LP(a) inhibitor compound and use thereof

Abstract

The present invention provides an LP(a) inhibitor compound and a use thereof. The LP(a) inhibitor compound is represented by the following formula (I). L(L1A)n (I)

Description

LP(a) inhibitor compound and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular, the present application relates to a LP(a) inhibitor compound and application thereof. BACKGROUND

[0002] Cardiovascular diseases (CVD) are common diseases that seriously threaten human health, especially the health of the elderly. According to the WHO estimate, the number of deaths from cardiovascular diseases each year accounts for one-third of all deaths worldwide. Among them, atherosclerosis-induced cardiovascular disease (ASCVD) is the world's leading cause of death. For a long time, LDL-C has been used as the primary target for blood lipid intervention of ASCVD, but there is still a high residual risk of cardiovascular events when LDL-C levels are controlled in the ideal range. Studies have shown that elevated lipoprotein(a) [Lp(a)] is an independent risk factor for ASCVD.

[0003] Lp(a) is an atherogenic lipoprotein produced in the liver, which is covalently linked by a disulfide bond between an LDL-like particle apolipoprotein B100 (apoB100) and an apolipoprotein a [Apo(a)] molecule. Elevated Lp(a) can increase the risk of cardiovascular disease by promoting atherosclerosis, thrombosis, and inflammation. Because the level of LP(a) is less affected by postnatal factors, lifestyle interventions such as healthy diet and exercise cannot directly reduce Lp(a) levels, and existing lipid-lowering drugs cannot achieve a significant clinical benefit in reducing Lp(a). Therefore, Lp(a) lipid-lowering therapy has become an important breakthrough point in the prevention and treatment of cardiovascular diseases. SUMMARY

[0004] One object of the present application is to provide a LP(a) inhibitor compound.

[0005] Another object of the present application is to provide the use of the compound.

[0006] To achieve the above object, in one aspect, the present application provides a LP(a) inhibitor compound, stereoisomer, metabolite, co-crystal, deuterated product or pharmaceutically acceptable salt thereof, the compound is shown as formula (I): L(L1A) n (I)

[0007] n is 2 or 3;

[0008] Each A is the same or different; each L1 is the same or different;

[0009] each L1is independently a bond, L2, L2-L3-, -NH-L2-L3-, -C(O)-, -NH-L2-, -L3-, C 3-6 cycloalkylene-L3-, -C 3-6 heterocycloalkylene-, -L2-NH-CO- or -L2-CO-NH-; said heterocycloalkylene contains 1, or 2 heteroatoms selected from N, O or S;

[0010] L2is selected from a bond or C 1-5 alkylene; L3is selected from S or O;

[0011] each A is independently

[0012] Cy1is a six-membered saturated or unsaturated carbocyclic ring, a phenyl ring, a six-membered saturated or unsaturated heterocyclic ring or a six-membered heteroaromatic ring; said heterocyclic or heteroaromatic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0013] Cy2is a five-membered heteroaromatic ring or a three- to five-membered saturated heterocyclic ring; said heteroaromatic or heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0014] each R1and each R8is independently H, F, Cl, Br, I, =0, C 1-6 alkyl, C 1-6 alkyloxy, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl or alkynyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl;

[0015] R2is H, -NR 21 R 22 , F, Cl, Br, I, C 1-6 alkyl, hydroxy, amino, carboxy, nitro, C 1-6 alkenyl, C 1-6 alkynyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-NH2, -C 1-6 alkylene-CONH2or a three- to six-membered heterocycloalkyl; said alkyl, alkylene, alkenyl, alkynyl or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0016] R 21 and R 22 are each independently H or C1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0017] optionally, R2and X and a carbon atom on Cy1form a five- or six-membered saturated or unsaturated carbocyclic ring, or a five- or six-membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O, or S; optionally, said carbocyclic or heterocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, =0, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0018] R3and R5are each independently selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0019] R4is H, F, Cl, Br, I, CN, C 1-6 alkyl, hydroxyl, amino, or carboxyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0020] R6is -COOR 61 or a four-, five-, six-, seven-, or eight-membered saturated or unsaturated heterocyclic ring containing one, two, three, four, or five heteroatoms selected from N, O, or S; optionally, said heterocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0021] R 61 is H or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0022] R7is H, CN, C 1-6 alkyl, hydroxyl, amino, carboxyl, or R7and R2and X form a four-, five-, six-, seven-, or eight-membered saturated or unsaturated carbocyclic ring; optionally, said carbocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C

[0023] X is CH or N;

[0024] n1and n5are each independently 1, 2, or 3;

[0025] when n is 2, L is selected from a four- to six-membered heteroaromatic ring containing one, two, three, or four heteroatoms selected from N, O, or S, or one of the following structures:

[0026] Ra is absent or selected from CN, NO2, hydroxyl, carboxyl, or amino;

[0027] Rb, Rc are each independently selected from H or =O;

[0028] Optionally, one of Rb and Rc and the carbon atom to which it is attached together form a C 3-6 saturated carbocyclic ring; optionally, said saturated carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl;

[0029] X1 is O, S, N, or CH;

[0030] X2, X3 are each independently a bond, C 1-5 alkylene, or C 1-5 alkylene-O-;

[0031] n2 is 0, 1, 2, or 3;

[0032] n3 is 1, 2, or 3;

[0033] when n is 3, L is selected from a four- to eight-membered saturated heterocyclylene, four- to eight-membered heteroarylene, three- to eight-membered saturated cycloalkylene, arylene, said heterocyclylene, heteroarylene, cycloalkylene, and arylene containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S; optionally, said heterocyclylene, heteroarylene, cycloalkylene, and arylene are substituted with a substituent selected from H, F, Cl, Br, I, =O, C 1-6 alkyl, hydroxyl, amino, carboxyl, nitro, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl, or alkynyl optionally substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl;

[0034] provided that,

[0035] (1) when L is each L1 is methylene, and each Cy1 is phenylene, at least one of R4 and R2 in structure A is not H;

[0036] (2) when L is A is not and

[0037] (3) when L is both L1 are -NH- at the same time, each Cy1 is phenylene, and each R6 is -COOH, at least one of R4 and R2 in structure A is not H.

[0038] According to some embodiments of the application, L1is C 3-6 cycloalkylene-L3- is attached via C 3-6 cycloalkylene is attached to L; L1is -L2-NH-CO- or -L2-CO-NH- is attached via L2to L; L1is L2-L3-, -NH-L2- is attached via L2to L; L1is -NH-L2-L3- is attached via N to L.

[0039] According to some embodiments of the application, wherein,

[0040] When n is 2, L is selected from one of the following structures:

[0041] When n is 3, L is selected from one of the following structures:

[0042] Rdis H, F, Cl, Br, I, =0, C 1-6 alkyl, hydroxy, amino, carboxyl, nitro, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl or alkynyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl;

[0043] X5is CH or N;

[0044] n4is 0, 1 or 2.

[0045] According to some embodiments of the application, wherein,

[0046] When n is 2, L is selected from one of the following structures:

[0047] X 11 selected from O, S, N or CH;

[0048] X 12 selected from S or O;

[0049] n3is 1, 2 or 3;

[0050] When n is 3, L is selected from one of the following structures:

[0051] Rdis H, F, Cl, Br, I, =0, C 1-6 alkyl; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6Substituents of alkyl groups;

[0052] X5 is CH or N;

[0053] n4 can be 0, 1, or 2.

[0054] According to some specific embodiments of the present invention, each L1 is independently selected from the following structures:

[0055] -NH-、 C 1-3 Alkylene -O-、

[0056] According to some specific embodiments of the present invention, wherein,

[0057] When n is 2, -L1-L-L1- is selected from the following structure:

[0058] When n is 3, L-(L1)3- is selected from the following structure:

[0059] X6 is O, -NH-, or C. 1-4 Alkylene;

[0060] X7 is C 3-6 Cycloalkylene;

[0061] Each L1 is independently L2, -O-, -NH-, -L2-O-, -NH-L2-, or -NH-CO-;

[0062] L2 is selected from C 1-5 Alkylene;

[0063] n 11 n 12 and n 13 Each value is either 0 or 1.

[0064] According to some specific embodiments of the present invention, wherein,

[0065] When n is 2, L is selected from one of the following structures:

[0066] When n is 3, L is selected from one of the following structures:

[0067] L1 is independently selected from the following structures:

[0068] -NH-, -L2-L3-, -NH-L2-, C 1-3 Alkylene -L3-、-C 3-5 Cycloalkylene-L3-

[0069] L2is selected from C 1-3 alkylene;

[0070] L3is selected from O or S.

[0071] According to some embodiments of the application, wherein A is of the following structure:

[0072] R 61 is H or C 1-6 alkyl;

[0073] Y1is O, S, NH or CH2;

[0074] Y2is CH2or C=O;

[0075] n 21 is 0 or 1;

[0076] n 22 is 0, 1 or 2.

[0077] According to some embodiments of the application, wherein,

[0078] Cy1is a phenyl ring, a six-membered saturated or unsaturated heterocyclic ring; said heterocyclic ring contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0079] Cy2is a five-membered heteroaromatic ring; said heteroaromatic ring contains 1 or 2 heteroatoms selected from N, O or S;

[0080] R1is H, F, Cl, Br, I, =O, C 1-6 alkyl, C 1-6 alkyloxy, hydroxy, amino, carboxyl, nitro, cyano; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl;

[0081] R2is H, -NR 21 R 22 , F, Cl, Br, I, C 1-6 alkyl, hydroxy, amino, carboxyl, nitro, -C 1-6 alkylene-OH, -C 1-6 alkylene-NH2, -C 1-6 alkylene-CONH2or a four- to six-membered heterocycloalkyl; said alkyl, alkylene or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S;

[0082] R21 and R 22 each independently H or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0083] R2and X, together with the carbon atoms on Cy1, form a five- or six-membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing one or two heteroatoms selected from N, O, or S; optionally, said carbocyclic or heterocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, =0, or C 1-6 alkyl;

[0084] R3and R5are each independently selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0085] R4is H, F, Cl, Br, I, CN, C 1-6 alkyl, hydroxyl, amino, or carboxyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0086] R6is -COOR 61 or a four-, five-, six-, seven-, or eight-membered unsaturated heterocyclic ring containing one, two, three, four, or five heteroatoms selected from N, O, or S; optionally, said heterocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0087] R 61 is H or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0088] R7is H, CN, C 1-6 alkyl, hydroxyl, amino, or R7and R2and X form a four-, five-, six-, seven-, or eight-membered saturated or unsaturated carbocyclic ring; optionally, said carbocyclic ring is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl;

[0089] X is CH or N;

[0090] n1is 1, 2, or 3.

[0091] According to some embodiments of the application, wherein,

[0092] Cy1is selected from the following structures:

[0093] a phenyl ring,

[0094] Cy2is selected from the following structures:

[0095] R1is H, F, Cl, Br, I, =0, C 1-4 alkyl, C 1-4 alkyl, alkoxy, hydroxy, cyano, or amino; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I;

[0096] R2is H, -NR 21 R 22 , F, Cl, Br, I, C 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-NH2, -C 1-4 alkylene-CONH2, or a four-, five-, or six-membered unsaturated heterocycloalkyl; said alkyl, alkylene, or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S;

[0097] R 21 and R 22 are each independently H or C 1-4 alkyl; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I;

[0098] Optionally, R2and X, together with the carbon atom on Cy1form a five- or six- membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing 1 heteroatom selected from N, O, or S; optionally, said carbocyclic or heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or =0;

[0099] R3and R5are each independently selected from H, F, Cl, Br, or I;

[0100] R4is H, F, Cl, Br, I, CN, or C 1-4 alkyl; optionally, said alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-4 alkyl;

[0101] R6is -COOR 61 or a four-, five-, or six-membered unsaturated heterocyclic ring containing 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S; optionally, said heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I;

[0102] R 61 is H or C 1-4 alkyl; optionally, said alkyl is substituted with a substituent selected from H, F, Cl, Br, or I;

[0103] R7 is H, C 1-4 alkyl, or R7 and R2 and X form a four-, five-, or six-membered saturated carbocyclic ring; optionally, said carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I;

[0104] X is CH or N;

[0105] n1 is 1 or 2.

[0106] According to some embodiments of the present application, wherein,

[0107] Cy1 is selected from the following structures:

[0108] a benzene ring,

[0109] Cy2 is selected from the following structures:

[0110] R1 is H, F, Cl, Br, I, =0, hydroxyl, cyano, or amino;

[0111] R2 is H, -NR 21 R 22 , C 1-3 alkyl, -C 1-3 alkylene-OH, -C 1-3 alkylene-NH2, -C 1-3 alkylene-CONH2, or a five-membered saturated heterocycloalkyl; said alkyl, alkylene, or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; said heterocycloalkyl contains one N atom;

[0112] R 21 and R 22 are each independently H or C 1-3 alkyl; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I;

[0113] Optionally, R2 and X and a carbon atom on Cy1 form a five- or six-membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing one heteroatom; said heteroatom is selected from N; optionally, said carbocyclic or heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or =0;

[0114] R3 and R5 are H;

[0115] R4 is H, F, Cl, Br, I, or CN;

[0116] R6is -COOR 61 or a five-membered unsaturated heterocyclic ring containing 3 or 4 heteroatoms; the heteroatoms are selected from N;

[0117] R 61 is H or C 1-4 alkyl;

[0118] R7is H, C 1-3 alkyl, or R7and R2and X form a five-membered saturated carbocyclic ring; optionally, the carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I;

[0119] X is CH or N;

[0120] n1is 1 or 2.

[0121] According to some embodiments of the present application, wherein,

[0122] when n is 3, L is selected from one of the following structures:

[0123] each L1is independently selected from one of the following structures:

[0124] C 1-3 alkylene, O or S; preferably, L2of L1is attached to L at the end of L2;

[0125] L2is selected from C 1-3 alkylene;

[0126] A is the following structure:

[0127] each of R1, R2, R3, R4is independently H, F, Cl, Br, or I;

[0128] R5and R7are H;

[0129] n1is 0, 1, or 2;

[0130] when n is 2, L is selected from one of the following structures:

[0131] or,

[0132] when n is 2, L is selected from one of the following structures:

[0133] or,

[0134] when n is 2, L is selected from one of the following structures:

[0135] X1is O, S;

[0136] X2, X3are each independently a bond or C 1-5 alkylene;

[0137] A is the following structure:

[0138] R1, R2, R3, R4are each independently H, F, Cl, Br, or I;

[0139] R5and R7are H;

[0140] n1is 0, 1, or 2.

[0141] According to some embodiments of the present application, wherein,

[0142] n is 3, and L is selected from

[0143] L1is each independently selected from the following structures:

[0144] C 1-3 alkylene, O or S;

[0145] L2is selected from C 1-3 alkylene; and L2of L1is connected to L;

[0146] A is the following structure:

[0147] R1, R2, R3, R4are each independently H, F, Cl, Br, or I;

[0148] R5and R7are H;

[0149] n1is 0, 1, or 2.

[0150] According to some embodiments of the present application, wherein, the compound is selected from the following structures:

[0151] In another aspect, the present application also provides a pharmaceutical composition containing the compound, stereoisomer, metabolite, co-crystal, deuterated product or pharmaceutically acceptable salt thereof of any one of the preceding embodiments of the present application, and a pharmaceutically acceptable carrier.

[0152] In still another aspect, the present application also provides use of the compound, stereoisomer, metabolite, co-crystal, deuterated analog or pharmaceutically acceptable salt thereof of any one of the preceding aspects of the present application, or the pharmaceutical composition of the present application in the manufacture of a medicament for treating cardiovascular diseases.

[0153] According to some embodiments of the present application, the cardiovascular disease is arteriosclerosis.

[0154] According to some embodiments of the present application, the cardiovascular disease is atherosclerosis.

[0155] In still another aspect, the present application also provides use of the compound, stereoisomer, metabolite, co-crystal, deuterated analog or pharmaceutically acceptable salt thereof of any one of the preceding aspects of the present application, or the pharmaceutical composition of the present application in the manufacture of a medicament for treating cardiovascular diseases. DETAILED DESCRIPTION

[0156] The technical solutions of the present application are described in detail below in combination with examples, but the protection scope of the present application includes but is not limited to the same.

[0157] Example 1

[0158] Reaction Scheme:

[0159] Experimental Operation:

[0160] Step 1.

[0161] To a solution of tert-butyl (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (1.0 g, 2.2 mmol, 1 eq) and diphenyl methanimine (518. mg, 2.8 mmol, 1.3 eq) and cesium carbonate (1.4 g, 4.4 mmol, 2 eq) in 1,4-dioxane (10 mL) was added XantPhos (127. mg, 0.2 mmol, 0.1 eq) and Pd2(dba)3 (201. mg, 0.2 mmol, 0.1 eq) portion wise under air protection at room temperature. The resulting residue was stirred at 100 °C overnight under nitrogen protection. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (2 X 50 ml), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether / ethyl acetate (7:1) to give tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(diphenylmethylene)amino]phenyl}-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (890 mg, 68.5% yield).

[0162] LCMS (ESI): [M+H] + = 454.2.

[0163] Step 2.

[0164] To a solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[(diphenylmethylene)amino]phenyl}-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (800 mg, 1.4 mmol, 1 eq) in tetrahydrofuran (6 mL) was added citric acid (6 mL, 50%) under air protection at room temperature. The reaction mixture was stirred for 2 hours at room temperature under nitrogen protection. The reaction mixture was quenched with water at room temperature. The reaction mixture was basified with saturated aqueous sodium bicarbonate solution to pH = 8. The reaction mixture was extracted with ethyl acetate (2 X 70 ml). The combined organic phase was backwashed with saturated brine (2 X 100 ml) and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by normal phase with petroleum ether / ethyl acetate (3:1) to give tert-butyl (3R)-3-[(2S)-3-(3- aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (550 mg, 91.8% yield).

[0165] LCMS (ESI): [M+H] + = 391.2.

[0166] Step 3.

[0167] To a solution of tert-butyl (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (350 mg, 0.9 mmol, 1 eq) in ACN (3 mL) was added 1-(imidazol-1-ylmethyl)imidazole (79. mg, 0.5 mmol, 0.5 eq) at room temperature under air protection. The resulting residue was stirred for 10 minutes at 0 °C under nitrogen protection. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure to give tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (400 mg, crude).

[0168] LCMS (ESI): [M+H] + = 823.2.

[0169] Step 4.

[0170] To a solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}amino)methyl]phenyl}amino)methyl]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (200 mg, 0.2 mmol, 1 eq) in 1,4-dioxane (1.00 mL) was added HCl in 1,4-dioxane (3 mL, 4 M) at room temperature. The reaction was stirred at room temperature for 1.5 hours. The resulting residue was concentrated under reduced pressure. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((thiocarbonylbis(azenediyl))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (32.55 mg, 25.7% yield) with the following conditions (column XBridge BEH C18 OBD Prep Column 130, 5 m, 30 mm x 150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 2% B to 15% B, 8 minutes; wavelength: 254 nm / 220 nm; RT1(min): 5.97; 6.63).

[0171] LCMS (ESI): [M+H] + = 511.25.

[0172] 1 H NMR (400 MHz, Methanol-d4) d 7.31 (t, J = 7.8 Hz, 2H), 7.17 - 7.08 (m, 6H), 3.50 - 3.43 (m, 2H), 3.38 - 3.29 (m, 2H), 3.20 - 3.11 (m, 2H), 2.96 - 2.88 (m, 2H), 2.76 (d, J = 6.6 Hz, 4H), 2.46 - 2.34 (m, 4H), 2.11 - 2.01 (m, 2H), 1.72 - 1.61 (m, 2H).

[0173] Example 2

[0174] Reaction Scheme:

[0175] Experimental Procedures:

[0176] Step 1.

[0177] In a single necked flask, imidazolidine-2-thione (60 mg, 0.6 mmol, 1 eq), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (667 mg, 1.5 mmol, 2.5 eq), 1,4-dioxane (8 mL), cesium carbonate (383 mg, 1.2 mmol, 2 eq), Pd2(dba)3 (54 mg, 0.06 mmol, 0.1 eq) and XantPhos (68 mg, 0.12 mmol, 0.2 eq) were added successively and the reaction was carried out at 100 °C under nitrogen overnight. Water 50 mL was added and the resulting mixture was extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was performed by column chromatography on silica gel eluting with CH2Cl2 / MeOH (10 / 1) to give 3,3'-((2S,2'S)-((2-thioxoimidazolidine-1,3-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) di-tert-butyl ester (130 mg, 26.07%).

[0178] LCMS (ESI, m / z): [M+H] + = 849.5.

[0179] Step 2.

[0180] In a single necked flask, 3,3'-((2S,2'S)-((2-thioxoimidazolidine-1,3-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) di-tert-butyl ester (100 mg, 0.1 mmol, 1.0 eq) and HCl in 1,4-dioxane (3 mL, 4 M) were added successively and the reaction was carried out at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: Atlantis T3 OBD Prep Column 5m, 19mm x 250mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 2% B to 20% B in 7 min; wavelength: 254 nm / 220 nm nm; RT1(min): 6.6) to give (2S,2'S)-3,3'-((2-thioxoimidazolidine-1,3-diyl)bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (2.35 mg, 3.62% yield).

[0181] LC-MS (ESI): [M+H] + = 537.2.

[0182] 1 H NMR (400 MHz, Methanol-d4) δ 7.52 - 7.36 (m, 5H), 7.36 - 7.22 (m, 3H), 4.33 (t, J = 10.1 Hz, 2H), 3.95 - 3.78 (m, 2H), 3.63 - 3.49 (m, 2H), 3.44 - 3.31 (m, 2H), 3.25 - 3.19 (m, 2H), 3.01 (t, J = 10.7 Hz, 2H), 2.94 - 2.69 (m, 4H), 2.68 - 2.37 (m, 4H), 2.18 - 2.01 (m, 2H), 1.82 - 1.59 (m, 2H).

[0183] Example 3

[0184] Reaction Scheme:

[0185] Experimental Procedure:

[0186] Step 1.

[0187] To a solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}amino]phenyl} amino-methyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (750 mg, 0.9 mmol, 1 equiv.) and H2O (7 mL) in EtOH (7 mL) was added chloroacetic acid (129. mg, 1.4 mmol, 1.5 equiv.) under air protection at room temperature. The resulting residue was stirred at 100 °C for 4 h under nitrogen protection. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (2 X 50 ml). The combined organic phase was washed with saturated brine (2 X 100 ml), dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography plate, petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 3,3'-((2S,2'S)-((4-oxo-2-thioxoimidazolidine-1,3-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropan-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (420 mg, 27.7% yield).

[0188] LCMS (ESI): [M+H] = 863.2. +

[0189] ​Step 2.

[0190] To a solution of 3,3'-((2S,2'S)-((4-oxo-2-thioxoimidazolidine-l,3-diyl)bis(3,l- phenylene))bis(3-(tert-butoxy)-3-oxopropane-l,2-diyl))(3R,3'R)-bis(pyrrolidine-l- carboxylate) di-tert-butyl ester (400 mg, 0.5 mmol, 1 equiv.) in dioxane (4 mL) was added HC1 in 1,4-dioxane (3 mL, 4 M) under air protection at room temperature. The resulting residue was stirred for 2 hours at room temperature under nitrogen protection. The resulting residue was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to give (2S,2'S)-3,3'-((4-oxo-2-thioxoimidazolidine-l,3-diyl)bis(3,l- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (46.63 mg, 16.9% yield) with the following conditions: Column: Xbridge BEH Phenyl 5 pm, 19 x 250 mm; Mobile Phase A: Water (10 mmol / L NH4HC03), Mobile Phase B: Acetonitrile; Flow Rate: 25 mL / min; Gradient: 8% B to 20% B in 7 minutes; Wavelength: 254 nm / 220 nm nm; RTl(min): 6.67.

[0191] LCMS (ESI): [M+H] + = 551.2.

[0192] 1 H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.42 (m, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.29 - 7.16 (m, 3H), 7.01 (d, J = 7.6 Hz, 1H), 6.81 - 6.74 (m, 2H), 4.09 - 4.03 (m, 2H), 3.46 - 3.28 (m, 4H), 3.21 - 3.10 (m, 2H), 2.95 - 2.66 (m, 6H), 2.50 - 2.31 (m, 4H), 2.14 - 1.99 (m, 2H), 1.74 - 1.61 (m, 2H).

[0193] Example 4

[0194] Reaction Scheme:

[0195] Experimental Procedures:

[0196] Step 1.

[0197] In a single neck flask, add 1,3-diazaspiro[4.4]nonane-2,4-dione (1 g, 6.6 mmol, 1.5 eq), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (2 g, 4.4 mmol, 1 eq), DMF (8 mL), Cu2O (630 mg, 4.4 mmol, 1 eq) under nitrogen at 150 °C overnight. The resulting mixture was filtered with ethyl acetate, the filtrate was concentrated under reduced pressure. Purified by reverse phase column chromatography eluted with H2O / ACN (1 / 2) to give (R)-3-((S)-1-(tert-butoxy)-3-(3-(2,4-dioxo-1,3-diazaspiro[4.4]nonan-3-yl)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 25.84 %).

[0198] LCMS (ESI, m / z): [M+H] + = 528.3.

[0199] Step 2.

[0200] In a single neck flask, add (R)-3-((S)-1-(tert-butoxy)-3-(3-(2,4-dioxo-1,3- diazaspiro[4.4]nonan-3-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.1 mmol, 1 eq), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl)pyrrolidine-1-carboxylate (723 mg, 1.6 mmol, 1.4 eq), toluene (20 mL), potassium phosphate (483 mg, 2.3 mmol, 2 eq), CuI (43 mg, 0.2 mmol, 0.2 eq) and (±)-trans-1,2- cyclohexanediamine (52 mg, 0.5 mmol, 0.4 eq) under nitrogen at 130 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure. Purified by reverse phase column chromatography eluted with H2O / ACN (1 / 4) to give 3,3'-((2S,2'S)-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-1,3-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropan-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (130 mg, 12.69 %).

[0201] LCMS (ESI, m / z): [M+H] + = 901.5.

[0202] Step 3.

[0203] In a single-necked flask, 3,3'-((2S,2'S)-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-1,3-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (130 mg, 0.1 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL, 4 M) were added successively and reacted at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: XBridge BEH C18 OBD Prep Column 19 x 250 mm, 5 m; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 25% B in 7 min; wavelength: 254 nm / 220 nm; RT1(min): 7.18) to obtain (2S,2'S)-3,3'-((2,4-dioxo-1,3-diazaspiro[4.4]nonane-1,3-diyl)bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (31.09 mg, yield 35.88%).

[0204] LC-MS (ESI): [M+H] + = 589.3.

[0205] 1 H NMR (400 MHz, Methanol-d4) d 7.41-7.33 (m, 2H), 7.26 (t, J = 6.7 Hz, 2H), 7.23-7.11 (m, 4H), 3.44-3.34 (m, 2H), 3.35-3.24 (m, 2H), 3.19-3.06 (m, 2H), 2.91-2.80 (m, 2H), 2.76 (d, J = 6.6 Hz, 4H), 2.45-2.27 (m, 4H), 2.14 (t, J = 6.3 Hz, 4H), 2.07-1.95 (m, 2H), 1.72-1.52 (m, 4H), 1.36 (d, J = 7.7 Hz, 2H).

[0206] Example 5

[0207] Reaction Scheme:

[0208] Experimental Procedures:

[0209] Step 1.

[0210] In a single neck flask, add 5,7-diazaspiro[3.4]octane-6,8-dione (694 mg, 6.0 mmol, 1.5 eq), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (1.5 g, 3.3 mmol, 1 eq), DMF (10 mL), Cu2O (472 mg, 3.3 mmol, 1 eq) under nitrogen atmosphere at 150 °C for overnight. The resulting mixture is filtered with ethyl acetate, the filtrate is concentrated under reduced pressure. Purify with reverse phase column chromatography eluting with H2O / ACN (1 / 2) to get (R)-3-((S)-1-(tert-butoxy)-3-(3-(6,8-dioxo-5,7-diazaspiro[3.4]octan-7-yl)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (500 mg, 29.49%).

[0211] LCMS (ESI, m / z): [M+H] + = 514.3.

[0212] Step 2.

[0213] In a single neck flask, add (R)-3-((S)-1-(tert-butoxy)-3-(3-(6,8-dioxo-5,7- diazaspiro[3.4]octan-7-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (440 mg, 0.9 mmol, 1 eq), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2- yl)pyrrolidine-1-carboxylate (545 mg, 1.2 mmol, 1.4 eq), toluene (20 mL), potassium phosphate (364 mg, 1.7 mmol, 2 eq), CuI (33 mg, 0.2 mmol, 0.2 eq) and trans-N,N"-dimethylcyclohexane-1,2-diamine (49 mg, 0.4 mmol, 0.4 eq) under nitrogen atmosphere at 130 °C for overnight. The resulting mixture is extracted with ethyl acetate (3 x 50 mL), the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purify with reverse phase column chromatography eluting with H2O / ACN (1 / 4) to get 3,3'-((2S,2'S)-((6,8-dioxo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (180 mg, 23.69%).

[0214] LCMS (ESI, m / z): [M+H] + = 887.5.

[0215] Step 3.

[0216] In a single-necked flask, 3,3'-((2S,2'S)-((6,8-dioxo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (180 mg, 0.2 mmol, 1.0 eq) and HC1 in 1,4-dioxane (5 mL) were added sequentially and reacted at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: Xselect CSH C18 5m, 30 mm x 150 mm, 5 m; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 5% B to 20% B in 7 min; wavelength: 254 nm / 220 nm nm; RT1(min): 5.83) to give (2S,2'S)-3,3'-((6,8-dioxo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (16.74 mg, yield 12.49%).

[0217] LC-MS (ESI): [M+H] + = 575.3.

[0218] 1 H NMR (400 MHz, Methanol-d4) δ 8.29 (s, 1H), 7.51 - 7.38 (m, 2H), 7.38 - 7.11 (m, 6H), 3.55 - 3.39 (m, 2H), 3.34 (d, J = 6.3 Hz, 2H), 3.18 (s, 2H), 2.97 - 2.92 (m, 2H), 2.84 (d, J = 7.6 Hz, 4H), 2.63 - 2.32 (m, 8H), 2.09 (d, J = 6.5 Hz, 2H), 1.93 (q, J = 9.5 Hz, 1H), 1.69 (t, J = 4.8 Hz, 2H), 1.54 (s, 1H).

[0219] Example 6

[0220] Reaction Scheme:

[0221] Experimental Procedures:

[0222] Step 1.

[0223] To a single necked flask was added (3R)-methyl pyrrolidine-3-carboxylate (250 mg, 1.5 mmol, 1 eq), (3R)-tert-butyl 3-[(2S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.0 g, 2.3 mmol, 1.5 eq), 1,4-dioxane (20 mL), cesium carbonate (984 mg, 3.0 mmol, 2 eq), Pd2(dba)3 (138 mg, 0.2 mmol, 0.1 eq) and XantPhos (175 mg, 0.3 mmol, 0.2 eq) and stirred at 100 °C under nitrogen atmosphere overnight. The resulting mixture was extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was done by reverse phase column chromatography eluting with H2O / ACN (1 / 2) to get (3R)-methyl 1-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}pyrrolidine-3-carboxylate (470 mg, 61.9 %).

[0224] LCMS (ESI, m / z): [M+H] + = 503.3.

[0225] Step 2.

[0226] To a single necked flask was added (3R)-methyl 1-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}pyrrolidine-3-carboxylate (450 mg, 0.9 mmol, 1.0 eq), tetrahydrofuran (10 mL), water (10 mL), lithium hydroxide (113 mg, 2.7 mmol, 3.0 eq) and stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. This resulted in (3R)-1-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}pyrrolidine-3-carboxylic acid (400 mg, 91.44 %). The crude product was used as such for the next step without further purification.

[0227] LCMS (ESI, m / z): [M+H] + = 489.3.

[0228] Step 3.

[0229] In a single-necked flask, (3R)-1-{3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}pyrrolidine-3-carboxylic acid (160 mg, 0.3 mmol, 1.0 eq), (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (128 mg, 0.3 mmol, 1.0 eq), HATU (187 mg, 0.5 mmol, 1.5 eq), DIEA (85 mg, 0.7 mmol, 2 eq) and DCM (5 mL) were added successively, and the reaction was allowed to proceed at room temperature for 2 h. The solvent was removed by evaporation, and the product was purified by reverse phase column chromatography eluting with H2O / ACN (1 / 2) to give (R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-1-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidine-3-carboxamido)phenyl)- 1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 46.10%).

[0230] LCMS (ESI, m / z): [M+H] + = 861.5.

[0231] Step 4.

[0232] In a single-necked flask, (R)-3-((S)-1-(tert-butoxy)-3-(3-((R)-1-((S)-3-(tert-butoxy)-2- ((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidine-3- carboxamido)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.2 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) were added successively, and the reaction was allowed to proceed at room temperature for 2 h. The crude product was purified by Prep-HPLC under the following conditions (column: XBridge BEH Shield RP18 5m, 19 mm x 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 20% B in 9 min; wavelength: 254 nm / 220 nm nm; RT1(min): 7.92) to give (S)-3-(3-((R)-3-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)carbamoyl)pyrrolidin-1- yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (31.54 mg, yield 36.17%).

[0233] LC-MS (ESI): [M+H] + = 549.3.

[0234] 1 H NMR (400 MHz, Methanol-d4) δ 7.32 - 7.14 (m, 4H), 7.07 - 6.99 (m, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.61 - 6.56 (m, 2H), 3.59 - 3.47 (m, 1H), 3.47 - 3.24 (m, 8H), 3.24 - 3.13 (m, 2H), 2.96 - 2.81 (m, 2H), 2.80 - 2.63 (m, 4H), 2.50 - 2.33 (m, 4H), 2.34 - 2.25 (m, 1H), 2.23 - 2.14 (m, 1H), 2.12 - 1.99 (m, 2H), 1.74 - 1.59 (m, 2H).

[0235] Example 7

[0236] Reaction Scheme:

[0237] Experimental Procedure:

[0238] Step 1.

[0239] (R)-3-((S)-3-(3-bromophenyl)-l-(tert-butoxy)-l-oxopropan-2-yl)pyrrolidine-l- carboxylate (1 g, 2.2 mmol, 1.0 eq), [l,l'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (180 mg, 0.2 mmol, 0.1 eq) and triethylamine (680 mg, 6.6 mmol, 3 eq) were dissolved in 1,4-dioxane (10 mL) and water (10 mL), passed 5 bar of carbon monoxide, stirred at 100 °C overnight. Cooled to room temperature, dissolved in 20 mL water, extracted with ethyl acetate (3 x 10 mL), the organic layer washed with saturated sodium chloride 200 mL, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The crude was purified by normal phase column chromatography with the following conditions (mobile phase A: dichloromethane, mobile phase B: methanol; flow rate: 80 mL / min; gradient: 0% B to 10% B in 30 min; wavelength: 254 nm; ) to get 3-((S)-3-(tert-butoxy)-2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl)benzoic acid (300 mg, yield 32.49%).

[0240] LCMS (ESI): [M+H] + = 420.25.

[0241] Step 2.

[0242] To a solution of 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl)benzoic acid (250 mg, 0.597 mmol, 1.0 eq) in dichloromethane (3 mL) was added oxalyl chloride (113 mg, 0.9 mmol, 1.5 eq) and N,N-dimethylformamide (0.1 mL) under nitrogen at room temperature. After stirring for 2 h, the reaction mixture was quickly rotary evaporated, and then ammonia water (5 mL) was added. After stirring at room temperature overnight, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 X 20 mL). The combined organic phase was washed with saturated sodium chloride (2 X 20 mL) and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether / ethyl acetate (1 / 1) to give (R)-tert-butyl 3-((S)-1-(tert-butoxy)-3-(3-carbamoylphenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (200 mg, 40.09% yield).

[0243] LCMS (ESI): [M+H] + = 419.35.

[0244] Step 3.

[0245] To a solution of 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl)benzoic acid (250 mg, 0.597 mmol, 1.0 eq) and N,N'-carbonyldiimidazole (106 mg, 0.6 mmol, 1.1 eq) in DCM (5 mL) was stirred for 5 min at room temperature. NaH (35 mg, 0.7 mmol, 1.2 eq) and (R)-tert-butyl 3-((S)-1-(tert-butoxy)-3-(3- carbamoylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (275 mg, 0.66 mmol, 1.1 eq) were added to the above system at 0 °C, respectively. After stirring at room temperature overnight, the resulting residue was concentrated under reduced pressure and purified by column chromatography on silica gel using dichloromethane / methanol (10 / 1) to give 3,3'-((2S,2'S)-((azenediylbis(carbonyl))bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (170 mg, 34.71% yield).

[0246] LCMS (ESI): [M+H] - = 819.47.

[0247] Step 4.

[0248] Step 4.

[0249] LCMS (ESI): [M+H] + = 508.25.

[0250] 1 H NMR (400 MHz, Deuterium Oxide) δ 8.302 (s, 1H), 7.71-7.63 (m, 4H), 7.46-7.46 (m, 2H), 3.53 - 3.50 (m, 2H), 3.40 - 3.34 (m, 2H), 3.22 - 3.18 (m, 2H), 2.98 (t, J = 10.6 Hz, 2H), 2.89-2.76 (m, 4H), 2.58-2.40 (m, 4H), 2.11-2.08 (m, 2H), 1.77-1.59 (m, 2H).

[0251] Example 8

[0252] Reaction Scheme:

[0253] Experimental Procedures:

[0254] Step 1.

[0255] To a solution of tert-butyl (3R)-3-[(2S)-1 -(tert-butoxy)-3-[3-(hydroxymethyl) phenyl]-1 -oxopropan-2-yl]pyrrolidine-1 -carboxylate (2.2 g, 5.4 mmol, 1.0 equiv) and N-bromosuccinimide (1.9 g, 10.8 mmol, 2.0 equiv) in DCM (30 mL) was added N,N'-dimethylthiourea (254 mg, 2.4 mmol, 0.45 equiv) under nitrogen at room temperature. The resulting residue was stirred for 1 h. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column size, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 min, UV 254 nm detector. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1 -(tert-butoxy)-1 - oxopropan-2-yl]pyrrolidine-1 -carboxylate (1.2 g, 47.2%).

[0256] LCMS (ESI, m / z): [M+H] + = 406.0.

[0257] Step 2.

[0258] To a solution of tert-butyl (3R)-3-[(2S)-1 -(tert-butoxy)-3-[3-(hydroxymethyl) phenyl]-1 -oxopropan-2-yl]pyrrolidine-1 -carboxylate (2.2 g, 5.4 mmol, 1.0 equiv) and N-bromosuccinimide (1.9 g, 10.8 mmol, 2.0 equiv) in DCM (30 mL) was added N,N'-dimethylthiourea (254 mg, 2.4 mmol, 0.45 equiv) under nitrogen at room temperature. The resulting residue was stirred for 1 h. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column size, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 min, UV 254 nm detector. This resulted in tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1 -(tert-butoxy)-1 - oxopropan-2-yl]pyrrolidine-1 -carboxylate (1.2 g, 47.2%).

[0259] LC-MS (ESI): [M+H] + = 470.2.

[0260] Step 3.

[0261] A mixture of (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-l-(tert-butoxy)-l- oxopropan-2-yl]pyrrolidine- 1 -carboxylic acid tert-butyl ester (600 mg, 0.6 mmol, 1.0 eq), 1 -hydroxy- 1 H-pyrazole-3-carboxylic acid pinacol ester (248 mg, 1.3 mmol, 1.0 eq), potassium phosphate tribasic (815 mg, 3.8 mmol, 3 eq), tetrakis(triphenylphosphine)palladium (148 mg, 1.3 mmol, 0.1 eq) in ethyleneglycol dimethyl ether (24 mL), water (6 mL), ethanol (6 mL) was stirred at 60 °C under nitrogen overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 minutes, UV 254 nm detector. This resulted in (3R)-3-[(2S)-l-(tert-butoxy)-l-oxo-3-[3-(2H-pyrazol-3- ylmethyl)phenyl]propan-2-yl]pyrrolidine- 1 -carboxylic acid tert-butyl ester (130 mg, 22.3%).

[0262] LC-MS (ESI): [M+H] + = 456.3.

[0263] Step 4.

[0264] To a solution of (3R)-3-[(2S)-1-(tert-butoxy)-1-oxo-3-[3-(2H-pyrazol-3- ylmethyl)phenyl]propan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 0.3 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added sodium hydride (23 mg, 0.6 mmol, 2.0 eq, 60%) portionwise at 0 °C under nitrogen. The resulting residue was stirred at room temperature for 30 minutes under nitrogen. To the above system was added (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (133 mg, 0.3 mmol, 1.0 eq) portionwise at room temperature. After the addition was complete, the system was stirred at room temperature overnight. The reaction mixture was quenched with water at 0 °C. The aqueous phase was extracted with ethyl acetate (3 X 10 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 minutes, UV 254 nm detector. This gave (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[2-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)pyrazol-3-yl]methyl}phenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (130 mg, 54.0%).

[0265] LC-MS (ESI): [M+H] + = 843.9.

[0266] Step 5.

[0267] A solution of tert-butyl (3R)-3-[(2S)-1 -(tert-butoxy)-3-(3-{[2-[(2S)-3-(tert- butoxy)-2-[(3R)-1 -(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl) pyrazol-3-yl]methyl}phenyl)-1 -oxopropan-2-yl]pyrrolidine-1 -carboxylate (100 mg, 0.1 mmol, 1.0 equiv) and N-iodosuccinimide (64 mg, 0.2 mmol, 2.0 equiv) in N,N-dimethylformamide (2 mL) was stirred at 80 °C under nitrogen overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 minutes, UV 254 nm detector. This gave tert-butyl 3,3'-((2S,2'S)-(((3-iodo-1 H-pyrazole-1,5-diyl)bis(methylene))bis(3,1 - phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1 - carboxylate) di-tert-butyl ester (90 mg, 54.2%).

[0268] LC-MS (ESI): [M+H] + = 969.8.

[0269] Step 6.

[0270] A solution of di-tert-butyl 3,3'-((2S,2'S)-(((3-iodo-1H-pyrazole-1,5-diyl)bis(methylene))bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (90 mg, 0.1 mmol, 1.0 equiv) and tert-butyl (3R)-3-[(2S)-3-(3- aminophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (36 mg, 0.1 mmol, 1.0 equiv), tris(dibenzylideneacetone)dipalladium-chloroform complex (10 mg, 0.01 mmol, 0.1 equiv), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (9 mg, 0.02 mmol, 0.2 equiv), potassium phosphate dibasic (38 mg, 0.3 mmol, 3.0 equiv) in 1,4-dioxane (5 mL) was stirred under nitrogen at 120 °C overnight. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 10% to 50% gradient over 10 minutes, UV 254 nm detector. This resulted in di-tert-butyl 3,3'-((2S,2'S)-((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)amino)-1H-pyrazole-1,5-diyl)bis(methylene))bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (15 mg, 13.1%).

[0271] LC-MS (ESI): [M+H] + = 1231.0.

[0272] Step 7.

[0273] A solution of ditert-butyl 3,3'-((2S,2'S)-((3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)amino)-1H-pyrazole-1,5- diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)- bis(pyrrolidine-1-carboxylate) (15 mg, 0.01 mmol, 1.0 equiv) hydrochloric acid in 1,4- dioxane (1 mL) was stirred at room temperature for 1 h. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: (column: YMC Triart C18 ExRs 5m, 19mm x 250mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: from 30% B to 47% B in 8 min; wavelength: 254 nm / 220 nm; RT1(min): 6.07). Yield (2S,2'S)-3,3'-((3-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)amino)-1H- pyrazole-1,5-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (1.97 mg, 19.5%).

[0274] LC-MS (ESI): [M+H] + = 763.4.

[0275] Example 9

[0276] Reaction Scheme:

[0277] Experimental Procedures:

[0278] Step 1.

[0279] To a solution of (R)-3-((S)-3-(3-bromophenyl)-l-(tert-butoxy)-l-oxopropan-2- yl)pyrrolidine-l-carboxylate (1.0 g, 2.2 mmol, 1.0 eq) and zinc cyanide (0.5 g, 4.4 mmol, 2.0 eq) in N,N-dimethylformamide (10 mL) was added tetrakis(triphenylphosphine)palladium (0.5 g, 0.4 mmol, 0.2 eq) in portions at room temperature under nitrogen. The reaction was stirred at 80 °C overnight under nitrogen. The reaction was evaporated under reduced pressure and purified by normal phase column chromatography, PE / EA = 5 / 1, to give (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-cyanophenyl)-l-oxopropan-2-yl]pyrrolidine-l- carboxylate (610 mg, yield 69.2%).

[0280] LCMS (ESI, m / z): [M+H] + = 401.2.

[0281] Step 2.

[0282] To a 50 mL reactor was added a solution of (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-cyanophenyl)- l-oxopropan-2-yl]pyrrolidine-l-carboxylate (400 mg, 0.1 mmol) in ethanol under nitrogen, followed by palladium on carbon (60%, 0.5 g). Hydrogen was bubbled through and the reaction was stirred at room temperature overnight. The reaction was filtered and the filter cake was washed with ethanol (3 X 10 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on a C18 column using a gradient of 10% to 50% acetonitrile in water over 20 minutes with a UV 254 nm detector to give (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-l-(tert-butoxy)-l-oxopropan-2- yl]pyrrolidine-l-carboxylate (250 mg, 61.88%).

[0283] LCMS (ESI, m / z): [M+H] + = 405.2.

[0284] Step 3.

[0285] To a solution of (3R)-3-[(2S)-3-[3-(aminomethyl)phenyl]-l-(tert- butoxy)-l-oxopropan-2-yl]pyrrolidine-l-carboxylic acid tert-butyl ester (150 mg, 0.4 mmol, 1.0 equiv) and (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-formylphenyl)-l- oxopropan-2-yl]pyrrolidine-l-carboxylic acid tert-butyl ester (149 mg, 0.4 mmol, 1.0 equiv) in methanol (2 mL) was added acetic acid (0.1 mL) under nitrogen at room temperature. After stirring for 15 min, sodium cyanoborohydride (233 mg, 3.7 mmol, 10.0 equiv) was added in portions at room temperature. The resulting residue was stirred at 75 °C for 4 h, then allowed to cool to room temperature and stirred overnight. The resulting residue was purified by reverse phase column chromatography using the following conditions: C18 column, mobile phase, water and acetonitrile, 10% to 90% gradient over 20 min, UV 254 nm detector to give (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-([(3-[(2S)-3-(tert-butoxy)-2-[(3R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenylmethyl)amino]methylphenyl)-l- oxopropan-2-yl]pyrrolidine-l-carboxylic acid tert-butyl ester (60 mg, 20.4% yield).

[0286] LCMS (ESI, m / z): [M+H] + = 792.5.

[0287] Step 4.

[0288] To a solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-([(3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl- methyl)amino]methylphenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert- butyl ester (120 mg, 0.2 mmol, 1.0 equiv) and 3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]benzoic acid (127 mg, 0.3 mmol, 2.0 equiv) in N,N-dimethylformamide (2 mL) was added HATU (86 mg, 0.3 mmol, 1.5 equiv) and N,N-diisopropylethylamine (39 mg, 0.3 mmol, 2 equiv) in portions under nitrogen at room temperature. The resulting residue was stirred at room temperature overnight under nitrogen. The resulting residue was purified by reverse phase column chromatography with the following conditions: C18 column dimensions, mobile phase, water and acetonitrile, 10% to 90% gradient over 20 minutes, UV 254 nm detector. Yield 3,3'-((2S,2'S)-((((3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)azenediyl)bis(methylene))bis(3, (3R,3'R)-bis(pyrrolidine-1-carboxylate) (60 mg, 33.1% yield).

[0289] LCMS (ESI, m / z): [M+H] + = 1193.7.

[0290] Step 5.

[0291] A solution of 3,3'-di-tert-butyl((2S,2'S)-(((3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzoyl)azanediyl)bis(methylene) bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1- carboxylate) (40 mg, 0.034 mmol, 1 equiv) and hydrochloric acid in 1,4-dioxane (2 mL, 4 M) was stirred under nitrogen at room temperature overnight. The crude product was purified by high performance liquid chromatography to give (2S,2'S)-3,3'-((((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzoyl)azanediyl)bis(methylene))bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (6.55 mg, 26.88%) under the following conditions (Column Type: SunFire CI 85 m, 19 mm X 250 mm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: Acetonitrile; Flow Rate: 25 mL / min; Gradient: 6% B to 17% B in 7 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 6.7).

[0292] LCMS (ESI, m / z): [M+H] + = 725.4.

[0293] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.36 - 7.30 (m, 3H), 7.28 - 7.22 (m, 3H), 7.13 - 7.11 (m, 1H), 7.11 - 7.06 (m, 2H), 7.06 - 7.01 (m, 1H), 6.75 - 6.95 (m, 2H), 4.62 - 4.52 (m, 2H), 4.40 - 4.20 (m, 2H), 3.50 - 3.20 (m, 6H), 3.20 - 3.10 (m, 3H), 2.95 - 2.80 (m, 2H), 2.80 - 2.60 (m, 7H), 2.60 - 2.30 (m, 6H), 2.15 - 1.95 (m, 3H), 1.75 - 1.55 (m, 3H).

[0294] Example 10

[0295] Reaction Scheme:

[0296] Experimental Procedures:

[0297] Step 1.

[0298] To a solution of 2,3-dihydro-lH-indole-6-carboxylic acid methyl ester (10.0 g, 56.4 mmol, 1.0 eq) in dichloromethane (250 mL) was added potassium carbonate (10.1 g, 73.4 mmol, 1.3 eq), triethylamine (17.1 g, 169.3 mmol, 3.0 eq), after stirring, benzyl chloroformate (11.6 g, 67.7 mmol, 1.2 eq) was added at 0 °C. The temperature was raised to room temperature and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was washed with saturated ammonium chloride solution (300 mL) and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: C18 column, mobile phase, water and acetonitrile, 50% to 70% gradient for 20 min, UV 254 nm detector. 1 -benzyl 6-methyl 2,3-dihydroindole-l,6-dicarboxylate (13.8 g, 78.55% yield) was obtained.

[0299] LC-MS (ESI): [M+H] + = 312.1.

[0300] Step 2.

[0301] To a solution of 1 -benzyl 6-methyl 2,3-dihydroindole- 1,6-dicarboxylate (10.0 g, 32.1 mmol, 1.0 eq) in tetrahydrofuran (93 mL) was added lithium aluminum hydride (1.2 g, 32.1 mmol, 1.0 eq) dropwise at 0 °C under nitrogen atmosphere. The temperature was raised to room temperature. Stirred for 2 h. After completion of the reaction, it was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL). The reaction mixture was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and washed with brine (100 mL) and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude 6-(hydroxymethyl)-2,3-dihydroindole-l-carboxylic acid benzyl ester (5.0 g, 54.94% yield) was obtained.

[0302] LC-MS (ESI): [M+H] + = 284.1.

[0303] Step 3.

[0304] To a solution of 6-(hydroxymethyl)-2,3-dihydroindole-1-carboxylic acid benzyl ester (2.7 g, 9.5 mmol, 1.0 eq) in dichloromethane (30 mL) was added a solution of phosphorous tribromide (3.9 g, 14.3 mmol, 1.5 eq) in dichloromethane (10 mL) dropwise at 0 °C. The reaction was stirred for 2 h. After the reaction was completed, the system was concentrated under reduced pressure to obtain the crude 6-(bromomethyl)-2,3-dihydroindole-1-carboxylic acid benzyl ester (2.5 g, yield 75.77%).

[0305] LC-MS (ESI): [M+H] + = 346.0.

[0306] Step 4.

[0307] To a solution of tert-butyl (3R)-3-{2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2- oxoethyl}pyrrolidine-1-carboxylate (4.5 g, 11.6 mmol, 1.0 eq) in tetrahydrofuran (270 mL) was added 1.0 M lithium bis(trimethylsilyl)amide in tetrahydrofuran (12.7 mL, 12.7 mmol, 1.1 eq) dropwise at 0 °C. After stirring for 10 min, a solution of 6-(bromomethyl)-2,3-dihydroindole-1-carboxylic acid benzyl ester (3.6 g, 10.4 mmol, 0.9 eq) in tetrahydrofuran (120 mL) was added dropwise. The reaction was stirred for 4 h. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to quench, and stirred for 15 min. Ethyl acetate (2 x 200 mL) was added to extract, and anhydrous sodium sulfate was added to dry. After filtration, the crude 6-[(2S)-3-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-[(3R)-1-(tert- butylcarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydroindole-1-carboxylic acid benzyl ester (7.0 g, yield 92.43%) was obtained after concentration.

[0308] LC-MS (ESI): [M+H] + = 654.3.

[0309] Step 5.

[0310] To a solution of 6-[(2S)-3-[(4S)-4-benzyl-2-oxo-l,3-oxazolidin-3-yl]-2-[(3R)-l-(tert- butylcarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydroindole-l -carboxylate (7.0 g, 10.7 mmol, 1.0 eq) in tetrahydrofuran (70 mL) was added 1.0 M aqueous hydrogen peroxide solution (18 mL) at 0 °C. Then 0.5 M lithium hydroxide solution (35 mL) was added dropwise. The reaction was stirred for 2 h. After the reaction was completed, saturated aqueous sodium sulfite solution (100 mL) was added to quench. The reaction mixture was basified with 5.0 M sodium hydroxide to pH > 12. Extracted with diethyl ether (100 mL). The aqueous phase was collected and acidified with 2.0 M hydrochloric acid solution to pH = 3. Extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give (2S)-3-{l-[(benzyloxy)carbonyl]-2,3-dihydroindol-6-yl}-2-[(3R)-l-(tert- butylcarbonyl)pyrrolidin-3-yl]propanoic acid (5.0 g, yield 94.42%).

[0311] LC-MS (ESI): [M+H] + = 495.2.

[0312] Step 6.

[0313] To a solution of (2S)-3-{l-[(benzyloxy)carbonyl]-2,3-dihydroindol-6-yl}-2-[(3R)-l-(tert- butylcarbonyl)pyrrolidin-3-yl]propanoic acid (5.0 g, 10.1 mmol, 1.0 eq) in 2-methyltetrahydrofuran (12 mL) was added O-tert-butyl-N,N'-diisopropylisourea (6.3 g, 31.2 mmol, 3.0 eq) at room temperature. After the reaction was stirred at 65 °C for 3 h, O-tert-butyl-N,N'-diisopropylisourea (2.5 g, 12.4 mmol, 1.2 eq) was added at 65 °C. The reaction was stirred overnight. After the reaction was completed, it was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (10: 1) to give 6-[(2S)-3-(tert-butyl)-2-[(3R)-l-(tert-butylcarbonyl)pyrrolidin-3-yl]-3-oxopropyl]-2,3- dihydroindole-l -carboxylate benzyl ester (2.5 g, yield 44.91%).

[0314] LC-MS (ESI): [M+H] + = 551.3.

[0315] Step 7.

[0316] To a solution of 6-[(2S)-3-(tert-butyl)-2-[(3R)-1-(tert-butyi carbonyl)pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydroindole-1-carboxylic acid benzyl ester (1.4 g, 2.5 mmol, 1.0 eq) in methanol (20 mL) was added Pd / C (0.1 g). The system was replaced with hydrogen. The system was stirred at room temperature for 2 hours under hydrogen atmosphere. After the reaction was completed, it was filtered. The filtrate was concentrated to give tert-butyl (3R)-3-[(2S)-1-(tert-butyl)-3-(2,3-dihydro-1H-indol-6-yl)-1-oxopropyl]pyrrolidine-1-carboxylate (1.1 g, yield 90.09%).

[0317] LC-MS (ESI): [M+H] + = 417.3.

[0318] Step 8.

[0319] To a solution of tert-butyl (R)-3-((S)-1-(tert-butoxy)-3-(indol-6-yl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (900 mg, 2.1 mmol, 1.0 eq) in tetrahydrofuran (40 mL) was added triethylamine (240 mg, 2.4 mmol, 1.1 eq). Triphosgene (103 mg, 0.3 mmol, 0.2 eq) in tetrahydrofuran (4 mL) was added dropwise at 0 °C, the reaction was raised to room temperature, and stirred at room temperature for 6 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to give crude tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(1-{6-[(2R)-3-(tert-butoxy)-2-[(3S)-1-(tert-butoxy)pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydroindole-1-carbonyl}-2,3-dihydroindol-6-yl)-1-oxopropyl]pyrrolidine-1-carboxylate (300 mg, yield 16.16%).

[0320] LC-MS (ESI): [M+H] + = 859.5.

[0321] Step 9.

[0322] A solution of hydrogen chloride in 1,4-dioxane (18 mL, 4.0 M) was added dropwise to (3R)-3-[(2S)-1-(tert-butoxy)-3-(1-{6-[(2R)-3-(tert-butoxy)-2-[(3S)-1-(tert- butoxy)pyrrolidin-3-yl]-3-oxopropyl]-2,3-dihydroindole-1-carbonyl}-2,3- dihydroindol-6-yl)-1-oxopropyl]pyrrolidine-1-carboxylate (300 mg, 0.3 mmol, 1.0 eq) in room temperature for 2 h. After the reaction was completed, the filter cake was obtained by filtration and washing with acetonitrile. Preparative reverse phase column chromatography was performed using the following method: Column: xselect CSH C185m, 30 mm x 150 mm; Mobile Phase A: water (0.1% formic acid), Mobile Phase B: acetonitrile; Flow Rate: 60 mL / min; Gradient: 4% B to 20% B in 7 min; Wavelength: 254 nm / 220 nm; RT1(min): 6.12. (2S)-3-(1-{6-[(2R)-2-carboxy-2-[(3S)-pyrrolidin-3-yl]ethyl]-2,3- dihydroindole-1-carbonyl}-2,3-dihydroindol-6-yl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (36.40 mg, yield 34.83%) was obtained.

[0323] LC-MS (ESI): [M+H] + = 547.25.

[0324] 1 H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 4H), 7.18 - 7.09 (m, 4H), 6.79 (d, J = 7.6 Hz, 2H), 3.99 (d, J = 8.3 Hz, 4H), 3.39 - 3.27 (m, 2H), 3.26 - 3.15 (m, 2H), 3.11 - 3.03 (m, 6H), 2.93 - 2.81 (m, 2H), 2.81 - 2.65 (m, 4H), 2.62 - 2.52 (m, 2H), 2.40 - 2.26 (m, 2H), 2.01 - 1.90 (m, 2H), 1.69 - 1.56 (m, 2H).

[0325] Example 11

[0326] Reaction Scheme:

[0327] Experimental Procedures:

[0328] Step 1.

[0329] Tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-((((E)-3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzylidene)amino)methyl)phenyl]-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.013 mmol, 1 eq) was dissolved in MeOH (30 mL) under nitrogen protection, NaBH4(76.61 mg, 2.026 mmol, 2.0 eq) was added at 0 °C, and the reaction was stirred overnight. The resulting residue was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (5 / 1), to give tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}phenyl]methyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (560 mg, 69.82%).

[0330] LC-MS (ESI): [M+H] + = 790.1.

[0331] Step 2.

[0332] Tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-((((E)-3-(S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzylidene)amino)methyl)phenyl]-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (800 mg, 1.013 mmol, 1 eq) was dissolved in MeOH (30 mL) under nitrogen protection, NaBH4(76.61 mg, 2.026 mmol, 2.0 eq) was added at 0 °C, and the reaction was stirred overnight. The resulting residue was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (5 / 1), to give tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}phenyl]methyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (560 mg, 69.82%).

[0333] LC-MS (ESI): [M+H] + = 792.5.

[0334] Step 3.

[0335] A solution of (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (390 mg, 0.999 mmol, 1 eq) and TEA (202.11 mg, 1.998 mmol, 2.0 eq) in DCM (15 mL) was added dropwise with bromoacetyl chloride (235.77 mg, 1.498 mmol, 1.5 eq) under nitrogen protection in ice bath. The reaction was stirred for 6 h. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, dichloromethane / methanol (10 / 1) to give (3R)-3-[(2S)-3-[3-(2-bromoacetamido)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 29.37%).

[0336] LC-MS (ESI): [M+H] + = 511.2.

[0337] Step 4.

[0338] A solution of (3R)-3-[(2S)-3-[3-(2-bromoacetamido)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (226 mg, 0.442 mmol, 1.00 eq) and tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[({3-[(2S-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}phenyl]methyl)amino]methyl}phenyl)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (350.00 mg, 0.442 mmol, 1.00 eq) and K2CO3 (152.67 mg, 1.105 mmol, 2.5 eq) in DMF (10 mL) was stirred at 60 °C under nitrogen protection overnight. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (10 / 1) to give tert-butyl-(3R)-3-[(2S)-1-(tert-butoxy)-3-[3-({[({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}carbamoyl)methyl]({3-[(2S)-3-(tert-butoxy)-2- [(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}phenyl)methyl)amino}methyl) phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (80 mg, 14.81%).

[0339] LC-MS (ESI): [M+H] + = 1223.6.

[0340] Step 5.

[0341] tert-Butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-{2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}aminocarbonyl)methyl]({3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino}methyl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (81 mg, 0.066 mmol, 1 equiv) was dissolved in a solution of HCl in 1,4-dioxane (10 mL, 4 M) and stirred overnight. The crude product was purified by high performance liquid chromatography to give (2S)-3-[3-({[({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}aminocarbonyl)methyl]-yl]ethyl]phenyl}methyl)amino}methyl)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid under the following conditions (Column Type: XBridge BEH C18 OBD Prep Column 130, 5 m, 19 mm x 250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 11% B to 25% B in 8 min; Wavelength: 254 nm / 220 nm; RT1(min): 5.75).

[0342] LC-MS (ESI): [M+H] + = 754.7.

[0343] 1 H NMR (400 MHz, Deuterium Oxide) d 7.25 (d, J = 4.5 Hz, 4H), 7.20 (s, 3H), 7.08 (s, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.93 (d, J = 8.0 Hz, 1H), 3.76 (s, 4H), 3.46 - 3.40 (m, 1H), 3.38 - 3.31 (m, 1H), 3.29 - 3.15 (m, 7H), 3.16 - 3.09 (m, 2H), 2.88 (t, J = 10.3 Hz, 1H), 2.77 - 2.62 (m, 6H), 2.62 - 2.58 (m, 2H), 2.51 - 2.22 (m, 6H), 1.99 (s, 3H), 1.75 - 1.52 (m, 3H).

[0344] Example 12

[0345] Reaction Scheme:

[0346] Experimental Procedure:

[0347] Step 1.

[0348] To a solution of tert-butyl (3R)-3-[(2S)-1-(tert-butoxy)-3-{3-[({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl}amino]phenyl} amino-methyl)amino]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (750 mg, 0.9 mmol, 1 equiv.) and H20 (7 mL) in EtOH (7 mL) was added chloroacetic acid (129. mg, 1.4 mmol, 1.5 equiv.) under air protection at room temperature. The resulting residue was stirred at 100 °C for 4 h under nitrogen protection. The reaction mixture was quenched with water at room temperature. The reaction mixture was extracted with ethyl acetate (2 X 50 ml). The combined organic phase was washed with brine (2 X 100 ml) and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography plate using petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 3,3'-((2S,2'S)-((4-hydroxy-2-thioxo-1H-imidazole-1,3(2H)- diyl)bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropan-1,2-diyl))(3R,3'R)-bis(pyrrolidine- 1-carboxylate) (420 mg, 27.7% yield).

[0349] LCMS (ESI): [M+H] + = 863.2

[0350] Step 2.

[0351] To a solution of 3,3'-((2S,2'S)-((4-hydroxy-2-thioxo-lH-imidazol-l,3(2H)- diyl)bis(3,l-phenylene))bis(3-(tert-butoxy)-3-oxopropane-l,2-diyl))(3R,3'R)- bis(pyrrolidine-l-carboxylate) di-tert-butyl ester (400 mg, 0.5 mmol, 1 equiv.) in dioxane (1.00 mL) was added HC1 in 1,4-dioxane (3 mL, 4 M) under air protection. The resulting residue was stirred at room temperature for 2 hours under nitrogen protection. The resulting residue was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to give (2S,2'S)-3,3'-((4-hydroxy-2-thioxo-lH-imidazol-l,3(2H)- diyl)bis(3,l-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (4.23 mg, 1.4% yield) with the following conditions: Column: Xbridge BEH Phenyl 5 pm, 19*250 mm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: Acetonitrile; Flow Rate: 25 mL / min; Gradient: 8% B to 20% B in 7 minutes; Wavelength: 254 nm / 220 nm nm; RT1(min): 6.67

[0352] LCMS (ESI): [M+H] + = 551.2

[0353] 1 H NMR (400 MHz, Methanol-d4) δ 7.49 - 7.43 (m, 1H), 7.37 - 7.30 (m, 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.24 - 7.20 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 9.4 Hz, 2H), 4.08 (s, 2H), 3.47 - 3.31 (m, 4H), 3.23 - 3.13 (m, 2H), 2.95 - 2.82 (m, 4H), 2.78 - 2.67 (m, 2H), 2.49 - 2.36 (m, 4H), 2.28 - 2.20 (m, 1H), 2.12 - 2.03 (m, 1H), 1.74 - 1.62 (m, 2H).

[0354] Example 13

[0355] Reaction Scheme:

[0356] Experimental Procedures:

[0357] Step 1.

[0358] A solution of 1 -aminocyclopropane-1 -carboxylic acid methyl ester (142 mg, 1.2 mmol, 1.2 equiv), N,N'-carbonyldiimidazole (310 mg, 3.0 mmol, 3.0 equiv.) and (R)-3-((S)-3-(3- aminophenyl)-1 -(tert-butoxy)-1 -oxopropan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (400 mg, 1.0 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was stirred at 50 °C under nitrogen overnight. The resulting residue was concentrated under reduced pressure and purified on a silica gel column, dichloromethane / methanol (10:1) to give (R)-3-((S)-1 -(tert-butoxy)-3-(3-(3-(1 -(methoxycarbonyl)cyclopropyl)ureido)phenyl)-1 - oxopropan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (150 mg, 24.79%).

[0359] LCMS (ESI): [M+H] + = 532.35

[0360] Step 2.

[0361] A solution of (R)-3-((S)-1 -(tert-butoxy)-3-(3-(3-(1 -(methoxycarbonyl)cyclopropyl)ureido)phenyl)-1 - oxopropan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (250 mg, 0.47 mmol, 1.0 equiv.) in ammonia in methanol (5 mL) was stirred at room temperature for 2 hours. The resulting residue was concentrated under reduced pressure and the resulting residue was purified on a silica gel column, dichloromethane / methanol (12:1) to give (R)-3-((S)-1 -(tert-butoxy)-3-(3-(5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)phenyl)-1 - oxopropan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (150 mg).

[0362] LCMS (ESI): [M+H] + = 500.30

[0363] Step 3.

[0364] A solution of (R)-3-((S)-1-(tert-butoxy)-3-(3-(5,7-dioxo-4,6- diazaspiro[2.4]heptan-6-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1 -carboxylate (100 mg, 0.2 mmol, 1.0 equiv.), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1 -carboxylate (109 mg, 0.24 mmol, 1.2 equiv.), cuprous iodide (19 mg, 0.1 mmol, 0.5 equiv.) and potassium phosphate (127 mg, 0.6 mmol, 3 equiv.) in toluene (10 mL) was stirred at 130 °C under nitrogen overnight. The resulting residue was concentrated under reduced pressure and purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 70% to 100% gradient over 20 minutes, UV 254 nm detector to give 3,3'-((2S,2'S)-((5,7-dioxo-4,6-diazaspiro[2.4]heptane-4,6-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1 - carboxylate) di-tert-butyl ester (100 mg, 57.22%).

[0365] LCMS (ESI): [M+H] + = 873.50

[0366] Step 4.

[0367] A solution of (2S,2'S)-3,3'-((5,7-dioxo-4,6-diazaspiro[2.4]heptane-4,6-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl) di-tert-butyl hydrogen chloride in 1,4 dioxane (5 mL, 4 M) was stirred at room temperature under nitrogen for 1 h. The resulting residue was concentrated under reduced pressure and the crude product was purified by high performance liquid chromatography to give (2S,2'S)-3,3'-((5,7-dioxo-4,6-diazaspiro[2.4]heptane-4,6-diyl)bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (13.80 mg, 21.13%) under the following conditions (column: XBridge BEH C18 5 μm, 30*150 mm; mobile phase A: Water (10 mmol / L NH4HCO3+0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 5% B to 15% B in 7 min; wavelength: 254 nm / 220 nm nm; RT1(min): 6.68)

[0368] LCMS (ESI): [M+H] + = 561.35

[0369] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.44 - 7.40 (m, 2H), 7.33 - 7.30 (m, J = 7.8, 2H), 7.27 - 7.20 (m, 2H), 7.19 - 7.12 (m, 2H), 3.46 - 3.42 (m, 4H), 3.36 - 3.32 (m, 2H), 3.19 - 3.15 (m, 2H), 2.87 - 2.75 (m, 4H), 2.51 - 2.32 (m, 4H), 2.06 (s, 2H), 1.70 - 1.66 (m, 2H), 1.55 - 1.43 (m, 2H), 1.41 - 1.26 (m, 2H).

[0370] Example 14

[0371] Reaction Scheme:

[0372] Experimental Procedures:

[0373] Step 1.

[0374] In a single necked flask was added (3R)-3-(1-(8-bromochroman-4-yl)-2-(tert- butoxy)-2-oxoethyl)pyrrolidine-1-carboxylate (1.1 g, 2.2 mmol, 1 eq), benzophenone imine (402 mg, 2.2 mmol, 1 eq), 1,4-dioxane (30 mL), cesium carbonate (2.2 g, 6.6 mmol, 3 eq), Pd2(dba)3 (203 mg, 0.2 mmol, 0.1 eq) and XantPhos (256 mg, 0.4 mmol, 0.2 eq) under nitrogen at 100 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. This resulted in crude (3R)-3-(2-(tert-butoxy)-1-(8-((diphenylmethylene)amino)chroman-4-yl)-2- oxoethyl)pyrrolidine-1-carboxylate (1.5 g, crude).

[0375] LCMS (ESI, m / z): [M+H] + = 597.3

[0376] Step 2.

[0377] In a single necked flask was added crude (3R)-3-(2-(tert-butoxy)-1-(8-((diphenylmethylene)amino)chroman-4-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (1.5 g, 2.5 mmol, 1 eq), saturated aqueous citric acid solution (15 mL) and tetrahydrofuran (15 mL) at room temperature overnight. The resulting mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was performed on a reverse phase column eluting with H2O / ACN (1 / 2) to give (3R)-3-(1-(8-aminochroman-4-yl)-2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1-carboxylate (700 mg, 64.3%).

[0378] LCMS (ESI, m / z): [M+H] + = 433.3

[0379] Step 3.

[0380] In a single necked flask, (3R)-3-(1-(8-aminochroman-4-yl)-2-(tert-butoxy)-2- oxoethyl)pyrrolidine-1 -carboxylate (300 mg, 0.7 mmol, 1 eq), (R)-3-((S)-3-(3- aminophenyl)-1 -(tert-butoxy)-1 -oxopropan-2-yl)pyrrolidine-1 -carboxylate (271 g, 0.7 mmol, 1 eq), N,N'-carbonyldiimidazole (112 g, 0.7 mmol, 1 eq) and tetrahydrofuran (6 mL) were added successively and the reaction was left at room temperature overnight. The resulting mixture was extracted with ethyl acetate (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 4) to give (3R)-3-(2-(tert-butoxy)-1-(8-(3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido)chroman-4-yl)-2- oxoethyl)pyrrolidine-1 -carboxylate (110 mg, 18.6%).

[0381] LCMS (ESI, m / z): [M+H]+ = 537.3 + = 849.5

[0382] Step 4.

[0383] In a single necked flask, (3R)-3-(2-(tert-butoxy)-1-(8-(3-(3-((S)-3-(tert-butoxy)-2- ((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido)chroman-4- yl)-2-oxoethyl)pyrrolidine-1 -carboxylate (110 mg, 0.1 mmol, 1.0 eq) and HC1 in 1,4-dioxane (3 mL) were added successively and the reaction was left at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 7% B to 17% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1 (min): 8.88) to give (S)-3-(3-(3-((R)-4-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)chroman-8-yl)ureido)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (39.57 mg, yield 47.92%).

[0384] LC-MS (ESI): [M+H]+ = 537.3

[0385] 1 H NMR (400 MHz, Deuterium Oxide) d 7.46 - 7.34 (m, 1H), 7.25 - 7.16 (m, 1H), 7.16 - 7.06 (m, 2H), 7.06 - 6.95 (m, 1H), 6.96 - 6.89 (m, 1H), 6.89 - 6.78 (m, 1H), 4.34 - 4.17 (m, 1H), 4.10 (d, J = 8.4 Hz, 1H), 3.41 - 3.28 (m, 2H), 3.27 - 3.07 (m, 3H), 3.07 - 2.93 (m, 2H), 2.92 - 2.80 (m, 1H), 2.79 - 2.60 (m, 3H),

[0386] Example 15

[0387] Reaction Scheme and Experimental Procedures:

[0388] In a single-necked flask, (3R)-3-(2-(tert-butoxy)-l-(8-(3-(3-((S)-3-(tert- butoxy)-2-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido) chroman-4-yl)-2-oxoethyl)pyrrolidine-l-carboxylate (110 mg, 0.1 mmol, 1.0 eq) and HCl in 1,4-dioxane (3 mL) were added successively, and the reaction was allowed to proceed at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 7% B to 17% B in 10 minutes; wavelength: 254 nm / 220 nm nm; RT1(min): 10.37) to give (S)-3-(3-(3-((S)-4-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)chroman-8-yl)ureido)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (29.51 mg, yield 30.82%).

[0389] LC-MS (ESI): [M+H]+= 537.3

[0390] 1H NMR (400 MHz, Deuterium Oxide) δ 7.48 - 6.78 (m, 7H), 4.35 - 4.21 (m, 1H), 4.21 - 4.03 (m, 1H), 3.49 - 2.96 (m, 8H), 2.97 - 2.78 (m, 1H), 2.78 - 2.58 (m, 3H), 2.59 - 2.41 (m, 2H), 2.41 - 2.33 (m, 1H), 2.22 - 1.88 (m, 4H), 1.80 - 1.59 (m, 1H), 1.57 - 1.21 (m, 1H).

[0391] Example 16

[0392] Reaction Scheme:

[0393] Experimental Procedure:

[0394] Step 1.

[0395] At room temperature, add tert-butyl (3R)-3-[(1S)-1-[(1S)-5-bromo-1,2,3,4- tetrahydronaphthalen-1-yl]-2-(tert-butyl)-2-oxoethyl]pyrrolidine-1-carboxylate (1.5 g, 3.0 mmol, 1.0 eq), benzophenone imine (0.8 g, 4.6 mmol, 1.5 eq), tris(dibenzylideneacetone)dipalladium (0.3 g, 0.3 mmol, 0.1 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.4 g, 0.6 mmol, 0.2 eq), cesium carbonate (3.0 g, 9.1 mmol, 3.0 eq), 1,4-dioxane (90 mL). After replacing nitrogen, warm to 100 °C and stir overnight. After the reaction is completed, cool to room temperature, and extract the reaction mixture with ethyl acetate (3*100 mL). Combine the organic phases and dry over sodium sulfate. Filter the resulting mixture and concentrate the filtrate under reduced pressure. Obtain tert-butyl (3R)-3-[2-(tert-butyl)-1-{5-[(diphenylmethylene)amino]-1,2,3,4- tetrahydronaphthalen-1-yl}-2-oxoethyl]pyrrolidine-1-carboxylate (1.6 g, 88.52%) as a crude product.

[0396] Step 2.

[0397] To a solution of tert-butyl (3R)-3-[2-(tert-butyl)-1-{5-[(diphenylmethylene)amino]-1,2,3,4- tetrahydronaphthalen-1-yl}-2-oxoethyl]pyrrolidine-1-carboxylate (1.6 g, 2.6 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added saturated citric acid solution (20 mL) at room temperature. Stirred at room temperature for 6 h. After completion of the reaction, pH was adjusted to neutral by adding saturated sodium bicarbonate solution. Extracted with ethyl acetate (3*100 mL). Dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, 70% to 90% gradient in 20 min, UV 254 nm detector. Obtained tert-butyl (3R)-3-[1-(5-amino-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)-2- oxoethyl]pyrrolidine-1-carboxylate (0.9 g, 77.70%).

[0398] Step 3.

[0399] To a solution of tert-butyl (3R)-3-[(2S)-3-(3-aminophenyl)-1-(tert-butyl)-1-oxopropan-2-yl]pyrrolidine-1- carboxylate (272 mg, 0.7 mmol, 1.0 eq), tert-butyl (3R)-3-[1-(5-amino-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(tert-butyl)-2- oxoethyl]pyrrolidine-1-carboxylate (300 mg, 0.7 mmol, 1.0 eq), N,N'-carbonyldiimidazole (113 mg, 0.7 mmol, 1.0 eq) in tetrahydrofuran (20 mL) was added at room temperature. Stirred at room temperature overnight. After completion of the reaction, concentrated under reduced pressure. The residue obtained was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, 85% to 95% gradient in 20 min, UV 254 nm detector. Obtained tert-butyl (3R)-3-[(2S)-1-(tert-butyl)-3-{3-[({5-[2-(tert-butyl)-1-[(3R)-1-(tert-butyl)-pyrrolidin-3-yl]-2-oxoethyl]-5,6,7,8- tetrahydronaphthalen-1-yl}carbamoyl)amino]phenyl}-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (300 mg, 50.83%).

[0400] Step 4.

[0401] To a solution of tert-butyl (3R)-3-[(2S)-1-(tert-butyl)-3-{3-[({5-[2-(tert-butyl)-1-[(3R)-1-(tert-butyl)-pyrrolidin-3-yl]-2-oxoethyl]-5,6,7,8-tetrahydronaphthalen-1-yl}carbamoyl)amino]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (300 mg, 0.4 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane) (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered to give the crude product. The crude product was purified by preparative purification with the following conditions: Column: xselect CSH C185 m, 19 mm*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 4% B to 17% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 8.57, to give (2S)-3-[3-({(5S)-5-[(R)-carboxy((3R)-pyrrolidin-3-yl)methyl]-5,6,7,8-tetrahydronaphthalen-1-yl}amino)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid (31.80 mg, yield 16.44%).

[0402] LC-MS (ESI): [M+H] + = 535.3

[0403] 1 H NMR (400 MHz, D2O) δ 7.25-7.06 (m, 6H), 6.93 (d, J = 7.6 Hz, 1H), 3.42 (t, J = 9.4 Hz, 2H), 3.36-3.27 (m, 1H), 3.26-3.10 (m, 3H), 3.09-2.95 (m, 2H), 2.91-2.83 (m, 1H), 2.77-2.67 (m, 3H), 2.63-2.48 (m, 3H), 2.43-2.31 (m, 2H), 2.11-1.96 (m, 1H), 1.89-1.51 (m, 6H), 1.24-1.08 (m, 1H).

[0404] Example 17

[0405] Reaction Scheme and Experimental Procedures:

[0406] To a solution of tert-butyl (3R)-3-[(2S)-1-(tert-butyl)-3-{3-[({5-[2-(tert-butyl)-1-[(3R)-1-(tert-butyl)-pyrrolidin-3-yl]-2-oxoethyl]-5,6,7,8-tetrahydronaphthalen-1-yl}carbamoyl)amino]phenyl}-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (300 mg, 0.4 mmol, 1.0 equiv) in 1,4-dioxane (10 mL) was added hydrogen chloride (4.0 M in 1,4-dioxane) (10 mL) at room temperature. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered to give the crude product. The crude product was purified by preparative purification with the following conditions: Column: xselect CSH C185 m, 19 mm*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 4% B to 17% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 9.65, to give (2S)-3-[3-({(5S)-5-[(R)-carboxy((3R)-pyrrolidin-3-yl)methyl]-5,6,7,8-tetrahydronaphthalen-1-yl}amino)phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid (10.36 mg, 5.43% yield).

[0407] LC-MS (ESI): [M+H] + = 535.3

[0408] 1 H NMR (400 MHz, D2O) δ 7.26-7.06 (m, 6H), 6.94 (d, J = 7.6 Hz, 1H), 3.45-3.37 (m, 2H), 3.35-3.22 (m, 2H), 3.19-2.96 (m, 4H), 2.91-2.83 (m, 1H), 2.76-2.66 (m, 2H), 2.65-2.53 (m, 3H), 2.48-2.29 (m, 3H), 2.09-1.98 (m, 1H), 1.97-1.85 (m, 1H), 1.86-1.76 (m, 2H), 1.76-1.69 (m, 1H), 1.69-1.52 (m, 2H), 1.50-1.33 (m, 1H).

[0409] Example 18

[0410] Reaction Scheme:

[0411] Experimental Procedures:

[0412] Step 1.

[0413] Under nitrogen protection, at 0°C, lithium bis(trimethylsilylamino)carboxylate tert-butyl ester (5 g, 17.5 mmol, 1.0 equivalent) in tetrahydrofuran (100 mL) was added to a solution of (3R)-3-[2-(tert-butoxy)-2-oxoethyl]pyrrolidine-1-carboxylate (1.0 M tetrahydrofuran) (3.2 mL, 19.3 mmol, 1.1 equivalent). After stirring for 30 min, 1,4-dibromo-2,3-dihydro-1H-indene (5.8 g, 21.0 mmol, 1.2 equivalent) was added to the solution at 0°C. Under nitrogen protection, the residue was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride aqueous solution at 0°C. The reaction mixture was extracted with ethyl acetate. The combined organic phases were backwashed with saturated brine and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography under the following conditions: 330 g C18 column, mobile phase: water and acetonitrile, gradient from 95% to 100% for 10 min, UV 254 nanometer detector, yielding (3R)-3-(1-(4-bromo-2,3-dihydro-1H-inden-1-yl)-2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (3.5 g).

[0414] LC-MS(ESI):[M+H] + =480.2

[0415] Step 2.

[0416] Under nitrogen protection and at room temperature, tert-butyl pyrrolidine-1-carboxylate (500 mg, 1.0 mmol, 1.0 equivalent) and benzophenone imine (245.2 mg, 1.4 mmol, 1.3 equivalent) in a 1,4-dioxane (20 mL) solution were added, along with cesium carbonate (1017.3 mg, 3.1 mmol, 3.0 equivalent), tris(dibenzylacetone)dipalladium(0) (95.3 mg, 0.1 mmol, 0.1 equivalent), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (60.2 mg, 0.1 mmol, 0.1 equivalent). The mixture was stirred for 2 hours under nitrogen protection and at 120°C. The filter cake was washed with acetonitrile, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reversed-phase column chromatography under the following conditions: column specifications, mobile phase, water and acetonitrile, 70% to 80% gradient for 10 minutes, UV 254 nanometer detector, yielding (3R)-3-[2-(tert-butoxy)-1-{4-[(diphenylmethylene)amino]-2,3-dihydro-1H-inden-1-yl}-2-oxoethyl]pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg).

[0417] LC-MS (ESI): [M+H] + = 581.3

[0418] Step 3.

[0419] A solution of (3R)-3-[2-(tert-butoxy)-l-{4-[(diphenylmethylene)amino]-2,3- dihydro-lH-inden-l-yl}-2-oxoethyl]pyrrolidine-l-carboxylic acid tert-butyl ester (700 mg, 1.2 mmol, 1.0 equiv) in saturated aqueous citric acid (7 mL) and tetrahydrofuran (7 mL) was stirred at room temperature for 2 hours. The reaction mixture was basified with saturated aqueous sodium bicarbonate solution to pH = 8. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, backwashed with saturated aqueous brine, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 50% to 60% gradient over 10 minutes, UV 254 nm detector to give (3R)-3-(l-(4-amino-2,3-dihydro-lH-inden-l-yl)-2-(tert-butoxy)-2- oxoethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (350 mg).

[0420] LC-MS (ESI): [M+H] + = 417.3

[0421] Step 4.

[0422] To a solution of tert-butyl (3R)-3-(l-(4-amino-2,3-dihydro-lH-inden-l-yl)-2-(tert- butoxy)-2-oxoethyl)piperidine-l-carboxylate (130 mg, 0.3 mmol, 1.0 equiv) in tetrahydrofuran (8 mL) was added l-[(lH-imidazol-l-yl)carbonyl]-lH-imidazole (50.6 mg, 0.3 mmol, 1.0 equiv) under nitrogen at room temperature. After stirring for 0.5 h, tert-butyl (3R)-3-[(2S)-3-(3-aminophenyl)-l-(tert-butoxy)-l- oxopropan-2-yl]piperidine-l-carboxylate (121.9 mg, 0.3 mmol, 1.0 equiv) was added under nitrogen at room temperature. The resulting residue was stirred overnight at room temperature under nitrogen. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: column dimensions, mobile phase, water and acetonitrile, 65% to 80% gradient over 10 min, UV 254 nm detector to give tert-butyl (3R)-3-(2-(tert-butoxy)-l-(4-(3-(3-((S)-3-(tert-butoxy)-2-((R)-l-(tert- butoxycarbonyl)piperidin-3-yl)-3-oxopropyl)phenyl)ureido)-2,3-dihydro-lH-inden-l-yl)-2- oxoethyl)piperidine-l-carboxylate (80 mg).

[0423] LC-MS (ESI): [M+H] + = 833.5

[0424] Step 5.

[0425] A solution of (3R)-3-(2-(tert-butoxy)-l-(4-(3-(3-((S)-3-(tert-butoxy)-2-((R)-l-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido)-2,3-dihydro-lH-inden-l- yl)-2-oxoethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (120 mg, 0.1 mmol, 1.0 equiv) in hydrogen chloride (4.0 M in 1,4-dioxane) (2 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (S)-3-(3-((S)-l-((S)-carboxy((R)-pyrrolidin-3-yl)methyl)-2,3-dihydro-lH-inden-4- yl)ureido)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (5.02 mg, 99.5% purity) with the following conditions (Column: Xbridge BEH Shield RP18, 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 8% B to 15% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 7.35)

[0426] LC-MS (ESI): [M+H] + = 521.3

[0427] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.50 - 7.03 (m, 6H), 6.98 - 6.88 (m, 1H), 3.52 - 3.36 (m, 2H), 3.36 - 3.22 (m, 2H), 3.19 - 2.99 (m, 3H), 2.95 - 2.75 (m, 2H), 2.75 - 2.64 (m, 3H), 2.64 - 2.53 (m, 1H), 2.53 - 2.43 (m, 2H), 2.43 - 2.32 (m, 2H), 2.29 - 1.97 (m, 3H), 1.98 - 1.84 (m, 1H), 1.80 - 1.57 (m, 2H).

[0428] Example 19

[0429] Reaction Scheme and Experimental Procedures

[0430] A solution of (3R)-3-(2-(tert-butoxy)-l-(4-(3-(3-((S)-3-(tert-butoxy)-2-((R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido)-2,3-dihydro-lH-inden-l- yl)-2-oxoethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (120 mg, 0.1 mmol, 1.0 equiv) in hydrogen chloride (4.0 M in 1,4-dioxane) (2 mL) was stirred at room temperature for 2 h. The crude product was purified by high performance liquid to give (S)-3-(3-((S)-l-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)-2,3-dihydro-lH-inden-4- yl)ureido)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (10.30 mg, 99.7% purity) with the following conditions (Column: Xbridge BEH Shield RP18, 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 8% B to 15% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 8.15)

[0431] LC-MS (ESI): [M+H] + = 521.3

[0432] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.45 - 7.01 (m, 6H), 6.99 - 6.92 (m, 1H), 3.50 - 3.22 (m, 5H), 3.22 - 3.02 (m, 3H), 2.97 - 2.78 (m, 2H), 2.78 - 2.64 (m, 3H), 2.65 - 2.52 (m, 1H), 2.53 - 2.45 (m, 1H), 2.40 (s, 2H), 2.19 (s, 1H), 2.10 - 1.85 (m, 3H), 1.75 - 1.58 (m, 1H), 1.56 - 1.41 (m, 1H).

[0433] Example 20

[0434] Reaction Scheme and Experimental Procedures:

[0435] A solution of (3R)-3-(2-(tert-butoxy)-l-(4-(3-(3-((S)-3-(tert-butoxy)-2-((R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)ureido)-2,3-dihydro-lH-inden-l- yl)-2-oxoethyl)pyrrolidine-l-carboxylic acid tert-butyl ester (120 mg, 0.1 mmol, 1.0 equiv) in hydrogen chloride (4.0 M in 1,4-dioxane) (2 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (S)-3-(3-(((E)-(((S)-l-((S)-carboxy((R)-pyrrolidin-3-yl)methyl)-2,3-dihydro-lH-inden-4- yl)amino)(hydroxy)methylene)amino)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (6.38 mg, 99.4% purity) with the following conditions (Column: Xbridge BEH Shield RP18, 5 pm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 8% B to 15% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 10.02)

[0436] LC-MS (ESI): [M+H] + = 521.3

[0437] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.26 - 7.05 (m, 6H), 6.97 - 6.90 (m, 1H), 3.46 - 3.26 (m, 5H), 3.22 - 3.08 (m, 2H), 3.07 - 2.99 (m, 1H), 2.93 - 2.76 (m, 2H), 2.76 - 2.61 (m, 3H), 2.62 - 2.49 (m, 2H), 2.46 - 2.33 (m, 2H), 2.18 - 1.99 (m, 4H), 1.71 - 1.56 (m, 2H).

[0438] Example 21

[0439] Scheme:

[0440] Experimental Procedures

[0441] Step 1.

[0442] A solution of 1 -aminocyclobutane-1 -carboxylic acid methyl ester (142 mg, 1.2 mmol, 1.2 equiv.), 1 -[(1 H-imidazol-1 -yl)carbothioyl]-1 H-imidazole (310 mg, 3.0 mmol, 3.0 equiv.) and (R)-3-((S)-3-(3-aminophenyl)-1 -(tert-butoxy)-1 -oxopropan-2- yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (400 mg, 1.0 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was stirred at 50 °C under nitrogen overnight. The resulting residue was concentrated under reduced pressure and purified on a silica gel column with dichloromethane / methanol (10:1) to give (R)-3-((S)-1 -(tert-butoxy)-1 -oxo-3-(3-(8-oxo-6- thioketo-5,7-diazaspiro[3.4]octane-7-yl)phenyl)propan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (100 mg, 24.79%).

[0443] LCMS (ESI): [M+H] + = 530.10

[0444] Step 2.

[0445] A solution of (R)-3-((S)-1 -(tert-butoxy)-1 -oxo-3-(3-(8-oxo-6-thioketo-5,7- diazaspiro[3.4]octane-7-yl)phenyl)propan-2-yl)pyrrolidine-1 -carboxylic acid tert- butyl ester (100 mg, 0.2 mmol, 1.0 equiv.), (R)-3-((S)-3-(3-bromophenyl)-1 -(tert- butoxy)-1 -oxopropan-2-yl)pyrrolidine-1 -carboxylic acid tert-butyl ester (109 mg, 0.24 mmol, 1.2 equiv.), Ephos (10 mg, 0.1 mmol, 0.5 equiv.), Ephos Pd G4 (17 mg, 0.1 mmol, 0.5 equiv.) and cesium carbonate (127 mg, 0.6 mmol, 3 equiv.) in 1,4-dioxane (10 mL) was stirred at 90 °C under nitrogen overnight. The resulting residue was concentrated under reduced pressure to give 3,3'-((2S,2'S)-((8-oxo-6-thioketo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1 - carboxylate) di-tert-butyl ester (120 mg, crude).

[0446] LCMS (ESI): [M+H] + = 903.25

[0447] Step 3.

[0448] A solution of 3,3'-((2S,2'S)-((8-oxo-6-thioxo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (120 mg, crude) in 1,4 dioxane (5 mL) of hydrochloric acid was stirred at room temperature for 1 hour under nitrogen. The resulting residue was concentrated under reduced pressure and the crude was purified by high performance liquid chromatography to give (2S,2'S)-3,3'-((8-oxo-6-thioxo-5,7-diazaspiro[3.4]octane-5,7-diyl)bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (9.68 mg, 8.13%) under the following conditions (Chromatography column: YMC Triart C18 ExRs5 m, 20mm X 250mm; Mobile Phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 8.68)

[0449] LCMS (ESI): [M+H] + = 561.35

[0450] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.48 - 6.87 (m, 8H), 3.50 - 3.25 (m, 4H), 3.22 - 3.08 (m, 2H), 2.98 - 2.63 (m, 6H), 2.59 - 2.26 (m, 8H), 2.12 - 1.90 (m, 4H), 1.76 - 1.51 (m, 2H).

[0451] Example 22

[0452] Reaction Scheme:

[0453] Experimental Procedures:

[0454] Step 1.

[0455] To a solution of 5-bromo-l-tetralone (5.0 g, 22.2 mmol, 1.0 eq) in methanol (100 mL) was added sodium borohydride (2.5 g, 66.6 mmol, 3.0 eq) slowly at 0 °C. The temperature was allowed to warm to room temperature. The stirring was continued at room temperature for 2 h. After completion of the reaction, saturated ammonium chloride solution (50 mL) was added to quench. The aqueous phase was extracted with dichloromethane (3*50 mL). The residue obtained was concentrated under reduced pressure. This resulted in crude 5-bromo-l-tetralanol (5.0 g, 99.11 %).

[0456] LC-MS (ESI): [M-H] - = 225.0

[0457] Step 2.

[0458] To a solution of 5-bromo-l-tetralanol (5.0 g, 22.0 mmol, 1.0 eq) in dichloromethane (100 mL) was added phosphorus tribromide (17.9 g, 66.1 mmol, 3.0 eq) slowly at 0 °C. The temperature was allowed to warm to room temperature. The stirring was continued at room temperature for 2 h. After completion of the reaction, water (100 mL) was added slowly at 0 °C to quench. Saturated sodium bicarbonate solution was added to adjust the pH to neutral. Dichloromethane (3*100 mL) was added to extract. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This resulted in crude l,5-dibromo-tetraline (5.0 g, 78.31 %).

[0459] Step 3.

[0460] To a solution of tert-butyl (3R)-3-[2-(tert-butyl)-2-oxoethyl]pyrrolidine-l-carboxylate (1.3 g, 4.5 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was added lithium bis(trimethylsilyl)amide (825 mg, 4.9 mmol, 1.1 eq) in tetrahydrofuran (5 mL) dropwise at 0 °C. After stirring for half an hour, l,5-dibromo-tetraline (1.3 g, 4.5 mmol, 1.0 eq) in tetrahydrofuran (5 mL) was added dropwise. The temperature was allowed to warm to room temperature. The stirring was continued overnight. After completion of the reaction, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at room temperature. The aqueous phase was extracted with ethyl acetate (3*100 mL). It was dried over anhydrous sodium sulfate. The residue obtained was concentrated under reduced pressure. The residue obtained was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, gradient 70 to 90 % in 20 minutes, UV 254 nm detector. This resulted in tert-butyl (3R)-3-[(lS)-l-[(lS)-5-bromo-l,2,3,4-tetrahydronaphthalen-l-yl]-2-(tert-butyl)-2- oxoethyl]pyrrolidine-l-carboxylate (1.5 g, 69.36 %).

[0461] LC-MS (ESI): [M+H]+ = 494.2

[0462] Step 4.

[0463] To a solution of tert-butyl (3R)-3-[(1S)-1-[(1S)-5-bromo-1,2,3,4-tetrahydronaphthalen-1-yl]-2-(tert-butyl)-2- oxoethyl]pyrrolidine-1-carboxylate (700 mg, 1.4 mmol, 1.0 eq) in toluene (35 mL) was added N,N'- dimethylethylenediamine (500 mg, 4.2 mmol, 3.0 eq), palladium acetate (30 mg, 0.1 mmol, 0.1 eq), n- butyldi(1-adamantyl)phosphine (100 mg, 0.3 mmol, 0.2 eq). The system was pressurized with CO:H2 = 1:1 (40 bar). The reaction was warmed to 105 °C. Stirred overnight. After the reaction was completed, it was cooled to room temperature, filtered, water (200 mL) was added, and the aqueous phase was extracted with ethyl acetate (3*100 mL). The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, 50% to 80% gradient in 20 minutes, UV 254 nm detector. tert-Butyl (3R)-3-[(1S)-2-(tert-butyl)-1-[(1S)-5-formyl-1,2,3,4-tetrahydronaphthalen-1-yl]-2- oxoethyl]pyrrolidine-1-carboxylate (300 mg, 47.77%) was obtained.

[0464] LC-MS (ESI): [M+H] + = 444.3

[0465] Step 5.

[0466] To a solution of tert-butyl (3R)-3-[(1S)-2-(tert-butyl)-1-[(1S)-5-formyl-1,2,3,4-tetrahydronaphthalen-1-yl]-2- oxoethyl]pyrrolidine-1-carboxylate (300 mg, 0.7 mmol, 1.0 eq) in methanol (20 mL) was added sodium borohydride (77 mg, 2.0 mmol, 3.0 eq) slowly at 0 °C. The reaction was warmed to room temperature. Stirred for 2 hours. After the reaction was completed, it was quenched by the addition of saturated ammonium chloride solution (20 mL). Extracted with ethyl acetate (3*40 mL). Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude tert-butyl (3R)-3-[(1S)-2-(tert-butyl)-1-[(1S)-5-(hydroxymethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-2- oxoethyl]pyrrolidine-1-carboxylate (290 mg, 96.23%).

[0467] LC-MS (ESI): [M+H]+ = 446.3

[0468] Step 6.

[0469] To a solution of tert-butyl (3R)-3-[(1S)-2-(tert-butyl)-1-[(1S)-5-(hydroxymethyl)-1,2,3,4- tetrahydronaphthalen-1-yl]-2-oxoethyl]pyrrolidine-1-carboxylate (290 mg, 0.6 mmol, 1.0 eq) in 1,2-dichloroethane (20 mL) was added 1,3-dimethylthiourea (34 mg, 0.3 mmol, 0.5 eq), N-bromosuccinimide (174 mg, 9.7 mmol, 1.5 eq). Stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (3*20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, 60% to 80% gradient for 15 minutes, UV 254 nm detector. tert-Butyl (3R)-3-[(1S)-1-[(1S)-5-(bromomethyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-2-(tert-butyl)-2- oxoethyl]pyrrolidine-1-carboxylate (160 mg, 48.42%) was obtained.

[0470] LC-MS (ESI): [M+H] + = 508.2

[0471] Step 7.

[0472] To a solution of tert-butyl (3R)-3-[(1S)-1-[(1S)-5-(bromomethyl)-1,2,3,4- tetrahydronaphthalen-1-yl]-2-(tert-butyl)-2-oxoethyl]pyrrolidine-1-carboxylate (100 mg, 0.2 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added tert-butyl (3R)-3-[(2S)-1-(tert-butyl)-3-(3-{({3-[(2S)-3-(tert-butyl)-3-(tert- butyl)-2-[(3R)-1-(tert-butyldimethylsilyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino] methyl}phenyl)-1-oxopropyl-2-yl]pyrrolidine-1-carboxylate (156 mg, 0.2 mmol, 1.0 equiv), cesium carbonate (192 mg, 0.6 mmol, 3.0 equiv). Stirred at room temperature for 2 hours. After the reaction was completed, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: mobile phase, water and acetonitrile, 80% to 100% gradient in 20 minutes, UV 254 nm detector. Obtained tert-butyl (2S)-3-{3-[({5S)-5-[(1S)-2-(tert-butyl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]ethyl]-5,6,7,8- tetrahydronaphthalen-1-yl}methyl}({3-[(2S)-3-(tert-butyl)-3-oxo-2-[(3R)-pyrrolidin-3- yl]propyl]phenyl}-2-[(3R)-pyrrolidin-3-yl]propyl)amino)methyl]phenyl}-2-[(3R)- pyrrolidin-3-yl]propanoate (85 mg, 47.02%).

[0473] LC-MS (ESI): [M+H] + = 1219.8

[0474] Step 8.

[0475] tert-butyl (2S)-3-{3-[({5S)-5-[(1S)-2-(tert-butyl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]ethyl]-5,6,7,8- tetrahydronaphthalen-1-yl}methyl}({3-[(2S)-3-(tert-butyl)-3-oxo-2-[(3R)-pyrrolidin-3-yl]propyl]phenyl}- 2-[(3R)-pyrrolidin-3-yl]propyl)amino)methyl]phenyl}-2-[(3R)-pyrrolidin-3-yl]propanoate (86 mg, 0.1 mmol, 1.0 equiv) in HC1 in 1,4-dioxane (3 mL). Stir at room temperature for 2 hours. After the reaction is completed, filter to get the filter cake. Get the crude product (50 mg). The crude product is prepared by reverse phase column chromatography with the following method: Column: xselect CSH C18 5 m, 19 mm*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 15% B to 28% B in 9 min; Wavelength: 254 nm / 220 nm; RT1(min): 7.67, get (2S)-3-(3-{({(5S)-5-[(R)-carboxy((3R)-pyrrolidin-3-yl)methyl]-5,6,7,8-tetrahydronaphthalen-1-yl}methyl)({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (12.22 mg, yield 22.97%).

[0476] LC-MS (ESI): [M+H] + = 751.4

[0477] 1 H NMR (400 MHz, D20) d 7.33-7.02 (m, 11H), 3.70-3.45 (m, 4H), 3.42-3.29 (m, 6H), 3.28-3.21 (m, 1H), 3.20-3.07 (m, 3H), 2.91-2.31 (m, 16H), 2.09-1.96 (m, 3H), 1.83-1.53 (m, 5H), 1.50-1.28 (m, 2H), 1.01-0.76 (m, 1H).

[0478] Example 23

[0479] Reaction Scheme and Experimental Procedures:

[0480] tert-butyl (2S)-3-{3-[({5S)-5-[(1S)-2-(tert-butyl)-2-oxo-1-[(3R)-pyrrolidin-3-yl]ethyl]-5,6,7,8- tetrahydronaphthalen-1-yl}methyl}({3-[(2S)-3-(tert-butyl)-3-oxo-2-[(3R)-pyrrolidin-3- yl]propyl]phenyl}-2-[(3R)-pyrrolidin-3-yl]propyl)amino)methyl]phenyl}-2-[(3R)-pyrrolidin-3- yl]propanoate (86 mg, 0.1 mmol, 1.0 equiv) in HC1 in 1,4-dioxane (3 mL, 4 M). Stir at room temperature for 2 h. After the reaction was completed, filter to get the crude product (50 mg, yield 94.57%). The crude product was prepared by reverse phase column chromatography with the following method: Column: xselect CSH C18 5 m, 19 mm*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 28% B in 9 min; wavelength: 254 nm / 220 nm; RT1(min): 8.45, to get (2S)-3-(3-{({(5R)-5-[(R)-carboxy((3R)-pyrrolidin-3-yl)methyl]-5,6,7,8- tetrahydronaphthalen-1-yl}methyl)({3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl}methyl)amino]methyl}phenyl)-2-[(3R)-pyrrolidin-3-yl]propanoic acid (3.01 mg, yield 5.89%).

[0481] LC-MS (ESI): [M+H] + = 751.4

[0482] 1 H NMR (400 MHz, D20) d 7.29 - 7.05 (m, 11H), 3.76 - 3.45 (m, 6H), 3.42 - 3.27 (m, 5H), 3.21 - 3.08 (m, 2H), 3.06 - 2.89 (m, 3H), 2.86 - 2.64 (m, 6H), 2.59 - 2.30 (m, 8H), 2.12 - 1.97 (m, 2H), 1.93 - 1.72 (m, 2H), 1.72 - 1.38 (m, 5H), 1.27 - 1.12 (m, 1H).

[0483] Example 24

[0484] Scheme:

[0485] Experimental procedure:

[0486] Step 1.

[0487] In a single-necked flask, (2S,4R)-1-[(benzyloxy)carbonyl]-4-hydroxypyrrolidine-2- carboxylic acid (3.5 g, 13.2 mmol, 3 eq), (3R)-3-[(2S)-3-(3-bromophenyl)-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (2.0 g, 4.4 mmol, 1 eq), DMA (40 mL), 1,2-dimethoxyethane-nickel dichloride (97 mg, 0.4 mmol, 0.1 eq), 4-tert-butyl-2-(4-tert- butylpyridin-2-yl)pyridine (177 mg, 0.6 mmol, 0.15 eq), 4,4'-di-tert-butyl-2,2'-bipyridine) bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (40 mg, 0.04 mmol, 0.01 eq), DBU (2 g, 13.2 mmol, 3 eq) were added under nitrogen atmosphere and the reaction was carried out in a photoreactor at a wavelength of 450 nm for 2 h. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) and the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was carried out by reverse phase column chromatography eluting with H2O / ACN (1 / 2) to obtain (4R)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl)phenyl)-4-hydroxypyrrolidine-1-carboxylate benzyl ester (450 mg, 17.2%).

[0488] LCMS (ESI, m / z): [M+H] + = 595.3

[0489] Step 2.

[0490] To a single-necked flask at room temperature was added (4R)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4- hydroxypyrrolidine-1 -carboxylate (450 mg, 0.8 mmol, 1 equiv), triethylamine (230 mg, 2.3 mmol, 3 equiv), DCM (10 mL), DMAP (9 mg, 0.08 mmol, 0.1 equiv) sequentially, to the resulting mixture was added p-toluenesulfonyl chloride (188 mg, 1.0 mmol, 1.3 equiv) at 0 °C, and the reaction was allowed to proceed at room temperature overnight. The resulting mixture was extracted with dichloromethane (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 3) to give (4R)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-(p-toluenesulfonyloxy)pyrrolidine- 1 -carboxylate (250 mg, 44.1 %).

[0491] LCMS (ESI, m / z): [M+H] + = 749.3

[0492] Step 3.

[0493] To a single-necked flask at room temperature was added (4R)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4- hydroxypyrrolidine-1 -carboxylate (450 mg, 0.8 mmol, 1 equiv), triethylamine (230 mg, 2.3 mmol, 3 equiv), DCM (10 mL), DMAP (9 mg, 0.08 mmol, 0.1 equiv) sequentially, to the resulting mixture was added p-toluenesulfonyl chloride (188 mg, 1.0 mmol, 1.3 equiv) at 0 °C, and the reaction was allowed to proceed at room temperature overnight. The resulting mixture was extracted with dichloromethane (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 3) to give (4R)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-(p-toluenesulfonyloxy)pyrrolidine- 1 -carboxylate (250 mg, 44.1 %).

[0494] LCMS (ESI, m / z): [M+H] + = 968.6

[0495] Step 4.

[0496] In a single-necked flask, was added (4S)-4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenoxy)-2-(3-((S)-3-(tert-butoxy)-2- ((R)-1-(tert-butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidine-1- carboxylate benzyl ester (150 mg, 0.2 mmol, 1.0 eq), Pd / C (17 mg, 0.2 mmol, 1.0 eq), and MeOH (5 mL) successively, and the reaction was carried out under hydrogen atmosphere at room temperature for 4 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3S)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (90 mg, 69.7%).

[0497] LCMS (ESI, m / z): [M+H] + = 834.5

[0498] Step 5.

[0499] To a single-necked flask was added (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3S)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (90 mg, 0.1 mmol, 1.0 equiv), (R)-3-((S)-1-(tert-butoxy)-3-(3-formylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (44 mg, 0.1 mmol, 1.0 equiv) and AcOH (5 mL) at room temperature. To the resulting mixture was added sodium triacetoxyborohydride (46 mg, 0.2 mmol, 2.0 equiv) at 0 °C. The reaction was stirred at room temperature overnight. The resulting mixture was extracted with dichloromethane (3 x 30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)pyrrolidin-3-yl)tert-butyl 3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (70 mg) was obtained.

[0500] LCMS (ESI, m / z): [M+H] + = 1221.8

[0501] Step 6.

[0502] In a single-necked flask, crude product (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)pyrrolidin-3-yl)tert- butyl 3-(tert-butoxy)-2-((R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin- 3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (70 mg, 0.1 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) was added at room temperature and the reaction was allowed to proceed for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 25% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.05) to give (S)-3-(3-((2S,4S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-(3-((S)-2- carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (7.46 mg, 13.02% yield).

[0503] LC-MS (ESI): [M+H]+= 753.4

[0504] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.28 (d, J = 9.4 Hz, 2H), 7.21 - 7.14 (m, 3H), 7.12 - 6.95 (m, 3H), 6.88 - 6.68 (m, 3H), 4.90 (s, 1H), 4.39 (s, 2H), 3.69 - 3.65 (m, 1H), 3.48 (t, J = 8.5 Hz, 1H), 3.34 - 3.28 (m, 6H), 3.16 - 3.10 (m, 4H), 3.05 - 2.76 (m, 5H), 2.74 - 2.68 (m, 6H), 2.39 - 2.31 (m, 6H), 2.10 - 2.03 (m, 3H), 1.88 - 1.82 (m, 1H), 1.69 - 1.62 (m, 3H).

[0505] Example 25

[0506] Reaction Scheme and Experimental Procedures:

[0507] To a single-neck flask was added crude product (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)pyrrolidin-3-yl)tert-butyl 3-(tert-butoxy)-2-((R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (70 mg, 0.1 mmol, 1.0 equiv) and HCl in 1,4-dioxane (5 mL) and allowed to react at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 25% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.7) to give (S)-3-(3-((2R,4S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (3.95 mg, 6.48% yield).

[0508] LC-MS (ESI): [M+H]+=753.4

[0509] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.32 - 7.27 (m, 3H), 7.22 - 7.15 (m, 3H), 7.11 - 6.97 (m, 3H), 6.86 - 6.70 (m, 3H), 4.92 (s, 1H), 3.71 - 3.65 (m, 1H), 3.49 (s, 1H), 3.48 - 3.21 (m, 7H), 3.21 - 3.04 (m, 4H), 3.02 - 2.51 (m, 11H), 2.38 (d, J=9.7 Hz, 6H), 2.18 (s, 1H), 2.05 (s, 2H), 1.87 (s, 1H), 1.76 - 1.57 (m, 3H).

[0510] Example 26

[0511] Reaction Scheme:

[0512] Experimental Procedure:

[0513] Step 1.

[0514] To a solution of 8-bromo-2,3-dihydro-l-benzopyran-4-one (5.0 g, 22.0 mmol, 1 eq) in methanol (100 mL) was added sodium borohydride (1.7 g, 44.0 mmol, 2 eq) at 0 °C and the resulting mixture was stirred for 1 h. After completion of the reaction, it was quenched with water and the resulting mixture was extracted with dichloromethane (3 x 300 mL) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get 8-bromochroman-4-ol (5 g, 99.1 %).

[0515] LCMS (ESI, m / z): [M+H] + = 229.0

[0516] Step 2.

[0517] To a solution of 8-bromochroman-4-ol (5.0 g, 21.8 mmol, 1 eq) in dichloromethane (100 mL) was added phosphorus tribromide (11.8 g, 43.6 mmol, 2 eq) at 0 °C and the resulting mixture was stirred for 1 h. After completion of the reaction, it was quenched with water and then sodium bicarbonate was added and the resulting mixture was extracted with dichloromethane (3 x 300 mL) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get 4,8-dibromochroman (6 g, 94.1 %).

[0518] LCMS (ESI, m / z): [M+H] + = 290.9

[0519] Step 3.

[0520] To a solution of (R)-tert-butyl 3-(2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1- carboxylate (2.5 g, 8.7 mmol, 1.0 eq) in tetrahydrofuran (50 mL) was added LiHMDS-THF (9.6 mL, 9.6 mmol, 1.1 eq) at 0 °C, the resulting mixture was stirred for another 15 min before 4,8-dibromo-1-bromomethane (3.1 g, 10.5 mmol, 1.2 eq) was added, the reaction was continued at room temperature overnight. After the reaction was completed, it was quenched with ammonium chloride, the resulting mixture was extracted with ethyl acetate (3 x 200 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluted with H2O / ACN (1 / 3) to give (3R)-tert-butyl 3-(1-(8-bromochroman-4-yl)-2-(tert-butoxy)-2-oxoethyl)pyrrolidine-1-carboxylate (2.1 g, 48.3%).

[0521] LCMS (ESI, m / z): [M+H] + = 496.2

[0522] Step 4.

[0523] In a high-pressure kettle, (3R)-tert-butyl 3-(1-(8-bromochroman-4-yl)-2-(tert-butoxy)-2- oxoethyl)pyrrolidine-1-carboxylate (2.1 g, 4.3 mmol, 1.0 eq), (n-butyldi(1-adamantyl)phosphine (312 mg, 0.9 mmol, 0.2 eq), palladium acetate (98 mg, 0.4 mmol, 0.1 eq), N,N,N',N'-tetramethylethylenediamine (1.5 g, 13.1 mmol, 3 eq) and toluene (20 mL) were added in sequence, CO:H2=1:1 was introduced to 40 atm, and the reaction was continued at 105 °C for 48 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluted with H2O / ACN (1 / 2) to give (3R)-tert-butyl 3-(2-(tert-butoxy)-1-(8-formylchroman-4-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (800 mg, 41.2%).

[0524] LCMS (ESI, m / z): [M+H] + = 446.2

[0525] Step 5.

[0526] To a solution of tert-butyl (3R)-3-(2-(tert-butoxy)-l-(8-formylchroman-4-yl)-2- oxoehtyl)pyrrolidine-l-carboxylate (800 mg, 1.8 mmol, 1.0 eq) in methanol (10 mL) was added sodium borohydride (136 mg, 3.6 mmol, 2.0 eq) at 0 °C, the resulting mixture was stirred for 1 h. After the reaction was completed, quenched with water, the resulting mixture was extracted with dichloromethane (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure. To give tert-butyl (3R)-3-(2-(tert-butoxy)-l-(8-(hydroxymethyl)chroman-4-yl)-2- oxoehtyl)pyrrolidine-l-carboxylate (750 mg, 93.3%).

[0527] LCMS (ESI, m / z): [M+H] + = 448.3

[0528] Step 6.

[0529] To a solution of tert-butyl (3R)-3-(2-(tert-butoxy)-l-(8-(hydroxymethyl)chroman-4-yl)-2- oxoehtyl)pyrrolidine-l-carboxylate (750 mg, 1.7 mmol, 1.0 eq), N,N'-dimethylthiourea (87 mg, 0.8 mmol, 0.5 eq), N-bromosuccinimide (447 mg, 2.5 mmol, 1.5 eq) and 1,2-dichloroethane (10 mL) was added in a single-necked flask, the reaction was carried out at room temperature overnight. The resulting mixture was concentrated under reduced pressure. Purified by reverse phase column chromatography, eluted with H2O / ACN (1 / 2) to give tert-butyl (3R)-3-(l-(8-(bromomethyl)chroman-4-yl)-2-(tert-butoxy)-2- oxoehtyl)pyrrolidine-l-carboxylate (120 mg, 14.0%).

[0530] LCMS (ESI, m / z): [M+H] + = 510.2

[0531] Step 7.

[0532] To a single-necked flask was added (3R)-3-(l-(8-(bromomethyl)chroman-4-yl)-2-(tert- butoxy)-2-oxoethyl)pyrrolidine-l-carboxylate (120 mg, 0.2 mmol, 1.0 equiv), 3,3'-((2S,2'S)- ((azanediyldi(methylene))bis(3, 1 -phenylene))bis(3-(tert-butoxy)-3-oxopropane- 1,2- diyl))bis(tert-butyl pyrrolidine- 1 -carboxylate) (186 mg, 0.2 mmol, 1.0 equiv), cesium carbonate (230 mg, 0.7 mmol, 3.0 equiv) and DMF (5 mL) at room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography eluting with ACN to give di-tert-butyl 3,3'-((2S,2'S)-(((((4-(2-(tert-butoxy)-l-((R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)chroman-8-yl)methyl)azanediyldi(methylene)) bis(3, 1 -phenylene))bis(3-(tert-butoxy)-3-oxopropane- 1,2-diyl))bis(tert-butyl pyrrolidine- 1 - carboxylate) (80 mg).

[0533] LCMS (ESI, m / z): [M+H] + = 1221.8

[0534] Step 8.

[0535] To a single-necked flask was added di-tert-butyl 3,3'-((2S,2'S)-(((((4-(2-(tert-butoxy)-l-((R)- 1 -(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)chroman-8-yl)methyl)azanediyldi(methylene)) bis(3, 1 -phenylene))bis(3-(tert-butoxy)-3-oxopropane- 1,2-diyl))bis(tert-butyl pyrrolidine- 1 - carboxylate) (80 mg, 0.1 mmol, 1.0 equiv) and HC1 in 1,4-dioxane (5 mL) at room temperature. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 7.82) to give (2S,2'S)-3,3'-((((((R)-4-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)chroman-8-yl)methyl) azanediyldi(methylene))bis(3, 1 -phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (2.20 mg, 3.06% yield).

[0536] LC-MS (ESI): [M+H]+ = 753.4 + = 753.4

[0537] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.38 - 6.72 (m, 11 H), 4.46 - 3.93 (m, 3 H), 3.93 - 3.43 (m, J = 21.7 Hz, 5 H), 3.43 - 3.21 (m, 5 H), 3.20 - 2.89 (m, 5 H), 2.90 - 2.58 (m, 7 H), 2.58 - 2.22 (m, 6 H), 2.23 - 1.78 (m, 5 H), 1.77 - 1.33 (m, 3 H).

[0538] Example 27

[0539] Reaction Scheme and Experimental Procedures:

[0540] In a single-necked flask, crude product di-tert-butyl 3,3'-((2S,2'S)-(((((4-(2-(tert- butoxy)-l-((R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)chroman-8-yl)methyl) azo diyl)bis(methylene))bis(3, (3R,3'R)-bis(pyrrolidine-l-carboxylate) (80 mg, 0.1 mmol, 1.0 equiv) and HCl in 1,4-dioxane (5 mL) were added sequentially and reacted at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: YMC Triart C18 ExRs5 m, 20 mm X 250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 25% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 8.47) to give (2S,2'S)-3,3'-((((((S)-4-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)chroman-8-yl)methyl)azo diyl)bis(methylene))bis(3, 1-phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (2.07 mg, 3.85% yield).

[0541] LC-MS (ESI): [M+H]+ = 753.4

[0542] 1H NMR (400 MHz, Deuterium Oxide) δ 7.49 - 6.78 (m, 11H), 4.25 - 4.00 (m, 2H), 3.99 - 3.46 (m, 6H), 3.45 - 3.15 (m, 6H), 3.14 - 2.96 (m, 4H), 2.96 - 2.59 (m, 7H), 2.60 - 2.23 (m, 6H), 2.18 - 1.77 (m, 5H), 1.67 - 1.35 (m, 3H).

[0543] Example 28

[0544] Reaction Scheme:

[0545] Experimental Procedures:

[0546] Step 1.

[0547] To a solution of tert-butyl (3R)-3-(l-(4-bromo-2,3-dihydro-lH-inden-l-yl)-2-(tert- butoxy)-2-oxoethyl)pyrrolidine-l-carboxylate (500.0 mg, 1.0 mmol, 1.0 equiv) in toluene (10 mL) in a pressure vessel was added palladium acetate (23.3 mg, 0.1 mmol, 0.1 equiv), bis(adamantyl)(butyl)phosphane (74.6 mg, 0.2 mmol, 0.2 equiv) and [2- (dimethylamino)ethyl]dimethylamine (362.8 mg, 3.1 mmol, 3.0 equiv) and carbon monoxide and hydrogen (1 : 1) were bubbled into the vessel to 40 atm and the reaction was stirred at 105 degrees Celsius for 3 days. The resulting residue was concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography, petroleum ether / ethyl acetate (22% B) to yield tert-butyl (3R)-3-[2-(tert-butoxy)-l-(4-formyl-2,3-dihydro-lH-inden-l-yl)-2- oxoethyl]pyrrolidine-l-carboxylate (250.0 mg, 55.9% yield).

[0548] LC-MS (ESI): [M+H] + = 430.3

[0549] Step 2.

[0550] To a solution of (3R)-3-[2-(tert-butoxy)-l-(4-formyl-2,3-dihydro-lH-inden-l- yl)-2-oxoethyl]pyrrolidine-l-carboxylate (250.0 mg, 0.1 mmol, 1.0 equiv) in methanol (20 mL) was added sodium borohydride (44.0 mg, 1.2 mmol, 2.0 equiv) portionwise at 0 °C. The resulting residue was stirred to react at room temperature for 2 hours. The reaction mixture was quenched with ice water at 0 °C. The resulting mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (3R)-3-[2-(tert-butoxy)-l-[4-(hydroxymethyl)-2,3-dihydro-lH-inden-l-yl]-2- oxoethyl]pyrrolidine-l-carboxylate (270.0 mg, crude).

[0551] LC-MS (ESI): [M+H] + = 432.3

[0552] Step 3.

[0553] To a solution of (3R)-3-[2-(tert-butoxy)-l-[4-(hydroxymethyl)-2,3-dihydro-lH-inden-l- yl]-2-oxoethyl]pyrrolidine-l-carboxylate (250.0 mg, 0.6 mmol, 1.0 equiv) and N- bromosuccinimide (154.6 mg, 0.9 mmol, 1.5 equiv) in 1,2-dichloroethane (25 mL) was added 1,3-dimethylthiourea (30.2 mg, 0.3 mmol, 0.5 equiv) at room temperature. The resulting residue was stirred to react at room temperature overnight. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 25 g C18 column, mobile phase, water and acetonitrile, 75% to 90% gradient for 10 minutes, UV 254 nm detector to give (3R)-3-{l-[4-(bromomethyl)-2,3-dihydro-lH-inden-l-yl]-2-(tert-butoxy)-2- oxoethyl}pyrrolidine-l-carboxylate (120.0 mg, 41.9% yield).

[0554] LC-MS (ESI): [M+H] + = 494.2

[0555] Step 4.

[0556] To a solution of tert-butyl (3R)-3-{l-[4-(bromomethyl)-2,3-dihydro-lH-inden-l- yl]-2-(tert-butoxy)-2-oxoethyl}pyrrolidine-l-carboxylate (100.0 mg, 0.2 mmol, 1.0 equiv) and tert-butyl (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-{[(3-[(2S)-3-(tert- butoxy)-2-[(3R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino] methyl}phenyl)-l-oxopropan-2-yl]pyrrolidine-l-carboxylate (160.2 mg, 0.2 mmol, 1.0 equiv) in N,N-dimethylformamide (10 mL) was added cesium carbonate (197.7 mg, 0.6 mmol, 3.0 equiv) at room temperature. The resulting residue was stirred at 80 °C overnight. The reaction mixture was extracted with ethyl acetate. The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 100% to 100% gradient in 10 minutes, UV 254 nm detector to give di-tert-butyl 3,3'-((2S,2'S)-(((((l-(2-(tert-butoxy)-l-((R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-2, (3R,3'R)-bis(pyrrolidine-l-carboxylate) (70.0 mg, 28.7% yield).

[0557] LC-MS (ESI): [M+H] + = 1205.8

[0558] Step 6.

[0559] To ditert-butyl 3,3'-((2S,2'S)-(((((1-(2-(tert-butoxy)-1-((R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-2, (3R,3'R)-bis(pyrrolidine-1- carboxylate) (60.0 mg, 0.1 mmol, 1.0 equiv) was added hydrogen chloride in 1,4- dioxane (2 mL) at room temperature. The crude was purified by high performance liquid to give (2S,2'S)-3,3'-((((((S)-1-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)-2,3- dihydro-1H-inden-4-yl)methyl)azondiyl)bis(methylene))bis(3,1-phenylene))bis(2- ((R)-pyrrolidin-3-yl)propanoic acid) (1.91 mg, 60.0% purity) with the following conditions (Column: Xbridge BEH Phenyl 5 pm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 15% B to 25% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 6.90 / 7.32)

[0560] LC-MS (ESI): [M+H] + = 737.4

[0561] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.29 - 7.06 (m, 11H), 3.57 - 3.44 (m, 5H), 3.44 - 3.24 (m, 6H), 3.16 - 3.04 (m, 3H), 2.88 - 2.55 (m, 9H), 2.53 - 2.30 (m, 7H), 2.13 - 1.97 (m, 4H), 1.83 (d, J = 5.1 Hz, 1H), 1.71 - 1.56 (m, 3H).

[0562] Example 29

[0563] Reaction Scheme and Experimental Procedures:

[0564] To di-tert-butyl 3,3'-((2S,2'S)-(((((1-(2-(tert-butoxy)-1-((R)-1-(tert- butyloxycarbonyl)pyrrolidin-3-yl)-2-oxoethyl)-2, (3R,3'R)-bis(pyrrolidine-1- carboxylate) (60.0 mg, 0.1 mmol, 1.0 equiv) was added hydrogen chloride in 1,4- dioxane (2 mL) at room temperature. The crude was purified by high performance liquid to give (2S,2'S)-3,3'-((((((R)-1-((R)-carboxy((R)-pyrrolidin-3-yl)methyl)-2,3- dihydro-1H-inden-4-yl)methyl)azondiyl)bis(methylene))bis(3,1-phenylene))bis(2- ((R)-pyrrolidin-3-yl)propanoic acid) (4.40 mg, 80.0% purity) with the following conditions (Column: Xbridge BEH Phenyl 5 pm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 15% B to 25% B in 10 min; Wavelength: 254 nm / 220 nm; RT1(min): 7.74 / 8.28)

[0565] LC-MS (ESI): [M-H] + = 737.4

[0566] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.27 - 6.98 (m, 11H), 3.55 - 3.43 (m, 5H), 3.43 - 3.27 (m, 6H), 3.19 - 2.92 (m, 5H), 2.82 - 2.59 (m, 7H), 2.56 - 2.26 (m, 7H), 1.72 - 1.26 (m, 4H).

[0567] Example 30

[0568] Reaction Scheme:

[0569] Experimental Procedures:

[0570] Step 1.

[0571] To a solution of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (500.0 mg, 1.0 mmol, 1.0 equiv) and 6-chloropyrimidin-2(1H)-one (156.2 mg, 1.2 mmol, 1.2 equiv) in 1,4-dioxane (10 mL) and water (2 mL) was added cesium carbonate (974.6 mg, 3.0 mmol, 3.0 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (72.9 mg, 0.1 mmol, 0.1 equiv) at room temperature. The resulting residue was stirred for 2 hours at 100 °C under nitrogen protection. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (20% B) to give (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(2-chloropyrimidin-4-yl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (350 mg).

[0572] LC-MS (ESI): [M+H] + = 488.2

[0573] Step 2.

[0574] To a solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(2-chloropyrimidin-4-yl)phenyl]-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (300.0 mg, 0.6 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) and water (5 mL) was added potassium carbonate (152.9 mg, 1.1 mmol, 1.8 equiv) and triethylenediamine (34.5 mg, 0.3 mmol, 0.5 equiv) at room temperature. The resulting residue was stirred for 2 hours at 70 °C. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography plate, dichloromethane / methanol (10:1) to give (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxo-2,3-dihydropyrimidin-4-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (250 mg).

[0575] LC-MS (ESI): [M+H] + = 470.3

[0576] Step 3.

[0577] To a solution of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxo-2,3-dihydropyrimidin-4- yl)phenyl)propan-2-yl)pyrrolidine-1 -carboxylate (200.0 mg, 0.4 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) and methanol (2 mL) was added ammonium formate (134.3 mg, 2.1 mmol, 5.0 equiv). The solution was stirred at 60 degrees Celsius. Then it was brought to room temperature and 10% palladium on carbon (200.0 mg) was added and the resulting residue was stirred for 2 hours. It was filtered, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 53% to 65% gradient over 10 minutes, UV 254 nm detector to give (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxohexahydropyrimidin-4- yl)phenyl)propan-2-yl)pyrrolidine-1 -carboxylate (180 mg).

[0578] LC-MS (ESI): [M+H] + = 474.3

[0579] Step 4.

[0580] To a solution of (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxohexahydropyrimidin-4- yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (150.0 mg, 0.3 mmol, 1.0 equiv) in N,N- dimethylformamide (5 mL) at 0 °C was added sodium hydride (63.0 mg, 60% dispersion in kerosene). The mixture was stirred for 15 minutes and (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1-(tert- butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (370.9 mg, 0.8 mmol, 2.5 equiv) was added. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with ice water at 0 °C. The reaction mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine and dried over anhydrous sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography using the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 90% to 100% gradient over 10 minutes, UV 254 nm detector to give di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine-1,3(2H,4H)- diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)- bis(pyrrolidine-1-carboxylate) (110 mg).

[0581] LC-MS (ESI): [M+H] + = 1249.8

[0582] Step 5.

[0583] A solution of di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine- 1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100.0 mg, 0.1 mmol, 1.0 equiv) in hydrogen chloride in 1,4-dioxane (4.0 M) (1 mL) was stirred at room temperature for 2 hours. The crude was purified by high performance liquid to give (2S,2'S)-3,3'-((((R)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2- oxodihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (1.80 mg, 78.8% purity) with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: Water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: Acetonitrile; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 7.47)

[0584] LC-MS (ESI): [M+H] + = 780.4

[0585] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 - 6.85 (m, 12 H), 5.09 - 4.99 (m, 1 H), 4.66 - 4.52 (m, 2 H), 4.46 - 4.35 (m, 1 H), 3.82 - 3.71 (m, 1 H), 3.44 - 3.25 (m, 6 H), 3.22 - 3.05 (m, 4 H), 3.01 - 2.61 (m, 10 H), 2.48 - 2.18 (m, 7 H), 2.10 - 1.99 (m, 3 H), 1.94 - 1.81 (m, 1 H), 1.74 - 1.58 (m, 3 H).

[0586] Example 31

[0587] Reaction Scheme and Experimental Procedures:

[0588] A solution of di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine- 1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100.0 mg, 0.1 mmol, 1.0 equiv) in 1,4-dioxane solution of hydrogen chloride (4.0 M) (1 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((((S)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2- oxodihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (21.64 mg, 88.9% purity) with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 9.32).

[0589] LC-MS (ESI): [M+H] + = 780.4

[0590] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.31 - 7.20 (m, 3H), 7.19 - 7.01 (m, 6H), 7.02 - 6.88 (m, 3H), 5.08 - 4.98 (m, 1H), 4.65 - 4.47 (m, 2H), 4.46 - 4.34 (m, 1H), 3.82 - 3.68 (m, 1H), 3.31 (s, 6H), 3.22 - 3.00 (m, 4H), 3.00 - 2.57 (m, 10H), 2.36 (s, 6H), 2.19 (s, 2H), 2.03 (s, 2H), 1.87 (s, 1H), 1.74 - 1.48 (m, 3H).

[0591] Example 32

[0592] Reaction Scheme and Experimental Procedures:

[0593] A solution of di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine- 1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100.0 mg, 0.1 mmol, 1.0 equiv) in 1,4-dioxane solution of hydrogen chloride (4.0 M) (1 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2- oxodihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (1.67 mg, 79.4% purity) with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 9.75).

[0594] LC-MS (ESI): [M+H]+= 780.4

[0595] 1H NMR (400 MHz, Deuterium Oxide) δ 7.33 - 6.88 (m, 12 H), 5.08 - 5.01 (m, 1 H), 4.66 - 4.49 (m, 2 H), 4.43 - 4.33 (m, 1 H), 3.81 - 3.72 (m, 1 H), 3.40 - 3.23 (m, 6 H), 3.21 - 3.04 (m, 4 H), 3.02 - 2.64 (m, 10 H), 2.45 - 2.27 (m, 6 H), 2.27 - 2.05 (m, 4 H), 1.95 - 1.80 (m, 1 H), 1.68 - 1.48 (m, 3 H).

[0596] Example 33

[0597] Reaction Scheme and Experimental Procedures:

[0598] A solution of di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine- 1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100.0 mg, 0.1 mmol, 1.0 equiv) in 1,4-dioxane solution of hydrogen chloride (4.0 M) (1 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((4-(3-(2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2- oxodihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (1.88 mg, 88.1% purity) with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 10.12).

[0599] LC-MS (ESI): [M+H] + = 780.4

[0600] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 - 6.87 (m, 12 H), 5.09 - 4.99 (m, 1 H), 4.62 - 4.54 (m, 2 H), 4.47 - 4.38 (m, 1 H), 3.83 - 3.73 (m, 1 H), 3.41 - 3.22 (m, 6 H), 3.22 - 3.03 (m, 4 H), 3.03 - 2.67 (m, 10 H), 2.43 - 2.27 (m, 6 H), 2.27 - 2.04 (m, 4 H), 1.97 - 1.84 (m, 1 H), 1.67 - 1.49 (m, 3 H).

[0601] Example 34

[0602] Reaction Scheme:

[0603] Experimental Procedures:

[0604] Step 1.

[0605] In a single neck flask, was added (2S,4S)-1-((benzyloxy)carbonyl)-4- hydroxypyrrolidine-2-carboxylic acid (8.76 g, 33.0 mmol, 3 eq), (3R)-3-[(2S)-3-(3- bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (5.0 g, 11.0 mmol, 1 eq), DMA (100 mL), 1,2-dimethoxyethane, nickel dichloride (486 mg, 2.2 mmol, 0.2 eq), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (886 mg, 3.3 mmol, 0.3 eq), 4,4'-di-tert-butyl-2,2'-bipyridyl)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (101 mg, 0.11 mmol, 0.01 eq), DBU (5.0 g, 33.0 mmol, 3 eq), and purged with nitrogen. The resulting mixture was placed in a photoreactor at 40 °C under a wavelength of 450 nm overnight. The resulting mixture was extracted with ethyl acetate (3 x 500 mL), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H2O / ACN (2 / 3) to give (4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3- oxopropyl)phenyl)-4-hydroxypyrrolidine-1-carboxylate benzyl ester (2.1 g, 28.9%).

[0606] LCMS (ESI, m / z): [M+H]+= 595.3

[0607] Step 2.

[0608] In a single neck flask, was added (4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-hydroxypyrrolidine-1- carboxylate benzyl ester (2.1 g, 3.5 mmol, 1.0 eq), Pd / C (380 mg), and MeOH (50 mL), and purged with hydrogen gas at room temperature for 4 h. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-4-hydroxypyrrolidin-2-yl)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate tert-butyl ester (1.7 g, 94.1%).

[0609] LCMS (ESI, m / z): [M+H]+= 461.3

[0610] Step 3.

[0611] (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-4-hydroxypyrrolidin-2-yl)phenyl)-1- oxopropan-2-yl)pyrrolidine-1 -carboxylate (900 mg, 1.9 mmol, 1.0 equiv), (R)-3- ((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (915 mg, 1.9 mmol, 1.0 equiv), potassium carbonate (810 mg, 5.7 mmol, 3.0 equiv) and DMF (20 mL) were added in a single-neck flask at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 3) to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-hydroxypyrrolidin-1-yl)methyl)phenyl)- 1-oxopropan-2-yl)pyrrolidine-1-carboxylate (1.0 g, 54.3%).

[0612] LCMS (ESI, m / z): [M+H]+=848.5

[0613] Step 4.

[0614] To a single-necked flask at room temperature was added (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-hydroxypyrrolidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1 -carboxylate (500 mg, 0.6 mmol, 1 equiv), triethylamine (298 mg, 3.0 mmol, 5 equiv), DCM (10 mL), DMAP (36 mg, 0.3 mmol, 0.5 equiv), followed by p-toluenesulfonyl chloride (225 mg, 1.2 mmol, 2 equiv) at 0 °C to the resulting mixture and stirred at 50 °C overnight. The resulting mixture was extracted with dichloromethane (3 x 30 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 10) to give tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-(p-toluenesulfonyloxy)pyrrolidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (260 mg, 39.6%).

[0615] LCMS (ESI, m / z): [M+H]+= 1002.5

[0616] Step 5.

[0617] To a single-necked flask at room temperature were added (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-(p-tolylsulfonyloxy)pyrrolidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (260 mg, 0.3 mmol, 1.0 equiv), (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate tert-butyl ester (102 mg, 0.3 mmol, 1.0 equiv), cesium carbonate (254 mg, 0.9 mmol, 3.0 equiv) and DMF (10 mL) sequentially. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure to give tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3- yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 85.2%).

[0618] LCMS (ESI, m / z): [M+H]+= 1221.8

[0619] Step 6.

[0620] In a single-necked flask, crude tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.2 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) was added at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 µm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 20% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 6.98)) to give (S)-3-(3-((2S,4R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (20.07 mg, yield 10.06%).

[0621] LC-MS (ESI): [M+H]+=753.4

[0622] 1H NMR (400 MHz, Deuterium Oxide) δ 7.34 - 7.23 (m, 3H), 7.23 - 7.10 (m, 3H), 7.10 - 6.95 (m, 3H), 6.82 - 6.67 (m, 3H), 4.87 (s, 1H), 3.64 (d, J = 12.8 Hz, 1H), 3.44 (t, J = 8.5 Hz, 1H), 3.39 - 3.23 (m, 6H), 3.25 - 3.01 (m, 5H), 2.95 - 2.56 (m, 11H), 2.51 - 2.26 (m, 6H), 2.12 - 1.97 (m, 3H), 1.82 (t, J = 11.9 Hz, 1H), 1.74 - 1.57 (m, 3H).

[0623] Example 35

[0624] Reaction Scheme and Experimental Procedures:

[0625] In a single-necked flask, add crude product tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.2 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) at room temperature for 2 h. Purify the crude product by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 μm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 20% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 8.43)) to give (S)-3-(3-((2R,4R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (32.88 mg, yield 17.12%).

[0626] LC-MS (ESI): [M+H]+=753.4

[0627] 1H NMR (400 MHz, Deuterium Oxide) δ 7.39 - 6.64 (m, 12 H), 4.88 (s, 1H), 3.68 - 3.62 (m, 1H), 3.50 - 3.25 (m, 7H), 3.25 - 3.03 (m, 5H), 2.98 - 2.59 (m, 10H), 2.52 (d, J=8.8 Hz, 1H), 2.48 - 2.25 (m, 6H), 2.19 (d, J=7.4 Hz, 1H), 2.10 - 1.98 (m, 2H), 1.82 (d, J=4.2 Hz, 1H), 1.76 - 1.50 (m, 3H).

[0628] Example 36

[0629] Reaction Scheme and Experimental Procedures:

[0630] In a single-necked flask, add crude tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3R)-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (300 mg, 0.2 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) at room temperature for 2 h. Purify the crude product by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 μm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 15% B to 20% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.63)) to give (2S)-3-(3-((4R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (20.64 mg, yield 10.59%).

[0631] LC-MS (ESI): [M+H]+=753.4

[0632] 1H NMR (400 MHz, Deuterium Oxide) δ 7.40 - 6.65 (m, 12H), 4.89 (s, 1H), 3.69 - 3.62 (m, 1H), 3.51 - 3.24 (m, 7H), 3.13 (s, 4H), 3.07 - 2.58 (m, 10H), 2.51 (s, 1H), 2.49 - 2.26 (m, 6H), 2.19 (s, 3H), 2.10 - 1.95 (m, 2H), 1.68 - 1.62 (m, 3H).

[0633] The following examples can be obtained by the above synthesis methods by using appropriate starting materials:

[0634] wherein the preparation of Examples 44, 73, 74, 75, 76, 78 and 79 in the above table is shown below:

[0635] Example 44

[0636] Reaction Scheme and Experimental Procedures:

[0637] Step 1.

[0638] To a solution of 1-bromo-3,5-dimethylbenzene (10.0 g, 54.0 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (9.6 g, 54.0 mmol) and 2-[(E)-2-(1-cyano-1-methylethyl)azo-1-yl]-2-methylpropanenitrile (0.9 g, 5.4 mmol) at room temperature. The resulting residue was stirred at 80 °C for 2 hours. It was filtered, the filter cake was washed with carbon tetrachloride, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give 1-bromo-3-(bromomethyl)-5-methylbenzene (18 g).

[0639] LC-MS (ESI): [M+H] + = 262.9

[0640] Step 2.

[0641] To a solution of (R)-tert-butyl 3-(2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2- oxoehtyl)pyrrolidine-1-carboxylate (5.0 g, 12.9 mmol) in tetrahydrofuran (200 mL) was added lithium bis(trimethylsilyl)amide (4.7 g, 28.3 mmol) dropwise at 0 °C under nitrogen. The resulting mixture was stirred for 15 minutes. To the reaction was added a solution of 1-bromo-3-(bromomethyl)-5-methylbenzene (8.2 g, 30.9 mmol) in tetrahydrofuran (200 mL) dropwise. The resulting residue was stirred at room temperature overnight under nitrogen. The reaction mixture was quenched with saturated aqueous ammonium chloride solution under ice bath. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to give (R)-tert-butyl 3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-5-methylphenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (10.0 g).

[0642] LC-MS (ESI): [M+H] + = 571.2

[0643] Step 3.

[0644] To a solution of (R)-3-((S)-1-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(3-bromo-5- methylphenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (6.0 g, 10.5 mmol, 1.0 eq) in tetrahydrofuran (100 mL) was added 1 M aqueous hydrogen peroxide (122.3 mL) under ice bath. Then lithium hydroxide (0.4 g, 15.7 mmol) in water was added dropwise, and the resulting residue was stirred for 3 hours. Under ice bath, saturated aqueous sodium sulfite (200 mL) was added to quench. The reaction mixture was basified with sodium hydroxide to pH > 12. Extracted with ethyl acetate (2 X 100 mL). The aqueous phase was collected and acidified with 2 M hydrochloric acid solution to pH = 3. Extracted with ethyl acetate (2 X 100 mL). The organic phases were combined and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give (2S)-3-(3-bromo-5-methylphenyl)-2-[(3R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl]propanoic acid (3.0 g).

[0645] LC-MS (ESI): [M+H] + = 412.1

[0646] Step 4.

[0647] (2S)-3-(3-bromo-5-methylphenyl)-2-[(3R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl]propanoic acid (3.0 g, 7.3 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL), and 2-tert-butyl-1,3-diisopropylisourea (3.6 g, 18.2 mmol) was added. After stirring at 75 °C for 3 hours, 2-tert-butyl-1,3-diisopropylisourea (1.5 g, 7.3 mmol) was added. The resulting reaction was stirred at 75 °C overnight. Filtration was performed, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methylphenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (1.8 g).

[0648] LC-MS (ESI): [M+H] + = 468.2

[0649] Step 5.

[0650] To a solution of tert-butyl (3R)-3-[(2S)-3-(3-bromo-5-methylphenyl)-l-(tert- butoxy)-l-oxopropan-2-yl]pyrrolidine-l-carboxylate (3.3 g, 7.1 mmol) in toluene (30 mL) was added palladium acetate (0.3 g, 1.4 mmol), n-butylbis(l-adamantyl)phosphine (1.0 g, 2.8 mmol) and N,N,N',N'-tetramethylethylenediamine (3.3 g, 28.1 mmol) and carbon monoxide and hydrogen were bubbled to 40 atm and the reaction was allowed to proceed at 105 °C overnight. The mixture was filtered and the filter cake was washed with acetonitrile and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give tert-butyl (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-formyl-5-methylphenyl)-l- oxopropan-2-yl]pyrrolidine-l-carboxylate (1.1 g).

[0651] LC-MS (ESI): [M+H] + = 418.3

[0652] Step 6.

[0653] To a solution of tert-butyl (3R)-3-[(2S)-l-(tert-butoxy)-3-(3-formyl-5- methylphenyl)-l-oxopropan-2-yl]pyrrolidine-l-carboxylate (2.5 g, 5.9 mmol) in methanol (100 mL) was added sodium borohydride (453.0 mg, 11.9 mmol) portionwise at 0 °C. The resulting residue was stirred at room temperature for 1 h. The reaction mixture was quenched with ice water at 0 °C. The mixture was extracted with ethyl acetate. The combined organic phase was washed with saturated brine and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give tert-butyl (3R)-3-[(2S)-l-(tert-butoxy)-3-[3-(hydroxymethyl)-5- methylphenyl]-l-oxopropan-2-yl]pyrrolidine-l-carboxylate (2.5 g).

[0654] LC-MS (ESI): [M+H] + = 420.3

[0655] Step 7.

[0656] To a solution of (3R)-3-[(2S)-1 -(tert-butoxy)-3-[3-(hydroxymethyl)-5- methylphenyl]-1 -oxopropan-2-yl]pyrrolidine-1 -carboxylate tert-butyl (2.5 g, 5.9 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added N-bromosuccinimide (1.6 g, 8.9 mmol) and 1,3-dimethylthiourea (0.3 g, 2.9 mmol) at room temperature. The resulting residue was stirred at room temperature overnight under nitrogen protection. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (12% B) to give (3R)-3-[(2S)-3-[3-(bromomethyl)-5-methylphenyl]-1 -(tert-butoxy)-1 - oxopropan-2-yl]pyrrolidine-1 -carboxylate tert-butyl (1.5 g).

[0657] LC-MS (ESI): [M+H] + = 482.2

[0658] Step 8.

[0659] To a solution of (3R)-3-[(2S)-3-[3-(bromomethyl)-5-methylphenyl]-1 -(tert-butoxy)-1 - oxopropan-2-yl]pyrrolidine-1 -carboxylate tert-butyl (517.4 mg, 1.1 mmol) and (3R)-3-((2S)-1 -(tert-butoxy)-3-(3-((4R)-4-hydroxypyrrolidin-2-yl)phenyl)-1 - oxopropan-2-yl)pyrrolidine-1 -carboxylate tert-butyl (400.0 mg, 0.9 mmol) in N,N- dimethylformamide (16 mL) was added potassium carbonate (240.1 mg, 1.7 mmol). The resulting residue was stirred at 80 °C for 2 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 80% to 100% gradient for 10 minutes, UV 220 nm detector to give (3R)-3-((2S)-1 -(tert-butoxy)-3-((4R)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1 -(tert- butoxycarbonyl)pyrrolidin-4-hydroxypyrrolidin-1 -yl)methyl)-5-methylphenyl(1 - oxopropan-2-yl)pyrrolidine-1 -carboxylate (600.0 mg).

[0660] LC-MS (ESI): [M+H] + = 862.6

[0661] Step 9.

[0662] In a microwave tube, to a solution of (3R)-3-((2S)-1 -(tert-butoxy)-3-((4R)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1 -(tert-butoxycarbonyl)pyrrolidin-4-yl)pyrrolidin-1 - yl)methyl)-5-methylphenyl)-1 -oxopropan-2-yl)pyrrolidine-1 -carboxylate (200.0 mg, 0.2 mmol) and triethylamine (70.4 mg, 0.7 mmol) in dichloromethane (12 mL) at 0 °C, was added N,N-dimethylaminopyridine (2.8 mg, 0.1 mmol) and 4-methylbenzenesulfonyl chloride (53.1 mg, 0.3 mmol). The resulting residue was stirred at 50 °C for 2 h. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 85% to 100% gradient over 10 min, UV 200 nm detector to give (3R)-3-[(2S)-1 -(tert-butoxy)-3-(3-((4R)-2-(3-((S)-3-(tert-butoxy)-2-((R)-1 -(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-(p-toluenesulfonyloxy)pyrrolidin-1 - yl)methyl)-5-methylphenyl)-1 -oxopropan-2-yl]pyrrolidine-1 -carboxylate (220.0 mg).

[0663] LC-MS (ESI): [M+H] + = 1016.6

[0664] Step 10.

[0665] To a solution of (3R)-3-[(2S)-1 -(tert-butoxy)-3-(3-((4R)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1 -(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4- (p-tolylsulfonyloxy)pyrrolidin-1 -yl)methyl)-5-methylphenyl)-1 -oxopropan-2-yl]pyrrolidine- 1 -carboxylate (87.8 mg, 0.2 mmol) in N,N-dimethylformamide (20 mL) was added cesium carbonate (192.4 mg, 0.6 mmol) at room temperature. The resulting residue was stirred at 80 °C overnight. The reaction mixture was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine and dried over sodium sulfate. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography on a 12 g C18 column with the following conditions: mobile phase, water and acetonitrile, 100% to 100% gradient over 10 minutes, UV 200 nm detector to give tert-butyl (3R)-3-((2S)-1 -(tert-butoxy)-3-(3-((3S)-1 -(3-((S)-3-(tert- butoxy)-2-((R)-1 -(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5-methylbenzyl)-5- (3-((S)-3-(tert-butoxy)-2-((R)-1 -(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl) pyrrolidin-3-yl)oxy)-5-methylphenyl)-1 -oxopropan-2-yl)pyrrolidine-1 -carboxylate (150.0 mg).

[0666] LC-MS (ESI): [M+H] + = 1249.8

[0667] Step 11.

[0668] A solution of tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((3S)-1-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)-5- methylbenzyl)-5-(3-((S)-3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)oxy)-5- methylphenyl)-1-oxopropan-2-yl)pyrrolidin-1-carboxylate (150.0 mg, 0.1 mmol) in 1,4-dioxane (5 mL) of hydrogen chloride (4.0 M) was stirred at room temperature for 2 hours. The crude was purified by high performance liquid to give (2S)-3-(3-((4S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-5- methylbenzyl)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)-5- methylphenoxy)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (9.88 mg, 95.0% purity) with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: Water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: Acetonitrile; Flow rate: 25 mL / min; Gradient: 18% B to 40% B in 12 min; Wavelength: 254 nm / 220 nm; RT1(min): 9.00)

[0669] LC-MS (ESI): [M+H] + = 781.4

[0670] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 - 6.51 (m, 10H), 3.74 - 3.56 (m, 2H), 3.56 - 3.19 (m, 7H), 3.19 - 2.99 (m, 4H), 2.99 - 2.39 (m, 11H), 2.38 - 2.23 (m, 6H), 2.22 - 2.00 (m, 6H), 2.00 - 1.48 (m, 8H).

[0671] Example 73

[0672] Reaction Scheme and Experimental Procedures:

[0673] Step 1.

[0674] To a solution of (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4- (1,3-dioxoisoindolin-2-yl)pyrrolidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine- 1-carboxylate (400 mg, 0.4 mmol), ethanol (5 mL), hydrazine hydrate (62 mg, 1.2 mmol) was added in a single-necked flask at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. (3R)-3-((2S)-3-(3-((4S)-4-amino-1-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)pyrrolidin-2- yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 61.3%) was obtained.

[0675] LCMS (ESI, m / z): [M+H] + = 977.6

[0676] Step 2.

[0677] To a solution of (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((4S)-2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4- (1,3-dioxoisoindolin-2-yl)pyrrolidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine- 1-carboxylate (400 mg, 0.4 mmol), ethanol (5 mL), hydrazine hydrate (62 mg, 1.2 mmol) was added in a single-necked flask at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. (3R)-3-((2S)-3-(3-((4S)-4-amino-1-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)pyrrolidin-2- yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 61.3%) was obtained.

[0678] LCMS (ESI, m / z): [M+H]+ = 847.6

[0679] Step 3.

[0680] In a single neck flask, (3R)-3-((2S)-3-(3-((4S)-4-amino-1-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)pyrrolidin- 2-yl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.3 mmol), (R)-3-((S)-3-(3-bromophenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (268 mg, 0.6 mmol), xylene (5 mL), sodium tert-butoxide (85 mg, 0.9 mmol), Pd2(dba)3(27 mg, 0.03 mmol) and Davephos (23 mg, 0.06 mmol) were added sequentially under nitrogen atmosphere and reacted at 135 °C overnight. The resulting mixture was filtered, the filtrate was extracted with ethyl acetate (3 x 20 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. The crude (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)phenyl)pyrrolidin-3-yl)tert-butyl 3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxy carbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)amino)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (220 mg) was obtained.

[0681] LCMS (ESI, m / z): [M+H] + = 1220.8

[0682] Step 4.

[0683] In a single neck flask was added crude (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-5-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)phenyl)pyrrolidin-3-yl)tert-butyl 3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)pyrrolidin-3-yl)amino)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (220 mg, 0.2 mmol) and HCl in 1,4-dioxane (5 mL) and allowed to react at room temperature for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge BEH Phenyl 5 pm, 30 mm*150 mm; Mobile Phase A: Water (10 mmol / L Ammonium bicarbonate + 0.1% Ammonia), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 5% B to 25% B in 8 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 6.67) to give (S)-3-(3-((2R,4S)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-4-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)amino)pyrrolidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (8.46 mg, 4.65% yield).

[0684] LC-MS (ESI): [M+H] + = 752.4

[0685] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.39 - 6.52 (m, 12 H), 4.06 - 3.65 (m, 3 H), 3.64 - 3.29 (m, 7 H), 3.27 - 3.06 (m, 4 H), 3.05 - 2.56 (m, 10 H), 2.56 - 2.12 (m, 8 H), 2.12 - 1.95 (m, 3 H), 1.79 - 1.56 (m, 3 H).

[0686] Example 74

[0687] Reaction Scheme and Experimental Procedures:

[0688] Step 1.

[0689] In a single-necked flask, add (R)-3-((S)-3-(3-bromophenyl)-l-(tert-butoxy)-l- oxopropan-2-yl)pyrrolidine-l-carboxylate (2.0 g, 4.4 mmol), bis(pinacolato)diboron (1.1 g, 4.4 mmol), dioxane (60 mL), potassium acetate (864 mg, 8.8 mmol), Pd(dppf)Cl2(322 mg, 0.4 mmol) successively, and react at 80 °C under nitrogen overnight. The resulting mixture is extracted with ethyl acetate (3 x 200 mL), the organic phase is dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure. Purification is performed by silica gel column chromatography, eluted with PE / EA (7 / 1) to obtain (R)-3-((S)-l-(tert-butoxy)-l-oxo-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-l- carboxylate (1.4 g, 57.1%).

[0690] LCMS (ESI, m / z): [M+H] + = 502.3

[0691] Step 2.

[0692] In a single-necked flask, add (R)-3-((S)-l-(tert-butoxy)-l-oxo-3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-l-carboxylate (1.4 g, 2.8 mmol), 6-bromo-3-hydroxypyridine (486 mg, 2.8 mmol), DMF (40 mL), H2O (8 mL), cesium carbonate (1.8 g, 5.6 mmol), potassium phosphate (1.2 g, 5.6 mmol), Pd(PPh3)4(323 mg, 0.3 mmol) successively, and react at 100 °C under nitrogen overnight. The resulting mixture is extracted with ethyl acetate (3 x 200 mL), the organic phase is dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure. Purification is performed by reverse phase column chromatography, eluted with H2O / ACN (1 / 1) to obtain (R)-3-((S)-l-(tert-butoxy)-3-(3-(5-hydroxypyridin-2-yl)phenyl)-l-oxopropan-2-yl)pyrrolidine-l- carboxylate (600 mg, 41.3%).

[0693] LCMS (ESI, m / z): [M+H] + = 469.3

[0694] Step 3.

[0695] In a single neck flask, add (R)-3-((S)-1-(tert-butoxy)-3-(3-(5- hydroxypyridin-2-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.3 mmol), Pd / C (545 mg, 5.2 mmol), and MeOH (10 mL) sequentially, and react at room temperature under hydrogen atmosphere overnight. The resulting mixture is filtered, and the filtrate is concentrated under reduced pressure to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(5- hydroxypiperidin-2-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 88.9%).

[0696] LCMS (ESI, m / z): [M+H] + = 475.3

[0697] Step 4.

[0698] In a single neck flask, add (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(5- hydroxypiperidin-2-yl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.3 mmol), (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (592 mg, 1.3 mmol), potassium carbonate (524 mg, 3.9 mmol), and DMF (10 mL) sequentially, and react at 80 °C overnight. The resulting mixture is extracted with ethyl acetate (3 x 100 mL), the organic phase is dried over anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure. Purification is performed by reverse phase column chromatography eluted with H2O / ACN (1 / 4) to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-5-hydroxypiperidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (210 mg, 17.3%).

[0699] LCMS (ESI, m / z): [M+H] + = 862.6

[0700] Step 5.

[0701] To a single-necked flask, (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-5- hydroxypiperidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (160 mg, 0.2 mmol), carbonic acid, tribromide (123 mg, 0.4 mmol), DCM (5 mL), triphenylphosphine (97 mg, 0.4 mmol) were added successively at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The resulting mixture was extracted with ethyl acetate (3 x 20 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 6) to give (3R)-3-((2S)-3-(3-(5-bromo-1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)piperidin-2-yl)phenyl)-1-(tert- butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (30 mg, 15.7%).

[0702] LCMS (ESI, m / z): [M+H] + = 924.5

[0703] Step 6.

[0704] In a single neck flask, (3R)-3-((2S)-3-(3-(5-bromo-l-(3-((S)-3-(tert-butoxy)-2-((R)- 1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)piperidin-2-yl)phenyl)- 1-(tert-butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (30 mg, 0.03 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(3-hydroxyphenyl)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (13 mg, 0.03 mmol), DMF (2 mL), cesium carbonate (32 mg, 0.09 mmol) were added successively under nitrogen at 80 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 10 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-6-(3-((S)-3-(tert-butoxy)-2- ((R)-1-(tert-butoxy carbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-3-yl)oxy)phenyl)- 1-oxopropan-2-yl)pyrrolidine-1-carboxylate (30 mg) was purified by reverse phase column chromatography eluted with H20 / ACN (1 / 9).

[0705] LCMS (ESI, m / z): [M+H] + = 1235.8

[0706] Step 7.

[0707] In a single neck flask, crude tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-6-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-3-yl)oxy)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (30 mg, 0.02 mmol) and HC1 in 1,4-dioxane (3 mL) was added at room temperature overnight. The crude product was purified by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 pm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 30% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.06) to give (2S)-3-(3-(1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-5-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)piperidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (4.52 mg, 15.58% yield).

[0708] LC-MS (ESI): [M+H] + = 767.4

[0709] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.41 - 6.60 (m, 12 H), 3.96 (d, J = 85.3 Hz, 3 H), 3.62 - 3.04 (m, 12 H), 3.04 - 2.60 (m, 9 H), 2.39 (d, J = 7.4 Hz, 8 H), 2.19 (s, 4 H), 1.95 - 1.42 (m, 4 H).

[0710] Example 75

[0711] Reaction Scheme and Experimental Procedures:

[0712] Step 1.

[0713] To a solution of 1,3-dioxoisoindoline-2-carboxaldehyde (8.8 g, 50.2 mmol, 1.0 equiv) and tert-butyldiphenylsilyl chloride (20.7 g, 75.3 mmol, 1.5 equiv) in dichloromethane (50 mL) was added diazabicyclo (9.2 g, 60.3 mmol, 1.2 equiv) dropwise under ice bath. The resulting residue was stirred at room temperature overnight under nitrogen protection. The reaction mixture was neutralized to pH = 7 with 2 M sulfuric acid. The reaction mixture was extracted with dichloromethane. The organic phases were combined, backwashed with saturated brine, and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-[(E)-2-[(tert-butyldiphenylsilyl)oxy]vinyl]isoindoline-1,3-dione (6.5 g).

[0714] LC-MS (ESI): [M+H] + = 428.2

[0715] Step 2.

[0716] To a solution of 2-[(E)-2-[(tert-butyldiphenylsilyl)oxy]vinyl]isoindoline-1,3-dione (3 g, 7.0 mmol, 1.0 equiv) and diethylzinc (1 M in n-hexane) (8.4 mL, 49.1 mmol, 7.0 equiv) in toluene (40 mL) was added iodomethane (13.2 g, 49.1 mmol, 7.0 equiv) at room temperature under nitrogen protection. The resulting residue was stirred at 70 °C overnight under nitrogen protection. The reaction mixture was quenched with water at room temperature. The reaction mixture was neutralized to pH = 6 with saturated aqueous ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (2 X 100 mL). The organic phases were combined, backwashed with saturated brine (2 X 150 mL), and dried over sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 2-{2-[(tert-butyldiphenylsilyl)oxy]cyclopropyl}isoindoline-1,3-dione (2 g).

[0717] LC-MS (ESI): [M+H] + = 442.2

[0718] Step 3.

[0719] To a solution of 2-{2-[(tert-butyldiphenylsilyl)oxy]cyclopropyl}isoindole-1,3-dione (2 g, 4.5 mmol, 1.0 equiv) in dichloromethane (100 mL) and ethanol (20 mL) was added hydrazine hydrate (85%) (1133.6 mg, 22.6 mmol, 5.0 equiv) under air protection at room temperature. The resulting residue was stirred to react for 1.5 hours at room temperature under nitrogen protection. Filtration, the filter cake was washed with dichloromethane (100 mL), and the filtrate was concentrated under reduced pressure to give 2-[(tert-butyldiphenylsilyl)oxy]cyclopropane-1-amine (1.5 g).

[0720] LC-MS (ESI): [M+H] + = 312.2

[0721] Step 4.

[0722] To a solution of 2-[(tert-butyldiphenylsilyl)oxy]cyclopropane-1-amine (450 mg, 1.4 mmol, 1.0 equiv) and tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (1353.4 mg, 2.9 mmol, 2.0 equiv) in N,N- dimethylformamide (10 mL) was added potassium carbonate (399.3 mg, 2.9 mmol, 2.0 equiv) at room temperature. The resulting residue was stirred to react overnight at 80 degrees Celsius. The resulting residue was purified by reverse phase column chromatography with the following conditions: 80 g C18 column, mobile phase, water and acetonitrile, 90% to 100% gradient for 10 minutes, UV 254 nm detector to give 3,3'-((2S,2'S)-((((2-((tert-butyldiphenylsiloxy)cyclopropyl)azenediyl)bis(methylene))bis(3,1- phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) di-tert-butyl ester (1 g).

[0723] LC-MS (ESI): [M+H] + = 1086.7

[0724] Step 5.

[0725] To a solution of 3,3'-((2S,2'S)-((((2-((tert-butyldiphenylsilyl) cyclopropyl) azo diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert- butoxy)-3-oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylic acid) di-tert- butyl ester) (1 g, 0.9 mmol, 1.0 equiv) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (10 mL) at room temperature. The resulting residue was stirred to react for 2 hours at room temperature. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 48 g C18 column, mobile phase, water and acetonitrile, 85% to 95% gradient for 10 minutes, UV 254 nm detector to give (3R)-3-[(2S)-1-(tert-butoxy)-3-(3-{[(3-[(2S)-3-(tert-butoxy)-2-[(3R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)(2-hydroxycyclopropyl)amino]methyl}phenyl)-1-oxopropan-2-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (800 mg).

[0726] LC-MS (ESI): [M+H] + = 848.5

[0727] Step 6.

[0728] To a solution of (3R)-3-[(2S)-3-(3-bromophenyl)-l-(tert-butoxy)-l-oxopropan-2- yl]pyrrolidine-l-carboxylate (482.2 mg, 1.1 mmol, 1.2 equiv) and (3R)-3-[(2S)-l-(tert- butoxy)-3-(3-{[(3-[(2S)-3-(tert-butoxy)-2-[(3R)-l-(tert-butoxycarbonyl)pyrrolidin-3-yl]- 3-oxopropyl]phenyl}methyl)(2-hydroxycyclopropyl)amino]methyl}phenyl)-l-oxopropan-2- yl]pyrrolidine-l-carboxylate (750 mg, 0.9 mmol, 1.0 equiv) in 1,4-dioxane (15 mL) at room temperature was added cesium carbonate (864.4 mg, 2.7 mmol, 3.0 equiv), 2- dicyclohexylphosphino-2-(N,N-dimethylamino)-biphenyl (69.6 mg, 0.2 mmol, 0.2 equiv), and 2'-(dicyclohexylphosphino)-N,N-dimethyl-[l,l'-biphenyl]-2-amine; [2'-(methylamino)- [l,l'-biphenyl]-2-yl]palladium methanesulfonate (68.7 mg, 0.1 mmol, 0.1 equiv). The resulting residue was stirred under nitrogen at 90 °C overnight. The reaction mixture was washed with acetonitrile. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 48 g C18column, mobile phase, water and acetonitrile, 95% to 100% gradient over 10 minutes, UV 254 nm detector to give (3R)-3-[(2S)-3-(3-{2-[bis({3-[(2S)-3-(tert-butoxy)-2-[(3R)-l-(tert- butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino]cyclopropoxy}phenyl)-l- (tert-butoxy)-l-oxopropan-2-yl]pyrrolidine-l-carboxylate (150 mg).

[0729] LC-MS (ESI): [M+H] + = 1221.8

[0730] Step 7.

[0731] To a 20 mL sample vial was added (3R)-3-[(2S)-3-(3-{2-[bis({3-[(2S)-3-(tert- butoxy)-2-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl]-3-oxopropyl]phenyl}methyl)amino] cyclopropoxy}phenyl)-1-(tert-butoxy)-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (150 mg, 0.1 mmol, 1.0 equiv) and a solution of hydrogen chloride in 1,4-dioxane (4.0 M) (2 mL) at room temperature. The resulting residue was stirred to react for 2 hours at room temperature. The resulting residue was concentrated under reduced pressure. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((((2-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenoxy)cyclopropyl)azondiyl)bis(methylene))bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (2.78 mg, 89.1% purity) with the following conditions (Column: XBridge BEH C18 OBD Prep Column 130, 5m, 30mm*150mm; Mobile Phase A: Water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: Acetonitrile; Flow rate: 60 mL / min; Gradient: 3% B to 17% B in 8 min; Wavelength: 254 / 220 nm; RT1(min): 7.75).

[0732] LC-MS (ESI): [M+H] + = 753.4

[0733] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.36 - 6.82 (m, 12 H), 3.92 - 3.81 (m, 1 H), 3.76 - 3.54 (m, 3 H), 3.44 - 3.22 (m, 7 H), 3.22 - 3.07 (m, 3 H), 2.97 - 2.57 (m, 12 H), 2.47 - 2.26 (m, 6 H), 2.03 (s, 3 H), 1.75 - 1.53 (m, 3 H).

[0734] Example 76

[0735] Reaction Scheme and Experimental Procedures:

[0736] Step 1.

[0737] To a solution of (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-5- hydroxypiperidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.3 mmol), (R)-3-((S)-1-(tert-butoxy)-3-(3-((4-nitrophenyl)sulfonamido)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (167 mg, 0.3 mmol), THF (5 mL) in a single neck flask at room temperature, under nitrogen atmosphere, to the resulting mixture was added diethyl azodicarboxylate (76 mg, 0.4 mmol) at 0 °C, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure and purified by reverse phase column chromatography eluting with H2O / ACN (1 / 10) to give tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((2-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-5-((N-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-4-nitrophenyl)sulfonamido)piperidin-1- yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (280 mg, 61.2%).

[0738] LCMS (ESI, m / z): [M+H] + = 1419.8

[0739] Step 2.

[0740] In a single neck flask, add (3R)-3-((2S)-1-(tert-butoxy)-3-(3-((2-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-5-((N-(3- ((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)- 4-nitrophenyl)sulfonamidyl)piperidin-1-yl)methyl)phenyl)-1-oxopropan-2-yl)pyrrolidine-1- carboxylate (250 mg, 0.2 mmol), sodium thiophenol (93 mg, 0.7 mmol), acetonitrile (5 mL), potassium carbonate (97 mg, 0.7 mmol) successively under nitrogen at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-6-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-3-yl)amino)phenyl)-1- oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg) was obtained.

[0741] LCMS (ESI, m / z): [M+H] + = 1234.8

[0742] Step 3.

[0743] In a single neck flask, crude tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-6-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)piperidin-3-yl)amino)phenyl)-1-oxopropan-2-yl)pyrrolidine-1-carboxylate (250 mg, 0.2 mmol) and HC1 in 1,4-dioxane (5 mL) was added at room temperature for 3 h. The crude product was purified by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 µm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 12% B to 22% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.82) to give (S)-3-(3-((2R,5R)-1-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)benzyl)-5-((3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)amino)piperidin-2-yl)phenyl)-2-((R)-pyrrolidin-3-yl)propanoic acid (43.24 mg, yield 25.90%).

[0744] LC-MS (ESI): [M+H] + = 766.4

[0745] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.27 (t, J = 7.6 Hz, 1H), 7.22 - 7.06 (m, 5H), 7.05 - 6.91 (m, 3H), 6.58 (d, J = 7.3 Hz, 1H), 6.42 (s, 1H), 6.27 (s, 1H), 4.26 (s, 1H), 3.70 - 3.45 (m, 3H), 3.44 - 3.20 (m, 7H), 3.21 - 3.05 (m, 3H), 3.05 - 2.91 (m, 1H), 2.92 - 2.63 (m, 7H), 2.59 (s, 2H), 2.48 - 2.19 (m, 8H), 2.03 (s, 4H), 1.80 (s, 1H), 1.66 (t, J = 11.2 Hz, 3H).

[0746] Example 78

[0747] Reaction Scheme and Experimental Procedures:

[0748] Step 1.

[0749] To a solution of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (500.0 mg, 1.0 mmol, 1.0 equiv) and 6-chloropyrimidin-2(1H)-one (156.2 mg, 1.2 mmol, 1.2 equiv) in 1,4-dioxane (10 mL) and water (2 mL) was added cesium carbonate (974.6 mg, 3.0 mmol, 3.0 equiv) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (72.9 mg, 0.1 mmol, 0.1 equiv) at room temperature. The resulting residue was stirred for 2 hours at 100 °C under nitrogen protection. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, petroleum ether / ethyl acetate (20% B) to give (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(2-chloropyrimidin-4-yl)phenyl]-1-oxopropan-2-yl]pyrrolidine-1-carboxylate (350 mg) as a white solid.

[0750] LC-MS (ESI): [M+H] + = 488.2

[0751] Step 2.

[0752] To a solution of (3R)-3-[(2S)-1-(tert-butoxy)-3-[3-(2-chloropyrimidin-4-yl)phenyl]-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (300.0 mg, 0.6 mmol, 1.0 equiv) in 1,4-dioxane (5 mL) and water (5 mL) was added potassium carbonate (152.9 mg, 1.1 mmol, 1.8 equiv) and triethylenediamine (34.5 mg, 0.3 mmol, 0.5 equiv) at room temperature. The resulting residue was stirred for 2 hours at 70 °C. The resulting residue was concentrated under reduced pressure. The resulting residue was purified by preparative chromatography plate, dichloromethane / methanol (10:1) to give (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxo-2,3-dihydropyrimidin-4-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (250 mg) as a white solid.

[0753] LC-MS (ESI): [M+H] + = 470.3

[0754] Step 3.

[0755] To a solution of (R)-3-((S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxo-2,3-dihydropyrimidin-4- yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (200.0 mg, 0.4 mmol, 1.0 equiv) in tetrahydrofuran (2 mL) and methanol (2 mL) was added ammonium formate (134.3 mg, 2.1 mmol, 5.0 equiv). The solution was stirred at 60 degrees Celsius. Then it was brought to room temperature and 10% palladium on carbon (200.0 mg) was added and the resulting residue was stirred for 2 hours. It was filtered, the filter cake was washed with methanol and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography with the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 53% to 65% gradient over 10 minutes, UV 254 nm detector to give (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(3-(2-oxohexahydropyrimidin-4- yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg) as a white solid.

[0756] LC-MS (ESI): [M+H] + = 474.3

[0757] Step 4.

[0758] To a solution of tert-butyl (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(3-(2- oxohexahydropyrimidin-4-yl)phenyl)propan-2-yl)pyrrolidine-1-carboxylate (150.0 mg, 0.3 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) at 0 °C was added sodium hydride (63.0 mg, 60% dispersion in kerosene). The mixture was stirred for 15 min, and tert-butyl (3R)-3-[(2S)-3-[3-(bromomethyl)phenyl]-1-(tert-butoxy)-1- oxopropan-2-yl]pyrrolidine-1-carboxylate (370.9 mg, 0.8 mmol, 2.5 equiv) was added. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with ice water at 0 °C. The reaction mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by reverse phase column chromatography using the following conditions: 12 g C18 column, mobile phase, water and acetonitrile, 90% to 100% gradient over 10 min, UV 254 nm detector to give tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine-1,3(2H,4H)- diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl))bis(pyrrolidine- 1-carboxylate) as a white solid (110 mg).

[0759] LC-MS (ESI): [M+H] + = 1249.8

[0760] Step 5.

[0761] A solution of di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1- (tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)phenyl)-2-oxodihydropyrimidine- 1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropane-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (100.0 mg, 0.1 mmol, 1.0 equiv) in 1,4-dioxane solution of hydrogen chloride (4.0 M) (1 mL) was stirred at room temperature for 2 hours. The crude product was purified by high performance liquid to give (2S,2'S)-3,3'-((((R)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3-yl)ethyl)phenyl)-2- oxodihydropyrimidine-1,3(2H,4H)-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (1.80 mg, 78.8% purity) as a white solid with the following conditions (Column: XBridge BEH C18 5 μm, 19*250 mm; Mobile Phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), Mobile Phase B: acetonitrile; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wavelength: 254 nm / 220 nm nm; RT1(min): 7.47).

[0762] LC-MS (ESI): [M+H] + = 780.4

[0763] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.33 - 6.85 (m, 12 H), 5.09 - 4.99 (m, 1 H), 4.66 - 4.52 (m, 2 H), 4.46 - 4.35 (m, 1 H), 3.82 - 3.71 (m, 1 H), 3.44 - 3.25 (m, 6 H), 3.22 - 3.05 (m, 4 H), 3.01 - 2.61 (m, 10 H), 2.48 - 2.18 (m, 7 H), 2.10 - 1.99 (m, 3 H), 1.94 - 1.81 (m, 1 H), 1.74 - 1.58 (m, 3 H).

[0764] Example 79

[0765] Reaction Scheme and Experimental Procedures:

[0766] Step 1.

[0767] In a single neck flask, 2-oxoimidazolidine-4-carboxylic acid (2.6 g, 19.8 mmol), (R)-3-((S)-3-(3-bromophenyl)-l-(tert-butoxy)-l-oxopropan-2-yl)pyrrolidine-l- carboxylate (3.0 g, 6.6 mmol), DMA (60 mL), 1,2-dimethoxyethane; nickel dichloride (290 mg, 1.3 mmol), 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine (532 mg, 2.0 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate (60 mg, 0.07 mmol), DBU (3.0 g, 19.8 mmol) were added sequentially under nitrogen and placed in a photoreactor at 40 °C under a wavelength of 450 nm overnight. The resulting mixture was extracted with ethyl acetate (3 x 200 mL) and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 1) to give (3R)-3-((2S)-l-(tert-butoxy)-l-oxo-3-(3-(2-oxoimidazolin-4- yl)phenyl)propan-2-yl)-2,3-dihydro-lH-pyrrole-l-carboxylate (800 mg, 23.8%).

[0768] LCMS (ESI, m / z): [M+H] + = 458.3

[0769] Step 2.

[0770] To a single necked flask was added (3R)-3-((2S)-1-(tert-butoxy)-1-oxo-3-(3-(2- oxoimidazolidin-4-yl)phenyl)propan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (800 mg, 1.7 mmol), (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert- butoxy)-1-oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (819 mg, 1.7 mmol), cesium carbonate (1.7 g, 5.2 mmol) and DMF (10 mL) at room temperature. The resulting mixture was stirred at 80 °C overnight. The resulting mixture was extracted with ethyl acetate (3 x 50 mL), the organic phase was dried over anhydrous sodium sulfate and the organic phase was concentrated under reduced pressure. Purification was performed by reverse phase column chromatography eluting with H20 / ACN (1 / 3) to give (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2-oxoimidazolidin-4-yl)phenyl)-1- oxopropan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (900 mg, 54.8%).

[0771] LCMS (ESI, m / z): [M+H] + = 845.5

[0772] Step 3.

[0773] To a three necked flask was added (3R)-3-((2S)-1-(tert-butoxy)-3-(3-(1-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-oxopropyl)benzyl)-2- oxooxazolidin-4-yl)phenyl)-1-oxopropan-2-yl)-2,3-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (900 mg, 1.0 mmol) and THF (10 mL) at room temperature. The flask was cooled to 0 °C under nitrogen and diisopropylamino lithium (2.0 M Solution in THF / Hexane) (2 mL, 4.0 mmol) was added. After stirring for 30 min, (R)-3-((S)-3-(3-(bromomethyl)phenyl)-1-(tert-butoxy)-1- oxopropan-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.0 mmol) was added and the reaction was allowed to proceed at room temperature overnight. The resulting mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by reverse phase column chromatography eluting with H2O / ACN (1 / 8) gave di-tert-butyl 3,3'-((2S,2'S)-((4-(3-((S)-3-(tert-butoxy)-2-((R)-1-(tert- butoxycarbonyl)-2,3-dihydro-1H-pyrrol-3-yl)-3-oxopropyl)benzyl)-2-oxooxazolidin-1,3- diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3-oxopropane-1,2-diyl)) (3R,3'R)- bis(pyrrolidine-1-carboxylate) (430 mg, 26.2%).

[0774] LCMS (ESI, m / z): [M+H] + = 1232.7

[0775] Step 4.

[0776] In a single-necked flask, (2S,2'S)-3,3'-((2S,2'S)-((4-(3-((S)-3-(tert- butoxy)-2-((R)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrol-3-yl)-3-oxopropyl)phenyl)- 2-oxoimidazolidine-1,3-diyl)bis(methylene))bis(3,1-phenylene))bis(3-(tert-butoxy)-3- oxopropan-1,2-diyl))(3R,3'R)-bis(pyrrolidine-1-carboxylate) (430 mg, 0.3 mmol, 1.0 eq) and HCl in 1,4-dioxane (5 mL) were added successively and reacted at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give (2S,2'S)-3,3'-((4-(3-((S)-2-carboxy-2-((R)-2,3-dihydro-1H-pyrrol-3-yl)ethyl)phenyl)- 2-oxoimidazolidine-1,3-diyl)bis(methylene))bis(3,1-phenylene))bis(2-((R)-pyrrolidin-3- yl)propanoic acid) (250 mg, 84.4%).

[0777] LCMS (ESI, m / z): [M+H] + = 764.4

[0778] Step 5.

[0779] In a single-necked flask, (2S,2'S)-3,3'-((4-(3-((S)-2-carboxy-2-((R)-2,3-dihydro-1H- pyrrol-3-yl)ethyl)phenyl)-2-oxoimidazolidine-1,3-diyl)bis(methylene))bis(3,1- phenylene))bis(2-((R)-pyrrolidin-3-yl)propanoic acid) (250 mg, 0.3 mmol), Pd / C (174 mg, 1.5 mmol), and MeOH (5 mL) were added successively and reacted at room temperature under hydrogen atmosphere overnight. The crude product was purified by Prep-HPLC with the following conditions (column: XBridge BEH C18 5 μm, 19*250 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 25 mL / min; gradient: 10% B to 20% B in 10 min; wavelength: 254 nm / 220 nm nm; RT1(min): 9.92) to give (2S,2'S)-3,3'-((((R)-4-(3-((S)-2-carboxy-2-((R)-pyrrolidin-3- yl)ethyl)phenyl)-2-oxoimidazolidine-1,3-diyl)bis(methylene))bis(3,1-phenyl))bis(2-((R)- pyrrolidin-3-yl)propanoic acid) (17.25 mg, yield 6.01%).

[0780] LC-MS (ESI): [M+H]+= 765.4

[0781] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.49 - 6.80 (m, 12 H), 4.37 (s, 1 H), 3.79 (q, J = 8.7 Hz, 1 H), 3.40 (t, J = 8.4 Hz, 3 H), 3.31 (s, 3 H), 3.25 - 3.02 (m, 5 H), 3.02 - 2.48 (m, 12 H), 2.42 - 2.37 (m, 5 H), 2.11 - 2.05 (m, 4 H), 1.96 - 1.78 (m, 1 H), 1.66 (s, 2 H).

[0782] Test Example 1

[0783] Inhibition of LP(a) assembly activity assay

[0784] 1. Cell culture:

[0785] On day 1, seed cells in T25 flasks (HePG2: DMEM-10% FBS-1*PS+20mM HEPES; Apoa-Hek293: DMEM-10% FBS+1*PS+20mM HEPES).

[0786] On day 5, collect cell culture supernatant.

[0787] 2. Compound treatment:

[0788] (1) Add 10 uL of diluted compound to each well of a 3599 plate.

[0789] (2) Add Apoa-HEK293 cell culture medium to the 3599 plate.

[0790] (3) Add 45 ul of HepG2 cell culture medium and incubate at 37°C for 2 hours.

[0791] (4) Stop the reaction by adding 10 uL of 1.5M EACA solution.

[0792] (5) Transfer 100 ul of supernatant to a 96-well Elisa plate.

[0793] 3. Enzyme-linked immunosorbent assay:

[0794] (1) Add 100 L / well of capture antibody, seal the plate, and incubate overnight at room temperature.

[0795] (2) Wash 3 times, 300 uL / well, 1 min / wash.

[0796] (3) Add 100 uL / well Block Buffer per well. Incubate at room temperature for 2 hours.

[0797] (4) Wash 3 times, 300 uL / well, 1 minute per wash.

[0798] (5) Add 100 uL / well sample. Seal plate and incubate at room temperature for 1 hour.

[0799] (6) Wash 3 times, 300 uL / well, 1 minute per wash.

[0800] (7) Add 100 uL / well detection antibody, seal plate and incubate at room temperature for 1 hour.

[0801] (8) Wash 3 times, 300 uL / well, 1 minute per wash.

[0802] (9) Add 100 uL / well substrate solution, 20 minutes, room temperature (dark, do not shake, seal wash).

[0803] (10) Add 50 uL / well stop solution, then gently shake plate to ensure mixing, and read OD450 by microplate reader within 5 minutes.

[0804] 4. Data Analysis:

[0805] Use H2O / PBS and HepG2 conditioned media well data for assay robustness check: H = Ave(H2O or PBS) L = Ave[HepG2 conditioned media (50-fold dilution)] SD(H) = STDEV(H2O or PBS) SD(L) = STDEV[HepG2 conditioned media (50-fold dilution)] CV%(H2O or PBS) = 100*(SD_H / Ave_H) CV%[HepG2 conditioned media (50-fold dilution)] = 100*SD_L / Ave_L Z' = 1-3*(SD_H+SD_L) / (Ave_H-Ave_L) % Inhibition = (Ave_H - Sample) / (Ave_H - Ave_L)

[0806] Fit cpd IC50 from nonlinear regression equation: Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0807] X: Log of cpd concentration

[0808] Y: % Inhibition

[0809] Top and Bottom: Plateau in the same units as Y.

[0810] logIC50: Logarithmic unit same as X

[0811] Hill Slope: Slope factor or Hill slope

[0812] The % inhibition was calculated by plugging the OD values into the formula, and the cpd IC50 values were fitted from the non-linear regression equation.

[0813] 5. The results are shown in Table 1 below:

[0814] Table 1

[0815] The structure and preparation of the positive control are shown in Table 2 below:

[0816] Table 2

[0817] Test Example 2

[0818] ICR mouse oral administration tissue distribution test

[0819] (1) Experimental materials

[0820] Animal system: ICR mice, SPF level, male, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0821] Reagents: methanol, acetonitrile (Germany Merck), hydrochloric acid (Tianjin Yongda Chemical Reagents Co., Ltd.), ammonium formate (Aldrin), formic acid (Mcclin), distilled water (Guangzhou Watsons Food and Beverage Co., Ltd.)

[0822] Instrument: LC-MS / MS (Triple Quad 5500), centrifuge (Thermo Fisher, USA), vortex mixer (Scientific Industries), ultrasonic cleaner (Dingtai (Hubei) Biochemical Science and Technology Equipment Manufacturing Co., Ltd.)

[0823] (2) Detection method

[0824] Chromatographic column: ACQUITY BEH, C18, 1.7 μm, 2.1 x 50 mm; injection volume: 5 μL; column temperature: 40 °C; mobile phase: A phase is 10 mM ammonium formate aqueous solution (pH is adjusted to 4 with formic acid, buffer pH range is 2.8-4.8); B phase is acetonitrile; gradient is shown in Table 3:

[0825] Table 3 Mobile phase gradient

[0826] Mass spectrometry conditions: tandem quadrupole mass spectrometry, ESI source, positive ion, MRM scanning mode.

[0827] (3) Test method

[0828] Dose: 10 mg / kg; Frequency: single; Route: oral; Time points: 1, 8, 24, 48 h after administration, orbital plexus blood collection, about 0.1 mL / time point, whole blood sample 3000 rpm 4°C centrifugation for 10 min, separate the upper plasma and store in the refrigerator at -20°C, and then test. After blood collection at each time point of 1, 8, 24, 48 h after administration, the mice were sacrificed by cervical dislocation, and the liver tissue was dissected, immediately washed with ice bath saline, filter paper dried, and stored in the refrigerator at -20°C.

[0829] Before testing, the sample was taken out from the refrigerator at -20°C and thawed at room temperature.

[0830] Tissue sample processing: weigh the liver tissue, cut it with scissors after weighing, add PBS solution at 1:5 (g:mL), and use a grinder to grind according to the program (program: 4 cycles of grinding, 6500 rpm for 30 s and waiting for 20 s each cycle).

[0831] Take 20 μL of plasma sample (or liver tissue homogenate) in a 1.5 mL EP tube, add 20 μL of diluent (mobile phase A), 20 μL of internal standard working solution (Muvalaplin internal standard is the compound of Example 24; Example 25 internal standard is Muvalaplin), 60 μL of methanol solution, 5-grade vortex for 5 min, and then centrifuge at 12000 rpm for 10 min; take 40 μL of supernatant, add 60 μL of diluent (mobile phase A), and add to the sample vial for LC-MS / MS analysis.

[0832] (4) Data collection and statistical analysis

[0833] The peak area ratio of the test substance to the internal standard was calculated. The weighted (W = 1 / X 2 ) least squares method was used for regression calculation, and the linear regression equation was obtained. The concentration of the test substance was calculated by substituting the ratio into the equation. According to the tissue concentration-time data, the main pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.3.5.340 pharmacokinetic software. The results are shown in Tables 4 and 5, and Tables 6 and 7:

[0834] Table 4 Tissue distribution results of Lp(a) inhibitor in ICR mice after single gavage of 10 mg / kg

[0835] Table 5

[0836] Table 6

[0837] wherein the compound "Muvalaplin" has the structure shown below:

Claims

A compound of Formula (I), a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof: L (L1A) n (I) wherein n is 2 or 3; each A is the same or different; each L1is the same or different; Each L1 is independently a bond, L2, L2-L3-, -NH-L2-L3-, -C(O)-, -NH-L2-, -L3-, -C 3-6 Cycloalkylene-L3-,-C 3-6 Heterocyclic alkyl group -, -L2-NH-CO- or -L2-CO-NH-; the heterocyclic alkyl group contains one or two heteroatoms selected from N, O or S; L2is selected from a bond or C 1-5 alkylene; L3is selected from S or O; each A is independently Cy1is a six-membered saturated or unsaturated carbocyclic ring, a phenyl ring, a six-membered saturated or unsaturated heterocyclic ring, or a six-membered heteroaromatic ring; the heterocyclic or heteroaromatic ring contains 1, 2, or 3 heteroatoms selected from N, O, or S; Cy2is a five-membered heteroaromatic ring or a three- to five-membered saturated heterocyclic ring; the heteroaromatic or heterocyclic ring contains 1, 2, or 3 heteroatoms selected from N, O, or S; each R1and each R8are each independently H, F, Cl, Br, I, =0, C 1-6 alkyl, C 1-6 alkyloxy, hydroxy, amino, carboxy, nitro, cyano, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl or alkynyl being optionally substituted with a substituent selected from the group consisting of H, F, Cl, Br, I or C 1-6 alkyl. R2is H, -NR 21 R 22 , F, Cl, Br, I, C 1-6 alkyl, hydroxyl, amino, carboxyl, nitro, C 1-6 alkenyl, C 1-6 alkynyl, -C 1-6 alkylene-OH, -C 1-6 alkylene-NH2, -C 1-6 alkylene-CONH2, or a three- to six-membered heterocycloalkyl; said alkyl, alkylene, alkenyl, alkynyl, or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl; said heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from N, O, or S; R 21 and R 22 each independently H or C 1-6 alkyl; said alkyl is optionally substituted with a substituent selected from the group consisting of H, F, Cl, Br, I or C 1-6 alkyl; R2and X, together with the carbon atom on Cy1, form a five- or six-membered saturated or unsaturated carbocyclic ring, or a five- or six-membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from N, O, or S; optionally, the carbocyclic or heterocyclic ring is substituted with one or more substituents selected from H, F, Cl, Br, I, =0, or C1-C4alkyl; 1-6 substituted with one or more substituents selected from H, F, Cl, Br, I, =0, or C1-C4alkyl; R3and R5are each independently selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C R4is H, F, Cl, Br, I, CN, C 1-6 alkyl, hydroxyl, amino, or carboxyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl; R6is -COOR 61 or a four-, five-, six-, seven-, or eight-membered saturated or unsaturated heterocyclic ring containing 1, 2, 3, 4, or 5 heteroatoms; the heteroatoms selected from N, O, or S; optionally, the heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 substituted with a substituent selected from H, F, Cl, Br, I, or C R 61 H or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C R7is H, CN, C 1-6 R7is H, CN, C 1-6 R7is H, CN, C X is CH or N; n1and n5are each independently 1, 2, or 3; when n is 2, L is selected from a four- to six-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, or one of the following structures: Ra is absent or selected from CN, NO2, hydroxyl, carboxyl, or amino; Rb, Rc are each independently selected from H or =O; Optionally, one of Rband Rctogether with the carbon atom to which they are attached forms C 3-6 saturated carbocyclic ring; optionally, the saturated carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 substituted with a substituent selected from H, F, Cl, Br, I, or C X1is O, S, N, or CH; X2, X3are each independently a bond, C 1-5 alkylene or C 1-5 alkylene-O-; n2is 0, 1, 2, or 3; n3is 1, 2, or 3; when n is 3, L is selected from a four- to eight-membered saturated heterocyclylene, four- to eight-membered heteroarylene, three- to eight-membered saturated cycloalkylene, arylene, said heterocyclylene, heteroarylene contains 1, 2, 3, or 4 heteroatoms selected from N, O, or S; optionally, said heterocyclylene, heteroarylene, cycloalkylene, and arylene are substituted with substituents selected from H, F, Cl, Br, I, =0, C 1-6 alkyl, hydroxyl, amino, carboxyl, nitro, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl, or alkynyl are optionally substituted with substituents selected from H, F, Cl, Br, I, or C 1-6 alkyl; said alkyl, alkenyl, or alkynyl are optionally substituted with substituents selected from H, F, Cl, Br, I, or C provided that: (1) when L is when each L1is methylene and each Cy1is phenylene, at least one of R4and R2in the structure of A is not H at the same time; (2) when L is A is not and (3) when L is when both L1are -NH-, each Cy1is phenylene, and each R6is -COOH, at least one of R4and R2in the structure of A is not H at the same time. The compound of claim 1, a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein, When n is 2, L is selected from one of the following structures: When n is 3, L is selected from one of the following structures: Rd is H, F, Cl, Br, I, =0, C 1-6 alkyl, hydroxy, amino, carboxyl, nitro, C 1-6 alkenyl, C 1-6 alkynyl; said alkyl, alkenyl or alkynyl is optionally substituted with a substituent selected from the group consisting of H, F, Cl, Br, I or C 1-6 alkyl. X5is CH or N; n4is 0, 1, or 2. The compound of claim 1 or 2, a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein, when n is 2, -L1-L-L1- is selected from the following structures: when n is 3, L-(L1)3- is selected from the following structures: X6is O, -NH- or C 1-4 alkylene; X7is C 3-6 cycloalkylene; each L1is independently L2, -O-, -NH-, -L2-O-, -NH-L2-, or -NH-CO-; L2is selected from C 1-5 alkylene; n 11 , n 12 , and n 13 are each independently 0 or 1. The compound, stereoisomer, metabolite, co-crystal, deuterated derivative, or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein, A is the following structure: R 61 is H or C 1-6 alkyl; Y1is O, S, NH, or CH2; Y2is CH2or C=O; n 21 is 0 or 1 ; n 22 is 0, 1 or 2. The compound of any one of claims 1-4, a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein, Cy1is a phenyl ring, a six-membered saturated or unsaturated heterocyclic ring; the heterocyclic ring contains 1, 2, or 3 heteroatoms selected from N, O, or S; Cy2is a five-membered heteroaromatic ring; the heteroaromatic ring contains 1 or 2 heteroatoms selected from N, O, or S; R1is H, F, Cl, Br, I, =0, C 1-6 alkyl, C 1-6 alkyloxy, hydroxy, amino, carboxy, nitro, cyano; said alkyl is optionally substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; R2is H, -NR 21 R 22 , F, Cl, Br, I, C 1-6 alkyl, hydroxyl, amino, carboxyl, nitro, -C 1-6 alkylene-OH, -C 1-6 alkylene-NH2, -C 1-6 alkylene-CONH2or a four- to six-membered heterocycloalkyl; said alkyl, alkylene or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, I or C 1-6 alkyl; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; R 21 and R 22 each independently is H or C 1-6 alkyl; said alkyl is optionally substituted with a substituent selected from the group consisting of H, F, Cl, Br, I or C 1-6 alkyl; R2and X, together with the carbon atom on Cy1, form a five- or six-membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, or S; optionally said carbocyclic or heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, =0, or C1-C4alkyl; 1-6 substituted with a substituent selected from H, F, Cl, Br, I, =0, or C1-C4alkyl; R3and R5are each independently selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C 1-6 alkyl; optionally, said alkyl is substituted with a substituent selected from the group consisting of H, F, Cl, Br, I, or C R4is H, F, Cl, Br, I, CN, C 1-6 alkyl, hydroxyl, amino, or carboxyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl; and R4is H, F, Cl, Br, I, CN, C R6is -COOR 61 or a four-, five-, six-, seven-, or eight-membered unsaturated heterocyclic ring containing 1, 2, 3, 4, or 5 heteroatoms; the heteroatoms selected from N, O, or S; optionally, the heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 substituted with a substituent selected from H, F, Cl, Br, I, or C R 61 is H or C 1-6 alkyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-6 alkyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C R7is H, CN, C 1-6 R7is H, CN, C 1-6 R7is H, CN, C X is CH or N; n1is 1, 2, or 3. The compound of any one of claims 1-5, a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein, Cy1is selected from the following structures: a benzene ring, Cy2is selected from the following structures: R1is H, F, Cl, Br, I, =0, C 1-4 alkyl, C 1-4 alkyloxy, hydroxy, cyano or amino; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br or I; R2is H, -NR 21 R 22 F, Cl, Br, I, C 1-4 alkyl, -C 1-4 alkylene-OH, -C 1-4 alkylene-NH2, -C 1-4 alkylene-CONH2or a four-, five- or six-membered heterocycloalkyl; said alkyl, alkylene or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; said heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from N, O or S; R 21 and R 22 each independently is H or C 1-4 alkyl; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; R2and X, and the carbon atom on Cy1form a five- or six-membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing 1 heteroatom selected from N, O, or S; optionally, the carbocyclic or heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or =O; R3and R5are each independently selected from H, F, Cl, Br, or I; R4is H, F, Cl, Br, I, CN, or C 1-4 alkyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C 1-4 alkyl; optionally, the alkyl is substituted with a substituent selected from H, F, Cl, Br, I, or C R6is -COOR 61 or a four-, five-, or six-membered unsaturated heterocyclic ring containing 1, 2, 3, 4, or 5 heteroatoms selected from N, O, or S; optionally, the heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I; R 61 is H or C 1-4 alkyl; optionally, said alkyl is substituted with a substituent selected from H, F, Cl, Br, or I; R7is H, C 1-4 alkyl, or R7and R2and X form a four-, five-, or six-membered saturated carbocyclic ring; optionally, the carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I; X is CH or N; n1is 1 or 2. The compound of any one of claims 1-6, a stereoisomer, a metabolite, a co-crystal, a deuterated derivative, or a pharmaceutically acceptable salt thereof, wherein, Cy1is selected from the following structures: a benzene ring, Cy2is selected from the following structures: R1is H, F, Cl, Br, I, =O, hydroxyl, or amino; R2is H, -NR 21 R 22 , C 1-3 alkyl, -C 1-3 alkylene-OH, -C 1-3 alkylene-NH2, -C 1-3 alkylene-CONH2, or a five-membered saturated heterocycloalkyl; said alkyl, alkylene, or heterocycloalkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; said heterocycloalkyl contains one N atom; R 21 and R 22 each independently is H or C 1-3 alkyl; said alkyl is optionally substituted with a substituent selected from H, F, Cl, Br, or I; R2and X, together with the carbon atom on Cy1, form a five- or six-membered saturated carbocyclic ring, or a five- or six-membered saturated heterocyclic ring containing 1 heteroatom selected from N; optionally, the carbocyclic or heterocyclic ring is substituted with a substituent selected from H, F, Cl, Br, I, or =O; R3and R5are H; R4is H, F, Cl, Br, I, or CN; R6is -COOR 61 or a five-membered unsaturated heterocyclic ring containing 3 or 4 heteroatoms; the heteroatoms being selected from N; R 61 is H or C 1-4 alkyl; R7is H, C 1-3 alkyl, or R7and R2and X form a five-membered saturated carbocyclic ring; optionally, the carbocyclic ring is substituted with a substituent selected from H, F, Cl, Br, or I; X is CH or N; n1is 1 or 2. The compound, stereoisomer, metabolite, co-crystal, deuterated derivative, or pharmaceutically acceptable salt thereof of claim 1, wherein, The compound is selected from the following structures: A pharmaceutical composition comprising a compound of any one of claims 1-8, a stereoisomer, metabolite, co-crystal, deuterated derivative, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Use of a compound of any one of claims 1-8, a stereoisomer, metabolite, co-crystal, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the manufacture of a medicament for treating a cardiovascular disease. The use according to claim 10, wherein The cardiovascular disease is arteriosclerosis; preferably, atherosclerosis. Use of a compound of any one of claims 1-8, a stereoisomer, metabolite, co-crystal, deuterated derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9, in the manufacture of an Lp(a) protein inhibitor.

Images