EA047234B1 - IMMUNOMODULATORS, COMPOSITIONS AND METHODS FOR THEIR USE - Google Patents

Description

Field of invention

The present invention relates to compounds that are inhibitors of the PD-1/PD-L1 protein-protein interaction. The present invention also relates to pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of cancer, precancerous syndromes and other diseases associated with inhibition of PD-1/PD-L1 protein-protein interaction.

Prior Art

Cancer immunotherapy is increasingly used to treat advanced-stage malignancies. The immune checkpoint signaling network has received considerable attention. Some types of cancer are highly resistant to conventional chemotherapy. Tumor survival is in some cases facilitated by immunomodulation of checkpoints to maintain an imbalance between immune surveillance and cancer cell proliferation. Immune checkpoint inhibitors are revolutionizing treatment options and expectations for cancer patients.

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. It functions as an internal negative feedback system that prevents 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 such as cancer and viral infection. The interaction between PD-1 and PD-L1 results in a decrease in the number of tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune evasion by cancer cells. Immune suppression 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-L2 is also blocked.

Development of a therapeutic approach to block the PD-1-mediated inhibitory signaling cascade to enhance or rescue the T cell response. Most currently approved immunotherapy drugs are monoclonal antibodies. These monoclonal antibodies have shown impressive clinical results in the treatment of several tumor types. Therapeutic antibodies, however, have several disadvantages, such as limited penetration into tissues and tumors, very long half-life, lack of oral bioavailability, immunogenicity, and complex and expensive production.

Small molecules that bind to PD-L1 have recently been described, see WO2015033299, WO2015033301, WO2015034820, WO2018183171, WO2018119224, WO2018119266 and others. Moreover, small molecule inhibitors that directly target PD-1 or PD-L1 are still not approved.

Accordingly, there continues to be a great need for more effective and easier to administer therapeutics against PD-1/PD-L1 protein-protein interactions. In this invention, the inventors have discovered effective small molecules that may be active as inhibitors of the interaction of PD-L1 with PD-1 and thereby may be useful 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 profiles that are critical to become effective drugs for promoting 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 cancer and infectious diseases.

The compounds of the invention have the general structure of formula (III).

Compound of formula (III) or a pharmaceutically acceptable salt thereof

Formula (III) wherein R ₁ and R 2 are each independently selected from halogen, CN, C _1-6 αlkyl or -OCH ₃ ;

ring C represents phenyl or 5-6 membered heteroaryl, and 5-6 membered heteroaryl contains 1 heteroatom N;

R ₃ represents halogen, -(CH ₂ )s-NR ₄ R ₅ , C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, CN, and

- 1 047234 designated C _1-4 alkyl, C _1-4 alkoxy are optionally substituted with one or more R ₆ substituents;

R4 and R5 are each independently selected from H, C _1-4 alkyl, C _3-6 cycloalkyl, or C _3-6 heterocyclyl having 1 heteroatom O, wherein said C _1-4 alkyl, C _3-6 cycloalkyl or C _{3- 6} heterocyclyl is optionally substituted with one or more R ₆ substituents; or

R4 and R5, together with the N atom to which they are attached, form a 4-10 membered heterocyclic ring, optionally substituted by one or more _R6 substituents, where the 4-10 membered heterocyclic ring optionally additionally has 1 heteroatom independently selected from N, S or O;

_R6 is halogen, hydroxyl, oxo, CN, -(CH2) _k -NR7R8, -COR7, -S(O)2R7, or _R6 is selected from substituted or unsubstituted _C1-4 alkyl, _C1-4 alkoxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C _3-10 heterocyclic ring, where said C _5-6 heteroaryl and C _3-10 heterocyclic ring contain 1 or 2 heteroatoms independently selected from N or O; where C _1-4 -alkyl, C _1-4 -alkoxy, C _2-6 -alkenyl, C _2-6 -alknyl, C _1-6 -haloalkyl, phenyl, C _5-6 -heteroaryl and C _3-10 - heterocyclic ring, each independently optionally substituted with one or more substituents selected from halogen, C _1-8 alkyl, C _3-12 cycloalkyl, =O, =S, -OH, ethoxy, propyloxy, isopropyloxy, n -butyloxy, isobutyloxy, tert-butyloxy, -SCH ₃ , -SC ₂ H ₅ , formaldehyde group, -COCH3, cyano, nitro, CF3, -OCF3, amino, dimethylamino, ^(O) ₂ -C _1-4 -alkyl and acetyl;

R ₇ and R ₈ are each independently selected from H, hydroxyl or -NH ₂ , or R ₇ and R ₈ are each independently selected from substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxyl or C _3-6 heterocycloalkyl; where said C _3-6 heterocycloalkyl contains 1 heteroatom O; wherein said C _1-4 alkyl, C _1-4 alkoxy and C _3-6 heterocycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, C _1-8 alkyl, C _3-12 cycloalkyl, =O, =S , -OH, ethoxy, propyloxy, isopropyloxy, nbutyloxy, isobutyloxy, tert-butyloxy, -SCH3, -SC2H5, formaldehyde group, -COCH3, cyano, nitro, CF3, -OCF3, amino, dimethylamino, S(O) ₂ -C _1-4 -alkyl and acetyl;

n is 0, 1, 2 or 3; k is equal to 0 or 1; and s is equal to 1.

In some embodiments of formula (III), R ₆ is halogen, -(CH ₂ ) _s -NR ₄ R ₅ , C _1-4 alkyl, C _1-4 alkoxy, -CN, wherein said C _1-4 alkyl and C The _1-4 alkoxy is optionally substituted with one or more R ₆ substituents.

In some embodiments of formula (III), R ₆ is halogen, hydroxyl, oxo, CN, -(CH ₂ ) _k -NR ₇ R ₈ , -COR7, -S(O) ₂ R ₇ , or R ₆ selected from C _1-4 alkyl, C _1-4 alkoxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C _3-10 heterocyclic ring, where the indicated C _5-6 heteroaryl and C _3-10 heterocyclic ring contain 1 or 2 heteroatoms, independently selected from N or O.

In some embodiments of formula (III), R6 is halogen, hydroxyl, oxo, CN, -(CH ₂ )-N-(C _1-4 alkyl) ₂ , -(ί.Ή2)-NΗ2. -Н-(С _1-4 alkyl) ₂ , -NH2, -CO-NH2. ^(O) ₂ -C _1-4 alkyl, C _1-4 alkyl-OH, C _1-4 alkyl, C _1-4 alkoxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C3-10 heterocyclic ring, wherein said C5-6 heteroaryl and C3-10 heterocyclic ring contain 1 or 2 heteroatoms independently selected from N or O.

In some embodiments of formula (III), R ₆ is halogen, oxo, -OH, -NH ₂ , -N(CH ₃ ) ₂ , -C _1-4 alkyl-OH, -C _1-4 alkyl-NH-CH ₃ , -NH-C _1-4 alkyl, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, phenyl, C _5-6 heteroaryl, C _3-6 heterocyclyl or ^(O) ₂ -C _{1 -4} alkyl.

In some embodiments of formula (III), wherein R ₁ and R ₂ are each independently selected from halogen, CN, C _1-6 alkyl;

ring C represents phenyl or 5-6 membered heteroaryl, and said 5-6 membered heteroaryl contains 1 N heteroatom;

R3 represents halogen, -(CH ₂ ) _s -NR ₄ R ₅ , -C _1-4 alkyl, -C _1-4 alkoxyl, wherein said -C _1-4 alkyl and -C1-4 alkoxyl are optionally substituted with one or more substituents , independently selected from halogen, -C _1-4 alkyl, -C _1-4 haloalkyl, -C _1-4 alkoxyl, C _5-6 heteroaryl, phenyl, carboxyl, amino, hydroxyl or ^(O) ₂ -C _{1- 4} alkyl;

R4 and R5 are each independently selected from H, -C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 heterocyclyl having 1 heteroatom O, wherein said -C _1-4 alkyl, C _3-6 cycloalkyl or C _{3 -6} heterocyclyl is possibly substituted with halogen, -OH, -Na(CH ₃ )2, -C _1-4 alkyl, -C _1-4 haloalkyl, -C _3-6 heterocyclyl, -NaH-C ₁ groups. ₄ alkyl or ^(O) ₂ -C _1-4 alkyl; or

R ₄ and R ₅ together with the N atom to which they are attached form a 4-6 membered heterocyclic ring, possibly substituted by one or more substituents independently selected from -OH, -^CH ₃ ) ₂ , -NH2, oxo, halogen , groups -C _1-4 alkyl, -C _1-4 alkoxy, -C _1-4 alkyl-OH, -C _1-4 alkyl-NH-CH ₃ or ^(O) ₂ -C _1-4 alkyl;

n is 0, 1, 2 or 3; s is equal to 1.

In some embodiments, R1 is selected from F, Cl, -CH ₃ , -CN or -O-CH3.

In some embodiments, R1 is selected from -CH3, F, or -O-CH3.

In some embodiments, R2 is selected from _-CH3 , F, Cl or Br,

In some embodiments, R ₂ is -CH ₃ .

In some embodiments, R3 is selected from F, Cl, -CH ₃ , -CF ₃ , -O-CF3, -O-CHF2,

- 2 047234

In certain embodiments of Formula III, said compound is the following:

1) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((((1 R,2 S)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo[s!] oxazol-2-yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

2) (2'8)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(d fluoromethoxy)benzo[(1]oxazole-2 ,5 -d yl ))b is(methylene))d i-L-prolein;

3) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((8)-2(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1, Gbiphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

4) ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2- methyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

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5) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1ylmethyl)benzo[(1]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)benzo[(1]oxazol-5yl)methyl)-L-proline;

6) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)- 5 -(pyrrolidin-1 ylmethyl)benzo[c!]oxazol-2-yl)-2'-fluoro-2- methyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5 yl)methyl)-E-proline;

7) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2hydroxyethyl)amino)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

8) ((2-(3'-(5-(azetidin-1-ylmethyl)-6-(difluoromethoxy)benzo[(1]oxazol-2-yl)-2,2'dimethyl-[1,G-biphenyl ]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-Eproline;

9) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3-fluoroazetidin-1 yl)methyl)benzo[c!]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-E-proline;

10) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoropyrrolidin-1 yl)methyl)benzo[c!]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

11) ((2-(3'-(5-(((8)-2-carbamoylpyrrolidin-1-yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c!]oxazol-5-yl)methyl)-E-proline;

12) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((8)-2(hydroxymethyl)pyrrolidin-1 -yl)methyl)benzo[c1]oxazol-2 -yl)-2,2'-dimethyl-[1, Gbiphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

13) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5(morpholinomethyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl-[1,G- biphenyl]-3yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

14) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxypyrrolidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-E-proline;

15) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5((methylamino)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl-[1 ,G-biphenyl]-3yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

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16) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5((dimethylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

17) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2hydroxyethyl)(methyl)amino)methyl)benzo[c!]oxazol-2-yl)-2 ,2'-dimethyl-[1,G-biphenyl]3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

18) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3K,4K)-3,4difluoropyrrolidin-1-yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

19) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((8)-5-oxopyrrolidin-2 yl)methyl)amino)methyl)benzo[c !]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

20) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxyazetidin-1yl)methyl)benzo[0]oxazol-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

21) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5((ethylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

22) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3,3,3-trifluoro-2hydroxypropyl)amino)methyl)benzo[c!]oxazole-2 -yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3,4-dimethylpiperazin-1 yl)methyl)benzo[0]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

24) ((2-(3'-(5-(aminomethyl)-6-(difluoromethoxy)benzo[<1]oxazol-2-yl)-2,2'dimethyl-[1,G-biphenyl]-3- yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-Eproline;

25) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1K,28)-2hydroxycyclopentyl)amino)methyl)benzo[c!]oxazol-2-yl )-2,2'-dimethyl-[1,G-biphenyl] 3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

26) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1K,28)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1,Hbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-O-proline;

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27) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((18.2K)-2hydroxycyclopentyl)amino)methyl)benzo[c!]oxazol-2-yl )-2,2'-dimethyl-[1,G-biphenyl]3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

28) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((oxetan-3ylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

29) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((K)-tetrahydrofuran-2yl)methyl)amino)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

30) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(((K)tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[c1]oxazole -2-yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

31) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((8)-2(hydroxymethyl)azetidin-1 -yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1, Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

32) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2(methylsulfonyl)ethyl)amino)methyl)benzo[c!]oxazol-2-yl)- 2,2'-dimethyl-[1,G-biphenyl] 3-yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

33) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3(dimethylamino)azetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1, Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

34) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1yl)methyl)benzo[0]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

35) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((K)-2(hydroxymethyl)azetidin-1 -yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1, Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

36) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1yl)methyl)benzo[0]oxazol-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

37) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-hydroxy-2methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)-b-proline;

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38) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylpyrrolidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

9) ((2-(3 '-(5 -((6-oxa-1 -azaspiro[3.3] heptan-1 -yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2 ,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

40) ((2-(3'-(5-((2-amino-2-methylazetidin-1-yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-E-proline;

41) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3(methylsulfonyl)azetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)- 2,2'-dimethyl-[1,1'biphenyl]-3-yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

42) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((K)-2-ethylazetidin-1yl)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3-methoxyazetidin-1 yl)methyl)benzo[c!]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

44) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxy-3methylazetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

45) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3((methylamino)methyl)azetidin-1-yl)methyl)benzo[c1]oxazol-2- yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-E-proline;

46) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxoazetidin-1 yl)methyl)benzo[0]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[0]oxazol-5yl)methyl)-b-proline;

47) ((2-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2 ,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

48) ((2-(3'-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

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49) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)benzo[c!]oxazol-2- yl)-2,2'-dimethyl[1,G-biphenyl]-3-yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

50) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)methyl)benzo[c1]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

51) ((2-(3'-(5-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)-6(difluoromethoxy)benzo[c!]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

52) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3(propylamino)propyl)amino)methyl)benzo[c!]oxazol-2-yl)- 2,2'-dimethyl-[1,G-biphenyl] 3-yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

53) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(3(propylamino)propyl)amino)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl] 3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

54) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dioxido-2-thia-6azaspiro[3.3]heptan-6-yl)methyl)benzo [c1]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

55) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((tetrahydro-1H-furo[3,4c]pyrrol-5(3H)-yl)methyl)benzo[ c1]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

56) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylazetidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

57) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1K,2K)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo[c1]oxazole-2 -yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

58) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3-((2hydroxyethyl)amino)propyl)amino)methyl)benzo[c1]oxazol-2- yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

59) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2(dimethylamino)ethyl)(methyl)amino)methyl)benzo[c1]oxazol-2-yl )-2,2'-dimethyl-[1,Hbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

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60) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

61) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylpyrrolidin-1 yl)methyl)benzo[(1]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[(1]oxazol-5yl)methyl)-L-proline;

62) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dimethylpyrrolidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2 ,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

64) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((8)-tetrahydrofuran-2yl)methyl)amino)methyl)benzo[(1]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[(1]oxazol-5-yl)methyl)-E-proline;

65) ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-(pyrrolidin-1ylmethyl)benzo[c!]oxazol-2-yl)-2-methyl-[1,1' -biphenyl]-3-yl)-6(difluoromethoxy)benzo[<1]oxazol-5-yl)methyl)proline;

66) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1ylmethyl)benzo[(1]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)benzo[(1]oxazol-5yl)methyl)-O-proline;

67) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5-((3,3-dimethylpyrrolidin-1yl)methyl)benzo[c!]oxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

68) ((2-(3'-(5-((3-(diethylamino)azetidin-1-yl)methyl)-6(difluoromethoxy)benzo[0]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

69) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(2-hydroxypropan-2yl)azetidin-1-yl)methyl)benzo[0]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[4]oxazol-5-yl)methyl)-L-proline;

70) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((2,5-dihydro-1H-pyrrol-1yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

71) ((2-(3'-(5-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[<1]oxazol-5-yl)methyl)-E-proline;

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72) ((2-(3'-(5-(((18.48)-7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2- yl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

74) ((2-(3'-(5-((5-azaspiro[2.3]hexan-5 -yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

75) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxo-6azabicyclo[3.2.1]octan-6-yl)methyl)benzo[(1] oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl]3-yl)benzo[c1]oxazol-5-yl)methyl)-E-proline;

76) ((2-(3'-(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-6(difluoromethoxy)benzo[c!]oxazol-2-yl )-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

77) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3methylpyrrolidin-1-yl)methyl)benzo[c1]oxazol-2-yl )-2,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

78) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3methylazetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl )-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)-b-proline;

79) ((2-(3'-(5-((3-cyano-3-methylazetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

80) ((2-(3'-(5-((3-cyanoazetidin-1-yl)methyl)-6-(difluoromethoxy)benzo[c1]oxazol 2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5yl)methyl)-L-proline;

81) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methyleneazetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

82) ((2-(3 '-(5 -((3 -(cyanomethylene)azetidin-1 -yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

83) ((2-(2,2'-dicyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1yl)methyl)benzo[c1]oxazol-2-yl)-[ 1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

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84) ((6-(difluoromethoxy)-2-(3'-(5-((3,4-dimethylpyrrolidin-1-yl)methyl)-7(trifluoromethyl)benzo[c1]oxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)-b-proline;

85) (R)-1 -((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c1]oxazol-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

86) (8)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c!]oxazol- 2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

87) ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1yl)methyl)benzo[c!]oxazol-2-yl)-2- methyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E)-proline;

88) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)7-(trifluoromethyl)benzo[c1]oxazol-2 -yl)-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

89) ((2-(3'-(5-((2-azabicyclo[2.1. 1]hexan-2-yl)methyl)-7(trifluoromethyl)benzo[c!]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c!]oxazol-5-yl)methyl)-E-proline;

90) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)7-(trifluoromethyl)benzo[c1]oxazol-2 -yl)-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-E)-proline;

91) (3R)-1 -((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1 yl)methyl)-7-(trifluoromethyl)benzo [0]oxazol-2-yl)-[1,G-biphenyl]-3-yl)benzo[0]oxazol5 -yl)methyl)pyrrolidine-3-carboxylic acid;

92) (3 S)-1 -((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1 yl)methyl)-7-(trifluoromethyl) benzo[0]oxazol-2-yl)-[1,G-biphenyl]-3-yl)benzo[0]oxazol5 -yl)methyl)pyrrolidine-3-carboxylic acid;

) ((6-(difluoromethoxy)-2-(3 '-(5 -((3,3-dimethylazetidin-1-yl)methyl)-7(trifluoromethyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)-b-proline;

94) ((2-(3'-(5-(azetidin-1-ylmethyl)-7-methylbenzo[c1]oxazol-2-yl)-2,2'-dimethyl[1,G-biphenyl]-3- yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

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95) ((6-(difluoromethoxy)-2-(3'-(7-fluoro-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl-[1 ,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

96) ((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-fluorobenzo[c1]oxazol-2yl)-2,2'-dimethyl-[1,G-biphenyl ]-3-yl)benzo[c1]oxazol-5-yl)methyl)-E-proline;

97) ((2-(3'-(6-chloro-5-((ethylamino)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl-[1,G biphenyl]-3 -yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

98) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1ylmethyl)benzo[(1]oxazol-2-yl)-[1,G-biphenyl] -3-yl)benzo[(1]oxazol-5-yl)methyl)-Eproline;

99) ((6-(difluoromethoxy)-2-(3'-(5-((((1K,28)-2-hydroxycyclopentyl)amino)methyl)benzo[c1]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline;

100) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-7(trifluoromethyl)benzo[(1]oxazol-2-yl)- [1,G-biphenyl]-3-yl)benzo[(1]oxazol-5-yl)methyl) L-proline;

101) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1 -ylmethyl)-6(trifluoromethyl)benzo[(1]oxazol-2-yl)- [1,G-biphenyl]-3-yl)benzo[(1]oxazol-5-yl)methyl) L-proline;

102) ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2-yl)-2,2'dimethyl-[1,G-biphenyl] -3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-bproline;

103) ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[c1]oxazol-2-yl)2,2'-dimethyl-[1 ,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-bproline;

104) ((6-(difluoromethoxy)-2-(3'-(5 -((2-hydroxy-2-methylazetidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

105) ((6-(difluoromethoxy)-2-(3'-(5-((2-(hydroxymethyl)azetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

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106) ((2-(3'-(5-((6-oxa-1 -azaspiro[3.3]heptan-1 -yl)methyl)benzo[0]oxazol-2-yl)2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Eproline;

107) ((2-(3'-(5-((1-azaspiro[3.3]heptan-1-yl)methyl)benzo[c1]oxazol-2-yl)-2,2'dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-Eproline;

108) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1ylmethyl)benzo[c!]oxazol-2-yl)-[1,G-biphenyl] -3-yl)benzo[c1]oxazol-5-yl)methyl)-Eproline;

109) ((6-(difluoromethoxy)-2-(3 '-(6-((3,3-dimethylazetidin-1 - yl)methyl)benzo[c!]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-E-proline;

110) ((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)2-methyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

111) ((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzo[c1]oxazol-2-yl)2-methyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Oproline;

112) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1ylmethyl)oxazolo[5,4-b]pyridin-2-yl)-[1,D -biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-E-proline;

113) ((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

114) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(((R)-3-methylpyrrolidin-1 yl)methyl)oxazolo[5,4-b]pyridine -2-yl)-[1,G-biphenyl]-3-yl)benzo[sG|oxazol-5yl)methyl)-E-proline;

115) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-((((5-oxopyrrolidin-2yl)methyl)amino)methyl)oxazolo[5,4-b] pyridin-2-yl)-[1,G-biphenyl]-3yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

116) ((6-(difluoromethoxy)-2-(3'-(6-((3-(dimethylamino)azetidin-1yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2 '-dimethyl-[1,1'-biphenyl]-3yl)benzo[c!]oxazol-5-yl)methyl)-E-proline;

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117) ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2-yl)-2'methoxy-2-methyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl) L-proline;

118) ((2-(2'-cyano-3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2yl)-2-methyl-[1,G-biphenyl ]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-Eproline;

119) ((2-(3'-(6-((6-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6 (difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

120) ((2-(3'-(6-((5-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[c!]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6 (difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

121) ((6-(difluoromethoxy)-2-(3 '-(5 -(((2-hydroxyethyl)amino)methyl)-6-((5 (methylsulfonyl)pyridin-3-yl)methoxy)benzo[s !]oxazol-2-yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

122) ((6-(difluoromethoxy)-2-(3 '-(5 -((ethylamino)methyl)-6-((5 (methylsulfonyl)pyridin-3-yl)methoxy)benzo[c!]oxazole-2 -yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

123) ((6-(difluoromethoxy)-2-(3 '-(5 -((dimethylamino)methyl)-6-((5 (methylsulfonyl)pyridin-3-yl)methoxy)benzo[c!]oxazole-2 -yl)-2,2'-dimethyl-[1,Gbiphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-b-proline;

124) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((3(methylsulfonyl)benzyl)oxy)benzo[s!] oxazol-2-yl)-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-L-proline;

125) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((4(methylsulfonyl)benzyl)oxy)benzo[c1]oxazole -2-yl)-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

126) ((6-(difluoromethoxy)-2-(3 '-(5-((dimethylamino)methyl)-6-((4(methylsulfonyl)benzyl)oxy)benzo[c1]oxazol-2-yl)-2 ,2'-dimethyl-[1,G-biphenyl]-3yl)benzo[0]oxazol-5-yl)methyl)-E-proline;

127) ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2-yl)-2,2'dimethyl-[1,G-biphenyl]-3 -yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-Eproline;

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128) ((2-(2-cyano-3 '-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1 yl)methyl)benzo[c!]oxazol-2-yl)-2' -methyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

129) ((2-(3 '-(7-cyano-5 -((3 -(hydroxymethyl)-3-methylazetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

130) ((2-(3 '-(7-cyano-5-(((8)-3-methylpyrrolidin-1 -yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

131) ((2-(3'-(7-cyano-5-(((K)-3-methylpyrrolidin-1-yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

132) ((2-(3'-(7-cyano-5-(((K)-3-methylpyrrolidin-1-yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)D-proline;

133) ((2-(3 '-(7-cyano-5 -(((3 -methyloxetan-3 -yl)amino)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[1 ,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

134) ((2-(3'-(7-cyano-5-((3-(dimethylamino)azetidin-1-yl)methyl)benzo[c1]oxazol 2-yl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5yl)methyl)-E-proline;

135) ((2-(3'-(7-cyano-5-((2-(2-hydroxyethyl)piperidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-c-proline;

136) ((2-(3'-(7-cyano-5-(((cyanomethyl)(methyl)amino)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

7) ((2-(3 '-(7-cyano-5 -((3 -(hydroxymethyl)azetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-c-proline;

138) ((2-(3'-(7-cyano-5-(((2-hydroxy-2-methylpropyl)amino)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-c-proline;

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139) ((2-(3'-(7-cyano-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)benzo[c!]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-E-proline;

140) ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[c1]oxazol-2-yl) 2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Oproline;

141) ((2-(3'-(7-cyano-5-((ethyl(2-hydroxyethyl)amino)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)L-proline;

142) ((2-(3'-(7-cyano-5-((3-cyanopyrrolidin-1-yl)methyl)benzo[c1]oxazol-2-yl)2,2'-dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-bproline;

143) ((2-(3 '-(7-cyano-5 -((3 -cyanopyrrolidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)2,2'-dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Oproline;

144) ((2-(3'-(7-cyano-5 -((3-ethynyl-3-hydroxyazetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

145) ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzo[c1]oxazol-2-yl)-2,2'dimethyl-[1,G-biphenyl]-3 -yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Oproline;

146) ((2-(3'-(7-cyano-5-((7-oxo-2,6-diazaspiro[3.4]octan-2yl)methyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

147) ((2-(3 '-(5 -((bis( 1 -hydroxypropan-2-yl)amino)methyl)-7cyanobenzo[c!]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

148) ((2-(3'-(7-cyano-5-((3-morpholinoazetidin-1-yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

149) ((2-(3 '-(7-cyano-5 -((3 -(methyl(oxetan-3-yl)amino)azetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)- 2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

- 16 047234

150) ((2-(3 '-(7-cyano-5 -((3 -hydroxy-3 -methyl-[1,3 '-biazetidine] - Gil)methyl)benzo[c1]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

151) ((2-(3'-(7-cyano-5-((6-oxo-2,5-diazaspiro[3.4]octan-2yl)methyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

152) ((2-(3'-(7-cyano-5-((3-((dimethylamino)methyl)pyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

153) ((2-(3'-(7-cyano-5-((1,1-difluoro-5-azaspiro[2.4]heptan-5yl)methyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

154) ((2-(3'-(7-cyano-5-(((K)-3-(hydroxymethyl)pyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

155) ((2-(3'-(7-cyano-5-(((3-hydroxycyclobutyl)amino)methyl)-benzo[c1]oxazol 2-yl)-2,2'-dimethyl-[1, G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5yl)methyl)-L-proline;

6) ((2-(3 '-(5 -((3 -amino-4-methylpyrrolidin-1 -yl)methyl)-7cyanobenzo[c!]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

157) ((2-(3'-(5-(((azetidin-3-ylmethyl)amino)methyl)-7-cyanobenzo[c1]oxazol-2yl)-2,2'-dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

158) ((2-(3'-(7-cyano-5 -((3 -(dimethylamino)-4-methylpyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

159) ((2-(3 '-(7-cyano-5 -((3 -((dimethylamino)methyl)-3-methylazetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

160) ((2-(3 '-(7-cyano-5 -((((1 -methyl-1 H-imidazol-4-yl)methyl)amino)methyl)benzo[c1]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

- 17 047234

161) ((2-(3 '-(5 -((3 -(aminomethyl)-3 -methylazetidin-1 -yl)methyl)-7cyanobenzo[c!]oxazol-2-yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-E-proline;

162) ((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[(1]oxazol-2-yl)2,2'-dimethyl-[1, G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Eproline;

163) ((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[c1]oxazol-2-yl)2,2'-dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)-Oproline;

164) ((2-(3'-(7-cyano-5-((3,4-difluoropyrrolidin-1-yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[1, G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

165) ((2-(3'-(7-cyano-5-(((K)-3-cyanopyrrolidin-1-yl)methyl)benzo[c1]oxazol-2yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

166) ((6-(difluoromethoxy)-2-(3 '-(5 -((3-fluoropyrrolidin-1-yl)methyl)-7(trifluoromethyl)benzo[c!]oxazol-2-yl)-2, 2'-dimethyl-[1,G-biphenyl]-3yl)benzo[(1]oxazol-5-yl)methyl)-L-proline;

167) ((2-(3'-(7-cyano-5 -((3-fluoro-3-methylpyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-L-proline;

168) ((2-(3'-(7-cyano-5-(((K)-3-(fluoromethyl)pyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2,2'- dimethyl-[1,G-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-L-proline;

169) (R)-1 -((2-(3'-(7-cyano-5-(pyrrolidin-1 -ylmethyl)benzo[c!]oxazol-2-yl)-2,2'· dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5yl)methyl)pyrrolide in-3-carboxylic acid;

170) ((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3yl)benzo[c!]oxazol-5-yl)methyl)-O-proline;

259) (8)-1-((2-(3'-(7-cyano-5-(((8)-3-methylpyrrolidin-1yl)methyl)benzo[c1]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

- 18 047234

261) ((2-(3'-(5-(((S)-3-chloropyrrolidin-1 -yl)methyl)-7-cyanobenzo[c!]oxazol-2yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[c1]oxazol-5-yl)methyl)L-proline;

310) ((6-(difluoromethoxy)-2-(3 '-(5 -((((1 R,2 8)-2-hydroxycyclopentyl)amino)methyl)benzo[(1]oxazol-2-yl)- 2,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo[(1]oxazol-5yl)methyl)-O-proline;

311) ((6-(difluoromethoxy)-2-(3'-(5-((2,2-dimethylpyrrolidin-1yl)methyl)benzo[0]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)benzo[c1]oxazol-5yl)methyl)-L-proline;

312) ((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1yl)methyl)benzo[0]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)benzo[c!]oxazol-5yl)methyl)-b-proline;

313) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((2-methylazetidin-1yl)methyl)benzo[0]oxazol-2-yl)-[1, G-biphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)-Eprolin;

315) ((2-(3'-(5-((3-carbamoylpyrrolidin-1-yl)methyl)-7-cyanobenzo[c1]oxazol-

2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5yl)methyl)-E-proline; or

316) ((2-(3 '-(7-cyano-5 -((3 -cyano-3 -methylpyrrolid in-1 -yl)methyl)- benzo[(1]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[(1]oxazol-5-yl)methyl)-b-prole and n.

The present invention also provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable carrier or excipient such as hydroxypropyl methylcellulose. In the composition, said compound, in weight ratio to said excipient, ranges from about 0.0001 to about 10.

The present invention further provides the use of a compound or pharmaceutical composition of a compound of formula III for the manufacture of a medicament for enhancing, stimulating and/or enhancing the immune response in a patient where the patient has a disease associated with inhibition of the interaction between PD-1 and PD-L1.

The present invention also provides some preferred technical solutions regarding the above-mentioned applications.

In some embodiments, a medicament so prepared may be used to treat or prevent, delay or prevent the onset or progression of cancer, cancer metastasis, or an immunological disorder. 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.

The present invention provides a method of inhibiting the PD-1/PD-L1 interaction, comprising administering to a patient the compound or a pharmaceutically acceptable salt or stereoisomer thereof.

The present invention provides a method of treating a disease associated with inhibition of 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, wherein said disease is colon cancer. colon, 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 a compound of the present invention or a pharmaceutical composition thereof for the manufacture of a medicament.

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

- 19 047234

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, and breast cancer.

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

In some embodiments, the drug is used to enhance, stimulate and/or enhance the immune response in a patient.

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, bromine or iodine. Preferred halogen groups include F, C1 and Br.

As used herein, unless otherwise indicated, alkyl 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, mpem-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2- methylbutyl, neoopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Likewise, C _1-4 , as in C _1-4 alkyl, is defined by identifying a group having 1, 2, 3 or 4 carbon atoms in a linear or branched configuration.

Alkenyl and alkynyl groups include straight, branched or cyclic alkenes and alkynes. Likewise, C _2-8 alkenyl and C _2-8 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 from the straight, branched or cyclic alkyl groups described above.

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

The term heterocycle, as used herein unless otherwise specified, is an unsubstituted or substituted stable 3-10 membered saturated or partially unsaturated monocyclic, spirocyclic, bridged bicyclic or fused bicyclic ring system that consists of carbon atoms and 1-3 heteroatoms, selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms may be optionally oxidized, and wherein said nitrogen heteroatom may be optionally quaternized. A heterocyclic group can be attached at any heteroatom or carbon atom that results in a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.

The term heteroaryl, as used herein unless otherwise specified, is an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9- or 10-membered benzo-fused heteroaromatic ring system or a bicyclic heteroaromatic ring system that consists of carbon atoms and 1-4 heteroatoms selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms may be optionally oxidized, and wherein said nitrogen heteroatom may be optionally quaternized. A heteroaryl group can be attached at any heteroatom or carbon atom that results in a stable structure. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, silt, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.

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

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 replaced by the same or different substituents.

Typical substituents include, but are not limited to, halogen (F, Cl, Br or I), _C1-8 alkyl, Ce-12cycloalkyl, -OR ¹ , SR ¹ , =O, =S, -C(O)R1, -C( S)R1, =NR1, -C(O)OR1, -C(S)OR1, -NR ¹ R ₂ , -C(O)NR1R ₂ , cyano, nitro, -S(O) ₂ R1, -OS( O ₂ )OR1, -OS(O) ₂ R1, -OP(O)(OR1)(OR ₂ ); where Ri and R ₂ are independently selected from -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, isopropyl

- 20 047234 cy, n-butyloxy, isobutyloxy, tert-butyloxy, -SCH3, -SC2H5, formaldehyde group, -C( _OCH3 ), cyano, nitro, CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl and acetyl.

The term composition, as used herein, is intended to cover a product containing the specified ingredients in the specified amounts, as well as any product that is the direct or indirect result of combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient, as well as methods for preparing the compounds to be prepared, 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 included within the scope of the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also 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 the substituted alkoxy group include, but are not limited to, 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 the present 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 is typically in a form in which the basic nitrogen is protonated with an inorganic or organic acid. Typical 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 acid, pamic acid, 2-naphthalene sulfonic acid, para-toluene sulfonic acid, cyclohexane sulfonic acid, salicylic acid, saccharin acid or trifluoroacetic acid. 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 the present invention. Typically, such prodrugs will be functional derivatives of compounds that are readily convertible in vivo into the desired compound. Thus, in the treatment methods of the present invention, the term administration should encompass the treatment of the various disorders described for the specifically disclosed compound or a compound that may not be specifically disclosed but which is converted to the specified compound in vivo upon administration to a subject. Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

The implication is that the definition of any substituent or variable at a particular location in a molecule is independent of its definitions elsewhere in that molecule. It will be understood that the substituents and substitution patterns in the compounds of the present invention can be selected by one skilled in the art to provide compounds that are chemically stable and that can be readily synthesized by methods known in the art, as well as the methods set forth herein.

The present invention includes compounds described herein which may contain one or more asymmetric centers and thus may produce 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.

The above formula I is shown without defined stereochemistry at certain 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. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures 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.

When a compound of formula I and its pharmaceutically acceptable salts exist in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. 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

- 21 047234 being 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, iron, lithium, magnesium, manganese, potassium, sodium, zinc and the like salts. Particularly preferred are ammonium, calcium, magnesium, 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 resins such as, for example, arginine, betaine, caffeine, choline, N'.N'-dibenzylethylenediamine. diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, purines, theobromine, triethylamine , trimethylamine, tripropylamine, tromethamine and the like.

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, pamic, pantothenic , phosphoric, succinic, sulfuric, tartaric, para-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids, with formic and hydrochloric acids particularly preferred. Since the compounds of formula I are intended for pharmaceutical use, they are preferably presented in substantially pure form, for example, at least 60% purity, more suitably at least 75% purity, especially at least 98% purity (% given by weight) .

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

In practice, the compounds represented by Formula I, or their prodrug or metabolite or pharmaceutically acceptable salts of the present invention, can be combined as the active ingredient in a uniform mixture with a pharmaceutical carrier in accordance with conventional methods for the preparation of pharmaceutical mixtures. The carrier may take a variety of forms depending on the form of preparation desired 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 in the form of a powder, granules, solution, suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a liquid water-in-oil emulsion. In addition to the conventional dosage forms set forth above, the compound represented by Formula I, or a pharmaceutically acceptable salt thereof, can also be administered via controlled release agents and/or delivery devices. The compositions can be prepared by any of the methods used in pharmacy. Typically such methods include the step of combining the active ingredient with a carrier that constitutes one or more of the required ingredients. Typically, compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be shaped into the desired shape.

Thus, the pharmaceutical compositions of the present invention may include a pharmaceutically acceptable carrier and a compound, or a pharmaceutically acceptable salt, of Formula I. The compounds of Formula I, or a pharmaceutically acceptable salt 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, solid, liquid or gaseous. Examples of solid carriers include carriers such as lactose, calcium sulfate, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate and stearic acid. Examples of liquid carriers include sugar syrup, peanut butter, olive oil and water. Examples of gaseous

- 22 047234 carriers include, for example, carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical vehicle may be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, dyes, etc. can be used to form liquid preparations for oral administration, such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants and the like can be used to form solid oral preparations such as powders, capsules and pills. Due to their ease of administration, tablets and capsules are the preferred oral dosage forms using solid pharmaceutical carriers. Optionally, tablets can be coated using standard aqueous or non-aqueous methods.

A tablet containing the composition of the present invention may be prepared by compression or molding, optionally with one or more additional ingredients or adjuvants. Compressed tablets can be prepared by compressing, on suitable equipment, the active ingredient in bulk form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersant. Molded tablets can be prepared by molding on suitable equipment a mixture of a powdered 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 composition for oral administration to a human may contain from about 0.5 mg to about 5 g of active agent admixed 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 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 growth of microorganisms.

Pharmaceutical compositions of the present invention suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the immediate preparation of such sterile injectable solutions or dispersions. In all cases, the final injection form must be sterile and must be effectively flowable so that it can be administered via a syringe. Pharmaceutical compositions must be stable under manufacturing and storage conditions; thus, it should preferably be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion 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 form suitable for topical administration, such as, for example, an aerosol, cream, ointment, lotion, powder or the like. In addition, the compositions may be in a form suitable for use in transdermal delivery devices. These compositions can be prepared using the compound represented by Formula I of the present invention, or a pharmaceutically acceptable salt thereof, by conventional processing methods. For example, a cream or ointment is prepared by mixing a hydrophilic material and water together with about 5-10 wt.% of the compound to obtain a cream or ointment of the desired consistency.

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

In addition to the above-mentioned carrier ingredients, the pharmaceutical compositions described above may include, as appropriate, one or more additional carrier ingredients, such as diluents, buffers, flavorings, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants) ) etc. In addition, other adjuvants may be included to render the composition isotonic with the blood of the intended recipient. Compositions containing a compound of Formula I, or pharmaceutically acceptable salts thereof, may also be prepared in the form of a powder or liquid concentrate.

Typically dosage levels are on the order of about 0.01 mg/kg to about 150 mg/kg body weight per day.

- 23 047234 tka are useful for the treatment of the above conditions or, alternatively, from about 0.5 mg to about 7 g per patient per day. For example, colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, esophageal squamous cell cancer, liposarcoma, T-cell lymphoma, melanoma, pancreatic cancer, glioblastoma, or lung cancer can be effectively treated by administering from about 0.01 to 50 mg of the compound per kilogram of body weight per day or, alternatively, from about 0.5 mg to about 3.5 g per patient per day.

However, it should be understood that lower or higher doses than those indicated above may be required. The specific dose level and treatment regimens for any particular subject will depend on a variety 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 administration, rate of excretion, drug combination, the severity and course of the particular disease being treated, the subject's predisposition to the disease, and the judgment of the treating physician.

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

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

The invention will be described in more detail using specific examples. The following examples are offered for illustrative purposes and are not intended to limit the invention in any way. Those 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 the 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 presented below. Purification by open-access preparative LCMS for some of the resulting compounds was performed on Waters mass-controlled fractionation systems. The basic hardware setup, protocols, and control software for operating these systems are 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 conventional methods, as shown below, using commercially available starting materials and reagents. The following abbreviations are used in the examples:

EA: ethyl acetate;

STAB: sodium triacetoxyborohydride;

TBAI: tetrabutylammonium iodide;

DMF: dimethylformamide;

THF: tetrahydrofuran;

TEA: triethylamine;

TLC: preparative thin layer chromatography;

AcOH or HO AC: ethanoic acid;

BSA: bovine serum albumin;

DCM: dichloromethane;

DDQ: 2,3-dichloro-5,b-dicyano-iora-benzoquinone;

DMSO: dimethyl sulfoxide;

EY Ac: ethyl acetate;

h: hour or hours;

HTRF: homogeneous time-resolved fluorescence;

MeOH: methanol;

min: minutes;

PE: petroleum ether;

Pd(dppf)C12: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium;

CT or CT: room temperature;

- 24 047234

TV AI: tetrabutylammonium iodide;

THF: tetrahydrofuran;

Pcb(cla)3: tris(dibenzylideneacetone)dipalladium;

NBS: N-bromosuccinimide

BPO: benzoyl peroxide

TLC: preparative thin layer chromatography.

Synthesis of intermediate compounds.

Example A: Synthesis of Intermediate A.

Methyl-((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2w)phenyl)benzo^]oxazole-5-w )methyl)^-prolinate

intermediate A

Step 1: preparation of methyl 2,4-dihydroxy-5-nitrobenzoate

Methyl 2,4-dihydroxybenzoate (850 g) was dissolved in a mixture of ice-cold AcOH (3.6 L) and Ac ₂ O (900 ml). After cooling the clear solution to 10°C (ice bath), a mixture of concentrated HNO3 (65%) (455 ml) in ice-cold AcOH (500 ml) was added over 1 h. The light brown solution was allowed to warm to 15-20°C and stirring was continued for another 1 hour. The reaction solution was poured into H ₂ O (3 L). The precipitate was filtered off and washed with small amounts of H ₂ O. This crude product was then poured into MeOH (2 L) with stirring. The precipitate was filtered off, washed with small amounts of MeOH, and dried in vacuo to give the title product, 480 g.

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

A mixture of compound a-2 (77.1 g) and 10% Pd(OH)/C (11.5 g) in methanol (2 l) was stirred under a pressure of 1.1 atm of hydrogen at room temperature for 3 hours. Then the catalyst was removed by filtration, the solid was washed with methanol (300 ml) and the solvent was removed in vacuo. The result was 72 g of methyl 5-amino-2,4-dihydroxybenzoate.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo^]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 resulting mixture was then concentrated under reduced pressure. To this mixture was added DCM (500 ml) and then DDQ (55.6 g) was added. The 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 phases were 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^]oxazole-5-carboxylate as a brown solid.

Step 4: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzo^]oxazole-5-carboxylate

Methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo^]oxazole-5-carboxylate (10.0 g), 2-bromo-2,2

- 25 047234 Sodium difluoroacetate (5.46 g), CS2CO3 (27.09 g), KI (4.59 g), TBAI (10.22 g) were added to 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)benzoY]oxazole-5-carboxylate.

Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzooxazol-5-yl)methanol

To a solution of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzoY]oxazole-5-carboxylate (1.30 g) in THF (50 ml) was added dropwise LiAlH4 in THF (2.5 M ) at -10°C. The mixture was warmed to room temperature. After 1 hour, this mixture was quenched with 1 ml of H ₂ O and 1 ml of 10% NaOH solution, washed with 1 M HCl, water and brine. The organic layers were dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated. The result was (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methanol as a yellow solid (1.2 g).

Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzooxazole-5-carbaldehyde

To a solution of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzooxazol-5-yl)methanol (1.40 g) in anhydrous THF (15 ml) was added portionwise Dess-Martin reagent (2.39 d) at 10°C. The resulting solution was stirred for 1 hour at room temperature. The mixture was filtered through celite. The solids were washed with DCM and the combined filtrates were washed with saturated aqueous sodium bicarbonate, 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-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzooxazole-5-carbaldehyde (1 ,27 g).

Step 7: preparation of methyl ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzoY]oxazol-5yl)methyl)-b-prolinate

A solution of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzoY]oxazole-5-carbaldehyde (1.0 g), methyl L-proline (1.7 g), HOAC (316 mg) in MeOH was stirred at room temperature for 30 min. NaBH ₃ CN (498 mg) was added to this mixture, then heated at 60° C. for 2 hours. The mixture was cooled, diluted with DCM and washed with H ₂ O and NaCl solution. The organic phases were dried over MgSO ₄ , filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH 10:1) to obtain 671 mg of methyl-((2-(3-bromo-2-methylphenyl)-6(difluoromethoxy)benzoY]oxazol-5-yl)methyl)-b- prolinate as a white solid.

Step 8: Preparation of methyl-((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)benzo^]oxazole -5-yl)methyl)-E-prolinate

^a '° intermediate A

To a solution of methyl-((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)-bprolinate (680 mg) in 1,4-dioxane (16, 0 ml) bis(pinacolato)diboron (1.20 g), Pd(dppf)Cl ₂ -DCM (100 mg) and KOAc (102 mg) were added under N ₂ protection. The reaction mixture was heated at 100°C for 10 hours. It was diluted with 30 ml of water and then extracted with DCM (90 mlx2). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified over silica gel (eluting with hexane-EtOAc using a 4:1 to 2:1 gradient) to give methyl ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)benzo^]oxazol-5-yl)methyl)-b-prolinate (500 mg). LC-MS (m/z): 543.2 (M+H)+.

Example B: Synthesis of Intermediate B.

- 26 047234

Methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1, 1'biphenyl]-3 -yl)benzo^]oxazol-5 -yl)methyl)^-prolinate

Stage

1:

preparation of (difluoromethoxy)benzo^]oxazol-5-yl)methyl)^-prolinate methyl-((2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl) -6Вг

COOMe intermediate A „ Br stage 1

b-1

To a solution of intermediate A (21.7 g) was added 1-bromo-3-iodo-2-methylbenzene (9.0 g) in toluene (150 ml), EtOH (30 ml), 10% Na ₂ CO ₃ aq. (30 ml), Pd(dppf)Cl ₂ .DCM (1.0 g) protected by N2. This mixture was left stirring at 90°C overnight. The reaction mixture was quenched with H ₂ O (100 ml) and extracted with EtOAc (100 ml) 3 times. The organic layers were combined and washed with brine. The resulting solution was concentrated and purified over silica gel (eluting with hexane-EtOAc using a 10:1 to 4:1 gradient) to give methyl ((2-(3'-bromo-2,2'-dimethyl-[1,1' -biphenyl]-3yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)^-prolinate (18.2 g) as a brown oil.

Step 2: preparation of methyl ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-[ 1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)-methyl)-b-prolinate

To a solution of compound b-1 (18.2 g) in 1,4-dioxane (120 ml) was added bis(pinacolato)diboron (12.4 g), Pd(dppf)Cl ₂ DCM (1.0 g) and KOAc (9.9 g) protected N2. The reaction mixture was heated at 100°C for 6 hours. It was diluted with 300 ml of water and then extracted with EtOAc (150 ml) three times. The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified over silica gel (eluting with hexane-EtOAc using a 20:1 to 10:1 gradient) to give methyl ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4, 4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-[1,G-biphenyl]-3-yl)-benzo^]oxazol-5-yl)methyl)-E-prolinate (15, 1 g) as brown butter. LC-MS (m/z): 633.9 (M+H)+.

Example 1: synthesis of compound 1.

((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((^, 2S)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo^]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl) benzo^]oxazol-5-yl) methyl)-L-proline

Stage

1:

He's getting

Compound 1 methyl-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5(hydroxymethyl)benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G -biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-Eprolinate

Connection A

To a mixture of intermediate A (5 g) in 1,4-dioxane (80 ml)/H ₂ O (16 ml) was added compound a-6 (3.9 g), K ₂ CO ₃ (3. 8 g) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (732 mg). This mixture was stirred at 80°C for 12 hours under N2 atmosphere. After almost complete consumption of the starting material and stopping the reaction, this mixture was poured into H2O (300 ml) and extracted with DCM (100 ml) three times. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated to leave a residue. This residue was further purified using a silica gel column to give compound 1-1 (3.7 g).

Step 2: preparation of methyl-((2-(3'-(5-(chloromethyl)-6-(difluoromethoxy)-benzo^]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl ]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)^-prolinate

Compound 1-1 (1.5 g) was dissolved in DCM (20 ml). SOCl ₂ (495 mg) was added dropwise and stirred at room temperature for 1 hour. After almost complete consumption of the starting material and the reaction had stopped, the resulting mixture was concentrated under reduced pressure. The result was 1.56 g of compound 1-2 (crude).

Step 3: preparation of methyl ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((^, 2S)-2hydroxycyclopentyl)amino)methyl)benzo^]oxazole-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl)benzo^]oxazol-5-yl)methyl)^-prolinate

Mixture of compound 1-2 (300 mg), (1S,2R)-2-aminocyclopentan-1-ol (168 mg), K ₂ CO ₃ (283 mg), KI (68 mg) in CH ₃ CN (10 ml) stirred at 50°C for 1.5 hours. After almost complete consumption of the starting material and stopping the reaction, the reaction solution was poured into H ₂ O (30 ml) and extracted with DCM (15 ml) three times. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This crude product was further purified using a silica gel column (DCM/MeOH) to obtain compound 1-3 (240 mg).

Step 4: preparation of methyl ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((^^)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo^]oxazole -2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl)benzo^]oxazol-5-yl)methyl)^-prolinate

A mixture of compound 1-3 (240 mg), HCHO (45 mg), CH3COOH (36 mg) in MeOH (5 ml)/OCM (5 ml) was stirred at 30°C for 30 min, then NaBH ₃ CN (57 mg) and continued stirring until the starting material was almost completely consumed and the reaction stopped. The reaction solution was poured into H ₂ O (30 ml) and extracted with DCM (15 ml) three times. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This crude product was further purified using a silica gel column (DCM/MeOH) to obtain compound 1-4 (200 mg).

Step 5: preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((^^)-2hydroxalopentyl)(methyl)amino)methyl)benzo^]oxazole-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl)benzo^]oxazol-5-yl)methyl)^-proline (compound 1)

- 28 047234

Compound 1-4 (200 mg) and LiOH (51 mg) were dissolved in a mixture of THF (8 ml)/H ₂ O (2 ml) and stirred at 35 ° C for 12 hours. The reaction solution was poured into H ₂ O (30 ml) and extracted with DCM (10 ml)/MeOH (5 ml) three times. The organic layers were combined, dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure. The result was 160 mg of ((6-(difluoromethoxy)-2-(3'(6-(difluoromethoxy)-5-((((^^)-2-hydroxycyclopentyl)(methyl)amino)methyl)-benzo^] Oxazol-2-yl)2,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-proline (compound 1). LC-MS (m/z): 803.3 (M+H)+.

Example 2: synthesis of compound 2.

(2^)-(((2,2'-Dimethyl-[1,G-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)-benzo^]oxazol-2,5diyl))bis( methylene))di^-proline

Connection 2

Step 1: preparation of methyl-6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)benzo^]oxazole-5 -carboxylate

To a solution of compound a-5 (880 mg) in 1,4-dioxane (16.0 ml) was added bis(pinacolato)diboron (1.80 g), Pd(dppf)Cl ₂ -DCM (150 mg) and KOAc ( 130 mg). The reaction mixture was heated at 100°C for 10 hours. It was diluted with 30 ml of water and then extracted with DCM (90 mlx2). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo to leave a residue. This residue was purified over silica gel (eluting with hexane-EtOAc using a 4:1 to 2:1 gradient) to give compound 2-1 (600 mg).

Step 2: preparation of dimethyl 2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6(difluoromethoxy)benzo^]oxazole-5-carboxylate)

A mixture of compound 2-1 (8 g), compound a-5 (8.95 g), K2CO3 (5.25 g) and Pd(dppf)Cl ₂ .DCM (1.65 g) in 1,4dioxane (160 ml )/H ₂ O (16 ml) was evacuated and refilled three times using nitrogen. This mixture was heated at reflux for 2 hours. 200 ml of H ₂ O was added to this reaction mixture and extracted with EtOAc (2 x 200 ml). The combined organic layers were washed with brine (100 ml) and then dried over Na ₂ SO ₄ . The resulting solution was filtered and concentrated to obtain a residue. This residue was purified by column chromatography (EA) to give compound 2-2 (6.3 g).

Step 3: Preparation of ((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6(difluoromethoxy)benzo[d]oxazol-2,5-diyl))dimethanol

LiAlH ₄ (2.5M) was added dropwise to a solution of compound 2-2 (6.3 g) in THF (150 ml) at 0°C. This mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with H ₂ O at 0°C. This mixture was dried over Na ₂ SO ₄ , filtered and concentrated to give compound 2-3 (5.7 g).

Step 4: Preparation of 2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-29 047234 (difluoromethoxy)benzo^]oxazole-5-carbaldehyde )

Dess-Martin reagent (11.95 g) was added to a solution of compound 2-3 (5.70 g) in THF (100 ml). The mixture was stirred at RT for 2 hours. The reaction mixture was quenched with NaHCO ₃ and Na ₂ SO ₃ and extracted with EtOAc (2x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 2-4 (5.5 g).

Step 5: preparation of (2^)-(((2,2'-dimethyl-[1,G-biphenyl]-3,3'-diyl)bis(6(difluoromethoxy)benzo^]oxazol-2,5-diyl ))bis(methylene))di^-proline (compound 2)

A mixture of compound 2-4 (4 g), L-proline (4.58 g) and AcOH (0.82 g) in MeOH (100 ml) was stirred for 30 minutes. NaBH ₃ CN was added to this mixture and the mixture was stirred for 12 hours. 200 ml of H ₂ O were added to the reaction solution and extracted with DCM (2x200 ml). The combined organic layers were dried over Na ₂ SO ₄ . The resulting solution was filtered and concentrated to obtain the crude product. This crude product was purified by column chromatography (DCM/MeOH 10:1) to give 2.56 g of (2^)-(((2,2'-dimethyl-[1,G-biphenyl]-3,3'-diyl )bis(6(difluoromethoxy)benzo^]oxazol-2,5-diyl))-bis(methylene))di^-proline (compound 2). LC-MS (m/z): 803.3 (M+H)+.

Example 3: synthesis of compound 3.

((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((^)-2-(methoxycarbonyl)-pyrrolidin-1yl)methyl)benzo^]oxazol-2-yl)- 2,2'-dimethyl-[1,G-biphenyl]-3-yl)-benzo^]oxazol-5-yl)methyl)^-proline

Connection 3

Step 1: preparation of methyl-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5formylbenzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl ]-3-yl)benzo^]oxazol-5-yl)-methyl)^prolinate

Dess-Martin reagent (11.79 g) was added in portions to a solution of compound 1-1 (10.00 g) in THF (200 ml). The mixture was stirred for 2 hours at RT. The reaction mixture was quenched with Na ₂ SO ₃ and an aqueous solution of sodium bicarbonate. This reaction mixture was extracted with EtOAc (2x150 ml). The combined organic phase was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give compound 3-1 (9.50 g).

Step 2: preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((^)-2(methoxycarbonyl)pyrrolidin-1 -yl)methyl)benzo^] oxazole-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo^]oxazol-5-yl)methyl)^-proline

- 30 047234

A mixture of compound 3-1 (5.90 g), L-proline (2.85 g) and AcOH (0.51 g) in MeOH (60 ml) was stirred for 30 minutes. NaBH ₃ CN (1.55 g) was then added to this mixture. The reaction mixture was stirred for 3 hours. 100 ml of H ₂ O was added to this reaction mixture and extracted with DCM (2x100 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to leave a residue. This residue was purified by column chromatography (DCM/MeOH 10:1) to give ((6(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((^)-2-(methoxycarbonyl) pyrrolidin-1yl)methyl)benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-proline ( 3.6 g). LC-MS (m/z): 817.3 (M+H)+.

Example 4: synthesis of compound 4.

((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)-benzo^]oxazol-2-yl)-2methyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)^-proline

Connection 4

Step 1: preparation of 2-bromo-6-vinylbenzonitrile

Mixture of 2-bromo-6-iodobenzonitrile (10 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5 g), [1,G-bis(diphenylphosphino)ferrocene] Dichloropalladium(P) (2.5 g) and potassium carbonate (13.4 g) in 1,4-dioxane (100 ml)/H ₂ O (20 ml) were stirred at 80°C for 12 hours under N ₂ atmosphere. The reaction solution was poured into H ₂ O (30 ml) and extracted with DCM (15 mlx3). The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product. This crude product was further purified using a silica gel column to give compound 4-1 (5 g).

Step 2: preparation of 2-bromo-6-formylbenzonitrile

A mixture of compound 4-1 (1 g) and sodium periodate (3.67 g) in THF (20 ml)/H ₂ O (6 ml) was stirred in an ice bath, then potassium osmate (20 mg) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into H ₂ O (150 ml) and extracted with EA (100 ml) twice, the organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to obtain the title compound 4-2 (800 mg).

Step 3: Preparation of methyl 2-(3-bromo-2-cyanophenyl)-6-hydroxybenzo^]oxazole-5-carboxylate

A mixture of compound 4-2 (1 g) and methyl 5-amino-2,4-dihydroxybenzoate (870 mg) in MeOH (150 ml) was stirred at 80°C for 2.5 hours, then the reaction mixture was concentrated under reduced pressure. pressure and dissolved in dichloromethane. 2,3-Dichloro-5,6-dicyano-1,4benzoquinone (1.3 g) was added to this solution and stirring was continued at room temperature. After 1 hour, the mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give the crude product. This crude product was suspended in methanol, the solution was filtered and the filter cake was dried in a vacuum oven to give the title compound (1.4 g).

Step 4: Preparation of methyl 2-(3-bromo-2-cyanophenyl)-6-(difluoromethoxy)-benzo^]oxazole-5-carboxylate

Sodium chlorodifluoroacetate (850 mg), cesium carbonate (2.62 g) were added to a stirred solution of methyl 2-(3-bromo-2-cyanophenyl)-6-hydroxybenzo^]oxazole-5-carboxylate (1 g) in DMF ( 20 ml)/H ₂ O (0.6 ml), the reaction mixture was heated to 80 ° C and stirred for 4 hours. This mixture was then poured into H ₂ O

- 31 047234 (100 ml) and extracted with EA (80 ml) twice. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the crude product. This crude product was further purified using a silica gel column to obtain the title compound 4-4 (800 mg).

Step 5: Preparation of 2-bromo-6-(6-(difluoromethoxy)-5-(hydroxymethyl)-benzo^]oxazol-2yl)benzonitrile

This compound was prepared using procedures similar to those described for step 5 in Example A, using compound 4-4 instead of compound a-4. The mixture was concentrated under reduced pressure to obtain the title compound 4-5.

Step 6: yl)benzonitrile

Preparation of 2-bromo-6-(5-(chloromethyl)-6-(difluoromethoxy)-benzo^]oxazole-2-

This compound was prepared using procedures similar to those described for step 2 in example 1, using compound 4-5 instead of compound 1-1. The crude product was used directly in the next step.

Step 7: Preparation of 2-bromo-6-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1yl)methyl)benzo^]oxazol-2-yl)benzonitrile

This compound was prepared using procedures similar to those described for Step 3 in Example 1, using compound 4-6 instead of compound 1-2 and using 3,3dimethylazetidine instead of (1S,2R)-2-aminocyclopentan-1-ol . The crude product was further purified using a silica gel column (PE/EA) to obtain the title compound (290 mg).

Step 8: preparation of methyl-((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2-yl )-2-methyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)L-prolinate

This compound was prepared using procedures similar to those described for step 1 in example 1, using compound 4-7 instead of compound a-6. The crude product was further purified using a silica gel column to give the title compound.

Step 9: preparation of ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2-yl)- 2-methyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)^proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 4-8 instead of compound 1-4. The mixture was concentrated under reduced pressure to give the title compound. LC-MS (m/z): 784.3 (M+H)+.

Connections table 1 was prepared similarly to the compounds of Examples 1-4 using other starting materials and suitable reagents.

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Table 1

No. Etc. Chemical name Structure Phys. data (MS) (Μ+Η) ⁺ 5 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(pyrrolidin1 -ylmethyl)-benzo[s!]oxazol-2yl)-2,2'-dimethyl-[1,1 ' -biphenyl]-3 yl)benzo[c1]oxazol-5-yl)methyl)L-proline 2 ⁵ °Х I 759.3 6 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(pyrrolidin1 -ylmethyl)-benzo[c!]oxazol-2yl)-2'-fluoro-2-methyl-[ 1, Hbiphenyl]-3-yl)-benzo[s!]oxazol- 5 - yl)methyl)-L-prole and n _ν haya / W” o ^F thx F^F 763.3 7 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((2hydroxyethyl)amino)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1 '-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ·χ : O 749.3 8 ((2-(3'-(5-(azetidin-1-ylmethyl)-6(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl] - 3 -yl)-6(difluoromethoxy)beiso[0]oxazol5 -yl)methyl)-E-proline :> th . 744.3 9 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 fluoroazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 -yl)benzo[(1]oxazol-5-yl)methyl)-Eproline xs^ya / SX Υ 763.3 10 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 fluoropyrrolidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 -yl)benzo[c1]oxazol-5-yl)methyl)-E- ΪΓ ο I 777.3

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proline AND ((2-(3'-(5-(((S)-2carbamoylpyrrolidin-1 -yl)methyl)-b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol5 -yl)methyl)-L-prole and n Λ I 802.3 12 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((8)-2(hydroxymethyl)pyrrolidin-1 yl)methyl)benzo[c!]oxazol-2-yl) 2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline ^F 'Y' ^F S—/ / N 1 / \__/ I o N /TA o% F^F 789.3 13 ((6-(difluoromethoxy)-2-(3'-(6(difluoromethoxy)-5(morpholinomethyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl] -3 -yl)benzo[c1]oxazol-5-yl)methyl)-Eproline ^F \^ ^F OXiW _z иИхУ \=/ F^F 775.3 14 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 hydroxypyrrolidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline O Os Ο^ζ A Os o I 775.3

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15 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5((methylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1 ' -biphenyl]-3 -yl)benzo[0]oxazol-5-yl)methyl)-bproline °V ^OH Ouchtso 719.2 16 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5((dimethylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1 ' -biphenyl]-3 -yl)benzo[0]oxazol-5-yl)methyl)-bproline G Z. o xOO 00^ o^z L o t 733.3 17 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((2hydroxyethyl)(methyl)amino)methyl)benzo[c!]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline θ^ί^,Ο /=\ /—\ tG \ / \ [ \ he ΛΆ/ ι ^Ν & ηο^ ^Νχ cmХХ \=/ o-^^o F^F 763.3 18 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((3K,4K)-3,4difluoropyrrolidin-1-yl)methyl)benzo[c!]oxazol-2- yl)-2,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline G Υλ_1 \ / V .on ΛΆ-/ J ^N 0 F ^s F 1 FF 795.3 19 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((((8)-5oxopyrrolidin-2yl)methyl)amino)methyl)- /=\G-\ ⁿ 802.3

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benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)benzo[0]oxazol-5-yl)methyl)-bproline 20 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 hydroxyazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 -yl)benzo[s!]oxazol-5-yl)methyl)-Eprolin _v AT ^o u_AD / ^- \.° ⁿ G / \__/ 1 o F W he A FF 761.3 21 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5((ethylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1 ' -biphenyl]-3 -yl)benzo[c!]oxazol-5-yl)methyl)-Eprolin ^F \^ ^{F Oh} ADg°\ AD Υ\^οη | / \__/ J o _r ^NH ΑΑΤι 1 \=/ F^F 733.3 22 ((6-(difluoromethoxy)-2-(3 '-(6(d fluoromethoxy)-5-(((3,3,3 trifluoro-2-hydroxypropyl)amino)methyl)benzo[c1]oxazol-2yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline ^F X]/ ^F Χΐ№ _ζ ον- < ^NH ^OH FF^F 817.2 23 ((6-(difluoromethoxy)-2-(3'-(6(d iforomethox and)-5 -((3,4dimethylpiperazin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2 ,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline ^r d ^r G T \__/ \ / \ ,oh LD/ j ⁿ o । A 802.3

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24 ((2-(3 '-(5 -(aminomethyl)-b(difluoromethoxy)benzo[c!]oxazol2-yl)-2,2'-dimethyl-[1,G-biphenyl]3-yl)-6- (difluoromethoxy)benzo[c!]oxazol5 -yl)methyl)-b-proline _ν Ld_/ ι ^Ν & ^ΝΗ = ΓΗ ^ν 1Π 705.2 25 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((((1 R,2 S)-2hydroxycyclopentyl)amino)methyl)benzo[0]oxazol-2-yl)- 2,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ₀ /=\ g-\ G V \_/ \ / \ mon ΛΆ/ ι ^Ν & x-A \=/ OH T F^F 789.3 26 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((((1 R,2 S)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo[c!]oxazol-2yl )-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)D-proline ^F ^ ^F O., x° ⁿ U-/ / NY 1 / \__/ 1 0 \=/ ΟΗ ϊ 803.3 27 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((((1 S,2R)-2hydroxycyclopentyl)amino)methyl)benzo[0]oxazol-2-yl)-2 ,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ^F y ^F /=\ gl τΓ \__/ \ / \ he but ' / WJ ^N 0 >Y ^NH M-J'YY F^F 789.3 28 ((6-(difluoromethoxy)-2-(3'-(6(d fluoromethoxy)-5 -((oxetan-3 ylamino)methyl)benzo[c!]oxazol2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]3-yl)benzo[c1]oxazol-5- ^F 'v ^F °^^-0 /=\ π ΊΓ \ / \ / \ ΌΗ Γ^ ^Ν ΛΛ/ JO o~J \=/ ъ-ААе F^F 761.3

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yl)methyl)-b-proline 29 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((((K)tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[c!]oxazol-2yl) -2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline / ^ΝΗ ό 789.3 thirty ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((methyl(((K)tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[c!]oxazol-2yl )-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ό X 803.3 31 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((8)-2(hydroxymethyl)azetidin-1 yl)methyl)benzo[0]oxazol-2-yl)2 ,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ^F ^/ ^F Xiw 9ϊ ^Η x/ \=/ oT^ _o F^F 775.3 32 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((2(methylsulfonyl)ethyl)amino)methyl)benzo[0]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline Ο=ω=ο ^оЧ о I 811.2

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33 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 (dimethylamino)azetidin-1 yl)methyl)benzo[0]oxazol-2-yl)2,2'- dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline o^\ o X 788.3 34 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline °v° ^H 773.3 35 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((K)-2(hydroxymethyl)azetidin-1 -yl)methyl)benzo[0]oxazol-2-yl) -2,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline ,°ν« " ^:ιχό 775.3 36 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline pi Voh 759.3 37 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2-hydroxy2-methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2, 2'- 775.3

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dimethyl-[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline 38 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2methylpyrrolidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline OchHHsO V™ ^ХХХ0 F^F 773.3 39 ((2-(3'-(5-((6-oxa-1azaspiro[3.3]heptan-1 -yl)methyl)b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol5 -yl)methyl)-L-prole and n Q v ^oh ° ³ 787.3 40 ((2-(3'-(5-((2-amino-2methylazetidin-1 -yl)methyl)-6(difluoromethoxy)benzo[(1]oxazol2-yl)-2,2'-dimethyl-[1, G-biphenyl]3-yl)-6(difluoromethoxy)benzo[(1]oxazol- 5-yl)methyl)-L-prole and n Η ₂ Ν-Ρ ^Ν ^θ^^ ^>- 4^ , V° ^H 774.3 41 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 (methylsulfonyl)azetidin-1 yl)methyl)benzo[c!]oxazol-2-yl)2,2' -dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline ω=ο У ζ. ο /00 00^ Ο^ζ -Α ο I 823.2

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42 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((K)-2ethylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline /=\ g~\ η \__/ \ / \ he Ld_/ J ^N o l,,/ XZ \=/ o-Ch>x _o F^F 773.3 43 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 methoxyazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 -yl)benzo[s!]oxazol-5-yl)methyl)-Eprolin ^F Y ^F /=\ /—\ K p \__/ \ / \ on LD_/ JO F wxH .o X FF 775.3 44 ((6-(difluoromethoxy)-2-(3 '-(6(d fluoromethoxy)-5 -((3 -hydroxy3 -methyl azetide in-1 -yl)methyl)benzo[s!]oxazol-2-yl)- 2,2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)-Eproline ^F ^ ^F /=x GL K V \ / \ / \ he LD/ J o $ QHiX Н° ^x 1 FF 775.3 45 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 ((methylamino)methyl)azetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)2, 2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline °у ^;гч у ⁰ \ / ⁼ \ Г~V/° ^H 0 cX ^N iX Y ⁴⁼⁷ HIT f^F 788.3 46 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 oxoazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'- F <? σϋΧ o X F F 759.2

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dimethyl-[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline 47 ((2-(3'-(5-((2-oxa-6azaspiro[3.3]heptan-6-yl)-methyl)b-(difluoromethoxy)benzo[s!]oxazol-2-yl)-2,2 'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol5 -yl)methyl)-L-prole and n F ₀ /=\ GL g \ / \ 1 V _U he Ld_/ ι ^Ν & 0 SIGU V ° A ⁰ F^F 787.3 48 ((2-(3'-(5 -((2-azaspiro[3.3 ] heptan2-yl)methyl)-6-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[ 1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol- 5-yl)methyl)-L-prole and n 1 ,th 'σ/o I 785.3 49 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)benzo[c!]oxazol-2-yl) -2,2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-Eprolin F ^f4 o^^o /=\ GL rn \ / \ I \ mon r^ ^N ΛΛ/ JO NA 8 ^L4 A 799.3 50 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5((hexahydropyrrolo[3,4c]pyrrol-2(1H)-yl)methyl)benzo[c!]oxazol-2-yl )-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)benzo[c1]oxazol-5-yl)methyl)-Eproline F °'A''tg' ^o y_AA AAz ^0H [ / \__/ J o 8 NFF H 800.3

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51 ((2-(3'-(5-((2,7- diazaspiro[3.5]nonan-2-yl)methyl)-b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3-yl)- 6(difluoromethoxy)benzo[c1]oxazole- 5-yl)methyl)-L-prole and n F /=\π G n \__/ \ 1 V .on '/W Jo δ n 814.3 52 ((6-(difluoromethoxy)-2-(3'-(6(d fluoromethoxy)-5 -(((3 (propylamino)propyl)amino)methyl)benzo[c!]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline ζ—/ s -8 d 2® o I 804.3 53 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((methyl(3(propylamino)propyl)amino)methyl)benzo[c!]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline k /=\ /—1 HN , N Vn _x ' ⁰ \=/ 818.4 54 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2,2dioxido-2-thia-6azaspiro[3.3]heptan-6-yl)methyl)benzo[c!]oxazole -2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline °Xi№, W about chxY <*>°A A ρΆ 0 0 835.2 55 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((tetrahydro1H-furo[3,4-c]pyrrole-5(3H)- 8.r U o z 801.3

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yl)methyl)benzo[s!]oxazol-2-yl)2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[s!]oxazol-5-yl)methyl)L-proline 56 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline About g/ Λ ' I 759.3 57 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)- 5 -((((1 R,2R)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo[c1]oxazol-2yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[(1]oxazol-5-yl)methyl)L-proline /=\ π g Υ \ / \ / \ he Γη ^ν ϊΎ Ъ и Ϊ FF 803.3 58 ((6-(difluoromethoxy)-2-(3 '-(6(d iforomethox and)-5 -(((3 -((2hydroxyethyl)amino)propyl)amino)methyl)benzo[c1]oxazol-2yl) -2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline V _o _ %-on O-<X3C ⁿ 0 F^F 806.3 59 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((2(dimethylamino)ethyl)(methyl)amino)methyl)benzo[c1]oxazol-2yl)-2,2 '-dimethyl-[1,1 '-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline G - m S 790.3

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60 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline %°n 759.3 61 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 methylpyrrolidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline Y , °V ^OH SHOUE 773.3 62 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((2,2dimethylpyrrolidin-1 -yl)methyl)benzo[0]oxazol-2-yl)-2,2'dimethyl -[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline 787.3 63 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(((8)-2(methoxymethyl)pyrrolidin-1 yl)methyl)benzo[0]oxazol-2-yl)2 ,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[0]oxazol-5-yl)methyl)L-proline °v-° ^H 803.3 64 ((6-(difluoromethoxy)-2-(3'-(6- (difluoromethoxy)-5-(((((8)tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[c!]oxazol-2- , Voh 789.3

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yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline 65 ((2-(2'-cyano-3'-(6(difluoromethoxy)-5-(pyrrolidin1 -ylmethyl)-benzo[c!]oxazol-2yl)-2-methyl-[1,1'-biphenyl]- 3 -yl)b-(difluoromethoxy)benzo[c!]oxazol-5-yl)methyl)proline Ah y L l 2° ^ν Ό 770.3 66 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-(pyrrolidin1 -ylmethyl)-benzo[s!]oxazol-2yl)-2,2'-dimethyl-[1,1 ' -biphenyl]-3 yl)-benzo[(1]oxazol-5-yl)methyl)D-proline ίΑν-Μ 7 /° ^Vz j 759.3 67 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5-((3,3dimethylpyrrolidin-1 -yl)methyl)benzo[0]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline a ⁰ \=/ 787.3 68 ((2-(3 '-(5 -((3 -(d etylamino)azetidin-1 -yl)methyl)-6(difluoromethoxy)benzo[s!]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol- 5-yl)methyl)-L-prole and n XkW _z W a 816.3

- 46 047234

69 ((6-(difluoromethoxy)-2-(3'-(6- (d fluoromethoxy)-5 -((3 -(2hydroxypropan-2-yl)azetidin-1 yl)methyl)benzo[c!]oxazol-2-yl)2,2'-dimethyl-[1,1'-biphenyl ]-3 yl)benzo[s!]oxazol-5-yl)methyl)- L-proline I O g g ² I 803.3 70 ((6-(difluoromethoxy)-2-(3'-(6(d fluoromethoxy)-5 -((2,5-d ihydro1H-pyrrol-1-yl)-methyl)benzo[c!]oxazol-2- yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)benzo[0]oxazol-5-yl)methyl)-bproline 0 . G -,I About t 757.3 71 ((2-(3'-(5-((2- azabicyclo[2.1.1]hexan-2yl)methyl)-b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3-yl)- 6(difluoromethoxy)benzo[c1]oxazol5 - yl)methyl)-L-prole and n F^F ΖΖ71 Ίτ ιΓλ ( \ L b ^he / \ / J o O-nXX \—f F^F 771.3 72 ((2-(3'-(5-(((1s,4s)-7azabicyclo[2.2.1] heptan-7yl)methyl)-b-(difluoromethoxy)benzo[s!]oxazol-2-yl)-2 ,2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[(1]oxazol5 -yl)methyl)-L-prole and n V° U. : Q X, 0° Ύ I 785.3 73 ((2-(3 '-(5 -((((3,3-difluoro-1 (hydroxymethyl)cyclobutyl)methyl)amino)methyl)-6(difluoromethoxy)benzo[c1]oxazol- about Ap about I 839.3

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2-yl)-2,2'-dimethyl-[1,G-biphenyl]3-yl)-6(difluoromethoxy)benzo[c!]oxazol- 5-yl)methyl)-L-prole and n 74 ((2-(3'-(5-((5-azaspiro[2.3]hexan5-yl)methyl)-6-(difluoro methox and)benzo[c!]oxazol-2-yl)-2,2'dimethyl - [1,1 '-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[c!]oxazol5 -yl)methyl)-L-prole and n fish soup?. οχ- § "And 771.3 75 ((6-(difluoromethoxy)-2-(3'-(6(d fluoromethoxy)-5 -((3-oxo-6azabicyclo[3.2.1]octan-6yl)methyl)benzo[c!]oxazol-2- yl)2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline S d ^υ / o-A o 813.3 76 ((2-(3 '-(5 -((1,1 -difluoro-5 azaspiro[2.3] hexan-5 -yl)methyl)b-(difluoromethoxy)benzo[s!]oxazol-2-yl)-2 ,2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c!]oxazol- 5-yl)methyl)-L-prole and n About ί 807.3 77 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 (hydroxymethyl)-3 methylpyrrolidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)- 2,2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline c } .¾ ^g 9- I 803.3

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78 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 (hydroxymethyl)-3 methylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)- 2,2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[c1]oxazol-5-yl)methyl)-Eproline G Z-.O /OO Λ Oh 789.3 79 ((2-(3 '-(5 -((3 -cyano-3 methylazetidin-1 -yl)methyl)-6(difluoromethoxy)benzo[c1]oxazol2-yl)-2,2'-dimethyl-[1, G-biphenyl]3-yl)-6- (difluoromethoxy)benzo[c1]oxazol5 - yl)methyl)-L-prole and n ^ΗθΛ ° 784.3 80 ((2-(3'-(5 -((3-cyanoazetidin-1 yl)methyl)-b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1 '-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[c!]oxazol5 - yl)methyl)-L-prole and n g 8 Λ σ·χ° o X 770.3 81 ((6-(difluoromethoxy)-2-(3 '-(6(difluoromethoxy)-5 -((3 methyleneazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl -[1,1 '-biphenyl]-3 -yl)benzo[c1]oxazol-5-yl)methyl)-Eproline /~~1 °W°\ /=\ butA _o F^F 757.3 82 ((2-(3'-(5-((3- (cyanomethylene)azetidin-1 yl)methyl)-b-(difluoromethoxy)benzo[c!]oxazol-2-yl)-2,2'- 8 uYa -η 782.3

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dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol- 5-yl)methyl)-L-prole and n 83 ((2-(2,2'-dicyano-3'-(6(difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)-[ 1, Gbiphenyl ] -3 -yl)-6(difluoromethoxy)benzo[s!]oxazol- 5-yl)methyl)-L-prole and n ·' About t 795.3 85 (R)-1 -((6-(d fluoromethoxy)-2-(3 (6-(difluoromethoxy)-5-((3,3- dimethylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl)-2,2'- dimethyl-[1,1 '-biphenyl]-3 -yl)benzo[c!]oxazol-5-yl)methyl)- pyrrolidine-3-carbonic acid O F /-νΥΎη v\ A ^{N 1} ΓήΥ y. _F F 773.3 86 (S)-1 -((6-(difluoromethoxy)-2-(3 (6-(difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c!]oxazol-2-yl) -2,2'dimethyl-[1,1'-biphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid 0 vx >=Λ ^Ν I Γ: X _F ^F 773.3 87 ((2-(2'-cyano-3'-(6- (difluoromethoxy)-5-((3,3dimethylazetidin-1 -yl)methyl)benzo[c1]oxazol-2-yl)-2-methyl[1,1 '-biphenyl]-3 -yl)-6(difluoromethoxy) benzo[c1]oxazole- ^F ^ ^FAA ? ⁿ °Le \=/ ιΑΑο F^F 784.3 5 -yl)methyl)-E)-proline 317 ((2-(3 '-(6-(d fluoromethoxy)-5 (pyrrolidin-1 -ylmethyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1 '-biphenyl] -3 -yl)benzo[c1]oxazol-5-yl)methyl)-Eproline o>-0 h A 693.3

Example 100: Synthesis of compound 100.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-7(trifluoromethyl)benzo^]oxazol-2-yl)-[1,G -biphenyl]-3-yl)benzo^]oxazol-5-yl)-methyl)^-proline

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Connection 100

Step 1: preparation of 4-hydroxy-3-nitro-5-(trifluoromethyl)benzaldehyde

4-Hydroxy-3-(trifluoromethyl)benzaldehyde (1 g) was dissolved in concentrated H2SO4 (10 ml). After cooling the mixture to 5°C (ice bath), concentrated HNO3 (65%) (612 mg) was added dropwise and the mixture was stirred for another 30 minutes. After almost complete consumption of the starting material and stopping the reaction, the mixture was poured into ice water (30 ml) and purified by filtration. The result was compound 100-2 (1 g).

Step 2: Preparation of 2-nitro-4-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)-phenol

A mixture of compound 100-2 (500 mg), pyrrolidine (454 mg), CH ₃ COOH (255 mg) in 1,4-dioxane (10 ml) was stirred for 30 min at 30°C, then sodium triacetoxyborohydride (1, 35 g) and continued stirring. After almost complete consumption of the starting material and stopping the reaction, this reaction solution was poured into H ₂ O (30 ml), extracted with DCM (15 ml) three times, brine and dried using anhydrous Na ₂ SO ₄ . The precipitate was filtered off and dried in vacuum. The crude product was further purified using a silica gel column (DCM/MeOH 20:1) to give compound 100-3 (420 mg).

Step 3: Preparation of 2-amino-4-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)-phenol

A mixture of compound 100-3 (420 mg) and 10% Pd(OH)/C (150 mg) in methanol (10 ml) was stirred under a pressure of 1.1 atm of hydrogen at room temperature for 3 hours. The catalyst was then removed by filtration, the solid residue was washed with methanol (300 ml) and the solvent was removed in vacuo. The result was 300 mg of compound 100-4.

Step 4: Preparation of 2-(3-bromo-2-methyl-phenyl)-5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1,3benzoxazole

This compound was prepared using procedures similar to those described for step 3 in Example A, using compound 100-4 instead of compound a-3. The crude product was used directly in the next step.

Step 5: Preparation of methyl-(2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidin-1ylmethyl)-7-(trifluoromethyl) -1,3-benzoxazol-2-w]phenyl]-phenyl]-1,3-benzoxazol-5yl]methyl]pyrrolidine-2-carboxylate

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Intermediate A (345.72 mg), compound 100-5 (280 mg), 1,1'bis(diphenylphosphino)ferrocenepalladium(P) dichloride (53 mg) and potassium carbonate (88.10 mg), dissolved in 1, 4dioxane (8 ml) and H ₂ O (2 ml), stirred for 12 hours at 80°C in an N2 atmosphere. The reaction solution was poured into H ₂ O (30 ml) and extracted with DCM (15 ml) three times. The organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. This crude product was further purified using a silica gel column to obtain compound 100-6 (300 mg).

Step 6: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidin-1ylmethyl)-7-(trifluoromethyl)-1 ,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5yl]methyl]pyrrolidine-2-carboxylic acid (compound 100)

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 100-6 instead of compound 1-4. The precipitate was filtered off and dried in vacuum. The result was (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)-1 ,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5yl]methyl]-pyrrolidine-2-carboxylic acid (compound 100). LC-MS (m/z): 761.3 (M+H)+.

Example 101: Synthesis of compound 101.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-6(trifluoromethyl)benzo^]oxazol-2-yl)-[1,G -biphenyl]-3-b)benzo^]oxazol-5-yl)-methyl)-E-proline

Connection 101

Step 1: preparation of methyl 4-hydroxy-2-(trifluoromethyl)benzoate

To prepare methyl 4-hydroxy-2-(trifluoromethyl)benzoate, concentrated sulfuric acid (10 ml) was added dropwise to a solution of 4-hydroxy-2(trifluoromethyl)benzoic acid (18.0 g) in methanol (300 ml). The mixture was stirred at reflux for 12 hours. After cooling to room temperature, water (200 ml) was added to this reaction mixture, methanol was distilled off under reduced pressure, and the mixture was extracted twice with ethyl acetate (200 ml). The organic layer was washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound was obtained (18 g).

Step 2: Preparation of methyl 4-hydroxy-5-nitro-2-(trifluoromethyl)benzoate

This compound was prepared using procedures similar to those described for Step 1 in Example 100, using compound 101-1 instead of compound 100-1. Unrefined product

- 52 047234 was purified using silica gel column chromatography (hexane/ethyl acetate) to give the title compound.

Step 3: Preparation of methyl 5-amino-4-hydroxy-2-(trifluoromethyl)benzoate

This compound was prepared using procedures similar to those described for step 3 in Example 100, using compound 101-2 instead of compound 100-3. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 4: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(trifluoromethyl)-benzo^]oxazole-5carboxylate

This compound was prepared using procedures similar to those described for step 3 in Example A, using compound 101-3 instead of compound a-3. The crude product was suspended in methanol, filtered and dried in a vacuum oven. We obtained the compound indicated in the title.

Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-6-(trifluoromethyl)-benzo^]oxazol-5-yl)methanol

101-4 101-5

This compound was prepared using a procedure similar to that described for step 5 in Example A, using compound 101-4 instead of compound a-5. The filtrate was concentrated under reduced pressure to give the title compound.

Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(chloromethyl)-6-(trifluoromethyl)benzo^]oxazole

This compound was prepared using a procedure similar to that of Application 202192030 73 The refined description of the invention is described for step 2 in example 1, using compound 1015 instead of compound 1-1. The crude product was used directly in the next step.

Step 7: Preparation of 2-(3-bromo-2-methylphenyl)-5-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)benzo^oxazole

This compound was prepared using a procedure similar to that described for Step 3 in Example 1, using compound 101-6 instead of compound 1-2 and using pyrrolidine instead of (1S,2R)-2-aminocyclopentan-1-ol. The crude product was further purified using a silica gel column (PE/EA) to obtain the title compound.

Step 8: preparation of methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-6(trifluoromethyl)benzo^]oxazol-2-yl )-[1,G-biphenyl]-3-yl) benzo^]oxazol-5-yl) methyl)-L-prolinate

F _y F

This compound was prepared using a procedure similar to that described for Step 1 in Example 1, using compound 101-7 instead of compound a-6. The crude product was further purified using a silica gel column to give the title compound.

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Step 9: preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-6(trifluoromethyl)benzo^]oxazol-2-yl)- [1,G-biphenyl]-3-yl)-benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 101-8 instead of compound 1-4. The mixture was concentrated under reduced pressure to give the title compound. LC-MS (m/z): 761.3 (M+H)+.

Example 102: Synthesis of compound 102.

((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl )-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)-E-proline

Connection 102

Step 1: Preparation of methyl 2,3-difluoro-4-hydroxy-5-nitrobenzoate

This compound was prepared using procedures similar to those described for Step 1 in Example A, using methyl 2,3-difluoro-4-hydroxybenzoate instead of compound a-1. The crude product was purified using silica gel column chromatography (hexane/ethyl acetate) to give the title compound.

Step 2: Preparation of methyl 5-amino-2,3-difluoro-4-hydroxybenzoate

This compound was prepared using procedures similar to those described for step 2 in Example A, using compound 102-1 instead of compound a-2. The filtrate was concentrated under reduced pressure to give the title compound.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6,7-difluorobenzo^]oxazole-5-carboxylate

This compound was prepared using procedures similar to those described for step 3 in Example A, using compound 102-2 instead of compound a-3. The crude product was dissolved in methanol, filtered and dried in a vacuum oven. We received the connection specified in the header.

Step 4: Preparation of (2-(3-bromo-2-methylphenyl)-6,7-difluorobenzo^]oxazol-5-yl)methanol

This compound was prepared using procedures similar to those described for step 5 in Example A, using compound 102-3 instead of compound a-5. The filtrate was concentrated under reduced pressure to give the title compound.

Step 5: obtaining methyl-((2-(3'-(6,7-difluoro-5-(hydroxymethyl)-benzo^]oxazol-2-yl)-2,2'-54 047234 dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)^-prolinate

This compound was prepared using procedures similar to those described for step 1 in example 1, using compound 102-4 instead of compound a-6. The crude product was further purified using a silica gel column to give the title compound.

Step 6: preparation of methyl-((2-(3'-(5-(chloromethyl)-6,7-difluorobenzo^]oxazol-2-yl)-2,2'-dimethyl[1,G-biphenyl]-3 -yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)-methyl)^-prolinate

This compound was prepared using a procedure similar to that described for Step 2 in Example 1, using compound 102-5 instead of compound 1-1. The crude product was used directly in the next step.

Step 7: preparation of methyl-((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzo^]oxazol-2-yl)-2,2'dimethyl-[1,G -biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)^-prolinate

This compound was prepared using a procedure similar to that described for Step 3 in Example 1, using compound 102-6 instead of compound 1-2 and using pyrrolidine instead of (1R,2R)-2-aminocyclopentan-1-ol. The crude product was further purified using a silica gel column (PE/EA) to obtain the title compound.

Step 8: preparation of ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)-benzo^]oxazol-2-yl)-2,2'dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using a procedure similar to that described for step 5 in Example 1, using compound 102-7 instead of compound 1-4. The crude product was further purified using a silica gel column to obtain the title compound. LC-MS (m/z): 729.3 (M+H)+. ¹ H NMR (500 MHz, DMSO-d6) δ 8.21 (dd, J=7.9, 1.4 Hz, 1H), 8.19-8.14 (m, 2H), 8.08 (s, 1H), 7.82 (s, 1H), 7.62-7.54 (m, 2H), 7.51-7.44 (m, 2H), 7.40 (t, J=71.9 Hz, 1H), 4.58 (s, 2H), 4.36-4.20 (m, 2H) , 3.91 (s, 1H), 3.46 (s, ZN), 3.20-3.07 (m, 2H), 2.96 (s, 1H), 2.45 (d, J=4.0 Hz, 6H), 2.35-2.25 (m , 1H), 2.08-1.76 (m, 8H).

Example 103: Synthesis of compound 103.

((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G ]biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)^-proline

CN

Connection 103

Step 1: Preparation of methyl 3-cyano-4-hydroxy-5-nitrobenzoate

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This compound was prepared using procedures similar to those described for Step 1 in Example A, using methyl 3-cyano-4-hydroxybenzoate instead of compound a-1. The crude product was purified using silica gel column chromatography (hexane/ethyl acetate) to give the title compound.

Step 2: Preparation of methyl 3-amino-5-cyano-4-hydroxybenzoate

This compound was prepared using procedures similar to those described for step 2 in Example A, using compound 103-1 instead of compound a-2. The filtrate was concentrated under reduced pressure to give the title compound.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-7-cyanobenzo^]oxazole-5-carboxylate

This compound was prepared using procedures similar to those described for step 3 in Example A, using compound 103-2 instead of compound a-3. The crude product was further purified using a silica gel column to obtain the title compound.

Step 4: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-benzo^]oxazole-7-carbonitrile

This compound was prepared using procedures similar to those described for step 5 in Example A, using compound 103-3 instead of compound a-5. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 5: preparation of methyl-((2-(3'-(7-cyano-5-(hydroxymethyl)benzo^]oxazol-2-yl)-2,2'-dimethyl[1,G-biphenyl]-3- yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)-methyl)^-prolinate

This compound was prepared using procedures similar to those described for step 1 in example 1, using compound 103-4 instead of compound a-6. The crude product was further purified using a silica gel column to obtain the title compound.

Step 6: preparation of methyl-((2-(3'-(5-(chloromethyl)-7-cyanobenzo^]oxazol-2-yl)-2,2'-dimethyl-[1,Hbiphenyl]-3-yl) -6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)^-prolinate

This compound was prepared using a procedure similar to that described for Step 2 in Example 1, using compound 103-5 instead of compound 1-1. The crude product was used directly in the next step.

Step 7: preparation of methyl-((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2yl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)^-prolinate

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This compound was prepared using a procedure similar to that described for Step 3 in Example 1, using compound 103-6 instead of compound 1-2 and using 3,3dimethylazetidine instead of (1S,2R)-2-aminocyclopentan-1-ol . The crude product was further purified using a silica gel column (PE/EA) to give the title compound.

Step 8: preparation of ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2-yl)2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 103-7 instead of compound 1-4. The crude product was further purified using a silica gel column to obtain the title compound. LC-MS (m/z): 732.3 (M+H)+. ¹ H NMR (500 MHz, DMSO-d ₆ ) 8.20 (dd, J=7.9, 1.4 Hz, 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 8.09 ( s, 1H), 7.97 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.62-7.51 (m, 2H), 7.50-7.41 (m, 2H), 7.38 (t, J= 71.9 Hz, 1H), 3.96 (s, 2H), 3.75 (s, 2H), 3.36 (dd, J=9.1, 5.4 Hz, 1H), 3.07 (td, J=9.4, 8.4, 3.3 Hz, 1H), 2.99 (s,3H), 2.56 (q, J=8.5 Hz, 1H), 2.44 (d, 6H, J=2.5 Hz), 2.17-2.08 (m, 1H), 1.90-1.68 (m, 4H), 1.20 (s, 6H).

Connections table 2 was prepared similarly to the compounds of Examples 100-103 using different reaction starting materials and suitable reagents.

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table 2

No. Etc. Chemical name Structure Phys. data (MS) (M+N) ⁺ 88 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((3-methylpyrrolidin1-yl)methyl)-7-(trifluoromethyl)benzo[c1]oxazol-2-yl)- [1,1'biphenyl]-3-yl)benzo[b]oxazol-5 yl)methyl)-b-proline Du ° ъ X 775.3 89 ((2-(3'-(5-((2- azabicyclo[2.1. 1]hexan-2yl)methyl)-7-(trifluoromethyl)benzoU]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d ] oxazol-5 yl)methyl)-b-proline F^F °'^X ^o yD ⁼ \ M o A/C/ Ji CF ₃ 773.3 90 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((3-methylpyrrolidin1-yl)methyl)-7-(trifluoromethyl)bsnzo| d |oxazol-2-yl)- | 1,1 'biphenyl]-3-yl)benzo | d |oxazol-5 yl)methyl)-O-proline ^but O \=/vV CF ₃ 775.3 91 (ZK)-1-((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((3-methylpyrrolidin1-yl)methyl)-7(trifluoromethyl)benzo[b]oxazol- 2yl)-[1,1 '-biphenyl]-3 yl)benzo[b]oxazol-5 yl)methyl)pyrrolidine-3-carboxylic acid Huo 775.3

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92 (3 S)-1 -((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((3-methylpyrrolidin1-yl)methyl)-7(trifluoromethyl)benzo [s!] Oxazol-2yl)-[1,1'-biphenyl]-3 yl)benzo[c!]oxazol-5 yl)methyl)pyrrolidine-3-carboxylic acid OAl] \—' \=/ 'oAf θΧ CF ₃ OH 775.3 93 ((6-(difluoromethoxy)-2-(3'-(5-((3,3dimethylazetidin-1 -yl)methyl)-7 (trifluoromethyl)-benzo[c1]oxazol-2yl)-2,2'-dimethyl - [1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline An o W . N kA AOyy ^ho A CF ₃ 775.3 94 ((2-(3 '-(5 -(azetidin-1 -ylmethyl)-7methylbenzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1 '-biphenyl]-3 -yl)- 6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline On ^H Ko YuuTb WvK to F^F 693.3 95 ((6-(difluoromethoxy)-2-(3'-(7-fluoro-5(pyrrolidin-1 ylmestil)bsnzo[oxazol-2-yl)-2.2'd and methyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -and l)methyl l)-Lproline F Α1Γ°\ ΛΛ / \ he lA/ JO f^f 711.3 96 ((6-(difluoromethoxy)-2-(3'-(5((ethylamino)methyl)-6 fluorobnso[oxazol-2-yl)-2.2'd and methyl-[1,1'-biphenyl]-3 yl )benzo[d]oxazol-5 -and l)methyl l)-Lproline WUA ΛΛ OH / nA [ / \ / 1 0 r ^NH Ш1П 1 \=/ V4A _O F^F 685.3

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97 ((2-(3'-(6-chloro-5-((ethylamino)methyl)benzo[c!]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl] -3 - yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)ven)-E-proline γ η \ / \ / \ he UD/ to r ^NH F^F 701.2 312 ((6-(difluoromethoxy)-2-(3'-(5-((3,3dimethylazetidin-1yl)methyl)benzo|c1]oxazol-2-yl)-2,2'd imethyl-[1,1 '-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline UDgD AD / \,on 707.3 313 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((2-methylazetidin-1 yl)ven)-bsnzo[oxazol-2-yl)[1,1'-biphenyl ]-3yl)benzo[d]oxazol-5-and l)methyl l)-Lproline DDr°\ DD / \_ he dX*' /D/ Do \/ \=/ oAD _o F^F 693.3 104 ((6-(difluoromethoxy)-2-(3 '-(5 -((2hydroxy-2-methylazetidin-1 yl)venstyl)bsnzo[oxazol-2-yl)-2.2'd and methyl- [1,1 ' -biphenyl]-3 yl)benzo[d]oxazol-5 -and l)methyl l)-Lproline Uu°\ DD / \ he UD/ up to \/N)H \=/ 709.3 105 ((6-(difluoromethoxy)-2-(3 '-(5 -((2(hydroxymethyl)azetidin-1 yl)venstyl)bsnzoI|oxazol-2-yl)-2.2'd and methyl- [1,1 '- biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline DDG°\ UD / \ .on /D_u to \=UDe-D^ ₀ F^F 709.3 106 ((2-(3'-(5 -((6-oxa-1 azaspiro [3.3] heptan-1 -yl)methyl)benzo^]oxazol-2-yl)-2,2'dimethyl-[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 - yl)venge)-E-proline UDg°\ UD / \ .on Α^ ^Ν /4/ to < X O K 7—\ 11 l ΧΖ X/ \—/ o^xD^ 721.3

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107 ((2-(3'-(5 -((1-azaspiro[3,3]heptan-1 yl)-methyl)benzo[b]oxazol-2-yl)2,2'-dimethyl-[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-0-proline Х%г°\ / \ / \ he ΛΆ/ J ^N about spirit (ΗΪ1 719.3 108 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-(pyrrolidin-1 ylmstil)bsnzo| d |oxazol-2-yl)-| 1,1'biphenyl] -3 - yl)-benzo[d]oxazol-5 yl)methyl)-0-proline U ' 00 O 693.3 109 ((6-(difluoromethoxy)-2-(3'-(6-((3,3dimethylazetidin-1yl)methyl)benzo[b]oxazol-2-yl)-2,2'd imethyl-[1,1 '-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline AXXND ^io ..." 707.3 BY ((2-(2'-chloro-3'-(6-((3,3- dimethylazetidin-1 yl)methyl)benzo[b]oxazol-2-yl)-2methyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)- L-proline 8 2 ² 0, ' 00 O 727.3 111 ((2-(2'-chloro-3'-(6-((3,3dimethylazetidin-1 yl)methyl)benzo[b]oxazol-2-yl)-2methyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-O-proline 2 ² < O 727.3 112 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-(pyrrolidin-1 ylmethyl)oxazolo[5,4-b] pyridin-2 yl)-[ 1,1 ' -biphenyl]-3 yl)benzo[d]oxazol-5 -and l)methyl l)-Lproline /=\ o but \ \—7 '—'' ^—f ° N 694.3

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113 ((6-(difluoromethoxy)-2-(3'-(6-((3,3dimethylazetidin-1 yl)methyl)oxazolo [5,4-b]pyridin-2 yl)-2,2'-dimethyl- [1,1 '-biphenyl]-3 yl)-benzo | d |oxazol-5-yl) revenge)-Lproline o ⁿ⁰ \__/ \=/>Α '-V 708.3 114 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-(((R)-3 methylpyrrolidin-1 -yl)methyl)oxazolo [5,4-b]pyr idin-2 yl)-[1,1'-biphenyl]-3-yl)benzo[s!]oxazol-5-yl)venstyl)-Lproline ..... i \-=/ ST N 01-AO 708.3 115 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-((((5-oxopyrrolidin2-yl)methyl)amino)methyl)oxazolo[5,4b]pyridin-2-yl )-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline 1\-~7 ⁴ (jN he^o 737.3 116 ((6-(difluoromethoxy)-2-(3 '-(6-((3 (dimethylamino)azetidin-1 -yl)methyl)oxazolo [5,4-b]pyr idin-2 yl)-2,2' -dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -and l)methyl l)-Lproline \ Z—' ό ь Λ/g-2 O ' CM ABOUT 723.3 117 ((2-(3 '-(6,7-difluoro-5 -(pyrrolidin1 -ylmethyl)-benzo | d |oxazol-2-yl)2'-methoxy-2-methyl-[ 1, G-biphenyl] 3 -yl)-b-(difluoromethoxy)- benzo | d |oxazol-5-yl )venstyl)-Lproline g about U A 745.3

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118 ((2-(2'-cyano-3'-(6,7-difluoro-5 (pyrrolidin-1-ylmethyl) benzo[c1]oxazol-2-yl)-2-methyl-[1, Gbiphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline °*™ OCHHH'S F 740.2 119 ((2-(3 '-(6-((6-cyanopyrid in-3 yl)methoxy)-5-(((2hydroxyethyl)amino)methyl)benzo[b]oxazol-2-yl)-2,2 '-dimethyl[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ‘7, O Z 815.3 120 ((2-(3 '-(6-((5 -cyanopyridin-3 yl)methoxy)-5-(((2hydroxyethyl)amino)methyl)benzo[b]oxazol-2-yl)-2,2'- dimethyl[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN /=\ ^h v ₀ VyU у/ 815.3 121 ((6-(difluoromethoxy)-2-(3 '-(5 -(((2hydroxyethyl)amino)methyl)-6-((5(methylsulfonyl)pyridin-3 yl)methoxy)benzo[b]oxazole-2 -yl)2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -and l)methyl l)-Lproline ζ. O 00^ A. ' C·-/ o 868.3 122 ((6-(difluoromethoxy)-2-(3'-(5((ethylamino)methyl)-6-((5(methylsulfonyl)pyridin-3 yl)methoxy)benzo[b]oxazol-2-yl)2 ,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline 8 852.3

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123 ((6-(difluoromethoxy)-2-(3'-(5((dimethylamino)methyl)-6-((5 (methylsulfonyl)pyridin-3 yl)methoxy)benzo[c1]oxazol-2-yl)2 ,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline z—\ O , / A—ώ=ο ^Χ ζ- }=/ 1 И >Я. ' S A O 852.3 124 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((methyl amino) methyl) - 6 -((3 - (methyl lsu l fonyl) benzyl)oxy)benzo| c1]oxazol-2-yl)[1,1 '-biphenyl]-3 -yl)benzo | d |oxazol-5-yl)ven)-L- proline o 00 . G z^o CJ^Z । /=\ Ο=ω—<\ /> ^x II V U O ^λ ' 837.3 125 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((methyl amino) methyl) - 6 -((4 - (methyl lsu l fonyl) bsnzyl)oxy)bsnzo| b|oxazol-2-yl)[1,1 '-biphenyl]-3-yl)benzo | d |oxazol-5-yl)ven)-Lproline 00. A Os o^z . «A C ¹ ' ^.w=o 837.3 126 ((6-(difluoromethoxy)-2-(3'-(5- ((dimethylamino)methyl)-6-((4(methylsulfonyl)benzyl)oxy)bsnzo|4|oxazol-2-yl)-2.2'-dimstil[1,1'-biphenyl]-3-yl)benzo | d |oxazol-5-yl )ventil)-L- proline R G oh oh X 851.3 127 ((2-(3'-(7-cyano-5-(pyrrolidin-1ylmstil)bsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1'-biphenyl]-3 -yl)-6 (difluoromethoxy)-benzo[d]oxazol-5 yl)venstyl)-E-proline V0 kDs/S? °>° ⁿ ill O-eTTTSL n \_/ 0-0 Ox ou '—f 718.3

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128 ((2-(2-cyano-3'-(6-(difluoromethoxy)5 -((3,3-dimethylazetidin-1 yl)methyl)-benzo[b]oxazol-2-yl)-2'methyl-[ 1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline F\^F gt Vr°\ /=\ X V but-% / Η-νΤΎ ¹ F^F 784.3 129 ((2-(3'-(7-cyano-5-((3 (hydroxymethyl)-3-methylazetidin1-yl)methyl)-benzo[b]oxazol-2-yl)2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline T ^0H , ArO / ho U JT o V 4===^ f ^/ ^ ^f 748.3 130 ((2-(3'-(7-cyano-5-(((8)-3methylpyrrolidin-1 yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1' -biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline N %-° ^H \\\ X \ ,o. / th , /—\ Χ/~ ^Ν / WA ,N—' l[ G O \ 732.3 131 ((2-(3 '-(7-cyano-5 -(((R)-3 methylpyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1, 1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline N %-° ^H \\\ X .....Cj ° A _f F 732.3 132 ((2-(3 '-(7-cyano-5 -(((R)-3 methylpyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1, 1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-O-proline NV ^H \\\ X ΓΛ >=/~ ^N / UCHA HGo ..... _f %f 732.3

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133 ((2-(3 '-(7-cyano-5 -(((3 -methyloxetan3 -yl)amino)-methyl)benzo[c!]oxazol2-yl)-2,2'-dimethyl-[1,1 '-biphenyl]-3 yl)-b-(difluoromethoxy)- benzo[c!]oxazol-5-yl[venger)-Lproline CN Ρχ°\ /=\ / \ he /X/ Jo F^T 734.3 134 ((2-(3'-(7-cyano-5-((3- (dimethylamino)azetidin-1 yl)methyl)benzo[c1]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)-benzo[d] Oxazol-5 yl)methyl)-E-proline ¹ X o Lu°y_/=\ ΛΛ,ΟΗ / \ / J o \=/ 747.3 135 ((2-(3'-(7-cyano-5 -((2-(2hydroxyethyl)piperidin-1yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-E-proline CN ho^^n <7 kJ 776.3 136 ((2-(3'-(7-cyano-5 (((cyanomethyl)(methyl)amino)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl ] -3 -yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-E-proline CN /=\ / \ .on \=/ ъ-ЧА ₀ F^F 717.3 137 ((2-(3'-(7-cyano-5-((3(hydroxymethyl)azetidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[ 1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 - yl)methyl)-E-proline CN rРг°\ / ⁼ \ Г~V ,° ^Н Y ⁴⁼⁷ ОН F^F 734.3

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138 ((2-(3 '-(7-cyano-5 -(((2-hydroxy-2methylπpoπyl)amino)methyl)benzo[c1]oxazol-2-yl)-2,2'-dimethyl[1,1 ' -biphenyl]-3 -yl)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN StG°\ / ⁼ \ / \ he Γ^ ^Ν LD_/ D O _r ^NH SiT'lGt Loh \—/ '„AD F^F 736.3 139 ((2-(3'-(7-cyano-5-((((5- oxopyrrolidin-2-yl)methyl)amino)methyl)benzo[b]oxazol-2-yl)2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[ d]oxazol-5 yl)methyl)-b-proline CN / ⁼ \ / \ he /D_U Do _g GmT1 f NH I H A 761.3 140 ((2-(3'-(7-cyano-5-((3,3dimethylazetidin-1 -yl)methyl)bsnzo|4|oxazol-2-yl)-2.2'-dimstil[1,1'-biphenyl] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-O-proline N 1' Al jmtV-O °> ^he 732.3 141 ((2-(3 '-(7-cyano-5 -((ethyl(2hydroxyethyl)amino)methyl)bsnzo|4|oxazol-2-yl)-2.2'-dimstil[1,1 '-biphenyl] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN / ⁼ \ / \ .OH r^ ^N /0/ but—zyCli '— oA^< _o 736.3 142 ((2-(3'-(7-cyano-5-((3cyanopyrrolidin-1 -yl)methyl)bsnzo|4|oxazol-2-yl)-2.2'-dimstyl[1,1'-biphenyl] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ^NC A HOUR ⁰ \=/ 743.3

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143 ((2-(3'-(7-cyano-5-((3cyanopyrrolidin-1 -yl)methyl)benzo[(1]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl ] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-O-proline NC A 0J) Qr H-nYY ⁰ \=/ 743.3 144 ((2-(3'-(7-cyano-5-((3-ethynyl-3 hydroxyazetidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1, 1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 - yl)methyl)-b-proline CN ⁿ h. Hell /=\ gl he 'U/ ⁰ ΟγΧΧ 744.3 145 ((2-(3'-(7-cyano-5-(pyrrolidin-1ylmstil)bsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1'-biphenyl]-3 -yl)-6 (difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-O-proline Hmm) X 718.3 146 ((2-(3'-(7-cyano-5-((7-oxo-2,6diazaspiro[3,4]octan-2yl)venstyl)bsnzo|4|oxazol-2-yl)-2.2'dimethyl- [1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline “Yj5xq _ζ YvcG 773.3 147 ((2-(3'-(5 -((bis( 1 -hydroxy-propan2-yl)amino)methyl)-7cyanobsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1'-biphenyl ] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline OH CN •ydiiXYQ . Vx° ^H 780.3 148 ((2-(3'-(7-cyano-5-((3morpholinoazetidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl] -3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline CN CA° ^H AV/ J ^N Y F^F 789.3

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149 ((2-(3'-(7-cyano-5-((3- (methyl(oxetan-3 -yl)amino)azetidin-1-yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)- 6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN Ρ ^Ν Ο-ΧΧΧ Od 789.3 150 ((2-(3 '-(7-cyano-5 -((3 -hydroxy-3 methyl-[1,3 '-biazetidine] -1 'yl)methyl)benzo[b]oxazol-2-yl)- 2,2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline \ CN no-ΥΛ 1 ^Vn va ίιΤθχΤ^ СХ/ ^0Н хВххУ ⁰ 789.3 151 ((2-(3'-(7-cyano-5-((6-oxo-2,5diazaspiro[3,4]octan-2-yl)methyl)benzo[b]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline % ^CN Xj5>O . TV HueU ⁰ \=/ 773.3 152 ((2-(3 '-(7-cyano-5-((3 - ((dimethyl amino)methyl)- pyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline CN ^Ν ί_/Ί CL/0H / \ / J 0 <2/ХХУ \=/ F^F 775.3 153 ((2-(3'-(7-cyano-5-((1,1-difluoro-5azaspiro[2,4]heptan-5-yl)methyl)benzo[b]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline CN φΩυ&λΟ / ^FF M-Xli F^F 780.3

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154 ((2-(3'-(7-cyano-5 -(((R)-3 (hydroxymethyl)pyrrolidin-1yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[ 1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)venstyl)-E-proline CN , OU- OYAH ° \=/ 748.3 155 ((2-(3 '-(7-cyano-5 -(((3 -hydroxycyclobutyl)amino)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1 '-biphenyl ] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN Yau- ⁰ -, /=\ / \ he jo ry ^NH (ΗΪΙ FT 734.3 156 ((2-(3'-(5-((3-amino-4methylpyrrolidin-1 -yl)methyl)-7cyanobsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1'-biphenyl] - 3 -yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)ven)-E-proline zC^·X ^s z. o x-CO o^z y_y o X 747.3 157 ((2-(3 '-(5 -(((azetidin-3 ylmethyl)amino)methyl)-7cyanobsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1 '-biphenyl] -3 - yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline I ^s ζτ I* I X 733.3 158 ((2-(3 '-(7-cyano-5-((3 - (dimethylamino)-4-methyl- pyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline X I u y_ u Yo? O X 775.3

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159 ((2-(3'-(7-cyano-5-((3- ((dimethyl amino) methyl)-3 methylazetidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6( difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline / CN , ϋύ ^{οη 0} \=/ 0-4^%^ 775.3 160 ((2-(3 '-(7-cyano-5 -((((1 -methyl- 1Nimidazo l-4 -i l) methyl) amino)methyl)benzo[b]oxazol-2-yl)2,2 '-dimethyl-[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol-5 yl)methyl)-b-proline I ZZ to® „ in about I 758.3 161 ((2-(3 '-(5 -((3 -(aminomethyl)-3 methylazetidin-1 -yl)methyl)-7cyanobsnzo|4|oxazol-2-yl)-2.2'dimethyl-[1,1 '- biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline CN Oiga ¹ °\=/ 747.3 162 ((2-(3'-(7-cyano-5-((3fluoropyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl] -3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline _F CN b jbcH> _z Ού ^οη Ойхь ° \=/ F^F 736.3 163 ((2-(3'-(7-cyano-5-((3fluoropyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl] -3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-O-proline _F CN b jtchQ , Q ύ ^οη Ойхь ⁰ F^F 736.3

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164 ((2-(3'-(7-cyano-5-((3,4- difluoropyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline _F CN Ayu, D* AU ⁰ 754.3 165 ((2-(3'-(7-cyano-5-(((K)-3cyanopyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline Ayu, Oh™ CHHx _o ⁰ 743.3 166 ((6-(difluoromethoxy)-2-(3 '-(5 -((3 fluoropyrrolidin-1 -yl)methyl)-7(trifluoromethyl)benzo[d]o xazol-2yl)-2,2'-dimethyl- [1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-and l)methyl l)-Lproline 1L Α and. J 779.3 167 ((2-(3'-(7-cyano-5-((3-fluoro-3- methylpyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline 1 ^CN α , A AU ⁰ 750.3 168 ((2-(3'-(7-cyano-5-(((K)-3- (fluoromethyl)pyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)-benzo[d ] oxazol-5 yl)methyl)-b-proline CN Ch'0Yu , ' U—U ⁰ (A D γ 750.3

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169 (R)-l-((2-(3'-(7-cyano-5- (pyrrolidin-1 -ylmethyl) benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)pyrrolidine-3-carboxylic acid OAHME 718.3 170 ((6-(difluoromethoxy)-2-(3'-(6-((3,3dimethylazetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2yl)-2,2'-dimethyl-[ 1,1 '-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)-Oproline _ν about DHDD/ 708.3 318 ((2-(3 '-(7-cyano-5 -((3,3dimethylazetidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1,1 '- biphenyl]-3-yl)benzo | d |oxazol-5-yl)venstyl)-Lproline CN D^U°\ /=D / \ OH J o < ^N > fVxT] 666.3 84 ((6-(difluoromethoxy)-2-(3'-(5-((3,4dimethylpyrrolidin-1 -yl)-methyl)-7(trifluoromethyl)-benzo[b]oxazol-2yl)-2,2'- dimethyl-[1,1'-biphenyl]-3 yl)-benzo | d |oxazol-5-yl) revenge)-Lproline b o I 789.3 259 (8)-1-((2-(3'-(7-cyano-5-(((8)-3- methylpyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)-benzo[d]oxazol- 5 yl)methyl)-pyrrolidine-3 - carboxylic acid ό O I 732.3

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((2-(3'-(5-(((8)-3-chloropyrrolidin-1yl)methyl)-7-cyanobenzo[b]oxazol2-yl)-2,2'-dimethyl-[1,1'- biphenyl]-3 yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ((2-(3'-(5 -((3-carbamoylpyrrolid in-1 -yl)methyl ) -7cyanobenzo[b]oxazol-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b -proline ((2-(3'-(7-cyano-5-((3-cyano-3methylpyrrolidin-1 -yl)methyl)benzo[b]oxazol-2-yl)-2,2'-dimethyl[1 ,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline

Example 171: Synthesis of compound 171.

^)-1-((8-((3'-(5-((^)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)-benzo^]oxazol-2-yl)2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthyridin-3-yl)-methyl)-2-methylpyrrolidine-2-carboxylic acid noos

soon

Connection 171

Step 1: Preparation of 8-chloro-3-vinyl-1,7-naphthyridine ci ।

Pd(dppf)CI ₂ , Na ₂ CO ₃

Vg toluene, EUN, NgO 171-1

Cl

171-2

To a solution of compound 171-1 (2.43 g) in toluene (30 ml) was added EtOH (10 ml), 10% Na ₂ CO ₃ aq. (10 ml) and Pd(dppf)Cl ₂ .DCM (420 mg) and then added dropwise 4,4,5,5-tetramethyl-2-vinyl-1,3,2dioxaborolane (3.1 g) under N2 protection . This mixture was left stirring at 100°C for 16 hours. The reaction mixture was quenched with H ₂ O (50 ml) and extracted with EtOAc three times. The organic layers were combined and washed with brine. The resulting solution was concentrated and purified over silica gel (eluting with hexane-EtOAc using a 8:1 to 5:1 gradient) to give 8-chloro-3-vinyl1,7-naphthyridine (1.1 g) as a brown solid.

Step 2: production of (8-chloro-1,7-naphthyridin-3-yl)methanol

To a solution of compound 171-2 (380 mg) in 1,4-dioxane (20 ml)/water (20 ml) was added K2OsO4 (4.0 mg) and stirred for 30 min at room temperature. NaIO ₄ (1.0 g) was added in small portions at the same temperature. After stirring for 3 hours, the reaction mixture was quenched with saturated Na ₂ S ₂ O ₃ solution and extracted with DCM (40 ml) three times. The organic layers were combined and dried over Na ₂ SO ₄ . The resulting solution was concentrated to give 8-chloro-1,7-naphthyridine-3-carbaldehyde.

The above 8-chloro-1,7-naphthyridine-3-carbaldehyde (320 mg) was dissolved in 20 ml MeOH and NaBH ₄ (200 mg) was added in one portion. The resulting mixture was stirred for 2 hours at room temperature, then quenched with water (30 ml). The mixture was extracted with DCM (20 ml) three times and the organic phases were dried over Na ₂ SO ₄ . The resulting solution was concentrated and purified over silica gel (eluting with DCM-EtOAc using a 1:1 to 1:2 gradient) to give (8-chloro-1,7naphthyridin-3-yl)methanol (240 mg) as a white solid .

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Step 3: Preparation of (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol

3-bromo-2-methylaniline (2.50 g), compound 171-3 (1.86 g), t-BuOH (15 ml) and HCl (4.0 M in 1,4-dioxane) were added to the microwave reaction vial , 3 ml). The vial was sealed and the reaction mixture was heated at 100°C for 4 hours in a microwave oven. The mixture was diluted with 20 ml water and then extracted with DCM (50 mlx2). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was concentrated and recrystallized in DCM:hexane (1:1) to give (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthyridin-3-yl)methanol (2.0 g) in as an off-white solid.

Step 4: preparation of methyl-((5-(difluoromethoxy)-2-(3'-((3-(hydroxymethyl)-1,7-naphthyridin-8yl)amino)-2,2'-dimethyl-[1,G -biphenyl]-3-yl)benzo^]oxazol-6-yl)-methyl)-E-prolinate

To a solution of compound 171-4 (0.69 g), intermediate A (1.5 g) in toluene (15 ml) was added EtOH (5 ml), 10% Na ₂ CO ₃ aq. (5 ml), Pd(dppf)Cl ₂ .DCM (78 mg) protected by N2. This mixture was left stirring at 110°C overnight. The reaction mixture was quenched with H ₂ O (20 ml) and extracted with EtOAc (50 ml) three times. The organic layers were combined and washed with brine. The resulting solution was concentrated and purified over silica gel (eluting with hexane-EtOAc using a 3:1 to 1:1 gradient) to give compound 171-5 (0.88 g) as a brown oil.

Step 5: preparation of methyl-^)-1-((8-((3'-(6-(difluoromethoxy)-5-((^)-2(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo^]oxazole -2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3yl)amino)-1,7-naphthyridin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylate

To a solution of compound 171-5 (250 mg) and TEA (100 mg) in DCM (5.0 ml) was added MsCl (89 mg) dropwise at 0°C. The reaction mixture was left stirring at room temperature for 4 hours. The resulting mixture was concentrated in vacuo and redissolved in THF (5 ml). To this solution were added methyl (N)-2-methylpyrrolidine-2-carboxylate (143 mg) and KI (1 mg), and then the reaction mixture was continued to stir at room temperature overnight until the above methanesulfonate was consumed. The residue was concentrated and purified directly on a reverse phase (RP) column (mobile phase: MeCN:water 10:90, with 0.1% HCl) to give compound 171-6 (105 mg) as an off-white solid.

Step 6: preparation of ^)-1-((8-((3'-(5-((^)-2-carboxypyrrolidin-1-yl)methyl)-6(difluoromethoxy)benzo^]oxazol-2-yl) -2,2'-dimethyl-[1,G-biphenyl]-3-yl)amino)-1,7-naphthyridin-3yl)methyl)-2-methylpyrrolidine-2-carboxylic acid

LiOH (40 mg) was added to a solution of compound 171-6 (105 mg) in a 1:1 THF/water mixture (4 mL). The resulting mixture was stirred for 24 hours at room temperature. The THF layer was separated and purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a gradient from 10:90 to 30:70) to give 78 mg ^)-1-((8-(( 3'-(5-((^)-2-carboxypyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl ]-3-yl)amino)-1,7-naphthyridin-3-yl)methyl)-2methylpyrrolidine-2-carboxylic acid (compound 171). LC-MS (m/z): 777.3 (M+H)+. ¹ H NMR (500 MHz, Methanol^4) δ 9.23 (d, 1H, J=2.1 Hz), 8.60 (d, 1H, J=2.0 Hz), 8.20 (dd, 1H, J=7, 9, 1.5 Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.69-7.63 (m, 2H), 7.57 (t, 1H, J=7.8 Hz), 7.53 (t, 1H , J=7.7 Hz), 7.46 (dd, 1H, J=7.6, 1.5 Hz), 7.38

- 75 047234 (dd, 1H, J=7.6, 1.4 Hz), 7.35 (d, 1H, J=6.9 Hz), 7.12 (t, 1H, JF _-H =72.6 Hz), 4.83 (d, 1H, J=13.2 Hz), 4.74 (d, 1H, J=13.3 Hz), 4.62 (d, 1H, J=13.2 Hz), 4.49 (d, lH, J= 13.2 ^),4.33(dd, 1H,J=9.6, 7.2 Hz), 3.66-3.62 (m, 1H), 3.523.37 (m, 3H), 2.63-2.56 (m, 1H) , 2.55 (s, 3H), 2.41-2.32 (m, 1H), 2.29-2.14 (m, 4H), 2.09 (s, 3H), 2.06-1.98 (m, 2H), 1.75 (s, 3H).

Connections table 3 was prepared analogously to Example 171 using different reaction starting materials and suitable reagents.

Table 3

No. Etc. Chemical name Structure Phys. data (MS) (M+H) ⁺ 172 ((2-(3'-((3 -(((carboxymethyl)amino)methyl)-1,7-naphthyridin-8yl)amino)-2,2'-dimethyl-[1, Gbiphenyl]-3-yl )-6(d fluoromethoxy)-benzo[d]oxazo l- 5-yl )venge)-L-prol in soon ΓΊ। n hPGH 4Λ* IV M soon 723.3 173 (S)-l-((8-((3'-(5-(((S)-2carboxypyrrolidin-1 -yl)methyl)-b-(difluoromethoxy)benzo[b]oxazol-2-yl)-2 ,2'dimethyl-[1,1'-biphenyl]-3 yl)amino)-1,7-naphthyr idine-3 and l)methyl l)piperide in-2 carboxylic acid coon ' b ₄ D I ХД ,!J coon 777.3 174 ((6-(difluoromethoxy)-2-(3'-((3-((3fluoropyrrolidin-1-yl)methyl)-1,7naphthyridin-8-yl)amino)-2,2' dimethyl-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-and l)methyl l)-Lproline A . n tPSchL-r Ch-rtf ' U V soon 737.3 175 ((6-(difluoromethoxy)-2-(3'-((3-((3hydroxypyrrolidin-1 -yl)methyl)1,7-naphthyridin-8-yl)amino)-2,2' dimethyl- [1, 1'-biphenyl]-3-yl)benzo[d]oxazol-5-and l)methyl l)-Lproline 1 R about ZE 735.3

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176 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-((3 -(morpholinomethyl)-1,7-naphthyridin-8yl)amino)-[1,1'-biphenyl]-3 yl )benzo[d]oxazol-5-yl)methyl)L-proline A . n f 0^05000^ i V V soon 735.3 177 ((2-(3'-((3 -(azetidin-1 -yl-methyl)1,7-naphthyridin-8-yl)-amino)-2,2'dimethyl-[1,1'-biphenyl] -3 -yl)-6(d fluoromethoxy)-benzo[d]oxazo l5 -and l)methyl)-proline HO 705.3 178 ((6-(difluoromethoxy)-2-(3'-((3-((3hydroxyazetidin-1 -yl)methyl)- 1,7-naphthyridin-8-yl)amino)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline ' / H _N =\ f \ If y-4 U Ni N^COOH _N « y-' ll y__J OH 721.3 179 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-((3 -((((5 oxopyrrolidin-2-yl)methyl)amino)methyl)-1,7-naphthyridin-8yl )amino)-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline Ouch & 762.3 180 (3 S)-1 -((6-(difluoromethoxy)-2-(3 '((3 -((3-hydroxy-pyrrolidin-1yl)methyl)- 1,7-naphthyridin-8yl)amino)- 2,2'-dimethyl-[1,1'biphenyl]-3-yl)benzo[d]oxazol-5 yl)methyl)pyrrolidine-3 carboxylic acid X О δ 0 xz -Ud 0. ABOUT 735.3

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proline ((6-(difluoromethoxy)-2-(3'-((3-((3hydroxypyrrolidin-1 -yl)methyl)1,7-naphthyridin-8-yl)amino)-2,2' dimethyl- [1 ,1 '-biphenyl]-3 -yl)benzo[c!]oxazol-5 -yl)methyl)-O(3R)-1 -((6-(difluoromethoxy)-2-(3'((3 -( (3-hydroxy-pyrrolidin-1yl)methyl)-1,7-naphthyridin-8yl)amino)-2,2'-dimethyl-[1,1'biphenyl]-3-yl)benzo[c!]oxazole -5 yl)methyl)pyrrolidin-3 carboxylic acid proline ((5-(difluoromethoxy)-2-(2,2'dimethyl-3'-((4-(pyrrolidin-1ylmethyl)pyridin-2-yl)amino )[1,1 '-biphenyl]-3 -yl)benzo[c!]oxazol-6-yl)methyl)-E-

Example 314: Synthesis of compound 314.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridin-2-yl) [1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-E-proline

Step 1: Preparation of benzyl-(3S,4S)-3-(3-bromo-2-methylbenzamido)-4-hydroxypiperidine-1 carboxylate

3-bromo-2-methylbenzoic acid (800 mg), benzyl-(3S,4S)-3-amino-4-hydroxyniperidine-1 carboxylate (931.13 mg), EDCI (1.43 g), HOBT (1, 01 g) and TEA (1.13 g) were added sequentially to DCM (50 ml). The mixture was stirred at room temperature overnight. The reaction solution was diluted with methylene chloride and washed successively with a saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium chloride solution. The organic phase was dried over Na ₂ SO ₄ and concentrated to give an off-white solid benzyl-(3S,4S)-3-(3-bromo-2-methylbenzamido)-4-hydroxypiperidine

1-carboxylate (1.4 g, crude).

Step 2: Preparation of benzyl-^)-3-(3-bromo-2-methylbenzamido)-4-oxopiperidine-1-carboxylate

Dess-Martin reagent (2.65 g) was added to a solution of compound 314-3 (1.4 g) in DCM (30 mL) at room temperature and stirred for 3 hours. The reaction was determined to be complete by LC-MS analysis; the reaction mixture was quenched with a solution of Na ₂ S ₂ O ₃ and extracted with EA three times. The organic layers were washed with NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated to give the title benzyl-N)-3-(3-bromo-2-methylbenzamido)-4-oxopiperidine-1-carboxylate (1.1 g, crude) as a light yellow solid.

Step 3: Preparation of benzyl 2-(3-bromo-2-methylphenyl)-6,7-dihydrooxazolo[4,5-c]pyridine-5(4H)carboxylate

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A solution of POC13 (757.52 mg) in 1,4-dioxane (5 ml) was added dropwise to a solution of compound 314-4 (891 mg) in 1,4-dioxane (15 ml). The temperature was then raised to 105° C. and stirring was continued for 2 hours. The reaction mixture was slowly added dropwise to ice water and extracted with ethyl acetate. The organic phase was washed with saturated aqueous NaHCO ₃ and saturated NaCl, dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by chromatography (DCM:MeOH 20:1) to give an off-white solid 314-5 (800 mg).

Step 4: preparation of benzyl-^)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)pyrrolidin-1yl)methyl)benzo^]oxazol-2-yl)-2,2 '-dimethyl-[1,G-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridine5 (4H)-carboxylate

Compound 314-5 (800 mg), intermediate A (1015 mg), Pd(dppf)Cl ₂ (343 mg) and K2CO3 (129.38 mg) were added to a mixture of 1,4-dioxane (20 ml) and H ₂ O (5 ml). The reaction mixture was evacuated and replenished three times with N2, heated to 80°C and stirred for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by TLC (PE:EA 1:3) to give benzyl-^)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)-pyrrolidin-1yl)methyl )benzo^]oxazol-2-yl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6,7-dihydrooxazolo[4,5-c]pyridin5(4H)-carboxylate ( 800 mg) as an almost white solid.

Step 5: preparation of methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5c]pyridin-2-yl)-[ 1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)-methyl)-E-prolinate

Pd/C (200 mg) was added to a solution of compound 314-7 (800 mg) in MeOH (50 ml). The mixture was stirred at room temperature for 5 hours under an H ₂ atmosphere. The reaction mixture was filtered and concentrated to give methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5c]pyridin-2-yl )-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-prolinate (500 mg, crude) as an off-white solid.

Step 6: preparation of methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7tetrahydrooxazolo[4,5-c]pyridine-2- yl)-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-prolinate

(CHO) _n (72 mg) was added to a solution of compound 314-8 (500 mg) in DCM (30 ml) and MeOH (10 ml). After stirring the mixture for 30 minutes, NaBH ₃ CN (150 mg) was added to the reaction solution in portions and stirred at room temperature overnight. The reaction mixture was concentrated and purified by TLC (DCM:MeOH 20:1) to give methyl ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5-methyl-4,5,6, 7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-prolinate (400 mg) as almost white solid.

Step 7: preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin-2-yl) -[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)-methyl)-E-proline

This compound was prepared using procedures similar to those described for step 5 in example 1, using compound 314-9 instead of compound 1-4. The crude product was purified by TLC purification (DCM:MeOH 4:1) to give 210 mg ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5-methyl-4,5 ,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-proline (compound 314 ) as an off-white solid.

LC-MS (m/z): 629.3 (m+H) ⁺ .

Connections table 4 was prepared analogously to Example 314 using different reaction starting materials and suitable reagents.

Table 4

No. Etc. Chemical name Structure Phys. data (MC) (M+H) ⁺ 184 ((2-(3 '-(5 -(carboxymethyl)-4,5,6,7tetrahydrooxazolo [4,5 -c]πpyridin2-yl)-2,2'-dimethyl-[l,Γ-biφenyl]-3yl )-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ZE 673.2 185 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5-(2(methylsulfonyl)ethyl)-4,5,6,7tetrahydrooxazolo [4,5 -c]pyridin2-yl)- [1,G-biphenyl]-3yl)benzo[d]o xazol-5-yl)methyl)-bproline <>g ⁰ \ / \ / V he y/ °'° ⁰ 721.3 186 ((2-(3'-(5-(1-carboxyethyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[1,G-biphenyl] -3il)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline „yw _Ν (Η ^Ν ϊΥ F^F 687.3 187 ((2-(3'-(5-(2-carboxyethyl)-4,5,6,7tetrahydrooxazolo [4,5 -c]πpyridin2-yl)-2,2'-dimethyl-[l,Γ-biphenyl] -3il)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ^ ^O y/=\ fV OH ^{0H 0} 687.3 188 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -methyl-4,5,6,7 tetrahydrooxazolo[5,4-c]pyridin2-yl)-[1,G -biphenyl]-3yl)benzo | d |o xazol-5 -yl)methyl)-Lproline / s °A I 629.3

- 80 047234

189 ((6-(difluoromethoxy)-2-(3'-(5-(2hydroxyethyl)-4,5,6,7tetrahydrooxazolo[5,4-c]pyridin2-yl)-2,2'-dimethyl -[1,1 '-biphenyl]-3 yl)-benzo[c!]oxazol-5 -yl)methyl)-Lproline A ^Z <s/O χΟό o^z b o I 659.3 190 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-[1,G-biphenyl]-3yl) benzo[c!]oxazol-5-yl)methyl)-Lproline bg ⁰ ) / \ldtj ^hn KnW ⁰ fA 615.2 191 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5-(4,4,4-trifluorobutyl)4,5,6,7-tetrahydrooxazolo[4.5 s]pyridine-2 -yl) - [1, G-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline _ν oLC _{z F} °An Αη ^ν Αι ^ν ''Ά ^ρ \=/ ^F 725.3 192 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(oxetan-2-ylmethyl)4,5,6,7-tetrahydrooxazolo [4.5 c]pyridin-2-yl ) - [1, G-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline ^F 'Y' ^F °An SHA \=/ 0^%/ 685.3 193 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -((5-oxopyrrolidin2-yl)methyl)-4,5,6,7tetrahydrooxazolo [4,5 -c]pyridin2- yl)-[1,G-biphenyl]-3yl)benzo[d]oxazol-5 yl)methyl)proline аъу А °An rOuu \=/ 0^·— 712.3

- 81 047234

194 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(pyridin-3-ylmethyl)4,5,6,7-tetrahydrooxazolo [4.5 c]pyridin-2-yl ) - [1, G-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline o )=</ ^but \__7 \=/nAJ B D 706.3 195 ((2-(3'-(5-(cyanomethyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[1,1'-biphenyl] - 3 il)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)proline ^F _Y ^F o r^ ^N g\_/ but \=/A ₀ 0 654.2 196 ((2-(3 '-(5 -(2-amino-2-oxoethyl)- 4,5,6,7-tetrahydrooxazolo[4,5 c]pyridin-2-yl)-2,2'-dimethyl-[1,1'biphenyl]-3-yl)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)proline ^F \^ ^F but \_j wAC o 672.3 197 ((6-(difluoromethoxy)-2-(3'-(5(ethylsulfonyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[1,1 '-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline θχχν-θ o ^N / \_J _N %— CMC ¹ '' ⁰ 707.2 198 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(3,3,3 trifluoropropyl)-4,5,6,7tetrahydrooxazolo [4,5 -c]pyridin2-yl) -[1,G-biphenyl]-3yl)benzo[d]oxazol-5 yl)methyl)proline AH) ₽ HA /[ ^ι γ^Ν ^ζ ^Α'ρ ho \j 711.2

- 82 047234

199 ((6-(difluoromethoxy)-2-(3'-(5 -(3 hydroxypropyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[ 1 ,1'-biphenyl]-3 yl)benzo[d]oxazol-5 yl)methyl)proline ^F \y ^F °ХХ°нЗ> о М/ DA / _ζ ^Ν Ύ^Ν^^^ΟΗ but \_/ \=W 673.3 200 ((6-(difluoromethoxy)-2-(3'-(5 -(3 fluoropropyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[ 1 ,1 '-biphenyl]-3 yl)-benzo | d |oxazol-5 yl)methyl)proline yF θχχν-ο YES but VJ V/yAJ 675.3 201 ((2-(3'-(5-(2,2-difluoroethyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[1,1' -biphenyl]-3 yl)-6- (difluoromethoxy)benzo[d]oxazol-5 yl)methyl)proline y F o r^ ^N )=</ _ Ka γΟϊΎΎ but VJ ^F 679.3 202 ((6-(difluoromethoxy)-2-(3'-(5,6dihydro-4H-pyrrolo[3,4-b]oxazol2-yl)-2,2'-dimethyl-[1,1'-biphenyl] - 3 yl)benzo[d]oxazol-5 yl)methyl)proline F^F ° OH ^NH 601.2 203 ((6-(difluoromethoxy)-2-(3'-(6,7d ihydro-4H-pyrano[3,4-d]oxazol-2yl)-2,2'-dimethyl-[1, G-biphenyl] - 3 yl)benzo[d]oxazol-5 yl)methyl)proline y,F °Хн ChTj \=/ οΎΑ 616.2 204 ((6-(difluoromethoxy)-2-(3'-(5,6dihydro-4H-cyclopsnta|4|oxazol2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo [d] oxazol-5 yl)methyl)proline Q °h> I 600.2

- 83 047234

205 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(4,5,6,7tetrahydrobenzo[b]oxazol-2-yl)[1,1'-biphenyl]-3 -yl) benzo[c1]oxazol5 -yl)methyl)proline But 614.2 206 ((6-(difluoromethoxy)-2-(3'-(5-(2hydroxyethyl)-4,5,6,7tetrahydrooxazolo[4,5-c]pyridin2-yl)-2,2'-dimethyl-[ 1 ,1 '-biphenyl]-3 yl)-benzo[c!]oxazol-5 -yl)methyl)-Lproline N 1 /) BUT ho-^ ⁿ ^ ^< n W / >° F^F 659.3 207 2-((2-(2'-cyano-2-methyl-3'-(4,5,6,7tetrahydrooxazolo [4,5 -c]pyridin2-yl)-[1,G-biphenyl]-3-yl )-6(difluoromethoxy)-benzo[d]oxazol-5 yl)-methyl)pyrrolidine-1-carboxylic acid CN py _Z ^NH J AAV* I u Xo HO 626.2

Example 208: Synthesis of compound 208.

((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((^)-3-hydroxypyrrolidin-1-yl)methyl)phenoxy )methyl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5yl)methyl)-1 .-proline

Connection 208

Step 1: Preparation of 1-bromo-3-(chloromethyl)-2-methylbenzene

(3-bromo-2-methylphenyl)methanol (20 g) was dissolved in DCM (200 ml), stirred at room temperature and 20 ml SOC12 was added slowly. This mixture was stirred for 2 hours and then concentrated to give 1-bromo-3-(chloromethyl)-2-methylbenzene (23.1 g).

Step 2: preparation of 4-((3-bromo-2-methylbenzaldehyde)oxy)-5-chloro-2-hydroxybenzaldehyde

A mixture of 1-bromo-3-(chloromethyl)-2-methylbenzene (2.0 g), 5-chloro-2,4-dihydroxybenzaldehyde (2.34 g), potassium carbonate (3.78 g), KI (1. 51 g) in acetonitrile (20 ml) was stirred at 80°C overnight. After the reaction was complete, 20 ml of water was added, concentrated, filtered and dried to obtain 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde (2.8 g).

Step 3: Preparation of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-((5-(difluoromethoxy)pyridin-3yl)methoxy)benzaldehyde

Compound 208-3 (500 mg), (5-(difluoromethoxy)pyridin-3-yl)methanol (408 mg), potassium carbonate (585 mg), KI (195 mg) was added to acetonitrile (10 ml), the reaction mixture was stirred at 80°C during

- 84 047234 night. 10 ml of water was added, the mixture was concentrated, filtered and dried to obtain 4-((3bromo-2-methylbenzyl)-oxy)-5-chloro-2-((5-(difluoromethoxy)pyridin-3-yl)methoxy)benzaldehyde ( 478 mg).

Step 4: preparation of methyl ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4formylphenoxy)methyl)-2,2'-dimethyl- [1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5yl)methyl)X-prolinate

208-4 208-5

Compound 208-4 (470 mg), intermediate A (597 mg) and potassium carbonate (236 mg) were added to 1,4-dioxane (12 ml) and water (3 ml) with stirring, and then Pd was added to this mixture (dppf)Cl ₂ in an N ₂ atmosphere. The reaction mixture was heated to 80°C and stirred overnight. The mixture was quenched with water (30 ml) and extracted with DCM (30 mlx3). The organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and column purified (DCM/MeOH 15/1) to give compound 208-5 (550 mg).

Step 5: preparation of methyl ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((^)-3hydroxypyrrolidin-1-yl )methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6difluoromethoxy)benzo^]oxazol-5-yl)methyl)X-prolinate

208-5

208-6

Compound 208-5 (270 mg), ^)-pyrrolidin-3-ol (80 mg), glacial acetic acid (40 mg) were added to 10 ml of methanol with stirring. The mixture was heated to 50°C and stirred for 1 hour. After cooling the mixture to room temperature, sodium cyanoborohydride was added and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (10 ml) and extracted with DCM (15 ml x 3), the organic layers were dried over anhydrous sodium sulfate, filtered, concentrated and column purified (DCM/MeOH 15/1) to give compound 208-6 (110 mg).

Step 6: preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((^)-3hydroxypyrrolidin-1-yl)methyl )phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo^]oxazol-5-yl)methyl)X-proline (compound 208)

Connection 208

Compound 208-6 (110 mg) was added to 5 ml of methanol with stirring, and 8 mg of LiOH was weighed and dissolved in 1 ml of water and then added to this mixture. The reaction mixture was heated to 35 °C overnight. This mixture was added to 10 ml of water and extracted with DCM (15 ml x 3). The organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 105 mg of ((2-(3'-((2chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((^ )-3-hydroxypyrrolidin-1yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,G-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5yl)methyl) X-proline (compound 208). LC-MS (m/z): 905.3 (M+H)+.

Connections table 5 was prepared analogously to Example 208 using different reaction starting materials and suitable reagents.

- 85 047234

Table 5

No. Etc. Chemical name Structure Phys. data (MS) (M+N) ⁺ 209 ((2-(3'-((2-chloro-5-((5(difluoromethoxy)pyridin-3 yl)methoxy)-4-((3 fluoropyrrolidin-1 yl)methyl)phenoxy)methyl)-2,2 'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5-i l) revenge l)-L- proline Ύ) ^with| ^-N / ⁼ ^\ MX , %on 907.3 210 ((2-(3'-((4-(((2- acetamidoethyl)amino)methyl)-2chloro-5-((3-cyanobenzyl)oxy)phenoxy)methyl)-2,2'- dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)- benzo[d]oxazol-5-and l) revenge l)-Lproline ν C> ^cn o noA _o UyU ⁵ V/ сг 878.3 211 ((2-(3'-((4-(((8)-2-carboxypyrrolidin-1 -i l) methyl)-2-chloro5-((3 -cyanobenzyl)oxy)phenoxy)methyl)-2,2 'dimethyl-[1,1'-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5-i l) revenge l)-L- proline QXrw / J o noA _o >OH \=/ c~ Q 891.3

- 86 047234

((6-(difluoromethoxy)-2-(3'-(((4,6dimethoxy-5 -(pyrrolidin-1ylmethyl)-pyrimidin-2yl)oxy)methyl)-2,2'-dimethyl[ 1,1' -biphenyl]-3yl)benzo[d]oxazol-5 -yl)methyl)L-proline ((6-(difluoromethoxy)-2-(3 '-(((5 ((3,3-dimethylazetidin-1 yl) methyl)-4,6-dimethoxypyr imide in-2-yl)oxy)methyl)2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-yl)methyl) L-proline ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-((5 -(((((S)-5 oxopyrrolidin-2-yl)methyl)amino)methyl)pyridine -2 yl)oxy)-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)L-proline

Example 242: Synthesis of compound 242.

((6-(Difluoromethoxy)-2-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,2'-dimethyl-[1,1':3'1-terphenyl]-3yl)benzo^ ] oxazol-5-yl)methyl)proline

Step 1: preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzaldehyde

To a solution of 4-bromobenzaldehyde (9.25 g) in 1,4-dioxane (120 ml) was added bis(pinacolato)diboron (15.8 g), Pd(dppf)Cl ₂ .DCM (0.48 g) and KOAc (20.0 g). The reaction mixture was heated at 100°C for 4 hours. The mixture was diluted with 150 ml water and then extracted with EtOAc (150 mlx2). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified over silica gel (eluting with hexane-EtOAc using a 20:1 to 10:1 gradient) to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- benzaldehyde (11.2 g) as a white solid.

Step 2: Preparation of 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde

242-2 242-3

To a solution of compound 242-2 (60 ml) in EtOH (20 ml) was added 10% Na ₂ CO ₃ aq. (20 ml) and

Pd(dppf)Cl ₂ .DCM (420 mg) and then 1-bromo-3-iodo-2-methylbenzene (9.0 g) was added dropwise under N2 protection. The mixture was stirred at 100°C for 16 hours. The reaction mixture was quenched with H ₂ O (50 ml) and extracted with EtOAc (100 ml) three times. The organic layers were combined and washed with brine. The resulting solution was concentrated and purified on silica gel (eluting with hexane-EtOAc using

- 87 047234 gradient from 20:1 to 10:1) to obtain 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (3.2 g) as a light yellow solid substances.

Step 3: Preparation of 1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)-3-fluoropyrrolidine

3'-Bromo-2'-methyl-[1,1'-biphenyl]-4-carbaldehyde (275 mg) was dissolved in 5 ml DCM. 3Fluoropyrrolidine (120 mg) and NOAC were added in one portion. The resulting mixture was stirred for 1 hour at room temperature, then STAB (420 mg) was added in one portion at the same temperature. The reaction mixture was left stirring at room temperature for 3 hours. The resulting mixture was quenched with saturated Na ₂ CO ₃ solution and extracted with EtOAc (20 ml) three times and the organic phase was dried over Na ₂ SO ₄ . The resulting solution was concentrated to give 1-((3'-bromo-2'methyl-[1,1'-biphenyl]-4-yl)methyl)-3-fluoropyrrolidine (320 mg) as a colorless oil.

Step 4: preparation of methyl-((6-(difluoromethoxy)-2-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,2'dimethyl-[1,1':3',1-terphenyl ]-3 -yl)benzo[d]oxazol-5 -yl)methyl)-prolinate

This compound was prepared using procedures similar to those described for step 4 in Example 171, using compound 242-4 instead of compound 171-4. The resulting mixture was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a 40:60 to 50:50 gradient) to give compound 242-5 (288 mg).

Step 5: Preparation of ((6-(difluoromethoxy)-2-(4-((3-fluoropyrrolidin-1-yl)-methyl)-2,2'-dimethyl[1,1':3',1-terphenyl] -3-yl)benzo[d]oxazol-5-yl)methyl)proline

This compound was prepared using procedures similar to those described for step 6 in Example 171, using compound 242-5 instead of compound 171-6. The crude product was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a 40:60 to 50:50 gradient) to give methyl ((6-(difluoromethoxy)-2-(4- ((3-fluoropyrrolidin-1-yl)methyl)-2,2'-dimethyl[1,G:3',1-terphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)prolinate in the form white solid (168 mg) (compound 242). LC-MS (m/z): 670.3 (M+H)+.

Example 243: Synthesis of compound 243.

((6-(difluoromethoxy)-2-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,2'-dimethyl-[1,1':3', 1-terphenyl]-3yl)benzo ^]oxazol-5-yl)methyl)proline \=/ U-A / coon ^F chf ₂

Connection 243

Step 1: preparation of methyl ((6-(difluoromethoxy)-2-(3-fluoro-4-formyl-2,2'-dimethyl-[1,1':3', 1terphenyl]-3 -yl)benzo[ d]oxazol-5-yl)methyl)^-prolinate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using 4-bromo-2-fluorobenzaldehyde instead of compound a-6 and using

- 88 047234 intermediate B instead of intermediate A. The resulting solution was concentrated and purified through silica gel (eluting with hexane-EtOAc using a 5:1 gradient from 5:1) to give the title compound as a yellow oil.

Step 2: preparation of methyl-((6-(difluoromethoxy)-2-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,2'dimethyl-[1,1':3',1-terphenyl ]-3-yl)benzo^]oxazol-5-yl)methyl)-prolinate

This compound was prepared using procedures similar to those described for step 5 in Example 2, using compound 243-1 instead of compound 2-4 and using pyrrolidine instead of L-proline. The resulting solution was concentrated to give the title compound as a colorless oil.

Step 5: preparation of ((6-(difluoromethoxy)-2-(3-fluoro-2,2'-dimethyl-4-(pyrrolidin-1-ylmethyl)[1,1':3', G'-terphenyl]- 3-yl)benzo^]oxazol-5-yl)methyl)X-proline

This compound was prepared using procedures similar to those described for step 5c

in example 1, using compound 243-2 instead of compound 1-4. The crude product was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a 10:90 to 30:70 gradient) to give the title compound. LC-MS (m/z): 670.3 (M+H)+. ^1H NMR(500 MHz, Methanol^4) δ: 8.16 (dd, 1H, J=7.9, 1.5 Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H , J=7.7 Hz), 7.50 (t, 1H, J=7.7 Hz), 7.43-7.27 (m, 5H), 7.20 (dd, 1H, J=7.5, 1.4 Hz), 7.12 (t, 1H, JF _-H =72.6 Hz), 4.75 (d, 1H, J=13.1 Hz), 4.54 (d, 1H, J=13.1 Hz), 4.54 (s, 2H) , 4.37 (dd, 1H, J=9.5, 7.4 Hz), 3.66-3.60 (m, 3H), 3.45-3.40 (m, 1H), 3.29-3.23 (m, 2H), 2.65-2.57 ( m, 1H), 2.49 (s, 3H), 2.28-2.14 (m, 4H), 2.10-2.00 (m, 3H), 1.96 (s, 3H).

Example 244: Synthesis of compound 244.

((6-(Difluoromethoxy)-2-(3-(difluoromethoxy)-2,2'-dimethyl-4-(pyrrolidin-1-ylmethyl)-[1,1':3',1terphenyl]-3 -yl) benzo^]oxazol-5-yl)methyl)X-proline

Step 1: preparation of 4-bromo-2-(difluoromethoxy)benzaldehyde

CS2CO3 (9.8 g), KI (400 mg) were added to a solution of 4-bromo-2-hydroxybenzaldehyde (4.0 g) in DMF (50 ml). The mixture was stirred at room temperature for 30 minutes and then 2-bromo-2,2-difluoroacetate (6.0 g) was added in small portions. This mixture was stirred at 75°C overnight. The mixture was diluted with 100 ml water and then extracted with EtOAc (100 ml) three times. The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified over silica gel (eluting with hexane-EtOAc using a 8:1 to 5:1 gradient) to give 4-bromo-2-(difluoromethoxy)benzaldehyde (2.8 g) as a brown oil.

Step 2: Preparation of 5-bromo-2-(pyrrolidin-1-ylmethyl)benzonitrile

This compound was prepared using procedures similar to those described for step 5

- 89 047234 in example 2, using compound 244-1 instead of compound 2-4 and using pyrrolidine instead of L-proline. The crude product was purified over silica gel (eluting with DCMMeOH using a 20:1 to 10:1 gradient) to give the title compound.

Step 3: preparation of methyl-((6-(difluoromethoxy)-2-(3-(difluoromethoxy)-2,2'-dimethyl-4(pyrrolidin-1-ylmethyl)-[1,1':3',1- terphenyl]-3-yl)benzo^]oxazol-5-yl)-methyl)-C-prolinate

Br

Intermediate B

244-2

244-3

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using compound 244-2 instead of compound a-6 and using intermediate B instead of intermediate A. The resulting solution was concentrated and purified using silica gel (eluting hexane-EtOAc using a 5:1 to 1:1 gradient to give the title compound.

Step 4: preparation of ((6-(difluoromethoxy)-2-(3-(difluoromethoxy)-2,2'-dimethyl-4-(pyrrolidin-1ylmethyl)-[1,1':3',1-terphenyl]- 3-yl)benzo^]oxazol-5-yl)-methyl)^-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 244-3 instead of compound 1-4. The crude product was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a 10:90 to 35:65 gradient) to give the title compound. LC-MS (m/z): 718.3 (M+H)+. ^1H NMR(500 MHz, methanol-04), δ: 8.16 (dd, 1H, J=7.9, 1.5 Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.73 (d, 1H, J=7.9 Hz), 7.50 (t, 1H, J=7.7 Hz), 7.42-7.36 (m, 3H), 7.34 (d, 1H, J=1.4 Hz), 7.30 (dd , 1H, J=7.7, 1.4 Hz), 7.21 (dd, 1H, J=7.4, 1.4 Hz), 7.13 (td, 2H, J=72.8, 2.4 Hz) , 4.73 (d, 1H, J=13.2 Hz), 4.61 (d, 1H, J=13.2 Hz), 4.53 (s, 2H), 4.30 (dd, 1H, J=9.7, 7, 1 Hz), 3.69-3.56 (m, 3H), 3.44-3.38 (m, 1H), 3.31-3.28 (m, 2H), 2.62-2.55 (m, 1H), 2.50 (s, 3H), 2.23-2.15 (m, 4H), 2.12-2.00 (m, 3H), 1.96 (s, 3H).

Example 245: Synthesis of compound 245.

((2-(3-cyano-2,2'-dimethyl-4-(pyrrolidin-1-ylmethyl)-[1,1':3'1-terphenyl]-3-yl)-6(difluoromethoxy)benzo^ ]oxazol-5-yl)methyl)^-proline

Connection 245

Step 1: Preparation of 5-bromo-2-(bromomethyl)benzonitrile

To a solution of 5-bromo-2-methylbenzonitrile (20.0 g), NBS (19.6 g) in CCl ₄ (300 ml) was added BPO (2.4 g) under N2 protection. This mixture was left stirring at 70°C overnight. The reaction mixture was quenched with saturated NaHCO ₃ solution (200 ml). The organic layers were combined and washed with brine. The resulting solution was concentrated and purified over silica gel (eluting with hexaneEtOAc using a 20:1 to 1:1 gradient) to give 5-bromo-2-(bromomethyl)-benzonitrile (15.2 g) as a yellow crude solid.

Step 2: Preparation of 5-bromo-2-(pyrrolidin-1-ylmethyl)benzonitrile

To a solution of compound 245-1 (5.4 g) in THF (60 ml) was added pyrrolidine (2.85 g) dropwise at 0°C. The reaction mixture was heated to 40°C for 5 hours. The reaction mixture was diluted with 200 ml of water and then extracted with EtOAc (150 ml) three times. Combined Organic Extracts

- 90 047234 washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified over silica gel (eluting with hexane-EtOAc using a 2:1 to 1:2 gradient) to give 5bromo-2-(pyrrolidin-1-ylmethyl)benzonitrile (3.8 g) as a brown oil.

Step 3: preparation of methyl-((2-(3-cyano-2,2'-dimethyl-4-(pyrrolidin-1-ylmethyl)-[1,G:3',1terphenyl]-3-yl)-6- (difluoromethoxy)benzo^]oxazol-5-yl)methyl)N-prolinate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using compound 245-2 instead of compound a-6 and using intermediate B instead of intermediate A. The crude product was purified through silica gel (eluting with hexane -EtOAc using a 5:1 to 1:1 gradient to give the title compound.

Step 4: Preparation of ((2-(3-cyano-2,2'-dimethyl-4-(pyrrolidin-1-ylmethyl)-[1,1':3',1-terphenyl]-3yl)-6-( difluoromethoxy)benzo^]oxazol-5-yl)methyl)N-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 245-3 instead of compound 1-4. The crude product was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a 10:90 to 35:65 gradient) to give the title compound. LC-MS (m/z): 677.3 (M+H)+. ^1H NMR(500 MHz, MethanolA δ: 8.21 (dd, 1H, J=7.9, 1.5 Hz), 8.10 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H, J= 7.7 Hz), 7.50 (t, 1H, J=7.7 Hz), 7.49-7.28 (m, 5H), 7.20 (dd, 1H, J=7.5, 1.4 Hz), 7.12 (t , 1H, J _FH = 2.6 Hz), 4.73 (d, 1H, J=13.1 Hz), 4.51 (d, 1H, J=13.1 Hz), 4.51 (s, 2H), 4.37 (dd , 1H, J=9.5, 7.4 Hz), 3.69-3.51 (m, 3H), 3.47-3.42 (m, 1H), 3.25-3.20 (m, 2H), 2.65-2.57 (m, 1H) , 2.49 (s, 3H), 2.28-2.12 (m, 4H), 2.10-2.00 (m, 3H), 1.96 (s, 3H).

Example 246: Synthesis of compound 246.

((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-((^)-3-methylpyrrolidin-1-yl)methyl)-pyridin-2-yl)-2,2'dimethyl- [1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-E-proline

Step 1: preparation of methyl-((6-(difluoromethoxy)-2-(3'-(5-formyl-6-methoxypyridin-2-yl)-2,2'dimethyl-[1,G-biphenyl]-3- yl)benzo^]oxazol-5-yl)methyl)-E-prolinate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using 6-chloro-2-methoxynicotinaldehyde instead of compound a-6 and using intermediate B instead of intermediate A. The crude product was purified using silica gel ( hexane-EtOAc 3:1) to obtain the title compound.

Step 2: methyl-((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-((^)-3-methylpyrrolidin-1yl)methyl)pyridin-2-yl)-2,2' -dimethyl-[1,G-biphenyl]-3-yl)-benzo^]oxazol-5-yl)methyl A-prolinate

- 91 047234

This compound was prepared using procedures similar to those described for step 5 in Example 2, using compound 246-1 instead of compound 2-4 and using (S)-3methylpyrrolidine instead of L-proline. The resulting solution was concentrated to give the title compound.

Step 3: ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-((^)-3-methylpyrrolidin-1 -yl)methyl)pyridin-2yl)-2,2'-dimethyl -[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)X-proline

This compound was prepared using procedures similar to those described for step 5 in example 1, using compound 246-2 instead of compound 1-4. The organic layer was separated and purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a gradient of 15:85 to 30:70) to give ((6-(difluoromethoxy)-2-(3- (difluoromethoxy)-2,2'-dimethyl-4-(pyrrolidin-1ylmethyl)-[1,G:3',1-terphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-E- proline (30.8 mg) as a white solid. LC-MS (m/z): 697.3 (M+H)+. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.11 (dd, 1H, J=7.9, 1.5 Hz), 7.96 (s, 1H), 7.77 (d, 1H, J=7.5 Hz ), 7.72 (s, 1H), 7.54-7.37 (m,5H), 7.24-7.19 (m, 1H), 7.16 (d, 1H, J=7.5 Hz), 3.95 (s, 2H), 3.89 ( s, 3H), 3.58 (s, 2H), 3.11-3.03 (m, 1H), 2.78 (t, 1H, J=2.8 Hz), 2.68-2.60 (m, 1H), 2.60-2.52 (m, 3H), 2.45 (s, 3H), 2.22-2.16 (m, 1H), 2.15-2.07 (m, 2H), 2.05 (s, 3H), 2.02-1.93 (m, 1H), 1.88-1.70 (m, 3H), 1.34-1.27 (m, 1H), 1.00 (d, J=6.7 Hz, 3H).

Example 247: Synthesis of compound 247.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(^)-pyrrolidin-2-yl)-III-imidazol-4-yl)-[1,G-biphenyl ]3 -yl)benzo^]oxazol-5-yl)methyl)X-proline

Receipt

Stage

1:

tert-butyl-^)-2-(4-(3'-(6-(difluoromethoxy)-5-((^)-2(methoxycarbonyl)pyrrolidin-1 -yl)methyl)benzo^]oxazol-2-yl )-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1Nimidazol-2-yl)pyrrolidin-1-carboxylate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using tert-butyl-N)-2-(4-bromo-III-imidazol-2-yl)pyrrolidin-1-carboxylate in place of the compound a-6 and using intermediate B instead of intermediate A. The resulting solution was concentrated and purified over silica gel (eluting with hexane-EtOAc using a 5:1 to 1:1 gradient) to give tert-butyl-^)-2- (4-(3'-(6(difluoromethoxy)-5-((^)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)-benzo^]oxazol-2-yl)-2,2'dimethyl- [1,G-biphenyl]-3-yl)-III-imidazol-2-yl)-pyrrolidine-1-carboxylate (98 mg) as a yellow oil.

Step 2: preparation of methyl-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(^)-pyrrolidin-2-yl)-1Nimidazol-4-yl)- [1 ,1 '-biphenyl]-3 -yl)benzo^]oxazol-5 -yl)methyl)X-prolinate

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MeOOS

247-1 247-2

A mixture of compound 247-1 (76.0 mg) in DCM/TFA 7:1 (4 ml) was stirred for 4 hours at room temperature. The resulting solution was concentrated under high vacuum to give compound 247-2 (60 mg) as a yellow semi-solid.

Step 3: preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(^)-pyrrolidin-2-yl)-1Nimidazol-4-yl)- [1,1 '-biphenyl]-3 -yl)benzo[d]oxazol-5 -yl)methyl)A-proline noos

247-2

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 247-2 instead of compound 1-4. The crude product was purified on an RP column (mobile phase: MeCN:water (0.1% HCl) using a gradient from 10:90 to 35:65) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(^)-pyrrolidin-2-yl)-III-imidazol-4yl)-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl) A-proline (70.6 mg) as a white solid. LC-MS (m/z): 628.3 (M+H)+. ¹ H NMR (500 MHz, Methanol^4), δ: 8.19 (dd, 1H, J=8.0, 1.5 Hz), 8.07 (s, 1H), 7.76 (d, 1H, J=10.8 Hz), 7.61 (dd, 1H, J=7.8, 1.3 Hz), 7.52 (t, 1H, J=7.8 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.38 (dd, 1H, J=7.6, 1.4 Hz), 7.32 (dd, 1H, J=7.6, 1.4 Hz), 7.13 (t, 1H, Jf-h=72.6 Hz) , 5.16 (t, 1H, J=9.3, 7.7 Hz), 4.79 (d, 1H, J=13.2), 4.62 (d, 1H, J=13.3), 4.48 (t, 1H, J =9.3 Hz), 3.67-3.55 (m, 3H), 3.50-3.42 (m, 1H), 2.75-2.60 (m, 2H), 2.58-2.50 (m, 1H), 2.49 (s, 3H), 2.43-2.34 (m, 1H), 2.29 -2.17 (m, 3H), 2.15 (s, 3H), 2.11-1.99 (m, 1H).

Connections table 6 was prepared analogously to Examples 242-247 using different reaction starting materials and suitable reagents.

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Table 6

No. Etc. Chemical name Structure Phys. data (MS) (M+H) ⁺ 215 ((6-(difluoromethoxy)-2-(2'-fluoro2-methyl-4-(((((8)-5oxopyrrolidin-2-yl)methyl)amino)methyl)- [1,G:3',1terphenyl ]-3-yl)benzo[c1]oxazol5-yl) methyl )-L-proleine qw F.T. 699.3 216 ((6-(difluoromethoxy)-2-(3(difluoromethoxy)-2'-fluoro-2methyl-4-(((((8)-5oxopyrrolidin-2-yl)methyl)amino)methyl)- [1,G :3',1terphenyl]-3-yl)benzo[c1]oxazol5-yl) methyl )-L-proleine F F ^F ~< Г rd· 0=/¾ « Л Г νη^,νη )=/ ^N ' °ν/ ^Ν ~Ί OH 765.3 217 ((6-(difluoromethoxy)-2-(4-(((2hydroxyethyl)amino)methyl)-2,2'dimethyl-[1,1':3',1-terphenyl]-3 yl)benzo[s !]oxazol-5-yl)methyl)L-proline but^ ' \=/ NX COO O-T'TOSGYA \=/ o-^Ά F^F 1 642.3 218 ((6-(difluoromethoxy)-2-(2,2',3trimethyl-4-(pyrrolidin-1yl methyl)-[1,G:3',1-terphenyl]-3 yl)benzo[c!]oxazol- 5yl)methyl)proline NOOS^ 666.3 219 ((2-(3-chloro-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)- [ 1, G: 3', 1 -terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c!]oxazol -5-yl)methyl)proline noos^ 686.3

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220 ((6-(difluoromethoxy)-2-(2-fluoro2,2'-dimethyl-4-(pyrrolidin-1 yl methyl)-[1,G:3',1-terphenyl]-3 yl)benzo[s! ]oxazol-5yl)methyl)proline noos^ 670.3 221 ((2-(2'-bromo-2-fluoro-2-methyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 31 -terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c1]oxazole -5-yl)methyl)proline noos^ 733.2 222 ((2-(2'-chloro-2-fluoro-2-methyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 31 -terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c1]oxazole -5-yl)methyl)proline HOOCj^ 690.2 223 ((2-(2'-chloro-2-fluoro-2-methyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 31 -terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c1]oxazole -5-yl)methyl)-E-proline I o = ^A 0 . 0z^o cP T ° V σ 690.2 224 ((2-(2'-chloro-2-fluoro-2-methyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 31 -terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c1]oxazole -5-yl)methyl)-O-proline O \ /X /=\ \_/ y // °<^OH ^Cl αρχχύ 690.2 225 ((6-(difluoromethoxy)-2-(4guanidino-2,2'-dimethyl[1,G:3',1-terphenyl]-3-yl)benzo[c!]oxazol-5-yl)methyl)- Eprolin I z z z 1 I T cP cAz -P. 'Of 626.3

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226 ((6-(difluoromethoxy)-2-(4-(((3(dimethylamino)propyl)(methyl)amino)methyl)-2,2'-dimethyl[ 1, G: 3G-terphenyl]-3-yl) benzo[0]oxazol-5-yl)methyl)-bproline / —Z 697.4 227 ((6-(difluoromethoxy)-2-(4-((3 methoxypyrrolidin-1 -yl)methyl)-2,2'-dimethyl-[ 1, G: 3', Gterphenyl]-3-yl)benzo[c1 ]oxazol5-yl) methyl )-L-proleine 1 ' \=/ / COOI ygchOOO \=/ F^F 682.3 228 ((6-(difluoromethoxy)-2-(4-((3 (dimethylamino)pyrrolidin-1 yl)methyl)-2,2'-dimethyl[ 1, G: 3G-terphenyl]-3 -yl)benzo[s !]oxazol-5-yl)methyl)-Gproline 1 ' V=z С? . suck 0-01000 \=/ VxA ₀ 0/ F^F 695.3 229 ((2-(3-chloro-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)- [ 1, G: 3', G-terphenyl]-3-yl)-6(difluoromethoxy)benzo[c!]oxazol -5-yl)methyl)-b-proline ^s| _h ' \=) ! UNO \=/ 0-/ F^F 686.3 230 ((6-(difluoromethoxy)-2-(2,2',3trimethyl-4-(pyrrolidin-1yl methyl)-[1,G:3',G-terphenyl]-3 yl)benzo[c!]oxazol- 5-yl)methyl)L-proline Qjhwo ' \=/Hell/son 666.3 231 ((2-(2-chloro-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 3', G-terphenyl]-3-yl)-6(difluoromethoxy)benzo[s! ]oxazol -5-yl)methyl)-E-proline ^{s| N} V ₄ Ov/ ⁼ \ ' \=) S-0 / coon 0^000^0/ 686.3

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232 ((6-(difluoromethoxy)-2-(2,2'dimethyl-4-(pyrrolidin-1 -ylmethyl)-3 -(trifluoromethoxy)[ 1, G: 31 -terphenyl]-3 -yl)benzo[0 ]oxazol-5-yl)methyl)-bproline F ₃ CO _n ^\=/X7 ^hooc> V ο QwrV chf ₂ 736.3 233 ((6-(difluoromethoxy)-2-(2,2'dimethyl-4-(pyrrolidin-1 ylmethyl)-3-(trifluoromethyl)[ 1, G: 31 -terphenyl]-3 -yl)benzo[0]oxazole -5-yl)methyl)-bproline F ₃ C NM) g-N >—Ch / ROON O (UchTKHSKH) chf ₂ 720.3 234 ((6-(difluoromethoxy)-2(2,2',3,5-tetramethyl-4(pyrrolidin-1-ylmethyl)[1,G:3',1-terphenyl]-3yl)benzo[c!]oxazole -5-yl)methyl)L-proline noos jOl 1 λί ΎΎτΥύ ^CHF2 680.3 235 ((6-(difluoromethoxy)-2-(3-fluoro5-methoxy-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 31 -terphenyl]-3 -yl)benzo[0] Oxazol-5-yl)methyl)-bproline noos 700.3 236 ((2-(3-carboxy-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)[1,G:3',1-terphenyl]-3-yl)-6(difluoromethoxy)benzo[s! ]oxazol -5-yl)methyl)-b-proline NOOS kXl 1 // 'chf ₂ <1 11 Ί T II Ί 696.3

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237 ((6-(difluoromethoxy)-2-(4-((3,3 dimethylazetidin-1 -yl)methyl)3-fluoro-2,2'-d imethyl-[ 1, G: 31 terphenyl]-3-yl )benzo[c1]oxazol5-yl) methyl )-L-proleine noos 684.3 238 ((6-(difluoromethoxy)-2-(3-fluoro2, 2'-dimethyl-4-((3-methylpyrrolidin-1-yl)methyl)[ 1, G: 3', 1-terphenyl]-3 -yl )benzo[c1]oxazol-5-yl)methyl)-Eproline noos _P 1 х YYTYV ^CHF2 684.3 239 ((6-(difluoromethoxy)-2-(3-fluoro4-(((2-hydroxyethyl)amino)methyl)-2,2'-dimethyl-[ 1, G: 3', 1 terphenyl]-3-yl) benzo[c1]oxazol5-yl) methyl )-L-proleine NOOS 660.3 240 ((2-(3-cyano-4-(((8)-3 (hydroxymethyl)pyrrolidin-1 yl)methyl)-2,2'-dimethyl[ 1, G: 3', 1 -terphenyl]-3 - yl)-6(difluoromethoxy)benzo[s!]oxazole -5-yl)methyl)-b-proline noos CN 707.3 241 ((6-(difluoromethoxy)-2-(3-fluoro4-(isoindolin-2-ylmethyl)-2,2'd imethyl-[1, G:3',1-terphenyl]-3 yl)benzo[s !]oxazol-5-yl)methyl)proline NOOS o. VNyy ¹ 718.3

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248 ((6-(difluoromethoxy)-2-(3-fluoro2,2'-dimethyl-4-(((8)-3phenylpyrrolidin-1 -yl)methyl)[ 1, G: 3', 1 -terphenyl]-3 -yl)benzo[s!]oxazol-5-yl)methyl)proline NOO^ 746.3 249 ((6-(difluoromethoxy)-2-(3 -(4fluorophenethoxy)-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 3', 1 -terphenyl]-3 -yl)benzo [c!]oxazol-5-yl)methyl)proline F χΎ noos 790.3 250 ((2-(3 -(cyclopropylmethoxy)2,2'-dimethyl-4-(pyrrolidin-1ylmethyl)-[1,1':3',1-terphenyl]-3 yl)-b-(difluoromethoxy)- benzo[c!]oxazol-5-yl)methyl)proline noos <1 722.3 251 ((2-(4-(((K)-3-(1H-tetrazol-5yl)pyrrolidin-1 -yl)methyl)-3 fluoro-2,2'-dimethyl-[1, G :3',1terphenyl ] -3 -yl)-6(difluoromethoxy)benzo[c!]oxazol -5-yl)methyl)proline noos^ 738.3 252 ((2-(4-(((8)-3-((benzyloxy)methyl)pyrrolidin-1 -yl)methyl)3 -fluoro-2,2'-d imethyl-[ 1, G: 3', 1 terphenyl]-3 -yl)-6(difluoromethoxy)benzo[c!]oxazol -5-yl)methyl)proline NOOS^ 790.3

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253 ((6-(difluoromethoxy)-2-(2-fluoro2,2'-dimethyl-4-(pyrrolidin-1 yl methyl)-[1,G:3',1-terphenyl]-3 yl)benzo[s! ]oxazol-5-yl)methyl)L-proline ' \=/ / COOH chf ₂ 670.3 254 hydrochloride ((6(difluoromethoxy)-2-(3, 5 dimethoxy-2,2'-dimethyl-4(pyrrolidin-1 -ylmethyl)[ 1, G: 3', 1 -terphenyl]-3 -yl)benzo[ c!]oxazol-5-yl)methyl)-Eproline noos Uts I //'Λζχ' ⁰ , /-- ¹ chf ₂ ΑΊ T Ί T II Ί 1 HCI OMe 748.3 255 ((6-(difluoromethoxy)-2-(2,2'dimethyl-4-(pyrrolidin-2-yl)[ 1, G: 3', 1 -terphenyl]-3 -yl)benzo[c!]oxazol- 5-yl)methyl)-Eproline ΗΝ^\ COOH 638.3 256 ((2-(4-((8)-amino(carboxy)methyl)-2,2'-dimethyl-[ 1, G: 3', 1 terphenyl]-3 -yl)-6(difluoromethoxy)benzo[s !]oxazol -5-yl)methyl)-b-proline τ Ο Ο Ο ΖΙ< A _s U. ο ζ ° Τ Ο'° 642.2 257 ((6-(difluoromethoxy)-2-(4-(((8)3 -((8)-2-((methoxycarbonyl)amino)-3 -methylbutanamide o)pyrrolidin-1 -yl)methyl)-2, 2'dimethyl-[1, G:3', 1-terphenyl]-3 yl)benzo[c!]oxazol-5-yl)methyl)L-proline NOOS Λ Ρ уУ 824.4

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258 ((6-(difluoromethoxy)-2-(3-fluoro2,2'-dimethyl-4-((5-ureidoisoindolin-2-yl)methyl)[ 1, G: 3', 1 -terphenyl]-3 -yl )benzo[c1]oxazol-5-yl)methyl)-Eproline noos 776.3 260 ((6-(difluoromethoxy)-2-(3-fluoro2,2'-dimethyl-4-((3-ureidopyrrolidin-1 -yl)methyl)[ 1, G: 3', 1 -terphenyl]-3 -yl )benzo[c1]oxazol-5-yl)methyl)-Eproline NOOS 728.3 262 ((6-(difluoromethoxy)-2-(3'-(4fluoro-6-(pyrrolidin-1ylmethyl)pyridin-3-yl)-2,2'dimethyl-[1,1'-biphenyl]-3-yl )benzo[c1]oxazol-5-yl)methyl)-Eproline noos 671.3 263 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-(pyrrolidin-1ylmethyl)pyridin-3-yl)-[1, Gbiphenyl]-3-yl)benzo[c1 ]oxazol5-yl) methyl )-L-proleine noos Yn-YV ¹ m 653.3 264 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(pyrrolidin-1ylmethyl)pyridin-2-yl)-[1,1 biphenyl]-3-yl)benzo[c1 ]oxazole- 5-yl)methyl)-L-proleine noos .A Az ^CHF2 653.3

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265 ((6-(d fluoromethoxy)-2-(3 '-(5 fluoro-6-(pyrrolidin-1 ylmethyl)pyridin-3-yl)-2,2'dimethyl-[1,1 '-biphenyl]-3 -yl)benzo[0]oxazol-5-yl)methyl)-bproline NOOS 671.3 266 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-(pyrrolidin-1 ylmethyl)pyridin-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl )benzo[0]oxazol-5-yl)methyl)-bproline NOOS 683.3 267 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(6-oxo-5(pyrrolidin-1 -ylmethyl)-1,6d ihydropyrid in-2-yl)- [1, Gbiphenyl] -3-yl)benzo[c!]oxazol5-yl) methyl )-L-proleine NOOS 669.3 268 ((6-(difluoromethoxy)-2-(2'(d iforomethyl)-3'-(5 -fluoro-6(pyrrolidin-1 -ylmethyl)pyridin-3 -yl)-2-methyl-[ 1, Gbiphenyl ]-3-yl)benzo[c!]oxazol5-yl) methyl )-L-proleine NOOS 707.3 269 ((6-(d fluoromethoxy)-2-(3'-(5 fluoro-6-(pyrrolidin-1 ylmethyl)pyridin-3 -yl)-2'(fluoromethyl)-2-methyl-[1, Gbiphenyl] -3-yl)benzo[c1]oxazol5-yl) methyl )-L-proleine NOOS 689.3

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270 ((6-(difluoromethoxy)-2-(3'-(2fluoro-6-(pyrrolidin-1 ylmethyl)pyridin-3 -yl)-2,2'dimethyl-[1,1'-biphenyl]-3 - yl)benzo[0]oxazol-5-yl)methyl)-bproline NOOS ahAU^° ^! 671.3 271 ((6-(d fluoromethoxy)-2-(3'-(5 ((3,3-dimethylazetidin-1yl)methyl)-6-methoxypyridin-2yl)-2,2'-dimethyl-[1,1' -biphenyl]3-yl)benzo[c1]oxazol-5- yl)methyl)-b-proline NOOS । GP1 । Chd °ύ ^ν ύτύύ ^λ Α ^chf * U-mХДД ¹ beat 697.3 272 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5 -(((R)-3 methylpyrrolidin-1 -yl)methyl)pyridin-2-yl)-2,2'-dimethyl[1, G-biphenyl]-3-yl)benzo[(1]oxazol-5-yl)methyl)-Eprolin NOOS .....ahAuA.” 697.3 273 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-(((8)-3methylpyrrolidin-1 -yl)methyl)pyridin-2-yl)-2,2'-dimethyl[1,G -biphenyl]-3-yl)benzo[<1]oxazol-5 -yl)methyl)-Oproline NOOS 697.3 274 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(pyrrolidin-1ylmethyl)-4-vinylpyridin-2yl)-[1,G-biphenyl]-3-yl)benzo |D]oxazol-5-yl)methyl)-Eprolin NOOS 679.3

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275 ((6-(d fluoromethoxy)-2-(3'-(5 -((3 (difluoromethyl)pyrrolidin-1yl)methyl)-6-methoxypyridin-2yl)-2,2'-dimethyl-[ 1,1 '-biphenyl]3-yl)benzo[c1]oxazol-5yl)methyl)-b-proline noos 733.3 276 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-((((5oxopyrrolidin-2yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl[1,G -biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline noos 726.3 277 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-(((8)-2methylpyrrolidin-1 -yl)methyl)pyridin-2-yl)-2,2'-dimethyl[1,G -biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline noos ^ioAyV ⁰ 697.3 278 ((2-(3'-(5-(((ls,4s)-7azabicyclo[2.2.1] heptan-7-yl)methyl)-6-methoxypyridin-2-yl)2,2'-dimethyl-[ 1,G-biphenyl]-3yl)-b-(difluoromethoxy)benzo[0]oxazol-5-yl)methyl)-bproline noos 709.3

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279 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-(((R)-2methylpyrrolidin-1 -yl)methyl)pyridin-2-yl)-2,2'-dimethyl[1,G -biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl)-bproline noos ¹ GS 1 I chf ₂ II Ί T II Ί 697.3 280 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(pyrrolidin-1ylmethyl)thiophen-2-yl)-[1, Hbiphenyl]-3-yl)benzo[c1] Oxazol5-yl) methyl )-L-proleine noos SAaa Vs 1 AC 658.3 281 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(2-(pyrrolidin-1ylmethyl)pyrimidin-5-yl)-[1, Hbiphenyl]-3-yl)benzo[c1] Oxazol5-yl) methyl )-L-proleine noos nWyVo^ chf ₂ 654.3 282 ((6-(difluoromethoxy)-2-(2,2'd imethyl-3'-(2-(4-methylpiperazin-1 -yl)pyrimid in-5 yl)-[1,G-biphenyl]-3- yl)benzo[s!]oxazol-5-yl)methyl)-Eprolin noos 669.3 283 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(2-(pyrrolidin-1 yl)pyrimidin-5-yl)-[1,Hbiphenyl]-3-yl)benzo[c1] Oxazol5-yl) methyl )-L-proleine NOOS 640.3

- 105 047234

284 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(5 -(pyrrolidin-1ylmethyl)pyrazin-2-yl)-[1, Hbiphenyl]-3-yl)benzo[c1] Oxazol5-yl) methyl )-L-proleine noos 654.3 285 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5-(pyrrolidin-1 ylmethyl)pyrazin-2-yl)-2,2'dimethyl-[1,1'-biphenyl]-3 -yl )benzo[c1]oxazol-5-yl)methyl)-Eproline noos 684.3 286 ((6-(difluoromethoxy)-2-(3'-(6methoxy-5 -(((R)-3 -methylpyrrolidin-1 -yl)methyl)pyrazin-2-yl)-2,2'-dimethyl-[ 1,1 'biphenyl]-3-yl)benzo[c1]oxazol5-yl) methyl )-L-proleine NOOS..... 698.3 287 ((2-(2'-chloro-3'-(6-methoxy-5-((((5oxopyrrolidin-2-yl)methyl)amino)methyl)pyrazin-2-yl)-2methyl-[1,1' -biphenyl]-3-yl)-6(difluoromethoxy)benzo[c1]oxazol -5-yl)methyl)-b-proline ΗΝ—/ A=nW_/ ι ^Ν & —0 Cl VK (ΗΪΙ 747.2 288 ((6-(difluoromethoxy)-2-(2,2'd imethyl-3'-(1,2,3,4tetrahydroisoquinolin-6-yl)[1,G-biphenyl]-3-yl)benzo[c1] Oxazol-5-yl)methyl)-Eproline ⁿ Oy~C) ν° ^Η F^F 624.3

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289 ((6-(difluoromethoxy)-2-(3'(isoindolin-5-yl)-2,2'-dimethyl[1,G-biphenyl]-3-yl)benzo[0]oxazol-5-yl)methyl )-bproline 'xCCCIC °·ν ^0Η 610.2 290 ((2-(3'-(2-(2-carboxyethyl)isoindolin-5-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[( 1]oxazole -5-yl)methyl)-b-proline O ^L ~O ^- O v° i 682.3 291 ((2-(3 '-(2-(carboxymethyl)isoindolin-5-yl)-2,2'-dimethyl[1,1 '-biphenyl]-3 -yl)-6(difluoromethoxy)benzo[(1] oxazole -5-yl)methyl)-E-proline ° Su °<v° ^h ' ^:χχύ F^F 668.3 292 ((2-(3'-(2-(1-carboxyethyl)isoindolin-5-yl)-2,2'-dimethyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoke)benzo[0 ]oxazol -5-yl)methyl)-E-proline ⁰ \Ζ/“Ο V ^Oh F^F 682.3 293 ((2-(3'-(2-amino-1Hbenzo[s!]imidazol-5-yl)-2,2'd imethyl-[1,1'-biphenyl]-3 -yl)-6(difluoromethokea) benzo[0]oxazol -5-yl)methyl)-E-proline HOOC jOl 1 I yy ° t Ύt H 624.2 294 ((6-(d fluoromethoxy)-2-(3'-(5 ((3,3-dimethylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)2,2'-dimethyl-[1, G-biphenyl]-3yl)benzo[c1]oxazol-5-yl)methyl)- L-proline HOOC 711.3

Example 295: Synthesis of compound 295.

((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-III-benzo^]imidazol-2-yl)-2,2'-dimethyl[1,G-biphenyl]3- yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)^-proline

Connection 295

Step 1: preparation of methyl 4-amino-3-iodo-5-nitrobenzoate

Methyl 4-amino-3-nitro-benzoate (5 g) was added to a mixture of Ag ₂ SO ₄ (7.93 g) and 12 (6.47 g) in EtOH (20 ml) at room temperature. This mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate. The organic layers were washed with aqueous Na2S2O3, dried over MgSO ₄ and evaporated to dryness. The residue was purified by

- 107 047234 chromatography on silica gel to obtain the target product methyl 4-amino-3-iodo-5-nitro-benzoate (7 g) in the form of a yellow solid.

Step 2: preparation of methyl 3,4-diamino-5-iodobenzoate

SnCl2 (8.42 g) was added to a solution of compound 295-1 (3 g) in EA (30 ml). The reaction mixture was stirred at 70°C for 16 hours. EA (50 ml) was added to this reaction mixture and the organic layer was washed with aqueous NaHCO ₃ , dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography to give the title product methyl 3,4-diamino-5-iodobenzoate (2.6 g) as a yellow solid.

Step 3: preparation of methyl 2-(3-bromo-2-methylphenyl)-7-iodo-III-benzo^]imidazole-5-carboxylate

A mixture of compound 295-2 (2.6 g), 3-bromo-2-methyl-benzaldehyde (1.77 g) and AcOH (30 ml) was stirred at 80°C for 16 hours. EA ( 50 ml) and the organic layer was washed with water, dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography to give the title product methyl 2-(3-bromo-2-methyl-phenyl)-7-iodoSh-benzimidazole-5-carboxylate (3.2 g) as a yellow solid.

Step 4: Preparation of 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo^]imidazole-5-carboxylic acid

To a solution of compound 295-3 (2 g) in MeOH (20 ml) was added a solution of NaOH (849.10 mg) in H ₂ O (6 ml). The reaction mixture was stirred at 50°C overnight. The mixture was concentrated. H ₂ O (10 ml) was added to this mixture and the pH was adjusted to 5 with 2 N. HCl. The precipitate was filtered and the filter cake was washed with H ₂ O. The product was dried in a vacuum oven (45°C, 3 hours) to obtain the title compound 2-(3-bromo-2-methyl-phenyl)-7-iodo-1H- benzimidazole-5-carboxylic acid (1.8 g) as an off-white solid.

Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo^]imidazol-5-yl)methanol

Borane-tetrahydrofuran complex (20 ml) was added to a solution of compound 295-4 (1.8 g) in THF (20 ml) at -30°C. The reaction mixture was then stirred at 60°C for 16 hours. The mixture was cooled to room temperature and 2N was added. HCl (20 ml). After 10 minutes, this mixture was diluted with ethyl acetate and washed with water.

The organic layer was dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography to give the title product [2-(3-bromo-2-methyl-phenyl)-7-iodoSh-benzimidazol-5-yl]methanol (1 g) as a white solid.

Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-III-benzo^]imidazole-7carbonitrile

A mixture of compound 295-5 (500 mg), Zn(CN)2 (66.02 mg) and d(PPh ₃ ) ₄ (130.34 mg) in DMF (10 ml) was stirred at 90°C for 3 hours in nitrogen atmosphere. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate. The organic layer was then washed with aqueous NaCl, dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography to give the title product 2-(3-bromo-2-methyl-phenyl)-6-(hydroxymethyl)-3H-benzimidazole-4-carbonitrile (150 mg) as a yellow oil.

Step 7: Preparation of 2-(3-bromo-2-methylphenyl)-5-(chloromethyl)-1H-benzo^]imidazole-7-carbonitrile

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This compound was prepared using procedures similar to those described for Step 2 in Example 1, using compound 295-6 instead of compound 1-1. The mixture was concentrated to give the title compound.

Step 8: Preparation of 2-(3-bromo-2-methylphenyl)-5-(pyrrolidin-1-ylmethyl)-1H-benzo^]imidazole-7carbonitrile

This compound was prepared using procedures similar to those described for Step 3 in Example 1, using compound 295-7 instead of compound 1-2 and using pyrrolidine instead of (1S,2R)-2-aminocyclopentan-1-ol. The crude product was purified by silica gel chromatography to give the title compound.

Step 9: preparation of methyl-((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo^]imidazol-2-yl)2,2'-dimethyl-[1, G-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)-E-prolinate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using compound 295-8 instead of compound a-6. The crude product was purified by silica gel chromatography to give the title compound.

Step 10: preparation of ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzo^]imidazol-2-yl)-2,2'dimethyl-[1,G- biphenyl]-3-yl)-6-(difluoromethoxy)-benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 295-9 instead of compound 1-4. The crude product was purified by preparative high performance liquid chromatography (HPLC) to obtain the target product (2S)-1-[[2-[3-[3-[7-cyano-5-(pyrrolidin-1-ylmethyl)-1H-benzimidazol- 2-yl]-2-methylphenyl]-2-methyl-phenyl]-6-(difluoromethoxy)-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid. LC-MS (m/z): 717.3 (M+H)+.

Connections table 7 was prepared analogously to Example 295 using different reaction starting materials and suitable reagents.

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Table 7

No. Etc. Chemical name Structure Phys. data (MS) (M+N) ⁺ 296 ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1ylmethyl)-1H-benzo[c1]imidazol-2-yl)2,2'-dimethyl-[1, G-biphenyl] - 3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline O U ΧΛ ΖυΡίΥΥ ^but cj υλυλα n Τ ^r F 728.3 297 ((6-(difluoromethoxy)-2-(3'-(6-fluoro-5(pyrrolidin-1 -ylmethyl)- 1Hbenzo[b]imide azol-2-yl)-2,2'-dimethyl[1,1 '-biphenyl]-3-yl)benzo[b]oxazol-5 yl)venstyl)-G-proline /=\ /—\ ο ΡΑΆΑ ι ^{ν ΗΟ} \_7 \=/\ΑΑ Η 710.3 298 ((2-(3 '-(6,7-difluoro-1 -methyl-5 (pyrrolidin-1 -ylmethyl)- 1Hbenzo[b]imide azol-2-yl)-2,2'-dimethyl[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline /=\ /--\ ο « 'J 742.3 299 ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1ylmethyl)-1 -(2,2,2-trifluoroethyl)- 1Hbenzo[b]imide azol-2-yl)-2,2 '-dimethyl[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline ^F X]/ ^F ρ 0 /Р_7 f rWiY ^ΗΟ UV FF 810.3 300 ((2-(3 '-(4,5-difluoro-6-(pyrrolidin-1ylmethyl)-1 -(2,2,2-trifluoroethyl)- 1Hbenzo[b]imide azol-2-yl)-2,2 '-dimethyl[1,1 '-biphenyl]-3-yl)-6(difluoromethoxy)benzo[d]oxazol-5 yl)methyl)-b-proline Άτ°^ν=\ VP Жги , о Г / \__/ ' J HO ^Z PJ VAA-Xp, F 810.3 301 ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'(5 -(pyrrolidin-1 -ylmethyl)-7 (trifluoromethoxy)-1H-bsnzo|4|imidazol-2yl)-[1, G-biphenyl]-3yl)benzo[d]oxazol-5-yl[methyl )-Lproline / _H CF, ^noL tHxw 760.3 302 ((2-(2'-chloro-3'-(5 -(((2-hydroxyethyl)amino)methyl)picolinamido)-2-methyl[1,1'-biphenyl]-3 -yl)-6(difluoromethoxy )benzo[d]oxazol-5 yl)venstyl)-G-proline °^oi 706.2 303 ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'(5,6,7,8-tetrahydroimidazo[1,2a]pyrazine-2-carboxamido)-[1,1'biphenyl] - 3 -yl)benzo[d]oxazol-5 yl)ven)-G-proline noos Ζ—/~~ ^Ν \Χ i o ^1st IU ^{0 CHF2} HN^ 657.3

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Example 304: Synthesis of compound 304.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(pyrrolidin-1-ylmethyl)-oxazol-2-yl)-[1,1'biphenyl] -3-yl)benzo[d]oxazol-5-yl)methyl)U-proline

Connection 304

Step 1: methyl 2-bromo-4-methyl-oxazole-5-carboxylate o 9

304-1 tert-butyl nitrite (2.24 g) was added to a suspension of methyl 2-amino-4-methyl-oxazole-5-carboxylate (1.7 g) and CuBR ₂ (7.28 g) in acetonitrile (20 ml ). This mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was then washed with aqueous NaCl, dried over MgSO ₄ and evaporated to dryness. The residue was purified by silica gel chromatography to give the title product methyl 2-bromo-4methyl-oxazole-5-carboxylate (800 mg) as a white solid.

Step 2: Preparation of methyl 2-(3-bromo-2-methyl-phenyl)-4-methyl-oxazole-5-carboxylate

³⁰⁴ ' ¹ 304-2

This compound was prepared using procedures similar to those described for Step 1 in Example 1. The crude product was purified by silica gel chromatography to give the title compound.

Step 3: Preparation of [2-(3-bromo-2-methyl-phenyl)-4-methyl-oxazol-5-yl]-methanol

This compound was prepared using procedures similar to those described for step 5 in Example A, using compound 304-2 instead of compound a-4. The crude product was purified by silica gel chromatography to give the title compound.

Step 4: preparation of 2-(3-bromo-2-methyl-phenyl)-5-(chloromethyl)-4-methyl-oxazole - ^with EC

304-3 304-4

This compound was prepared using procedures similar to those described for Step 2 in Example 1, using compound 304-3 instead of compound 1-1. The mixture was concentrated to give the title compound.

Step 5: Preparation of 2-(3-bromo-2-methyl-phenyl)-4-methyl-5-(pyrrolidin-1-ylmethyl)oxazole

This compound was prepared using procedures similar to those described for Step 3 in Example 1, using compound 304-4 instead of compound 1-2 and using pyrrolidine instead of (1S,2R)-2-aminocyclopentan-1-ol. The crude product was purified by silica gel chromatography to give the title compound.

Step 6: preparation of methyl-^)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[4-methyl-5(pyrrolidin-1-ylmethyl)oxazol- 2-w]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2carboxylate

- 111 047234

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using compound 304-5 instead of compound a-6. The crude product was purified by silica gel chromatography to give the title compound.

Step 7: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(pyrrolidin-1ylmethyl)oxazol-2-yl)-[1,1'- biphenyl]-3 - yl)benzo[d]oxazol-5-yl)methyl)a-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 304-6 instead of compound 1-4. The crude product was purified by preparative HPLC to give the title compound. LC-MS (m/z): 657.3 (M+H)+.

Example 305: Synthesis of compound 305.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5-a]pyridin2-yl )-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)^-proline

Step 1: Preparation of ethyl X-[[5-(hydroxymethyl)-2-pyridyl]carbamothioyl]-carbamate

To a solution of (6-aminopyridin-3-yl)methanol (5

d) Ethyl N(thioxomethylene)carbamate (7.92 g) was added to 1,4-dioxane (25 ml). The reaction mixture was stirred at 50°C for 3 hours. The mixture was concentrated to obtain a residue. This residue was used directly in the next step.

Step 2: Preparation of (2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol

BUT N S O n n

EtN(Pr-i)2, MeOH, EtOH, 3 h C/U

305-1 305-2

Hydroxylamine hydrochloride (5.13 g) was added to a solution of compound 305-1 (9.5 g) in methanol (15 ml)/ethanol (15 ml), followed by the addition of yUdiisopropylethylamine (9.62 g). The reaction mixture was then stirred at 50°C for 3 hours. The crude product was cooled and the precipitate was filtered to obtain the desired product (5.0 g) as a green oil.

Step 3: production of (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)methanol ^ηο '^Ύ^Ϊ'Υνη ₂ ________. ΗΟ'^^Ν'Ν

305-2 ^305-3 tert-butyl nitrite (5.6 g) was added to a suspension of compound 305-2 (5 g) and copper(II) bromide (1.22 g) in acetonitrile (50 ml). This mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried, filtered and concentrated to near dryness. The residue was purified by silica gel chromatography to give the title product (3.2 g) as a white solid.

Step 4: Preparation of [2-(3-bromo-2-methyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methanol

- 112 047234

This compound was prepared using procedures similar to those described for Step 1 in Example 1. The residue was purified by silica gel chromatography to give the title compound.

Step 5: Preparation of 2-(3-bromo-2-methyl-phenyl)-6-(chloromethyl)-[1,2,4]triazolo[1,5-a]pyridine

This compound was prepared using procedures similar to those described for step 2 in example 1, using compound 305-4 instead of compound 1-1. The crude product was used directly in the next step.

Step 6: Preparation of 2-(3-bromo-2-methyl-phenyl)-6-(pyrrolidin-1-ylmethyl)-[1,2,4]triazolo[1,5a]pyridine

This compound was prepared using procedures similar to those described for Step 3 in Example 1, using compound 305-5 instead of compound 1-2 and using pyrrolidine instead of (1S,2R)-2-aminocyclopentan-1-ol. The crude product was purified by silica gel chromatography to give the title compound.

Step 7: preparation of methyl-^)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[6-(pyrrolidin-1ylmethyl)-[1,2,4 ]triazolo[1,5-a]pyridin-2-yl]phenyl]-phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylate

This compound was prepared using procedures similar to those described for Step 1 in Example 1, using compound 305-6 instead of compound a-6. The crude product was purified by silica gel chromatography to give the title compound.

Step 8: preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)[1,2,4]triazolo[1,5-a] pyridin-2-yl)-[1,G-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using procedures similar to those described for step 5 in Example 1, using compound 305-7 instead of compound 1-4. The crude product was purified by preparative HPLC to give the title compound. LC-MS (m/z): 693.3 (M+H)+.

Example 306: Synthesis of compound 306.

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidin-1-yl)piperidin-1-yl)-[1,1'-biphenyl]-3yl)benzo ^]oxazol-5-yl)methyl)^-proline

OOHE °<v° ^h \=/

F^F

Compound 306 Step 1: Preparation of 1-(3-bromo-2-methyl-phenyl)-4-pyrrolidin-1-yl-piperidine

- 113 047234

Mixture of 1,3-dibromo-2-methyl-benzene (1 g), 4-pyrrolidin-1-ylpiperidine (617.18 mg), CS ₂ CO ₃ (3.91 g), Pd ₂ (dba) ₃ (366 .10 mg) and Xantphos (462.53 mg) in toluene (20 ml) were stirred at 100°C overnight under nitrogen atmosphere. The mixture was concentrated to obtain a residue. This residue was purified by silica gel chromatography to give the title product 1-(3-bromo-2-methyl-phenyl)-4-pyrrolidin1-yl-piperidine (450 mg) as a red oil.

Step 2: Preparation of methyl-(2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-(4-pyrrolidin-1yl-1-piperidyl)phenyl]phenyl ]-1,3-benzoxazol-5-yl]methyl]-pyrrolidine-2-carboxylate

This compound was prepared using a procedure similar to that described for Step 1 in Example 1, using compound 306-1 instead of compound a-6. The crude product was purified by silica gel chromatography to give the title compound.

Step 3: preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidin-1-yl)piperidin-1-yl)[1,G-biphenyl]-3 -yl)benzo^]oxazol-5-yl)methyl)-E-proline

This compound was prepared using a procedure similar to that described for step 5 in Example 1, using compound 306-2 instead of compound 1-4. The crude product was purified by preparative HPLC to give the title compound. LC-MS (m/z): 645.3 (M+H) ⁺ .

Connections table 8 was prepared similarly to Examples 304-306 using different reaction starting materials and suitable reagents.

- 114 047234

Table 8

No. Etc. Chemical name Structure Phys. data (MS) (M+H) ⁺ 307 ((6-(difluoromethoxy)-2-(3 '-(4-((( 1 (hydroxymethyl)cyclopropyl)methyl)amino) piperidin-1 -yl)-2,2'-dimethyl[1,1 '-biphenyl ] -3 -yl) benzo [d] oxazol-5 -yl)methyl) -Lproline u° ⁿ nsA U \=/οΆΑ _ο Ά F^F 675.3 308 ((6-(difluoromethoxy)-2-(3'-(4-((3,3dimethylazetidin-1 -yl)methyl)piperidin-1 -yl)-2,2'dimethyl-[1,1'-biphenyl] -3 yl)benzo[b]oxazol-5-yl)methyl)L-proline 8. /00 QCy οΆ o I 673.4 309 ((6-(difluoromethoxy)-2-(2,2'dimethyl-3'-(4-(pyrrolidin-1 ylmethyl)piperidin-1 -yl)-[ 1, G biphenyl]-3 -yl)-benzo [ d]oxazol5 -yl) methyl) -L-npo lin 0^-0 . 0 8 659.3

Below are 1H NMR data for compounds 34, 61, 85, 88, 93, 113, 127, 130, 131, 135, 142 and 146.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 8.17 (dd, J=8.0, 2.2 Hz, 2H), 8.08 (s, 1H), 7.88 (s, 1H) , 7.81 (s, 1H), 7.64-7.51 (m, 2H), 7.49-7.20 (m, 4H), 4.52 (s, 2H), 4.38-4.12 (m, 2H), 3.94-3.84 (m, 4H) , 3.26-2.86 (m, 3H), 2.45 (s, 6H), 2.37-1.71 (m, 4H), 1.31 (d, J=43.4 Hz, 6H). (Compound 34).

1H NMR(500 MHz, Chloroform-d) δ 8.30-8.03 (m, 4H), 7.66-7.54 (m, 2H), 7.49-7.41 (m, 2H), 7.40-7.35 (m, 2H), 7.10 -6.77 (m, 2H), 4.86-4.18 (m, 5H), 3.94-3.57 (m, 3H), 3.43-3.25 (m, 2H), 2.71-2.55 (m, 2H), 2.48 (d, J= 3.7 Hz, 6H), 2.37-1.58 (m, 6H), 1.27-1.08 (m, 3H). (Compound 61).

1H NMR(500 MHz, Chloroform-d) δ 8.13 (dd, J=7.8, 6.1 Hz, 2H), 7.99 (d, J=9.8 Hz, 2H), 7.52 (d, J=17 ,9 Hz, 2H), 7.48-7.42 (m, 2H), 7.37-7.34 (m, 2H), 6.83 (t, J=71.9 Hz, 1H), 6.80 (t, J=71.9 Hz, 1H), 4.29 (d, J=25.2 Hz, 4H), 3.70 (s, 4H), 3.42 (dd, J=10.6, 4.4 Hz, 1H), 3.21 (q, J=8, 3 Hz, 2H), 3.09 (d, J=22.7 Hz, 2H), 2.46 (d, J=7.9 Hz, 6H), 2.34-2.22 (m, 2H), 1.35 (s, 6H). (Compound 85).

1H NMR(500 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.22 (dd, J=7.9, 1.5 Hz, 1H), 8.17-8.07 (m, 2H), 7.99 (s, 1H ), 7.59 (s, 1H), 7.46 (dt, J=12.7, 7.7 Hz, 2H), 7.42-7.34 (m, 2H), 6.93 (t, J=72.1 Hz, 1H), 4.78-4.62 (m, 2H), 4.52 (t, J=12.8 Hz, 2H), 4.21 (t, J=8.0 Hz, 1H), 3.87-3.58 (m, 3H), 3.21-3.00 ( m, 2H), 2.75-2.53 (m, 3H), 2.47 (d, J=15.4 Hz, 6H), 2.39-2.23 (m, 2H), 2.16 (t, J=7.9 Hz, 2H) , 1.78 (d, J=62.1 Hz, 1H), 1.21-1.10 (m, 3H). (Compound 88).

1H NMR(500 MHz, Chloroform-d) δ 8.18 (d, J=7.9 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.93-7.76 (m, 2H), 7.55 ( s, 1H), 7.49-7.26 (m, 5H), 6.76 (t, J=72.9 Hz, 1H), 4.29-3.39 (m, 6H), 3.23-2.91 (m, 6H), 2.38-2.47( d, J=25.5 Hz, 6H), 2.09-1.60 (m, 3H), 1.23 (s, 6H). (Compound 93).

1H NMR (500 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.26 (s, 1H), 8.20 (dd, J=7.9, 1.4 Hz, 1H), 8.13 (ddd, J=23 ,5, 7.9, 1.5 Hz, 1H), 7.96 (d, J=10.1 Hz, 1H), 7.72 (d, J=13.9 Hz, 1H), 7.61-7.49 (m, 2H ), 7.45 (ddd, J=13.6, 7.6, 1.5 Hz, 2H), 7.38 (d, J=71.9 Hz, 1H), 3.96 (s, 2H), 3.44-3.22 (m , 5H), 3.11-2.99 (m, 2H), 2.57 (q, J=8.5 Hz, 1H), 2.45 (d, J=5.8 Hz, 6H), 2.19-2.06 (m, 1H), 1.93-1.64 (m, 4H), 1.22 (d, J=7.5 Hz, 6H). (Compound 113).

1H NMR(500 MHz, Chloroform-d) δ 8.24 (dd, J=7.9, 1.4 Hz, 1H), 8.17-8.07 (m, 2H), 8.03 (s, 1H), 7.79 (s, 1H ), 7.60 (s, 1H), 7.48 (dt, J=15.0, 7.7 Hz, 2H), 7.43-7.35 (m, 2H), 6.94 (t, J=71.9 Hz, 1H), 4.60 (d, J=13.1 Hz, 1H), 4.50 (d, J=13.2 Hz, 1H), 3.97 (s, 3H), 3.71-3.60 (m, 1H), 3.15 (q, J= 9.9 Hz, 1H), 2.76 (s, 4H), 2.47(s, 6H), 2.33-2.24 (m, 1H), 2.15-2.06 (m, 1H), 2.06-1.97 (m, 2H), 1.91 (q, J=3.5, 3.0 Hz, 4H). (Compound 127).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.20 (dd, J=7.9, 1.4 Hz, 1H), 8.16 (dd, J=7.9, 1.4 Hz, 1H), 8.11 ( d, J=1.5 Hz, 1H), 7.97 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.73 (s, 1H),7.63-7.51 (m, 2H), 7.48 (dd, J=7.6, 1.4 Hz, 1H), 7.44 (dd, J=7.6, 1.4 Hz, 1H), 7.38 (t, J=73.7 Hz, 1H), 3.96 (s, 2H), 3.79-3.68 (m, 2H), 3.38-3.31 (m, 1H), 3.09-3.03 (m, 1H), 2.74-2.48 (m, 5H), 2.44 (d, J=2, 9 Hz, 6H), 2.26-1.68 (m, 6H), 1.36-1.20 (m, 1H), 0.99 (d, J=6.7 Hz,

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3H). (Compound 130).

1H NMR(500 MHz, DMSO-d6) δ 8.21 (dd, J=7.9, 1.4 Hz, 1H), 8.19 (s, 1H), 8.15 (dd, J=7.9, 1.4 Hz , 1H), 7.97 (s, 1H), 7.95 (s, 1H), 7.73 (s, 1H), 7.63-7.51 (m, 2H), 7.48 (dd, J=7.6, 1.4 Hz, 1H ), 7.44 (dd, J=7.5, 1.4 Hz, 1H), 7.38 (t, J=73.7 Hz, 1H), 3.97 (s, 2H), 3.92-3.86 (m, 2H), 3.38-3.31 (m, 1H), 3.11-3.05 (m, 1H), 2.83-2.51 (m, 5H), 2.44 (d, J=4.1 Hz, 6H), 2.31-1.70 (m, 6H), 1.46-1.14 (m, 1H), 1.00 (d, J=6.3 Hz, 3H). (Compound 131).

¹ H NMR (500 MHz, Chloroform-d) δ 8.25 (d, J=7.8 Hz, 1H), 8.14 (dd, J=7.9, 1.3 Hz, 1H), 8.10 (s, 1H) , 7.94 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.48 (dt, J=15.2, 7.7 Hz, 2H), 7.42-7.34 (m, 2H), 6.93 (t, J=71.9 Hz, 1H), 4.55 (d, J=13.0 Hz, 1H), 4.37 (d, J=13.1 Hz, 2H), 3.94-3.35 (m, 5H), 3.17-2.82 (m, 4H), 2.51 (s, 3H), 2.47 (s, 3H), 2.47-2.29 (m, 2H), 2.16-1.46 (m, 10H). (Compound 135).

1H NMR(500 MHz, DMSO-d ₆ ) δ 8.35-8.30 (m, 1H), 8.23 (dd, J=8.0, 1.5 Hz, 1H), 8.18 (dt, J=7.9, 1 ,3 Hz, 1H), 8.12 (d, J=1.4 Hz, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.61 (dt, J=13.6, 7.7 Hz, 2H), 7.57-7.45 (m, 2H), 7.40 (t, J=73.2 Hz, 1H), 4.62-4.25 (m, 4H), 3.58-3.07 (m, 5H), 2.52-2.50 (m, 1H), 2.49-2.48 (m, 4H), 2.45 (d, J=5.5 Hz, 6H), 2.26-1.80 (m, 4H). (Compound 142).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.35 (s, 1H), 8.23 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.13-8.07 (m, 2H), 7.87 (s, 1H), 7.70 (s, 1H), 7.60 (dt, J=14.9, 7.7 Hz, 2H), 7.56-7.44 (m, 2H), 7.32 (t , J=73.2 Hz, 1H),4.56-4.01 (m, 7H), 3.50 (s, 2H), 3.45-3.12 (m, 2H), 2.56 (s, 2H), 2.50-2.48 (m, 2H ), 2.45 (d, J=5.5 Hz, 6H), 2.43-2.33 (m, 1H) 2.08-1.79 (m, 3H). (Compound 146).

Comparison examples

The following comparison example compound (as shown in Table 9) was prepared essentially as described in Example 7 in WO2018119266.

Example Table 9 Chemical reference name (2 S,2' S)-1,1 '-(((2,2'-dimethyl-[1, Gbiphenyl]-3,3'-diyl)bis(61 (cyanomethoxy)benzo [c!]oxazole2,5-diyl))bis(methylene))bis(piperidine-2-carboxylic

acid)

PD-1/PD-L1 binding assay (Alphascreen).

Assays were performed in a standard black polystyrene 384-well plate with a final volume of 20 μl. The inhibitors were first serially diluted in DMSO and then added to the wells of the plate, followed by the addition of other reaction components. The final concentration of DMSO in the assay was 1%. 100 nL/well of compound was added to a 384-well reaction plate (6008280, PerkinElmer) using Echo and centrifuged at 1000 rpm for 1 min. To this 384-well reaction plate, add 5 μl/well of 4X PD-L1 solutions, centrifuge at 1000 rpm for 1 min and add 5 μl/well of 4X PD-1 solutions, centrifuge at

1000 rpm for 1 min and incubated at 25°C for 15 min. The concentrations of the compounds were 300, 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, 0.046, 0.015, 0 nM, respectively. To the above 384-well reaction plate, 10 μl/well of 2X anti6xHis AlphaLISA acceptor beads and streptavidin donor bead solution (PerkinElmer-AL356F) were added, centrifuged at 1000 rpm for 1 min and incubated at 25°C in the dark for 120 min. The AlphaLISA signal value was read using an Envision reader. Determination of IC ₅₀ was carried out by fitting a curve of the percentage of control activity depending on the logarithm of the inhibitor concentration using GraphPad Prism 8.0 software.

The compounds of the present invention illustrated in the Examples showed IC ₅₀ values in the following ranges: * means 0.1 nM < 1C ₅₀ < 5 nM; ** means 5 nM<1C ₅₀ <50 nM; *** means IC ₅₀ >50 nM.

Data obtained for the compounds of the Examples using the PD-1/PD-L1 binding assay (Alphascreen) described above are shown in table. 10.

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Table 10

No. Etc. ICso(hM) No. Etc. ICso(hM) No. Etc. ICso(hM) No. Etc. ICso(hM) 1 0.89 80 ** 159 * 238 2.3 2 0.2 81 ** 160 * 239 0.99 3 89 82 * 161 * 240 ** 4 1.4 83 ** 162 ** 241 ** 5 0.4 84 * 163 ** 242 * 6 4.3 85 * 164 ** 243 2.5 7 0.61 86 And 165 * 244 2 8 0.75 87 * 166 ** 245 3.8 9 18 88 * 167 ** 246 1.8 10 19 89 * 168 * 247 5.2 AND 33 90 0.88 169 * 248 ** 12 1.1 91 * 170 ** 249 ** 13 26 92 * 171 * 250 * 14 1.2 93 * 172 0.3 251 ** 15 0.5 94 1.9 173 0.93 252 * 16 1.1 95 1.4 174 21 253 4.7 17 1.2 96 0.6 175 3.4 254 16 18 164 97 * 176 0.9 255 2.3 19 1.3 98 * 177 0.94 256 *** 20 1.6 99 0.82 178 3.9 257 4.4 21 0.59 100 * 179 * 258 ** 22 25 101 2.2 180 * 259 * 23 7.7 102 18 181 * 260 ** 24 0.98 103 0.13 182 * 261 * 25 o, s 104 0.19 183 ** 262 ** 26 * 105 * 184 2.3 263 0.98 27 0.66 106 * 185 * 264 * 28 3.2 107 * 186 * 265 0.73 29 1.2 108 * 187 * 266 ** thirty * 109 1.6 188 * 267 ** 31 0.5 110 * 189 * 268 * 32 3.8 111 * 190 0.2 269 ** 33 1.5 112 * 191 ** 270 ** 34 1.3 FROM 0.5 192 ** 271 * 35 0.91 114 1 193 ** 272 1.9 36 1.1 115 * 194 ** 273 **

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37 * 116 * 195 ** 274 * 38 * 117 * 196 ** 275 ** 39 2.4 118 78 197 ** 276 * 40 * 119 1.9 198 *** 277 * 41 ** 120 1.1 199 ** 278 * 42 * 121 0.6 200 ** 279 * 43 ** 122 * 201 *** 280 5.7 44 1.1 123 * 202 0.37 281 1.3 45 * 124 * 203 12 282 ** 46 ** 125 * 204 * 283 ** 47 * 126 * 205 * 284 ** 48 * 127 3.1 206 1.4 285 * 49 * 128 0.14 207 ** 286 * 50 * 129 1.7 208 114 287 * 51 * 130 * 209 1.4 288 1.5 52 * 131 2.3 210 * 289 0.66 53 * 132 2 211 * 290 * 54 6.3 133 * 212 8.4 291 * 55 0.57 134 * 213 ** 292 ** 56 0.83 135 * 214 *** 293 And 57 1.2 136 * 215 2.8 294 * 58 0.79 137 * 216 * 295 ** 59 2.5 138 * 217 0.67 296 12 60 * 139 * 218 * 297 26 61 1.6 140 * 219 * 298 ** 62 2.6 141 * 220 * 299 *** 63 5.7 142 * 221 * 300 *** 64 1.8 143 * 222 * 301 ** 65 1.3 144 * 223 * 302 0.29 66 1.8 145 * 224 * 303 1.6 67 6.7 146 * 225 2 304 27 68 2.4 147 * 226 4.7 305 0.87 69 0.49 148 ** 227 4.1 306 1.5 70 3.3 149 * 228 4.3 307 * 71 0.37 150 * 229 6.9 308 * 72 0.98 151 * 230 1.5 309 * 73 0.42 152 * 231 78 310 * 74 1.1 153 * 232 7.8 311 * 75 10 154 ** 233 41 312 * 76 32 155 * 234 0.52 313 * 77 1.2 156 * 235 1.8 314 8 78 * 157 * 236 290 315 * 79 * 158 * 237 2.7 316 **

Pharmacokinetic analysis.

Adult female C57 mice were administered a single dose of test compounds with 10% DMSO,

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10% Kolliphor@HS 15 and 80% saline as excipients, and these mice (n=9) were administered orally (intragastric) at a dose of 100 mg/kg. Blood collection time: 15, 30 min, 1, 2, 4, 7, 24 h. Approximately 0.1 ml of whole blood was collected from the retroorbital venous plexus of 3 mice at each time point and placed in tubes containing K ₂ -EDTA in as an anticoagulant. Whole blood was centrifuged at 4°C and 4000 rpm for 10 min. Plasma was transferred into centrifuge tubes and stored at -20°C until analysis. Concentrations of test compounds in plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time data for individual animals were analyzed using Microsoft Excel 2010. A non-compartmental model was included in the concentration analysis. Pharmacokinetic parameters of the test compounds were calculated using WinNonlin software (version 4.1; Pharsight). The data is presented in table. eleven.

Adult female C57 mice were administered a single dose of test compounds with 15% DMSO, 10% Kolliphor@HS 15 and 75% saline as excipients, and these mice (n=3) were administered orally (intragastric) at a dose of 5 mg/kg . Blood collection time: 30 minutes, 2, 4 hours. Approximately 0.1 ml of whole blood was collected from the retroorbital venous plexus and placed in tubes containing K2-EDTA as an anticoagulant. Whole blood was centrifuged at 4°C and 4000 rpm for 10 minutes. Plasma was transferred into centrifuge tubes and stored at -20°C until analysis. Concentrations of test compounds in plasma samples were analyzed using liquid chromatography-tandem mass spectrometry (LCMS/MS). Plasma concentration-time data for individual animals were analyzed using Microsoft Excel 2010. Data are presented in Table. 12.

Table 11

No. Etc. Dose (mg/kg) T1/2 (hour) _Tah (hour) Stakh (ng/ml) AUC (hour*ng/ml) Etc. comparison No.l 100 1.94 1 76 196 2 100 3.30 0.5 218 271 3 100 0.39 1 374 461 5 100 5.07 4 2597 25686 8 100 3.97 4 974 8243 12 100 7.97 2 1383 14536 14 100 6.20 1 589 3453 15 100 9.83 1 931 5711 16 100 4.80 4 1473 20947 95 100 6.48 4 2033 22866 98 100 4.47 1 1007 8699 28 100 2.79 1 1283 5805 29 100 4.67 1 3720 42711 108 100 21.7 1 713 10139 31 100 9.81 1 1003 6605 33 100 11.00 4 727 8915 34 100 6.99 4 4257 56146 36 100 8.26 1 1667 21381

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61 100 5.37 4 8653 117700 62 100 9.69 4 4280 46470 63 100 5.80 1 2923 43669 64 100 7.20 7 4317 61468 65 10.74 4 2457 40371 100 100 10.5 4 18900 235468 171 100 3.66 1 965 3474 175 100 3.63 2 1627 19943 314 100 5.43 2 6353 28971 190 100 3.57 1 1280 8572 243 100 6.93 1 4887 67353 244 100 7.01 2 5737 78121 88 100 ΝΑ 24 117333 2024036 74 100 8.20 4 4463 59508 93 100 ΝΑ 4 9217 162649 103 100 23.40 4 5587 96382

Table 12

No. Etc. Dose (mg/kg) Concentration (ng/ml) 0.5 h 2 hours 4h Etc. comparison No.l 5.0 N.A. N.A. N.A. 5 5.0 43.9 55.7 61.2 10 5.0 80.9 221 214 13 5.0 79.3 241 301 18 5.0 303 642 626 22 5.0 68.6 155 81.1 23 5.0 46.2 148 94.7 34 5.0 46.8 136 154 56 5.0 19.9 192 155 57 5.0 27.1 149 90.0 66 5.0 N.A. 137 111

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67 5.0 143 418 462 70 5.0 36.4 151 158 72 5.0 42.6 140 132 80 5.0 247 299 167 81 5.0 115 468 383 85 5.0 75.9 146 135 89 5.0 21.3 124 109 101 5.0 178 640 579 102 5.0 85.9 282 292 103 5.0 48.9 185 135 114 5.0 65.6 237 152 117 5.0 121 319 243 127 5.0 61.3 253 216 131 5.0 108 301 470 136 5.0 673 736 545 142 5.0 211 243 171 144 5.0 243 386 222 162 5.0 277 670 441 164 5.0 294 877 853 165 5.0 376 404 219 191 5.0 520 1167 1333 192 5.0 469 440 268 195 5.0 256 255 125 197 5.0 527 741 369 198 5.0 674 1440 1097 201 5.0 428 792 527 203 5.0 819 1026 833 204 5.0 740 872 820 205 5.0 1002 1437 1420 209 5.0 21.4 54.9 19.2 227 5.0 36.9 149 114 231 5.0 36.9 160 156

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233 5.0 143 322 296 237 5.0 58.5 178 186 241 5.0 102 234 294 242 5.0 90.4 223 202 245 5.0 101 237 191 246 5.0 87.2 261 285 248 5.0 89.0 271 369 252 5.0 694 2873 4153 253 5.0 42.3 199 181 272 5.0 66.1 198 141 276 5.0 131 291 238 280 5.0 33.6 171 FROM 283 5.0 522 1173 965 285 5.0 39.1 80.0 41.8 286 5.0 20.5 73.8 52.2 288 5.0 8.36 25.4 9.68 293 5.0 6.68 10.8 3.57 294 5.0 80.4 193 186 299 5.0 27.9 212 89.2 304 5.0 131 150 74.2 317 5.0 20.6 88.5 44.3

NA: no data.

As can be seen from table. 11 and table. 12, exemplary compounds of the present invention exhibit surprisingly better pharmacokinetic properties than known compounds, see Comparative Example No. 1.

NFAT (nuclear factor of activated T cells) assay.

The PD-1/PD-L1 blockade bioassay contains two cell types: PD-1 effector cells, which are Jurkat T cells expressing hPD-1 and luciferase reporter genes; and PD-L1 aAPC/CHO-K1 cells, which are Cho-Κι cells that express hPD-L1 and activate TCR cell surface proteins. The antibody or small molecule is incubated with these two cell types for a certain period of time, and the amount of product is determined using Bio-Glo luciferase reagent and chemiluminescence method to show the effect of the antibody or small molecule on the PD-1/PD-L1 interaction.

Assay buffer: 49.5 ml RPMI-1640; 0.5 ml FBS.

Cell medium: 36 ml Ham's F-12; 4 ml FBS.

Reaction process:

1) on the first day, PD-L1 aAPC/CHO-K1 cells were restored, the cells were suspended and counted in cell recovery medium. Cells were diluted with cell medium to a concentration of 2.65*105/ml. Cells were seeded at a density of 6000 cells/well in 384-well plates, incubator for 16-24 hours;

2) the compound was diluted with DMSO to a concentration of 5 mM. This 5 mM solution was used as the first concentration and a 3-fold gradient dilution was performed, for a total of 9 concentration gradients, and the tenth concentration was used as a DMSO control;

3) Atezolizumab antibody as a positive control was diluted with assay buffer to a concentration of 4 μg/ml. The indicated concentration of 4 μg/ml was used as the first concentration and a 2.5-fold gradient dilution was performed, for a total of 9 concentration gradients, and the tenth concentration was used as a control buffer for the assay;

4) aspirate the medium from the indicated 384-well plate. Add 10 μl/well of compound to this 384-well plate and incubate for 2 hours;

5) PD-1 effector cells were recovered, and the cells were suspended and counted in cell recovery medium. Cells were diluted with cell medium to a concentration of 8.75*105/ml. Cells were seeded at a density of 8000 cells/well in 384-well stage 4 plates, incubator for 17 h;

6) 20 μl/well of luciferase reactor was added to the reaction 384-well plate of stage 5

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7) read the RLU (relative luminescence unit) value using an Envision multiplate reader. Experimental data were plotted using compound concentration as the X value and RLU as the Y value.

The results were expressed as EC50 values, which are presented in table. 13.

Claims (12)

[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; or 316) ((2-(3'-(7-cyano-5-((3-cyano-3-methylpyrrolidin-1-yl)methyl)-benzo H]oxazol-2-yl)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)-benzo K]oxazol-5-yl)methyl)-b-proline. [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 166) ((6-(difluoromethoxy)-2-(3'-(5-((3-fluoropyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzoK]oxazol-2-yl)-2,2' -dimethyl-[1,1'-biphenyl]-3-yl)benzoK]oxazol-5-yl)methyl)-Eproline; 167) ((2-(3'-(7-cyano-5 -((3-fluoro-3-methylpyrrolidin-1-yl)methyl)benzo K]oxazol-2-yl)-2,2'-dimethyl[ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 168) ((2-(3'-(7-cyano-5-((A)-3-(fluoromethyl)pyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo A]oxazol-5-yl)methyl)-G-proline; 169) U)-1-((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1' - biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)pyrrolidine-3-carboxylic acid; 170) ((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)2,2 '-dimethyl-[1,1'-biphenyl]-3-yl)benzo A]oxazol-5-yl)methyl)-O-proline; 259) ^)-1-((2-(3'-(7-cyano-5-((^)-3-methylpyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid; 261) ((2-(3 '-(5-(((S)-3 -chloropyrrolidin-1 -yl)methyl)-7 -cyanobenzo K]oxazol-2-yl)-2,2'-dimethyl-[ 1,1'biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-b-proline; 310) ((6-(difluoromethoxy)-2-(3'-(5-((((N^)-2-hydroxycyclopentyl)amino)-methyl)benzoK]oxazol2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-E-proline; 311) ((6-(difluoromethoxy)-2-(3'-(5-((2,2-dimethylpyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'dimethyl-[1 ,1'-biphenyl]-3-yl)benzo A]oxazol-5-yl)methyl)-G-proline; 312) ((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1-yl)methyl)benzo H]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)benzo A]oxazol-5-yl)methyl)-G-proline; 313) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((2-methylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)-[ 1, 1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-b-proline; 315) ((2-(3'-(5-((3-carbamoylpyrrolidin-1-yl)methyl)-7-cyanobenzo K]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 165) ((2-(3 '-(7-cyano-5 -(((R)-3 -cyanopyrrolidin-1 -yl)methyl)benzo K]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo Octazol-5-yl)methyl)-b-proline; 134) ((2-(3'-(7-cyano-5-((3-(dimethylamino)azetidin-1-yl)methyl)benzoSoxazol-2-yl)-2,2'-dimethyl[1,1 ' -biphenyl]-3-yl)-6-(difluoromethoxy)benzo oxazol-5-yl)methyl)-b-proline; 135) ((2-(3'-(7-cyano-5-((2-(2-hydroxyethyl)piperidin-1-yl)methyl)benzo A|oxazol-2-yl)-2,2'-dimethyl - [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 136) ((2-(3 '-(7-cyano-5 -(((cyanomethyl) (methyl)amino)methyl)benzo Schoxazol-2-yl)-2,2'-dimethyl-[1,1 'biphenyl ]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 137) ((2-(3'-(7 -cyano -5-((3 -(hydroxymethyl)azetidin-1 -yl)methyl)benzo[d]oxazol-2 -yl)-2,2'-dimethyl[ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo oxazol-5-yl)methyl)-b-proline; 138) ((2-(3'-(7-cyano-5-(((2-hydroxy-2-methylpropyl)amino)methyl)benzooxazol-2-yl)-2,2'-dimethyl-[1,1 '-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 139) ((2-(3'-(7-cyano-5-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)benzoSchoxazol-2-yl)-2,2'-dimethyl- [ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 140) ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzooxazol-2-yl)-2,2'-dimethyl-[1,1' biphenyl]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-E-proline; 141) ((2-(3'-(7-cyano-5-((ethyl(2-hydroxyethyl)amino)methyl)benzooxazol-2-yl)-2,2'-dimethyl-[1,1'biphenyl] -3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 142) ((2-(3 '-(7-cyano-5-((3 -cyanopyrrolidin-1 -yl)methyl)benzo Schoxazol-2-yl)-2,2'-dimethyl-[1,1 '- biphenyl]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 143) ((2-(3'-(7-cyano-5-((3-cyanopyrrolidin-1-yl)methyl)benzooxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl ]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-E-proline; 144) ((2-(3'-(7-cyano-5-((3-ethynyl-3-hydroxyazetidin-1-yl)methyl)benzo H|oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 145) ((2-(3'-(7-cyano-5-(pyrrolidin-1-ylmethyl)benzoSoxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl)- 6-(difluoromethoxy)benzooxazol-5-yl)methyl)-E-proline; 146) ((2-(3'-(7-cyano-5-((7-oxo-2,6-diazaspiro[3.4]octan-2-yl)methyl)benzoSoxazol-2-yl)-2,2' - dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 147) ((2-(3'-(5-((bis(1-hydroxypropan-2-yl)amino)methyl)-7-cyanobenzoSchoxazol-2-yl)-2,2'dimethyl-[1,1' -biphenyl]-3-yl)-6-(difluoromethoxy)benzo oxazol-5-yl)methyl)-b-proline; 148) ((2-(3'-(7-cyano-5-((3-morpholinoazetidin-1-yl)methyl)benzooxazol-2-yl)-2,2'-dimethyl-[1,1'biphenyl] -3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 149) ((2-(3 '-(7-cyano-5-((3 -(methyl(oxetan-3-yl)amino)azetidin-1-yl)methyl)benzo A|oxazol-2-yl) - 130 047234 [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo Schoxazol-5-yl)methyl)-E-proline; 133) ((2-(3 '-(7-cyano-5-(((3 -methyloxetan-3 -yl)amino)methyl)benzo A|oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo A|oxazol-5-yl)methyl)-b-proline; 132) ((2-(3 '-(7-cyano-5-((A)-3 -methylpyrrolidin-1 -yl)methyl)benzo A|oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo A|oxazol-5-yl)methyl)-b-proline; 131) ((2-(3 '-(7-cyano-5-((A)-3 -methylpyrrolidin-1 -yl)methyl)benzo A|oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-b-proline; 97) ((2-(3 '-(6-chloro-5-((ethylamino)methyl)benzo A|oxazol-2-yl)-2,2'-dimethyl-|1,1 '-biphenyl] -3 -yl)-6(difluoromethoxy)benzoK]oxazol-5-yl)methyl)^-proline; 98) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1 -ylmethyl)benzo K]oxazol-2-yl)-[1,1'biphenyl] -3-yl)benzoK]oxazol-5-yl)methyl)^-proline; 99) ((6-(difluoromethoxy)-2-(3'-(5-((((^^)-2-hydroxycyclopentyl)amino)-methyl)benzoK]oxazol2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 100) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-b-proline; 101) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidin-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)- [1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-b-proline; 102) ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl] -3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 103) ((2-(3'-(7-cyano-5-((3,3-dimethylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1, 1'biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 104) ((6-(difluoromethoxy)-2-(3'-(5-((2-hydroxy-2-methylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)2,2'-dimethyl- [1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5 -yl)methyl)-b-proline; 105) ((6-(difluoromethoxy)-2-(3'-(5-((2-(hydroxymethyl)azetidin-1-yl)methyl)benzoK]oxazol-2-yl)2,2'-dimethyl-[ 1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5 -yl)methyl)-b-proline; 106) ((2-(3'-(5-((6-oxa-1-azaspiro[3.3]heptan-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[ 1,G-biphenyl]-3-yl)-6 -(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 107) ((2-(3'-(5-((1-azaspiro[3.3]heptan-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,G- biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 108) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1 -ylmethyl)benzo K]oxazol-2-yl)-[1,1'biphenyl] -3-yl)benzoK]oxazol-5-yl)methyl)^-proline; 109) ((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)^-proline; 110) ((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)-2-methyl-[1,1' - biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 111) ((2-(2'-chloro-3'-(6-((3,3-dimethylazetidin-1-yl)methyl)benzoK]oxazol-2-yl)-2-methyl-[1,1' - biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl) -D-proline; 112) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidin-1-ylmethyl)oxazolo[5,4-b]pyridin-2yl)-[1,1 '-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)^-proline; 113) ((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazetidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)2,2 '-dimethyl-[1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5 -yl)methyl)^-proline; 114) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-((^)-3-methylpyrrolidin-1-yl)methyl)oxazolo[5,4b]pyridin-2 -yl)-[1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)^-proline; 115) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-((((5-oxopyrrolidin-2-yl)methyl)amino)methyl)oxazolo[5,4- b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzoK]oxazol-5-yl)methyl)L-proline; 116) ((6-(difluoromethoxy)-2-(3'-(6-((3-(dimethylamino)azetidin-1-yl)methyl)oxazolo[5,4-b]pyridin2-yl)-2,2 '-dimethyl-[1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)^-proline; 117) ((2-(3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)-2'-methoxy-2-methyl-[1,1'- biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 118) ((2-(2'-cyano-3'-(6,7-difluoro-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)-2-methyl-[1,1'- biphenyl]-3 -yl)-6 -(difluoromethoxy)benzo[d]oxazol-5 -yl)methyl)-L-proline; 119) ((2-(3'-(6-((6-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzoK]oxazol2-yl)-2,2' -dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)^-proline; 120) ((2-(3'-(6-((5-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzoK]oxazol2-yl)-2,2' -dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)^-proline; 121) ((6-(difluoromethoxy)-2-(3'-(5-(((2-hydroxyethyl)amino)methyl)-6-((5-(methylsulfonyl)pyridine - 129 047234 [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline; 66) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)2,2'-dimethyl-[1, 1'-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)^-proline; 67) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3,3-dimethylpyrrolidin-1 - yl)methyl)benzo K]oxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 68) ((2-(3'-(5-((3-(diethylamino)azetidin-1-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2'dimethyl- [ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 69) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(2-hydroxypropan-2-yl)azetidin-1-yl)methyl)benzo K]oxazole -2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)-b-proline; 70) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,5-dihydro-1H-pyrrol-1yl)methyl)benzo K]oxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 71) ((2-(3'-(5-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 72) ((2-(3'-(5-(((C^)-7-azabicyclo[2.2.1]heptan-7-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-b-proline; 74) ((2-(3'-(5-((5-azaspiro[2.3]hexan-5-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2'-dimethyl - [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 75) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxo-6-azabicyclo[3.2.1]octan-6-yl)methyl)benzo K] oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 76) ((2-(3'-(5-((1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-b-proline; 77) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)methyl)benzo K]oxazol-2- yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)-b-proline; 78) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylazetidin-1yl)methyl)benzo K]oxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 79) ((2-(3'-(5-((3-cyano-3-methylazetidin-1-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 80) ((2-(3'-(5-((3-cyanoazetidin-1-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2'-dimethyl[1,1 '-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 81) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methyleneazetidin-1-yl)methyl)benzo K]oxazol-2-yl)-2,2 '-dimethyl-[1,1 '-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)-b-proline; 82) ((2-(3'-(5-((3-(cyanomethylene)azetidin-1-yl)methyl)-6-(difluoromethoxy)benzoK]oxazol-2-yl)-2,2'dimethyl- [ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 83) ((2-(2,2'-dicyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1 -yl)methyl)benzoK]oxazol-2yl)-[1, 1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 84) ((6-(difluoromethoxy)-2-(3'-(5-((3,4-dimethylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzoK]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)benzoK]oxazol-5-yl)methyl)-bproline; 85) U)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol- 2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5 yl)methyl)pyrrolidine-3-carboxylic acid; 86) ^)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo[d]oxazol- 2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5 yl)methyl)pyrrolidine-3-carboxylic acid; 87) ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1 -yl)methyl)benzoK]oxazol-2-yl)2-methyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)^-proline; 88) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol- 2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-b-proline; 89) ((2-(3'-(5-((2-azabicyclo[2.1.1]hexan-2-yl)methyl)-7-(trifluoromethyl)benzoK]oxazol-2-yl)-2,2' dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 90) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7(trifluoromethyl)benzo[d]oxazol-2 -yl)-[1,1'-biphenyl]-3 -yl)benzo[d]oxazol-5-yl)methyl)-0-proline; 91) (3R)-1 -((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7 - (trifluoromethyl) benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3 carboxylic acid; - 128 047234 92) (3S)-1 -((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidin-1-yl)methyl)-7 - (trifluoromethyl) benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3 carboxylic acid; 93) ((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazetidin-1-yl)methyl)-7-(trifluoromethyl)benzoK]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)benzoK]oxazol-5-yl)methyl)^proline; 94) ((2-(3'-(5-(azetidin-1-ylmethyl)-7-methylbenzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3- yl)6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)^-proline; 95) ((6-(difluoromethoxy)-2-(3'-(7-fluoro-5-(pyrrolidin-1-ylmethyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1 '-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-c-proline; 96) ((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-fluorobenzoK]oxazol-2-yl)-2,2'-dimethyl- 1) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((III^)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo^]oxazole-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo^]oxazol-5-yl)methyl)-b-proline; 1. A compound of formula (III) or a pharmaceutically acceptable salt thereof noos Formula (III) wherein R ₁ and R ₂ are each independently selected from halogen, CN, C _1-6 αlkyl or -OCH ₃ ; ring C represents phenyl or 5-6 membered heteroaryl, which contains 1 heteroatom N; R ₃ represents halogen, -(CH ₂ ) _s -NR4R ₅ , C _1-4 alkyl, C _1-4 alkoxy, hydroxyl, CN; wherein said C _1-4 alkyl, C _1-4 alkoxy is optionally substituted with one or more R6 substituents; R4 and R5 are each independently selected from H, C _1-4 alkyl, C _3-6 cycloalkyl, or C _3-6 heterocyclyl having 1 heteroatom O, wherein said C _1-4 alkyl, C _3-6 cycloalkyl or C _{3- 6} heterocyclyl is optionally substituted with one or more R ₆ substituents; or R4 and R5 together with the N atom to which they are attached form a 4-10 membered heterocyclic ring, optionally substituted by one or more R6 substituents, wherein the 4-10 membered heterocyclic ring optionally additionally has 1 heteroatom independently selected from N, S or O; R6 is halogen, hydroxyl, oxo, CN, -(CH ₂ ) _k -NR ₇ R8, -COR ₇ , -S(O) ₂ R ₇ , or R6 is selected from substituted or unsubstituted C _1-4 alkyl, C _{1 -4} alkoxyl, ^^alkenyl, _C2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C _3-10 heterocyclic ring, where said C _5-6 heteroaryl and C _3-10 heterocyclic ring contain 1 or 2 heteroatoms independently selected from N or O; where C _1-4 -αalkyl, C _1-4 -alkoxyl, ^^-alkenyl, C _2-6 -alknyl, C _1-6 -haloalkyl, phenyl, C _5-6 -heteroaryl and C _3-10 -heterocyclic ring , each independently optionally substituted with one or more substituents selected from halogen, C _1-8 alkyl, C _3-12 cycloalkyl, =O, =S, -OH, ethoxy, propyloxy, isopropyloxy, n-butyloxy , isobutyloxy, tert-butyloxy, -SCH ₃ , -SC2H5, formaldehyde group, -COCH3, cyano, nitro, CF ₃ , -OCF3, amino, dimethylamino, ^^^^^-alkyl and acetyl; R ₇ and R ₈ are each independently selected from H, hydroxyl or -NH ₂ , or R ₇ and R ₈ are each independently selected from substituted or unsubstituted C _1-4 alkyl, C _1-4 alkoxyl or C _3-6 heterocycloalkyl, wherein said C _3-6 heterocycloalkyl contains 1 heteroatom O; wherein said C _1-4 alkyl, C _1-4 alkoxy and C _3-6 heterocycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, C _1-8 alkyl, C _3-12 cycloalkyl, =O, =S , -OH, ethoxy, propyloxy, isopropyloxy, nbutyloxy, isobutyloxy, tert-butyloxy, -SCH ₃ , -SC2H5, formaldehyde group, -COCH3), cyano, nitro, CF ₃ , -OCF3, amino, dimethylamino, S(O) ₂ -C _1-4 -alkyl and acetyl; n is 0, 1, 2 or 3; k is 0 or 1; s is equal to 1. 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 161) ((2-(3'-(5-((3-(aminomethyl)-3-methylazetidin-1-yl)methyl)-7-cyanobenzoK]oxazol-2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 162) ((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1' - biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-b-proline; 163) ((2-(3'-(7-cyano-5-((3-fluoropyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl-[1,1' - biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-E-proline; 164) ((2-(3'-(7-cyano-5-((3,4-difluoropyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'-dimethyl- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo (Q]oxazol-5-yl)methyl)-b-proline; 153) ((2-(3'-(7-cyano-5-((1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)methyl)benzoK]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 154) ((2-(3'-(7-cyano-5-((A)-3-(hydroxymethyl)pyrrolidin-1-yl)methyl)benzoK]oxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 155) ((2-(3'-(7-cyano-5-(((3-hydroxycyclobutyl)amino)methyl)-benzoK]oxazol-2-yl)-2,2'-dimethyl[1,1 '- biphenyl]-3-yl)-6-(difluoromethoxy)benzo B]oxazol-5-yl)methyl)-G-proline; 156) ((2-(3'-(5-((3-amino-4-methylpyrrolidin-1-yl)methyl)-7-cyanobenzo H]oxazol-2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 157) ((2-(3 '-(5-(((azetidin-3 -ylmethyl)amino)methyl)-7 -cyanobenzo K]oxazol-2-yl)-2,2'-dimethyl-[1,1 'biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-b-proline; 158) ((2-(3'-(7-cyano-5 -((3 -(dimethylamino)-4 -methylpyrrolidin-1 -yl)methyl)benzo[d]oxazol-2-yl) 2,2'- dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 159) ((2-(3'-(7-cyano-5 -((3 -((dimethylamino)methyl)-3-methylazetidin-1 -yl)methyl)benzo[d]oxazol-2yl)-2,2 '-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzoK]oxazol-5-yl)methyl)-E-proline; 160) ((2-(3 '-(7-cyano-5-(((( 1 -methyl-1H-imidazol-4-yl)methyl)amino)methyl)benzo H]oxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 151) ((2-(3'-(7-cyano-5-((6-oxo-2,5-diazaspiro[3.4]octan-2-yl)methyl)benzoA]oxazol-2-yl)-2, 2'dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-b-proline; 152) ((2-(3 '-(7-cyano-5 -((3 -((dimethylamino)methyl)pyrrolidin-1-yl)methyl)benzo H]oxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo K]oxazol-5-yl)methyl)-b-proline; 150) ((2-(3'-(7-cyano-5-((3-hydroxy-3-methyl-[1,3'-biazetidin]-G-yl)methyl)benzoK]oxazol-2-yl) - 2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)benzo |d| oxazol-5-yl)methyl)-L-proline; 2) (2'8)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo^]oxazole-2,5 - diyl))bis(methylene))di-E-proline; 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ₃ represents halogen, -(CH ₂ ) _s -NR4Rs, -CN, C _1-4 alkyl, C _1-4 alkoxy, and said C _1-4 alkyl and C _1-4 alkoxy are optionally substituted with one or more R ₆ substituents. 3 -yl)methoxy)benzo ^]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo Aoxazol-5-yl)methyl)-bproline; 122) ((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-((5-(methylsulfonyl)pyridin-3-yl)methoxy)benzo^]oxazol-2- yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo doxazol-5-yl)methyl)-bproline; 123) ((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((5-(methylsulfonyl)pyridin-3yl)methoxy)benzo^]oxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo doxazol-5-yl)methyl)-bproline; 124) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((3-(methylsulfonyl)benzyl)oxy)benzo A|oxazole -2-yl)-[1,1'-biphenyl]-3-yl)benzo N|oxazol-5-yl)methyl)-bproline; 125) ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((4-(methylsulfonyl)benzyl)oxy)benzo A|oxazole -2-yl)-[1,1'-biphenyl]-3-yl)benzo N|oxazol-5-yl)methyl)-bproline; 126) ((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((4-(methylsulfonyl)benzyl)oxy)benzo A|oxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo N|oxazol5-yl)methyl)-b-proline; 127) ((2-(3 '-(7-cyano-5 -(pyrrolidin-1 -ylmethyl)benzo A|oxazol-2-yl)-2,2'-dimethyl-[1,1 '-biphenyl] - 3 yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 128) ((2-(2-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzoSoxazol-2-yl)2'-methyl-[1 ,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo A|oxazol-5-yl)methyl)-b-proline; 129) ((2-(3'-(7-cyano-5-((3-(hydroxymethyl)-3-methylazetidin-1-yl)methyl)benzooxazol-2-yl)-2,2'dimethyl-[1 ,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo A|oxazol-5-yl)methyl)-b-proline; 130) ((2-(3'-(7-cyano-5-((^)-3-methylpyrrolidin-1-yl)methyl)benzoSoxazol-2-yl)-2,2'-dimethyl- 3 8) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5-((2-methylpyrrolidin-1 yl)methyl)benzo Schoxazol-2-yl)-2,2'- dimethyl-[1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)N-proline; 39) ((2-(3'-(5-((6-oxa-1-azaspiro[3.3] heptan-1-yl)methyl)-6 -(difluoromethoxy)benzo[d]oxazol-2-yl) 2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo Achoxazol-5-yl)methyl)A-proline; 40) ((2-(3'-(5-((2-amino-2-methylazetidin-1-yl)methyl)-6-(difluoromethoxy)benzooxazol-2-yl)-2,2'dimethyl-[1 ,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo Achoxazol-5-yl)methyl)A-proline; 41) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(methylsulfonyl)azetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)-b-proline; 42) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((U)-2-ethylazetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)-b-proline; 43) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methoxyazetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2,2'- dimethyl-[1,1'-biphenyl]-3-yl)benzo oxazol-5-yl)methyl)-b-proline; 44) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3 -hydroxy-3-methylazetidin-1 -yl)methyl)benzo Schoxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Octazol-5-yl)methyl)-b-proline; 45) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-((methylamino)methyl)azetidin-1-yl)methyl)benzo Schoxazol-2-yl) -2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo oxazol-5-yl)methyl)-b-proline; 46) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxoazetidin-1-yl)methyl)benzooxazol2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)-b-proline; 47) ((2-(3'-(5-((2-oxa-6-azaspiro[3.3]heptan-6-yl)methyl)-6-(difluoromethoxy)benzoschoxazol-2-yl)2,2'- dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzooxazol-5-yl)methyl)-b-proline; 48) ((2-(3'-(5-((2-azaspiro[3.3]heptan-2-yl)methyl)-6-(difluoromethoxy)benzooxazol-2-yl)-2,2'dimethyl-[1 ,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo oxazol-5-yl)methyl)-b-proline; 49) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)benzo Schoxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Octazol-5-yl)methyl)-b-proline; 50) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)benzo Schoxazol-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzooxazol-5-yl)methyl)-b-proline; 51) ((2-(3'-(5-((2,7-diazaspiro[3.5]nonan-2-yl)methyl)-6-(difluoromethoxy)benzooxazol-2-yl)-2,2'dimethyl- [1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo Octazol-5-yl)methyl)-b-proline; 52) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3-(propylamino)propyl)amino)methyl)benzo Schoxazol-2-yl)-2,2 '-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)-L-proline; 53) ((b-(difluoromethoxy)-2-(3'-(6 -(difluoromethoxy)-5 -((methyl(3 - (propylamino)propyl)amino)methyl)benzo Schoxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)-b-proline; 54) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dioxido-2-thia-6-azaspiro[3.3]heptan-6yl)methyl)benzo Schoxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Schoxazol-5-yl)methyl)-b-proline; 55) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)yl)methyl)benzo Schoxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Schoxazol-5-yl)methyl)-b-proline; 56) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylazetidin-1-yl)methyl)benzooxazol2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)-b-proline; 57) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((N^)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo Schoxazol-2-yl )-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)-L-proline; 58) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3-((2-hydroxyethyl)amino)propyl)amino)methyl)benzo Schoxazol-2-yl )-2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5 -yl)methyl)N-proline; 59) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)benzo Schoxazol-2-yl)- 2,2'-dimethyl-[1,1'-biphenyl]-3 yl)benzo[d]oxazol-5-yl)methyl)N-proline; 60) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1-yl)methyl)benzooxazol2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)N-proline; 61) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylpyrrolidine-1 - 127 047234 yl)methyl)benzo K]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo K]oxazol-5-yl)methyl)-b -proline; 62) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((2,2-dimethylpyrrolidin-1 - yl)methyl)benzo K]oxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo K]oxazol-5-yl)methyl)-b-proline; 64) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((^)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo A|oxazol-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo N]oxazol-5yl)methyl)-b-proline; 65) ((2-(2'-cyano-3'-(6-(di(|)tormethoxy)-5-(pyrrolidin-1-ylmethyl)benzoA|oxazol-2-yl)-2-methyl- 3) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((^)-2-(methoxycarbonyl)pyrrolidin-1-yl)methyl)benzo^]oxazol-2- yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-b-proline; 3. A compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, where R6 represents halogen, hydroxyl, oxo, CN, -(CH ₂ ) _k -NR ₇ R ₈ , -COR ₇ , -S(O) ₂ R ₇ , or R6 is selected from C _1-4 alkyl, C _1-4 alkoxyl, ^^alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C _3-10 heterocyclic ring wherein said C _5-6 heteroaryl and C _3-10 heterocyclic ring contain 1 or 2 heteroatoms independently selected from N or O, preferably R ₆ is a halo - 123 047234 gene, hydroxyl, oxo, CN, -(CH ₂ )-H-(C _1-4 alkyl) ₂ , -(CH2)-NH2, -Н-(C _1-4 alkyl) ₂ , -NH2, -CO-NH2, ^(O) ₂ -C _1-4 alkyl, C _1-4 alkyl-OH, C _1-4 alkyl, C _1-4 alkoxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, phenyl, C _5-6 heteroaryl, C _3-10 heterocyclic ring, wherein said C _5-6 heteroaryl and C _3-10 heterocyclic ring contain 1 or 2 heteroatoms independently selected from N or O, more preferably R ₆ represents halogen, oxo, -OH, -NH2, -N(CH ₃ ) ₂ , -C _1-4 alkyl-OH, -C _1-4 alkylNH-CH ₃ , -CI-C^alkyl, C _{1- 4} alkyl, C _1-4 haloalkyl, C _1-4 alkoxyl, phenyl, C _5-6 heteroaryl, C _3-6 heterocyclyl or ^(O) ₂ -C _1-4 alkyl. 4) ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazetidin-1-yl)methyl)benzo^]oxazol-2-yl)-2methyl- [1,G-biphenyl]-3-yl)-6-(difluoromethoxy)benzo^]oxazol-5-yl)methyl)-L-proline; 4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from halogen, CN, -C _1-6 alkyl; ring C represents phenyl or 5-6 membered heteroaryl, and said 5-6 membered heteroaryl contains 1 N heteroatom; R3 represents halogen, -(CH ₂ ) _s -NR ₄ R ₅ , -C _1-4 alkyl, -C _1-4 alkoxy, wherein said -C _1-4 alkyl and -C _1-4 alkoxy are optionally substituted by one or more substituents independently selected from halogen, -C _1-4 alkyl, -C _1-4 haloalkyl, -C _1-4 alkoxyl, C _5-6 heteroaryl, phenyl, carboxyl, amino, hydroxyl or ^(O) ₂ -C _1-4 alkyl; R4 and R5 are each independently selected from H, -C _1-4 alkyl, C _3-6 cycloalkyl or C _3-6 heterocyclyl having 1 heteroatom O, wherein said -C _1-4 alkyl, C _3-6 cycloalkyl or C _{3 -6} heterocyclyl is possibly substituted with halogen, -OH, -H(CH ₃ ) ₂ , -C _1-4 alkyl, -C _1-4 haloalkyl, -C _3-6 heterocyclyl, -NH-C _1-4 alkyl or ^ groups (O) ₂ -C _1-4 alkyl; or R ₄ and R ₅ together with the N atom to which they are attached form a 4-6-membered heterocyclic ring, possibly substituted by one or more substituents independently selected from -OH, -N(CH ₃ ) ₂ , -NH2, oxo, halogen, -C _1-4 alkyl, -C _1-4 alkoxy, -C _1-4 alkyl-OH, -C _1-4 alkyl-NH-CH ₃ or ^(O) ₂ -C _1-4 alkyl groups; n selected from 0, 1,2 or 3; s is equal to 1. 5) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-ylmethyl)benzo^]oxazol-2-yl)2,2'-dimethyl-[1 ,1'-biphenyl]-3-yl)benzo^]oxazol-5-yl)methyl)-b-proline; 5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from F, Cl, _-CH3 , -CN or -O-CH3, preferably Ri is selected from _-CH3 , F or -O- CH3. 6) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidin-1-ylmethyl)benzo[p]oxazol-2-yl) - 125 047234 6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from _-CH3 , F, Cl or Br, preferably R2 is _-CH3 . 7) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-hydroxyethyl)amino)methyl)benzoK]oxazol2-yl)-2,2'-dimethyl- [1,1'-biphenyl]-3-yl)benzo K|oxazol-5-yl)methyl)N-proline; 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, where R3 is selected from, F, Cl, -CH3, -CF3, -O-CF3, -O-CHF2, -O-CH3, -CN, - 124 047234 8) ((2-(3 '-(5-(azetidin-1-ylmethyl)-6-(difluoromethoxy)benzo A|oxazol-2-yl)-2.2'-dimethyl-|1,1 '- bi(| )enyl|-3-yl)-6-(di(|)tormethoxy)benzo[oxazol-5-yl)methyl)X-proline; 8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is the following: 9. A pharmaceutical composition containing a compound according to any one of claims 1 to 8 or its pharmaceuticals - - 131 047234 a commercially acceptable salt and at least one pharmaceutically acceptable carrier or excipient. 9) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoroazetidin-1-yl)methyl)benzoK]oxazol-2yl)-2.2'-dimethyl-| 1.1'-bi(|)enyl|-3-yl)benzoA|oxazol-5-yl)methyl)X-proline; 10. Use of a compound according to any one of claims 1 to 8 for the manufacture of a medicament for enhancing, stimulating and/or enhancing the immune response in a patient, where the patient has a disease associated with inhibition of the interaction between PD-1 (programmed cell death protein-1) and PD-L1 (programmed cell death receptor ligand 1). 10) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoropyrrolidin-1-yl)methyl)benzo[d]oxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl|-3-yl)benzo A|oxazol-5-yl)methyl)X-proline; 11. Use of a pharmaceutical composition according to claim 9 for the manufacture of a medicament for enhancing, stimulating and/or enhancing the immune response in a patient, where the patient has a disease associated with inhibition of the interaction between PD-1 and PD-L1. 11) ((2-(3'-(5-(((S)-2-carbamoylpyrrolidin-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)2,2'- dimethyl-[1, 1'-biphenyl|-3-yl)-6-(difluoromethoxy)benzo(xazol-5-yl)methyl)X-proline; 12) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((^)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)benzo[d]oxazole-2 -yl)-2,2'-dimethyl-[1,1'-biphenyl|-3-yl)benzo(xazol-5-yl)methyl)X-proline; 13) ((6-(di(|)tormethoxy)-2-(3'-(6-(di(|)tormethoxy)-5-(mor(|)olinomethyl)benzoI|oxazol-2-yl)-2.2 '-dimethyl-[1,1 '-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)-G-proline; 14) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxypyrrolidin-1-yl)methyl)benzo A|oxazol-2-yl)-2.2'- dimethyl-|1,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)X-proline; 15) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methylamino)methyl)benzo[d]oxazol-2-yl)-2,2'dimethyl-[1 ,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)-G-proline; 16) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((dimethylamino)methyl)benzo[d]oxazol-2-yl)2,2'-dimethyl-[1 ,1'-biphenyl]-3 -yl)benzo A|oxazol-5-yl)methyl)X-proline; 17) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-hydroxyethyl)(methyl)amino)methyl)benzo A|oxazol-2-yl)-2.2 '-dimethyl-|1,1 '-biphenyl]-3 yl)benzo |d| oxazol-5 -yl)methyl)-L-proline; 18) ((6-(di(tormethoxy)-2-(3 '-(6-(difluoromethoxy)-5-(((3R,4R)-3,4-difluoropyrrolidin-1 - yl)methyl)benzo oxazol-2-yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 -yl)benzo (H|oxazol-5-yl)methyl)X-proline; 19) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((S)-5-oxopyrrolidin-2-yl)methyl)amino)methyl)benzo oxazol-2-yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 -yl)benzo N|oxazol-5yl)methyl)-b-proline; 20) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxyazetidin-1 - yl)methyl)benzo A|oxazol-2-yl)-2.2'- dimethyl-|1,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)X-proline; 21) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((ethylamino)methyl)benzo[d]oxazol-2-yl)-2,2'dimethyl-|1 ,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)-k-proline; 22) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3,3,3-trifluoro-2hydroxypropyl)amino)methyl)benzo Schoxazol^-ylUD'-dimethyl -C, 1'-biphenyl]-3-yl)benzo N|oxazol-5yl)methyl)-b-proline; 23) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,4-dimethylpiperazin-1yl)methyl)benzo A|oxazol-2-yl)-2.2'- dimethyl-|1,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)X-proline; 24) ((2-(3'-(5-(aminomethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3yl )-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 25) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2hydroxycyclopentyl)amino)methyl)benzo A|oxazol-2-yl)- 2.2'-dimethyl-|1,1'-biphenyl]-3 yl)benzo |d| oxazol-5 -yl)methyl)-L-proline; 26) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2hydroxycyclopentyl)(methyl)amino)methyl)benzo A|oxazol-2- yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 yl)benzo |d| oxazol-5 -yl)methyl)-D-proline; 27) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1S,2R)-2hydroxycyclopentyl)amino)methyl)benzo A|oxazol-2-yl)- 2.2'-dimethyl-|1,1'-biphenyl]-3 yl)benzo |d| oxazol-5 -yl)methyl)-L-proline; 28) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((oxetan-3-ylamino)methyl)benzo[d]oxazol-2yl)-2,2'-dimethyl -[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 29) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo 2-yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 -yl)benzo 1|oxazol-5yl)methyl)X-proline; 30) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo A|oxazole -2-yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 -yl)benzo(xazol-5yl)methyl)X-proline; 31) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)azetidin-1-yl)methyl)benzo A|oxazol-2 -yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 -yl)benzo A|oxazol-5-yl)methyl)X-proline; 32) ((6-(di(tormethoxy)-2-(3 '-(6-(difluoromethoxy)-5-(((2- (methylsul(onyl)ethyl)amino)methyl)benzo A|oxazol-2- yl)-2.2'-dimethyl-|1,1'-biphenyl]-3 yl)benzo |d| oxazol-5 -yl)methyl)-L-proline; - 126 047234 33) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(dimethylamino)azetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2, 2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)N-proline; 34) ((6-(difluoromethoxy)-2-(3 '-(6-(difluoromethoxy)-5 -((3,3-dimethylazetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2,2 '-dimethyl-[1,1 '-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)Sh-proline; 35) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((A)-2-(hydroxymethyl)azetidin-1-yl)methyl)benzo A|oxazol-2- yl)-2,2'-dimethyl-[1,1'-biphenyl]-3 -yl)benzo(xazol-5-yl)methyl)-c-proline; 36) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazetidin-1-yl)methyl)benzooxazol2-yl)-2,2'-dimethyl-[ 1,1'-biphenyl]-3-yl)benzo A|oxazol-5-yl)methyl)-k-proline; 37) ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-hydroxy-2-methylazetidin-1-yl)methyl)benzo Schoxazol-2-yl)-2 ,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo Choxazol-5-yl)methyl)N-proline; 12. Use according to claim 10 or 11, wherein the disease is cancer, preferably said 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.