HK40050972B - Immunomodulators, compositions and methods thereof - Google Patents

Description

Immunomodulators, compositions and methods thereof

Technical Field

This invention relates to compounds as inhibitors of PD-1/PD-L1 protein/protein interactions. The invention also relates to pharmaceutical compositions comprising the above-described compounds, and the use of these compounds in the treatment of cancer, precancerous syndromes, and other diseases associated with inhibition of PD-1/PD-L1 protein/protein interactions.

Background Technology

Cancer immunotherapy is increasingly being used to treat advanced malignant tumors. The signaling network of immune checkpoints has attracted widespread attention. Some cancers are very difficult to cure with conventional chemotherapy. In some cases, tumor survival can be assisted by checkpoint immune modulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Immune checkpoint inhibitors have revolutionized treatment options and expectations for cancer patients.

Programmed cell death-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. Its function is an intrinsic negative feedback system that prevents T-cell activation, thereby reducing autoimmunity and enhancing self-tolerance. Furthermore, PD-1 is well-known for its crucial role in suppressing antigen-specific T-cell responses in diseases such as cancer and viral infections. The interaction between PD-1 and PD-L1 leads to a reduction in tumor-infiltrating lymphocytes, a decrease in T-cell receptor-mediated proliferation, and immune evasion by cancer cells. Immunosuppression can be reversed by inhibiting the local interaction between immunosuppressive PD-1 and PD-L1, and this effect is additive when the interaction between PD-1 and PD-L2 is also blocked.

The development of treatment methods involves blocking the PD-1-mediated inhibitory signaling cascade to enhance or “rescue” T-cell responses. Currently, most approved drugs in the field of immunotherapy are monoclonal antibodies. These monoclonal antibodies have demonstrated impressive clinical results in the treatment of some types of tumors. However, therapeutic antibodies have several drawbacks, such as limited tissue and tumor penetration, very long half-life, lack of oral bioavailability, immunogenicity, and difficult and expensive production.

Recently, small molecule binding to PD-L1 has been described in WO2015033299, WO2015033301, WO2015034820, WO2018183171, WO2018119224, and WO2018119266. However, small molecule inhibitors that directly target PD-1 or PD-L1 are currently not approved.

Therefore, there remains a need for more effective and readily implementable therapeutic agents to combat PD-1/PD-L1 protein/protein interactions. In this invention, the applicant has discovered potent small molecules with activity as inhibitors of PD-1 and PD-L1 interactions, which can therefore be used for therapeutic administration to enhance immunity against cancer and/or infectious diseases. These small molecules hold promise as potent drugs with the desired stability, solubility, bioavailability, therapeutic index, and toxicity, which is crucial for becoming effective medicines that promote human health.

Summary of the Invention

This invention relates to a compound that acts as an inhibitor of the functional interaction between PD-L1 and PD-1, and the aforementioned PD-L1 and PD-1 interaction inhibitor can be used to treat cancer and infectious diseases.

The compound of the present invention has the structure shown in formula (I).

The compound represented by formula (I) or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes or solvates,

in,

_R1 and _R2 are each individually selected from halogens, CN, _C1-6 alkyl or _C1-4 haloalkyl;

Q is a bond, -NH- or -( _CH2 ) _m -O-;

Ring A is a _C5-6 aryl, _C5-6 heteroaryl, _C4-6 cycloalkyl, or _C4-6 heterocycloalkyl group, wherein the _C5-6 heteroaryl and _C4-6 heterocycloalkyl groups optionally contain one, two, or three heteroatoms independently selected from N, S, or O; or

Ring A is a _C8-10 fused bicyclic ring;

_R3 is H, halogen, -( _CH2 ) _{s - NR4R5} , _C1-4 alkyl, _C1-4 alkoxy, hydroxyl, oxygen, CN, ( _CH2 ) _q - _CONR4R5 , _-COR4 , _-NR4R5 , _-NR4C (=O) _NR4R5 , _-NR4C (=NR4) _NR4R5 , -S(O) _2R4 , _-S ( _O ) _2NR4R5 , _-S ( _O ) _R4 , -S(O) _NR4R5 , _C2-6 alkenyl, _C2-6 alkynyl _{, C1-6} haloalkyl, _{C5-6 aryl} , _{C5-6 heteroaryl} , _{C3-6 cycloalkyl} or _{C3-6 heterocycloalkyl} , wherein _C5-6 heteroaryl and C _{The 3-6} heterocyclic alkyl group optionally contains 1, 2, or 3 heteroatoms, each independently selected from N, S, or O; the _C1-4 alkyl, _C1-4 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C5-6 aryl, _C5-6 heteroaryl, _C3-6 cycloalkyl, and _C3-6 heterocyclic alkyl group are optionally substituted by one or more substituents independently selected from _R6 ;

_R4 and _R5 are independently selected from H, _C1-4 alkyl, _C3-6 cycloalkyl, or _C3-6 heterocyclic groups, wherein the _C1-4 alkyl, _C3-6 cycloalkyl, or _C3-6 heterocyclic group is optionally substituted by one or more substituents independently selected from _R6 ; or

_R4 and _R5 together with the atoms they are attached to form 4-10 membered heterocycles, which are optionally substituted by one or more substituents independently selected from _R6 ;

_R6 is H, halogen, hydroxyl, oxy, CN, -( _CH2 ) _{k- NR7R8 , -COR7} , _{-NR7R8 ,} -NR7C(=O) _NR7R8 , _-NR7C (= _NR7 ) _NR7R8 , -S(O) _2R7 , _-S (O) _2NR7R8 , _-S (O) _R7 , -S(O) _NR7R8 , or _R6 is selected from substituted or _{unsubstituted C1-4} alkyl, _{C1-4 alkoxy} , _C2-6 alkenyl, _C2-6 alkynyl, _{C1-6 haloalkyl, C5-6 aryl} , _C5-6 heteroaryl, _C3-10 heterocyclic, wherein _{the C5-6} heteroaryl and C3-10 heterocyclic groups are _{... 3-10} The heterocyclic group may contain 1, 2 or 3 heteroatoms, each independently selected from N, S or O;

_R7 and _R8 are independently selected from H, halogen, hydroxyl, oxy, CN, -S(O) ₂ - _C1-4 alkyl, _-NH2 , -NH- _C1-4 alkyl, -( _CH2 )-N( _C1-4 alkyl) ₂ , or _R7 and _R8 are independently selected from substituted or unsubstituted _C1-4 alkyl, _C1-4 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 haloalkyl, _C5-6 aryl, _C5-6 heteroaryl, _C3-6 cycloalkyl, _C3-6 heterocycloalkyl; wherein the _C5-6 heteroaryl and _C3-6 heterocycloalkyl optionally contain 1, 2 or 3 heteroatoms independently selected from N, S or O;

m, n, q, k, and s are independently selected from 0, 1, 2, 3, or 4.

In some embodiments, _R3 in formula (I) is H, a halogen, -( _{CH2 ) s} - _NR4R5 , _C1-4 alkyl, _C1-4 alkoxy, hydroxyl, oxy, CN, ( _CH2 ) _q - _CONR4R5 , _-NR4R5 , _-NR4C (＝ _NR4 ) _NR4R5 , -S(O) _2R4 , _C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, or _C3-6 heterocyclic alkyl, wherein _{the C3-6 heterocyclic} alkyl optionally contains 1, 2, or 3 heteroatoms _, each independently selected from N, S, or O; _{the C1-4 alkyl , C1-4} alkoxy, _C2-6 alkenyl, _C2-6 ynyl, _C1-6 haloalkyl, and _C3-6 heterocyclic alkyl are optionally selected by one or more independently selected from R The substituent of ₆ is replaced.

In some embodiments, _R3 in formula (I) is H, halogen, -( _CH2 ) _{s - NR4R5} , CN, -S(O) _2R4 , _C1-4 alkyl, _C1-4 alkoxy, wherein _the -( _CH2 ) _{s -NR4R5 , C1-4} alkyl, _C1-4 alkoxy is optionally substituted by one or more substituents independently selected from _R6 .

In some embodiments, _R6 in formula (I) is H, halogen, hydroxyl, oxy, CN, -( _CH2 ) _{k- NR7R8 , -COR7} , _-NR7R8 , _-NR7C (=O) _NR7R8 , -S(O) _2R7 , or _R6 is selected from substituted or unsubstituted _C1-4 alkyl, _C1-4 alkoxy, _{C2-6 alkenyl} , _C2-6 alkynyl, _C1-6 haloalkyl, _{C5-6 aryl} , _C5-6 heteroaryl, _C3-10 heterocyclic, wherein the _C5-6 heteroaryl and _C3-10 heterocyclic groups optionally contain 1, 2 or 3 heteroatoms _, each independently selected from N, S or O.

In some embodiments, _R6 in formula (I) is H, halogen, hydroxyl, oxy, CN, -( _CH2 )-N-( _C1-4 alkyl) ₂ , -( _CH2 )-NH2, -N- _{(C1-4 alkyl)2 , -NH2 ,} -CO-N-( _C1-4 alkyl) ₂ , -CO-NH2, -S(O) _{2 - C1-4} alkyl, _C1-4 alkyl-OH, _C1-4 alkyl, _C1-4 alkoxy, _{C2-6 alkenyl, C2-6 alkynyl} , _C1-6 haloalkyl, _C5-6 aryl, _C5-6 heteroaryl, _C3-10 heterocyclic, wherein the _C5-6 heteroaryl and _C3-10 heterocyclic groups optionally contain 1, 2 or 3 heteroatoms independently selected from N, S or O.

In some embodiments, _R6 in formula (I) is a halogen, an oxygen group, -OH, _-NH2 , -N( _CH3 ) ₂ , _-C1-4 alkyl-OH, _-C1-4 alkyl-NH- _CH3 , -NH- _C1-4 alkyl, _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, _C5-6 aryl, _C5-6 heteroaryl, _C3-6 heterocyclic, guanidine, or sulfone.

In some implementations, in formula (I),

_R1 and _R2 are independently selected from halogens, CN, _-C1-6 alkyl or _-C1-4 haloalkyl;

Q is a bond, -NH- or -( _CH2 ) _m -O-;

Ring A is a _C5-6 aryl or _C5-6 heteroaryl, wherein the _C5-6 heteroaryl group arbitrarily contains one, two, or three heteroatoms independently selected from N, S, or O; or

Ring A is a _C8-10 fused bicyclic ring;

_R3 is H, halogen, -( _CH2 ) _{s- NR4R5 , -C1-4} alkyl, _-C1-4 alkoxy, wherein the -( _CH2 ) _{s- NR4R5} , _{-C1-4 alkyl, -C1-4 alkoxy} is optionally substituted by _one or more substituents independently selected from halogen, _-C1-4 alkyl, _-C1-4 haloalkyl, _-C1-4 alkoxy, _C5-6 heteroaryl, _C5-6 aryl, carboxyl, amino, hydroxyl, guanidinyl or sulfone;

_R4 and _R5 are independently selected from H, _-C1-4 alkyl or _C3-6 cycloalkyl, _C3-6 heterocyclic group, wherein the _-C1-4 alkyl or _C3-6 cycloalkyl, _C3-6 heterocyclic group is optionally substituted by halogen, -OH, N( _CH3 ) ₂ , _-C1-4 alkyl, _-C1-4 haloalkyl, _-C3-6 heterocyclic group, -NH- _C1-4 alkyl or sulfone; or

_R4 and _R5 together with the atoms they are attached to form a 4-6 membered heterocycle, which is optionally substituted by one or more substituents independently selected from -OH, -N( _CH3 ) ₂ , _-NH2 , oxy, halogen, _-C1-4 alkyl, _-C1-4 alkoxy, _-C1-4 alkyl-OH, _-C1-4 alkyl-NH- _CH3 or sulfone;

m, n, and s are independently selected from 0, 1, 2, 3, or 4.

In some implementations, Q in formula (I) is selected from bond, -NH- or -CH2 _- O-.

In some implementations, ring A in formula (I) is selected from...

In some implementations, ring A in formula (I) is selected from...

In some implementations, ring A in formula (I) is selected from...

In some embodiments, the compound is as shown in formula (II):

Or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates, wherein,

Ring B is a _C5-6 cycloalkyl or a _C5-6 heterocycloalkyl;

_R1 , _R2 , _R3 and the subscript n are as defined in any embodiment of formula (I).

In some embodiments, the compound is as shown in formula (III):

Or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates, wherein,

The C ring is a benzene ring or a heteroaryl group, wherein the heteroaryl group contains 1, 2 or 3 N atoms;

_R1 , _R2 , _R3 and the subscript n are as defined in any embodiment of formula (I).

In some embodiments, the compound is as shown in formula (IV):

Or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates, wherein,

The D ring is a _C5-6 aryl, _C5-6 heteroaryl, or _C5-6 heterocyclic alkyl group, wherein the _C5-6 heteroaryl and _C5-6 heterocyclic alkyl groups may contain 1, 2, or 3 heteroatoms, each independently selected from N, S, or O.

_R1 , _R2 , _R3 and the subscript n are as defined in any embodiment of formula (I).

In some embodiments, the compound is as shown in formula (V):

Or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates, wherein,

_R1 , _R2 , _R3 and the subscript n are as defined in any embodiment of formula (I).

In some embodiments, the compound is as shown in formula (VI):

Or its stereoisomers, tautomers, pharmaceutically acceptable salts, prodrugs, chelates, non-covalent complexes, or solvates, wherein,

Ring A, Q, _R1 , _R2 , _R3 and the subscript n are as defined in any embodiment of formula (I).

In some implementations, _R1 is selected from F, Cl, _-CH3 , -CN or -O- _CH3 .

In some implementations, _R1 is selected from _-CH3 , F, or -O- _CH3 .

In some implementations, _R2 is selected from _-CH3 , F, Cl, or Br.

In some implementations, _R2 is _-CH3 .

In some embodiments, _R3 is selected from H, F, Cl, _-CH3 , _-CF3 , -O- _CF3 , -O- _CHF2 , -O- _CH3 , -CN, _-NH2 ,

In some implementations, n is 1, 2, or 3.

In some implementations, m is 1.

In some implementations, s is 1.

In some implementations, q is 1.

In some implementations, k is 1.

In some embodiments, the compound in formula (I) is:

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

2)(2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-2,5-diyl))bis(methylene))di-L-proline;

3)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

4)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

6)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-2'-fluoro-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

8)((2-(3'-(5-(azacyclobutane-1-ylmethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

9)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluorozacricyclobutan-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

10)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoropyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

11)((2-(3'-(5-(((S)-2-carbamoylpyrrolidone-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

12)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)pyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

14)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxypyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-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[d]oxazol-5-yl)methyl)-L-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[d]oxazol-5-yl)methyl)-L-proline;

17)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-hydroxyethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

18)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3R,4R)-3,4-difluoropyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

19)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((S)-5-oxopyrrolidone-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

20)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxyazine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-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[d]oxazol-5-yl)methyl)-L-proline;

22)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

23)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,4-dimethylpiperazin-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

24)((2-(3'-(5-(aminomethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

25)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)benzo[d]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)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]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)-2-hydroxycyclopentyl)amino)methyl)benzo[d]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-((oxecyclobutane-3-ylamino)methyl)benzo[d]oxazol-2-yl)-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[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

30)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((methyl(((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

31)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

32)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-(methanesulfonyl)ethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

33)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(dimethylamino)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

34)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

35)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((R)-2-(hydroxymethyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

36)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

37)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-hydroxy-2-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

38)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

39)((2-(3'-(5-((6-oxa-1-azaspiro[3.3]hept-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

40)((2-(3'-(5-(((2-amino-2-methylazacyclobutane-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

41)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(methanesulfonyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

42)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((R)-2-ethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

43)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methoxyazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

44)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxy-3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

45)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(((methylamino)methyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

46)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxoazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

47)((2-(3'-(5-((2-oxa-6-azaspiro[3.3]hept-6-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

48)((2-(3'-(5-((2-azaspiro[3.3]hept-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

49)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((hexahydrocyclopentano[c]pyrrole-2(1H)-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

51)((2-(3'-(5-((2,7-diazaspiro[3.5]non-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

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

54)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dioxo-2-thia-6-azaspiro[3.3]hept-6-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

55)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

56)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

57)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2R)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-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[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

59)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

60)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

62)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dimethylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

63)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxymethyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

65)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

66)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

67)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

68)((2-(3'-(5-((3-(diethylamino)azacyclobutane-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

69)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(2-hydroxypropyl-2-yl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

70)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,5-dihydro-1H-pyrrolo-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

71)((2-(3'-(5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

72)((2-(3'-(5-(((1s,4s)-7-azabicyclo[2.2.1]hept-7-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

73)((2-(3'-(5-((((3,3-difluoro-1-(hydroxymethyl)cyclobutyl)methyl)amino)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

74)((2-(3'-(5-((5-azaspiro[2.3]hex-5-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

75)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-oxo-6-azabicyclo[3.2.1]octane-6-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

76)((2-(3'-(5-((1,1-difluoro-5-azaspiro[2.3]hex-5-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

77)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

78)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(hydroxymethyl)-3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

79)((2-(3'-(5-(((3-cyano-3-methylazacyclobutane-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

81)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methyleneazonobutan-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

82)((2-(3'-(5-((3-(cyanomethylene)azacyclobutane-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

83)((2-(2,2'-dicyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

85)(R)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-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)(S)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-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-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-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)-L-proline;

89)((2-(3'-(5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-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)-D-proline;

91)(3R)-1-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidone-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidone-3-carboxylic acid;

92)(3S)-1-((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((3-methylpyrrolidone-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidone-3-carboxylic acid;

93)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazacyclobutane-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

94)((2-(3'-(5-(azacyclobutane-1-yl-methyl)-7-methylbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

96)((6-(difluoromethoxy)-2-(3'-(5-(((ethylamino)methyl)-6-fluoro-benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

98)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

99)((6-(difluoromethoxy)-2-(3'-(5-((((1R,2S)-2-hydroxycyclopentyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

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

102)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-yl-methyl)benzo[d]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-dimethylazacyclobutane-1-yl)methyl)benzo[d]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-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

106)((2-(3'-(5-((6-oxa-1-azaspiro[3.3]hept-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

107)((2-(3'-(5-((1-azaspiro[3.3]hept-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

108)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

109)((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

110)((2-(2'-chloro-3'-(6-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]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-dimethylazacyclobutane-1-yl)methyl)benzo[d]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-(pyrrolidone-1-ylmethyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

113)((6-(difluoromethoxy)-2-(3'-(6-((3,3-dimethylazacyclobutane-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

114)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(((R)-3-methylpyrrolidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

115)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

116)((6-(difluoromethoxy)-2-(3'-(6-((3-(dimethylamino)azacyclobutane-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

117)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-ylmethyl)benzo[d]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-(pyrrolidone-1-ylmethyl)benzo[d]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)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

120)((2-(3'-(6-((5-cyanopyridin-3-yl)methoxy)-5-(((2-hydroxyethyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

121)((6-(difluoromethoxy)-2-(3'-(5-(((2-hydroxyethyl)amino)methyl)-6-((5-(methanesulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

122)((6-(difluoromethoxy)-2-(3'-(5-((ethylamino)methyl)-6-((5-(methanesulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

123)((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((5-(methanesulfonyl)pyridin-3-yl)methoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

124)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((3-(methanesulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

125)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((methylamino)methyl)-6-((4-(methanesulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

126)((6-(difluoromethoxy)-2-(3'-(5-((dimethylamino)methyl)-6-((4-(methanesulfonyl)benzyl)oxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

127)((2-(3'-(7-cyano-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

128)((2-(2-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

129)((2-(3'-(7-cyano-5-((3-(hydroxymethyl)-3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

130)((2-(3'-(7-cyano-5-(((S)-3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

131)((2-(3'-(7-cyano-5-(((R)-3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

132)((2-(3'-(7-cyano-5-(((R)-3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

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

134)((2-(3'-(7-cyano-5-((3-(dimethylamino)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

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

137)((2-(3'-(7-cyano-5-((3-(hydroxymethyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

139)((2-(3'-(7-cyano-5-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

140)((2-(3'-(7-cyano-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

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

142)((2-(3'-(7-cyano-5-((3-cyanopyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

143)((2-(3'-(7-cyano-5-((3-cyanopyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

144)((2-(3'-(7-cyano-5-((3-ethynyl-3-hydroxyazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

145)((2-(3'-(7-cyano-5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

146)((2-(3'-(7-cyano-5-((7-oxo-2,6-diazaspiro[3.4]octane-2-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

147)((2-(3'-(5-((bis(1-hydroxypropyl-2-yl)amino)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

148)((2-(3'-(7-cyano-5-((3-morpholinylazacyclobutane-1-yl)methyl)benzo[d]oxazol-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(oxecyclobutane-3-yl)amino)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

150)((2-(3'-(7-cyano-5-((3-hydroxy-3-methyl-[1,3'-diazacyclobutane]-1'-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

151)((2-(3'-(7-cyano-5-((6-oxo-2,5-diazaspiro[3.4]octane-2-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

152)((2-(3'-(7-cyano-5-((3-((dimethylamino)methyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

153)((2-(3'-(7-cyano-5-((1,1-difluoro-5-azaspiro[2.4]hept-5-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

154)((2-(3'-(7-cyano-5-(((R)-3-(hydroxymethyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

156)((2-(3'-(5-(((3-amino-4-methylpyrrolidone-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

158)((2-(3'-(7-cyano-5-((3-(dimethylamino)-4-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

159)((2-(3'-(7-cyano-5-((3-((dimethylamino)methyl)-3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

161)((2-(3'-(5-((3-(aminomethyl)-3-methylazacyclobutane-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

162)((2-(3'-(7-cyano-5-((3-fluoropyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

163)((2-(3'-(7-cyano-5-((3-fluoropyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

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

165)((2-(3'-(7-cyano-5-(((R)-3-cyanopyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

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

168)((2-(3'-(7-cyano-5-(((R)-3-(fluoromethyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

169)(R)-1-((2-(3'-(7-cyano-5-(pyrrolidine-1-ylmethyl)benzo[d]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-dimethylazacyclobutane-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-D-proline;

171)S)-1-((8-((3'-(5-((((S)-2-carboxypyrrolidine-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid;

172)((2-(3'-((3-(((carboxymethyl)amino)methyl)-1,7-naphthid-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

173)(S)-1-((8-((3'-(5-((((S)-2-carboxypyrrolidone-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidin-3-yl)methyl)piperidine-2-carboxylic acid;

174)((6-(difluoromethoxy)-2-(3'-((3-((3-fluoropyrrolidone-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

175)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidone-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

176)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((3-(morpholinomethyl)-1,7-naphthid-8-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

177)((2-(3'-((3-(azacyclobutane-1-ylmethyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

178)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxyazacyclobutane-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

179)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((3-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)-1,7-naphthid-8-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

180)(3S)-1-((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

181)(3R)-1-((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidine-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid;

182)((6-(difluoromethoxy)-2-(3'-((3-((3-hydroxypyrrolidone-1-yl)methyl)-1,7-naphthidin-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

183)((5-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((4-(pyrrolidone-1-ylmethyl)pyridin-2-yl)amino)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-yl)methyl)-L-proline;

184)((2-(3'-(5-(carboxymethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)-L-proline;

185)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(2-(methanesulfonyl)ethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

186)((2-(3'-(5-(1-carboxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)-L-proline;

187)((2-(3'-(5-(2-carboxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)-L-proline;

188)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

189)((6-(difluoromethoxy)-2-(3'-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

190)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

191)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(4,4,4-trifluorobutyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

192)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(oxecyclobutane-2-ylmethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

193)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((5-oxopyrrolidone-2-yl)methyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

194)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyridin-3-ylmethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

195)((2-(3'-(5-(cyanomethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)proline;

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]oxazolo-5-yl)methyl)proline;

197)((6-(difluoromethoxy)-2-(3'-(5-(ethylsulfonyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

198)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

199)((6-(difluoromethoxy)-2-(3'-(5-(3-hydroxypropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

200)((6-(difluoromethoxy)-2-(3'-(5-(3-fluoropropyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)proline;

201)((2-(3'-(5-(2,2-difluoroethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)proline;

202)((6-(difluoromethoxy)-2-(3'-(5,6-dihydro-4H-pyrrolo[3,4-d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

203)((6-(difluoromethoxy)-2-(3'-(6,7-dihydro-4H-pyrano[3,4-d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

204)((6-(difluoromethoxy)-2-(3'-(5,6-dihydro-4H-cyclopenten[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

205)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrobenzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

206)((6-(difluoromethoxy)-2-(3'-(5-(2-hydroxyethyl)-4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline;

207)2-((2-(2'-cyano-2-methyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazolo-5-yl)methyl)pyrrolidine-1-carboxylic acid;

208)((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-(((R)-3-hydroxypyrrolidine-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

209)((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl)methoxy)-4-((3-fluoropyrrolidone-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

210)((2-(3'-((4-((((2-acetaminoethyl)amino)methyl)-2-chloro-5-((3-cyanobenzyl)oxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

211)((2-(3'-((4-(((S)-2-carboxypyrrolidone-1-yl)methyl)-2-chloro-5-((3-cyanobenzyl)oxy)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

212)((6-(difluoromethoxy)-2-(3'-(((4,6-dimethoxy-5-(pyrrolidone-1-yl-methyl)pyrimidin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

213)((6-(difluoromethoxy)-2-(3'-(((5-((3,3-dimethylazonobutan-1-yl)methyl)-4,6-dimethoxypyrimidin-2-yl)oxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

214)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-((5-(((((S)-5-oxopyrrolidone-2-yl)methyl)amino)methyl)pyridin-2-yl)oxy)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

215)((6-(difluoromethoxy)-2-(2'-fluoro-2-methyl-4”-(((((S)-5-oxopyrrolidine-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

216)((6-(difluoromethoxy)-2-(3”-(difluoromethoxy)-2'-fluoro-2-methyl-4”-(((((S)-5-oxopyrrolidine-2-yl)methyl)amino)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

217)((6-(difluoromethoxy)-2-(4”-(((2-hydroxyethyl)amino)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

218)((6-(difluoromethoxy)-2-(2,2',3”-trimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

219)((2-(3”-chloro-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

220)((6-(difluoromethoxy)-2-(2”-fluoro-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

221)((2-(2'-bromo-2”-fluoro-2-methyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

222)((2-(2'-chloro-2”-fluoro-2-methyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

223)((2-(2'-chloro-2”-fluoro-2-methyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

224)((2-(2'-chloro-2”-fluoro-2-methyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-D-proline;

225)((6-(difluoromethoxy)-2-(4”-guanidinyl-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

226)((6-(difluoromethoxy)-2-(4”-(((3-(dimethylamino)propyl)(methyl)amino)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

227)((6-(difluoromethoxy)-2-(4”-((3-methoxypyrrolidone-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

228)((6-(difluoromethoxy)-2-(4”-((3-(dimethylamino)pyrrolidone-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

229)((2-(3”-chloro-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

230)((6-(difluoromethoxy)-2-(2,2',3”-trimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

231)((2-(2”-chloro-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

232)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-3”-(trifluoromethoxy)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

233)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-3”-(trifluoromethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

234)((6-(difluoromethoxy)-2-(2,2',3”,5”-tetramethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

235)((6-(difluoromethoxy)-2-(3”-fluoro-5”-methoxy-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

236)((2-(3”-carboxy-2,2'-dimethyl-4”-(pyrrolidone-1-yl-methyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

237)((6-(difluoromethoxy)-2-(4”-((3,3-dimethylazacyclobutane-1-yl)methyl)-3”-fluoro-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

238)((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-((3-methylpyrrolidone-1-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

239)((6-(difluoromethoxy)-2-(3”-fluoro-4”-(((2-hydroxyethyl)amino)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

240)((2-(3”-cyano-4”-(((S)-3-(hydroxymethyl)pyrrolidine-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

241)((6-(difluoromethoxy)-2-(3”-fluoro-4”-(isoindoline-2-ylmethyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

242)((6-(difluoromethoxy)-2-(4”-((3-fluoropyrrolidone-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

243)((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

244)((6-(difluoromethoxy)-2-(3”-(difluoromethoxy)-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

245)((2-(3”-cyano-2,2'-dimethyl-4”-(pyrrolidone-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

246)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

247)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidone-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

248)((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-(((S)-3-phenylpyrrolidone-1-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

249)((6-(difluoromethoxy)-2-(3”-(4-fluorophenylethoxy)-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline;

250)((2-(3”-(cyclopropylmethoxy)-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

251)((2-(4”-(((R)-3-(1H-tetrazol-5-yl)pyrrolidine-1-yl)methyl)-3”-fluoro-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

252)((2-(4”-(((S)-3-((benzyloxy)methyl)pyrrolidine-1-yl)methyl)-3”-fluoro-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline;

253)((6-(difluoromethoxy)-2-(2”-fluoro-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

254)((6-(difluoromethoxy)-2-(3”,5”-dimethoxy-2,2'-dimethyl-4”-(pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline hydrochloride;

255)((6-(difluoromethoxy)-2-(2,2'-dimethyl-4”-(pyrrolidine-2-yl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

256)((2-(4”-((S)-amino(carboxyl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

257)((6-(difluoromethoxy)-2-(4”-(((S)-3-((S)-2-((methoxycarbonyl)amino)-3-methylbutyramide)pyrrolidine-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

258)((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-((5-ureidoisoindoline-2-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

260)((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-((3-ureidopyrrolidone-1-yl)methyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

261)((2-(3'-(5-(((S)-3-chloropyrrolidine-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

262)((6-(difluoromethoxy)-2-(3'-(4-fluoro-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

263)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

264)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

265)((6-(difluoromethoxy)-2-(3'-(5-fluoro-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

266)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(pyrrolidone-1-ylmethyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

267)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-oxo-5-(pyrrolidone-1-ylmethyl)-1,6-dihydropyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

268)((6-(difluoromethoxy)-2-(2'-(difluoromethyl)-3'-(5-fluoro-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

269)((6-(difluoromethoxy)-2-(3'-(5-fluoro-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-2'-(fluoromethyl)-2-methyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

270)((6-(difluoromethoxy)-2-(3'-(2-fluoro-6-(pyrrolidone-1-ylmethyl)pyridin-3-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

271)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazacyclobutane-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

272)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-3-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

273)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline;

274)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)-4-vinylpyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

275)((6-(difluoromethoxy)-2-(3'-(5-((3-(difluoromethyl)pyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

276)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

277)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-2-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

278)((2-(3'-(5-(((1s,4s)-7-azabicyclo[2.2.1]hept-7-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

279)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-2-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

280)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)thiophen-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

281)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(pyrrolidone-1-ylmethyl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

282)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

283)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-(pyrrolidone-1-yl)pyrimidin-5-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

284)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)pyrazin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

285)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(pyrrolidone-1-ylmethyl)pyrazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

286)((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((R)-3-methylpyrrolidone-1-yl)methyl)pyrazin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

287)((2-(2'-chloro-3'-(6-methoxy-5-((((5-oxopyrrolidone-2-yl)methyl)amino)methyl)pyrazin-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

288)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(1,2,3,4-tetrahydroisoquinoline-6-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

289)((6-(difluoromethoxy)-2-(3'-(isoindoline-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

290)((2-(3'-(2-(2-carboxyethyl)isoindoline-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

291)((2-(3'-(2-(carboxymethyl)isoindoline-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

292)((2-(3'-(2-(1-carboxyethyl)isoindoline-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

293)((2-(3'-(2-amino-1H-benzo[d]imidazol-5-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

294)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylpyrrolidin-1-yl)methyl)-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

295)((2-(3'-(7-cyano-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

296)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

297)((6-(difluoromethoxy)-2-(3'-(6-fluoro-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

298)((2-(3'-(6,7-difluoro-1-methyl-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

299)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

300)((2-(3'-(4,5-difluoro-6-(pyrrolidone-1-ylmethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

301)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)-7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

302)((2-(2'-chloro-3'-(5-((((2-hydroxyethyl)amino)methyl)pyridinecarboxamido)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline;

303)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-2-carboxamido)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

304)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-methyl-5-(pyrrolidone-1-ylmethyl)oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

305)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidone-1-ylmethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

306)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidone-1-yl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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)-L-proline;

308)((6-(difluoromethoxy)-2-(3'-(4-((3,3-dimethylazacyclobutane-1-yl)methyl)piperidin-1-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

309)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4-(pyrrolidone-1-ylmethyl)piperidin-1-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

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

311)((6-(difluoromethoxy)-2-(3'-(5-((2,2-dimethylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

312)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

313)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-((2-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline;

314)((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[d]oxazolo-5-yl)methyl)-L-proline;

315)((2-(3'-(5-((3-carbamoylpyrrolidone-1-yl)methyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; or

316)((2-(3'-(7-cyano-5-((3-cyano-3-methylpyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline.

The present invention also provides a pharmaceutical composition comprising any compound of the present invention and a pharmaceutically acceptable excipient, such as hydroxypropyl methylcellulose. In the composition, the weight ratio of the compound to the excipient is in the range of about 0.0001 to about 10.

The present invention also provides the use of the pharmaceutical composition of formula (I) in the preparation of a medicament for treating a subject’s disease.

The present invention further provides a preferred technical solution for the aforementioned application.

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

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

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

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

In some embodiments, the drug is used to enhance, stimulate, and/or increase the patient's immune response.

The general chemical terms used in the formulas have their usual meanings. For example, unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include F, Cl, and Br.

Unless otherwise stated, alkyl groups as used in this invention include saturated monovalent hydrocarbon groups having straight-chain, branched, or cyclic groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, n-n-butyl, isobutyl, sec-butyl, t-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, and cyclohexyl. Similarly, _C1-4 in _C1-4 alkyl refers to a group containing 1, 2, 3, or 4 carbon atoms arranged in a straight-chain, branched, or cyclic form.

Alkenyl and alkynyl groups include straight-chain, branched, or cyclic alkenes and alkynes. Similarly, "C _2-8 alkenyl" and "C _2-8 alkynyl" refer to alkenyl or alkynyl groups containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms arranged in a straight-chain, branched, or cyclic form.

Alkoxy groups are oxygen ethers formed from the aforementioned straight-chain, branched, or cyclic alkyl groups.

Unless otherwise stated, the term "aryl" as used in this invention refers to a monocyclic or polycyclic system containing a carbon ring atom, whether unsubstituted or substituted. Preferred aryl groups are 6-8 membered aromatic ring systems, whether monocyclic or bicyclic. Preferred aryl groups are benzene or naphthalene rings. Most preferred aryl groups are benzene rings.

Unless otherwise stated, the term "heterocyclic group" as used in this invention refers to an unsubstituted or substituted 3- to 10-membered saturated or partially unsaturated monocyclic, spirocyclic, bridged bicyclic, or fused bicyclic system containing a carbon atom and 1-3 heteroatoms selected from N, O, or S, wherein the N or S heteroatoms may optionally be oxidized, or the N heteroatoms may optionally be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom forming a stable structure. Examples of heterocyclic groups include, but are not limited to, aziridine, pyrrolidinyl, pyridinyl, piperazinyl, oxoperazinyl, oxazoryl, aziridine-heptadienyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

Unless otherwise stated, the term "heteroaryl" as used in this invention refers to an unsubstituted or substituted stable 5- or 6-membered monoaromatic ring system, or an unsubstituted or substituted 9- or 10-membered benzo[a]-fused heteroaromatic ring system, or a bicyclic heteroaromatic ring system, wherein the "heteroaryl" comprises a carbon atom and 1 to 4 heteroatoms selected from N, O, or S, wherein the N or S atom may optionally be oxidized, and the N atom may optionally be quaternized. The heteroaryl group may be attached to any heteroatom or carbon atom forming a stable structure. Examples of the heteroaryl group include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrroleyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiopheneyl, benziisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenyl, quinolinyl, or isoquinolinyl.

The term "olefinic group" refers to an -O-olefinic group, which is defined as described above.

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

The term "cycloalkyl" refers to a cyclic saturated alkyl chain containing 3 to 12 carbon atoms, such as cyclopropyl and cyclobutyl.

The term "substitution" refers to a group in which one or more hydrogen atoms are independently replaced by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br or I), _C1-8 alkyl, _C3-12 cycloalkyl, ^-OR1 , ^SR1 , =O, =S, -C(O) ^R1 , -C(S) ^R1 , = ^NR1 , -C(O) ^OR1 , -C( ^S ) ^OR1 , ^-NR1R2 , C(O) ^NR1R2 , ^cyano , nitro, -S(O) _2R1 , -OS( _O2 ) ^OR1 , -OS(O) _2R1 , ^-OP (O)( ^OR1 )( ^OR2 ); wherein ^R1 and ^R2 are independently selected from -H, lower alkyl, ^and lower haloalkyl. In some embodiments, the substituents are independently selected from -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, isobutoxy, t-butoxy, _-SCH3 , _-SC2H5 , formaldehyde, -C( _OCH3 ), cyano, nitro, _CF3 , _{-OCF3 ,} amino, dimethylamino, methyl thio, sulfonyl, and acetyl.

The term "composition" as used in this invention is intended to cover products containing a specified amount of a specified ingredient, and any product resulting directly or indirectly from a combination of specified amounts of the specified ingredients. Therefore, pharmaceutical compositions containing the compounds of this invention as active ingredients, and methods for preparing the compounds of this invention, are also part of this invention. Furthermore, some crystal forms of the compounds may exist in polymorphic forms, which are also intended to be included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, which are also intended to be included within the scope of this invention.

Examples of substituted alkyl groups include, but are not limited to, 2-aminoethyl, 2-hydroxyethyl, pentachloroethane, trifluoromethyl, methoxymethyl, pentafluoroethyl, and piperazinemethyl.

Examples of substituted alkoxy groups include, but are not limited to, aminomethoxy, trifluoromethoxy, 2-ethoxyaminoethoxy, 2-ethoxycarbonylethoxy, and 3-hydroxypropoxy.

The compounds described in this invention may also exist in pharmaceutically acceptable salt forms. When used in pharmaceuticals, the salt form of the compounds of this invention refers to a non-toxic "pharmaceutically acceptable salt." The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salts typically form a basic N atom protonated by an inorganic or organic acid. Represented organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, oxalic acid, pyruvic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, succinic acid, or trifluoroacetic acid. The pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum salts, calcium salts, chloroprocaine salts, choline, diethanolamine salts, ethylenediamine salts, lithium salts, magnesium salts, potassium salts, sodium salts, and zinc salts.

The drug prodrugs of the compounds of this invention are included within the scope of protection of this invention. Typically, the drug prodrugs are functional derivatives that are readily converted in vivo into the desired compound. Therefore, the term "administration" in the treatment methods provided by this invention includes the administration of the compounds disclosed herein, or, although not explicitly disclosed, the administration to the subject that allows for conversion in vivo into the compounds disclosed herein to treat the various diseases. Conventional methods for selecting and preparing suitable drug prodrug derivatives have been described in books such as *Design of Prodrugs* (ed. H. Bundgaard, Elsevier, 1985).

Clearly, the definition of any substituent or positional variable in one molecule is independent of the definition of any substituent or positional variable in other molecules. It is readily understood that the compounds of this invention can be prepared by selecting suitable substituents or substitution forms according to existing techniques in this field, providing chemical stability and ease of preparation and synthesis using existing techniques or the methods described in this invention.

The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

Formula (I) above does not precisely define the stereostructure of the compound at any particular position. This invention includes all stereoisomers of the compound shown in Formula (I) and their pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers and specific isolated stereoisomers are also included in this invention. The products obtained during the synthesis of such compounds, or using racemization or epimerization processes known to those skilled in the art, can be mixtures of stereoisomers.

When the compounds shown in formula (I) are present in tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

The present invention includes any possible solvates and polymorphs when the compound represented by formula (I) and its pharmaceutically acceptable salt are present in a solvate or polymorph. There are no particular limitations on the type of solvent forming the solvate, provided that the solvent is pharmacologically acceptable. For example, solvents such as water, ethanol, propanol, and acetone can be used.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid. When the compound provided by this invention is an acid, its corresponding salt can be prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (IC and OH), iron, ferrous, lithium, magnesium, manganese (IC and OH), potassium, sodium, zinc, etc. In particular, salts of ammonium, calcium, magnesium, potassium, and sodium are preferred. Non-toxic organic bases capable of being derived into pharmaceutically acceptable salts include primary, secondary, and tertiary amines, as well as cyclic amines and amines containing substituents, such as naturally occurring and synthetic amines containing substituents. Other pharmaceutically acceptable non-toxic organic bases that can form salts include ion exchange resins, as well as arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

When the compound provided by this invention is a base, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc. More preferably, methanesulfonic acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. More preferably, phosphoric acid, hydrochloric acid, and malic acid. Since the compound shown in formula (I) will be used as a pharmaceutical, it is preferred to use a substantially pure form, for example, at least 60% purity, more preferably at least 75% purity, and particularly preferably at least 98% purity (% is by weight).

The pharmaceutical compositions provided by this invention comprise a compound of formula (I) (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable excipient, and other optional therapeutic components or excipients. Although the most suitable route of administration of the active ingredient in any given case depends on the specific subject receiving the drug, the nature of the subject, and the severity of the condition, the pharmaceutical compositions of this invention include those suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration). The pharmaceutical compositions of this invention can be readily prepared in unit dosage forms known in the art and by any method of preparation known in the pharmaceutical field.

In practice, according to conventional drug mixing techniques, the compound represented by formula (I) of this invention, or a drug prodrug, or a metabolite, or a pharmaceutically acceptable salt, can be mixed as an active ingredient with a drug carrier to form a pharmaceutical composition. The drug carrier can take various forms depending on the desired route of administration, such as oral or injectable (including intravenous) administration. Therefore, the pharmaceutical compositions of this invention can be in the form of individual units suitable for oral administration, such as capsules, pouches, or tablets containing a predetermined dose of the active ingredient. Further, the pharmaceutical compositions of this invention can be in the form of powder, granules, solution, aqueous suspension, non-aqueous liquid, oil-in-water emulsion, or water-in-oil emulsion. In addition to the common dosage forms mentioned above, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can also be administered via controlled release and/or a delivery device. The pharmaceutical compositions of this invention can be prepared using any pharmaceutical method. Generally, this method includes the step of associating the active ingredient with a carrier constituting one or more essential components. Generally, the pharmaceutical composition is prepared by homogeneous and close mixing of the active ingredient with a liquid carrier or a finely segmented solid carrier or a mixture of both. In addition, the product can be easily prepared to meet the desired appearance.

Therefore, the pharmaceutical compositions of the present invention comprise a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more other pharmaceutically active agents, is also included in the pharmaceutical compositions of the present invention.

The drug carrier used in this invention can be, for example, a solid carrier, a liquid carrier, or a gaseous carrier. Examples of solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers include syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing oral drug formulations, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oils, alcohols, flavor enhancers, preservatives, colorants, etc., can be used in the preparation of oral liquid formulations, such as suspensions, elixirs, and solutions; while carriers, such as starches, sugars, microcrystalline cellulose, diluents, granulators, lubricants, binders, disintegrants, etc., can be used in oral solid formulations such as powders, capsules, and tablets. For ease of administration, tablets and capsules are preferred for oral formulations. Optionally, tablet coating can use standard aqueous or non-aqueous formulation techniques.

Tablets containing the compounds or pharmaceutical compositions of the present invention can be prepared by compression or molding, optionally, together with one or more excipients or adjuvants. The active ingredient, in a free-flowing form such as powder or granules, can be mixed with a lubricant, an inert diluent, a surfactant, or a dispersant, and compressed into tablets by compression in a suitable machine. Molded tablets can be prepared by wetting a powdered compound or pharmaceutical composition with an inert liquid diluent and then molding it in a suitable machine. Preferably, each tablet contains about 0.05 mg to 5 g of the active ingredient, and each sac or capsule contains about 0.05 mg to 5 g of the active ingredient. For example, dosage forms intended for oral administration to humans contain about 0.5 mg to about 5 g of the active ingredient, combined with a suitable and easily measurable excipient comprising about 5% to 95% of the total pharmaceutical composition. Unit dosage forms typically contain approximately 1 mg to approximately 2 g of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.

The pharmaceutical compositions for parenteral administration provided by this invention can be prepared by adding the active ingredient to water to form an aqueous solution or suspension. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersion systems can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Furthermore, preservatives may also be included in the pharmaceutical compositions of this invention to prevent the growth of harmful microorganisms.

This invention provides pharmaceutical compositions suitable for injection, comprising sterile aqueous solutions or dispersion systems. Further, the pharmaceutical compositions can be prepared in the form of sterile powders for immediate reconstitution of sterile injectable solutions. In any case, the final injectable form must be sterile and, for ease of injection, must be readily flowable. Furthermore, the pharmaceutical compositions must be stable during preparation and storage. Therefore, preservation against contamination by microorganisms such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, such as water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical compositions provided by this invention can be in forms suitable for topical application, such as aerosols, emulsions, ointments, lotions, powders, or other similar dosage forms. Furthermore, the pharmaceutical compositions provided by this invention can be in forms suitable for use with transdermal drug delivery devices. These formulations can be prepared using the compounds represented by formula (I) of this invention, or pharmaceutically acceptable salts thereof, through conventional processing methods. As an example, the preparation of emulsions or ointments involves adding a hydrophilic material and water (total of approximately 5 wt% to 10 wt% of the compound) to the aforementioned compounds to obtain an emulsion or ointment with desired consistency.

The pharmaceutical composition provided by this invention can be formulated into a form suitable for rectal administration using a solid carrier. The preferred dosage form is a suppository containing a single dose. Suitable excipients include cocoa butter and other materials commonly used in the art. The suppositories can be readily prepared by first mixing the pharmaceutical composition with softened or melted excipients, followed by cooling and molding.

In addition to the carrier components mentioned above, the pharmaceutical preparations may also include suitable, one or more additional excipient components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. Furthermore, other excipients may include penetration enhancers that adjust the isotonicity of the drug with blood. Pharmaceutical compositions comprising compounds of formula (I), or pharmaceutically acceptable salts thereof, may also be prepared in the form of powders or concentrates.

Generally, the dosage level for treating the conditions described above is approximately 0.01 mg/kg body weight to 150 mg/kg body weight per day, or 0.5 mg to 7 g per patient per day. For example, for colon cancer, rectal cancer, mantle cell lymphoma, multiple myeloma, breast cancer, prostate cancer, glioblastoma, squamous cell esophageal cancer, liposarcoma, T-cell lymphoma, melanoma, pancreatic cancer, glioblastoma, or lung cancer, the effective dosage level may be approximately 0.01 mg/kg body weight to 50 mg/kg body weight per day, or 0.5 mg to 3.5 g per patient per day.

However, it is understood that doses below or above the levels listed above are acceptable. The specific dosage level and quality regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, overall health status, sex, diet, timing of administration, route of administration, excretion rate, combination of drugs, severity and duration of the specific 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 provided to better illustrate the invention. Unless otherwise expressly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

The invention is described in more detail through specific embodiments. The following embodiments are merely exemplary and are not intended to limit the invention in any way. Those skilled in the art can readily identify various non-critical parameters that can be changed or modified to obtain substantially the same results. According to at least one assay method described in the invention, it can be found that the compounds disclosed in the embodiments can inhibit the activity of PD-1/PD-L1 protein/protein interactions.

Example

The laboratory preparation methods for the compounds described in this invention are as follows. Open-access preparative LCMS purification of some compounds is performed in Waters mass-directed fractionation systems. The basic equipment setup, protocols, and control software of these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al, "Optimizing Preparative LC-MS Configurations and Methods for Par allelSynthesis 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 are commercially available or synthesized using commercially available starting materials and reagents via the conventional methods shown below. The abbreviations used in the examples are as follows:

EA: Ethyl acetate;

STAB: Sodium triacetoxyborohydride;

TBAI: Tetrabutylammonium iodide;

DMF: Methyl dimethylformamide;

THF: Tetrahydrofuran;

TEA: Triethylamine;

TLC: Preparative thin-layer chromatography;

AcOH or HOAC: Acetic acid;

BSA: Bovine serum albumin;

DCM: Dichloromethane;

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

DMSO: Methyl dimethyl sulfoxide;

EtOAc: Ethyl acetate;

h or hrs: hours;

HTRF: Homogeneous time-resolved fluorescence;

MeOH: Methanol;

min: minutes;

PE: Petroleum ether;

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

rt or RT: room temperature;

TBAI: Tetrabutylammonium iodide;

THF: Tetrahydrofuran;

_Pd₂ (dba) _₃ : tris(dibenzylacetone)dipalladium;

NBS: N-bromosuccinimide;

BPO: Benzoyl peroxide;

TLC: Preparative thin-layer chromatography.

Preparation of intermediates

Preparation of intermediate A in Example A

((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

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

Methyl 2,4-dihydroxybenzoate (850 g) was dissolved in a mixed solution of ice-cold AcOH (3.6 L) and _Ac₂O (900 mL). After the clear solution was cooled to 10 °C (ice bath), concentrated _HNO₃ (65%) dissolved in ice-cold AcOH (500 mL) was added over 1 hour. The light brown solution was heated to 15-20 °C and stirred for another 1 hour. The reaction solution was poured into _H₂O (3 L), the precipitate was filtered, and the filter cake was washed with a small amount of _H₂O . Then, the crude product was poured into MeOH (2 L) with stirring, the precipitate was filtered, the filter cake was washed with a small amount of MeOH, and the product was dried under vacuum to obtain 480 g of the title product.

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

A methanol (2 L) solution of compound a-2 (77.1 g) and 10% Pd(OH)/C (11.5 g) was stirred at 1.1 atm for 3 hours at room temperature. The catalyst was removed by filtration, the solid residue was washed with methanol (300 mL), and the solvent was removed under vacuum. 72 g of methyl 5-amino-2,4-dihydroxybenzoate was obtained.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazol-5-carboxylic acid

A solution of methyl 5-amino-2,4-dihydroxybenzoate (32.9 g) and 3-bromo-2-methylbenzaldehyde (32.5 g) in MeOH (1 L) was stirred at 80 °C for 2.5 h, followed by concentration under reduced pressure. DCM (500 mL) and DDQ (55.6 g) were added to the mixture. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM and washed with _{aqueous Na₂S₂O₃ solution and NaHCO₃} solution. The organic layer was dried over _MgSO₄ , filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (PE:DCM = 1/1) to give 45 g of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazol-5-carboxylic acid as a brown solid.

Step 4: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxylic acid

10.0 g of methyl 2-(3-bromo-2-methylphenyl)-6-hydroxybenzo[d]oxazol-5-carboxylate, 5.46 g of sodium ₂ -bromo-2,2-difluoroacetate, 27.09 _g of Cs₂CO₃, 4.59 g of KI, and 10.22 g of TBAI were added to 200 mL of DMF, and the mixture was stirred at 100 °C for 3 hours. The reaction mixture was diluted with DCM and washed with saturated NaCl solution. The crude product was purified by column chromatography (PE:DCM = 1/1) to obtain 5 g of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxylate.

Step 5: Preparation of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methanol

A 2.5 M THF solution of LiAlH₄ was added dropwise to a ₅₀ mL THF solution of methyl 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxylic acid (1.30 g) at -10 °C. The mixture was then brought to room temperature. After 1 _h , the mixture was quenched with 1 mL _H₂O and 1 mL 10% NaOH, and washed with 1 M HCl, water, and brine. The organic layer was dried over _Na₂SO₄ , filtered, and the filtrate was concentrated to give (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methanol as a yellow solid (1.2 g).

Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxaldehyde

Dess-Martin (2.39 g) was added in portions to a dry THF (15 mL) solution of (1.40 g) of (2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methanol at 10 °C. The resulting solution was stirred at room temperature for 1 h. The mixture was filtered through diatomaceous earth. The solid was washed with DCM, and the combined filtrates were washed with aqueous sodium bicarbonate solution, water, and brine, dried, and concentrated. The residue was purified by column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 5:1) to give 1.27 g of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxaldehyde.

Step 7: Preparation of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

A solution of 1.0 g of 2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxaldehyde, 1.7 g of L-proline methyl ester, and 316 mg of HOAC in MeOH was stirred at room temperature for 30 mins. 498 mg of _NaBH3CN was added to the mixture, and the mixture was heated to 60 °C and stirred for 2 hrs. The mixture was cooled, diluted with DCM, and washed with _H2O and NaCl solutions. The organic phase was dried over _MgSO4 , filtered, and the filtrate was concentrated. The residue was purified by column chromatography (DCM:MeOH = 10:1) to give 671 mg of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester as a white solid.

Step 8: Preparation of ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Under _N2 protection, 1.20 g of dipinalloyl diborone, 100 mg of Pd(dppf)Cl2·DCM, and 102 mg of KOAc were added to a solution of ((2-(3-bromo-2-methylphenyl)-6-(difluoromethoxy)benzo[d]oxazol- ₅ -yl)methyl)-L-proline methyl ester (680 mg) in 1,4-dioxane (16.0 mL). The reaction mixture was heated to 100 °C for 10 hs. The reaction mixture was then diluted with 30 mL of water and extracted with DCM (90 mL × 2). The combined organic phases were washed with brine, dried over _MgSO4 , and concentrated under vacuum. The residue was purified by column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 4:1 to 2:1) to give methyl ((6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (500 mg). LC-MS (m/z): 543.2 (M+H) ⁺ .

Synthesis of Intermediate B in Example B

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Step 1: Preparation of ((2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Under _N2 protection, EtOH (30 mL), 10% _{Na2CO3 aq} . (30 mL), and Pd(dppf)Cl2·DCM (1.0 g) were added to a solution of intermediate A (21.7 g), 1-bromo-3-iodo- ₂ -toluene (9.0 g) in toluene (150 mL). The mixture was stirred overnight at 90 °C. The reaction was quenched with _H2O (100 mL) and extracted three times with EtOAc (100 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by column chromatography to give methyl ((2-(3'-bromo-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline (18.2 g) as a brown oil.

Step 2: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Under _N2 protection, 12.4 g of dipinallodiboron, 1.0 g of Pd(dppf) _Cl2 ·DCM, and 9.9 g of KOAc were added to a 120 mL solution of compound b-1 (18.2 g) in 1,4-dioxane. The reaction mixture was heated to 100 °C for 6 hours. The reaction mixture was quenched with 300 mL of water and extracted three times with EtOAc (150 mL). The combined organic phases were washed with brine, dried over _MgSO4 , and concentrated under vacuum. The residue was purified by column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 10:1) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester (15.1 g), a brown oil. LC-MS (m/z): 633.9 (M+H) ⁺ .

Example 1: Preparation of Compound 1

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

Compound 1

Step 1: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Compound a-6 (3.9 g), _K₂CO₃ (3.8 g), and Pd(dppf) _{Cl₂CH₂Cl₂} (732 mg) were added to a solution of intermediate A (5 g) in _1,4 -dioxane (80 mL)/ _H₂O ( ₁₆ mL). The mixture was stirred at 80 ° _C for 12 hrs under _N₂ protection. When the reaction proceeded almost completely and the reaction stopped, the mixture was poured into _H₂O (300 mL) and extracted three times with DCM (100 mL). The organic phase was washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and concentrated to obtain the residue. The residue was further purified by silica gel column chromatography to obtain compound 1-1 (3.7 g).

Step 2: Preparation of ((2-(3'-(5-(chloromethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)-yl)methyl)-L-proline methyl ester

Compound 1-1 (1.5 g) was dissolved in DCM (20 mL). _SOCl2 (495 mg) was added dropwise to the solution and the mixture was reacted at room temperature for 1 h. When the starting material was almost completely reacted and the reaction stopped, the resulting mixture was concentrated under reduced pressure to give 1.56 g of compound 1-2 (crude product).

Step 3: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentane)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

A solution of compounds 1-2 (300 mg), (1S,2R)-2-aminocyclopentan-1-ol (168 mg), _K₂CO₃ ( ₂₈₃ mg), and KI (68 mg) in _CH₃CN (10 mL) was stirred at 50 °C for _1.5 hrs. The reaction proceeded until the reactants were almost completely reacted and the reaction stopped. The reaction mixture was poured into _H₂O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (DCM/MeOH) to obtain compounds 1-3 (240 mg).

Step 4: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Compounds 1-3 (240 mg), HCHO (45 mg), and _CH3COOH (36 mg) were stirred in a MeOH (5 mL)/DCM (5 mL) solution at 30 °C for 30 min. Then, _NaBH3CN (57 mg) was added and stirring continued until the reactants were almost completely reacted and the reaction stopped. The reaction solution was poured into _H2O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried _over anhydrous _Na2SO4 , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography (DCM/MeOH) to obtain compounds 1-4 (200 mg).

Step 5: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 1)

Compounds 1-4 (200 mg) and LiOH (51 mg) were dissolved in a mixture of THF (8 mL) and _H₂O (2 mL) and stirred at 35 °C for 12 hrs. The reaction solution was poured into _H₂O (30 mL) and extracted three times with DCM (10 mL) and MeOH (5 mL). The organic phases were combined, dried over anhydrous _MgSO₄ , filtered, and concentrated under reduced pressure to give 160 mg of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2S)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (compound 1). LC-MS (m/z): 803.3 (M+H) ^⁺ .

Example 2 Preparation of Compound 2

(2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-2,5-diyl))bis(methylene))di-L-proline

Compound 2

Step 1: Preparation of methyl 6-(difluoromethoxy)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl)benzo[d]oxazol-5-carboxylic acid

To a solution of compound a-5 (880 mg) in 1,4-dioxane (16.0 mL), bis-pinacol diboron (1.80 g), Pd(dppf) _Cl₂ ·DCM (150 mg), and KOAc (130 mg) were added. The reaction mixture was heated to 100 °C and reacted for 10 hs. The reaction mixture was diluted with 30 mL and extracted with DCM (90 mL × 2). The combined organic phases were washed with brine, dried over _MgSO₄ , and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 4:1 to 2:1) to give compound 2-1 (600 mg).

Step 2: Preparation of 2,2’-(2,2’-dimethyl-[1,1’-biphenyl]-3,3’-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-5-carboxylic acid methyl ester)

Compound 2-1 (8 g), compound a-5 (8.95 g), _K₂CO₃ ( _5.25 g), and Pd(dppf) _cl₂.DCM (1.65 g) were purged and purged with nitrogen three times in a solution of 1,4-dioxane (160 mL)/ _H₂O (16 mL). The mixture was heated to reflux for 2 hours. 200 mL of _H₂O was added to the reaction mixture, and it was extracted with EtOAc (2 × 200 mL). The combined organic phases were washed with brine (100 mL), dried _{over Na₂SO₄} , filtered, and concentrated to obtain the residue. The 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 e-2,5-diyl))diethanol

_LiAlH₄ (2.5M) was added dropwise at 0°C to a THF (150mL) solution of compound 2-2 (6.3g). The mixture was stirred at 0°C for 30 mins. The reaction mixture was quenched with water at 0°C, dried _{over Na₂SO₄} , filtered, and concentrated to obtain compound 2-3 (5.7g).

Step 4: Preparation of 2,2'-(2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-5-carboxaldehyde)

Dess-Martin (11.95 g) was added to a THF (100 mL) solution of compound 2-3 (5.70 g). The mixture was stirred at room temperature for 2 hours. The reaction was _quenched with _NaHCO3 and _Na2SO3 and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with brine (100 mL), dried _{over Na2SO4} , filtered, and concentrated to give compound 2-4 (5.5 g).

Step 5: Preparation of (2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-2,5-diyl))bis(methylene))di-L-proline (Compound 2)

Compounds 2-4 (4 g), L-proline (4.58 g), and AcOH (0.82 g) were stirred in a MeOH ( ₁₀₀ mL) solution for 30 mins. _NaBH3CN was added to the mixture and stirring was continued for 12 hrs. 200 mL of _H2O was added to the reaction mixture and extracted with DCM (2 × 200 mL). The combined organic phases were dried over _Na2SO4 , filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (DCM/MeOH = 10:1) to obtain 2.56 g of (2'S)-(((2,2'-dimethyl-[1,1'-biphenyl]-3,3'-diyl)bis(6-(difluoromethoxy)benzo[d]oxazol-2,5-diyl))bis(methylene))di-L-proline (compound 2). LC-MS (m/z): 803.3 (M+H) ⁺ .

Example 3: Synthesis of Compound 3

((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 3

Step 1: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-formyllbenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Dess-Martin (11.79 g) was added in portions to a 200 ml THF solution of compound 1-1 (10.00 g). The mixture was stirred at room temperature for 2 h. The reaction was quenched with _{Na₂SO₃ and} sodium bicarbonate solution and extracted with EtOAc (2 × 150 ml). The combined organic phases were washed with brine (100 ml), dried _{over Na₂SO₄} , and concentrated to give compound 3-1 (9.50 g).

Step 2: Preparation of ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 3-1 (5.90 g), L-proline (2.85 g), and AcOH (0.51 g) were stirred in a solution of MeOH (60 mL) for 30 mins. Then, _NaBH3CN (1.55 g) was added to the mixture. The reaction was stirred for 3 hrs. 100 mL of water was added to the reaction mixture, and the mixture was extracted with DCM (2 × 100 mL). The combined organic phases were dried over _Na2SO4 , _filtered , and concentrated to obtain the residue. The residue was purified by column chromatography (DCM/MeOH = 10:1) to give ((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-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-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 4

Step 1: Preparation of 2-bromo-6-vinylcyanobenzene

Under a _nitrogen atmosphere, 2-bromo-6-m-iodophenylcyanide (10 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (5 g), [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) (2.5 g) and potassium carbonate (13.4 g) were stirred at 80 °C for 12 hs in a solution of 1,4-dioxane (100 mL)/ _H₂O (20 mL). The reaction solution was poured into _H₂O (30 mL) and extracted with DCM (15 mL × 3). The organic phase was washed with brine, dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain compound 4-1 (5 g).

Step 2: Preparation of 2-bromo-6-cyanobenzaldehyde

Compound 4-1 (1 g) and sodium periodate (3.67 g) were stirred in a THF (20 mL)/ _H₂O (6 mL) solution in an ice bath. Potassium osmium tetroxide (20 mg) was then added to the mixture, and stirring was continued at room temperature for 4 hours. The reaction mixture was poured into _H₂O (150 mL) and extracted twice with EA (100 mL). The organic phase was washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and concentrated to give the title compound 4-2 (800 mg).

Step 3: Preparation of methyl 2-(3-bromo-2-phenylcyanide)-6-hydroxybenzo[d]oxazol-5-carboxylic acid

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

Step 4: Preparation of methyl 2-(3-bromo-2-phenylcyanide)-6-(difluoromethoxy)benzo[d]oxazol-5-carboxylic acid

Sodium difluorochloroacetate (850 mg) and cesium carbonate (2.62 g) were added to a DMF (20 mL)/H₂O (0.6 mL) solution of methyl 2-(3-bromo-2-phenylcyanide)-6-hydroxybenzo[d]oxazol-5-carboxylic acid ( ₁ g) under stirring. The reaction mixture was heated to 80 °C and stirred for 4 hours. The mixture was then poured into _H₂O (100 mL) and extracted twice with EA (80 mL). The combined organic phases were washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and concentrated to give a crude product. The crude product was further purified by silica gel column chromatography to give the title compound 4-4 (800 mg).

Step 5: Preparation of 2-bromo-6-(6-(difluoromethoxy)-5-(hydroxymethyl)benzo[d]oxazol-2-yl)cyanobenzene

The compound was prepared using a method similar to that described in step 5 of 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: Preparation of 2-bromo-6-(5-(chloromethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)cyanobenzene

The compound was prepared using a method similar to that described in step 2 of Example 1, with compound 4-5 replacing 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-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)cyanobenzene

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compounds 1-2 were replaced with compounds 4-6, and (1S,2R)-2-aminocyclopentan-1-ol was replaced with 3,3-dimethylazacyclobutane. The crude product was further purified by silica gel column chromatography (PE/EA) to give the title compound (290 mg).

Step 8: Preparation of ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compounds 4-7. The crude product was further purified by silica gel column chromatography to obtain the title compound.

Step 9: Preparation of ((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, except that compounds 1-4 were replaced with compounds 4-8. The mixture was concentrated under reduced pressure to obtain the title compound. LC-MS (m/z): 784.3 (M+H) ⁺ .

The compounds in Table 1 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Examples 1-4.

Table 1

Example 100 Synthesis of Compound 100

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-yl-methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 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 the mixture was cooled to 5 °C (ice bath), concentrated _HNO₃ (65%) (612 mg) was added dropwise to the mixture while stirring for 30 mins. When the reactants had almost completely reacted and the reaction was finished, the mixture was poured into ice water (30 mL), filtered, and the collected solution yielded compound 100⁻² (1 g).

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

Compound 100-2 (500 mg), pyrrolidine (454 mg), and _CH3COOH (255 mg) were stirred in a 1,4-dioxane (10 mL) solution for 30 min at 30 °C. Then, sodium triacetoxyborohydride (1.35 g) was added and stirring continued. The reaction was continued until the reactants were almost completely reacted and the reaction stopped. The reaction solution was poured into _H2O (30 mL), extracted three times with DCM (15 mL), washed with brine, dried over anhydrous _{Na2SO4 ,} filtered, and vacuum dried. The crude product was further purified by silica gel column chromatography (DCM/MeOH = 20:1) to obtain compound 100-3 (420 mg).

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

Compound 100-3 (420 mg) and 10% Pd(OH)/C (150 mg) in a methanol (10 mL) solution were reacted at room temperature under a hydrogen pressure of 1.1 atm for 3 hours. The catalyst was removed by filtration, and the solid residue was washed with methanol (300 mL). The solvent was then removed to obtain 300 mg of compound 100-4.

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

The compound was prepared using a method similar to that described in step 3 of Example A, with compound 100-4 used instead of compound a-3. The crude product was used directly in the next reaction.

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

Intermediate A (345.72 mg), compound 100-5 (280 mg), 1,1′-bis(diphenylphosphine)ferrocene dichloropalladium(II) (53 mg), and potassium carbonate (88.10 mg) were dissolved in 1,4-dioxane (8 mL) and _H₂O (2 mL) and stirred at 80 °C for 12 hrs under _N₂ protection. The reaction solution was poured into _H₂O (30 mL) and extracted three times with DCM (15 mL). The organic phase was washed with brine, dried _over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was further purified by silica gel column chromatography to obtain compound 100-6 (300 mg).

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

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 100-6 replacing compounds 1-4. After filtration and vacuum drying, (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[5-(pyrrolidine-1-ylmethyl)-7-(trifluoromethyl)-1,3-benzoxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]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-(pyrrolidone-1-yl-methyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 101

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

Concentrated sulfuric acid (10 ml) was added dropwise to a methanol (300 ml) solution of 18.0 g of 4-hydroxy-2-(trifluoromethyl)benzoic acid, and the mixture was refluxed and stirred for 12 hours. After cooling to room temperature, water (200 ml) was added to the reaction mixture, and the methanol was removed by concentration under reduced pressure. The mixture was then extracted twice with ethyl acetate (200 ml). The organic phase was washed with water, saturated aqueous sodium bicarbonate solution, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (18 g).

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

The compound was prepared using a method similar to that described in step 1 of Example 100, except that compound 100-1 was replaced with compound 101-1. The crude product was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 100-3 was replaced with compound 101-2. 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[d]oxazol-5-carboxylic acid

The compound was prepared using a method similar to that described in step 3 of Example A, except that compound a-3 was replaced with compound 101-3. The crude product was suspended in methanol, filtered, and dried in a vacuum drying oven to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example A, except that compound a-5 was replaced with compound 101-4. The filtrate was concentrated under reduced pressure to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 2 of Example 1, with compound 101-5 used 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-(-pyrrolidine-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazole

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 101-6 and (1S,2R)-2-aminocyclopentan-1-ol was replaced with pyrrolidine. The crude product was further purified by silica gel column chromatography (PE/EA) to obtain the title compound.

Step 8: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(-pyrrolidone-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound 101-7 was used instead of compound a-6. The crude product was further purified by silica gel column chromatography to obtain the title compound.

Step 9: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(-pyrrolidone-1-ylmethyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, except that compound 1-4 was replaced with compound 101-8. The title compound was obtained by concentration under reduced pressure. LC-MS (m/z): 761.3 (M+H) ⁺ .

Example 102 Synthesis of Compound 102

((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 102

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

The compound was prepared using a method similar to that described in step 1 of Example A, except that compound a-1 was replaced with methyl 2,3-difluoro-4-hydroxybenzoate. The crude product was further purified by silica gel column chromatography (n-hexane/ethyl acetate) to give the title compound.

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

The compound was prepared using a method similar to that described in step 2 of Example A, except that compound a-2 was replaced with compound 102-1. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-6,7-difluorobenzo[d]oxazol-5-carboxylic acid

The compound was prepared using a method similar to that described in step 3 of Example A, except that compound a-3 was replaced with compound 102-2. The crude product was dissolved in methanol, filtered, and dried in a vacuum drying oven to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example A, except that compound a-5 was replaced with compound 102-3. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 5: Preparation of ((2-(3'-(6,7-difluoro-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound 102-4 was used instead of compound a-6. The crude product was further purified by silica gel column chromatography to obtain the title compound.

Step 6: Preparation of ((2-(3'-(5-(chloromethyl)-6,7-difluorobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 2 of Example 1, except that compound 1-1 was replaced with compound 102-5. The crude product was used directly in the next step.

Step 7: Preparation of ((2-(3'-(6,7-difluoro-5-(-pyrrolidine-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 102-6 and (1S,2R)-2-aminocyclopentan-1-ol was replaced with pyrrolidine. The crude product was further purified by silica gel column chromatography (PE/EA) to obtain the title compound.

Step 8: Preparation of ((2-(3'-(6,7-difluoro-5-(-pyrrolidine-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 102-7 used instead of compounds 1-4. The crude product was further purified by silica gel column chromatography to obtain the title compound. LC-MS (m/z): 729.3 (M+H) ⁺ . ¹ H NMR(500MHz,DMSO-d6)δ8.21(dd,J＝7.9,1.4Hz,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＝71.9Hz, 1H),4.58(s,2H),4.36-4.20(m,2H),3.91(s,1H),3.46(s,3H),3.20-3.07(m, 2H), 2.96 (s, 1H), 2.45 (d, J = 4.0Hz, 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-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 103

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

The compound was prepared using a method similar to that described in step 1 of Example A, except that compound a-1 was replaced with methyl 3-cyano-4-hydroxybenzoate. The crude product was further purified by silica gel column chromatography (n-hexane/ethyl acetate) to give the title compound.

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

The compound was prepared using a method similar to that described in step 2 of Example A, except that compound a-2 was replaced with compound 103-1. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 3: Preparation of methyl 2-(3-bromo-2-methylphenyl)-7-cyanobenzo[d]oxazol-5-carboxylic acid

The compound was prepared using a method similar to that described in step 3 of Example A, except that compound a-3 was replaced with compound 103-2. The crude product was further purified by silica gel column chromatography to obtain the title compound.

Step 4: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)benzo[d]oxazol-7-nitrile

The compound was prepared using a method similar to that described in step 5 of Example A, except that compound a-5 was replaced with compound 103-3. The filtrate was concentrated under reduced pressure to obtain the title compound.

Step 5: Preparation of ((2-(3'-(7-cyano-5-(hydroxymethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound 103-4 was used instead of compound a-6. The crude product was further purified by silica gel column chromatography to obtain the title compound.

Step 6: Preparation of ((2-(3'-(5-(chloromethyl)-7-cyanobenzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

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

Step 7: Preparation of ((2-(3'-(7-cyano-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 103-6 and (1S,2R)-2-aminocyclopentan-1-ol was replaced with 3,3-dimethylazacyclobutane. The crude product was further purified by silica gel column chromatography (PE/EA) to obtain the title compound.

Step 8: Preparation of ((2-(3'-(7-cyano-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 103-7 replacing compounds 1-4. The crude product was further purified by silica gel column chromatography to obtain the title compound. LC-MS (m/z): 732.3 (M+H) ⁺ . ^1H NMR (500MHz, DMSO-d6) 8.20 (dd, J = 7.9, 1.4Hz, 1H), 8.16 (dd, J = 7.9, 1.5Hz, 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 = 71.9Hz, 1H), 3 .96(s,2H),3.75(s,2H),3.36(dd,J＝9.1,5.4Hz,1H),3.07(td,J＝9.4,8.4,3.3Hz,1H),2.99(s,3H ), 2.56 (q, J = 8.5Hz, 1H), 2.44 (d, 6H, J = 2.5Hz), 2.17-2.08 (m, 1H), 1.90–1.68 (m, 4H), 1.20 (s, 6H).

The compounds in Table 2 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Examples 100-103.

Table 2

Example 171: Synthesis of Compound 171

(S)-1-((8-((3'-(5-((((S)-2-carboxypyrrolidine-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid

Compound 171

Step 1: Preparation of 8-chloro-3-vinyl-1,7-naphthidine

To a toluene (30 mL) solution of compound 171-1 (2.43 g), EtOH (10 mL), 10% _{Na₂CO₃ aq} . (10 mL), and Pd(dppf) _Cl₂ ·DCM (420 mg) were added. Then, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborane (3.1 g) was added dropwise under _N₂ protection. The mixture was stirred at 100 °C for 16 hours. The reaction was quenched with _H₂O (50 mL) and extracted three times with EtOAc. The combined organic phases were washed with brine. The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 8:1 to 5:1) to give 8-chloro-3-vinyl-1,7-naphthidine (1.1 g) as a brown solid.

Step 2: Preparation of (8-chloro-1,7-naphthid-3-yl)methanol

_{K₂O₅O₄ (} 4.0 mg) was added to a 1,4-dioxane (20 mL)/water (20 mL) solution of compound 171-2 (380 mg), and the mixture was stirred at room temperature for 30 min. _NaIO₄ (1.0 g) was added in portions at the same temperature. After stirring for 3 hours _, the reaction mixture was quenched with saturated _{Na₂S₂O₃} solution and extracted three times with DCM (40 mL). The organic phases were combined, dried _{over Na₂SO₄} , and the resulting solution _was concentrated to give 8-chloro-1,7-naphthyl-3-carboxaldehyde.

The above-mentioned 8-chloro-1,7-naphthidine-3-carboxaldehyde was dissolved in 20 mL of MeOH, and _NaBH₄ (200 mg) was added all at once. The resulting mixture was stirred at room temperature, and quenched with water (30 mL) after two hours. The mixture was extracted three times with DCM (20 mL), and the organic phase was dried _{over Na₂SO₄} . The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 1:1 to 1:2) to obtain (8-chloro-1,7-naphthidine-3-yl)methanol (240 mg), a white solid.

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

3-Bromo-2-methylaniline (2.50 g), compound 171-3 (1.86 g), t-BuOH (15 mL), and HCl (3 mL of 4.0 M 1,4-dioxane solution) were added to a microwave-safe reaction flask. The flask was capped, and the reaction mixture was reacted in a microwave oven at 100 °C for 4 h. The reaction mixture was diluted with 20 mL of water and extracted with DCM (50 mL × 2). The combined organic phases were washed with brine, dried over _MgSO4 , and concentrated under vacuum. The residue was concentrated and recrystallized from DCM:n-hexane (1:1) to give (8-((3-bromo-2-methylphenyl)amino)-1,7-naphthid-3-yl)methanol (2.0 g) as an off-white solid.

Step 4: Preparation of ((5-(difluoromethoxy)-2-(3'-((3-(hydroxymethyl)-1,7-naphthid-8-yl)amino)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-6-yl)methyl)-L-proline methyl ester

Under _N2 protection, EtOH (5 mL), 10% _{Na2CO3 aq} . (5 mL), and Pd(dppf) _Cl2 ·DCM (78 mg) were added to a toluene (15 mL) solution of compound 171-4 (0.69 g) and intermediate A (1.5 g). The mixture was stirred overnight at 110 °C. The reaction was quenched with _H2O (20 mL) and extracted three times with EtOAc (50 mL). The organic phases were combined, washed with brine, concentrated, and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 3:1 to 1:1) to give compound 171-5 (0.88 g) as a brown oil.

Step 5: Preparation of (S)-1-((8-((3'-(6-(difluoromethoxy)-5-((((S)-2-(methoxycarbonyl)-pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidium-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid methyl ester

MsCl (89 mg) was added dropwise to a DCM (5.0 mL) solution of compound 171-5 (250 mg) and TEA (100 mg) at 0 °C. The reaction was carried out at room temperature for 4 hours. The resulting mixture was concentrated under vacuum and dissolved in THF (5 mL). Methyl(S)-2-methylpyrrolidine-2-carboxylic acid ester (143 mg) and KI (1 mg) were added to the solution, and the reaction was continued overnight at room temperature with stirring until the methanesulfonate was consumed. The residue was concentrated and purified by RP column chromatography (mobile phase: MeCN:water = 10:90 containing 0.1% HCl) to give an off-white solid.

Step 6: Preparation of (S)-1-((8-((3'-(5-((((S)-2-carboxypyrrolidine-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid

LiOH (40 mg) was added to a THF/water solution of 105 mg (4 mL). The resulting mixture was stirred at room temperature for 24 hours. The mixture was separated by THF chromatography and purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient 10:90 to 30:70) to give 78 mg of (S)-1-((8-((3'-(5-((((S)-2-carboxypyrrolidine-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)amino)-1,7-naphthidin-3-yl)methyl)-2-methylpyrrolidine-2-carboxylic acid (compound 171). LC-MS (m/z): 777.3 (M+H) ⁺ . ¹ H NMR (500MHz, methanol-d4) δ9.23(d,1H,J＝2.1Hz),8.60(d,1H,J＝2.0Hz),8.20(dd,1H,J＝7.9,1.5Hz),8.07(s,1H),7.76(s,1H),7.69–7.63(m,2H) ,7.57(t,1H,J＝7.8Hz),7.53(t,1H,J＝7.7Hz),7.46(dd,1H,J＝7.6,1.5Hz),7.38(dd,1H,J＝7.6,1.4Hz),7.35(d,1H,J＝6.9Hz),7.12(t,1H,J _FH ＝72.6Hz), 4.83(d,1H,J＝13.2Hz), 4.74(d,1H,J＝13.3Hz), 4.62(d,1H,J＝13.2Hz), 4.49(d,1H,J＝13.2Hz), 4.33(dd,1H,J＝9.6,7.2Hz), 3.66-3.6 2(m,1H),3.52–3.37(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).

The compounds in Table 3 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Example 171.

Table 3

Example 314 Synthesis of Compound 314

((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[d]oxazolo-5-yl)methyl)-L-proline

Compound 314

Step 1: Preparation of benzyl(3S,4S)-3-(3-bromo-2-methylbenzamide)-4-hydroxypiperidine-1-carboxylic acid ester

3-Bromo-2-methylbenzoic acid (800 mg), benzyl(3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylic acid ester (931.13 mg), EDCI (1.43 g), HOBT (1.01 g), and TEA (1.13 g) were added sequentially to DCM (50 mL), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with dichloromethane and washed sequentially with saturated aqueous solutions of sodium bicarbonate and sodium chloride. The organic phase was dried _{over Na₂SO₄} and concentrated to give an off-white solid, which was benzyl(3S,4S)-3-(3-bromo-2-methylbenzamide)-4-hydroxypiperidine-1-carboxylic acid ester (1.4 g, crude product).

Step 2: Preparation of benzyl(S)-3-(3-bromo-2-methylbenzamide)-4-oxoperidine-1-carboxylic acid ester

At room temperature, Dess-Martin (2.65 g) was added in portions to a ₃₀ mL solution of compound 314-3 (1.4 g) in DCM, and the mixture was stirred for ₃ hours. The reaction was monitored by LC-MS until complete. The reaction mixture was quenched with _{Na₂S₂O₃} solution and extracted three times with EA. The organic phase was washed with _NaHCO₃ solution, dried _{over Na₂SO₄} , and concentrated to give benzyl(S)-3-(3-bromo-2-methylbenzamide)-4-oxopiperidin-1-carboxylic acid ester (1.1 g, crude product) as a pale yellow solid.

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

A solution of _POCl3 (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 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 _NaHCO3 solution and NaCl solution, dried, and concentrated to obtain the residue. The residue was purified by chromatography (DCM:MeOH = 20:1) to obtain an off-white solid, which was compound 314-5 (800 mg).

Step 4: Preparation of benzyl(S)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)-pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazol[4,5-c]pyridine-5(4H)-carboxylic acid ester

Compound 314-5 (800 mg), intermediate A (1015 mg), Pd(dppf) _Cl₂ (343 mg), and _K₂CO₃ (129.38 _mg ) were added to a mixture of 1,4-dioxane (20 mL) and _H₂O (5 mL). The reaction mixture was evacuated and filled with _N₂ three times, heated to 80 °C, and stirred for 3 hours. The reaction was monitored by LC-MS to ensure complete reaction. The reaction mixture was concentrated and purified with TCL (PE:EA = 1:3) to obtain benzyl (S)-2-(3'-(6-(difluoromethoxy)-5-((2-(methoxycarbonyl)-pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6,7-dihydrooxazol[4,5-c]pyridine-5(4H)-carboxylic acid ester (800 mg) as an off-white solid.

Step 5: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline methyl ester

Pd/C (200 mg) was added to a MeOH (50 mL) solution of compound 314-7 (800 mg). The mixture was stirred at room temperature for 5 hours under a _H2 atmosphere. The reaction mixture was filtered and concentrated to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(4,5,6,7-tetrahydrooxazolo[4,5-c]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline methyl ester (500 mg, crude product), as an off-white solid.

Step 6: Preparation of ((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[d]oxazolo-5-yl)methyl)-L-proline methyl ester

(CHO) _n (72 mg) was added to a mixture of compound 314-8 (500 mg) in DCM (30 mL) and MeOH (10 mL). After stirring the mixture for 30 min, _NaBH3CN (150 mg) was added in portions to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction was concentrated and purified by TLC (DCM:MeOH = 20:1) to give ((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[d]oxazolo-5-yl)methyl)-L-proline methyl ester (400 mg), an off-white solid.

Step 7: Preparation of ((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[d]oxazolo-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 314-9 replacing compounds 1-4. The crude product was purified by TLC (DCM:MeOH = 4:1) to give 210 mg of ((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[d]oxazolo-5-yl)methyl)-L-proline (compound 314), as a white solid. LC-MS (m/z): 629.3 (M+H) ⁺ .

The compounds in Table 4 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Example 314.

Table 4

Example 208 Preparation of compound 208

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

Compound 208

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

(3-Bromo-2-methylphenyl)methanol (20 g) was dissolved in DCM (200 ml) and stirred at room temperature. Then, ₂₀ ml of SOCl2 was slowly added. The mixture was stirred for 2 hours and concentrated to obtain 1-bromo-3-(chloromethyl)-2-toluene (23.1 g).

Step 2: Preparation of 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-hydroxybenzaldehyde

A solution of 1-bromo-3-(chloromethyl)-2-toluene (2.0 g), 5-chloro-2,4-dihydroxybenzaldehyde (2.34 g), potassium carbonate (3.78 g), and KI (1.51 g) in acetonitrile (20 mL) was stirred overnight at 80 °C. After the reaction was complete, 20 mL of water was added, the mixture was 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-3-yl))methoxy)benzaldehyde

Compound 208-3 (500 mg), (5-(difluoromethoxy)pyridin-3-yl)methanol (408 mg), potassium carbonate (585 mg), and KI (195 mg) were added to acetonitrile (10 mL), and the reaction mixture was stirred overnight at 80 °C. After adding 20 mL of water, the mixture was concentrated, filtered, and dried to give 4-((3-bromo-2-methylbenzyl)oxy)-5-chloro-2-((5-(difluoromethoxy)pyridin-3-yl)-yl)methoxy)benzaldehyde (478 mg).

Step 4: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-formylphenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Compound 208-4 (470 mg), intermediate A (597 mg), and potassium carbonate (236 mg) were added to a mixture of 1,4-dioxane (12 mL) and water (3 mL) under stirring. Then, Pd(dppf) _Cl₂ was added to the mixture under a _nitrogen 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 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (DCM/MeOH: 15/1) to give compound 208-5 (550 mg).

Step 5: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidine-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Compound 208-5 (270 mg), (R)-pyrrolidinebut-3-ol (80 mg), and glacial acetic acid (40 mg) were added to 10 mL of methanol under stirring. The mixture was heated to 50 °C and stirred for 1 hour. After the mixture cooled 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), extracted with DCM (15 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM/MeOH = 15/1) to obtain compound 208-6 (110 mg).

Step 6: Preparation of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidine-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline (Compound 208)

Compound 208-6 (110 mg) was added to 5 mL of methanol with stirring. 8 mg of LiOH was weighed and dissolved in 1 mL of water, then added to the mixture. The reaction mixture was heated to 35 °C and stirred overnight. 10 mL of water was added to the mixture, and it was extracted with DCM (15 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 105 mg of ((2-(3'-((2-chloro-5-((5-(difluoromethoxy)pyridin-3-yl))methoxy)-4-(((R)-3-hydroxy-pyrrolidine-1-yl)methyl)phenoxy)methyl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline (compound 208). LC-MS (m/z): 905.3 (M+H) ⁺ .

The compounds in Table 5 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Example 208.

Table 5

Example 242 Preparation of compound 242

((6-(difluoromethoxy)-2-(4”-((3-fluoropyrrolidone-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline

Compound 242

Step 1: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzaldehyde

To a solution of 9.25 g of 4-bromobenzaldehyde in 1,4-dioxane (120 mL), 15.8 g of dipinalenoyl diboron, 0.48 g of Pd(dppf) _Cl₂ ·DCM, and 20.0 g of KOAc were added. The reaction mixture was heated to 100 °C for 4 hours. The mixture was diluted with 150 mL of water and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with brine, dried over _MgSO₄ , and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 10:1) to give 11.2 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzaldehyde as a white solid.

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

To a solution of compound 242-2 (60 mL) in EtOH (20 mL), 10% _{Na₂CO₃ aq} . (20 mL) and Pd(dppf) _Cl₂ ·DCM (420 mg) were added, followed by dropwise addition of 1-bromo-3-iodo-2-toluene (9.0 g) under _N₂ protection. The mixture was stirred at 100 °C for 16 hrs. The reaction was then quenched with water (50 mL) and extracted three times with ethyl acetate (100 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 10:1) to give 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carboxaldehyde (3.2 g) as a pale yellow solid.

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

275 mg of 3'-bromo-2'-methyl-[1,1'-biphenyl]-4-carboxaldehyde was dissolved in 5 mL of DCM. 120 mg of ₃ -fluoropyrrolidine and HOAC were added at once. The resulting mixture was stirred at room temperature for 1 hour, and then 420 mg of STAB was added at the same temperature. The reaction was stirred at room temperature for 3 hours. The resulting mixture was quenched with saturated _Na₂CO₃ , extracted three times with ₂₀ mL of ethyl acetate, and the organic phase was dried over _Na₂SO₄ . The resulting solution was concentrated to give 320 mg of 1-((3'-bromo-2'-methyl-[1,1'-biphenyl]-4-yl)methyl)-3-fluoropyrrolidine as a colorless oil.

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

The compound was prepared using a method similar to that described in step 4 of Example 171, except that compound 171-4 was replaced with compound 242-4. The resulting mixture was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient elution 40:60 to 50:50) to give compound 242-5 (288 mg).

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

The compound was prepared using a method similar to that described in step 6 of Example 171, with compound 242-5 used instead of compound 171-6. The crude product was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient elution 40:60 to 50:50) to give ((6-(difluoromethoxy)-2-(4”-((3-fluoro-pyrrolidine-1-yl)methyl)-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)proline (168 mg) as a white solid (compound 242). LC-MS (m/z): 670.3 (M+H) ⁺ .

Example 243 Preparation of compound 243

((6-(difluoromethoxy)-2-(3”-fluoro-2,2'-dimethyl-4”-(pyrrolid-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 243

Step 1: Preparation of ((6-(difluoromethoxy)-2-(3”-fluoro-4”-formyl-2,2'-dimethyl-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with 4-bromo-2-fluorobenzaldehyde and intermediate A was replaced with intermediate B. The resulting solution was concentrated and purified by silica gel column chromatography (with n-hexane-ethyl acetate 5:1) to give the title compound as a yellow oil.

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

The compound was prepared using a method similar to that described in step 5 of Example 2, except that compound 2-4 was replaced with compound 243-1 and L-proline was replaced with pyrrolidine. 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”-(-pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 243-2 replacing compounds 1-4. The crude product was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient elution 10:90 to 30:70) to give the title compound. LC-MS (m/z): 670.3 (M+H) ⁺ . ^1H NMR (500MHz, methanol-d4) δ: 8.16 (dd, 1H, J = 7.9, 1.5Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H, J = 7.7Hz), 7.50 (t, 1H, J = 7.7Hz), 7.43–7.27 (m, 5H), 7.20 (dd, 1H, J = 7.5, 1.4Hz), 7.12 (t, 1H, J _FH) ＝72.6Hz),4.75(d,1H,J＝13.1Hz),4.54(d,1H,J＝13.1Hz),4.54(s,2H),4.37(dd,1H,J＝9.5,7.4Hz),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 Preparation of compound 244

((6-(difluoromethoxy)-2-(3”-(difluoromethoxy)-2,2'-dimethyl-4”-(pyrrolid-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 244

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

To a DMF (50 mL) solution of 4-bromo-2-hydroxybenzaldehyde (4.0 g), _Cs₂CO₃ (9.8 _g ) and KI (400 mg) were added. The mixture was stirred at room temperature for 30 minutes, and then sodium 2-bromo-2,2-difluoroacetate (6.0 g) was added in small batches. The mixture was stirred overnight at 75 °C. The mixture was diluted with 100 mL of water and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with brine, dried over _MgSO₄ , and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 8:1 to 5:1) to give 4-bromo-2-(difluoromethoxy)benzaldehyde (2.8 g) as a brown oil.

Step 2: Preparation of 5-bromo-2-(pyrrolidone-1-ylmethyl)benzylnitrile

The compound was prepared using a method similar to that described in step 5 of Example 2, except that compound 2-4 was replaced with compound 244-1 and L-proline was replaced with pyrrolidine. The crude product was purified by silica gel column chromatography (eluting with a DCM-MeOH gradient from 20:1 to 10:1) to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compound 244-2 and intermediate A was replaced with intermediate B. The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 5:1 to 1:1) to give the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 244-3 replacing compounds 1-4. The crude product was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient 10:90 to 35:65) to give the title compound. LC-MS (m/z): 718.3 (M+H) ⁺ . ¹ H NMR (500MHz, methanol-d4), δ: 8.16 (dd, 1H, J = 7.9, 1.5Hz), 8.07 (s, 1H), 7.76 (s, 1H), 7.73 (d, 1H, J = 7.9Hz), 7.50 (t, 1H, J = 7.7H z),7.42–7.36(m,3H),7.34(d,1H,J＝1.4Hz),7.30(dd,1H,J＝7.7,1.4Hz),7.21(dd,1H,J＝7.4,1.4Hz),7.13(td,2H,J＝72 .8,2.4Hz),4.73(d,1H,J＝13.2Hz),4.61(d,1H,J＝13.2Hz),4.53(s,2H),4.30(dd,1H,J＝9.7,7.1Hz),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 Preparation of compound 245

((2-(3”-Cyano-2,2'-Dimethyl-4”-(pyrrolid-1-ylmethyl)-[1,1':3',1”-Triphenyl]-3-yl)-6-(Difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 245

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

Under _N2 protection, BPO (2.4 g) was added to a solution of 5-bromo-2-methylcyanobenzene (20.0 g) and NBS (19.6 g) in _CCl4 (300 mL). The mixture was stirred overnight at 70 °C. The reaction was quenched with saturated _NaHCO3 solution (200 mL). The organic phases were combined and washed with brine. The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 20:1 to 1:1) to give crude 5-bromo-2-(bromomethyl)cyanobenzene as a yellow solid.

Step 2: Preparation of 5-bromo-2-(-ylpyrrolidine-1-ylmethyl)cyanobenzene

At 0 °C, pyrrolidine (2.85 g) was added dropwise to a THF (60 mL) solution of compound 245-1 (5.4 g). The reaction mixture was heated to 40 °C and reacted for 5 hours. The reaction mixture was diluted with 200 mL of water and then extracted three times with ethyl acetate (150 mL). The combined organic phases were washed with brine, dried over _MgSO4 , and concentrated under vacuum. The residue was purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 2:1 to 1:2) to give 5-bromo-2-(-ylpyrrolidine-1-ylmethyl)cyanobenzene (3.8 g) as a brown oil.

Step 3: Preparation of ((2-(3”-cyano-2,2'-dimethyl-4”-(-pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced by compound 245-2 and intermediate A was replaced by intermediate B. The crude product was purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 5:1 to 1:1) to give the title compound.

Step 4: Preparation of ((2-(3”-cyano-2,2'-dimethyl-4”-(-pyrrolidine-1-ylmethyl)-[1,1':3',1”-triphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 245-3 replacing compounds 1-4. The crude product was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient elution 10:90 to 35:65) to give the title compound. LC-MS (m/z): 677.3 (M+H) ⁺ . ^1H NMR (500MHz, methanol-d4) δ: 8.21 (dd, 1H, J = 7.9, 1.5Hz), 8.10 (s, 1H), 7.76 (s, 1H), 7.70 (t, 1H, J = 7.7Hz), 7.50 (t, 1H, J = 7.7Hz), 7.49-7.28 (m, 5H), 7.20 (dd, 1H, J = 7.5, 1.4Hz), 7.12 (t, 1H, J _FH) ＝72.6Hz),4.73(d,1H,J＝13.1Hz),4.51(d,1H,J＝13.1Hz),4.51(s,2H),4.37(dd,1H,J＝9.5,7.4Hz),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 Preparation of compound 246

((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidin-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 246

Step 1: Preparation of ((6-(difluoromethoxy)-2-(3'-(5-formyl-6-methoxypyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with 6-chloro-2-methoxypyridinecarboxaldehyde and intermediate A was replaced with intermediate B. The crude product was purified by silica gel column chromatography (n-hexane-ethyl acetate = 3:1) to give the title compound.

Step 2: ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methyl-pyrrolidine-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 5 of Example 2, except that compound 2-4 was replaced with compound 246-1 and L-proline was replaced with (S)-3-methylpyrrolidine. The resulting solution was concentrated to give the title compound.

Step 3: ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methyl-pyrrolidine-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 246-2 replacing compounds 1-4. The organic phase was separated and purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient elution 15:85 to 30:70) to give ((6-(difluoromethoxy)-2-(3'-(6-methoxy-5-(((S)-3-methylpyrrolidone-1-yl)methyl)pyridin-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (30.8 mg), a white solid. LC-MS (m/z): 697.3 (M+H) ⁺ . ^1H NMR (500 MHz, DMSO-d6 ₎ )δ8.11(dd,1H,J＝7.9,1.5Hz),7.96(s,1H),7.77(d,1H,J＝7.5Hz),7.72(s,1H),7.54-7.37(m,5H),7 .24-7.19(m,1H),7.16(d,1H,J=7.5Hz),3.95(s,2H),3.89(s,3H),3.58(s,2H),3.11-3.03(m,1H),2. 78(t,1H,J＝2.8Hz),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＝6.7Hz,3H).

Example 247 Preparation of compound 247

((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolid-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 247

Step 1: Preparation of tert-butyl(S)-2-(4-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)-pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester

The compound was prepared using a method similar to that described in step 1 of Example 1, with tert-butyl(S)-2-(4-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester instead of compound a-6, and intermediate B instead of intermediate A. The resulting solution was concentrated and purified by silica gel column chromatography (eluting with a gradient of n-hexane-ethyl acetate from 5:1 to 1:1) to give tert-butyl(S)-2-(4-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxycarbonyl)-pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid ester (98 mg), as a yellow oil.

Step 2: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidone-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

Compound 247-1 (76.0 mg) was stirred in a DCM/TFA mixture of 7:1 (4 mL) at room temperature for 4 hours. 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-((S)-pyrrolidone-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 247-2 replacing compounds 1-4. The crude product was purified by RP column chromatography (mobile phase: MeCN:water (0.1% HCl) gradient 10:90 to 35:65) to give ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(2-((S)-pyrrolidone-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline (70.6 mg), a white solid. LC-MS (m/z): 628.3 (M+H) ⁺ . ¹ H NMR (500MHz, methanol-d4), δ: 8.19 (dd, 1H, J = 8.0, 1.5Hz), 8.07 (s, 1H), 7.76 (d, 1H, J = 10.8Hz), 7.61 (dd, 1H, J = 7.8, 1.3Hz) ,7.52(t,1H,J＝7.8Hz),7.46(t,1H,J＝7.6Hz),7.38(dd,1H,J＝7.6,1.4Hz),7.32(dd,1H,J＝7.6,1.4Hz),7.13(t,1H,J _FH =72.6Hz),5.16(t,1H,J＝9.3,7.7Hz),4.79(d,1H,J＝13.2),4.62(d,1H,J＝13.3),4.48(t,1H,J＝9.3Hz),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).

The compounds in Table 6 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Examples 242-247.

Table 6

Example 295 Preparation of compound 295

((2-(3'-(7-cyano-5-(pyrrolid-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 295

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

5 g of methyl 4-amino-3-nitro-benzoic _acid was added to a mixture of _Ag₂SO₄ (7.93 g) and _I₂ (6.47 g) in 20 mL of EtOH at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was diluted with 20 mL of water and extracted with ethyl acetate. The organic phase was washed with an aqueous solution _{of Na₂S₂O₃} , dried over _MgSO₄ , and concentrated to dryness. The residue _was purified by silica gel column chromatography to give methyl 4-amino-3-iodo-5-nitro-benzoate (7 g) as a yellow solid.

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

_SnCl₂ (8.42 g) was added to a 30 mL solution of compound 295-1 (3 g) in EA. The reaction mixture was stirred at 70 °C for 16 hrs. EA (50 mL) was added to the reaction mixture, the organic layer was washed with _NaHCO₃ aqueous solution, dried over _MgSO₄ , and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired compound, 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-1H-benzo[d]imidazolium-5-carboxylic acid

A mixture of compound 295-2 (2.6 g), 3-bromo-2-methylbenzaldehyde (1.77 g), and AcOH (30 mL) was stirred at 80 °C for 16 hrs. EA (50 mL) was added to the reaction mixture, the organic phase was washed with water, dried over _MgSO₄ , and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired compound methyl 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazolium-5-carboxylic acid, as a yellow solid.

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

A solution of NaOH (849.10 mg) in _H₂O (6 mL) was added to a solution of compound 295-3 (2 g) in MeOH (20 mL). The reaction mixture was stirred overnight at 50 °C. The mixture was concentrated. Water was added to the mixture, and the pH was adjusted to 5 with 2N HCl. The precipitate was filtered, and the filter cake was washed with water. The product was dried in a vacuum drying oven (45 °C, 3 h) to give the title compound 2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazol-5-carboxylic acid as a white solid.

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

At -30°C, 20 mL of the boranetetrahydrofuran complex was added to a solution of compound 295-4 (1.8 g) in 20 mL of THF. The reaction mixture was stirred at 60°C for 16 hrs. After cooling to room temperature, 2 N HCl (20 mL) was added. After 10 mins, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over _MgSO4 and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired compound (2-(3-bromo-2-methylphenyl)-7-iodo-1H-benzo[d]imidazol-5-yl)methanol (1 g) as a white solid.

Step 6: Preparation of 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-1H-benzo[d]imidazolium-7-onitrile

A solution of compound 295-5 (500 mg), Zn(CN) _₂ (66.02 mg), and Pd( _PPh₃ ) _₄ (130.34 mg) in DMF (10 mL) was stirred at 90 °C for 3 hours under _N₂ protection. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate. The organic phase was then washed with aqueous NaCl solution, dried over _MgSO₄ , and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired compound 2-(3-bromo-2-methylphenyl)-5-(hydroxymethyl)-1H-benzo[d]imidazolium-7-onitrile (150 mg) as a yellow oil.

Step 7: Preparation of 2-(3-bromo-2-methylphenyl)-5-(chloromethyl)-1H-benzo[d]imidazolium-7-onitrile

The compound was prepared using a method similar to that described in step 2 of Example 1, except that compound 1-1 was replaced with compound 295-6. The mixture was concentrated to obtain the title compound.

Step 8: Preparation of 2-(3-bromo-2-methylphenyl)-5-(-ylpyrrolidine-1-ylmethyl)-1H-benzo[d]imidazolium-7-onitrile

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 295-7 and (1S,2R)-2-aminocyclopentane-1-ol was replaced with pyrrolidine. The crude product was purified by silica gel column chromatography to obtain the title compound.

Step 9: Preparation of ((2-(3'-(7-cyano-5-(-pyrrolidine-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compound 295-8. The crude product was purified by silica gel column chromatography to obtain the title compound.

Step 10: Preparation of ((2-(3'-(7-cyano-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 295-9 replacing compounds 1-4. The crude product was purified by pre-HPLC to obtain the desired product ((2-(3'-(7-cyano-5-(pyrrolidone-1-ylmethyl)-1H-benzo[d]imidazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline. LC-MS (m/z): 717.3 (M+H) ⁺ .

The compounds in Table 7 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Example 295.

Table 7

Example 304 Preparation of compound 304

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

Compound 304

Step 1: Methyl 2-bromo-4-methyl-oxazol-5-carboxylic acid

2.24 g of tert-butyl nitrite was added to a suspension of methyl 2-amino-4-methyl-oxazol-5-carboxylic acid (1.7 g) and _CuBr₂ (7.28 g) in acetonitrile (20 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate. The organic phase was then washed with aqueous NaCl solution, dried over _MgSO₄ , and concentrated to dryness. The residue was purified by silica gel column chromatography to give the desired product, methyl 2-bromo-4-methyl-oxazol-5-carboxylic acid (800 mg), as a white solid.

Step 2: Preparation of methyl 2-(3-bromo-2-methyl-phenyl)-4-methyl-oxazol-5-carboxylic acid

The compound was prepared using a method similar to that described in step 1 of Example 1, and the crude product was purified by silica gel column chromatography to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example A, except that compound a-4 was replaced with compound 304-2. The crude product was purified by silica gel column chromatography to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 2 of Example 1, except that compound 1-1 was replaced with compound 304-3. The mixture was concentrated to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 304-4 and (1S,2R)-2-aminocyclopentane-1-ol was replaced with pyrrolidine. The crude product was purified by silica gel column chromatography to obtain the title compound.

Step 6: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[4-methyl-5-(-pyrrolidine-1-ylmethyl)oxazol-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compound 304-5. The crude product was purified by silica gel column chromatography to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 304-6 replacing compounds 1-4. The crude product was purified by pre-HPLC to obtain 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]triazol[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

Compound 305

Step 1: Preparation of N-[[5-(hydroxymethyl)-2-pyridyl]aminomethylthio]carbamate ethyl ester

N-(thiomethylene)carbamate (7.92 g) was added to a solution of (6-aminopyridin-3-yl)methanol (5 g) in 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]triazol[1,5-a]pyridin-6-yl)methanol

Hydroxylamine hydrochloride (5.13 g) was added to a methanol (15 mL)/ethanol (15 mL) solution of compound 305-1 (9.5 g), followed by the addition of N,N-diisopropylethylamine (9.62 g). The reaction mixture was 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), which was a green oil.

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

5.6 g of tert-butyl nitrite was added to a suspension of compound 305-2 (5 g) and copper bromide (1.22 g) in acetonitrile (50 mL). The mixture was stirred at room temperature for 1 hour. The reaction solution 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 column chromatography to give the desired product (3.2 g) as a white solid.

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

The compound was prepared using a method similar to that described in step 1 of Example 1. The residue was purified by silica gel column chromatography to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 2 of Example 1, except that compound 1-1 was prepared using compound 305-4. The crude product was used directly in the next step.

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

The compound was prepared using a method similar to that described in step 3 of Example 1, except that compound 1-2 was replaced with compound 305-5 and (1S,2R)-2-aminocyclopentane-1-ol was replaced with pyrrolidine. The crude product was purified by silica gel column chromatography to obtain the title compound.

Step 7: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-[6-(-ylpyrrolidine-1-ylmethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl]phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidine-2-carboxylic acid methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compound 305-6. The crude product was purified by silica gel column chromatography to obtain the title compound.

Step 8: Preparation of ((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(-pyrrolidone-1-ylmethyl)-[1,2,4]triazol[1,5-a]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 305-7 replacing compounds 1-4. The crude product was purified by pre-HPLC to obtain the title compound. LC-MS (m/z): 693.3 (M+H) ⁺ .

Example 306 Preparation of compound 306

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

Compound 306

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

Under a _nitrogen atmosphere, a mixture of 1,3-dibromo-2-methylbenzene (1 g), 4-ylpyrrolidine-1-ylpiperidine (617.18 mg), _Cs₂CO₃ ( _3.91 g), _Pd₂ (dba) _₃ (366.10 mg), and 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (462.53 mg) in toluene (20 mL) was stirred overnight at 100 °C. The mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography to obtain the desired product 1-(3-bromo-2-methylphenyl)-4-ylpyrrolidine-1-ylpiperidine (450 mg), as a red oil.

Step 2: Preparation of (2S)-1-[[6-(difluoromethoxy)-2-[2-methyl-3-[2-methyl-3-(4-ylpyrrolidone-1-yl-1-piperidinyl)phenyl]phenyl]-1,3-benzoxazol-5-yl]methyl]pyrrolidone-2-carboxylic acid methyl ester

The compound was prepared using a method similar to that described in step 1 of Example 1, except that compound a-6 was replaced with compound 306-1. The crude product was purified by silica gel column chromatography to obtain the title compound.

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

The compound was prepared using a method similar to that described in step 5 of Example 1, with compound 306-2 replacing compounds 1-4. The crude product was purified by pre-HPLC to obtain the title compound. LC-MS (m/z): 645.3 (M+H) ⁺ .

The compounds in Table 8 can be prepared using different reaction starting materials and suitable reagents, through a method similar to that in Examples 304-306.

Table 8

The ^1H NMR data of compounds 34, 61, 85, 88, 93, 113, 127, 130, 131, 135, 142, and 146 are shown below:

^¹H NMR (500MHz, DMSO- _d⁶ ) δ 8.24 (s, ¹H), 8.17 (dd, J = 8.0, 2.2Hz, 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 = 43.4Hz, 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)

¹ H NMR (500MHz, chloroform-d) δ8.13(dd,J＝7.8,6.1Hz,2H),7.99(d,J＝9.8Hz,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＝71.9Hz,1H),6.80(t,J＝71.9H z, 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 (500MHz, chloroform-d) δ 8.36 (s, ¹H), 8.22 (dd, J = 7.9, 1.5Hz, ¹H), 8.17–8.07 (m, 2H), 7.99 (s, ¹H), 7.59 (s, ¹H), 7.46 (dt, J = 12.7, 7.7Hz, 2H), 7.42–7.34 (m, 2H), 6.93 (t, J = 72.1Hz, 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)

¹ H NMR (500MHz, DMSO-d ₆ )δ8.38(s,1H),8.26(s,1H),8.20(dd,J＝7.9,1.4Hz,1H),8.13(ddd,J＝23.5,7.9,1.5Hz,1H),7 .96(d,J＝10.1Hz,1H),7.72(d,J＝13.9Hz,1H),7.61–7.49(m,2H),7.45(ddd,J＝13.6,7.6,1.5H z,2H),7.38(d,J＝71.9Hz,1H),3.96(s,2H),3.44-3.22(m,5H),3.11-2.99(m,2H),2.57(q,J＝8 .5Hz,1H),2.45(d,J＝5.8Hz,6H),2.19-2.06(m,1H),1.93–1.64(m,4H),1.22(d,J＝7.5Hz,6H). (Compound 113)

¹ H NMR(500MHz, chloroform-d)δ8.24(dd,J＝7.9,1.4Hz,1H),8.17–8.07(m,2H),8.03(s,1H),7.79(s,1H),7.6 0(s,1H),7.48(dt,J＝15.0,7.7Hz,2H),7.43–7.35(m,2H),6.94(t,J＝71.9Hz,1H),4.60(d,J＝13.1H z, 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)

¹ H NMR (500MHz, DMSO-d ₆ )δ8.20(dd,J＝7.9,1.4Hz,1H),8.16(dd,J＝7.9,1.4Hz,1H),8.11(d,J＝1.5Hz,1H),7.97(s,1H),7.88 (d,J＝1.5Hz,1H),7.73(s,1H),7.63–7.51(m,2H),7.48(dd,J＝7.6,1.4Hz,1H),7.44(dd,J＝7.6,1.4Hz ,1H), 7.38 (t, J＝73.7Hz,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＝2.9Hz,6H), 2.26–1.68 (m,6H), 1.36–1.20 (m,1H), 0.99 (d, J＝6.7Hz,3H). (Compound 130)

¹ H NMR (500MHz, DMSO-d ₆ )δ8.21(dd,J＝7.9,1.4Hz,1H),8.19(s,1H),8.15(dd,J＝7.9,1.4Hz,1H),7.97(s,1H),7.95(s,1 H),7.73(s,1H),7.63–7.51(m,2H),7.48(dd,J＝7.6,1.4Hz,1H),7.44(dd,J＝7.5,1.4Hz,1H),7.3 8 (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)

^¹H NMR (500MHz, chloroform-d) δ 8.25 (d, J = 7.8Hz, 1H), 8.14 (dd, J = 7.9, 1.3Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.48 (dt, J = 15.2, 7.7Hz, 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 (500MHz, DMSO-d6 ₎ )δ8.35–8.30(m,1H),8.23(dd,J＝8.0,1.5Hz,1H),8.18(dt,J＝7.9,1.3Hz,1H), 8.12(d,J＝1.4Hz,1H),8.08(s,1H),7.89(s,1H),7.61(dt,J＝13.6,7.7Hz,2H),7 .57–7.45(m,2H),7.40(t,J＝73.2Hz,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=5.5Hz,6H),2.26–1.80(m,4H). (Compound 142)

¹ H NMR (500MHz, DMSO-d ₆ )δ8.35(s,1H),8.23(d,J＝7.9Hz,1H),8.18(d,J＝7.8Hz,1H),8.13–8.07(m,2H), 7.87(s,1H),7.70(s,1H),7.60(dt,J＝14.9,7.7Hz,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)

Comparative Examples

The following comparative examples were prepared in accordance with the method described in Example 7 of WO2018119266 (as shown in Table 9).

Table 9

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

The tests were performed in standard black 384-well polystyrene plates, with a final volume of 20 μL. The inhibitor was first serially diluted in DMSO and then added to the wells before adding other reactants. The final DMSO concentration for the test was 1%. 100 nL/well of the compound was added to a 384 reaction plate (6008280, PerkinElmer) and centrifuged at 1000 rpm for 1 min. 5 μL/well of 4X PD-L1 solution was added to the 384 reaction plate, centrifuged at 1000 rpm for 1 min, followed by 5 μL/well of 4X PD-1 solution, centrifuged at 1000 rpm for 1 min, and then incubated at 25 °C for 15 min. The compound concentrations were 300, 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.137, 0.046, 0.015, and 0 nM. Add 10 μL/well of 2X anti-6xHis AlphaLISA acceptor beads and streptavidin donor beads (PerkinElmer-AL356F) solution to the 384 reaction plate described above, centrifuge at 1000 rpm for 1 minute, and incubate at 25°C in the dark for 120 minutes. Read the AlphaLISA signal values using an Envision reader. Determine the IC50 by fitting a curve of control activity percentage versus the logarithm of inhibitor concentration using GraphPad Prism 8.0 software.

The compounds of the present invention shown in the examples have IC ₅₀ values in the following ranges: "*" represents "0.1 nM < IC ₅₀ ≤ 5 nM";"**" represents "5 nM < IC ₅₀ ≤ 50 nM";"***" represents "IC ₅₀ > 50 nM".

The compound data of the examples obtained by applying the above PD-1/PD-L1 binding assay (Alphascreen) are shown in Table 10.

Table 10

Pharmacokinetic studies

Adult female C57 mice were administered a single oral (oral gavage) dose of the test compound, with 10% DMSO, 10% Kolliphor ^@ HS 15, and 80% saline as excipients, to mice (n=9) at a dose of 100 mg/kg. Blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h. Approximately 0.1 mL of whole blood was collected from the retro-orbital venous plexus of three mice at each collection point and placed in tubes containing _K₂ -EDTA as an anticoagulant. The whole blood was centrifuged at 4 °C and 4000 rpm for 10 min. Plasma was transferred to centrifuge tubes and stored at -20 °C until analysis. The concentration of the test compound in the plasma samples was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time data for each animal were analyzed using Microsoft Excel 2010. A non-compartmental model was introduced in the concentration analysis. The pharmacokinetic parameters of the test compounds were collected using WinNonlin (version 4.1; Pharsight) software, and the data are shown in Table 11.

Adult female C57 mice received a single oral (oral gavage) dose of the test compound, using 15% DMSO, 10% Kolliphor ^@ HS 15, and 75% saline as excipients, in mice (n=3) at a dose of 5 mg/kg. Blood was collected at 30 min, 2 h, and 4 h. Approximately 0.1 mL of whole blood was collected from the retro-orbital venous plexus and placed in a tube containing _K2 -EDTA as an anticoagulant. The whole blood was centrifuged at 4 °C and 4000 rpm for 10 min. Plasma was transferred to centrifuge tubes and stored at -20 °C until analysis. The concentration of the test compound in the plasma samples was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma concentration-time data for each animal were analyzed using Microsoft Excel 2010, and the data are shown in Table 12.

Table 11

Table 12

NA = Not applicable

As shown in Tables 11 and 12, we can see that the example compounds of the present invention exhibit unexpectedly superior pharmacokinetic properties compared to the known compounds of Comparative Example 1.

NFAT test

The PD-1/PD-L1 Blockade Bioassay comprises two cell lines: PD-1 effector cells, Jurkat T cells expressing hPD-1 and a luciferase reporter gene; and PD-L1 aAPC/CHO-K1 cells, CHO-K1 cells expressing hPD-L1 and a cell surface protein that activates the TCR. Antibodies or small molecule compounds are co-incubated with these two cell lines for a period of time, and the amount of product is detected using Bio-Glo luciferase reagent and chemiluminescence to reflect the effect of the antibody or small molecule compound on the PD-1/PD-L1 interaction.

Test buffer: 49.5 mL RPMI-1640; 0.5 mL FBS

Cell culture medium: 36 mL Ham’s F-12; 4 mL FBS

Reaction steps:

1) On day 1, revive PD-L1 aAPC/CHO-K1 cells and count them by hanging them in cell resuscitation medium. Dilute to 2.65* ^10⁵ /ml with cell culture medium. Seed the cells at a density of 6000 cells/well in 384-well plates and culture for 16-24 hours;

2) Dilute the compound to 5 mM with DMSO. Use 5 mM as the first concentration and perform serial dilutions of 3-fold for a total of 9 concentration gradients. The 10th concentration is the DMSO control.

3) Dilute the positive control antibody to 4 μg/ml with test buffer. Use 4 μg/ml as the first concentration, and perform 2.5-fold dilutions for a total of 9 concentration gradients. The 10th concentration is the test buffer control.

4) Remove the cell culture medium from the 384-well plate, add 10 μL of the compound per well to the 384-well plate and incubate for 2 hours;

5) Resuscitate PD-1 effector cells and count them by suspension in test buffer. Dilute the cells to 8.75 × ^10⁵ /ml with cell culture medium. Seed the cells at a density of 8000 cells/well in 384-well plates from step 4 and incubate for 17 hours;

6) Add 20 μL/well of Bio-Glo luciferase reagent to the 384-reaction plate from step 5 and incubate at 25°C for 5-30 minutes.

7) Use an Envision multi-function plate reader to read the RLU (Relative Luminescent Unit) values. Plot the experimental data with compound concentration as X value and RLU as Y value.

The results are represented by _EC50 values as shown in Table 13.

Table 13

Example number <![CDATA[EC₅₀(nM)]]> 5 317 103 254 317 4697 318 3225

Claims (5)

1. A compound, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is: 5)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 8)((2-(3'-(5-(azacyclobutane-1-ylmethyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 10)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-fluoropyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 12)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 13)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(morpholinomethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 14)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-hydroxypyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-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[d]oxazol-5-yl)methyl)-L-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[d]oxazol-5-yl)methyl)-L-proline; 18)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3R,4R)-3,4-difluoropyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 22)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((3,3,3-trifluoro-2-hydroxypropyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 23)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,4-dimethylpiperazin-1-yl)methyl)benzo[d]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-((oxecyclobutane-3-ylamino)methyl)benzo[d]oxazol-2-yl)-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[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 31)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(hydroxymethyl)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 33)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-(dimethylamino)azacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 34)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 36)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 56)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 57)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((((1R,2R)-2-hydroxycyclopentyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 61)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 62)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,2-dimethylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 63)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((S)-2-(methoxymethyl)pyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 64)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(((((S)-tetrahydrofuran-2-yl)methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 65)((2-(2'-cyano-3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)proline; 66)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-D-proline; 67)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 70)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((2,5-dihydro-1H-pyrrolo-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 72)((2-(3'-(5-(((1s,4s)-7-azabicyclo[2.2.1]hept-7-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 74)((2-(3'-(5-((5-azaspiro[2.3]hex-5-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 80)((2-(3'-(5-((3-cyanozynebutane-1-yl)methyl)-6-(difluoromethoxy)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 81)((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3-methyleneazonobutan-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 85)(R)-1-((6-(difluoromethoxy)-2-(3'-(6-(difluoromethoxy)-5-((3,3-dimethylazacyclobutane-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; 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)-L-proline; 89)((2-(3'-(5-((2-azabicyclo[2.1.1]hex-2-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 93)((6-(difluoromethoxy)-2-(3'-(5-((3,3-dimethylazacyclobutane-1-yl)methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 95)((6-(difluoromethoxy)-2-(3'-(7-fluoro-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 98)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 100)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-yl-methyl)-7-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 101)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(5-(pyrrolidone-1-yl-methyl)-6-(trifluoromethyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 102)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-yl-methyl)benzo[d]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-dimethylazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 108)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl)methyl)-L-proline; 114)((6-(difluoromethoxy)-2-(2,2'-dimethyl-3'-(6-(((R)-3-methylpyrrolidin-1-yl)methyl)oxazolo[5,4-b]pyridin-2-yl)-[1,1'-biphenyl]-3-yl)benzo[d]oxazolo-5-yl)methyl)-L-proline; 117)((2-(3'-(6,7-difluoro-5-(pyrrolidone-1-ylmethyl)benzo[d]oxazol-2-yl)-2'-methoxy-2-methyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 127)((2-(3'-(7-cyano-5-(pyrrolidone-1-yl-methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 131)((2-(3'-(7-cyano-5-(((R)-3-methylpyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 136)((2-(3'-(7-cyano-5-(((cyanomethyl)(methyl)amino)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 142)((2-(3'-(7-cyano-5-((3-cyanopyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 144)((2-(3'-(7-cyano-5-((3-ethynyl-3-hydroxyazacyclobutane-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 162)((2-(3'-(7-cyano-5-((3-fluoropyrrolidone-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; 164)((2-(3'-(7-cyano-5-((3,4-difluoropyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline; or 165)((2-(3'-(7-cyano-5-(((R)-3-cyanopyrrolidine-1-yl)methyl)benzo[d]oxazol-2-yl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)-6-(difluoromethoxy)benzo[d]oxazol-5-yl)methyl)-L-proline. 2. A pharmaceutical composition comprising the compound of claim 1, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 3. The use of the pharmaceutical composition of claim 2 or the compound of claim 1, or its stereoisomers, tautomers or pharmaceutically acceptable salts, in the preparation of a medicament for treating diseases related to the inhibition of PD-1/PD-L1 interaction. 4. The application as described in claim 3, wherein the disease is cancer. 5. The application as described in claim 4, wherein the cancer is colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.