COMPOUND HAVING PD-L1 INHIBITORY ACTIVITY, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided are a compound for the prevention and treatment of diseases associated with PD-L1, a preparation method therefor and use thereof. Specifically, provided are the compound of formula I, the stereoisomer and the racemate thereof, or pharmaceutically acceptable salts thereof, and also provided is an application thereof in the preparation of a drug for the prevention and treatment of diseases associated with PD-Ll.

##STR00001##

Claims

1. A compound of formula Ia, or a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof: ##STR00152## wherein, R.sub.1 is selected from the group consisting of CN, OH, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; and the substituted means having the one or more (such as 1, 2, or 3) substituents selected from halogen, and substituted or unsubstituted phenoxy; each X.sub.1 is independently CH or N; Y.sub.1 is selected from substituted or unsubstituted C1-C4 alkyl; and the heteroaryl has 1-4 heteroatoms selected from N or O; Y.sub.2 is O; B and B are each independently selected from the group consisting of H, substituted or unsubstituted amino, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, and the heteroaryl has 1-3 heteroatoms selected from S, O, N, substituted or unsubstituted NHC(O), substituted or unsubstituted C1-C4 alkyl; and the B ring and B ring cannot be absent at the same time; and the substituted means having one or more (such as 1, 2, 3 or 4) substituents selected from the group Z: group Z substituents are selected from the group consisting of H, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; and the substituted means having one or more (such as 1, 2, 3, or 4) substituents selected from the Z group; wherein the Z substituent is selected from: substituted or unsubstituted 5-7 membered aryl, C1-C4 alkylamino, substituted or unsubstituted C1-C4 alkyl, methylcarbonyl, substituted or unsubstituted 5-6 membered saturated carbocyclic ring, substituted or unsubstituted 5-7 membered saturated heterocyclic group, substituted or unsubstituted 5-7 membered heteroaryl, and the heteroaryl or heterocyclic group has 1-3 heteroatoms selected from S, O and N; and, in Y.sub.1 and Z substituents, the substituted means substituted by groups selected from the group consisting of OH, CN, COOH, O, aminocarbonyl, C1-C4 alkyl, hydroxy C1-C4 alkyl, ##STR00153## C1-C4 alkylcarbonyl; and the compound of formula Ia is other than compounds selected from the group consisting of: ##STR00154##

2. The compound, or a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof of claim 1, wherein B and B are each independently selected from substituted or unsubstituted 5-10 membered heteroaryl group, and the heteroaryl group has 1-3 heteroatoms selected from S, O, and N.

3. The compound, or a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof of claim 1, wherein Y.sub.1 is CH.sub.2.

4. The compound, or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof of claim 1, wherein B and B are each independently selected from: ##STR00155## NH.sub.2; wherein R.sub.1 is selected from H, CN, OH, halogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C1-C4 alkoxy; X.sub.1-X.sub.3 are each independently selected from C, N, S or 0; and when each X.sub.1X.sub.3 is N or C, X.sub.1X.sub.3 can optionally comprises 1-2H atoms for forming a stable structure.

5. (canceled)

6. (canceled)

7. A compound, or a stereoisomer, a racemate or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: ##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161##

8. A pharmaceutical composition, wherein comprising a therapeutically effective amount of a compound, or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof of claim 1, and pharmaceutically acceptable excipients thereof.

9. A method for preparing the compound of formula (I): method I: ##STR00162## In a suitable solvent, reacting compound 1 (wherein Q is selected from 0 or N) with compound 2 (n=1, 2) under the action of a palladium catalyst and in the presence of a base and a phosphine compound to obtain compound 3; Subjecting compound 3 to a reductive amination reaction to obtain the compound of formula 4, wherein, R.sub.1, R.sub.2, X.sub.1-X.sub.3 are as defined as in claim 1.

10. A use of the compound, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of claim 1, or the composition of claim 8 in the preparation of a medicine for treating or preventing diseases related to PD-L1, which comprises: (1) For the treatment of various tumors, comprising but not limited to melanoma (such as metastatic malignant melanoma), kidney cancer (such as clear cell carcinoma), prostate cancer (such as hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, and lung cancer (e.g., non-small cell lung cancer); Bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or eye malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastrointestinal, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penis cancer, chronic or acute leukemia (comprising acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), childhood solid tumor, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal pelvis cancer, central nervous system (CNS) neoplasm/tumor, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcomas, epidermoid carcinomas, squamous cell carcinomas, T-cell lymphomas, environmentally induced cancers (including those caused by asbestos), and combinations therefore; Metastatic cancer, especially metastatic cancer expressing PD-L1; (2) For combined therapy regimen, such as combined tumor chemotherapy regimen, other tumor immunotherapeutics (small molecule compounds and antibodies, etc.), radiotherapy regimen, tumor-targeted drugs, tumor vaccines, etc such as human papilloma virus (HPV), hepatitis virus (HBV and HCV) and Kaposi herpes sarcoma virus (KHSV); The agents may be administered before, after or at the same time or may be co-administered with other known therapies; (3) For the treatment of patients exposed to specific toxins or pathogens, used alone or in combination; which comprises but are not limited to the treatment of various viruses, pathogenic bacteria, pathogenic fungi, pathogenic parasites, etc; such as HIV, hepatitis virus (A, B, C), influenza virus, herpes virus, Giardia, malaria, Leishmania, Staphylococcus aureus, Pseudomonas aeruginosa and other established infections; (4) For inducing therapeutic autoimmune response to treat patients with inappropriate accumulation of other autoantigens, such as amyloid deposits, comprising A type of Alzheimer's disease, cytokines such as TNF and IgE.

11. A compound selected from the following group, or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, TABLE-US-00003 No. Structure of compound 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82

12. A compound selected from the following group, or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, TABLE-US-00004 No. Structure of compound 6 9 20 21 22 24 26 27 28 30 33 34 35 36 37 39 41 42 43 45 46 47 49 50 51 52 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82

13. A compound selected from the following group, or a stereoisomer, a racemate, or a pharmaceutically acceptable salt thereof, TABLE-US-00005 No. Structure of compound 9 26 27 30 35 36 37 42 43 45 46 47 49 50 51 56 58 60 62 63 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 81

Description

EXAMPLE 1

2,2,2-trifluoro-N-((6-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)acetamide

[0158] ##STR00039##

Tert-butyl((6((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-meth oxypyridin-3-yl)methyl)carbamate

[0159] ##STR00040##

[0160] To intermediate A (50.0 mg, 0.20 mmol), tert-butyl ((6-chloro-2-methoxypyridin-3-yl)methyl)carbamate (56.0 mg, 0.20 mmol), cesium carbonate (134.0 mg, 0.41 mmol) in toluene (1 mL), palladium acetate (4.6 mg, 0.02 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (17.5 mg, 0.041 mmol) were added, the mixture was exchanged with nitrogen for 3 minutes and heated to 110 C. to react overnight under argon atomsphere in sealed vessel. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified with Prep-TLC (petroleum ether/ethyl acetate=4/1) to obtain the target compound (20.0 mg, 20%) as a yellow oil.

[0161] MS (ESI): m/z=479.3 [M+H].sup.+.

[0162] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.47-7.33 (m, 3H), 7.22-7.14 (m, 3H), 6.99 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.5 Hz, 1H), 6.40 (d, J=8.0 Hz, 1H), 5.41-5.31 (m, 2H), 5.09 (t, J=5.4 Hz, 1H), 4.50 (t, J=7.1 Hz, 2H), 3.95 (d, J=5.8 Hz, 2H), 3.84 (s, 3H), 1.96 (s, 3H), 1.86 (s, 3H), 1.35 (s, 7H).

2,2,2-trifluoro-N-(((6-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)acetamide (Compound 1)

[0163] ##STR00041##

[0164] Under 0 C., trifluoroacetic acid (1 mL) was added to the solution of example 1A (20.0 mg, 0.041 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, then water (5 mL) and dichloromethane (10 mL) were added. A saturated sodium bicarbonate solution was added to in portion adjust pH to 9. The organic layer was separated, washed with brine, dried (anhydrous sodium sulfate), filtered and concentrated. The residue was separated and purified by combiflash column chromatography (methanol/water) to obtain the target compound Example 1 (4.0 mg, 20%) as an orange solid.

[0165] MS (ESI): m/z=475.1 [M+H].sup.+.

[0166] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.72 (s, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.38 (dd, J=10.9, 7.5 Hz, 2H), 7.20 (dd, J=14.0, 7.3 Hz, 2H), 7.00 (d, J=6.5 Hz, 1H), 6.93 (d, J=7.0 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 5.38 (s, 2H), 5.09 (t, J=5.4 Hz, 1H), 4.51 (d, J=5.0 Hz, 2H), 4.21 (s, 2H), 3.86 (s, 3H), 1.96 (s, 3H), 1.87 (s, 3H).

EXAMPLE 2

N-(2-(((6-(3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-methoxypyridin-3-yl)methyl)amino)ethyl)acetamide

[0167] ##STR00042##

N-(2-(((6-chloro-2-methoxypyridin-3-yl)methyl)amino)ethyl)acetamide

[0168] ##STR00043##

[0169] 6-chloro-2-methoxynicotyraldehyde (400.0 mg, 2.34 mmol) and N-(2-aminoethyl)acetamide (240.0 mg, 2.34 mmol) were mixed into ethanol (10 mL), and the mixture was stirred at reflux for 2 hours, then concentrated under reduced pressure. The crude product was redissolved in methanol (10 mL), sodium borohydride (89.0 mg, 2.34 mmol) was added in portions, the mixture was reacted under stirring at room temperature for 2 hours. The solvent was removed under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with dichloromethane/methanol from 50/1 to 10/1) to obtain compound 2A (350.0 mg, 58%).

[0170] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.78 (brs, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.06 (d, J=7.56 Hz, 1H), 3.88 (s, 3H), 3.61 (s, 2H), 3.15-3.10 (m, 2H), 2.54-2.50 (m, 2H), 1.79 (s, 3H).

Tert-butyl (2-acetylaminoethyl)((6-chloro-2-methoxypyridin-3-yl)methyl)carbamate

[0171] ##STR00044##

[0172] In ice bath, di-tert-butyl dicarbonate (360.0 mg, 1.63 mmol) was added to a mixture of compound 2A (350.0 mg, 1.36 mmol) and triethylamine (10 mL) in dichloromethane (10 mL). The mixture was reacted under stirring at room temperature for 2 hours, then concentrated to afford crude product, and purified by silica gel column chromatography (eluted with dichloromethane/methanol=50/1) to give compound 2B (285.0 mg, 58%) as a colorless oil.

[0173] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.89 (brs, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 4.27 (s, 2H), 3.88 (s, 3H), 3.23-3.14 (m, 4H), 1.79 (s, 3H), 1.41 (s, 9H).

N-(2-(((6-(3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-methoxy pyridin-3-yl)methyl)amino)ethyl)acetamide (Compound 2)

[0174] ##STR00045##

[0175] Palladium acetate (18.0 mg, 0.083 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (70.0 mg, 0.165 mmol) were added to a mixture of intermediate A (200.0 mg, 0.83 mmol), compound 2B (295.0 mg, 0.83 mmol), cesium carbonate (538.0 mg, 1.65 mmol) and toluene (3 mL). The mixture was exchanged with nitrogen for 3 minutes, and reacted at 110 C. under nitrogen in sealed vessel overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was separated and purified with a combiflash column chromatography (methanol/water) to obtain the target compound example 2 (120.0 mg, 31%) as a yellow oil.

[0176] MS (ESI): m/z=362.1 [M101].sup.+.

[0177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.86 (s, 1H), 7.40-7.36 (m, 3H), 7.22-7.17 (m, 2H), 6.99 (d, J=6.6 Hz, 1H), 6.93 (d, J=6.6 Hz, 1H), 6.42 (d, J=8.0 Hz, 1H), 5.37 (s, 2H), 5.09 (t, J=5.4 Hz, 1H), 4.49 (dd, J=14.2, 5.3 Hz, 2H), 4.20 (s, 2H), 3.85 (s, 3H), 3.20-3.03 (m, 4H), 1.96 (s, 3H), 1.86 (s, 3H), 1.73 (s, 3H).

EXAMPLE 3

(3-(((5-(aminomethyl)-6-methoxypyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol

[0178] ##STR00046##

Tert-butyl((6-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2-meth oxypyridin-3-yl)methyl)carbamate

[0179] ##STR00047##

[0180] To intermediate A (500.0 mg, 2.0 mmol), tert-butyl ((6-chloro-2-methoxypyridin-3-yl)methyl)carbamate (560.0 mg, 2.0 mmol), cesium carbonate (1340.0 mg, 4.1 mmol) in toluene (5 mL), palladium acetate (46.0 mg, 0.2 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (175.0 mg, 0.41 mmol) were added. The mixture was exchanged with nitrogen for 3 minutes, and reacted at 110 C. under nitrogen in sealed vessel overnight. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=5/1) to obtain the target compound 3A (450.0 mg, 45%) as a yellow oil.

[0181] MS (ESI): m/z=479.3 [M+H].sup.+.

(3-(((5-(aminomethyl)-6-methoxypyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol (Compound 3)

[0182] ##STR00048##

[0183] Under 0 C., 1,4-dioxane hydrochloride solution (4 M, 3 mL) was added to compound 3A (65.0 mg, 0.13 mmol), the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was separated and purified with combiflash column chromatography (methanol/water) to obtain the target compound example 3 (15.0 mg, 29%) as a transparent gum.

[0184] MS (ESI): m/z=362.1 [M16].sup.+.

[0185] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.15 (s, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.38 (dd, J=10.4, 7.8 Hz, 2H), 7.20 (dd, J=7.8, 7.3 Hz, 2H), 7.00 (d, J=6.8 Hz, 1H), 6.92 (d, J=6.9 Hz, 1H), 6.48 (d, J=8.0 Hz, 1H), 5.41 (s, 2H), 5.13 (t, J=5.2 Hz, 1H), 4.51 (d, J=4.5 Hz, 2H), 3.89 (s, 3H), 3.85 (s, 2H), 1.96 (s, 3H), 1.86 (s, 3H).

EXAMPLE 4

N,N-((((((((2,2-dimethyl-[1,1-biphenyl)-3,3-diyl)bis(methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diethylamide

[0186] ##STR00049##

6,6-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxo))bis(2-methoxy nicotyraldehyde)

[0187] ##STR00050##

[0188] Palladium acetate (25 mg, 0.11 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (93.0 mg, 0.22 mmol) were added to a mixture of intermediate A (133.0 mg, 0.55 mmol), 6-chloro-2-methoxynicotyraldehyde (188.0 mg, 1.1 mmol) and cesium carbonate (716.0 mg, 2.2 mmol) in toluene (3 mL), the mixture was exchanged with nitrogen for 3 minutes, and reacted at 110 C. under nitrogen in sealed vessel overnight. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=8/1) to obtain the target compound 4A (40.0 mg, 14%) as a white solid.

[0189] MS (ESI): m/z=513.0 [M+H].sup.+.

N,N-((((((((2,2-dimethyl-[1,1-biphenyl)-3,3-diyl)bis(methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diethylamide (Compound 4)

[0190] ##STR00051##

[0191] Acetic acid (2 drops) was added to a mixture of 4A (40.0 mg, 0.078 mmol) and N-(2-aminoethyl) acetamide (24.0 mg, 0.23 mmol) in N, N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 1 hour, sodium cyanoborohydride (19.0 mg, 0.31 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was separated and purified with combiflash column chromatography (acetonitrile/ammonium bicarbonate aqueous solution (10 mmol/L)) to obtain the target compound example 4 (3 mg, 5.6%) as a transparent gum.

[0192] MS (ESI): m/z=343.2 [M/2+H].sup.+.

[0193] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.75 (s, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.3 Hz, 2H), 7.22 (t, J=7.5 Hz, 2H), 7.02 (d, J=7.6 Hz, 2H), 6.39 (d, J=7.9 Hz, 2H), 5.36 (s, 4H), 3.83 (s, 6H), 3.51 (s, 4H), 3.34 (s, 4H), 3.07 (dd, J=12.5, 6.4 Hz, 4H), 1.97 (s, 6H), 1.74 (s, 6H).

EXAMPLE 5

6,6-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo)) di(2-methoxynicotyronitrile) (Compound 5)

[0194] ##STR00052##

[0195] Palladium acetate (55 mg, 0.248 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (210.0 mg, 0.496 mmol) were added to a mixture of intermediate A (300.0 mg, 1.24 mmol), 6-chloro-2-methoxynicotyronitrile (416 mg, 2.48 mmol) and cesium carbonate (1616.0 mg, 4.96 mmol) in toluene (5 mL). The mixture was exchanged with nitrogen for 3 minutes, and reacted at 110 C. under nitrogen in sealed vessel overnight. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain the target compound example 5 (300.0 mg, 47.8%) as a white solid.

[0196] MS (ESI): m/z=507.2 [M+H].sup.+.

[0197] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=8.4 Hz, 2H), 7.43 (d, J=7.5 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.06 (d, J=7.3 Hz, 2H), 6.60 (d, J=8.3 Hz, 2H), 5.49 (s, 4H), 3.98 (s, 6H), 1.97 (s, 6H).

EXAMPLE 6

((((2,2-dimethyl-[1,1-biphenyl)-3,3-diyl) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) dimethylamine (Compound 6)

[0198] ##STR00053##

[0199] Raney nickel (45.0 mg, 50%) was added to a mixture of compound example 5 (90.0 mg, 0.17 mmol) and aqueous ammonia (0.5 mL) in tetrahydrofuran (1 mL) and methanol (3 mL), and the mixture was stirred at room temperature under hydrogen overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated. The residue was separated and purified with combiflash column chromatography (acetonitrileaqueous ammonium bicarbonate solution (10 mmol/L)) to obtain the target compound example 6 (32.0 mg, 35%) as a transparent gum.

[0200] MS (ESI): m/z=241.1 [(M32)/2].sup.+.

[0201] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.60 (d, J=7.9 Hz, 2H), 7.40 (d, J=7.5 Hz, 2H), 7.21 (t, J=7.5 Hz, 2H), 7.02 (d, J=7.5 Hz, 2H), 6.38 (d, J=7.9 Hz, 2H), 5.36 (s, 4H), 3.83 (s, 6H), 3.53 (s, 4H), 1.97 (s, 6H).

EXAMPLE 7

(3-(((6-(aminomethyl)pyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol

[0202] ##STR00054##

6-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)cyanopyridine

[0203] ##STR00055##

[0204] The intermediate A (400.0 mg, 1.65 mmol), 6-chlorocyanopyridine (150.0 mg, 1.08 mmol), palladium acetate (22.4 mg, 0.1 mmol), 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (120.0 mg, 0.28 mmol) and cesium carbonate (700.0 mg, 2.13 mmol) were added into anhydrous toluene. The mixture was replaced with nitrogen for three times, heated to reflux overnight, cooled, filtered, and concentrated, then the residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=1/5) to provide the target compound 7A (58.0 mg, 15%).

[0205] MS (ESI): m/z=367.1[M+23].sup.+.

(3-(((6-(aminomethyl)pyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol (Compound 7)

[0206] ##STR00056##

[0207] Compound 7A (58.0 mg, 0.17 mmol) was dissolved in methanol (5 mL), raney Ni and a drop of saturated ammonia water were added, the mixture was replaced with hydrogen for three times and stirred overnight under hydrogen atmosphere. The mixture was filtered and concentrated, and the residue was separated and purified with combiflash column chromatography (methanol/water) to obtain the target compound Example 7 (16 mg, 27%).

[0208] MS (ESI): m/z=349.1 [M+H].sup.+.

[0209] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (dd, J=8.1, 7.4 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.05 (d, J=8.2 Hz, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 5.47 (s, 2H), 4.71 (s, 2H), 3.83 (s, 2H), 2.08 (s, 3H), 2.03 (s, 3H).

EXAMPLE 8

(3-(((6-(aminomethyl)pyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol

[0210] ##STR00057##

(3-(((6-methoxy-5-nitropyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol

[0211] ##STR00058##

[0212] Intermediate A (290.0 mg, 1.2 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60.0 mg, 1.5 mmol) was added under ice bath. after the mixture was stirred for half an hour, 6-chloro-2-methoxy-3-nitropyridine (188.0 mg, 1.0 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=1/5) to give the target compound 8A (50.0 mg, 12%).

[0213] MS (ESI): m/z=377.1 [M-OH].sup.+.

(3-(((6-(aminomethyl)pyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol (Compound 8)

[0214] ##STR00059##

[0215] Compound 8A (50.0 mg, 0.12 mmol) was dissolved in methanol (8 mL), iron powder (30.0 mg, 0.6 mmol) and satured ammonium chloride solution (1 mL) were added, and the mixture was stirred at reflux overnight under nitrogen protection. The mixture was filtered and concentrated, and the residue was separated and purified by Prep-HPLC to obtain the target compound Example 8 (25.0 mg, 54%).

[0216] MS (ESI): m/z=365.1[M+H].sup.+.

[0217] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.41 (d, J=8.6 Hz, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.09 (d, J=8.2 Hz, 1H), 7.03 (dd, J=6.7, 4.9 Hz, 2H), 6.27 (d, J=8.1 Hz, 1H), 5.35 (s, 2H), 4.70 (s, 2H), 3.97 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H).

EXAMPLE 9

[0218] 1,1-(((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo))bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (piperidine-2-carboxylic acid) (Compound 9)

##STR00060##

[0219] Intermediate 4A (60.0 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (3 mL), and piperidine-2-carboxylic acid (75.0 mg, 0.5 mmol) was added and stirred at 80 C. under nitrogen protection for 2 hours. After cooled, sodium cyanoborohydride (32.0 mg, 0.5 mmol) was added to the system, stirred at room temperature overnight, and concentrated. The residue was purified by Prep-HPLC to obtain the target compound example 9 (5.0 mg, 6%).

[0220] MS (ESI): m/z=739.3[M+H].sup.+.

[0221] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.18 (s, 2H), 7.79 (d, J=8.1 Hz, 2H), 7.46 (d, J=7.4 Hz, 2H), 7.25 (t, J=7.6 Hz, 2H), 7.12-7.01 (m, 2H), 6.52 (d, J=8.1 Hz, 2H), 5.52 (s, 4H), 4.34 (m, 4H), 4.03 (s, 6H), 3.46 (m, 4H), 2.97 (t, J=11.8 Hz, 2H), 2.25 (m, 2H), 2.07 (s, 6H), 1.92-1.46 (m, 10H).

EXAMPLE 10

N-(2-((4-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methoxy)-2,6-dimethoxybenzyl)amino)ethyl) acetamide

[0222] ##STR00061##

4-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methoxy)-2,6-dimethoxy benzaldehyde

[0223] ##STR00062##

[0224] Intermediate A (200.0 mg, 0.83 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (331.0 mg, 1.8 mmol), and triphenylphosphine (551.0 mg, 2.1 mmol) in tetrahydrofuran (4 mL) was cooled to 0 C. A solution of diisopropyl azodicarboxylate (420.0 mg, 2.1 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature and then concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=9/1-3/7) to provide a mixture, then the mixture was further separated and purified with combiflash column chromatography (eluted with 0.01% of trifluoroacetic acid aqueous solution/acetonitrile=90/10-50/50) to obtain the target compound 10A (138.0 mg, 39%) as a white solid.

[0225] MS (ESI): m/z=407 [M+H].sup.+.

N-(2-((4-((3 -(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methoxy)-2, 6-Dimethoxybenzyl) amino) ethyl) acetamide (Compound 10)

[0226] ##STR00063##

[0227] A mixed solution of compound 10A (50.0 mg, 0.12 mmol), N-(2-aminoethyl) acetamide (18.0 mg, 0.18 mmol) and acetic acid (4 mg, 0.06 mmol) in N, N-dimethylformamide (0.2 mL) and methanol (0.2 mL) was stirred at room temperature for 1 hour. Then sodium cyanoborohydride (30.0 mg, 0.48 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was directly separated and purified with combiflash column chromatography (eluted with 0.1% formic acid aqueous solution/acetonitrile=95/5-70/30) to obtain the target compound example 10 (24.0 mg, 40%) as a white solid.

[0228] MS (ESI): m/z=493 [M+H].sup.+.

[0229] .sup.1H NMR (400 MHz, CD3OD) 8.52 (s, 1H), 7.47-7.34 (m, 2H), 7.25-7.18 (m, 2H), 7.07-6.95 (m, 2H), 6.37 (s, 2H), 5.17 (s, 2H), 4.67 (s, 2H), 4.09 (s, 2H), 3.85 (s, 6H), 3.41 (t, J=5.9 Hz, 2H), 2.97 (t, J=6.0 Hz, 2H), 2.03 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H).

EXAMPLE 11

(3-((4-(aminomethyl)-3,5-dimethoxyphenoxy)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol (Compound 11)

[0230] ##STR00064##

[0231] A mixture of compound 10A (50.0 mg, 0.12 mmol) and ammonium acetate (46.0 mg, 0.60 mmol) in N, N-dimethylformamide (0.2 mL) and methanol (0.2 mL) was stirred at room temperature for 1 hour, and sodium cyanoborohydride (30.0 mg, 0.48 mmol) was added to the reaction mixture and the reaction mixture was stirred overnight at room temperature. The reaction mixture was directly separated and purified with combiflash column chromatography (eluted with 0.1% formic acid aqueous solution/acetonitrile=95/5-70/30) to obtain the target compound example 11 (12.0 mg, 22%) as a white solid.

[0232] MS (ESI): m/z=391 [M+HNH3].sup.+.

[0233] .sup.1H NMR (400 MHz, CD.sub.3OD): 8.40 (s, 1H), 7.43 (d, J=6.9 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.27-7.14 (m, 2H), 7.02 (d, J=6.7 Hz, 1H), 6.93 (d, J=6.8 Hz, 1H), 6.36 (s, 2H), 5.20-5.08 (m, 2H), 4.59-4.41 (m, 2H), 3.76 (s, 6H), 1.96 (s, 3H), 1.87 (s, 3H).

EXAMPLE 12

(3-(((4-amino-6-methoxypyridin-2-yl)oxo)methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl)methanol (Compound 12)

[0234] ##STR00065##

Tert-butyl (2-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methoxy)-6-methoxypyridin-4-yl) carbamate

[0235] ##STR00066##

[0236] Palladium acetate (13.0 mg, 0.06 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (51 mg, 0.12 mmol) were added to a mixture of intermediate A (150.0 mg, 0.60 mmol), tert-butyl ((2-chloro-6-methoxypyridin-4-yl)carbamate (156.0 mg, 0.60 mmol), cesium carbonate (390.0 mg, 1.2 mmol) in toluene (3 mL), the mixture was exchanged with nitrogen for 3 minutes, and was allowed to react at 100 C. under nitrogen in sealed vessel overnight. The reaction mixture was concentrated, and residue was separated and purified with combiflash column chromatography (eluted with 0.05% trifluoroacetic acid aqueous solution/acetonitrile=99/1-30/70) to obtain the target compound 12A (100.0 mg, 36%) as a white solid.

[0237] MS (ESI): m/z=465 [M+H].sup.+.

(34(4-amino-6-methoxypyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methanol

[0238] ##STR00067##

[0239] Compound 12A (50.0 mg, 0.11 mmol) was dissolved in dioxane hydrochloride solution (4 M, 2 mL), and the reaction mixture was stirred for 2 hours. The reaction mixture was concentrated, and residue was separated and purified with combiflash column chromatography (eluted with 0.1% formic acid aqueous solution/acetonitrile=99/1-30/70) to obtain the target compound example 12 (16.0 mg, 40%) as a white solid.

[0240] MS (ESI): m/z=365 [M+H].sup.+.

[0241] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.36 (dd, J=7.0, 3.5 Hz, 2H), 7.19 (t, J=7.5 Hz, 2H), 6.97 (d, J=6.9 Hz, 1H), 6.93 (d, J=6.9 Hz, 1H), 5.84 (s, 2H), 5.56 (d, J=1.4 Hz, 1H), 5.50 (d, J=1.4 Hz, 1H), 5.09 (s, 1H), 4.51 (s, 2H), 3.67 (s, 3H), 1.94 (s, 3H), 1.87 (s, 3H).

EXAMPLE 13

(3(((6-aminopyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methanol

[0242] ##STR00068##

(2,2-dimethyl-3(((6-nitropyridin-2-yl) oxo) methyl)-[1,1-biphenyl]-3-yl) methanol

[0243] ##STR00069##

[0244] Palladium acetate (37.0 mg, 0.165 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (140.0 mg, 0.33 mmol) were added to a solution of intermediate A (400.0 mg, 1.65 mmol), 2-bromo-6-nitropyridine (335.0 mg, 1.65 mmol), cesium carbonate (1.08 g, 3.30 mmol) in toluene (3 mL), the mixture was exchanged with nitrogen for 3 minutes, and reacted at 100 C. under nitrogen in sealed vessel overnight. The reaction mixture was concentrated, and residue was purified with combiflash column chromatography (eluted with 0.05% trifluoroacetic acid aqueous solution/acetonitrile=99/1-30/70) to obtain the target compound 13A (50.0 mg, 8%) as a pale yellow solid.

[0245] MS (ESI): m/z=365 [M+H].sup.+.

(3(((6-aminopyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methanol (Compound 13)

[0246] ##STR00070##

[0247] A mixture of compound 13A (50.0 mg, 0.14 mmol), iron powder (50.0 mg, 0.90 mmol) and satured ammonium chloride (50.0 mg, 0.94 mmol) in ethanol (4 mL) and water (1 mL) was heated to 80 C. and stirred for 3 hours. The reaction mixture was diluted with ethyl acetate and methanol and then filtered. The filtrate was concentrated, and residue was separated and purified with combiflash column chromatography (eluted with 0.1% formic acid aqueous solution/acetonitrile=99/1-30/70) to obtain the target compound example 13 (12.0 mg, 26%) as a white solid.

[0248] MS (ESI): m/z=335 [M+H].sup.+.

[0249] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.41-7.34 (m, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.19 (m, 2H), 6.98 (d, J=7.5 Hz, 1H), 6.93 (d, J=7.4 Hz, 1H), 5.98 (d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 5.83 (s, 2H), 5.23 (s, 2H), 4.51 (s, 2H), 1.93 (s, 3H), 1.88 (s, 3H).

EXAMPLE 14

N, N-((((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxo))bis (2,6-dimethoxy-4,1-phenylene)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl) diacetamide

[0250] ##STR00071##

4,4-(((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo)) di (2,6-dimethoxybenzaldehyde)

[0251] ##STR00072##

[0252] The mixture of intermediate A (500.0 mg, 2.1 mmol), 4-hydroxy-2,6-dimethoxybenzaldehyde (950.0 mg, 5.2 mmol) and triphenylphosphine (1.4 g, 5.2 mmol) in tetrahydrofuran (10 mL) was cooled to 0 C. A solution of diisopropyl azodicarboxylate (1.1 g, 5.2 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 24 hours, concentrated. The residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=4/1-1/4) to obtain the target compound 14A (710.0 mg, 60%) as a white solid.

[0253] MS (ESI): m/z=571 [M+H].sup.+.

N, N-((((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl)bis(methylene))bis(oxo))bis (2,6-dimethoxy-4,1-phenylene)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl) diacetamide (Compound 14)

[0254] ##STR00073##

[0255] A mixture of compound 14A (50.0 mg, 0.087 mmol), N-(2-aminoethyl) acetamide (27.0 mg, 0.26 mmol) and acetic acid (1 drop) in N, N-dimethylformamide (1 mL) was stirred at room temperature for 1 hour. Cyanoborohydride (22.0 mg, 0.35 mmol) was added to the reaction mixture and stirred at room temperature for 2 hours. The reaction mixture was directly separated and purified with combiflash column chromatography (eluted with 10 mM NH.sub.4HCO.sub.3 aqueous solution/acetonitrile=99/1-40/60) to obtain the target compound example 14 (24.0 mg, 40%) as a white solid.

[0256] MS (ESI): m/z=372 [M/2+H].sup.+.

[0257] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73 (s, 2H), 7.46 (d, J=7.7 Hz, 2H), 7.26 (m, 2H), 7.06 (d, J=7.5 Hz, 2H), 6.32 (s, 4H), 5.13 (s, 4H), 3.72 (s, 12H), 3.57 (s, 4H), 3.04 (dd, J=12.2, 6.1 Hz, 4H), 2.42 (t, J=6.4 Hz, 4H), 1.99 (s, 6H), 1.74 (s, 6H).

EXAMPLE 15

(3-(((5-(2-aminoethyl)-6-methoxypyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methanol

[0258] ##STR00074##

Tert-butyl (2-(6-((3-(hydroxymethyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methoxy)-2-methoxypyridin-3-yl) ethyl) carbamate

[0259] ##STR00075##

[0260] Palladium acetate (16.0 mg, 0.07 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (30 mg, 0.07 mmol) were added to a mixture of intermediate A (181.0 mg, 0.75 mmol), tert-butyl (2-(6-chloro(2-methoxypyridin-3-yl)ethyl)carbamate (214.0 mg, 0.75 mmol), cesium carbonate (489.0 mg, 1.50 mmol) in toluene (2 mL), the mixture was exchanged with nitrogen for 3 minutes, and was allowed to heat to 100 C. under nitrogen in sealed vessel overnight. The reaction mixture was concentrated, and the residue was purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=5/1) and combiflash column chromatography (eluted with acetonitrile/water) to obtain an aqueous solution (5 mL) of the target compound 15A.

[0261] MS (ESI): m/z=493.2 [M+H].sup.+

(3-(((5-(2-aminoethyl)-6-methoxypyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methanol (Compound 15)

[0262] ##STR00076##

[0263] Hydrochloric acid/1,4-dioxane solution (4 M, 4 mL) was added to an aqueous solution (5 mL) of compound 15A, and the reaction was stirred at room temperature for 24 hours. The reaction mixture was concentrated to 4 mL, the residue was purified with combiflash column chromatography (eluted with acetonitrile/water) to obtain the target compound example 15 (30.0 mg, 10.2%) as a white solid.

[0264] MS (ESI): m/z=393.2 [M+H].sup.+.

[0265] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.25 (s, 3H), 7.42-7.33 (m, 3H), 7.20 (m, 2H), 7.05 (m, 2H), 6.29 (d, J=7.9 Hz, 1H), 5.37 (s, 2H), 4.73 (s, 2H), 3.92 (s, 3H), 3.18 (s, 2H), 2.93 (m, 2H), 2.02 (s, 3H), 1.94 (s, 3H).

EXAMPLE 16

(6-((3-(aminomethyl)-2-methyl-[1,1-biphenyl]-3-yOmethoxy)-2-methoxypyridin-3-yl) methylamine

[0266] ##STR00077##

3-(hydroxymethyl)-2-methyl-[1,1-biphenyl]-3-carbonitrile

[0267] ##STR00078##

[0268] Tetrakis (triphenylphosphine) palladium (58.0 mg, 0.05 mmol) was added to a mixture of 3-bromo-2-methylbenzonitrile (195.0 mg, 1.0 mmol), 3-hydroxymethylphenylborate (304.0 mg, 1.30 mmol), sodium carbonate (318.0 mg, 3.0 mmol) in 1,4-dioxane (3 mL). The mixture was exchanged with nitrogen for 1 minute, and reacted at 100 C. under argon atmosphere in sealed vessel for two days. The reaction mixture was cooled and concentrated. The crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate=1/2) to obtain the target compound 16A (230.0 mg, 100%) as a colorless oil.

[0269] MS (ESI): m/z=224.1 [M+H].sup.+.

6-((3-cyano-2-methyl-[1,1-biphenyl]-3-yl)methoxy)-2-methoxynicotyronitrile

[0270] ##STR00079##

[0271] Palladium acetate (44.0 mg, 0.2 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (45 mg, 0.1 mmol) was added to a mixture of intermediate 16A (223.0 mg, 1.00 mmol), 6-chloro-2-methoxy-3-pyridinecarbonitrile (168.0 mg, 1.00 mmol), cesium carbonate (652.0 mg, 2.00 mmol) in toluene (2 mL). The mixture was exchanged with nitrogen for 3 minutes, and reacted at 100 C. under argon atmosphere in sealed vessel overnight. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate=3/1) to obtain target compound 16B (240.0 mg, 67.6%) as a white solid.

[0272] MS (ESI): m/z=356.1 [M+H].sup.+.

(6-((3-(aminomethyl)-2-methyl-[1,1-biphenyl]-3-yOmethoxy)-2-methoxypyridin-3-yl) methylamine (Compound 16)

[0273] ##STR00080##

[0274] Ammonia (2 mL) and Raney nickel (20.0 mg) was added to a mixture of compound 16B (90.0 mg, 0.25 mmol) in Methanol (10 mL) and tetrahydrofuran (5 mL), and the mixture was reacted at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by combiflash column chromatography (eluted with acetonitrile/water gradient) to obtain the target compound Example 16 (20.0 mg, 22.2%) as a colorless oil.

[0275] MS (ESI): m/z=347.1 [M16].sup.+.

[0276] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.42-7.37 (m, 3H), 7.36-7.34 (m, 1H), 7.33-7.30 (m, 1H), 7.23-7.19 (m, 2H), 7.14-7.10 (m, 1H), 6.31 (d, J=7.8 Hz, 1H), 5.39 (s, 2H), 3.91 (s, 5H), 3.69 (s, 2H), 2.18 (s, 3H).

EXAMPLE 17

N-(2-(((6-((3-(((5-cyano-6-methoxypyridin-2-yl) oxo) methyl)-2,2-dimethyl-[1,1-biphenyl]-3-yl) methoxy)-2-methoxypyridin-3-yl) methyl) amino) ethyl) acetamide (Compound 17)

[0277] ##STR00081##

[0278] Palladium acetate (8.0 mg, 0.04 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (8.0 mg, 0.02 mmol) was added to a mixture of Example compound 2 (223.0 mg, 1.0 mmol), 6-chloro-2-methoxy-3-pyridinecarbonitrile (8.0 mg, 0.05 mmol), cesium carbonate (33.0 mg, 0.1 mmol) in toluene (2 mL). The mixture was exchanged with nitrogen for 3 minutes, and was allowed to react at 100 C. under nitrogen in sealed vessel overnight. The reaction mixture was concentrated, and the crude product was separated and purified by silica gel column chromatography (eluted with petroleum ether/ethyl acetate=1/10) to obtain target compound example 17 (15.0 mg, 50%) as a white solid.

[0279] MS (ESI): m/z=596.3 [M+H].sup.+.

[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.71 (d, J=8.3 Hz, 1H), 7.45-7.33 (m, 3H), 7.24-7.19 (m, 2H), 7.12 (dd, J=7.6, 1.4 Hz, 1H), 7.08 (dd, J=7.6, 1.5 Hz, 1H), 6.48 (s, 1H), 6.42 (d, J=8.3 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 5.46 (s, 2H), 5.39 (s, 2H), 4.34-4.26 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.44-3.31 (m, 4H), 2.05 (s, 6H), 1.91 (s, 3H).

EXAMPLE 18

N,N-((((((pyridine-2,6-diyl-bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diacetamide

[0281] ##STR00082##

6,6-((pyridine-2,6-diyl-bis (methylene)) bis (oxo)) bis (2-methoxynicotyraldehyde)

[0282] ##STR00083##

[0283] Palladium acetate (22.0 mg, 0.1 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (85.0 mg, 0.2 mmol) was added to pyridine-2,6-diyl-dimethanol (70.0 mg, 0.5 mmol), 6-chloro-2-methoxynicotyraldehyde (214 mg, 1.25 mmol), cesium carbonate (977.0 mg, 3.0 mmol) in toluene (5 mL). The mixture was exchanged by bubbling nitrogen for 1 minute. Then the mixture was quickly capped and sealed, heated to 110 C., and reacted overnight at that temperature. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified with combiflash column chromatography (eluted with petroleum ether/ethyl acetate=4/1) to obtain the target compound 18A (170.0 mg, 83%) as a white solid.

[0284] MS (ESI): m/z=410.1 [M+H].sup.+.

N,N-((((((pyridine-2,6-diyl-bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diacetamide (Compound 18)

[0285] ##STR00084##

[0286] Acetic acid (3 drops) was added to a mixture of compound 18A (170.0 mg, 0.42 mmol) and N-(2-aminoethyl) acetamide (129.0 mg, 1.26 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for one hour, then sodium cyanoborohydride (79.0 mg, 1.26 mmol) was added to mixture and the mixture was stirred at room temperature overnight. The reaction mixture was separated and purified by combiflash column chromatography (eluted with acetonitrile/ammonium bicarbonate aqueous solution (10 mmol/L)=30%) to obtain example compound 18 (30.0 mg, 12%) as a transparent gum.

[0287] MS (ESI): m/z=291.7 [M/2+H].sup.+.

[0288] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.77 (t, J=7.8 Hz, 1H), 7.53 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 6.42 (d, J=7.9 Hz, 2H), 5.44 (s, 4H), 3.80 (s, 6H), 3.63 (s, 4H), 3.29-3.24 (m, 4H), 2.64 (t, J=6.4 Hz, 4H), 1.90 (s, 6H).

EXAMPLE 19

N, N-((((((((2-methyl-1,3-phenylene) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diacetamide

[0289] ##STR00085##

(2-methyl-1,3-phenylene) dimethanol

[0290] ##STR00086##

[0291] Under 0 C., a solution of lithium borohydride in tetrahydrofuran (2 M, 19 mL, 37.5 mmol) was added to dimethyl 2-methylisophthalate (780.0 mg, 3.75 mmol), and the reaction was carried out at room temperature under nitrogen atmosphere overnight. The mixture was quenched by adding methanol (20 mL) and water (5 mL), neutralized to neutral with dilute hydrochloric acid (1 M), and concentrated. The residue was separated and purified by reversed-phase column chromatography (methanol/water), and the product was filtered through silica gel (eluted with ethyl acetate). The filtrate was concentrated to obtain the target compound 19A (310.0 mg, 54%) as a white solid.

[0292] MS (ESI): m/z=135.1 [M17].sup.+.

[0293] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.22 (d, J=7.6 Hz, 2H), 7.09 (t, J=7.5 Hz, 1H), 4.97 (t, J=5.4 Hz, 2H), 4.46 (d, J=5.4 Hz, 4H), 2.12 (s, 3H).

6,6-(((2-methyl-1,3-phenylene) bis (methylene)) bis (oxo)) bis (2-methoxynicotyraldehyde)

[0294] ##STR00087##

[0295] Palladium acetate (53.0 mg, 0.23 mmol) and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (200.0 mg, 0.47 mmol) were added to a mixture of compound 19A (120.0 mg, 0.78 mmol), 6-chloro-2-methoxynicotyraldehyde (270.0 mg, 1.57 mmol) and cesium carbonate (1029.0 mg, 3.15 mmol) in toluene (7 mL). The mixture was exchanged with nitrogen for 5 minutes, and reacted at 120 C. under nitrogen in sealed vessel overnight. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was separated and purified by combiflash column chromatography (eluted with petroleum ether/ethyl acetate=8/1), and the product was further purified by combiflash column chromatography (methanol/water) to obtain the target compound 19B (18.0 mg, 5%) as a white solid.

[0296] MS (ESI): m/z=423.1 [M+H].sup.+.

N, N-((((((((2-methyl-1,3-phenylene) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-2,1-diyl)) diacetamide (Compound 19)

[0297] ##STR00088##

[0298] Acetic acid (1 drop) was added to a mixture of compound 19B (18.0 mg, 0.042 mmol) and N-(2-aminoethyl) acetamide (17.0 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for one hour, then sodium cyanoborohydride (11.0 mg, 0.17 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was separated and purified by combiflash column chromatography (eluted with acetonitrile/ammonium bicarbonate aqueous solution (10 mmol/L)) to obtain example compound 19 (2.0 mg, 7.8%) as a white solid.

[0299] MS (ESI): m/z=298.2 [M/2+H]+.

[0300] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.74 (s, 2H), 7.57 (d, J=7.8 Hz, 2H), 7.38 (d, J=7.5 Hz, 2H), 7.16 (t, J=7.7 Hz, 1H), 6.35 (d, J=7.8 Hz, 2H), 5.34 (s, 4H), 3.84 (s, 6H), 3.52 (s, 3H), 3.23 (s, 4H), 3.10-3.04 (m, 4H), 2.31 (s, 4H), 1.74 (s, 6H).

EXAMPLE 20

1,1-(((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (2-methylpropane-2-ol) (Compound 20)

[0301] ##STR00089##

[0302] The target compound was prepared from compound 4A and 1-amino-2-methyl-2-propanol under conditions similar to those of example 4.

[0303] MS (ESI): m/z=330.2[1/2M+H].sup.+.

[0304] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.51 (d, J=7.9 Hz, 2H), 7.40 (d, J=7.3 Hz, 2H), 7.20 (t, J=7.6 Hz, 2H), 7.02 (d, J=7.6 Hz, 2H), 6.35 (d, J=7.9 Hz, 2H), 5.41 (s, 4H), 3.93 (s, 6H), 3.65 (s, 4H), 2.48 (s, 4H), 2.03 (s, 6H), 1.17 (s, 12H).

EXAMPLE 21

2,2-(((((((2,2-dimethyl-[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) bis (ethane-1-ol) (Compound 21)

[0305] ##STR00090##

[0306] The target compound was prepared from compound 4A and ethanolamine under conditions similar to those of example 4.

[0307] MS (ESI): m/z=302.2[1/2M+H].sup.+.

[0308] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.67 (d, J=8.0 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H), 7.21 (t, J=7.6 Hz, 2H), 7.03 (d, J=7.3 Hz, 2H), 6.45 (d, J=8.0 Hz, 2H), 5.47 (s, 4H), 4.12 (s, 4H), 4.01 (s, 6H), 3.78 (t, J=4.0 Hz, 4H), 3.07 (t, J=4.0 Hz, 4H), 2.04 (s, 6H).

EXAMPLE 22

3,3-(((((((2,2-dimethyl[1,1-biphenyl]-3,3-diyl) bis (methylene)) bis (oxo)) bis (2-methoxypyridine-6,3-diyl)) bis (methylene)) bis (azetanediyl)) dipropionamide (Compound 22)

[0309] ##STR00091##

[0310] The target compound was prepared from compounds 4A and 3-aminopropionamide under conditions similar to those of example 4.

[0311] MS (ESI): m/z=657.3[M+H].sup.+.

[0312] .sup.1H NMR (400 MHz, CD.sub.3OD) 7.65 (d, J=8.0 Hz, 2H), 7.42 (d, J=7.4 Hz, 2H), 7.21 (t, J=7.6 Hz, 2H), 7.03 (d, J=7.5 Hz, 2H), 6.45 (d, J=8.0 Hz, 2H), 5.47 (s, 4H), 4.10 (s, 4H), 4.02 (s, 6H), 3.21 (t, J=6.1 Hz, 4H), 2.65 (t, J=6.2 Hz, 4H), 2.04 (s, 6H).

[0313] Each of the following compounds was prepared by a method similar to that of Example 1-22, by using the corresponding raw materials:

TABLE-US-00001 TABLE 1 No. Compound structure LCMS, HNMR 23 [00092] MS (ESI): m/z = 318.1[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.47 (d, J = 8.0 Hz, 1H), 7.44-7.37 (m, 3H), 7.37-7.29 (m, 1H), 7.29-7.24 (m, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.17-7.16 (m, 1H), 7.16-7.09 (m, 1H), 6.98 (s, 1H), 6.38 (d, J = 7.9 Hz, 1H), 5.36 (s, 2H), 3.85 (s, 3H), 3.58 (s, 2H), 2.17 (s, 3H) 24 [00093] MS (ESI): m/z = 711.4[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.40 (m, 3H), 7.67 (dd, J = 8.0, 5.3 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 7.21 (m, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 8.0 Hz, 2H), 5.47 (d, J = 3.8 Hz, 4H), 4.14 (m, 4H), 4.06-3.98 (m, 6H), 3.18-3.04 (m, 2H), 2.91-2.67 (m, 1H), 2.29-2.14 (m, 1H), 2.04 (s, 6H), 1.91-1.26 (m, 16H). 25 [00094] MS: [M + H]+ m/z 657.2. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.95 (s, 2H), 8.18 (s, 2H), 7.91-7.87 (m, 4H), 7.54 (s, 2H), 7.17 (m, 2H), 6.97 (d, J = 6.8 Hz, 2H), 6.83 (d, J = 7.6 Hz, 2H), 5.32 (s, 4H), 3.27 (s, 4H), 3.14-3.10 (m, 4H), 2.59-2.57 (m, 4H), 1.89 (s, 6H), 1.77 (s, 6H) 26 [00095] MS (ESI): m/z = 739.3[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.18 (s, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.25 (m, 2H), 7.12-7.01 (m, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.52 (s, 4H), 4.34 (m, 4H), 4.03 (s, 6H), 3.46 (m, 4H), 2.97 (m, 2H), 2.25 (m, 2H), 2.07 (s, 6H), 1.92-1.46 (m, 10H) 27 [00096] MS (ESI): m/z = 739.3[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.18 (s, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.25 (m, 2H), 7.12-7.01 (m, 2H), 6.52 (d, J = 8.1 Hz, 2H), 5.52 (s, 4H), 4.34 (m, 4H), 4.03 (s, 6H), 3.46 (m, 4H), 2.97 (m, 2H), 2.25 (m, 2H), 2.07 (s, 6H), 1.92-1.46 (m, 10H) 28 [00097] MS-ESI: m/z 285.1 [M/2 + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49 (s, 2H), 7.64 (dd, J = 8.1, 5.8 Hz, 2H), 7.41 (m, 3H), 7.33 (s, 1H), 7.22-7.17 (m, 2H), 7.13 (d, J = 6.6 Hz, 1H), 6.45 (d, J = 2.9 Hz, 1H), 6.43 (d, J = 2.9 Hz, 1H), 5.46 (d, J = 4.3 Hz, 4H), 4.05 (d, J = 8.1 Hz, 4H), 4.01 (s, 3H), 3.96 (s, 3H), 3.44 (m,4H), 3.05 (m, 4H), 2.20 (s, 3H), 1.94 (d, J = 3.5 Hz, 6H) 29 [00098] MS-ESI: m/z 345.2 [M/2 + H]+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.59 (d, J = 7.5 Hz, 1H), 7.52 (dd, J = 7.9, 1.6 Hz, 2H), 7.33 (m, 1H), 7.21 (d, J = 7.7 Hz, 1H), 6.33 (m, 2H), 5.45 (s, 2H), 5.28 (s, 2H), 3.99 (s, 3H), 3.93 (s, 3H), 3.65 (d, J = 7.2 Hz, 3H), 3.29 (m, 4H), 2.65 (m, 4H), 2.28 (s, 3H), 2.07 (s, 3H), 1.98 (s, 3H), 1.91 (d, J = 3.3 Hz, 6H) 30 [00099] MS-ESI: m/z 704.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.67 (m, 2H), 7.52 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.34 (m, 1H), 7.22 (m, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 5.55 (s, 2H), 5.47 (m, 2H), 4.08 (s, 4H), 4.00 (s, 3H), 3.95 (s, 3H), 3.45 (m, 4H), 3.08 (m, 4H), 2.08 (s, 3H), 1.95 (s, 6H) 31 [00100] MS-ESI: m/z 676.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.71-7.66 (m, 3H), 7.42 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 8.0 Hz, 1H), 5.56 (s, 2H), 5.53 (s, 2H), 4.11 (s, 2H), 4.09 (s, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 3.47 (m, 4H), 3.10 (m, 4H), 2.19 (s, 3H), 1.99 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H) 32 [00101] MS (ESI): m/z = 535.0[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.06 (brs, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.44 (d, J = 7.2 Hz, 2H), 7.22 (m, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.54 (d, J = 8.8 Hz, 2H), 6.23 (s, 2H), 5.36 (brs, 4H), 5.27 (m, 2H), 4.58 (d, J = 5.2 Hz, 4H), 2.00 (s, 6H) 33 [00102] MS (ESI): m/z = 687.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.63 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.7 Hz, 2H), 7.20 (m, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.43 (d, J = 7.9 Hz, 2H), 5.45 (m, 4H), 4.08 (s, 4H), 4.02 (s, 6H), 2.98 (m, 4H), 2.54 (d, J = 7.4 Hz, 2H), 2.03 (s, 6H), 1.18 (d, J = 7.3 Hz, 6H) 34 [00103] MS (ESI): m/z = 703.2[M + H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.65 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 7.2 Hz, 2H), 7.23 (m, 2H), 7.06 (d, J = 6.4 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 6.39 (s, 2H), 5.38 (s, 4H), 3.92 (s, 4H), 3.31-3.29 (m, 4H), 2.72 (m, 4H), 2.06 (s, 6H), 1.91 (s, 6H) 35 [00104] MS (ESI): m/z = 683.1[M + H]+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.38 (s, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 7.21 (m, 2H), 7.04 (d, J = 6.6 Hz, 2H), 6.42 (d, J = 8.0 Hz, 2H), 5.45 (s, 4H), 4.60 (m, 2H), 4.24 (m, 4H), 3.99 (m, 6H), 3.93 (m, 2H), 3.89-3.79 (m, 2H), 2.67-2.57 (m, 2H), 2.46-2.35 (m, 2H), 2.03 (s, 6H). 36 [00105] MS (ESI): m/z = 691.2[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.51 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 7.0 Hz, 1H), 7.17 (s, 1H), 7.08-7.02 (m, 2H), 6.36-6.27 (m, 2H), 5.52 (s, 2H), 5.40 (s, 2H), 4.01 (s, 3H), 3.93 (s, 3H), 3.65 (s, 2H), 3.63 (s, 2H), 3.32-3.22 (m, 4H), 2.68-2.60 (m, 4H), 2.10 (s, 3H), 1.97 (s, 3H), 1.91 (s, 3H), 1.90 (s, 3H) 37 [00106] MS (ESI): m/z = 683.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.50 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 6.4 Hz, 2H), 7.23 (m, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.47 (d, J = 8.4 Hz, 2H), 5.50 (s, 4H), 4.29 (s, 3H), 4.03 (s, 6H), 2.07 (s, 6H), 1.40-1.18 (m, 5H), 0.92 (m, 4H) 38 [00107] MS (ESI): m/z = 675.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.48 (s, 2H), 7.70-7.60 (m, 4H), 7.37 (m, 1H), 7.27-7.21 (m, 1H), 6.46 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.51 (s, 2H), 5.40-5.31 (m, 2H), 4.11 (s, 2H), 4.10 (s, 2H), 4.06 (s, 3H), 4.01 (s, 3H), 3.53-3.40 (m, 4H), 3.10 (m, 4H), 2.04 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H), 1.95 (s, 3H) 39 [00108] MS (ESI): m/z = 739.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.69 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.0 Hz, 2H), 7.21 (m, 2H), 7.04 (d, J = 6.7 Hz, 2H), 6.45 (d, J = 8.0 Hz, 2H), 5.53-5.36 (m, 4H), 4.43 (m, 2H), 4.07 (m, 2H), 3.75-3.60 (m, 2H), 3.47-3.34 (m, 2H), 3.16 (m, 2H), 2.65 (m, 2H), 2.51 (m, 2H), 2.33 (m, 2H), 2.10-1.87 (m, 10H), 1.89-1.69 (m, 2H) 40 [00109] MS (ESI): m/z = 615.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.54 (d, J = 8.0 Hz,1H), 7.53 (d, J = 8.0 Hz,1H), 6.31 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 5.46 (s, 2H), 5.25 (s, 2H), 4.04 (s, 3H), 4.01(s, 3H), 3.70 (s, 2H), 3.69 (s, 2H), 3.31-3.36 (m, 4H), 2.70 (m, 2H), 2.69 (m, 2H), 2.45 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.94 (s, 3H) 41 [00110] MS (ESI): m/z = 771.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.30 (s, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.3 Hz, 2H), 7.21 (m, 2H), 7.03 (d, J = 7.4 Hz, 2H), 6.39 (d, J = 8.0 Hz, 2H), 5.44 (s, 4H), 4.28 (s, 2H), 3.93 (s, 6H), 3.86 (s, 4H), 3.63 (s, 6H), 3.54 (m, 2H), 3.11 (m, 2H), 2.79 (m, 2H), 2.53 (m, 2H), 2.04 (s, 6H), 1.88 (m, 2H) 42 [00111] MS (ESI): m/z = 715.0[M + H] .sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.22 (s, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.42 (d, J = 7.3 Hz, 2H), 7.21 (m, 2H), 7.04 (d, J = 7.5 Hz, 2H), 6.46 (d, J = 8.0 Hz, 2H), 5.55-5.36 (m, 4H), 4.53-4.23 (m, 8H), 4.21-3.82 (m, 10H), 1.99 (s, 6H) 43 [00112] MS (ESI): m/z = 725.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.71 (d, J = 8.1 Hz, 2H), 7.56 (dd, J = 7.7, 1.4 Hz, 2H), 7.37 (m, 2H), 7.22 (dd, J = 7.6, 1.5 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.58 (m, 4H), 4.13 (s, 4H), 3.97 (s, 6H), 3.48 (m, 4H), 3.12 (m, 4H), 1.96 (s, 6H) 44 [00113] MS-ESI: m/z 689[M + H]+. .sup.1H NMR (400 MHz, CD3OD) 7.69-7.62 (m, 3H), 7.40 (m, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.41 (d, J = 8.0 Hz, 1H), 5.52 (s, 2H), 5.31 (d, J = 3.2 Hz, 2H), 4.12 (m, 4H), 4.05 (s, 3H), 4.00 (s, 3H), 3.47 (m, 4H), 3.12 (m, 4H), 2.80(m, 1H), 2.07 (s, 3H), 1.99 (s, 3H), 1.96 (s, 3H), 1.95 (s, 6H) 45 [00114] MS (ESI): m/z = 713.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.77 (s, 2H), 7.89 (s, 1H), 7.87 (s, 3H), 7.42 (m, 2H), 7.31 (s, 1H), 7.29 (s, 1H), 3.91 (s, 4H), 3.33 (m, 4H), 2.76 (m, 4H), 2.29 (s, 6H), 1.93 (s, 6H) 46 [00115] MS (ESI): m/z = 783.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.70 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 7.7 Hz, 2H), 7.37 (m, 2H), 7.22 (m, 2H), 6.51 (d, J = 8.0 Hz, 2H), 5.63-5.49 (m, 4H), 4.44-4.39 (m, 2H), 4.30 (m, 4H), 3.98 (s, 6H), 3.95-3.88 (m, 2H), 3.39 (m, 2H), 3.25-3.17 (m, 2H), 2.62-2.52 (m, 2H), 2.24-2.16 (m, 2H) 47 [00116] MS (ESI): m/z = 699.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 2H), 7.69 (dd, J = 14.6, 8.1 Hz, 2H), 7.42 (d, J = 7.4 Hz, 2H), 7.22 (m, 2H), 7.04 (d, J = 7.5 Hz, 2H), 6.45 (m, 2H), 5.58-5.37 (m, 4H), 4.52 (s, 1H), 4.42 (s, 1H), 4.35-4.19 (m, 4H), 4.03 (m, 6H), 3.95 (m, 1H), 3.60-3.35 (m, 4H), 3.23 (m, 2H), 2.58 (s, 1H), 2.23 (s, 2H), 2.04 (m, 7H) 48 [00117] MS (ESI): m/z = 811.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.58 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 6.9 Hz, 2H), 7.35 (m, 2H), 7.19 (dd, J = 7.6, 1.6 Hz, 2H), 6.42 (d, J = 7.9 Hz, 2H), 5.60-5.46 (m, 4H), 4.23-4.20 (m, 2H), 3.82 (d, J = 0.4 Hz, 6H), 3.66-3.64 (m, 4H), 3.58 (d, J = 1.1 Hz, 6H), 3.18 (m, 2H), 2.94 (d, J = 10.2 Hz, 2H), 2.60-2.54 (m, 2H), 2.50-2.42 (m, 2H), 1.79-1.72 (m, 2H) 49 [00118] MS (ESI): m/z = 745.0[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.25 (s, 1H), 7.70-7.62 (m, 4H), 7.41 (d, J = 7.6 Hz, 2H), 7.22 (m, 2H), 7.03-7.01 (m, 3H), 6.42 (d, J = 8.4 Hz, 2H), 5.34 (s, 4H), 3.85 (s, 6H), 2.58-2.55 (m, 2H), 2.40-2.32 (m, 2H), 1.96 (s, 6H) 50 [00119] MS (ESI): m/z = 691.1[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.76 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 7.20 (m, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.44 (d, J = 8.4 Hz, 2H), 5.47 (s, 4H), 4.18 (s, 4H), 4.01 (s, 6H), 3.73-3.60 (m, 8H), 2.04 (s, 6H), 1.31 (s, 6H) 51 [00120] MS (ESI): m/z = 719.0[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.70 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.7 Hz, 2H), 7.26 (m, 2H), 7.06 (d, J = 6.7 Hz, 2H), 6.46 (d, J = 8.0 Hz, 2H), 5.42 (s, 4H), 3.89 (s, 6H), 3.86-3.83 (m, 4H), 3.76 (m, 4H), 2.92 (m, 2H), 2.00 (s, 6H), 1.12 (d, J = 6.3 Hz, 6H) 52 [00121] MS (ESI): m/z = 369.1 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.28 (s, 2H), 7.99 (d, J = 7.1 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.26 (m, 2H), 7.06 (d, J = 7.3 Hz, 2H), 6.44 (d, J = 8 Hz, 2H), 5.41 (s, 4H), 4.12-4.01 (m, 2H), 3.87 (s, 6H), 3.46 (m, 4H), 2.63-2.51 (m, 4H), 2.38 (m, 2H), 2.29 (m, 2H), 2.07-1.99 (m, 2H), 2.01 (s, 6H), 1.76 (s, 6H), 1.55-1.47 (m, 2H) 53 [00122] MS (ESI): m/z = 369.1 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.56 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.32 (s, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.06 (d, J = 7.5 Hz, 2H), 6.76 (s, 2H), 6.44 (d, J = 7.9 Hz, 2H), 5.41 (s, 4H), 3.86 (s, 6H), 3.37-3.28 (m, 4H), 2.67 (m, 4H), 2.32-2.25 (m, J = 10.2, 5.1 Hz, 2H), 2.09-2.03 (m, 2H), 2.01 (s, 6H), 1.95 (m, 2H), 1.74-1.52 (m, 4H), 1.48-1.25 (m, 4H) 54 [00123] MS (ESI): m/z = 737.1[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.54 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.20 (m, 2H), 7.03 (d, J = 6.8 Hz, 2H), 6.36 (d, J = 8.0 Hz, 2H), 5.42 (brs, 4H), 4.29-4.23 (m, 2H), 3.91 (s, 6H), 3.59-3.51 (m, 4H), 2.84-2.82 (m, 2H), 2.73-2.67 (m, 2H), 2.56-2.52 (m, 2H), 2.42-2.38 (m, 2H), 2.24-2.15 (m, 2H), 2.03 (s, 6H), 1.87 (s, 6H), 1.64-1.56 (m, 2H) 55 [00124] MS (ESI): m/z = 681.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.53 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 7.2 Hz, 2H), 7.19 (m, 2H), 7.02 (d, J = 7.2 Hz, 2H), 6.36 (d, J = 8.0 Hz, 2H), 5.42 (s, 4H), 3.94 (s, 6H), 3.67-3.60 (m, 4H), 3.57-3.52 (m, 4H), 3.20-3.14 (m, 2H), 2.56-2.49 (m, 2H), 2.21-2.15 (m, 2H), 2.03 (s, 6H) 56 [00125] MS (ESI): m/z = 754.0[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.37 (s, 2H), 7.70 (m, 4H), 7.52 (d, J = 7.7 Hz, 1H), 7.42-7.30 (m, 1H), 7.28 (m, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.48 (m, 2H), 5.73-5.57 (m, 2H), 5.49 (m, 2H), 4.50-4.30 (m, 4H), 4.26 (m, 2H), 4.01 (d, J = 6.2 Hz, 6H), 3.93 (m, 2H), 3.39 (m, 2H), 3.23-3.11 (m, 2H), 2.68-2.47 (m, 2H), 2.21 (m, 2H), 2.16 (s, 3H) 57 [00126] MS (ESI): m/z = 651.9[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.70 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 (m, 2H), 7.35 (m, 2H), 7.24-7.16 (m, 2H), 6.54-6.41 (m, 2H), 5.63-5.45 (m, 4H), 4.48 (s, 2H), 4.41 (s, 1H), 4.39-4.22 (m, 2H), 4.04-3.90 (m, 4H), 3.85 (s, 3H), 3.40 (m, 1H), 3.22 (m, 1H), 2.63-2.53 (m, 1H), 2.22 (m, 1H) 58 [00127] MS (ESI): m/z = 738.9[M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.72-7.67 (m, 2H), 7.56 (d, J = 7.9 Hz, 2H), 7.37 (m, 2H), 7.22 (d, J = 7.3 Hz, 2H), 6.53-6.48 (m, 2H), 5.64-5.49 (m, 4H), 4.56-4.43 (m, 2H), 4.37-4.20 (m, 3H), 4.13-4.03 (m, 2H), 3.98 (s, 3H), 3.93 (s, 3H), 3.91-3.85 (m, 1H), 3.45-3.10 (m, 4H), 3.05-2.95 (m, 1H), 2.61-2.51 (m, 1H), 2.24-2.14 (m, 2H), 1.97-1.87 (m, 1H) 59 [00128] MS (ESI): m/z = 729.1 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.45 (s, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.42 (dd, J = 7.7, 1.4 Hz, 2H), 7.21 (m, 2H), 7.04 (dd, J = 7.6, 1.4 Hz, 2H), 6.47 (d, J = 8.1 Hz, 2H), 5.47 (s, 4H), 4.04 (s, 4H), 3.99 (s, 6H), 3.36 (m, 4H), 2.84 (m, 4H), 2.50 (m, 4H), 2.04 (s, 6H), 2.00-1.88 (m, 6H), 1.63-1.51 (m, 4H) 60 [00129] MS (ESI): m/z = 761.1 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.55 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.6 Hz, 2H), 7.20 (m, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 8.0 Hz, 2H), 5.42 (s, 4H), 3.92 (s, 6H), 3.55 (s, 4H), 2.74 (m, 2H), 2.67-2.54 (m, 6H), 2.31 (m, 4H), 2.20-1.90 (m, 14H) 61 [00130] MS (ESI): m/z = 673.0 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.19 (m, 2H), 7.02 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 8.0 Hz, 2H), 5.42 (s, 4H), 3.93 (s, 6H), 3.70 (s, 4H), 3.63 (m, 4H), 3.25 (m, 4H), 2.89-2.78 (m, 2H), 2.71 (m, 4H), 2.02 (s, 6H) 62 [00131] MS (ESI): m/z = 694.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.46 (s, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 6.7 Hz, 2H), 7.38 (m, 2H), 7.23 (dd, J = 7.6, 1.3 Hz, 2H), 6.55 (d, J = 8.1 Hz, 2H), 5.63-5.42 (m, 4H), 4.51 (m, 2H), 4.31-4.19 (m, 4H), 3.96 (s, 6H), 3.47 (m, 2H), 3.35 (m, 4H), 3.20 (m, 2H), 2.29-2.15 (m, 2H), 2.08-1.92 (m, 2H). 63 [00132] MS (ESI): m/z = 681.0 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.41 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 7.6, 1.4 Hz, 2H), 7.21 (m, 2H), 7.04 (dd, J = 7.6, 1.4 Hz, 2H), 6.44 (d, J = 8.1 Hz, 2H), 5.46 (s, 4H), 4.16 (s, 4H), 4.13-4.02 (m, 8H), 4.00 (s, 6H), 3.57-3.49 (m, 2H), 2.04 (s, 6H) 64 [00133] MS (ESI): m/z = 704.9[M + 23].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.57 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.5 Hz, 2H), 7.20 (m, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.39 (dd, J = 12.4, 8.1 Hz, 2H), 5.43 (brs, 4H), 4.39 (m, 2H), 4.27-4.15 (m, 2H), 3.93 (s, 6H), 3.83 (m, 4H), 3.65 (m, 2H), 2.53 (m, 2H), 2.14-2.06 (m, 2H), 2.03 (s, 6H) 65 [00134] MS (ESI): m/z = 733.1 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.43 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.41 (dd, J = 7.6, 1.4 Hz, 2H), 7.21 (m, 2H), 7.04 (dd, J = 7.6, 1.4 Hz, 2H), 6.42 (d, J = 8.0 Hz, 2H), 5.45 (s, 4H), 4.12-4.05 (m, 2H), 3.96 (s, 5H), 3.88 (s, 3H), 3.33-3.30 (m, 2H), 3.13 (dd, J = 11.1, 6.3 Hz, 2H), 2.88 (m, 2H), 2.73-2.57 (m, 6H), 2.44-2.34 (m, 2H), 2.04 (s, 6H) 66 [00135] MS (ESI): m/z = 747.0 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.68 (d, J = 8.0 Hz, 2H), 7.60-7.56 (m, 1H), 7.51 (d, J = 7.1 Hz, 1H), 7.34-7.26 (m, 3H), 7.20 (d, J = 6.9 Hz, 1H), 6.46 (d, J = 8.0 Hz, 2H), 5.47 (s, 2H), 5.43 (s, 2H), 4.19 (d, J = 2.5 Hz, 2H), 3.91 (s, 4H), 3.87 (s, 4H), 3.75 (d, J = 8 Hz, 1H), 3.72 (d, J = 8 Hz, 1H), 3.39-3.33 (m, 2H), 2.99-2.88 (m, 2H), 2.74-2.63 (m, 2H), 2.38-2.28 (m, 2H), 2.14 (s, 3H), 1.87-1.77 (m, 2H). 67 [00136] MS (ESI): m/z = 719.0 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.63 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.21 (m, 2H), 7.03 (d, J = 6.9 Hz, 2H), 6.43 (d, J = 8.0 Hz, 2H), 5.46 (brs, 4H), 4.13 (m, 4H), 4.00 (s, 6H), 3.87-3.67 (m, 4H), 3.60 (m, 2H), 2.19-2.05 (m, 2H), 2.3 (s, 6H), 2.01-1.88 (m, 2H) 68 [00137] MS (ESI): m/z = 703.6 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23 (d, J = 8.1 Hz, 2H), 7.70 (dd, J = 7.9, 2.7 Hz, 2H), 7.62 7.62 (d, J = 7.7 Hz, 2H), 7.46 (m, 2H), 7.31 (d, J = 7.4 Hz, 2H), 6.49 (dd, J = 7.9, 1.3 Hz, 2H), 5.51 (m, 4H), 3.83 (s, 6H), 3.68 (m, 4H), 3.46-3.31 (m, 8H), 2.59-2.53 (m, 2H), 2.14 (m, 1H) 69 [00138] MS (ESI): m/z = 378.0 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.17 (s, 1H), 7.62 (m, 4H), 7.45 (m, 2H), 7.31 (d, J = 6.3 Hz, 2H), 6.48 (d, J = 7.9 Hz, 2H), 5.49 (dd, J = 12.1, 6.7 Hz, 4H), 4.11-4.03 (m, 2H), 3.86 (s, 2H), 3.81 (s, 6H), 3.43 (m, 4H), 3.29 (m, 2H), 3.02 (m, 2H), 2.85-2.80 (m, 2H), 2.14 (m, 2H), 1.78-1.64 (m, 4H) 70 [00139] MS (ESI): m/z = 778.9 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.70 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H), 7.46 (m, 2H), 7.32 (d, J = 7.5 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.50 (m, 4H), 3.81 (s, 6H), 3.66 (m, 4H), 3.12-3.09 (m, 2H), 2.97-2.84 (m, 2H), 2.32-2.26 (m, 2H), 1.79 (s, 2H), 1.73-1.64 (m, 2H), 1.50 (s, 6H), 1.39-1.35 (m, 2H) 71 [00140] MS (ESI): m/z = 726.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49 (s, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.37 (m, 2H), 7.22 (dd, J = 7.6, 1.5 Hz, 2H), 6.53 (d, J = 8.1 Hz, 2H), 5.57 (brs, 4H), 4.18 (m, 8H), 3.94 (s, 6H), 3.49 (m, 4H), 3.15 (m, 4H) 72 [00141] MS (ESI): m/z = 730.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.66 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 7.7, 1.7 Hz, 2H), 7.36 (m, 2H), 7.20 (dd, J = 7.6, 1.7 Hz, 2H), 6.45 (d, J = 8.0 Hz, 2H), 5.58-5.48 (m, 4H), 3.86 (s, 6H), 3.74 (s, 4H), 3.64 (m, 8H), 2.82-2.69(m, 8H) 73 [00142] MS (ESI): m/z = 668.9 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.66 (d, J = 7.9 Hz, 2H), 7.61 (dd, J = 7.7, 1.5 Hz, 2H), 7.45 (m, 2H), 7.31 (dd, J = 7.6, 1.5 Hz, 4H), 7.07 (s, 2H), 6.48 (d, J = 7.9 Hz, 2H), 5.50 (m, 4H), 3.82 (s, 6H), 3.54 (s, 4H), 3.02 (m, 4H) 74 [00143] MS (ESI): m/z = 748.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 8.47 (s, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.55 (dd, J = 7.7, 1.6 Hz, 2H), 7.36 (m, 2H), 7.21 (dd, J = 7.6, 1.7 Hz, 2H), 6.49 (d, J = 8.0 Hz, 2H), 5.55 (m, 4H), 4.50-4.41(m, 2H), 4.07-3.97 (m, 8H), 3.91 (s, 6H), 3.71 (m, 4H), 1.93 (s, 6H) 75 [00144] MS (ESI): m/z = 718.9 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.73 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.42 (m, 2H), 7.28 (d, J = 7.2 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 5.54-5.45 (m, 4H), 4.12 (s, 4H), 3.94 (s, 4H), 3.82 (s, 6H) 76 [00145] MS (ESI): m/z = 748.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.61 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 6.2 Hz, 2H), 7.36 (m, 2H), 7.21 (dd, J = 7.6, 1.6 Hz, 2H), 6.48 (d, J = 8.0 Hz, 2H), 5.55 (brs, 4H), 3.94 (m, 4H), 3.91 (s, 6H), 3.87 (m, 4H), 3.60-3.50 (m, 4H), 3.05-2.89 (m, 2H), 2.52 (m, 4H), 1.90 (m, 5H) 77 [00146] MS-ESI: m/z 696.9[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.74 (d, J = 4.8 Hz, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.57 (dd, J = 7.7, 1.4 Hz, 2H), 7.41 (m, 2H), 7.27 (dd, J = 7.6, 1.6 Hz, 2H), 6.45 (d, J = 7.9 Hz, 2H), 5.46 (m, 4H), 3.79 (s, 6H), 3.49 (s, 4H), 3.00 (brs, 4H), 2.56 (d, J = 4.7 Hz, 6H) 78 [00147] MS-ESI: m/z 769.0[M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.62 (d, J = 8.0 Hz, 2H), 7.57 (dd, J = 1.2, 7.6 Hz, 2H), 7.41 (m, 2H), 7.27 (dd, J = 1.2, 7.6 Hz, 2H), 6.78 (s, 3H), 6.46 (d, J = 7.6 Hz, 1H), 5.47 (m, 2H), 3.79 (s, 6H), 3.57 (s, 3H), 3.10 (m, 4H), 2.85 (m, 4H), 1.18-1.08 (m, 4H) 79 [00148] MS (ESI): m/z = 786.9 [M + H].sup.+. .sup.1H NMR (400 MHz, CD.sub.3OD) 7.73 (m, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.38 (m, 2H), 7.22 (dd, J = 7.6, 1.5 Hz, 2H), 6.56-6.46 (m, 2H), 5.57 (m, 4H), 5.36 (d, J = 3.6 Hz, 1H), 5.23 (d, J = 3.4 Hz, 1H), 4.43-4.27 (m, 4H), 4.08-3.93 (m, 8H), 3.92-3.76 (m, 2H), 3.44 (m, 1H), 3.35 (m, 1H), 2.82-2.60 (m, 2H), 2.55-2.40 (m, 2H) 80 [00149] MS (ESI): m/z = 796.8 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.37 (s, 2H), 7.66-7.58 (m, 4H), 7.45 (m, 2H), 7.30 (dd, J = 7.6, 1.6 Hz, 2H), 6.86 (s, 2H), 6.49 (d, J = 7.9 Hz, 2H), 5.50 (m, 4H), 3.82 (s, 6H), 3.57 (brs, 4H), 3.14 (m, 4H), 2.80 (m, 4H), 2.55 (m, 4H) 81 [00150] MS (ESI): m/z = 775.2 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.68-7.61 (m, 4H), 7.45 (m, 2H), 7.31 (d, J = 7.7 Hz, 2H), 6.50 (m, 2H), 6.11-5.81 (m, 2H), 5.50 (m, 4H), 5.19 (s, 1H), 5.05 (s, 1H), 3.90-3.78 (m, 6H), 3.61-3.41 (m, 4H), 3.20-3.01 (m, 3H), 2.63-2.53 (m, 2H), 2.49-2.39 (m, 1H), 2.09-1.84 (m, 3H), 1.67-1.62 (m, 1H) 82 [00151] MS (ESI): m/z = 777.2 [M + H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.22-1.64 (m, 2H), 7.61 (d, J = 7.4 Hz, 2H), 7.45 (m, 2H), 7.30 (d, J = 8 Hz, 2H), 6.49 (dd, J = 7.9, 1.8 Hz, 2H), 5.50 (m, 4H), 3.86-3.79 (m, 6H), 3.71 (s, 2H), 3.59 (m, 4H), 3.07 (s, 2H), 2.83 (m, 1H), 2.68 (m, 2H), 2.57 (m, 1H)

Test Example 1 Effect of the Compound of the Invention on PD-L1 Activity at the Molecular Level

[0314] PD-1/PD-L1 homogeneous time-resolved fluorescence (HTRF) detection technology was used to detect the binding ability of the compound to PD-L1.

[0315] PD1/PD-L1 binding assay kit (Cisbio, Cat #63ADK000CPDEC) was used, which includes two proteins, Tag 1-PD-L1 and Tag 2-PD-1, and two antibodies, Anti-Tag1-Eu.sup.3+ and Anti-Tag2-XL 665. Assay principle: Anti-tagl-Eu.sup.3+ is the HTRF donor, and Anti-Tag2-XL 665 is the HTRF acceptor. When Tag 1-PD-L1 and Tag 2-PD-1 interact, the added HTRF donor and the acceptor are close to each other. After the donor receives the excitation energy, it transfers part of the energy to the acceptor, thus producing 665 nm emission signal. When the compound is added to block the PD1/PD-L1 interaction, only 620 nm emission light was detected. The inhibitory effect of the compound was determined by analyzing the ratio of 665 nm/620 nm. Tag 1-PD-L1 was diluted with Diluent buffer (cat #62DLBDDF) to a working concentration of 10 nM, Tag 2-PD-1 was diluted with Diluent buffer to a working concentration of 500 nM, and Anti-Tag1-Eu.sup.3+ was diluted with detection buffer (cat #62DB1FDG) by 1:100, Anti-Tag2-XL 665 was diluted with detection buffer by 1:20, and the test compound was diluted with Diluent buffer to a final concentration of 2. In a 384-well plate, 2 L of compound was added to each well, and then 4 L of Tag 1-PD-L1, 4 L of Tag 2-PD-1 were added and incubated at room temperature for 15 minutes. 5 L Anti-Tag1-Eu.sup.3+ and 5 L Anti-Tag2-XL 665 were added and incubated overnight at room temperature, and detected with BioTek Synergy Neo2 Multifunctional Microplate Reader to obtain the ratio of 665 nm/620 nm. The IC50 curve was fitted by GraphPad Prism 5.02.

TABLE-US-00002 TABLE 1 IC.sub.50 values of some compounds of the present invention Compound no. PD-Ll IC.sub.50 (nM) 1 D 2 D 3 D 5 D 6 B 7 D 8 D 9 A 10 D 11 D 12 D 13 D 15 C 16 D 17 D 18 D 19 C 20 B 22 B 23 C 24 B 25 D 26 A 27 A 28 B 29 D 30 A 31 D 32 D 33 B 34 B 35 A 36 A 37 A 38 D 39 B 40 D 41 B 42 A 43 A 44 D 45 A 46 A 47 A 48 C 49 A 50 A 51 A 52 B 53 C 54 B 55 B 56 A 57 B 58 A 59 B 60 A 61 B 62 A 63 A 64 B 65 A 66 A 67 A 68 A 69 A 70 A 71 A 72 A 73 A 74 A 75 A 76 A 77 A 78 A 79 A 80 B 81 A 82 B

[0316] The letter A represents IC.sub.50 less than 10 nM;

[0317] The letter B represents IC.sub.50 from 10 nM to 100 nM;

[0318] The letter C represents IC.sub.50 from 100 nM to 1 M;

[0319] The letter D represents IC.sub.50 greater than 1 M.

[0320] The results showed that the compounds of the present invention could effectively inhibit the binding of PD-1/PD-L1 at different concentrations. Therefore, the compounds of the present invention can be used in the treatment of diseases related to the mutual binding of PD-1/PD-L1.

Test Example 2 Effect of the Compound of the Invention on PD-L1 Activity at the Cellular Level

[0321] Two types of cells were used in the cytology experiments of PD1/PD-L1, PD-1 effector cells and PD-L1 aAPC cells, wherein PD-1 effector cells express human PD-1 protein, TCR and luciferase reporter gene driven by NFAT-RE, PD-L1 aAPC cells express PD-L1 protein and engineered cell surface protein, which can activate TCR independently of specific antigens. When these two cells were co-cultured, the PD-1/PD-L1 interaction could inhibit the signal transmission from TCR to NFAT-RE and interrupt the NFAT-RE-mediated fluorescent signal. When an inhibitor of PD-1 or PD-L1 was added, the PD-1/PD-L1 interaction was blocked, and the signal inhibition of the TCR to NFAT-RE pathway was removed, and the fluorescence signal was enhanced. The blocking effect of the inhibitors was assayed according to the strength of fluorescence signal.

[0322] On the first day of the experiment, the recovered PD-L1 aAPC cells were digested. After centrifugation, the concentration was diluted to 2.5*10.sup.5/mL with medium (90% Ham's F-12/10% FBS). 40 L cells (1*10.sup.4) were plated in each well of 384-well plates and cultured overnight in an incubator. On the second day, the test compound was diluted with assay buffer (99% RPMI1640/1% FBS) to 2* of final concentration. PD-1 cells were centrifuged and diluted to a concentration of 6.25*10.sup.5/mL with detection buffer. Remove the culture medium from the overnight cultured 384-well plate. Transfer 20 L of the diluted compound and 20 L of PD-1 cells to each well. After incubated in the cell incubator for 6 hours, 20 L of Bio-Glo reagent was added to each well (Promega, cat #G7940). After 10 minutes, the fluorescence signal was read by a multi-functional microplate reader. Negative control (only cells and no compounds) and a blank control (only detection buffers) were set for each plate. Based on the fluorescence value, Prism5 was used to analyze the inhibitory activity of each compound.

[0323] The results showed that the compounds of the present invention exhibited inhibitory activity on PD-1 cells at the cellular level, and the inhibitory activity was equivalent to or better than known PD-1 inhibitors in the art.

[0324] All literatures cited in the present application are incorporated herein as reference, the same as individually cited ones. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents shall also fall within the scope defined by the appended claims.