EA044307B1 - IMMUNOMODULATORS, THEIR COMPOSITIONS AND METHODS OF APPLICATION - Google Patents

Description

Field of invention

The application for this invention concerns pharmaceutically active compounds. This disclosure provides compounds, as well as compositions and methods of use thereof. These compounds modulate the PD-1/PD-L1 protein/protein interaction and are useful in the treatment of various diseases, including infectious diseases and cancer.

Prior Art

The immune system plays an important role in controlling and eliminating diseases such as cancer. However, cancer cells often develop strategies to evade or suppress the immune system to favor their growth. One such mechanism is changes in the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow et al., J. Clinical. Oncology, 2015, 1-9). Blocking inhibitory immune checkpoint signaling such as PD-1 has proven to be a promising and effective treatment.

The interaction between PD-1 and PD-L1 results in decreased levels of tumor-infiltrating lymphocytes, decreased T-cell receptor-mediated proliferation, and evasion of cancer cells from immune recognition (Dong et al., J. Mol. Med., 81:281- 287 (2003); Blank et al., Cancer Immunol. Immunother., 54:307-314 (2005); Konishi et al., Clin. Cancer Res., 10:5094-5100 (2004)). Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and this effect is additive when the interaction of PD-1 with PD-L1 is also blocked (Iwai et al., Proc. Natl. Acad. Sci. USA, 99:12293 -12297 (2002); Brown et al., J. Immunol., 170:1257-1266 (2003)).

Programmed cell death protein-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells and macrophages (Greenwald et al., Annu. Rev. Immunol., 2005, 23:515-548; Okazaki and Honjo, Trends Immunol., 2006, 4:195-201). It functions as an innate feedback system to prevent T cell activation, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play a critical role in suppressing antigen-specific T cell responses in diseases like cancer and viral infection (Sharpe et al., Nat. Immunol., 2007, 8, 239-245; Postow et al., Nat. Immunol., 2007, 8, 239-245 al., J. Clinical. Oncol., 2015, 1-9).

The structure of PD-1 consists of an extracellular domain, similar to the immunoglobulin variable region, followed by a transmembrane region and an intracellular domain (Parry et al., Mol. Cell Biol., 2005, 9543-9553). The intracellular domain contains two phosphorylation sites located in the immunoreceptor tyrosine-based inhibitory motif and the immunoreceptor tyrosine-based switch motif, suggesting that PD-1 negatively regulates T cell receptor-mediated signals. PD-1 has two ligands: PD-L1 and PD-L2 (Parry et al., Mol. Cell Biol., 2005, 9543-9553; Latchman et al., Nat. Immunol. 2001, 2, 261-268), and they differ in their expression patterns. PD-L1 protein is up-regulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF (granulocyte-macrophage colony-stimulating factor) treatment, and on T cells and B cells through signaling from the T-cell receptor and B-cell receptor. cells. PD-L1 is also highly expressed on almost all cancer cells, and this expression is further enhanced by IFN-γ (interferon-gamma) treatment (Iwai et al., PNAS2002, 99(19):12293-7; Blank et al., Cancer Res., 2004, 64(3):1140-5). In fact, PD-L1 expression status has been shown to be prognostic in many tumor types (Wang et al., Eur. J. Surg. Oncol., 2015; Huang et al., Oncol. Rep. 2015; Sabatier et al. ., Oncotarget., 2015, 6(7):5449-5464). Expression of PD-L2, in contrast, is more limited, and it is expressed primarily by dendritic cells (Nakae et al., J. Immunol. 2006, 177:566-73). Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal that inhibits the production of IL-2 (interleukin-2) and IFN-γ (interferon-gamma), as well as cell proliferation induced upon activation T cell receptor (Carter et al., Eur. J. Immunol. 2002, 32(3):634-43; Freeman et al., J. Exp. Med. 2000, 192(7):1027-34). This mechanism involves the recruitment of the phosphatases SHP-2 or SHP-1 with inhibition of T cell receptor signaling, such as Syk and Lck phosphorylation (Sharpe et al., Nat. Immunol. 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates phosphorylation of the PKC-E activating loop, which is required for activation of the NF-κB and API pathways and for the production of cytokines such as IL-2, IFN-γ and TNF (tumor necrosis factor) (Sharpe et al., Nat. Immunol. 2007, 8, 239-245; Carter et al., Eur. J. Immunol., 2002, 32(3):634-43; Freeman et al., J. Exp. Med. 2000 , 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al., Immunity, 1999, 11:41-151; Nishimura et al., Science, 2001, 291:319-322). Using an LCMV model of chronic infection, it was shown that the PD-1/PD-L1 interaction inhibits the activation, expansion and acquisition of effector functions of virus-specific CD8 T cells (Barber et al., Nature, 2006, 439, 682-7).

Together, these data support the development of a therapeutic approach to block

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PD-1-mediated inhibitory signaling cascade in order to enhance or rescue the response

T cells. Most of the currently approved immunotherapy drugs are monoclonal antibodies. However, small molecule inhibitors that directly target PD-1 or PD-L1 are still not approved, with only CA170 being evaluated clinically.

Accordingly, there is still a great need for more potent and easier to administer therapeutics against PD-1/PD-L1 protein/protein interactions. In this invention, the applicant has discovered effective small molecules that may have PD-L1-PD-1 interaction inhibitory activity and thus may be suitable for therapeutic administration to enhance immunity against cancer and/or infectious diseases. These small molecules are expected to be useful as pharmaceuticals with desirable stability, solubility, bioavailability, therapeutic index and toxicity values that are critical for them to become effective drugs for supporting human health.

Summary of the invention

The present invention relates to compounds that are used as inhibitors of the functional interaction between PD-L1 and PD-1. Inhibitors of the interaction between PD-L1 and PD-1 are useful in the treatment of cancers and infectious diseases.

The compounds of the invention have the same general structures as in Formula I. A compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof:

Formula I in which X is selected from C;

= represents a single bond or double bond;

R1 is selected from H, halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl or -OC _1-8 alkyl;

R ₂ , R ₃ and R ₄ are each independently selected from H, halogen, -CN or

R3 and _R4 , together with the atoms to which they are attached, form a 2,3-dihydro-1,4-dioxine ring;

Y selected from the missing group, O, S, -NR9-;

R ₉ is selected from H, -C _1-8 alkyl or -C _1-8 haloalkyl;

R ₅ is selected from halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl, -C _2-8 alkenyl, SO ₂ -C _1-4 alkyl, methylsulfinyl, with the proviso that if Y is O then R ₅ is not -C _1-8 alkyl;

R6 is H;

R ₇ and R ₈ are each independently selected from H, -C _1-8 alkyl, -C _1-6 alkyl-COOH, phenyl, wherein -C _1-6 alkyl-COOH and phenyl are optionally substituted with -C _1-8 alkyl , -C _0-4 alkyl-COOH, -C _0-4 alkyl-OH; or

R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring; wherein the heterocyclic ring optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein this heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH;

R ₅ and R ₈ together with the atoms to which they are attached form a 6-10 membered heterocyclic ring; wherein the heterocyclic ring optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein this heterocyclic ring is possibly substituted with oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH, -C _0-4 alkyl-OH.

In some embodiments of Formula I, Y is selected from the missing group, -O-, -S-, -NH-.

In some embodiments of Formula I, R1 is selected from CH3 and CN.

In some embodiments of the formula, IR ₅ is selected from H, -CH3, -CHF2, -CF ₃ , o $ ¹¹ fS-CH3

-CH2CF3, F, Cl, CN, o and provided that if Y is O then _R5 is not -CH3.

A compound of formula II or a stereoisomer thereof or a pharmaceutically acceptable salt:

in which R1 is selected from H, halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl or -O-C _1-8 alkyl; R2, R3 and _R4 are each independently selected from H, halogen, -CN;

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R5 is selected from -C _1-4 haloalkyl, -SO ₂ -C _1-4 alkyl;

R ₇ and R ₈ are each independently selected from H, -C _1-8 alkyl, -C _1-6 alkyl-COOH, phenyl, where

-C _1-6 alkyl-COOH and phenyl are possibly substituted with -C _1-8 alkyl, -C _0-4 alkyl-COOH, -C _0-4 alkyl-OH; or

R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring; wherein the heterocyclic ring optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein this heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH.

In some embodiments of Formula II, R1 is selected from CH ₃ and CN.

In certain embodiments of Formula II, _R2 , _R3 , and R4 are each independently selected from H, CN, and F.

In some embodiments of Formula II, R5 is -C _1-4 haloalkyl.

In some embodiments of Formula II, R5 is -C _1-4 alkyl substituted with 1-3 fluorine atoms.

In some embodiments of Formula II, R5 is methyl or ethyl substituted with 2-3 fluorine atoms.

In some embodiments of Formula II, R5 is -CF ₃ , -CHF2, -CH2CHF2 or -CH2CF3.

In some embodiments of Formula II, R5 is -SO ₂ -C _1-4 alkyl.

In some embodiments of Formula II, R5 is -SO2-CH3.

In certain embodiments of Formula II, R ₇ and R ₈ are each independently selected from H, CH ₃ , he he

In some embodiments of Formula II, R7 and R8, together with the atoms to which they are attached, form a 4-6 membered heterocyclic ring; wherein the heterocyclic ring is substituted with 1-2 substituents independently selected from -C _1-4 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH.

In certain embodiments of Formula II, the heterocyclic ring is

In some embodiments of Formula II, the substituted heterocyclic ring is selected from

A compound of formula III or a stereoisomer thereof or a pharmaceutically acceptable salt:

r ₇

Formula III wherein R1 is selected from H, halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl or -OC _1-8 alkyl;

R ₂ , R ₃ and R 4 are each independently selected from H, halogen, -CN;

R5 is selected from halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl, -NH-C _1-4 alkyl or -S-C _1-4 alkyl, SO ₂ -C _1-4 alkyl or methylsulfinyl;

R ₇ and R ₈ are each independently selected from H, -C _1-8 alkyl, -C _1-6 alkyl-COOH, phenyl, wherein -C _1-6 alkyl-COOH and phenyl are optionally substituted with -C _1-8 alkyl , -C _0-4 alkyl-COOH, -C _0-4 alkyl-OH; or

R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring; wherein the heterocyclic ring optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein this heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH.

In some embodiments of Formula III, wherein R1 is selected from CH ₃ or CN.

In some embodiments of Formula III, R5 is selected from F, Cl, -CH ₃ , -CF ₃ , -SO-CH ₃ , -SO ₂ -CH ₃ or -CN.

In certain embodiments of Formula III, R ₇ and R ₈ are each independently selected from H, CH ₃ , Y he he

A /? U —, he νΎ° ^Η /° ^Н °^_/ but^)—< he

OH > he, M, 0,^0, ’OH or “ Ά .

In some embodiments of formula III, R ₇ and R ₈ together with the atoms to which they are attached form a 5-6 membered heterocyclic ring; where this heterocyclic ring is substituted with -C0-4alkyl-COOH.

In some embodiments of Formula III, the substituted heterocyclic ring is selected from

O

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In certain embodiments of Formula III, wherein:

“ represents a double bond;

R1 is selected from H, halogen, CN, -C1_8alkyl, _{-C1_4haloalkyl} or _-O - _{1_8alkyl} ;

R2, R3 and R4 are each independently selected from H, halogen, -CN;

Y is selected from S or -NR9-;

R ₉ represents H;

R5 represents -C _1-4 alkyl;

R ₇ and R 8 are each independently selected from H, -C _1-8 alkyl, -C 1 -balkyl-COOH, phenyl, where -C ^ alkyl COOH and phenyl are optionally substituted with -C 1 . ₈ alkyl, -C ₀ . ₄ alkyl-COOH, -C ₀ . ₄ alkyl-OH; or

R ₇ and R8, together with the atoms to which they are attached, form a 3-7 membered heterocyclic ring; wherein said heterocyclic ring optionally contains 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein said heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH or -C ₀ . ₄ alkyl-OH,

A compound of formula I, wherein the compound is the following:

1) (8)-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)piperidin- 2-carboxylic acid;

2) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

3) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-O-allotreonine;

4) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-allotreonine;

5) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-alanine;

6) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-O-alanine;

7) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-O-proline;

8) (1 -((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)piperidin-2-yl )methanol;

9) (5)-4-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)morpholin- 3-carboxylic acid;

10) (5)-2-(((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)amino )butanoic acid;

11) (R)-2-(((2-(2-MeTHn-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)amino )butanoic acid;

12) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-O-serine;

13) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-serine;

14) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

15) ((2-(2,2'-dicyano-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

16) 2-methyl-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[c1]oxazol-

5-yl)methyl)pyrrolidine-2-carboxylic acid;

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17) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[c1]oxazol-5-yl)methyl)-Oproline;

18) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[c1]oxazol-5-yl)methyl)-1_proline;

19) (8)-4-((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[c1]oxazol-5-yl)methyl)morpholine-3-carboxylic acid;

20) ((6-chloro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-1_- proline;

21) (8)-1-((6-methyl-2-(2-methyl-[1,1'-biphenl]-3-yl)benzo[c1]oxazol-5-yl)methyl)piperidin-2- carboxylic acid;

22) (8)-1-((6-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)pyrrolidin-3- ol;

23) ((6-fluoro-2-(2-methyl-[1,1 '-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-1_proline;

24) (8)-1-((6-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)piperidin-2- carboxylic acid;

25) 1 -((6-cyano-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)piperidine-2-carboxylic acid;

26) 1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylamino)benzo[c1]oxazol-5yl)methyl)piperidine-2-carboxylic acid;

27) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(trifluoromethyl)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

28) (8)-1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)piperidin- 2-carboxylic acid;

29) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-O-allotreonine;

30) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-1_-allotreonine;

31) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)4_-tyrosine hydrochloride;

32) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-1_-alanine;

33) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-O-alanine;

34) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl) glycine;

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35) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-1_-proline;

36) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-O-proline;

37) (1-((6-(difluoromethoxy)-2-(2-methyl-[1,T-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)piperidin-2-yl)methanol;

38) (5)-4-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)morpholine- 3-carboxylic acid;

39) (5)-2-(((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)amino )butanoic acid;

40) (U-2-(((6-(difluoromethoxy)-2-(2-methyl-[1,1 '-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)amino) butanoic acid;

41) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-O-serine;

42) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-1_-serine;

43) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-(d fluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

44) ((2-(2,2'-dicyano-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol5-yl)methyl)-1_-proline;

45) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-2-methylpyrrolidine-2-carboxylic acid;

46) ((6-(difluoromethoxy)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2methylphenyl)benzo[c1]oxazol-5-yl)methyl) -1_-proline;

47) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)azetidine-2-carboxylic acid;

48) ((6-(difluoromethoxy)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2methylphenyl)benzo[c1]oxazol-5-yl)methyl) -1_-proline;

49) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-2-methylpyrrolidine-2-carboxylic acid;

50) ((2-(2'-cyano-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)proline;

51) ((6-(difluoromethoxy)-2-(2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-1_- proline;

52) (5)-3-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)oxazolidine -4-carboxylic acid;

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53) (8)-1-((2-(2-methyl-[1,T-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl )methyl)piperidine-2-carboxylic acid;

54) 1 -((6-(2,2-difluoroethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol5-yl)methyl)piperidin-2- carboxylic acid;

55) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl)methyl)-O -alanine;

56) (8)-4-((2-(2-cyano-[1,T-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl )methyl)morpholine-3-carboxylic acid;

57) (8)-4-((2-(2-methyl-[1,T-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl )methyl)morpholine-3-carboxylic acid;

58) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl)methyl)-1_ -alanine;

59) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5-yl)methyl)-1_ -proline;

60) 2-methyl-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c1]oxazol-5- yl)methyl)pyrrolidine-2-carboxylic acid;

61) ((2-(2-methyl-[1,T-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[c!]oxazol-5-yl)methyl)-O -alanine;

62) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(trifluoromethoxy)benzo[c1]oxazol-5yl)methyl)-1_-proline;

63) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-((methylsulfonyl)oxy)benzo[c1]oxazol-5-yl)methyl)-1_-proline;

64) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[c1]oxazol-5yl)methyl)-1_-proline;

65) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfonyl)benzo[c1]oxazol-5yl)methyl)-1_-proline;

66) 8-methyl-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f][1,4]oxazepine;

67) (8)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f][1,4]oxazepine-7-carboxylic acid;

68) 2-(2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-f] [1,4]oxazepin-8(9H)-yl)acetic acid;

69) (E)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f][1,4]oxazepine-7-carboxylic acid. The present invention also provides a pharmaceutical composition comprising a compound according to any of the embodiments of the present invention and a pharmaceutically acceptable excipient such as hydroxypropyl methylcellulose. In this composition, the specified compound is in a weight ratio with the specified excipient within the range of from about 0.0001 to about 10.

The present invention further provides the use of a pharmaceutical composition of Formula I for the preparation of a medicament for treating a disease in a subject.

The present invention further provides some advantageous technical solutions with respect to the above-mentioned applications.

In some embodiments, the drug thus obtained can be used to treat or prevent, or to delay or prevent the onset or progression of a cancer, cancer metastasis, or immunological disorder. This cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer or breast cancer.

According to the present invention, there is provided a method of inhibiting the PD-1/PD-L1 interaction, comprising administering to a patient a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer thereof.

The present invention provides a method of treating a disease associated with inhibition of the PD-1/PD-L1 interaction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, when the disease presents include colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer or breast cancer.

The present invention provides a method of enhancing, stimulating and/or enhancing the immune response in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof.

The present invention also provides the use of the present compound or a pharmaceutical composition thereof for the preparation of a medicament.

In some embodiments, the drug is used to treat or prevent cancer.

In some embodiments, the cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

In some embodiments, the drug is used as an inhibitor of the PD-1/PD-L1 interaction.

The general chemical terms used in the above formula have their usual meanings. For example, the term halogen as used herein, unless otherwise noted, means fluorine, chlorine, bromo, or iodine. Preferred halogen groups include F, Cl and Br.

The term alkyl as used herein, unless otherwise specified, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2- methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Likewise, C ₁ - ₈ , as in C ₁ . ₈ alkyl is defined to identify a group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched configuration.

Alkenyl and alkynyl groups include straight-chain, branched-chain and cyclic alkenes and alkynes. Similarly, _{C2_8 alkenyl} and _{C2_8} alkynyl mean alkenyl or alkynyl _radicals having 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched configuration.

Alkoxy radicals are oxygen ethers formed with the previously described straight-chain, branched-chain, and cyclic alkyl groups.

The term aryl as used herein, unless otherwise noted, refers to an unsubstituted or substituted mono- or polycyclic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.

The term heterocyclyl as used herein, unless otherwise indicated, is an unsubstituted or substituted stable three to eight membered monocyclic saturated ring system which consists of carbon atoms and one to three heteroatoms selected from N, O and S, wherein the nitrogen or sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heterocyclyl group can attach on any heteroatom or carbon atom, resulting in a stable structure. Examples of such heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thio morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and oxadiazolyl.

The term heteroaryl as used herein, unless otherwise noted, is an unsubstituted or substituted stable five or six membered monocyclic aromatic ring system, or an unsubstituted or substituted nine or ten membered benzo-fused heteroaromatic ring system, or a bicyclic heteroaromatic ring system a system which consists of carbon atoms and one to four heteroatoms selected from N, O or S, wherein the nitrogen and sulfur heteroatoms may optionally be oxylenized and the nitrogen heteroatom may optionally be quaternized. This heteroaryl group can attach on any heteroatom or carbon atom, resulting in a stable structure. Examples of heteroaryl groups include thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzo thiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

The term alkenyloxy refers to the group -O-alkenyl, where alkenyl is defined as above.

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The term alkynyloxy refers to the group -O-alkynyl, where alkynyl is defined as above.

The term cycloalkyl refers to a cyclic saturated alkyl chain having from 3 to 12 carbon atoms, for example cyclopropyl, cyclobutyl, cyclobutyl, cyclobutyl.

The term substituted refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituent(s). Typical substituents include halogen (F, Cl, Br or I), C ₁ . ₈ alkyl, C ₃ _ ₁₂ cycloalkyl, -OR ¹ , SR ¹ , =O, =S, -C(O)R ¹ , -C(S)R ¹ , =NR ¹ , -C(O)OR ¹ , -C(S)OR ¹ , -NR1R ² , -C(O)NR1R ² , cyano, nitro, -S(O)2R ¹ , -OS(O2)OR ¹ , -OS(O)2R ¹ , -OP (O)(OR1)( ^OR2 ), wherein R ¹ and R ² are independently selected from, but are not limited to -H, lower alkyl, lower haloalkyl. In some embodiments, the substituent(s) are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde group, -C(OCH ₃ ), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl and acetyl.

The term composition as used herein is intended to cover a product containing precisely defined ingredients in precisely defined quantities, as well as any product that is directly or indirectly obtained from combinations of precisely defined ingredients in precisely defined quantities. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient, as well as methods for preparing the present compounds, are also part of the present invention. In addition, some of the crystalline forms of these compounds may exist as polymorphs and, as such, are intended to be included in the present invention. In addition, some of these compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also intended to be included within the scope of this invention.

Examples of the substituted alkyl group include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinylmethyl.

Examples of substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.

The compounds of the present invention may also be present in the form of pharmaceutically acceptable salts. For medical use, the salts of the compounds of this invention are non-toxic pharmaceutically acceptable salts. Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anionic or basic/cationic salts. The pharmaceutically acceptable acid/anionic salt typically takes a form in which a basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalene sulfonic, p-toluene sulfonic, cyclohexane sulfamic, salicylic, saccharic or trifluoroacetic acids. Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc salts.

The present invention includes, within its scope, prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of compounds that are readily convertible in vivo into the desired compound. Thus, in the methods of treatment of the present invention, the term administration should encompass the treatment of various described disorders using a specifically disclosed compound or using a compound that may not be specifically disclosed but which is converted to a specific compound in vivo upon administration to a subject. Traditional techniques for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

It is intended that the definition of any substituent or variable at a particular position in the molecule is independent of its definitions elsewhere in the molecule. It is understood that the substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be easily synthesized by techniques known in the art, as well as the methods set forth herein. document.

The present invention includes compounds described herein which may contain one or more asymmetric centers and may thus result in diastereomers and optical isomers. The present invention includes all such possible diastereomers, as well as racemic mixtures thereof, substantially pure separated enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

Formula I above is shown without exhaustive stereochemistry at specific positions. The present invention includes all stereoisomers of formula I and their pharmaceutically acceptable salts. In addition, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. In the course of the synthetic techniques used to prepare such compounds, or using racemization or epimerization techniques known to those skilled in the art, the products of such techniques may be a mixture of stereoisomers.

When a tautomer of a compound of Formula I exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof and mixtures thereof, unless specifically stated otherwise.

While the compound of formula I and its pharmaceutically acceptable salts exist as solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

The term pharmaceutically acceptable salts refers to salts derived from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper((II) and (I)), iron(III), iron(II), lithium, magnesium, manganese(IV) and (II) salts. , potassium, sodium, zinc and similar salts. Particularly preferred are the ammonium, calcium, manganese, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange salts such as, for example, arginine, betaine, caffeine, choline, K',K'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine , ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. P.

When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acids, etc. Preferred are citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid, with formic acid and hydrochloric acid being particularly preferred. Since the compounds of formula I are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% expressed on a w/w basis).

The pharmaceutical compositions of the present invention include the compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as the active ingredient, a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. These compositions include compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the particular host, nature and severity of the conditions against which the active ingredient is administered. The pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods well known in the pharmaceutical field.

In practice, the compounds represented by Formula I, or the prodrug or metabolite, or pharmaceutically acceptable salts thereof of this invention may be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. This carrier can take a wide variety of forms, depending on the desired form of the drug for administration, for example, oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may be presented in discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. In addition, the compositions may be presented as a powder, as a granule, as a solution or suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a liquid water-in-oil emulsion. In addition to the usual dosage forms set forth above, the compound represented by Formula I, or its pharmaceutical

- 10 044307 acceptable salt can also be administered by means and/or controlled release delivery devices. These compositions can be obtained by any pharmaceutical methods. In general, such methods include the step of bringing the active ingredient into association with a carrier that contains one or more required ingredients. In general, these compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers or both. This product can then be conveniently molded into the desired presentation form.

Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or pharmaceutically acceptable salt of Formula I. Compounds of Formula I or pharmaceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

The pharmaceutical carrier used may be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, kaolin, sucrose, talc, gelatin, agar, pectin, gum acacia, magnesium stearate and stearic acid. Examples of liquid carriers include sugar syrup, peanut butter, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, etc. can be used to form liquid oral preparations such as suspensions, elixirs and solutions; whereas for the formation of solid oral preparations such as powders, capsules and tablets, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used. Due to the lightness For their administration, tablets and capsules are the preferred oral dosage forms, and solid pharmaceutical carriers are used. Optionally, tablets can be coated using standard aqueous or non-aqueous techniques.

A tablet containing the composition of this invention may be prepared by compression or casting, optionally with one or more one auxiliary ingredient or adjuvant. Compressed tablets can be prepared by compressing in a suitable apparatus the active ingredient in a free-flowing form such as powder or granules, possibly mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Cast tablets can be prepared by casting in a suitable apparatus a mixture of the powder compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for oral administration to a human may contain from about 0.5 mg to about 5 g of active agent formulated with a suitable and convenient amount of carrier material, which may range from about 5 to about 95% of the total composition. Unit dosage forms will typically contain from about 1 mg to about 2 g of active ingredient, typically 25, 50, 100, 200, 300, 400, 500, 600, 800 or 1000 mg.

The pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant may be included, such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols and mixtures thereof in oils. In addition, a preservative may be included to prevent harmful microbial growth.

Suitable injectable pharmaceutical compositions of the present invention include sterile aqueous solutions or dispersions. In addition, these compositions may be in the form of sterile powders for immediate preparation before administration of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and flow efficiently for easy syringe collection. These pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be protected against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersing medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions of the present invention may be in a suitable form for topical administration, such as, for example, an aerosol, cream, ointment, lotion, powder, or the like. In addition, these compositions may be in a suitable form for use in transdermal devices. These preparations can be prepared using the compound represented by Formula I of this invention, or a pharmaceutically acceptable salt thereof, through conventional processing methods. By way of example, a cream or ointment is prepared by mixing a hydrophilic substance and water together with about 5-10% by weight of the compound to obtain a cream or ointment having the desired consistency.

The pharmaceutical compositions of this invention may be in a suitable form for rectal administration, wherein the carrier is a solid. It is preferred that the mixture forms single-dose suppositories. Suitable carriers include cocoa butter and other substances commonly used in the art. These suppositories can be conveniently formed by initially mixing the composition with softened or melted carrier(s), followed by cooling and molding.

In addition to the above-mentioned carrier ingredients, the pharmaceutical preparations described above may include, as appropriate, one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) ) and so on. In addition, other adjuvants may be included to make the drug isotonic with the blood of the intended recipient. Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof, may also be prepared as a powder or liquid concentrate.

In general, dosage levels of from about 0.01 to about 150 mg/kg body weight per day, or alternatively from about 0.5 mg to about 7 g per patient per day, are useful in the treatment of the above conditions. For example, by administering about 0.01 to 50 mg of the compound per kg of body weight per day, or alternatively from about 0.5 mg to about 3.5 g per patient per day, colon cancer, rectal cancer can be effectively treated , mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell carcinoma of the esophagus, liposarcoma, T-cell lymphoma-melanoma, pancreatic cancer, glioblastoma or lung cancer.

However, it is understood that lower or higher doses than those listed above may be required. The specific dose level and treatment regimen for any particular subject will depend on a number of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, rate of elimination, drug combination, severity and the course of the particular disease being treated, the subject's attitude toward the disease, and the decision of the treating physician.

These and other aspects will become apparent from the following written description of the present invention.

The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless expressly stated otherwise.

The present invention will be described in more detail by means of specific examples. The following examples are offered for illustrative purposes and are not intended to limit the present invention in any way. One skilled in the art will readily recognize many non-critical parameters that can be changed or modified to obtain substantially the same results. The compounds of these Examples were found to inhibit PD-1/PD-L1 protein/protein interaction activity according to at least one assay described herein.

Examples

Experimental procedures for the compounds of the invention are given below. Preparative open-access LC-MS (liquid chromatography-mass spectrometry) purification of some of the resulting compounds was performed on mass-directed fractionation systems from Waters. The basic hardware setup, protocols, and control programs for operating these systems have been described in detail in the literature. See, for example, Blom, Two-Pump At Column Dilution Configuration for Preparative LC-MS, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blom et al., Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification, J. Combi. Chem., 2003, 5, 670-83 and Blom et al., Preparative LC-MS Purification: Improved Compound Specific Method Optimization, J. Combi. Chem., 2004, 6, 874-883.

The compounds described herein can be obtained from commercial sources or synthesized by traditional methods, as shown below, using commercially available starting materials and reagents.

The following abbreviations were used in the examples:

AcOH or HOAC: ethanoic acid;

BSA: bovine serum albumin;

DCM: dichloromethane;

DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone;

DMSO: dimethyl sulfoxide;

EtOAc: ethyl acetate;

h: hour or hours;

HTRF: homogeneous time-resolved fluorescence;

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MeOH: methanol min: minute;

PE: petroleum ether;

Pd(dppf)Cl ₂ : [1,1'-bis-(diphenylphosphino)ferrocene]dichloropalladium;

room temp.: room temperature;

TBAI: tetrabutylammonium iodide;

THF: tetrahydrofuran.

Example 1. Synthesis of compound 1.

(S)-1-((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)piperidine-2carboxylic acid

Step 1. Preparation of methyl 4-hydroxy-2-(methylthio)-5-nitrobenzoate

Methyl 2-fluoro-4-hydroxybenzoate (20.00 g) was dissolved in 200 ml acetic acid, cooled to 010°C in an ice bath and then concentrated nitric acid (10.1 ml, 0.236 mol) was dissolved in 40 ml acetic acid and slowly added dropwise to the above reaction solution; After addition, the ice bath was removed, the temperature was naturally raised to room temperature, and stirring was carried out for 4-6 hours. This reaction solution was poured into ice water and quenched. After stirring for 0.5 h, the solid precipitated completely, filtered and the filter cake was washed 2-3 times with water, dried, the crude product was purified by flash chromatography (A: hexane; B: EA; B% of 0-30% , 20 min) to obtain 13.00 g of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate as a light yellow solid.

A mixture of methyl 2-fluoro-4-hydroxy-5-nitrobenzoate (8.00 g) and solid sodium thiomethoxide (50%) (15.56 g) in methanol (80 ml) was stirred at room temperature, then stirred at 80° C for 20 hours. The solid was obtained by filtration and then dried under vacuum to obtain 7.60 g of crude product methyl 4-hydroxy-2-(methylthio)-5-nitrobenzoate.

Step 2. Preparation of methyl 5-amino-2,4-dihydroxybenzoate

A mixture of methyl 4-hydroxy-2-(methylthio)-5-nitrobenzoate (77.1 g) and 10% Pd/C (11.5 g) in methanol (2 L) was stirred under 107.9 kPa hydrogen pressure at room temperature for 3 hours. This catalyst was removed by filtration, the solid residue was washed with methanol (300 ml) and then dried under vacuum to obtain 72 g of the crude product methyl 5-amino-4-hydroxy-2-(methylthio)benzoate.

Step 3. Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(methylthio)benzo[d]oxazole-5-carboxylate

A mixture of methyl 5-amino-4-hydroxy-2-(methylthio)benzoate (32.9 g) and 3-bromo-2-methylbenzaldehyde (32.5 g) in MeOH (1 L) was stirred for 2.5 h at 80°C, then this mixture was concentrated under reduced pressure. DCM (500 ml) and DDQ (55.6 g) were added to the mixture. This mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with DCM and washed with an aqueous Na ₂ S ₂ O ₃ solution and a NaHCO ₃ solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE:DCM = 1:1) to obtain 45 g of methyl 2-(3-bromo-2-methylphenyl)-6-(methylthio)benzo[d]oxazole-5-carboxylate as a brown solid substances.

Step 4. Preparation of methyl 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazole-5carboxylate

Methyl 2-(3-bromo-2-methylphenyl)-6-(methylthio)benzo[th]oxazole-5-carboxylate (6.00 g), phenylboron

- 13 044307 acid (2.70 g), K ₂ CO ₃ (6.10 g), Pd(dppf)Cl ₂ (1.10 g) was added to dioxane (50 ml) under nitrogen at 80 ° C for 120 min. This mixture was cooled and diluted using DCM, then washed with H ₂ O and NaCl solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated.

The crude product was purified by column chromatography (PE:DCM = 1:5) to obtain 5 g of methyl-2(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazole -5-carboxylate.

Step 5. Preparation of (2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxαzol-5-yl)methanol

In a solution of methyl 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazole-5-carboxylαtα (1.30 g) and THF (50 ml ) was added dropwise LiAlH ₄ in THF (2.5 M, 5 ml) at 0°C. This mixture was heated to room temperature. After 1 hour, this mixture was quenched with 1 ml of H ₂ O and 1 ml of 10% NaOH solution, then washed separately with 1 M HCl, water and brine. The organic phase was dried over Na ₂ SO ₄ , filtered, and the filtrate was concentrated to give (2-(2-methyl-[1,1'-biphenyl]-3-yl)-6(methylthio)benzo[d]oxazol-5- yl)methanol as a yellow solid (1.2 g).

Step 6. Preparation of 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazole-5-carbaldehyde

DessaOH Martin reagent

In a solution of (2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxαzol-5-yl)methanolα (1.40 g) in dry THF ( 15 ml) Dess-Martin reagent (2.39 g) was added at 10°C. The mixture solution was then stirred for 1 hour at room temperature. This mixture was filtered through celite. The solid was washed with DCM and the combined filtrate was washed separately with aqueous NaHCO ₃ solution, water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a 20:1 to 5:1 gradient) to give 2-(2-methyl-[1,1'-biphenyl]-3yl)-6-(methylthio)benzo[d ]oxazole-5-carbaldehyde as a solid (1.27 g).

Step 7. Preparation of (S)-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5yl)methyl)piperidin- 2-carboxylic acid

Mixture of 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazole-5-carbaldehyde (1.00 g), (S)-piperidine-2 -carboxylic acid (1.70 g), HOAC (316 mg) in MeOH was stirred at room temperature for 0.5 hours. Then NaBH ₃ CN (498 mg) was added, heated at 60°C for 2 hours. This mixture cooled and diluted with DCM, then washed separately with H ₂ O and NaCl. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 8%) to give (S)-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[ d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid as a white solid (671 mg).

Example 2. Synthesis of compound 2.

((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 2 is prepared essentially as described in Example 1 using an appropriate intermediate, eg using L-proline instead of (S)-piperidine-2carboxylic acid in the last step (Step 7) described above.

The following examples (shown in Table 1) are prepared essentially as described for Example 1 using

in step 1 or instead of example 29, in some examples using a different acid amide, for example L-proline instead of (S)-piperidine-2-carboxylic acid in step 7 above.

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Table 1

No. pr. Chemical name Structure Physical data (MS) (M+N) ⁺ 1 (8)-1-((2-(2-methyl-[1,T- biphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5-yl)methyl)piperidine-2carboxylic acid /=\ O^OH \—/ o-^U^z 1 473.2 2 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-1_-proline About ν™ ШХХ0\ 459.2 3 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-O-allotreonine he 0=6 / /—NH OH O^I ⁸ ' 463.2 4 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-1_-allotreonine ^^-NH ЪН η 1 Yij ° 463.2 5 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-1_-alanine Η /—NH OH 433.2 6 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-O-alanine U)/ ¹ ζ-ΝΗ OH η I ΗζΚ 433.2 7 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-O-proline 459.2 8 (1-((2-(2-methyl-[1,G- biphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5-yl)methyl)piperidin-2yl)methanol A. 1 τΎ ⁸ ' 459.2 9 (8)-4-((2-(2-methyl-[1,Tbiphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5-yl)methyl)morpholine-3carboxylic acid Ρ ^Η Π 1 475.2

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10 (8)-2-(((2-(2-methyl-[1,Tbiphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5yl)methyl)amino)butanoic acid —UU NH O 447.2 eleven (P)-2-(((2-(2-methyl-[1,Tbiphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5yl)methyl)amino)butanoic acid —\ / ^N G- NH O Qi O' 447.2 12 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-0-serine OH W /—NH 0 QI OJ ⁰ 449.2 13 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)4_-serine O^O &S' Z from h y 449.2 14 ((2-(2-cyano-[1,1-biphenyl]3-yl)-6- (methylthio)benzo[c1]oxazol5-yl)methyl)-1_-proline Q ON V° ^H wххс 1 470.2 15 ((2-(2,2'-dicyano-[1, Tbiphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5-yl)methyl)-1_-proline О CN V ^{OH nc} УУуууУ) \=/ oOO _s 1 495.1 16 2-methyl-1-((2-(2-methyl[1,1'-biphenyl]-3-yl)-6(methylthio)benzo[c1]oxazol5-yl)methyl)pyrrolidine-2carboxylic acid Q y™ ШХХо 1 473.2 17 ((2-(2-cyano-[1,1-biphenyl]3-yl)-6methylbenzo[c1]oxazol-5yl)methyl)-0-proline Q ^ON 438.2 18 ((2-(2-cyano-[1,1-biphenyl]3-yl)-6methylbenzo[c1]oxazol-5yl)methyl)-!_-proline Q ON V ^OH ШЗХ0 438.2 19 (8)-4-((2-(2-cyano-[1,Tbiphenyl]-3-yl)-6methylbenzo[c!]oxazol-5- o^/OH V/CN/ 454.2

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yl)methyl)morpholine-3carboxylic acid 20 ((6-chloro-2-(2-methyl-[1,1 biphenyl]-3- yl)benzo[c1]oxazol-5yl)methyl)-1_-proline U#'A-he 448.1 21 ((6-hydroxy-2-(2-methyl[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-proline °v-oh occqc 429.2 22 (8)-1-((6-methyl-2-(2-methyl[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)piperidine-2carboxylic acid O °^ ^he ШХХ0 441.2 23 (S)-1 -((6-fluoro-2-(2-methyl[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)pyrrolidin-3-ol O \=/ o^xI^r 403.2 24 ((6-fluoro-2-(2-methyl-[1,1 biphenyl]-3- yl)benzo[c1]oxazol-5yl)methyl)-1_-proline About Voh SHOA 431.2 25 (S)-1 -((6-fluoro-2-(2-methyl[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)piperidine-2carboxylic acid CHA SOON UuAdAAiA 445.2 26 1 -((6-cyano-2-(2-methyl-[1,1 biphenyl]-3- yl)benzo[c1]oxazol-5yl)methyl)piperidine-2carboxylic acid He O=^ 452.2 27 1-((2-(2-methyl-[1,1'biphenyl]-3-yl)-6(methylamino)benzo[c1]oxaz ol-5-yl)methyl)piperidine2-carboxylic acid O^on ACCQ0 I 456.2 28 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6- (trifluoromethyl)benzo[c1]ox azol-5-yl)methyl)-1_-proline Aon SHHHS 481.2

Example 29. Synthesis of compound 29.

(S)-1-((6-(Difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine2-carboxylic acid

Stage 1. Preparation of methyl 2,4-dihydroxy-5-nitrobenzoate

Methyl 2,4-dihydroxybenzoate (850 g, 5.06 mol) was dissolved in a mixture of AcOH (3.6 L) and Ac ₂ O (900 ml). After cooling the clarified solution to 10°C (ice bath), a mixture of HNO3 (65%) (455 ml) in AcOH (500 ml) was added over 1 hour. When the addition was completed, the temperature of this mixture solution increased to 15-20°C, and stirring was carried out for another 1 hour until the raw material was almost exhausted and the reaction continued. The reaction solution was poured into H ₂ O (3 L), then this mixture was added over a further 30 minutes without stirring. The precipitate was filtered off and washed with small amounts of H ₂ O. Then the crude product was poured into MeOH (2 L) with stirring. The precipitate was filtered and washed with small amounts of MeOH. Dried under vacuum to obtain 480 g of methyl 2,4-dihydroxy-5-nitrobenzoate product.

Step 2. Preparation of methyl 5-amino-2,4-dihydroxybenzoate

A mixture of methyl 2,4-dihydroxy-5-nitrobenzoate (77.1 g) and 10% Pd/C (11.5 g) in methanol (2 L) was stirred under 107.9 kPa hydrogen pressure at room temperature for 3 h. This catalyst was removed by filtration, the solid residue was washed with methanol (300 ml) and then dried under vacuum to obtain 72 g of the crude product methyl 5-amino-2,4-dihydroxybenzoate.

Step 3. Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazole-5-carboxylate

A mixture of methyl 5-amino-2,4-dihydroxybenzoate (32.9 g) and 3-bromo-2-methylbenzaldehyde (32.5 g) in MeOH (1 L) was stirred for 2.5 hours at 80°C. the mixture was then concentrated under reduced pressure. DCM (500 ml) and DDQ (55.6 g) were added to the mixture. This mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with aqueous Na ₂ S ₂ O ₃ solution and NaHCO ₃ solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE:DCM 1:1) to obtain 45 g of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazole-5-carboxylate as a brown solid.

Step 4. Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5carboxylate

Methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxαzole-5-carboxylate (10.0 g), sodium

2-bromo-2,2-difluoroacetate (5.46 g), Cs ₂ CO ₃ (27.09 g), KI (4.59 g), TBAI (10.22 g) were dissolved in DMF (200 ml), this mixture was stirred at 100°C for 3 hours, the reaction mixture was diluted with DCM and washed with saturated NaCl solution. The crude product was purified by column chromatography (PE:DCM = 1:1) to obtain 5 g of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylate.

Step 5. Preparation of methyl 6-(difluoromethoxy)-2-(2-methyl-[1,G-biphenyl]-3-yl)benzooxazol-5 carboxylate

Methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazole-5-carboxylate (6.00 g), phenylboronic acid (2.70 g), K ₂ CO ₃ (6 .10 g), Pd(dppf)Cl ₂ (1.10 g) was added to dioxane (50 ml) under nitrogen at 80°C for 120 min. This mixture was cooled and diluted with DCM, then washed with H ₂ O and NaCl solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The crude product was purified by column chromatography (PE:DCM 1:5) to obtain 5 g of methyl6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol- 5-carboxylate.

Step 6. Preparation of (6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5yl)methanol

In a solution of methyl 6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5-carboxylate (1.30 g) and THF (50 ml ) was added dropwise LiAlH ₄ in THF (2.5 M, 5 ml) at 0°C. This mixture was heated to room temperature. After 1 hour, this mixture was quenched with 1 ml of H ₂ O and 1 ml of 10% NaOH solution, then washed separately with 1 M HCl, water and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to give (6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]3-yl)benzo[d]oxazol-5-yl )methanol as a yellow solid (1.2 g).

Step 7. Preparation of 6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5carbaldehyde

In a solution of (6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methanol (1.40 g) in dry THF ( 15 ml) Dess-Martin reagent (2.39 g) was added at 10°C. Then this solution

- 18 044307 the mixture was stirred for 1 hour at room temperature. This mixture was filtered through celite. The solid was washed with DCM and the combined filtrate was washed separately with aqueous NaHCO ₃ solution, water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a 20:1 to 5:1 gradient) to give 6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo [d]oxazole-5-carbaldehyde as a solid (1.27 g).

Step 8. Preparation of (S)-1 -((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5 yl)methyl)piperidine -2-carboxylic acid

Mixture of 6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde (1.00 g), (8)-piperidin-2 -carboxylic acid (1.70 g), AcOH (316 mg) in MeOH was stirred at room temperature for 0.5 hours. Then NaBH ₃ CN (498 mg) was added and heated at 60°C for 2 hours. This mixture cooled and diluted with DCM and then washed separately with H ₂ O and NaCl solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 8%) to give (S)-1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'biphenyl]-3-yl)benzo[b ]oxazol-5-yl)methyl)piperidine-2-carboxylic acid as a white solid (671 mg).

Example 30. Synthesis of compound 30.

((6-(Difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-allotreonine he

NH OH

Compound 30 was prepared essentially as described for Example 29 using the corresponding o=( / w

ΛΛ f\ ^on the intermediate compound. For example, using ^H 2 ^N instead of ^{H 0} in the last step (step 8) described above.

Example 36. Synthesis of compound 36.

((6-(Difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-nroline

Compound 36 was prepared essentially as described in Example 29 using the appropriate intermediate. For example, using L-proline instead of (S)-piperidine-2carboxylic acid in the last step (step 8) described above. A typical procedure for preparing compound 29 was described as follows.

Solution of 6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5-carbaldehyde (1.00 g), L-proline (1.60 d), HOAC (325 mg) in MeOH was stirred at room temperature for 0.5 hours. NaBH ₃ CN (498 mg) was added to this mixture, then heated at 60°C for 2 hours. This mixture was cooled, diluted with DCM and washed with H ₂ O and NaCl solution. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 8%) to give ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol5-yl) methyl)-L-proline as a white solid (650 mg).

The following examples (shown in Table 2) are prepared essentially as described for Example 29 using the appropriate intermediates, i.e. amino acids, eg L-alanine, glycine, L-proline instead of (S)-piperidine-2-carboxylic acid in step 8 above.

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table 2

No. note Chemical name Structure Physical data (MS) (M+N) ₊ 29 (5)-1-((6-(difluoromethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)piperidine-2carboxylic acid ^but ^° 493.2 thirty ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-O-allotreonine HE °=C y ^NH OH Q I 483.2 31 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-allotreonine he ⁰ \ / /—NH He 483.2 32 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-tyrosine hydrochloride but——W ^H NH O A । gS/T _F ^HCI _F 581.2 33 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-alanine W ^NH OH η 1 ° ^F 453.2 34 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-O-alanine ^NH OH 453.2 35 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)glycine ^ΝΗ O A । _F ^0H F 439.1 36 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-proline 9° X 479.2 37 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-O-proline ° ^F 479.2 38 (1-((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)piperidin-2yl)methanol And 479.2 39 (5)-4-((6-(difluoromethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)morpholine-3carboxylic acid he ots fl 1 - τχ· ^{0 ρ} 495.2 40 (5)-2-(((6-(difluoromethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)amino)butanoic acid — ^ΝΗ Ο q ι rp^y _F ^F 467.2 41 (^-2-(((6-(difluoromethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)amino)butanoic acid —θ ^Η ^NH O Of n 'Ο ^f 467.2

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42 ((6-(difluoromethoxy)-2-(2methyl-[1,1-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-O-serine OH W /—NH O 469.2 43 ((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-serine He W /—NH O 469.2 44 ((2-(2-cyano-[1,1-biphenyl]3-yl)-6- (difluoromethoxy)benzo[c1]ox azol-5-yl)methyl)-1_-proline O CN V ^OH 490.2 45 ((2-(2,2'-dicyano-[1,1'biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]ox azol-5-yl)methyl)-1_-proline Ζ α° I z o^z A s 515.2 46 1-((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-2methylpyrrolidine-2carboxylic acid SE °-^OH chf ₂ 493.2 47 ((6-(difluoromethoxy)-2-(3(2,3dihydrobenzo[b][1,4]dioxin6-yl)-2methylphenyl)benzo[c1]oxazol-5-yl)methyl)-1_-proline voh chf ₂ 537.2 48 1-((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)azetidine-2carboxylic acid O o M/Voh chf ₂ 465.2 49 ((6-(difluoromethoxy)-2-(3(2,3dihydrobenzo[b][1,4]dioxin6-yl)-2methylphenyl)benzo[c1]oxazol-5-yl)methyl)-1_-proline ο> Ό g η® 537.2 50 1-((6-(difluoromethoxy)-2-(2methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-2methylpyrrolidine-2carboxylic acid CHF ₂ 493.2 51 ((2-(2'-cyano-2-methyl-[1,1'biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]ox azol-5-yl)methyl)proline C3 °<^ΟΗ \=/ " F^F 504.2 52 ((6-(difluoromethoxy)-2-(2'fluoro-2-methyl-[1, Tbiphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)-1_-proline A 8 497.2 53 (5)-3-((6-(difluoromethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)oxazolidine-4carboxylic acid NW °v°h \=/ ⁰ F^F 481.2

Example 54. Synthesis of compound 54.

(S)-1-((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[d]oxazol-5-yl) methyl)piperidine-2-carboxylic acid

Compound 54 was prepared essentially as described for Example 1 using the corresponding

- 21 044307 forming intermediate compound, for example, using

°G^br instead of ^ONO in step 4 described above. A typical procedure for the preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(2,2,2trifluoroethoxy)benzo[d]oxazole-5-carboxylate has been described in the following way:

Into a reflux mixture of acetone (20 ml), methyl 2-(3-bromo-2-methylphenyl)6-hydroxybenzo[d]oxazole-5-carboxylate (2.0 g) and potassium carbonate (3.1 g ) 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.9 g) was added dropwise to a 40 ml sealed vial. This mixture was stirred at reflux overnight and then concentrated under reduced pressure. The residue was dissolved in water (50 ml) and dichloromethane (50 ml).

The layers were separated and the aqueous layer was extracted with dichloromethane (3x50 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated to obtain 1.8 g of crude methyl 2-(3-bromo-2-methylphenyl)-6-(2,2,2-trifluoroethoxy)benzo[0] oxazole-5-carboxylate.

The following examples (shown in Table 3) are prepared essentially as described for Example 54 using the appropriate intermediates, i.e. amino acids, for example L-alanine, glycine, L-proline instead of (S)-piperidine-2-carboxylic acid.

Table 3

No. note Chemical name Structure Physical data (MS) (M+N) ⁺ 54 (8)-1-((2-(2-methyl-[1,T- biphenyl]-3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)piperidine-2carboxylic acid X/ o^on ^SRz 525.2 55 1 -((6-(2,2-d iforoethoxy)-2(2-methyl-[1,1'-biphenyl]-3yl)benzo[c1]oxazol-5yl)methyl)piperidine-2carboxylic acid <О ° _Y ^oH \=/ о^Ч>% ^chf ₂ 507.2 56 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)-O-alanine ^NH OH P X ^cf ₃ XlX° 485.2 57 (8)-4-((2-(2-cyano-[1,T- biphenyl]-3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)morpholine-3carboxylic acid 3 538.2 58 (8)-4-((2-(2-methyl-[1,T- biphenyl]-3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)morpholine-3carboxylic acid O, No. OCH1KHO Zr ₃ 527.2 59 ((2-(2-methyl-[1,1'-biphenyl]3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)-1_-alanine Ή° /—ΝΗ OH 485.2

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((2-(2-methyl-[1,1'-biphenyl]3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)-O-alanine

((2-(2-methyl-[1,1'-biphenyl]3-yl)-6(trifluoromethoxy)benzo[c1]ox azol-5-yl)methyl)-1_-proline ((2-(2- methyl-[1,1'-biphenyl]3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl)-1_-proline

2-methyl-1-((2-(2-methyl-[1,1'biphenyl]-3-yl)-6-(2,2,2trifluoroethoxy)benzo[c1]oxaz ol-5-yl)methyl) pyrrolidine2-carboxylic acid

Example 64. Synthesis of compound 64.

((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-((methylsulfonyl)oxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 64 is prepared essentially as described for Example 29 using an appropriate intermediate, for example using L-proline instead of (S)-pineridine-S-CIθν^ΒΓ

2-carboxylic acid in the last step (step 8) and using ° instead of ^ONa in step 4 above. Typical procedure for preparing methyl 2-(3-bromo-2-methylphenyl)-6-((methylsulfonyl)oxy)benzo[ 0]oxazole-5-carboxylate was described as follows:

Triethylamine (1.2 g) was charged into a stirred solution of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[0]oxazole-5carboxylate (1 g) in 30 ml of methylene chloride. This mixture was cooled to -5-0°C and methanesulfonyl chloride (1.13 g) in methylene chloride (10 ml) was added at 0-5°C over a period of 1 hour, maintained at 0°C for 1 hour, temperature increased to 22-25°C and maintained for 3 hours. TLC (thin layer chromatography) showed a conversion greater than 98%, add 20 ml of water and stir at 22-25°C for 1 hour. The organic layer is separated and the aqueous layer is extracted with 20 ml methylene chloride. The combined organic layer was washed with 20 ml of water and the solvent was evaporated to obtain 1.2 g of 2-(3-bromo-2-methylphenyl)-6-((methylsulfonyl)oxy)benzo[0]oxazole-5-carboxylate.

Example 65. Synthesis of compound 65.

Stage 1. carbaldehyde

Preparation of 2-(2-methyl-[1,G-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[0]oxazol-5-

2-(2-methyl-[1,G-biphenyl]-3-yl)-6-(methylthio)benzo[0]oxazole-5-carbaldehyde was

The preparation is described as step 6 in example 1.

To a solution of 2-(2-methyl-[1,G-biphenyl]-3-yl)-6-(methylthio)benzo[0]oxazole-5-carbaldehyde (700 mg) in dry DCM (15 ml) was added m- SRVA (336 mg) at 0°. Then the solution of this mixture was stirred for 0.5 h at 0°C. This mixture was filtered through celite. The solid was washed with DCM and the combined filtrate was washed separately with aqueous NaHCO ₃ solution, water and brine, dried and concentrated. The residue was purified by column chromatography (eluting with hexane-EtOAc using a 20:1 to 5:1 gradient) to give 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo [e]oxazole-5-carbaldehyde as a solid (1.27 g).

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Step 2. Preparation of ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[d]oxazol-5yl)methyl)-L-proline

A mixture of 2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[d]oxazole-5-carbaldehyde,

L-proline (1.70 g), HOAC (316 mg) in MeOH was stirred at room temperature for 0.5 hours. Then NaBH ₃ CN (498 mg) was added, heated at 60°C for 2 hours. This mixture cooled and diluted with DCM and then washed separately with H ₂ O and NaCl. The organic phase was dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 8%) to give (2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[d]oxazol-5 yl )methyl)-L-proline as a white solid (671 mg).

Example 66. Synthesis of compound 66.

((2-(2-Methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfonyl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 66 was prepared essentially as described in Example 65 using the appropriate intermediate.

Example 67. Synthesis of compound 67.

8-Methyl-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1,2 -f][1,4]oxazepine

Step 1. Preparation of 5-(hydroxymethyl)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-ol

To methyl 6-hydroxy-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole-5-carboxylate (0.5 g) was added THF (15 ml) under protection N2, cooled to 0°C, a solution of LiAlH ₄ (2.5 M) in THF (0.56 ml) was slowly added dropwise, after completion of the reaction, 2 ml of EA was added to quench, then a saturated solution of NH ₄ Cl (10 ml) was added ) and EA (10 ml) for extraction. Wash twice with 20 ml NaCl solution. The organic phase was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated to obtain 0.42 g of 5-(hydroxymethyl)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazole -6-ol as a white solid.

LC-MS (liquid chromatography-mass spectrometry): [M+H] =332.0.

Step 2. Preparation of 1 -(6-hydroxy-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)ethan-1-one

To 5-(hydroxymethyl)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-ol (0.42 g) was added DCM (15 ml), MnO ₂ (4 g), stirred overnight at room temperature. This reaction solution was filtered using cellite, and the filtrate was concentrated. The crude product was purified by column chromatography (hexane/EA = 30/1) to obtain 0.1 g of 1-(6-hydroxy-2-(2-methyl[1,1'-biphenyl]-3-yl)benzo[d] oxazol-5-yl)ethan-1-one as a brown solid.

LCMS: [M+H] = 344.0.

Step 3. Preparation of 2-(2-methyl-[1,1'-biphenyl]-3-yl)-5-((methylamino)methyl)benzo[d]oxazol-6-ol

1-(6-hydroxy-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)ethan-1-one (0.1 g) was added MeOH (2 ml), slowly add methylamine to MeOH (5 ml), stir at room temperature for 2 hours and add NaCNBH3 (0.1 g). Stirred at temperature for 1 hour, concentrated, the crude product was purified by column chromatography (DCM/MeOH = 30/1) to obtain

2-(2-methyl-[1,1'-biphenyl]-3-yl)-5-((methylamino)methyl)benzo[d]oxazol-6-ol as a light yellow solid.

LC-MS: [M+H] = 345.1.

Step 4. Preparation of 8-methyl-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo [1,2-f][1,4]oxazepine

Cs ₂ CO ₃ (100 mg), THF (5 ml) and 1,2-dibromoethane (2 ml), stirred at 80°C for 3 hours, concentrated, the crude product was purified by column chromatography (hexane/EA = 30/1) to obtain 9 mg 8 -methyl-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1,2- f][1,4]oxazepine as an off-white solid.

LC-MS: [M+H] is 371.1.

The following examples (shown in Table 4) are prepared essentially as described for Example 67 using appropriate starting materials and intermediates.

Table 4

No. pr. Chemical name Structure Physical data (MS) (M+N) ⁺ 67 8-methyl-2-(2-methyl-[1,1 biphenyl]-3-yl)-6,7,8,9tetrahydrooxazolo[5',4':4,5] benzo[1,2-f][ 1,4]oxazepine 371.2 68 1-((2-(2-methyl-[1,1'biphenyl]-3-yl)-8-oxo-7,8dihydrobenzofuro[5,4c1]oxazol-5yl)methyl)piperidine-2carboxylic acid 0^4 483.2 69 1-((8-(2-methyl-[1,1'biphenyl]-3-yl)oxazolo[5,4c][1,2,4]triazolo[1,5a]pyridin-5yl)methyl)piperidin- 2carboxylic acid He YES Q jryXl 468.2 70 (5)-2-(2-methyl-[1,T- biphenyl]-3-yl)-6,7,8,9tetrahydrooxazolo[5',4':4,5] benzo[1,2-f][1,4]oxazepine-7carboxylic acid N o A _on Q ι 1# ⁰ 401.2 71 2-(2-(2-methyl-[1,1'-biphenyl]3-yl)-6,7- Dihydrooxazolo[5',4':4,5]benzo[1,2-f][1,4]oxazepin-8(9H)yl)acetic acid HE ΐΓ 415.2 72 (C)-2-(2-methyl-[1,Tbiphenyl]-3-yl)-6,7,8,9tetrahydrooxazolo[5',4':4,5]benzo[1,2-f][1 ,4]oxazepine-7carboxylic acid n O P 1 gi ⁰ ° 401.2 73 1-((2-(2-methyl-[1,1'biphenyl]-3-yl)-8-oxo-7,8dihydrobenzofuro[5,4c1]oxazol-5yl)methyl)piperidine-2carboxylic acid he °\ 4/4’ 483.2

- 25 044307

Examples for comparison

The following comparative examples (as shown in Table 5) were prepared essentially as described for Example 26 and Example 31 in WO 2017/087777.

Table 5

Comp. no. example Chemical name Structure IR ₅₀ (NM) HTRF PD1/PD-L1 1 1-((6-(cyanomethoxy)-2(2-methyl-[1,Tbiphenyl]-3yl)benzo[c!]oxazol-5yl)methyl)piperidine-2carboxylic acid 2nd ^f A T * 2 2-(((6-methoxy-2-(2methyl-[1,1'-biphenyl]3-yl)benzo[c1]oxazol5- yl)methyl)amino)ethan1-ol /—ΝΗ η 1 gU 5 *

*Data obtained for the above examples for comparison using the Homogeneous Time Resolved Fluorescence (HTRF) binding assay described below.

Binding analysis by homogeneous time-resolved fluorescence (HTRF).

These assays were performed in a standard black 384-well polystyrene plate with a final volume of 20 μl. The inhibitors were first serially diluted in DMSO (dimethyl sulfoxide) and then added to the wells of the plate before adding other reaction components. The final concentration of DMSO in this assay was 1%. These assays were performed at 25°C in PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with an Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in assay buffer and 10 μl was added to the wells of the plate. The plates were centrifuged and the proteins were preincubated with inhibitors for 40 min. Incubation was monitored by the addition of 10 μl of HTFR detection buffer supplemented with europium cryptate-labeled anti-human IgG antibody (PerkinElmer-AD0212) specific for Fc and SureLight®-allophykocyanin-conjugated anti-His antibody (APC, PerkinElmer-AD0059H). After centrifugation, the plate was incubated at 25°C for 60 minutes. Before reading on a PHERAstar FS plate reader (665 nm/620 nm ratio), the final concentrations in this assay were 2 nM PD1, 10 nM PDL1, 1 nM europium-labeled anti-human IgG, and 20 nM allophycocyanin-labeled anti-His. Determination of IC ₅₀ was carried out by fitting the curve of the percentage of control activity relative to the log concentration of the inhibitor using the GraphPad Prism 5.0 program.

The compounds of the present disclosure, as exemplified, exhibited IC ₅₀ values in the following ranges: * denotes 0.1 nM less than IC ₅₀ less than or equal to 10 nM; ** denotes 10 nM less than IR ₅₀ less than or equal to 100 nM; *** indicates 100 nM less than IR ₅₀ less than or equal to 1000 nM.

Data obtained for the example compounds using the PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay described in Example A are shown in Table. 6.

- 26 044307

Table 6

No. note IR ₅₀ No. note IR ₅₀ 1 1.9 38 * 2 * 39 1.1 3 ** 40 * 4 * 41 ** 5 * 42 3.4 6 ** 43 1.8 7 * 44 * 8 ** 45 ** 9 * 46 * 10 * 47 * eleven ** 48 * 12 * 49 * 13 * 50 * 14 * 51 ** 15 ** 52 ** 16 * 53 ** 17 * 54 ** 18 * 55 ** 19 * 56 ** 20 1.8 57 ** 21 ** 58 ** 22 1.8 59 ** 23 ** 60 24 7.2 61 ** 25 7.4 62 ** 26 * 63 * 27 * 64 * 28 1.4 65 5 29 * 66 * thirty 4.8 67 *** 31 3.2 68 *** 32 * 69 *** 33 * 70 *** 34 ** 71 *** 35 * 72 *** 36 * 73 *** 37 **

As shown in table. 5 and 6, most of the exemplified compounds of the present invention exhibit the same level of inhibition as the known comparators. approx. No. 1 and 2 in table. 5.

Pharmacokinetic analysis.

Healthy adult male rats were exposed to a single dose of test compounds with 10%

DMSO, 10% Kolliphor® HS 15 and 80% saline as excipients, and these rats were given oral administration (intragastric administration) of the compounds at a dose of 25 mg/kg. Before the experiment, the animals were fasted overnight, and the fasting time lasted from 12 hours before administration to 4 hours after administration. Blood collection time: 15, 30 minutes, 1, 2, 4, 7, 24 hours. Approximately 0.3 ml of whole blood was collected from the retroorbital venous sinus and placed in tubes that contained EDTA (ethylenediaminetetraacetic acid) as an anticoagulant. Samples were centrifuged at 4°C and 4000 rpm for 5 min. Plasma was transferred into centrifuge tubes and stored at -20°C until analysis. Concentrations of analytes in plasma samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time data from individual animals were analyzed using WinNonlin software (version 4.1; Pharsight). A non-compartmental model was introduced into the concentration analysis. The pharmacokinetic parameters of the analyzed compounds were calculated. The data is shown in table. 7.

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Claims (69)

Table 7 Examples Dose (mg/kg) ТШЧч) Tmax(4) Stach (ng/ml) AUC (h*ng/ml) Comp. Etc. No. 1 25 3.42 0.5 881 5840 Comp. Etc. No. 2 25 14.4 4.0 329 5154 Connection 2 25 17.7 1.0 12167 124960 Connection 20 25 7.52 1.0 8270 74524 Connection 22 25 42.3 1.0 10327 151108 Connection 28 25 41.2 0.3 14447 318799 Connection 29 25 4.27 1.0 23300 200701 Connection 36 25 9.3 0.5 10167 118937 Connection 39 25 10.8 1.0 30967 121277 Connection 52 25 7.72 2.0 20660 246225 As shown in table. 7, the present inventors can see that the exemplified compounds of the present invention exhibit surprisingly better pharmacokinetic properties than the known compounds - cf. approx. No. 1 and 2 in table. 5. CLAIM 1. A compound of formula I or a stereoisomer thereof or a pharmaceutically acceptable salt: *4 •'And ^R2 #4, \=/νγχ _Ύ Re ^R 5 Formula I in which X is selected from C; ~ represents a single bond or double bond; R1 is selected from H, halogen, CN, -C1. ₈ alkyl, -C ₁ . ₄ haloalkyl or -O-C1. ₈ alkyl; R ₂ , R ₃ and R 4 are each independently selected from H, halogen, -CN or R ₃ and R 4 together with the atoms to which they are attached form a 2,3-dihydro-1,4-dioxine ring; Y selected from the missing group, O, S, -NR ₉ -; R9 is selected from H, -C _1-8 alkyl or -C _1-8 haloalkyl; R ₅ is selected from halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl, -C _2-8 alkenyl, SO ₂ -C ₁ . ₄ alkyl, methylsulfinyl, provided that if Y is O, then R5 is not -C1. ₈ alkyl; R6 is H; R ₇ and R ₈ are each independently selected from H, -C1. ₈ alkyl, -C ₁ .6 alkyl-COOH, phenyl, where -C ₁ .6 alkyl-COOH and phenyl are possibly substituted with -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH, -C ₀ . ₄ alkyl-OH; or R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, said heterocyclic ring possibly containing 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein said heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH or -C ₀ . ₄ alkyl-OH; R5 and _R8 together with the atoms to which they are attached form a 6-10 membered heterocyclic ring, said heterocyclic ring possibly containing 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein said heterocyclic ring is possibly substituted with oxo, -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH, -C ₀ . ₄ alkyl-OH. 2. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein Y is selected from the missing group, -O-, -S-, -NH-. 3. A compound according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt, wherein said compound has the formula II r ₇ R /=\ ° r ₂ Formula II in which R1 is selected from H, halogen, CN, -C1. ₈ alkyl, -C1. ₄ alogenalkyl or -O-C1. ₈ alkyl; R ₂ , R ₃ and R ₄ are each independently selected from H, halogen, -CN; R5 is selected from -C1. ₄ alogenalkyl, -SO ₂ -C ₁ . ₄ alkyl; R ₇ and R ₈ are each independently selected from H, -C _1-8 alkyl, -C ₁ . ₆ alkyl-COOH, phenyl, where -C ₁ . ₆ alkyl-COOH and phenyl are possibly substituted -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH, -C ₀ . ₄ alkyl-OH; or R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, and said heterocyclic ring possibly contains 1, 2 or 3 heteroatoms, regardless - 28 044307 simo selected from N, S or O; wherein said heterocyclic ring is possibly substituted 1-2 substituents independently selected from oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH. 4. A compound or a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R5 is -C _1-4 haloalkyl. 5. The compound or stereoisomer or pharmaceutically acceptable salt thereof according to claim 4, wherein R5 is -C _1-4 alkyl substituted with 1-3 fluorine atoms. 6. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 5, in which R ₅ represents methyl or ethyl substituted with 2-3 fluorine atoms. 7. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 6, wherein R5 is -CF ₃ , -CHF ₂ , -CH ₂ CHF ₂ or -CH ₂ CF ₃ . 8. The compound or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 7, in which R ₇ and R 8 together with the atoms to which they are attached form a 4-6 membered heterocyclic ring; wherein said heterocyclic ring is substituted with 1-2 substituents independently selected from -C _1-4 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH. 9. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 8, in which the heterocyclic ring is 10. The compound or its stereoisomer or pharmaceutically acceptable salt according to claim 8, in which substituted heterocyclic ring selected 11. A compound according to claim 1 or a stereoisomer thereof or a pharmaceutically acceptable salt, wherein said compound has formula III Formula III in which R1 is selected from H, halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl or -O-C _1-8 alkyl; R ₂ , R ₃ and R ₄ are each independently selected from H, halogen, -CN; R5 is selected from halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl, SO ₂ -C _1-4 alkyl or methylsulfinyl; R ₇ and R8 are each independently selected from H, -C _1-8 alkyl, -C _1-6 alkyl-COOH, phenyl, where -C _1-6 alkyl-COOH and phenyl are optionally substituted with -C _1-8 alkyl, -C _0-4 alkyl-COOH, -C _0-4 alkyl-OH; or R ₇ and R ₈ together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, said heterocyclic ring possibly containing 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein said heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C _1-8 alkyl, -C _0-4 alkyl-COOH or -C _0-4 alkyl-OH. 12. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt according to any one of claims 1 to 11, wherein R1 is selected from CH3 or CN. 13. The compound or its stereoisomer or pharmaceutically acceptable salt according to any one of claims 11, 12, in which R5 is selected from F, Cl, -CH ₃ , -CF ₃ , -SO-CH ₃ , -SO ₂ -CH ₃ or - CN. 14. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt according to any one of claims 11 to 13, wherein R ₇ and R 8 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein said heterocyclic ring is substituted with -C _0-4 alkyl-COOH. 15. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt according to claim 14, wherein the compound is ^OH O O J ° ⁿ substituted heterocyclic ring selected from ^or 16. A compound according to claim 1 or a stereoisomer or pharmaceutically acceptable salt thereof, in which: ~ represents a double bond; R1 is selected from H, halogen, CN, -C _1-8 alkyl, -C _1-4 haloalkyl or -O-C _1-8 alkyl; R ₂ , R ₃ and R ₄ are each independently selected from H, halogen, -CN; Y is selected from S or -NR9-; R9 represents H; R5 represents -C _1-4 alkyl; - 29 044307 R7 and R8 are each independently selected from H, -C1_ ₈ alkyl, -C1_ ₆ alkyl-COOH, phenyl, where -C _1- balkyl-COOH and phenyl are possibly substituted with -C1_ ₈ alkyl, -C ₀ - ₄ alkyl-COOH, -C ₀ - ₄ alkyl-OH; or R7 and R8 together with the atoms to which they are attached form a 3-7 membered heterocyclic ring, said heterocyclic ring possibly containing 1, 2 or 3 heteroatoms independently selected from N, S or O; wherein said heterocyclic ring is optionally substituted with 1-2 substituents independently selected from oxo, -C1. ₈ alkyl, -C ₀ . ₄ alkyl-COOH or -C ₀ . ₄ alkyl-OH. 17. A compound or pharmaceutically acceptable salt according to claim 1, wherein said compound is the following: 1) (S)-1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)piperidin- 2carboxylic acid; 2) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-proline; 3) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-D-allotreonine; 4) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-allotreonine; 5) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-alanine; 6) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-D-alanine; 7) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-D-proline; 8) (1-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)piperidin-2-yl )methanol; 9) (S)-4-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)morpholin- 3 - carboxylic acid; 10) (S)-2-(((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)amino ) - butanoic acid; 11) (R)-2-(((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)amino ) - butanoic acid; 12) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-D-serine; 13) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-serine; 14) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-proline; 15) ((2-(2,2'-dicyano-[1,1'-biphenyl]-3-yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-L-proline; 16) 2-methyl-1 -((2-(2-methyl-[1,1 '-biphenyl]-3 -yl)-6-(methylthio)benzo[d]oxazol-5-yl)methyl)-pyrrolidine -2-carboxylic acid; 17) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[d]oxazol-5-yl)methyl)-D-proline; 18) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[d]oxazol-5-yl)methyl)-L-proline; 19) (S)-4-((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-methylbenzo[d]oxazol-5-yl)methyl)morpholine-3carboxylic acid; 20) ((6-chloro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 21) (S)-1 -((6-methyl-2-(2-methyl-[1,1'-biphenl]-3 -yl)benzo[d]oxazol-5-yl)methyl)piperidin-2- carboxylic acid; 22) (S)-1-((6-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidin-3- ol; 23) ((6-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 24) (S)-1 -((6-fluoro-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin-2- carboxylic acid; 25) 1 -((6-cyano-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid; 26) 1 -((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylamino)benzo[d]oxazol-5-yl)methyl)piperidine-2-carboxylic acid ; 27) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(trifluoromethyl)benzo[d]oxazol-5-yl)methyl)-L-proline; 28) (S)-1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-piperidine -2-carboxylic acid; 29) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-allotreonine; 30) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-allotreonine; 31) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-tyrosine hydrochloride; 32) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-alanine; 33) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-alanine; 34) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)glycine; 35) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 36) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline; 37) (1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)piperidin2-yl)methanol ; 38) (S)-4-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-morpholine -3-carboxylic acid; - 30 044307 39) (8)-2-(((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl) amino)butanoic acid; 40) (K)-2-(((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl) amino)butanoic acid; 41) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)-B-serine; 42) ((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)-P-serine; 43) ((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[<1]oxazol-5-yl)methyl)-P-proline; 44) ((2-(2,2'-dicyano-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[<1]oxazol-5-yl)methyl)-P-proline ; 45) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)-2-methyl- pyrrolidine-2-carboxylic acid; 46) ((6-(difluoromethoxy)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)benzo[<1]oxazol-5-yl )methyl)-b-proline; 47) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)azetidine-2carboxylic acid; 48) ((6-(difluoromethoxy)-2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methylphenyl)benzo[<1]oxazol-5-yl )methyl)-b-proline; 49) 1-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)-2-methyl- pyrrolidine-2-carboxylic acid; 50) ((2-(2'-cyano-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[<1]oxazol-5-yl)methyl)proline; 51) ((6-(difluoromethoxy)-2-(2'-fluoro-2-methyl-[1,G-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)-P- proline; 52) (8)-3-((6-(difluoromethoxy)-2-(2-methyl-[1,1'-biphenyl]-3-yl)benzo[<1]oxazol-5-yl)methyl)- oxazolidine-4-carboxylic acid; 53) (S)-l-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5 -yl)methyl)-piperidine-2-carboxylic acid; 54) 1 -((6-(2,2-difluoroethoxy)-2-(2-methyl-[1,1 '-biphenyl]-3 -yl)benzo[<1]oxazol-5-yl)methyl)- piperidine-2-carboxylic acid; 55) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5-yl)methyl)- B-alanine; 56) (8)-4-((2-(2-cyano-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5 -yl)methyl)-morpholine-3-carboxylic acid; 57) (8)-4-((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5 -yl)methyl)-morpholine-3-carboxylic acid; 58) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5-yl)methyl)- R-alanine; 59) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5-yl)methyl)- P-proline; 60) 2-methyl-1 -((2-(2-methyl-[1,1 '-biphenyl]-3 -yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5 - yl)methyl)pyrrolidine-2-carboxylic acid; 61) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(2,2,2-trifluoroethoxy)benzo[<1]oxazol-5-yl)methyl)- B-alanine; 62) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(trifluoromethoxy)benzo[<1]oxazol-5-yl)methyl)-P-proline; 63) ((2-(2-methyl-[1,1-biphenyl]-3-yl)-6-((methylsulfonyl)oxy)benzo[<1]oxazol-5-yl)methyl)-P-proline; 64) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfinyl)benzo[<1]oxazol-5-yl)methyl)-P-proline; 65) ((2-(2-methyl-[1,1'-biphenyl]-3-yl)-6-(methylsulfonyl)benzo[<1]oxazol-5-yl)methyl)-P-proline; 66) 8-methyl-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f] [1,4]- oxazepine; 67) (8)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f][1,4]-oxazepine-7-carboxylic acid; 68) 2-(2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazolo[5',4':4,5]benzo[1,2-f] [1,4]oxazepine- 8(9H)-yl)acetic acid; or 69) (H)-2-(2-methyl-[1,1'-biphenyl]-3-yl)-6,7,8,9-tetrahydrooxazolo[5',4':4,5]benzo[1 ,2-f][1,4]-oxazepine-7-carboxylic acid. 18. A pharmaceutical composition containing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient. 19. A method of treating a disease associated with inhibition of the PD-1/PD-L1 interaction, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt or stereoisomer thereof. 20. The method of claim 19, wherein the disease is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer or cancer mammary gland. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2