:

[0286] [ka] To a solution of compound 2b (13 g, 19.4 mmol) in acetonitrile (130 ml) was added room temperature acetic acid (10.0 mL) and refluxed at 85° C. for 12 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure to give a crude semi-solid, which was diluted with water and ethyl acetate. The organic layer was washed with NaHCO3 solution, followed by citric acid solution and brine solution. The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude solid, which was diluted with 10% acetonitrile in hexane (500 ml) and stirred for 2 h to give a white solid. The white solid was filtered, washed with n-pentane (500 L) and dried to give compound 2c 13 g. LCMS: 653.4 (M+H) + , 675.6(M+Na) + .

[0287] Step 2d:

[0288] [ka] Compound 2c (13 g, 19.9 mmol) was added to a solution of 20% piperidine in DCM (150 mL) at 0° C. and stirred at 0° C. for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was concentrated under reduced pressure, diluted with hexanes, stirred and filtered. The filtered solid was dissolved in EtOAc, washed with saturated NaHCO3 solution, brine solution, dried over Na2SO4, filtered and evaporated to give compound 2d as a white solid. LCMS 431.1 (M+H). + ;453.4(M+Na) + .

[0289] Step 2e:

[0290] [ka] DIPEA was added to a solution of compound 2e (5 g, 11.6 mmol) and compound 2d (5.3 g, 11.6 mmol) in anhydrous THF (50 mL) at 0° C. and stirred for 2 h. The reaction mixture was stirred at ambient temperature for an additional 4 h. The volatiles were evaporated and partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, 10% citric acid, brine solution, dried over Na2SO4, and concentrated in vacuo. The crude compound was purified by column chromatography on neutral alumina using 25% ethyl acetate in hexane to give compound 2f. LCMS: 772.5 (M+Na) + .

[0291] Step 2f:

[0292] [ka] A solution of compound 2f (6.5 g, 8.7 mmol) and trifluoroacetic acid (16 mL) in DCM (16 mL) was stirred at 0° C. for 1 h. The reaction mixture was evaporated under reduced pressure, diluted with diethyl ether and filtered to give crude compound 4g. The crude solid material was purified by preparative HPLC method described in the experimental conditions. LCMS: 482.3 (M+H). + ;HPLC:t R =12.92min.

[0293] Synthesis of compound 2e:

[0294] [ka] By using H-Tyr(tBu)-OtBu instead of H-Ala-OtBu, This compound was synthesized using a procedure similar to that given for compound 1h in Example 1.

[0295] The following compounds were prepared by procedures similar to those described in Example 2 (Compound 7) with moderate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Analytical data for the compounds are summarized in the table below.

[0296] [Table 4] TIFF0007659015000049.tif236170 TIFF0007659015000050.tif255170 TIFF0007659015000051.tif243170 TIFF0007659015000052.tif244170 TIFF0007659015000053.tif236170 TIFF0007659015000054.tif248170 TIFF0007659015000055.tif237170 TIFF0007659015000056.tif117170

[0297] Example 3: Synthesis of Compound 75

[0298] [ka] The compound was synthesized using a procedure similar to that shown in Example 2 by using compound 3b (prepared according to the procedure shown below) instead of Fmoc-Pro-OH. The crude solid material was purified using preparative HPLC as described in the experimental conditions. LCMS: 417.5 (M+H). + ,HPLC:t R =12.2min.

[0299] Synthesis of compound 3b: Step 3a:

[0300] [ka] Propylamine (2.9 mL, 35.25 mmol), HATU (14.8 g, 38.8 mmol) and DIPEA (12.3 mL, 70.5 mmol) were added to a solution of Fmoc-Glu-OtBu (15.0 g, 35.3 mmol) in DMF (50 mL) at 0° C. and stirred at room temperature for 1.5 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with water and the resulting solid was filtered, washed with diethyl ether and dried under reduced pressure to give compound 3a (19.0 g), which was used in the next step without purification. LCMS: 489.4 (M+Na+H). + .

[0301] Step 3b:

[0302] [ka] To a solution of compound 3a (19.0 g, 40.72 mmol) in trifluoroacetic acid (19.0 mL), a catalytic amount of triisopropylsilane was added and stirred at room temperature for 4 h. The resulting solution was evaporated under nitrogen and washed with diethyl ether to give crude compound 13.3 g, which was used in the next step without purification. LCMS: 417.5 (M+H). + .

[0303] The following compounds were prepared by procedures similar to those described in Example 3, with moderate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Analytical data for the compounds are summarized in the table below.

[0304] [Table 5]

[0305] Example 4: Synthesis of Compound 79

[0306] [ka] The compound was synthesized using a procedure similar to that shown in Example 2 by using compound 4f (according to the procedure shown below) instead of H-Tyr(tBu)-OtBu. The crude solid material was purified using preparative HPLC as described in the experimental conditions. LCMS: 415.0 (M+H). + ,HPLC:t R =13.1min.

[0307] Synthesis of compound 4f: Step 4a:

[0308] [ka] Methyl iodide (4.9 g, 34 mmol) and potassium carbonate (6.0 g, 44 mmol) l) was added to a solution of compound 4a (7.1 g, 22 mmol) in DMF (70 mL) and stirred at room temperature for 3 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and evaporated under reduced pressure to give compound 4b 6.4 g. LCMS: 324.0 (M+H) + .

[0309] Step 4b:

[0310] [ka] Hydrazine hydrate (6.4 mL) was added to a solution of compound 4b (6.4 g) in methanol (64 mL) and stirred at room temperature for 12 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and evaporated under reduced pressure to give compound 4c 5.5 g. LCMS: 324.2 (M+H). + .

[0311] Step 4c:

[0312] [ka] 2-(tert-butoxy)acetic acid (1.16 g, 8.8 mmol), HOBT (1.3 g, 9.6 mmol), EDC.HCl (1.83 g, 9.6 mmol), DIPEA (2.5 g, 21 mmol) were added to a solution of compound 4c (2.6 g, 8.8 mmol) in DMF (50 mL) and stirred at room temperature for 4 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with NaHCO3, citric acid, brine solution, dried over Na2SO4, and evaporated under reduced pressure to give crude compound 6, which was further purified by silica gel column chromatography (eluent: 0-50% ethyl acetate in hexane) to give product 4d 3 g. LCMS: 438.2 (M+H) + .

[0313] Step 4d:

[0314] [ka] Triphenylphosphine (6.5 g, 24 mmol), iodine (6.2 g, 24 mmol), TEA (3.5 g, 35 mmol) were added to a solution of compound 4d (3.1 g, 7.0 mmol) in THF (50 mL) and DMF (10 mL) and stirred at room temperature for 3 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between sodium thiosulfate solution and ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated. Evaporation under reduced pressure gave crude compound 4e, which was further purified by silica gel column chromatography (eluent: 0-50% ethyl acetate in hexane) to give product 4e 2.4g. LCMS: 420.2 (M+H). + .

[0315] Step 4e:

[0316] [ka] Palladium hydroxide (0.5 g) was added to a solution of compound 4e (2.3 g) in methanol (30 mL) and stirred under H2 gas at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction was filtered through a celite bed and the filtrate was evaporated under reduced pressure to give product 4f 1.2 g. LCMS: 286.1 (M+H). + .

[0317] Step 4f:

[0318] [ka] 4-Nitrophenyl chloroformate (0.85 g, 4.2 mmol), pyridine (0.36 g, 4.6 mmol) were added to a solution of compound 4f (1.2 g, 4.2 mmol) in CHCl (40 mL) and stirred at room temperature for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between ice water and ethyl acetate. The organic layer was washed with citric acid, brine solution, dried over NaSO, and evaporated under reduced pressure to give crude compound 4g, which was further purified by silica gel column chromatography (eluent: 0-40% ethyl acetate in hexane) to give product 4g 1.8 g.

[0319] Example 5: Synthesis of Compound 80

[0320] [ka] The compound was synthesized using a procedure similar to that shown in Example 2 by using compound 5b (prepared according to the procedure shown below) instead of H-Tyr(tBu)-OtBu. The crude solid material was purified using preparative HPLC as described in the experimental conditions. LCMS: 431.5 (M+H). + ,HPLC:t R =12.6min.

[0321] Synthesis of compound 5b: Step 5a:

[0322] [ka] To a solution of Fmoc-Thr(tBu)-OH (5.5 g, 13.8 mmol) in DMF (25.0 mL) was added K2CO3 (2.9 g, 20.8 mmol) at 0 °C and stirred for 30 min, followed by iodopentane (2.1 mL, 16.6 mmol) at 0 °C. The above reaction mixture was stirred at room temperature for 14 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4, and evaporated under reduced pressure to give compound 5a (6.86 g), which was used in the next step without purification. LCMS: 246.4 (M-Fmoc+H). + .

[0323] Step 5b:

[0324] [ka] To compound 5a (6.86 g, 14.67 mmol) was added 20% piperidine in CH2Cl2 (34.3 mL) and the reaction mixture was stirred at room temperature for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under nitrogen and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4, and evaporated under reduced pressure. Crude compound 5b was purified by silica gel column chromatography (eluent: 0-40% ethyl acetate in hexane) to give 5b 2.5 g. LCMS: 246.1 (M+H) + .

[0325] Example 6: Synthesis of Compound 81

[0326] [ka] The compound was synthesized using a procedure similar to that shown in Example 2 by using compound 6b (prepared by the procedure shown below) instead of H-Tyr(tBu)-OtBu. The crude solid material was purified using preparative HPLC as described in the experimental conditions. LCMS: 443.8 (M+H). + , HPLC:t R =8.8min.

[0327] Synthesis of compound 6b: Step 6a:

[0328] [ka] To a solution of Fmoc-Gln(Trt)-OH (5.0 g, 8.2 mmol) in DMF (25.0 mL) was added HATU (3.4 g, 9.0 mmol), H-Thr(OtBu)-OtBu (1.9 g, 8.2 mmol) and DIPEA (2.9 mL, 16.4 mmol) at 0° C. and stirred at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with water and the resulting solid was filtered, washed with hexane and dried to give compound 6a 7.4 g. LCMS: 824.1 (M+H). + .

[0329] Step 6b

[0330] [ka] To compound 6a (7.4 g, 8.9 mmol) was added 20% piperidine in CH2Cl2 (37.0 mL) and the reaction mixture was stirred at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under nitrogen and partitioned between water and DCM. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4 and evaporated under reduced pressure. The crude compound was washed with hexane and dried under reduced pressure to give compound 6b 3.7 g. LCMS: 601.8 (M+H) + .

[0331] Example 7: Synthesis of Compound 82

[0332] [ka] The compound was synthesized using a procedure similar to that shown in Example 2 by substituting compound 7c (prepared by the procedure shown below) for compound 2d. The crude solid material was purified using preparative HPLC as described in the experimental conditions. LCMS: 443.8 (M+H). + , HPLC:t R =8.8min.

[0333] Synthesis of compound 7c: Step 7a:

[0334] [ka] EDC.HCl (2.9 g, 14.97 mmol), HOBt (2.3 g, 14.97 mmol), Fmoc-Gly-OH (2.97 g, 9.98 mmol) and NMM (2.7 mL, 24.95 mmol) were added to a solution of compound 7a (5.83 g, 9.98 mmol. Compound 7a was synthesized using a procedure similar to that shown for compound 2d in Example 2) in DMF (30.0 mL) at 0° C. and stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with citric acid, NaHCO3, brine solution, dried over Na2SO4, evaporated under reduced pressure and further purified by silica gel column chromatography (eluent: 10% ethyl acetate in hexane-100% ethyl acetate) to give compound 7d 6.0 g. LCMS: 885.4 (M+Na+H) + .

[0335] Step 7b:

[0336] [ka] Diethylamine (24.0 mL) was added to a solution of compound 7b (6.0 g, 6.95 mmol) in CHCl (24.0 mL). The reaction was stirred at room temperature for 6 h, and the resulting solution was concentrated under nitrogen atmosphere to give compound 7c, which was purified by silica gel column chromatography (eluent: 0-10% ethyl acetate in hexanes, followed by 2% methanol in DCM) to give compound 7c 4.5 g. LCMS: 641.2 (M+H). + .

[0337] Example 8: Synthesis of Compound 83

[0338] [ka]

[0339] Step 8a:

[0340] [ka] Ethyl chloroformate (2.35 mL, 25.05 mmol) and N-methylmorpholine (2.75 mL, 25.05 mmol) were added to a solution of compound 8a (5.0 g, 8.35 mmol) in THF (50 mL) and stirred at -20 °C. After 20 min, aqueous ammonia (3.0 mL) was added to the in situ formed activated mixed anhydride and stirred at 0-5 °C for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was poured into water and hexane, and the resulting solid was filtered, washed with hexane, and dried to give compound 8b 4.2 g. LCMS: 596.3 (M+H) + .

[0341] Step 8b:

[0342] [ka] Triethylamine (3.5 mL, 24.7 mmol) and trifluoroacetic anhydride (1.5 mL, 10.6 mmol) were added to a solution of compound 8b (4.2 g, 7.1 mmol) in THF (70 mL) and stirred at 0° C. for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4, and evaporated under reduced pressure to give 4 g of crude compound 8c, which was used in the next step without further purification. LCMS: 578.2 (M+H). + , 600.2(M+Na) + .

[0343] Step 8c:

[0344] [ka] To compound 8c (1.5 g, 2.59 mmol) was added 20% piperidine in CH2Cl2 (20.0 mL) and the reaction mixture was stirred at 0 °C for 1 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under nitrogen and partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4, and evaporated under reduced pressure. The crude compound was washed with hexane and 20% diethyl ether in hexane to give compound 8d 0.8 g, which was used in the next step without further purification. LCMS: 378.4 (M+Na). + .

[0345] Step 8d:

[0346] [ka] Triethylamine was added over 2 min to a solution of compound 8d (0.8 g, 2.3 mmol) in DMF (15.0 mL) at 0° C. After this, compound 8i (1.0 g, 27.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was poured into water and the resulting solid was filtered and washed with hexane and 20% diethyl ether in hexane to give compound 8e 1.2 g. LCMS 613.6 (M+H). + .

[0347] Step 8e:

[0348] [ka] Hydroxylamine hydrochloride (0.204 g, 29.37 mmol), water (10.0 mL) and potassium carbonate (0.4 g, 29.37 mmol) were added to a solution of compound 8e (1.2 g, 19.58 mmol) in EtOH (26.0 mL) and stirred at 85° C. for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, quenched with water, and the resulting solid was filtered, washed with hexane and dried to give compound 8f 1.0 g. LCMS: 646.9 (M+H). + .

[0349] Step 8f:

[0350] [ka] DIC (0.29 mL, 18.58 mmol) and HOBt (0.25 g, 18.58 mmol) were added to a solution of Boc-Ser(tBu)-OH (0.4 g, 15.48 mmol) in DMF (20.0 mL) at 0° C. and stirred for 30 min, then compound 8f (1.0 g, 15.48 mmol) was added and stirred at room temperature for 1.5 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was quenched with water, and the resulting solid was filtered, washed with diethyl ether, and dried under reduced pressure to give compound 8g 1.4 g, which was used in the next step without further purification. LCMS: 889.4 (M+H) + .

[0351] Step 8g:

[0352] [ka] Acetic acid (1.2 mL) was added to a solution of compound 8g (1.2 g, 13.49 mmol) in 2-methyl THF (30.0 mL). The reaction mixture was stirred at 84° C. for 12 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3, brine solution, dried over Na2SO4, and evaporated under reduced pressure. The crude compound was washed with hexane and 5% diethyl ether in hexane to give compound 8h 0.45 g, which was used in the next step without further purification. LCMS: 871.4 (M+H) + .

[0353] Step 8h:

[0354] [ka] To a solution of compound 8h (0.4 g, 4.55 mmol) in trifluoroacetic acid (9.5 mL), triisopropylsilane (0.25 mL) and water (0.25 mL) were added and stirred at room temperature for 2 h. The resulting solution was evaporated under nitrogen to give crude compound 83 0.1 g. The crude solid material was purified using the preparative HPLC method described in the experimental conditions. LCMS: 361.1 (M+H).+ ;HPLC:t R =13.9min.

[0355] Synthesis of compound 8i:

[0356] [ka] HCl.H-Thr( t Bu)-O t To a solution of Bu (8 g, 29.9 mmol), pyridine (5.9 g, 74.0 mmol) was added and the solution was stirred at room temperature for 5-10 min. To this, a solution of 4-nitrophenyl chloroformate (7.2 g, 35.0 mmol) in CHCl was added and the resulting mixture was stirred at room temperature for 30 min. Completion of the reaction was confirmed by TLC analysis. After completion of the reaction, the reaction mixture was diluted with CHCl and washed with water and 5.0 M citric acid solution. The separated organic layer was dried over NaSO, filtered and evaporated under reduced pressure to obtain the crude compound, which was purified by silica gel column chromatography (eluent: 0-20% ethyl acetate in hexane) to obtain compound 8i 9g. LCMS: 397.3 (M+H) + .

[0357] Example 9: Synthesis of Compound 84

[0358] [ka]

[0359] Step 9a:

[0360] [ka] To a stirred solution of compound 9a (1.00 g) in DCM (40.0 mL), pyridine (0.33 mL) was added followed by cyclopropanesulfonyl chloride (0.33 mL), and the resulting mixture was stirred at ambient conditions for 16 h when TLC analysis showed the reaction was complete. The reaction mixture was partitioned between water and DCM, and the organic layer was washed with dilute hydrochloric acid (1.0 N). The organic phase was then dried over Na2SO4 and concentrated under reduced pressure to give the crude sulfonamide, which was further purified by column chromatography (neutral alumina, eluent hexane-EtOAc (2:3)) to give the desired compound 9b (1.10 g). LCMS: 735.4 (M+H+H2O). + .

[0361] Step 9b:

[0362] [ka] Compound 84 was prepared from compound 9b according to the procedure described in step 1g of Example 1, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. LCMS (M+H) + :319.9.

[0363] The following compounds were prepared by procedures similar to those described in Example 9 (Compound 84), with appropriate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Compounds The analytical data are summarized in the table below.

[0364] [Table 6] TIFF0007659015000091.tif174170

[0365] Example 10: Synthesis of Compound 91

[0366] [ka]

[0367] Step 10a:

[0368] [ka] To a stirred solution containing compound 10a (0.25 g, 0.4 mmol), carboxylic acid 10c (74 mg, 0.44 mmol) and HATU (0.23 g, 0.61 mmol) in anhydrous DMF (3.0 mL) was added DIPEA (0.11 g, 0.89 mmol) under inert atmosphere. The reaction mixture was stirred at ambient conditions for 16 h (hand). The resulting reaction mixture was partitioned between water (50 mL) and EtOAc (25 mL) and the aqueous layer was extracted with EtOAc (3×25 mL). The combined organic phase was washed once with cold water, dried over Na2SO4 and the solvent was removed under reduced pressure to give compound 10b (0.12 g). LCMS: 779.0 (M+H+H2O). + .

[0369] Step 10b:

[0370] [ka] Compound 90 was prepared from compound 10b following the procedure described in step 1g of Example 1, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. LCMS (M+H) + :363.9.

[0371] The following compounds were prepared by procedures similar to those described in Example 10 (Compound 91) with moderate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Analytical data for the compounds are summarized in the table below.

[0372] [Table 7]

[0373] Example 11: Synthesis of Compound 94

[0374] [ka]

[0375] Step 11a:

[0376] [ka] To a stirred solution of 11a (2.00 g) in DCM (40.0 mL) was added pyridine (0.53 mL) followed by 4-nitrophenyl chloroformate (0.65 g) and the resulting mixture was stirred at ambient conditions for 16 h. The reaction mixture was further partitioned between water and DCM and the organic layer was washed with dilute hydrochloric acid (1.0 N). The organic phase was then dried over Na2SO4 and concentrated under reduced pressure to give the crude sulfonamide, which was further purified by column chromatography (neutral alumina, eluent hexane-EtOAc (2:3)) to give the desired carbamate 11b (2.66 g). LCMS: 801.4 (M+H+Na). + .

[0377] Step 11b:

[0378] [ka] Amine 11e (0.55 g, 4.09 mmol) was added to a stirred solution of compound 11b (2.66 g, 3.41 mmol) in ethanol (30.0 mL) and the resulting mixture was refluxed at 75° C. for 16 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure, diluted with ethyl acetate (75 mL) and washed successively with water (80 mL), followed by saturated K2CO3 solution (50 mL) and brine (50 mL). After the organics were dried over Na2SO4, the solvent was removed under reduced pressure to give compound 11c (1.0 g). LCMS: 775.3 (M+H) + .

[0379] Step 11c:

[0380] [ka] Compound 91 was prepared from compound 11c following the procedure described in step 1g of Example 1, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. LCMS (M+H) + :377.2.

[0381] Example 12: Synthesis of Compound 95

[0382] [ka]

[0383] Step 12a:

[0384] [ka] Acetic acid (0.2 mL) was added to a stirred solution of compound 12a (500 mg) and compound 12d (134 mg) in anhydrous DCE (20.0 mL), and the resulting mixture was stirred at RT for 12 h. Sodium borohydride (77.0 mg) was added to the above mixture, and the resulting mixture was stirred at ambient temperature for 4 h. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3 x 25 mL). The combined organic phase was washed with brine and water, dried over Na2SO4, and the solvent was removed under reduced pressure to give crude compound 12b, which was carried on to the next step without further purification (200 mg). LCMS: 708.0 (M+H). + .

[0385] Step 12b:

[0386] [ka] Compound 92 was prepared from 12b following the procedure described in step 1g of Example 1, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. LCMS (M+H) + :310.2.

[0387] Example 13: Synthesis of Compound 96

[0388] [ka]

[0389] Step 13a:

[0390] [ka] Compound 13d (77.0 mg) was added to a stirred solution of compound 13a (0.3 g) in toluene (10.0 mL) under inert atmosphere, and the resulting mixture was heated at 60° C. for 16 h. The solvent was removed under reduced pressure, and the crude product was washed repeatedly with pentane (10 mL×2 times) and diethyl ether (10 mL×2 times) and dried under reduced pressure to give compound 13b (200.0 mg). LCMS: 702.0 (M+H- t Bu) + .

[0391] Step 2:

[0392] [ka] Compound 96 was prepared from 13b following the procedure described in step 1g of Example 1, with appropriate changes in reactants, amounts of reagents, solvents and reaction conditions. LCMS (M+H) + :360.0.

[0393] Example 14: Synthesis of Compound 97

[0394] [ka]

[0395] Step 14a:

[0396] [ka] A solution of 4-nitrophenol (1.3 g, 9.99 mmol) and pyridine (0.8 mL, 9.99 mmol) in Et2O (20 mL) was added dropwise to a solution of SO2Cl2 (0.8 mL, 9.99 mmol) in Et2O (20 mL) at -78 °C under argon. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (eluent: 0-3% ethyl acetate in hexane) to yield 1.2 g of compound 14a. 1 H NMR (400MHz, CDCl3): δ8.39-8.36(m,2H), 7.61-7.57(m,2H).

[0397] Step 14b:

[0398] [ka] A mixture of compound 14b (0.6 g, 2.59 mmol), molecular sieves (1.0 g), 4-nitrophenol (0.72 g, 5.18 mmol), and Et3N (1.1 mL, 7.77 mmol) in anhydrous CHCl2 (25.0 mL) was added dropwise to a solution of compound 14a (1.2 g, 5.18 mmol) in anhydrous CHCl2 (5.0 mL) at -78 °C under argon atmosphere. After stirring for 30 min, the reaction mixture was allowed to warm to room temperature for 2 h. Completion of the reaction was confirmed by TLC analysis. The reaction mixture was evaporated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (eluent: 0-7% ethyl acetate in hexane) to yield compound 14c 0.7 g. 1 H NMR (300MHz, CDCl3): δ8.30-8.27(m2H),7.52-7.49(m2H),5.70-5.67(1H d,J9.6),4.17-3.90(1H,m),1.49(9H,s),1.28-1.23(3H,m),1.15(9H,s). .

[0399] Step 14c:

[0400] [ka] Compound 14c (0.69 g, 1.59 mmol) in THF (5.0 mL) was added to a stirred solution of compound 14d (0.7 g, 1.14 mmol) and Et3N (0.5 mL, 3.42 mmol) in anhydrous THF (10.0 mL), and the resulting reaction mixture was stirred at 70 °C for 3 h. Completion of the reaction was confirmed by TLC analysis. Volatiles were evaporated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography (eluent: 0-33% ethyl acetate in hexane) to give compound 14e 0.55 g. LCMS: 907.4 (M+H) + .

[0401] Step 14d:

[0402] [ka] To a solution of compound 14e (0.55 g, 0.55 mmol) in trifluoroacetic acid (9.5 mL), triisopropylsilane (0.25 mL) and water (0.25 mL) were added and stirred at room temperature for 2 h. The resulting solution was evaporated under nitrogen to give crude compound 97, 0.3 g. The crude solid material was purified using the preparative HPLC method described in the experimental conditions. LCMS: 397.0 (M+H). + ;HPLC:t R =10.547min.

[0403] The following compounds were prepared by procedures similar to those described in Example 14 (Compound 97) with moderate variations in reactants or amino acids, solvents, amounts of reagents and reaction conditions. Analytical data for the compounds are summarized in the table below.

[0404] [Table 8] TIFF0007659015000112.tif196170

[0405] Although the present application is illustrated by the above specific examples, the present application should not be considered limited by them, but rather encompasses the general area disclosed above.Various improvements and embodiments can be made without departing from the spirit and scope of the present application.For example, the following compounds, which can be prepared by the following procedures similar to those described above, with suitable improvements known to those skilled in the art, are also included in the scope of the present application.

[0406] [Table 9] TIFF0007659015000114.tif241170Previous page | Next page TIFF0007659015000115.tif126170

[0407] Example 15: Rescue of mouse splenocyte proliferation in the presence of recombinant PD-L1 Recombinant mouse PD-L1 (rm-PDL-1, cat no: 1019-B7-100; R&D Systems) was used as a source of PD-L1.

[0408] Requirements: Mouse splenocytes harvested from 6-8 week-old C57 BL6 mice; RPMI 1640 (GIBCO, Cat# 11875); high glucose DMEM (GIBCO, Cat# D6429); fetal bovine serum [Hyclone, Cat# SH30071.03]; penicillin (10,000 units / mL)-streptomycin (10,000 μg / mL) Liquid (GIBCO, Cat# 15140-122); MEM sodium pyruvate solution 100 mM (100×), Liquid (GIBCO, Cat# 11360); non-essential amino acids (GIBCO, Cat# 11140); L-glutamine (GIBCO, Cat# 25030); anti-CD3 antibody (eBiosciences-16-0032); anti-CD28 antibody (eBiosciences-16-0281); ACK lysis buffer (1mL) (GIBCO, Cat#-A10492); Histopaque (specific gravity 1.083g / mL) (SIGMA 10831); Trypan blue solution (SIGMA-T8154); 2mL Norm Ject Luer Lock syringe (Sigma 2014-12); 40μm nylon cell strainer (BD FALCON 35230); Hemacytometer (Bright line-SIGMA Z359629); FACS buffer (PBS / 0.1%BSA): phosphate buffered saline (PBS) pH 7.2 containing 0.1% bovine serum albumin (BSA) (SIGMA A7050) and sodium azide (SIGMA 08591) (HiMedia TS1006); 5 mM CFSE stock solution: CFSE stock solution was prepared by diluting lyophilized CFSE with 180 μL of dimethyl sulfoxide (DMSO CHSO, SIGMA-D-5879) and aliquoted into test tubes for further use. Standard concentrations were titrated from 10 μM to 1 μM. (e Bioscience-650850-85); 0.05% trypsin and 0.02% EDTA (SIGMA 59417C); 96-well format ELISA plate (Corning CLS3390); BD FACS caliber (E6016); recombinant mouse B7-H1 / PDL1 Fc Chimera (rm-PD-L1 cat no:1019-B7-100).

[0409] Protocol Splenocyte preparation and culture: Splenocytes collected in 50mL Falcon tubes by grinding mouse spleens in a 40μm cell strainer were further treated with 1mL ACK lysis buffer at room temperature for 5 minutes. After washing with 9mL RPMI complete medium, cells were resuspended in 3mL 1x PBS in a 15mL tube. 3mL Histopaque was carefully added to the bottom of the tube without disturbing the layer of splenocyte suspension. After centrifugation at 800xg and room temperature for 20 minutes, the opaque splenocyte layer was carefully collected without disturbing / mixing the layer. Splenocytes were washed twice with cold 1x PBS, and then the total number of cells was counted using trypan blue exclusion and further used for cell-based assays.

[0410] Splenocytes were cultured in RPMI complete medium (RPMI + 10% fetal bovine serum + 1 mM sodium pyruvate + 10,000 units / mL penicillin and 10,000 μg / mL streptomycin) and kept in a CO2 incubator at 5% CO2 and 37°C.

[0411] CFSE Proliferation Assay: CFSE is a dye that passively diffuses into cells and binds to intracellular proteins. 6 Harvested splenocytes at 1x10 cells / mL were treated with 5 μM CFSE in pre-warmed 1x PBS / 0.1% BSA solution at 37°C for 10 min. Excess CFSE was quenched with 5x the volume of ice-cold medium relative to the cells and incubated on ice for 5 min. CFSE-labeled splenocytes were further washed three times with ice-cold complete RPMI medium. CFSE-labeled splenocytes at 1x10 cells / mL were treated with 5 μM CFSE in pre-warmed 1x PBS / 0.1% BSA solution at 37°C for 10 min. 5 1 × 10 cells cultured in high glucose DMEM medium 5Either human PDL-1 (100 ng / mL) or recombinant human PDL-1 (100 ng / mL) and test compounds were added to wells containing the cells. Splenocytes were stimulated with anti-mouse CD3 and anti-mouse CD28 antibodies (1 μg / mL each) and cultures were further incubated for 72 h at 37° C. and 5% CO2. Cells were harvested, washed three times with ice-cold FACS buffer and analyzed for % proliferation by flow cytometry using a 488 nM excitation filter and a 521 nM emission filter.

[0412] Data compilation, processing and inference: The % splenocyte proliferation was analyzed using CellQuest FACS program, and the % rescue of splenocyte proliferation by the compounds was estimated after subtracting the % background proliferation and normalized to the % stimulated splenocyte proliferation (positive control) as 100%. The results are shown in Table I. Stimulated splenocytes: splenocytes + anti-CD3 / CD28 stimulation Background proliferation: splenocytes + anti-CD3 / CD28 + PD-L1 Compound-containing proliferation: splenocytes + anti-CD3 / CD28 + PD-L1 + compound The effect of the compounds is examined by adding the required concentrations to splenocytes stimulated with anti-CD3 / CD28 in the presence of ligand (PDL-1).

[0413] [Table 10] TIFF0007659015000117.tif241170 TIFF0007659015000118.tif82170

Claims

1. A compound selected from the following table: 【Table 1-1】 【Table 1-2】 or a pharma- ceutically acceptable salt thereof.

2. The compound, 【Chemistry 2】 2. The compound of claim 1, wherein:

3. The compound, 【Chemistry 3】 2. The compound of claim 1, wherein:

4. The compound, 【Chemistry 4】 2. The compound of claim 1, wherein:

5. The compound, 【Chemistry 5】 2. The compound of claim 1, wherein:

6. The compound, 【Chemistry 6】 2. The compound of claim 1, wherein:

7. The compound, 【Chemistry 7】 2. The compound of claim 1, wherein:

8. The compound, 【Chemistry 8】 2. The compound of claim 1, wherein:

9. The compound, 【Chemistry 9】 2. The compound of claim 1, wherein:

10. The compound of claim 1, 【Chemistry 10】 2. The compound of claim 1, wherein:

11. The compound of claim 1 【Chemistry 11】 2. The compound of claim 1, wherein:

12. The compound comprising: 【Chemistry 12】 2. The compound of claim 1, wherein:

13. The compound of claim 12, 【Chemistry 13】 2. The compound of claim 1, wherein:

14. The compound of claim 1, 【Chemistry 14】 2. The compound of claim 1, wherein:

15. The compound of claim 1, 【Chemistry 15】 2. The compound of claim 1, wherein:

16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharma- ceutically acceptable carrier.

17. 20. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for the treatment of cancer, a bacterial infection, a viral infection, a fungal infection, or an immune disease infection.

18. The use according to claim 17, which is a drug for the treatment of cancer.

19. 19. The use according to claim 18 for the treatment, wherein the cancer is selected from lung cancer, breast cancer, colon cancer, kidney cancer, bladder cancer, thyroid cancer, prostate cancer, osteosarcoma and Hodgkin's lymphoma.

20. 16. A method of inhibiting the PD-1 pathway (e.g., PD-1, PD-L1 or PD-L2) in a cell in a subject in vitro, comprising contacting the cell with a compound of any one of claims 1-15.

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