PYRIDINE OXYNITRIDE, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention belongs to the field of medicinal chemistry. Disclosed are a pyridine oxynitride, a preparation method therefor and the use thereof. Specifically, the present invention relates to a series of sodium ion channel blockers with a new structure, a preparation method therefor and the use thereof. The structure thereof is as shown in general formula (I) below. The compounds or a stereoisomer, a racemate, a geometric isomer, a tautomer, a prodrug, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof and a pharmaceutical composition can be used for treating or/and preventing related diseases mediated by a sodium ion channel (NaV).

##STR00001##

Claims

1. A compound as shown in formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, ##STR00168## wherein, T.sub.1 is selected from N or C(R.sub.7); T.sub.2 is selected from N or C(R.sub.8); T.sub.3 is selected from N or C(R.sub.9); T.sub.4 is selected from N or C(R.sub.10); R.sub.1, R.sub.2, R.sub.8, R.sub.9 are each independently selected from H, halogen, OH, NH.sub.2, CN, SF.sub.5, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, vinyl-C.sub.1-6 alkyl-, C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl-O—, phenyl-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-O—, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-NH—, 5-6 membered heteroaryl-C.sub.1-3 alkyl-, 5-6 membered heteroaryl-C.sub.1-3 alkyl-O— and 5-6 membered heteroaryl-C.sub.1-3 alkyl-NH—, the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylamino, vinyl-C.sub.1-6 alkyl-, C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl-O—, phenyl-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-O—, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-NH—, 5-6 membered heteroaryl-C.sub.1-3 alkyl-, 5-6 membered heteroaryl-C.sub.1-3 alkyl-O— or 5-6 membered heteroaryl-C.sub.1-3 alkyl-NH— is optionally substituted by 1, 2 or 3 R; and, when T.sub.3 is selected from N, R.sub.1 is not H; R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.10 are each independently selected from H, halogen, OH, NH.sub.2, SF.sub.5, CN, C.sub.1-6 alkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkayl, —O—C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl- and 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl-, the C.sub.1-6 alkyl, C.sub.1-6 alkylamino, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkayl, —O—C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-6 alkyl- or 3-6 membered heterocycloalkyl-C.sub.1-6 alkyl- is optionally substituted by 1, 2 or 3 R; R.sub.7 is selected from H, F, Cl, Br, I, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.1-6 alkylamino, the C.sub.1-6 alkyl, C.sub.1-6 alkoxy or C.sub.1-6 alkylamino is optionally substituted by 1, 2 or 3 R; L.sub.1 is selected from C(═O), NH and ##STR00169## L.sub.2 is selected from O, S, NH and CH.sub.2, the CH.sub.2 is optionally substituted by 1 or 2 R, and NH is optionally substituted by R; R.sub.11 and R.sub.12 are each independently selected from H, halogen, OH, NH.sub.2 and C.sub.1-6 alkyl, the C.sub.1-6 alkyl is optionally substituted by 1, 2 or 3 R; or, R.sub.1 and R.sub.12 are connected together to form a 3-6 membered ring; each of R.sub.13 is independently selected from H, halogen and C.sub.1-6 alkyl, the C.sub.1-6 alkyl is optionally substituted by 1, 2 or 3 R; n is selected from 1, 2 or 3; each of R is independently selected from H, D, halogen, OH, NH.sub.2, CN, NH.sub.2, ##STR00170##  C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio and C.sub.1-6 alkylamino, the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio or C.sub.1-6 alkylamino is optionally substituted by 1, 2 or 3 R′; R′ is selected from F, Cl, Br, I, OH, NH.sub.2 and CH.sub.3; the 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from —O—, —NH—, —S—, —C(═O)—, —C(═O)O—, —S(═O)—, —S(═O).sub.2— and N.

2. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R is selected from H, D, F, Cl, Br, I, OH, NH.sub.2, ##STR00171## Me, CF.sub.3, CHF.sub.2, CH.sub.2F, ##STR00172##

3. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.1, R.sub.2, R.sub.8, R.sub.9 are each independently selected from H, halogen, OH, NH.sub.2, CN, SF.sub.5, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylamino, vinyl-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-, phenyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-NH—, pyridyl-C.sub.1-3 alkyl-, pyrimidinyl-C.sub.1-3 alkyl-, thiophenyl-C.sub.1-3 alkyl-, thiazolyl-C.sub.1-3 alkyl-, pyrazolyl-C.sub.1-3 alkyl-, imidazolyl-C.sub.1-3 alkyl-, pyridyl-C.sub.1-3 alkyl-O—, pyrimidinyl-C.sub.1-3 alkyl-O—, thiophenyl-C.sub.1-3 alkyl-O—, thiazolyl-C.sub.1-3 alkyl-O—, pyrazolyl-C.sub.1-3 alkyl-O—, imidazolyl-C.sub.1-3 alkyl-O—, pyridyl-C.sub.1-3 alkyl-NH—, pyrimidinyl-C.sub.1-3 alkyl-NH—, thiophenyl-C.sub.1-3 alkyl-NH—, thiazolyl-C.sub.1-3 alkyl-NH—, pyrazolyl-C.sub.1-3 alkyl-NH— and imidazolyl-C.sub.1-3 alkyl-NH—, the C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 alkylamino, vinyl-C.sub.1-3 alkyl-, C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-, 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-, phenyl-C.sub.1-3 alkyl-O—, phenyl-C.sub.1-3 alkyl-NH—, pyridyl-C.sub.1-3 alkyl-, pyrimidinyl-C.sub.1-3 alkyl-, thiophenyl-C.sub.1-3 alkyl-, thiazolyl-C.sub.1-3 alkyl-, pyrazolyl-C.sub.1-3 alkyl-, imidazolyl-C.sub.1-3 alkyl-, pyridyl-C.sub.1-3 alkyl-O—, pyrimidinyl-C.sub.1-3 alkyl-O—, thiophenyl-C.sub.1-3 alkyl-O—, thiazolyl-C.sub.1-3 alkyl-O—, pyrazolyl-C.sub.1-3 alkyl-O—, imidazolyl-C.sub.1-3 alkyl-O—, pyridyl-C.sub.1-3 alkyl-NH—, pyrimidinyl-C.sub.1-3 alkyl-NH—, thiophenyl-C.sub.1-3 alkyl-NH—, thiazolyl-C.sub.1-3 alkyl-NH—, pyrazolyl-C.sub.1-3 alkyl-NH— or imidazolyl-C.sub.1-3 alkyl-NH— is optionally substituted by 1, 2 or 3 R.

4. The compound as defined in claim 3, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.1, R.sub.2, R.sub.8, R.sub.9 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, CN, SF.sub.5, Me, CF.sub.3, CHF.sub.2, CF.sub.3CF.sub.2, CH.sub.2F, OCF.sub.3, HOCH.sub.2CH.sub.2O, CH.sub.3NHCH.sub.2CH.sub.2O, (CH.sub.3).sub.2NCH.sub.2CH.sub.2O, ##STR00173##

5. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, the structural moiety ##STR00174## is selected from ##STR00175## ##STR00176## ##STR00177## ##STR00178##

6. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.10 are each independently selected from H, halogen, OH, NH.sub.2, SF.sub.5, CN, C.sub.1-3 alkyl, C.sub.1-3 alkylamino, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkayl, —O—C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl- and 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl-, the C.sub.1-3 alkyl, C.sub.1-3 alkylamino, C.sub.1-3 alkoxy, C.sub.3-6 cycloalkayl, —O—C.sub.3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C.sub.3-6 cycloalkyl-C.sub.1-3 alkyl- or 3-6 membered heterocycloalkyl-C.sub.1-3 alkyl- is optionally substituted by 1, 2 or 3 R.

7. The compound as defined in claim 6, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.10 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, SF.sub.5, Me, CF.sub.3, CHF.sub.2, CH.sub.2F, CN, CH(F.sub.2)CH.sub.3, CD.sub.3, OCD.sub.3, ##STR00179##

8. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, the structural moiety ##STR00180## is selected from ##STR00181## ##STR00182##

9. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, the structural moiety ##STR00183## is selected from ##STR00184##

10. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.11, R.sub.12 are each independently selected from H, F, Cl, Br, I, OH, NH.sub.2, Me, CHF.sub.2, CF.sub.3, ##STR00185##

11. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, R.sub.11 and R.sub.12 are connected together to form a cyclopropyl, oxetanyl, azetidinyl and cyclopentanonyl.

12. The compound as defined in claim 10, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, L.sub.1 is selected from C(═O), CH.sub.2, NH, CH(CH.sub.3), CHF, CF.sub.2, CHCHF.sub.2, CHCF.sub.3, ##STR00186##

13. The compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof, wherein, the compound is selected from ##STR00187## wherein, T.sub.1, R.sub.1, R.sub.2, T.sub.2, T.sub.3, R.sub.3, R.sub.4, R.sub.5, R.sub.6, T.sub.4, L.sub.1, L.sub.2 and R are as define above; R.sub.13a, R.sub.13b are each independently selected from H, halogen and C.sub.1-6 alkyl, the C.sub.1-6 alkyl is optionally substituted by 1, 2 or 3 R.

14. A compound as shown in the formula below, an optical isomer thereof or a pharmaceutically acceptable salt thereof selected from ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209##

15. A pharmaceutical composition, wherein, the pharmaceutical composition comprises the compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition as defined in claim 15, wherein, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

17. A method of inhibiting the voltage-gated sodium ion channel in a subject in need thereof, comprising administering an effective amount of the compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof to the subject.

18. The method as defined in claim 17, wherein, the voltage-gated sodium ion channel is Nav1.8.

19. A method for treating and/or preventing pain or cough, or relieving the severity of pain or cough in a subject in need thereof, comprising administering an effective amount of the compound as defined in claim 1, the optical isomer thereof or the pharmaceutically acceptable salt thereof to the subject.

20. The method as defined in claim 19, wherein, the pain is selected from chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot, Marfan and Down syndrome, incontinence and arrhythmia.

Description

DETAILED DESCRIPTION OF THE EMBODIMENTS

Embodiment

[0107] The present disclosure will be further explained below with specific embodiments. It should be understood that these embodiments are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. In the following embodiment, if no specific conditions are specified, the experimental methods usually follow the conventional conditions of this type of reaction or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and parts by weight. Unless otherwise specified, the ratio of liquids is a volume ratio.

[0108] The experimental materials and reagents used in the following embodiment can be obtained from commercial available sources unless otherwise specified.

[0109] In the following embodiment, the .sup.1H-NMR spectrum was recorded with the Bluker AVANCE III HD 400 MHz nuclear magnetic resonance instrument; the .sup.13C-NMR spectrum was recorded with the Bluker AVANCE III HD 400 MHz nuclear magnetic resonance instrument, and the chemical shift was expressed in δ (ppm); mass spectrum was recorded with Agilent 1260 (ESI) or Shimadzu LCMS-2020 (ESI) or Agilent 6215 (ESI) mass spectrometer; reversed-phase preparative HPLC separation was performed with Agilent 1290 UV-guided automatic purification system (Xtimate® Prep C18 OBD™ 21.2*250 mm 10 μm column) or Gilson GX281 UV-guided automatic purification system (xBridge® Prep C18 OBD™ 19*250 mm 10 μm column) or Waters QDa-guided automatic purification system (SunFire® Prep C18 OBD 29*250 mm 10 μm Column).

[0110] Wherein, the names of reagents represented by chemical formulas or English abbreviations are as follows:

[0111] Aq refers to aqueous solution; Ar refers to argon; BH.sub.3 refers to borane; br refers to wide peak; B.sub.2Pin.sub.2 refers to bis(pinacolato)diboron; ° C. refers to degrees celsius; CD.sub.3OD refers to deuterated methanol; CDCl.sub.3 refers to deuterated chloroform; conc. refers to concentrated; (COCI).sub.2 refers to oxalyl chloride; Cs.sub.2CO.sub.3 refers to cesium carbonate; CuI refers to cuprous iodide; d refers to double peak; DCM refers to dichloromethane; dioxane or 1,4-dioxane refers to dioxane; DIPEA or DIEA refers to N, N-diisopropylethylamine; DMF refers to dimethylformamide; DMSO refers to dimethyl sulfoxide; EA or EtOAc refers to ethyl acetate; ESI refers to electrospray ionization; g refers to gram; h refers to hour; H.sub.2O refers to water; HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HOBt refers to 1-hydroxybenzotriazole; HPLC refers to high performance liquid chromatography; K.sub.2CO.sub.3 refers to potassium carbonate; KOAc refers to potassium acetate; LCMS refers to liquid chromatography-mass spectrometry; LiOH refers to lithium hydroxide; m refers to multiple peaks; m/z refers to mass charge ratio; MeCN, ACN or CH.sub.3CN refers to acetonitrile; m-CPBA refers to m-chloroperoxybenzoic acid; MeOH refers to methanol; min refers to minute; mg refers to milligram; mL refers to millilitre; mmol refers to millimole; N.sub.2 refers to nitrogen; Na.sub.2CO.sub.3 refers to sodium carbonate; NaCl refers to sodium chloride; NaHCO.sub.3 refers to sodium bicarbonate; NaOH refers to sodium hydroxide; Na.sub.2SO.sub.4 refers to sodium sulfate; NMP refers to N-methyl-2-pyrrolidone; PBr.sub.3 refers to phosphorus tribromide; Pd(dppf)Cl.sub.2 or PdCl.sub.2(dppf) refers to [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; PE refers to petroleum ether; r. t. or RT refers to room temperature; s refers to single peak; SOCl.sub.2 refers to dichlorosulfoxide; t refers to triple peak; TLC refers to thin layer chromatography; THF refers to tetrahydrofuran; Toluene or tol. refers to toluene.

Synthesis of embodiment A1

[0112] ##STR00053##

[0113] Step 1, Synthesis of Intermediate 3

[0114] Compound 1 (2.2 g, 10.57 mmol) was added to DMF (10 mL), HATU (5.23 g, 13.75 mmol) was added thereto at 0° C., and the mixture was stirred for 10 min and compound 2 (1.09 g, 11.62 mmol) was added, then DIEA (1.78 g, 13.79 mmol) was slowly added dropwise, the reaction mixture was stirred at room temperature for 2 h, LC-MS showed that the reaction was complete, H.sub.2O (20 mL) was added to the reaction mixture, a solid precipitated out, then the mixture was filtered, the filter cake was the target compound, and was dried to obtain compound 3, white solid, 2.2 g, yield: 73%. LCMS: m/z 285.0 (M+H)+.

[0115] Step 2, Synthesis of Intermediate 5

[0116] Compound 3 (500 mg, 1.76 mmol) was dissolved in NMP (5 mL), compound 4 (333 mg, 2.64 mmol) and K.sub.2CO.sub.3 (730 mg, 5.28 mmol) were added to the mixture, and the reaction mixture was stirred at 100° C. overnight, LC-MS showed that the reaction was complete, H.sub.2O (20 mL) was added to the reaction mixture, and the reaction mixture was extracted with EA (15 mL*3), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4 and concentrated, and the crude product was purified by normal phase column (PE/EA=0-100%) to obtain compound 5, yellow solid, 500 mg, yield: 72.8%. LCMS: m/z 391.1 (M+H)+.

[0117] Step 3, Synthesis of Embodiment A1

[0118] Compound 5 (200 mg, 0.51 mmol) was dissolved in DCM (2 mL), m-CPBA (133 mg, 0.77 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h, LC-MS showed that the reaction was complete. The pH value was adjusted by adding saturated NaHCO.sub.3 to weakly basic, the mixture was extracted with EA (20 mL*2), the organic phase was combined, washed with saturated NaCl (20 mL), dried over anhydrous Na.sub.2SO.sub.4, and concentrated to obtain a crude product, the crude product was prepared (5-95% acetonitrile in water (containing 0.05% NH.sub.4HCO.sub.3)) to obtain compound A1. LCMS: m/z 407.2 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.93 (s, 1H), 8.68 (s, 1H), 8.01 (ddd, J=6.4, 1.7, 0.9 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.62 (dd, J=7.9, 0.8 Hz, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.39 (dd, J=8.4, 6.4 Hz, 1H), 7.22 (dd, J=9.2, 2.5 Hz, 1H), 7.13-7.05 (m, 2H), 7.01 (s, 1H), 2.17 (s, 3H).

[0119] Similar to the synthesis of embodiment A1, the following embodiments A2-A40 were synthesized, as shown in Table 1 below:

TABLE-US-00001 TABLE 1 Structural formula and analysis data of embodiments A2-A40 Embodiment Structural formula Analysis data A2  [00054] LCMS: m/z 407.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.02 (s, 1H), 8.19-8.12 (m, 2H), 7.88 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 7.5 Hz, 2H), 7.62 (dd, J = 7.9, 0.8 Hz, 1H), 7.21 (dd, J = 9.1, 2.3 Hz, 1H), 7.09 (dd, J = 6.8, 3.1 Hz, 2H), 7.00 (s, 1H), 2.16 (s, 3H). A3  [00055] LCMS: m/z 408.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 8.79-8.78 (d, J = 3.2 Hz, 1H), 8.28-8.26 (d, J = 6.8 Hz, 1H), 8.13-8.10 (m, 1H), 7.91-7.89 (d, J = 8.0 Hz, 1H), 7.64-7.62 (d, J = 8.0 Hz, 1H), 7.24-7.21 (m, 1H), 7.11- 7.08 (m, 2H), 7.0 (s, 1H), 2.16 (s, 3H). A4  [00056] LCMS: m/z 408.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.36 (s, 1H), 8.66-8.65 (d, J = 1.2 Hz, 1H), 8.47-8.46 (d, J = 6.4 Hz, 1H), 7.92-7.90 (d, J = 7.6 Hz, 1H), 7.65-7.63 (m, 1H), 7.43-7.41 (m, 1H), 7.24-7.21 (m, 1H), 7.14-7.07 (m, 2H), 7.01 (s, 1H), 2.16 (s, 3H). A5  [00057] LCMS: m/z 423.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.79 (s, 1H), 8.70 (s, 1H), 8.01 (dd, J = 6.3, 0.8 Hz, 1H), 7.94 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.40 (dd, J = 8.4, 6.4 Hz, 1H), 7.26 (dd, J = 8.8, 5.8 Hz, 1H), 7.13 (dd, J = 10.7, 2.9 Hz, 1H), 6.89 (s, 1H), 6.86-6.77 (m, 1H), 3.75 (s, 3H). A6  [00058] LCMS: m/z 423.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.86 (s, 1H), 8.73 (s, 1H), 8.04-7.99 (m, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.60-7.52 (m, 2H), 7.40 (dd, J = 8.4, 6.4 Hz, 1H), 7.29 (dd, J = 8.8, 5.9 Hz, 1H), 7.15 (dd, J = 10.7, 2.9 Hz, 1H), 6.86 (dt, J = 8.6, 2.9 Hz, 2H), 3.75 (s, 3H). A7  [00059] LCMS: m/z 407.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.17 (s, 1H), 8.67 (t, J = 1.6 Hz, 1H), 8.07-7.97 (m, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.50 (dd, J = 8.5, 0.9 Hz, 1H), 7.43- 7.35 (m, 1H), 7.25-7.19 (m, 1H), 7.12 (dd, J = 6.7, 3.3 Hz, 2H), 6.70 (d, J = 1.8 Hz, 1H), 2.14 (s, 3H). A8  [00060] LCMS: m/z 465.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.66 (s, 1H), 8.02 (ddd, J = 6.3, 1.6, 0.9 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.83 (dd, J = 8.5, 2.1 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.40 (dd, J = 8.4, 6.4 Hz, 1H), 7.23 (dd, J = 9.3, 2.8 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 7.14-7.03 (m, 2H), 2.17 (s, 3H). A9  [00061] LCMS: m/z 466.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 8.76 (d, J = 3.2 Hz, 1H), 8.28 (d, J = 7.1 Hz, 1H), 8.09 (dd, J = 7.1, 3.4 Hz, 1H), 7.99-7.76 (m, 2H), 7.24 (dd, J = 9.3, 2.8 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.15-7.05 (m, 2H), 2.16 (s, 3H). A10 [00062] LCMS: m/z 466.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.71 (s, 1H), 8.62 (d, J = 1.1 Hz, 1H), 8.45 (d, J = 6.2 Hz, 1H), 7.98-7.77 (m, 2H), 7.38 (dd, J = 6.3, 1.6 Hz, 1H), 7.24 (dd, J = 9.2, 2.8 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.14-7.03 (m, 2H), 2.17 (s, 3H). A11 [00063] LCMS: m/z 459.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.83 (s, 1H), 8.61 (s, 1H), 8.03 (s, 1H), 8.00-7.98 (m, 1H), 7.47-7.44 (m, 2H), 7.40-7.34 (m, 3H), 7.21-7.16 (m, 2H). A12 [00064] LCMS: m/z 477.3 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.90 (s, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 7.71-7.62 (m, 3H), 7.39-7.30 (m, 3H), 6.90 (s, 1H). A13 [00065] LCMS: m/z 453.10 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.78 (s, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.02 (ddd, J = 6.4, 1.8, 0.9 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.63-7.48 (m, 2H), 7.40 (dd, J = 8.5, 6.3 Hz, 1H), 7.29 (dd, J = 8.9, 5.8 Hz, 1H), 7.17 (dd, J = 10.7, 2.9 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 6.89- 6.77 (m, 1H), 4.83 (t, J = 5.4 Hz, 1H), 4.00 (t, J = 5.1 Hz, 2H), 3.53-3.48 (m, 2H). A14 [00066] LCMS: m/z 422.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.82 (s, 1H), 8.66 (s, 1H), 8.01-7.98 (m, 2H), 7.51-7.48 (d, J = 8.8 Hz, 1H), 7.40-7.37 (m, 1H), 7.22-7.13 (m, 3H), 6.96-6.93 (m, 1H), 3.83 (s, 3H). A15 [00067] LCMS: m/z 475.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.42 (s, 1H), 8.65 (s, 1H), 8.05-8.04 (t, J = 5.2 Hz, 1H), 7.96 (s, 1H), 7.49-7.39 (m, 2H), 7.28-7.12 (m, 4H), 2.15 (s, 3H). A16 [00068] LCMS: m/z 459.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.32 (s, 1H), 8.68 (s, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.88 (t, J = 8.4 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.44-7.04 (m, 6H), 6.83 (d, J = 8.0 Hz, 1H). A17 [00069] LCMS: m/z 504.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.20 (s, 1H), 8.63 (s, 1H), 8.02 (d, J = 6.2 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.52-7.29 (m, 4H), 7.27-7.11 (m, 2H), 6.98 (d, J = 8.9 Hz, 1H). A18 [00070] LCMS: m/z 527.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.32 (s, 1H), 8.67 (s, 1H), 8.04 (d, J = 6.2 Hz, 1H), 7.84 (t, J = 8.7 Hz, 1H), 7.49 (t, J = 8.4 Hz, 3H), 7.43-7.36 (m, 3H), 6.94 (d, J = 8.9 Hz, 1H). A19 [00071] LCMS: m/z 492.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.30 (s, 1H), 8.64 (s, 1H), 8.03 (d, J = 6.4 Hz, 1H), 7.73 (t, J = 9.2 Hz, 1H), 7.51-7.35 (m, 4H), 7.31-7.23 (m, 2H), 6.94 (dd, J = 9.2, 1.2 Hz, 1H). A20 [00072] LCMS: m/z 492.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.22 (s, 1H), 8.63 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.49- 7.42 (m, 4H), 7.41-7.35 (m, 1H), 7.29-7.24 (m, 2H), 6.92 (s, 1H). A21 [00073] LCMS: m/z 494.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.21 (s, 1H), 8.58 (d, J = 1.6 Hz, 1H), 8.03 (dt, J = 5.6, 1.7 Hz, 1H), 7.60 (t, J = 8.5 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.45-7.33 (m, 3H), 7.06 (ddd, J = 9.1, 2.9, 1.6 Hz, 1H). A22 [00074] LCMS: m/z 477.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.22 (s, 1H), 8.59 (s, 1H), 8.02 (dd, J = 6.0, 1.6 Hz, 1H), 7.40 (dt, J = 14.4, 7.7 Hz, 4H), 7.32 (d, J = 1.9 Hz, 1H), 7.29-7.20 (m, 2H). A23 [00075] LCMS: m/z 536.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (s, 1H), 8.56 (s, 1H), 8.45 (d, J = 6.2 Hz, 1H), 8.02-7.92 (m, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 6.1 Hz, 1H), 7.26-7.17 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H). A24 [00076] LCMS: m/z 535.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.45 (s, 1H), 8.71 (d, J = 3.3 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 8.07 (dd, J = 7.1, 3.4 Hz, 1H), 8.01-7.91 (m, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.25-7.16 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H). A25 [00077] LCMS: m/z 460.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, MeOD) δ 8.72 (d, J = 3.2 Hz, 1H), 8.27-8.25 (m, 1H), 8.23-8.20 (m, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 1.2 Hz, 2H), 7.23 (d, J = 1.2 Hz, 2H), 7.13-7.12 (m, 0.3H), 7.11-7.10 (m, 0.5H), 6.92-6.82 (m, 1H), 6.80-6.78 (m, 0.2H). A26 [00078] LCMS: m/z 478.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.34 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.45 (d, J = 6.4 Hz, 1H), 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.63-7.58 (m, 2H), 7.38 (dd, J = 6.4, 1.6 Hz, 1H), 7.31 (dd, J = 9.2, 2.8 Hz, 1H), 6.99-6.96 (m, 1H). A27 [00079] LCMS: m/z 494.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.67 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.45-7.41 (m, 2H), 7.34 (dd, J = 6.4, 1.6 Hz, 1H), 7.30-7.25 (m, 2H), 7.00 (d, 8.8 Hz, 1H). A28 [00080] LCMS: m/z 494.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.53 (s, 1H), 8.69 (dd, J = 3.6, 0.8 Hz, 1H), 8.20 (dd, J = 7.2, 0.8 Hz, 1H), 8.08-8.05 (m, 1H), 7.88 (d, J = 9.2 Hz, 1H), 7.44- 7.40 (m, 2H), 7.29-7.25 (m, 2H), 7.99 (d, J = 9.2 Hz, 1H). A29 [00081] LCMS: m/z 493.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.32 (s, 1H), 8.65 (s, 1H), 8.05-8.03 (m, 1H), 7.94 (s, 1H), 7.88-7.86 (m, 1H), 7.47-7.38 (m, 4H), 7.29-7.25 (m, 2H). A30 [00082] LCMS: m/z 473.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.93 (s, 1H), 8.74 (s, 1H), 8.07 (d, J = 6.1 Hz, 1H), 7.98 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.5, 6.4 Hz, 1H), 7.20-7.04 (m, 5H), 4.75 (q, J = 8.9 Hz, 2H). A31 [00083] LCMS: m/z 517.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.18 (s, 1H), 8.67 (t, J = 1.7 Hz, 1H), 8.08-7.98 (m, 1H), 7.82 (d, J = 9.0 Hz, 1H), 7.52-7.43 (m, 1H), 7.41-7.33 (m, 1H), 7.12 (s, 4H), 6.78 (d, J = 9.0 Hz, 1H), 4.75 (q, J = 8.9 Hz, 2H). A32 [00084] LCMS: m/z 491.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.29 (s, 1H), 8.69 (s, 1H), 8.04 (d, J = 6.0 Hz, 1H), 7.85 (t, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46-7.36 (m, 1H), 7.25- 7.14 (m, 4H), 8.74 (d, J = 8.8 Hz, 1H), 4.78 (q, J = 8.8 Hz, 2H). A33 [00085] LCMS: m/z 488.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.71 (s, 1H), 8.56 (s, 1H), 8.46-8.38 (m, 1H), 7.90-7.77 (m, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.37-7.31 (m, 1H), 7.27-7.17 (m, 2H), 6.87 (dd, J = 9.1, 0.8 Hz, 1H). A34 [00086] LCMS: m/z 488.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.51 (s, 1H), 8.71 (d, J = 3.l Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.07 (dd, J = 7.1, 3.4 Hz, 1H), 7.85 (t, J = 8.5 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.25-7.16 (m, 2H), 6.88 (dd, J = 9.0, 0.9 Hz, 1H). A35 [00087] LCMS: m/z 460.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.27 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.44 (d, J = 6.3 Hz, 1H), 8.07 (d, J = 5.0 Hz, 1H), 7.47 (s, 1H), 7.44-7.34 (m, 3H), 7.27-7.06 (m, 2H). A36 [00088] LCMS: m/z 460.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.15 (s, 1H), 8.73 (d, J = 3.2 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 8.10-7.99 (m, 2H), 7.47 (s, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.25-7.07 (m, 2H). A37 [00089] LCMS: m/z 478.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.30 (s, 1H), 8.57 (d, J = 1.1 Hz, 1H), 8.43 (d, J = 6.3 Hz, 1H), 8.08 (s, 1H), 7.63 (s, 1H), 7.58 (t, J = 8.6 Hz, 1H), 7.37 (dd, J = 6.3, 1.6 Hz, 1H), 7.31 (dd, J = 11.4, 2.9 Hz, 1H), 6.98 (ddd, J = 9.1, 2.9, 1.5 Hz, 1H). A38 [00090] LCMS: m/z 478.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.16 (s, 1H), 8.72 (d, J = 3.2 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 8.09-8.03 (m, 2H), 7.64 (s, 1H), 7.57 (t, J = 8.6 Hz, 1H), 7.30 (dd, J = 11.4, 2.9 Hz, 1H), 6.98 (ddd, J = 9.1, 2.8, 1.5 Hz, 1H). A39 [00091] LCMS: m/z 592.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.28 (s, 1H), 8.62 (s, 1H), 8.04 (dt, J = 5.9, 1.5 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.52 (dd, J = 11.1, 2.8 Hz, 1H), 7.47-7.36 (m, 3H), 7.22-7.10 (m, 1H). A40 [00092] LCMS: m/z 511.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.33 (s, 1H), 8.64 (s, 1H), 8.04 (d, J = 6.1 Hz, 1H), 7.55-7.31 (m, 6H), 7.16 (s, 1H).

Synthesis of Embodiment A41

[0120] ##STR00093##

[0121] Step 1, Synthesis of Intermediate 8

[0122] Compound 6 (450 mg, 1.6 mmol) was added to toluene (10 mL), Cs.sub.2CO.sub.3 (1.25 g, 3.84 mmol) and compound 7 (391 mg, 1.9 mmol) were added, the mixture was stirred at 100° C. under nitrogen protection for 1.5 h, LC-MS showed that the reaction of the raw materials was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (30 mL*3), the combined organic phase was evaporated to dryness and purified by normal phase column (PE/EA=0-100%) to obtain compound 8, white solid, 300 mg, yield 45%, LCMS: m/z 415.2 (M+H)+.

[0123] Step 2, Synthesis of Intermediate 9

[0124] Compound 8 (200 mg, 0.48 mmol) was dissolved into DCM (8 mL), cooled to 0° C. in an ice bath, three drops of DMF were added, oxalyl chloride (245 mg, 1.93 mmol) was added dropwise, after the addition, the mixture was stirred at room temperature for 1 h, sampled, and the reaction was quenched by adding methanol, TLC showed that the reaction of the raw material was complete, and the reaction mixture was evaporated to dryness. DCM (10 mL) was added to the mixture, and the mixture was cooled to 0° C. in an ice bath, DIPEA (250 mg, 1.93 mmol) and compound 2 (68 mg, 0.72 mmol) were added thereto, the mixture was stirred at room temperature for 2 h, the reaction was quenched by adding methanol (10 mL), the mixture was then evaporated to dryness and purified by normal phase column (PE/EA=0-100%) to obtain compound 9, white solid, 70 mg, yield: 30%. LCMS: m/z 491.0 (M+H)+.

[0125] Step 3, Synthesis of Embodiment A41

[0126] Compound 9 (70 mg, 0.14 mmol) was dissolved in DCM (10 mL), m-CPBA (50 mg, 0.29 mmol) was added, and the mixture was stirred for 4 h at room temperature, LCMS showed that the reaction of the raw materials was complete, saturated NaHCO.sub.3 (20 mL) was added thereto, the mixture was then stirred for 30 min, the phases were separated, the aqueous phase was extracted with DCM (20 mL*2), the organic phase was washed with saturated NaCl (30 mL), dried over anhydrous Na.sub.2SO.sub.4, and evaporated to dryness (5-95% acetonitrile in water (containing 0.05% NH.sub.4HCO.sub.3)) to obtain compound A41. LCMS: m/z 507.2 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.28 (s, 1H), 8.691-8.68 (t, J=1.2 Hz, 1H), 8.05-8.03 (d, J=7.2 Hz, 1H), 7.83-7.79 (t, J=8.4 Hz, 1H), 7.54-7.52 (d, J=9.2 Hz, 1H), 7.43-7.36 (m, 2H), 7.27-7.26 (d, J=2.4 Hz, 1H), 7.06-7.04 (m, 1H), 6.69-6.67 (d, J=8.8 Hz, 1H), 3.79 (s, 3H).

[0127] Similar to the synthesis of embodiments A1 and A41, the following embodiments A42-A114 were synthesized, as shown in Table 2 below:

TABLE-US-00002 TABLE 2 Structural formula and analysis data of embodiments A42-A114 Embodiment Structural formula Analysis data A42 [00094] LCMS: m/z 477.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.32 (s, 1H), 8.66 (t, J = 1.6 Hz, 1H), 8.08-8.00 (m, 1H), 7.89 (t, J = 8.7 Hz, 1H), 7.52-7.45 (m, 3H), 7.40 (dd, J = 8.4, 6.3 Hz, 1H), 7.37-7.31 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H). A43 [00095] LCMS: m/z 511.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (s, 1H), 8.39 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 2.9 Hz, 1H), 7.91 (t, J = 8.7 Hz, 1H), 7.63-7.42 (m, 3H), 7.35 (d, J = 9.1 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H). A44 [00096] LCMS: m/z 477.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.41 (s, 1H), 8.20-8.12 (m, 2H), 7.89 (t, J = 8.7 Hz, 1H), 7.68-7.60 (m, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.39-7.29 (m, 2H), 6.91 (d, J = 8.9 Hz, 1H). A45 [00097] LCMS: m/z 478.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.61 (s, 1H), 8.81-8.69 (m, 1H), 8.28 (d, J = 7.1 Hz, 1H), 8.12 (dd, J = 7.1, 3.4 Hz, 1H), 7.91 (t, J = 8.7 Hz, 1H), 7.54- 7.45 (m, 2H), 7.39-7.29 (m, 2H), 6.93 (d, J = 8.9 Hz, 1H). A46 [00098] LCMS: m/z 478.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.73 (s, 1H), 8.60 (d, J = 1.1 Hz, 1H), 8.49 (d, J = 6.3 Hz, 1H), 7.92 (t, J = 8.7 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.42- 7.31 (m, 3H), 6.93 (d, J = 8.9 Hz, 1H). A47 [00099] LCMS: m/z 495.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.30 (s, 1H), 8.65 (t, J = 1.6 Hz, 1H), 8.05 (dd, J = 6.3, 1.6 Hz, 1H), 7.93 (t, J = 8.7 Hz, 1H), 7.69 (t, J = 8.9 Hz, 1H), 7.55- 7.37 (m, 3H), 7.16 (ddd, J = 9.1, 2.8, 1.6 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H). A48 [00100] LCMS: m/z 441.10 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.96 (s, 1H), 8.85 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.56 (dd, J = 8.2, 1.6 Hz, 1H), 7.44 (dd, J = 9.0, 2.2 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.09- 6.98 (m, 2H), 6.94 (d, J = 1.6 Hz, 1H), 2.09 (s, 3H). A49 [00101] LCMS: m/z 418.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, CH.sub.3OH-d.sub.6) δ 8.36 (s, 1H), 8.24-8.02 (m, 1H), 7.74-7.50 (m, 3H), 7.42- 7.35 (m, 3H), 7.06 (d, J = 8.0 Hz, 1H), 6.82 (s, 1H). A50 [00102] LCMS: m/z 445.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.33 (s, 1H), 8.68 (s, 1H), 8.06 (d, J = 6.4 Hz, 1H), 7.87 (t, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.0, 2.8 Hz, 1H), 7.54-7.47 (m, 2H), 7.44-7.36 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H). A51 [00103] LCMS: m/z 491.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.34 (s, 1H), 8.68 (t, J = 1.6 Hz, 1H), 8.05 (d, J = 6.3 Hz, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.50 (d, J = 9.3 Hz, 1H), 7.44- 7.40 (m, 2H), 7.36-7.24 (m, 2H), 6.74 (d, J = 8.9 Hz, 1H), 2.18 (s, 3H). A52 [00104] LCMS: m/z 495.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.37 (s, 1H), 8.67 (t, J = 1.6 Hz, 1H), 8.05 (d, J = 6.3 Hz, 1H), 7.90 (t, J = 8.7 Hz, 1H), 7.73 (dd, J = 10.8, 2.5 Hz, 1H), 7.53 (dd, J = 18.5, 9.4 Hz, 2H), 7.46-7.33 (m, 2H), 6.97 (d, J = 8.9 Hz, 1H). A53 [00105] LCMS: m/z 491.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.29 (s, 1H), 8.69 (s, 1H), 8.04 (d, J = 6.3 Hz, 1H), 7.85 (t, J = 8.7 Hz, 1H), 7.51 (d, J = 9.3 Hz, 1H), 7.41 (dd, J = 8.5, 6.4 Hz, 1H), 7.28-7.12 (m, 4H), 6.74 (d, J = 8.9 Hz, 1H), 4.78 (q, J = 8.9 Hz, 2H). A54 [00106] LCMS: m/z 511.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.34 (s, 1H), 8.67 (t, J = 1.6 Hz, 1H), 8.06 (d, J = 7.0 Hz, 1H), 7.90 (t, J = 8.7 Hz, 1H), 7.84 (s, 1H), 7.57-7.38 (m, 4H), 6.88 (d, J = 8.8 Hz, 1H). A55 [00107] LC-MS: m/z 496.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.58 (s, 1H), 8.73 (d, J = 3.4 Hz, 1H), 8.28 (dd, J = 7.1, 0.6 Hz, 1H), 8.10 (dd, J = 7.1, 3.4 Hz, 1H), 7.94 (t, J = 8.7 Hz, 1H), 7.69 (t, J = 8.5 Hz, 1H), 7.51 (dd, J = 11.1, 2.9 Hz, 1H), 7.16 (ddd, J = 9.0, 2.8, 1.5 Hz, 1H), 7.10 (d, J = 8.9 Hz, 1H). A56 [00108] LCMS: m/z 496.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.54 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.48 (d, J = 6.2 Hz, 1H), 7.95 (t, J = 8.6 Hz, 1H), 7.69 (t, J = 9.0 Hz, 1H), 7.52 (dd, J = 11.1, 2.8 Hz, 1H), 7.38 (dd, J = 6.3, 1.6 Hz, 1H), 7.22- 7.13 (m, 1H), 7.09 (d, J = 8.9 Hz, 1H). A57 [00109] LC-MS: m/z 493.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.34 (s, 1H), 8.69 (t, J = 1.5 Hz, 1H), 8.04 (d, J = 6.3 Hz, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.62-7.22 (m, 6H), 7.06 (d, J = 8.8 Hz, 1H). A58 [00110] LCMS: m/z 477.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.38 (s, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.03 (dd, J = 6.3, 1.6 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.50-7.34 (m, 4H), 7.31- 7.10 (m, 3H). A59 [00111] LCMS: m/z 478.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.60 (s, 1H), 8.43 (s, 1H), 8.04 (d, J = 5.7 Hz, 1H), 7.41 (ddd, J = 13.6, 12.4, 5.7 Hz, 7H). A60 [00112] LCMS: m/z 479.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.78 (s, 1H), 8.68 (d, J = 3.3 Hz, 1H), 8.46 (s, 1H), 8.26 (d, J = 7.1 Hz, 1H), 8.06 (dd, J = 7.1, 3.4 Hz, 1H), 7.56-7.16 (m, 4H). A61 [00113] LCMS: m/z 479.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.86 (s, 1H), 8.55 (s, 1H), 8.49 (d, J = 6.1 Hz, 2H), 7.48-7.34 (m, 5H). A62 [00114] LCMS: m/z 496.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (d, J = 8.7 Hz, 2H), 8.06 (d, J = 5.8 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J = 11.2, 2.8 Hz, 1H), 7.49-7.32 (m, 2H), 7.23 (d, J = 9.0 Hz, 1H). A63 [00115] LCMS: m/z 494.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.43 (s, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 8.06 (dt, J = 5.2, 1.6 Hz, 1H), 7.52-7.32 (m, 6H). A64 [00116] LCMS: m/z 494.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ11.89 (s, 1H), 8.69 (d, J = 2.8 Hz, 1H), 8.51 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.08 (dd, J = 7.2, 3.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.40-7.33 (m, 2H). A65 [00117] LCMS: m/z 495.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ12.03 (s, 1H), 8.52 (d, J = 12.8 Hz, 2H), 8.43 (d, J = 6.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.41-7.28 (m, 3H). A66 [00118] LCMS: m/z 450.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 8.62 (s, 1H), 8.47 (s, 1H), 8.01 (d, J = 5.8 Hz, 1H), 7.47-7.18 (m, 4H), 7.07-6.92 (m, 2H), 2.15-2.05 (m, 1H), 2.03-1.90 (m, 1H), 0.99-0.70 (m, 3H). A67 [00119] LCMS: m/z 493.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.90 (s, 1H), 8.66 (s, 1H), 8.20 (s, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.49-7.42(m, 3H), 7.41-7.30 (m, 4H). A68 [00120] LCMS: m/z 510.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.35 (s, 1H), 8.59 (s, 1H), 8.06-8.00 (m, 1H), 7.47-7.36 (m, 5H), 7.29-7.24 (m, 2H). A69 [00121] LCMS: m/z 493.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.99 (s, 1H), 8.60 (d, J = 1.9 Hz, 1H), 8.13 (s, 1H), 8.01 (dt, J = 6.3, 1.3 Hz, 1H), 7.56 (s, 1H), 7.48-7.33 (m, 4H), 7.24- 7.14 (m, 2H). A70 [00122] LC-MS: m/z 425.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.30 (s, 1H), 8.66 (s, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 6.4 Hz, 1H), 7.27-7.21 (m, 1H), 7.20-7.07 (m, 2H), 6.82 (s, 1H), 2.15 (s, 3H). A71 [00123] LCMS: m/z 460.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.66 (s, 1H), 8.76 (d, J = 3.2 Hz, 1H), 8.27 (d, J = 7.1 Hz, 1H), 8.13 (dd, J = 7.1, 3.4 Hz, 1H), 7.88 (t, J = 8.7 Hz, 1H), 7.52-6.97 (m, 5H), 6.83 (d, J = 8.9 Hz, 1H). A72 [00124] LCMS: m/z 460.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.78 (s, 1H), 8.62 (s, 1H), 8.47 (d, J = 6.2 Hz, 1H), 7.89 (t, J = 8.7 Hz, 1H), 7.49-7.00 (m, 6H), 6.81 (t, J = 13.7 Hz, 1H). A73 [00125] LCMS: m/z 535.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.16 (s, 1H), 8.62 (s, 1H), 8.01 (d, J = 6.2 Hz, 1H), 7.98- 7.92 (m, 1H), 7.41 (td, J = 15.7, 8.9 Hz, 4H), 7.22 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 8.8 Hz, 1H). A74 [00126] LCMS: m/z 488.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 8.62 (s, 1H), 8.02 (d, J = 6.5 Hz, 1H), 7.84 (t, J = 8.5 Hz, 1H), 7.52-7.33 (m, 4H), 7.29-7.17 (m, 2H), 6.87 (d, J = 9.0 Hz, 1H). A75 [00127] LCMS: m/z 443.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.01 (s, 1H), 8.56 (s, 1H), 7.95 (d, J = 6.4 Hz, 1H), 7.67 (t, J = 8.8 Hz, 1H), 7.40-7.30 (m, 4H), 7.15 (d, J = 9.2 Hz, 2H), 6.86 (d, J = 9.2 Hz, 1H). A76 [00128] LCMS: m/z 444.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.13 (s, 1H), 8.65 (s, 1H), 8.18 (d, J = 6.8 Hz, 1H), 8.02- 7.99 (m, 1H), 7.69 (t, J = 8.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 6.87 (dd, J = 9.2, 1.2 Hz, 1H). A77 [00129] LCMS: m/z 444.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (s, 1H), 8.50 (s, 1H), 8.39 (d, J = 6.4 Hz, 1H), 7.70 (t, J = 8.8 Hz, 1H), 7.37-7.34 (m, 2H), 7.29 (dd, J = 6.4, 1.2 Hz, 1H), 7.19-7.15 (m, 2H), 6.87 (dd, J = 9.2, 1.2 Hz, 1H). A78 [00130] LCMS: m/z 507.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.12 (s, 1H), 8.60 (s, 1H), 8.05-7.97 (m, 1H), 7.47-7.33 (m, 4H), 7.33-7.23 (m, 2H), 6.73 (s, 1H), 3.32 (s, 3H). A79 [00131] LCMS: m/z 478.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.55 (s, 1H), 8.71 (dd, J = 3.4, 0.8 Hz, 1H), 8.27 (dd, J = 7.1, 0.7 Hz, 1H), 8.07 (dd, J = 7.1, 3.4 Hz, 1H), 7.81 (dd, J = 8.9, 1.4 Hz, 1H), 7.51-7.40 (m, 2H), 7.35-7.19 (m, 3H). A80 [00132] LCMS: m/z 478.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.67 (s, 1H). 8.57 (d, J = 1.6 Hz, 1H), 8.48 (d, J = 6.2 Hz, 1H), 7.82 (dd, J = 9.0, 1.4 Hz, 1H), 7.48-7.43 (m, 2H), 7.36 (dd, J = 6.3, 1.7 Hz, 1H), 7.31-7.25 (m, 3H). A81 [00133] LCMS: m/z 476.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.36 (s, 1H), 8.22-8.07 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 7.67-7.55 (m, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.34-7.19 (m, 3H). A82 [00134] LCMS: m/z 497.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.74 (s, 1H), 8.69 (dd, J = 3.5, 0.8 Hz, 1H), 8.61 (s, 1H), 8.28 (dd, J = 7.1, 0.8 Hz, 1H), 8.06 (dd, J = 7.1, 3.4 Hz, 1H), 7.67 (td, J = 9.0, 1.2 Hz, 1H), 7.57 (dd, J = 11.1, 2.9 Hz, 1H), 7.22 (ddd, J = 9.1, 2.9, 1.6 Hz, 1H). A83 [00135] LCMS: m/z 497.2 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.88 (s, 1H), 8.61 (s, 1H), 8.53 (d, J = 1.6 Hz, 1H), 8.49 (d, J = 6.3 Hz, 1H), 7.67 (td, J = 9.0, 1.3 Hz, 1H), 7.58 (dd, J = 11.1, 2.9 Hz, 1H), 7.34 (dd, J = 6.2, 1.7 Hz, 1H), 7.22 (ddd, J = 9.1, 3.0, 1.6 Hz, 1H). A84 [00136] LCMS: m/z 528.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.26 (s, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.61 (m, 2H), 7.45- 7.26 (m, 2H), 7.07 (m, 1H). A85 [00137] LCMS: m/z 456.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.70 (s, 1H), 8.04 (m, 2H), 7.53 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.4, 6.4 Hz, 1H), 7.28 (dd, J = 8.9, 5.8 Hz, 1H), 7.15 (dd, J = 10.6, 2.9 Hz, 1H), 7.01 (s, 1H), 6.85 (td, J = 8.5, 2.9 Hz, 1H), 3.74 (s, 3H). A86 [00138] LCMS: m/z 475.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ11.28 (s, 1H), 8.64-8.63 (m, 1H), 8.04-8.03 (m, 1H), 7.49- 7.46 (m, 1H), 7.42-7.39 (m, 1H), 7.28-7.24 (m, 1H), 7.16- 7.13 (m, 1H), 6.86-6.81 (m, 2H), 3.74 (s, 3H). A87 [00139] LCMS: m/z 487.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ11.13 (s, 1H). 8.70-8.69 (m, 1H), 8.05-8.03 (m, 1H), 7.52- 7.50 (m, 1H), 7.43-7.39 (m, 1H), 7.26-7.22 (m, 1H), 7.17- 7.14 (m, 1H), 6.88-6.83 (m, 1H), 6.76 (s, 1H), 3.92 (s, 3H), 3.77 (s, 3H). A88 [00140] LCMS: m/z 434.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.66 (t, J = 1.8 Hz, 1H), 8.11-7.96 (m, 2H), 7.53-7.45 (m, 3H), 7.43-7.39 (m, 1H), 7.38-7.32 (m, 2H), 6.93 (dd, J = 8.9, 0.8 Hz, 1H). A89 [00141] LCMS: m/z 522.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.48-7.32 (m, 4H), 7.32- 7.12 (m, 4H), 3.94 (s, 3H). A90 [00142] LCMS: m/z 473.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.03-7.96 (m, 2H), 7.53-7.33 (m, 4H), 7.27-7.20 (m, 2H), 7.12 (s, 1H), 2.44 (s, 3H). A91 [00143] LCMS: m/z 508.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.60 (t, J = 1.8 Hz, 1H), 8.11 (s, 1H), 8.00 (ddd, J = 6.3, 1.8, 1.0 Hz, 1H), 7.48-7.34 (m, 5H), 7.22-7.16 (m, 2H). A92 [00144] LCMS: m/z 438.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.62 (t, J = 1.8 Hz, 1H), 7.98 (ddd, J = 6.4, 1.8, 0.9 Hz, 1H), 7.78 (s, 1H), 7.48 (dt, J = 8.7, 1.1 Hz, 1H), 7.39- 7.32 (m, 3H), 7.18 (d, J = 0.8 Hz, 1H), 7.13-7.08 (m, 2H), 2.35 (s, 3H). A93 [00145] LCMS: m/z 439.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ10.97 (s, 1H), 8.67 (s, 1H), 8.02-8.00 (d, 1H), 7.48-7.46 (m, 1H), 7.41-7.39 (m, 3H), 7.38-7.30 (m, 1H), 7.20-7.18 (m, 2H), 6.93-6.92 (s, 1H), 2.34 (s, 1H). A94 [00146] LCMS: m/z 430.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.16 (s, 1H), 8.04- 7.96 (m, 1H), 7.52-7.41 (m, 3H), 7.38 (dd, J = 8.5, 6.4 Hz, 1H), 7.30-7.23 (m, 2H), 7.09 (s, 1H), 2.48 (s, 3H). A95 [00147] LCMS: m/z 465.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.57 (s, 1H), 7.96 (d, 1H), 7.78 (s, 1H), 7.44 (d, 1H), 7.35-7.31 (m, 3H), 7.02 (d, 2H), 6.81 (s, 1H), 2.21-2.18 (m, 1H), 1.08-1.03 (m, 2H), 0.72-0.71 (m, 2H). A96 [00148] LCMS: m/z 504.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.60 (s, 1H), 8.05-7.89 (m, 2H), 7.54 (s, 1H), 7.47-7.44 (m, 1H), 7.40-7.34 (m, 3H), 7.17 (m, 2H). A97 [00149] LCMS: m/z 499.1 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.61 (s, 1H), 7.98 (d, J = 5.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 1H), 7.41-7.28 (m, 3H), 7.20-7.05 (m, 2H), 6.77 (s, 1H), 2.21-2.08 (m, 1H), 1.08 (m, 2H), 0.74 (m, 2H). A98 [00150] LCMS: m/z 463.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, MeOD) δ 8.95 (t, 1H), 8.11 (d, 1H), 7.69 (dd, 1H), 7.53-7.42 (m, 2H), 7.26 (d, 2H), 7.15-7.05 (m, 2H), 6.81 (d, 1H), 2.60 (d, 2H), 1.10-0.94 (m, 1H), 0.59-0.47 (m, 2H), 0.26-0.22 (m, 2H). A99 [00151] LCMS: m/z 463.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.64 (s, 1H), 8.02 (d, J = 7.1 Hz, 1H), 7.48 (d, J = 9.3 Hz, 1H), 7.44-7.33 (m, 3H), 7.24-7.11 (m, 3H), 6.82 (s, 1H), 2.54-2.50 (m, 2H), 1.02-0.89 (m, 1H), 0.51-0.41 (m, 2H), 0.26-0.14 (m, 2H). A100 [00152] LCMS: m/z 477.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.36 (s, 1H), 8.21-8.05 (m, 2H), 7.64-7.54 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 1.9 Hz, 2H), 7.28-7.20 (m, 1H). A101 [00153] LCMS: m/z 491.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.64 (t, J = 1.6 Hz, 1H), 8.08-7.96 (m, 1H), 7.51-7.34 (m, 2H), 7.21-7.08 (m, 3H), 6.96 (d, J = 1.8 Hz, 1H), 4.76 (dt, J = 8.9, 5.9 Hz, 2H). A102 [00154] LCMS: m/z 494.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.50 (s, 1H), 8.16 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.2 Hz,, 2H), 7.46 (d, J = 8.8 Hz,, 2H), 7.40-7.32 (m, 2H). A103 [00155] LCMS: m/z 440.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.65 (t, J = 1.9 Hz, 1H), 8.10 (s, 1H), 8.02 (dt, J = 6.5, 1.3 Hz, 1H), 7.48 (dt, J = 8.6, 1.1 Hz, 1H), 7.40 (dd, J = 8.5, 6.3 Hz, 1H), 7.21 (dd, J = 8.9, 1.9 Hz, 1H), 7.14 (s, 1H), 7.09 (dd, J = 6.6, 1.7 Hz, 2H), 2.17 (s, 3H). A104 [00156] LCMS: m/z 459.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.33 (s, 1H), 8.64 (s, 1H), 8.11-8.03 (m, 1H), 7.48-7.40 (m, 2H), 7.26-7.23 (m, 1H), 7.21-7.09 (m, 2H), 6.99 (s, 1H), 2.16 (s, 3H). A105 [00157] LCMS: m/z 471.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.67 (s, 1H), 8.04 (d, J = 6.2 Hz, 1H), 7.51- 7.36 (m, 2H), 7.24-7.21 (m, 1H), 7.17-7.08 (m, 2H), 6.85 (s, 1H), 3.94 (s, 3H), 2.15 (s, 3H). A106 [00158] LCMS: m/z 466.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.41 (dd, J = 8.4, 6.4 Hz, 1H), 7.15 (dd, J = 8.9, 5.1 Hz, 1H), 7.08 (s, 1H), 7.07-7.01 (m, 1H), 6.86 (dd, J = 10.0, 3.0 Hz, 1H), 2.04-1.94 (m, 1H), 0.89- 0.79 (m, 2H), 0.73-0.63 (m, 2H). A107 [00159] LCMS: m/z 487.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.65 (t, J = 1.8 Hz, 1H), 8.22 (s, 1H), 8.02 (ddd, J = 6.3, 1.8, 1.0 Hz, 1H), 7.51-7.45 (m, 1H), 7.40 (dd, J = 8.5, 6.3 Hz, 1H), 7.25-7.19 (m, 1H), 7.13-7.07 (m, 3H), 2.17 (s, 3H). A108 [00160] LCMS: m/z 483.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.68 (s, 1H), 8.03 (d, J = 6.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 6.3 Hz, 1H), 7.29 (ddd, J = 14.6, 9.6, 4.4 Hz, 2H), 7.00 (s, 1H), 6.88 (td, J = 8.6, 2.9 Hz, 1H), 4.00-3.87 (m, 1H), 0.75 (q, J = 5.8 Hz, 2H), 0.50-0.29 (m, 2H). A109 [00161] LCMS: m/z 510.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 6.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.52-7.38 (m, 3H), 7.35 (d, J = 5.8 Hz, 2H). A110 [00162] LCMS: m/z 502.8 (M + H) .sup.+; .sup.1H NMR (400 MHz, Chloroform- d) 8 11.33 (s, 1H), 8.60 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 6.3 Hz, 1H), 7.19 (s, 1H), 7.11-7.00 (m, 1H), 7.00- 6.85 (m, 2H), 6.70 (s, 1H), 2.17 (d, J = 2.4 Hz, 3H). A111 [00163] LCMS: m/z 485.0 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 8.65 (s, 1H), 8.06 (d, J = 6.1 Hz, 1H), 7.52- 7.38 (m, 2H), 7.20 (m, 1H), 7.08 (td, J = 8.4, 3.0 Hz, 1H), 6.94 (s, 1H), 6.89 (dd, J = 10.0, 3.0 Hz, 1H), 1.97-1.90 (m, 1H), 0.89-0.82 (m, 2H), 0.72-0.66 (m, 2H). A112 [00164] LCMS: m/z 500.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO) δ 11.36 (s, 1H), 8.60 (s, 1H), 8.00 (d, J = 6.3 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.39-7.35 (m, 1H), 7.29-7.21 (m, 2H), 6.86- 6.79 (m, 2H), 3.92-3.87 (m, 1H), 0.77-0.65 (m, 2H), 0.47- 0.37 (m, 2H). A113 [00165] LCMS: m/z 528.9 (M + H) .sup.+; .sup.1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.55 (s, 1H), 7.99 (dt, J = 5.4, 1.7 Hz, 1H), 7.56 (dd, J = 8.6, 1.5 Hz, 1H), 7.42-7.29 (m, 4H), 7.25 (s, 1H).

Synthesis of Embodiment A114

[0128] ##STR00166## ##STR00167##

[0129] Step 1, Synthesis of Intermediate 11

[0130] Compound 10 (5 g, 32.4 mmol) was added to anhydrous THF (20 mL), under nitrogen protection, 1M tetrahydrofuran borane complex (65 mL) was added dropwise in an ice-water bath, and the reaction was carried out for 3 h, TLC showed that the reaction was complete, the reaction was quenched by adding methanol (5 mL), the reaction mixture was concentrated, EA (100 mL) was added, and the mixture was washed with water (50 mL), and then washed with saturated NaCl (50 mL), then dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to obtain compound 11, 4.46 g, white solid, yield 98%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.40-7.29 (m, 1H), 7.03-6.90 (m, 2H), 5.10 (t, J=5.4 Hz, 1H), 4.45 (d, J=5.4 Hz, 2H), 2.25 (s, 3H).

[0131] Step 2, Synthesis of Intermediate 12

[0132] Compound 11 (4.4 g, 31.4 mmol) was added to dichloromethane (40 mL), under nitrogen protection, PBr.sub.3 (3.6 mL) was added dropwise in an ice water bath, and the reaction was carried out at room temperature for 2 h, TLC showed that the reaction was complete, the reaction mixture was poured into ice water and extracted by DCM (50 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4, then purified by normal phase column (PE/EA=0-100%) to obtain compound 12, colorless liquid, 5.6 g, yield: 88%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.51-7.40 (m, 1H), 7.15-6.95 (m, 2H), 4.72 (s, 2H), 2.36 (s, 3H).

[0133] Step 3, Synthesis of Intermediate 14

[0134] Compound 13 (2 g, 7.09 mmol), bis(pinacolato)diboron (1.98 g, 7.80 mmol), KOAc (2.09 g, 21.3 mmol) and Pd(dppf)(Cl).sub.2 (0.26 g, 0.35 mmol) were added to a 50 mL three-necked flask, after ventilated with nitrogen for 3 times, 1,4-dioxane (20 mL) was added as solvent, the reaction was carried out in an oil bath at 85° C. for 4 h, LC-MS showed that the reaction was complete, the reaction mixture was poured into ice water and extracted with EA (50 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4 and purified by normal phase column (PE/EA=0-100%) to obtain compound 14, 1.8 g, yield: 77%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (d, J=8.2 Hz, 1H), 7.74 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 3.95 (s, 3H), 1.43 (s, 12H).

[0135] Step 4, Synthesis of Intermediate 15

[0136] Compound 14 (359 mg, 1.1 mmol), compound 12 (200 mg, 1 mmol), K.sub.2CO.sub.3 (273 mg, 1.98 mmol) and Pd(dppf)(Cl).sub.2 (36 mg, 0.05 mmol) were added to a 25 mL three-necked flask, after ventilated with nitrogen for 3 times, a mixed solvent of 1,4-dioxane (10 mL) and water (3 mL) was added, the reaction was carried out in an oil bath at 100° C. for 2 h, LC-MS showed that the reaction was complete, the reaction mixture was poured into ice water and extracted with EA (20 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4, and purified by normal phase column (PE/EA=0-100%) to obtain compound 15, colorless oil, 200 mg, yield: 62%. LC-MS: m/z 327 (M+H)+.

[0137] Step 5, Synthesis of Intermediate 16

[0138] Compound 15 (160 mg, 0.49 mmol) was added to a mixed solvent of tetrahydrofuran (6 mL) and methanol (3 mL), and lithium hydroxide monohydrate (82 mg, 1.96 mmol) was added in an ice-water bath, then water (2 mL) was added thereto. The reaction was carried out at room temperature for 2 h, TLC showed that the reaction mixture was complete, then the reaction mixture was poured into ice water, the PH value was adjusted to 3-4 with dilute hydrochloric acid, and then the mixture was extracted with EA (10 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to obtain compound 16, white solid, yield 98%. LCMS: m/z 311 (M−H).sup.−.

[0139] Step 6, Synthesis of Intermediate 17

[0140] Compound 16 (150 mg, 0.48 mmol) was added to DCM (5 mL), 0.2 mL of oxalyl chloride was added dropwise in an ice-water bath, and 2 drops of DMF was used to catalyze, the reaction was carried out at room temperature for 2 h, TLC showed that the reaction was complete, and the reaction mixture was directly concentrated to dryness to obtain 160 mg of product. The product was added to dichloromethane (20 mL), DIPEA (0.24 mL, 1.45 mmol) was added dropwise in an ice-water bath, then compound 2 (160 mg, 0.48 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 h, LC-MS showed that the reaction was complete, the reaction mixture was poured into ice water, extracted with DCM (20 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4, concentrated and purified by normal phase column (PE/EA=0-100%) to obtain compound 17, white solid, 63 mg, yield: 33%. LCMS: m/z 389(M+H)+.

[0141] Step 7, Synthesis of Embodiment A114

[0142] Compound 17 (63 mg, 0.16 mmol) was added to DCM (5 mL), m-CPBA (56 mg, 0.32 mmol) was added at 0° C., and the reaction was carried out at room temperature for 2 h, LC-MS showed that the reaction was complete, the reaction mixture was poured into ice water, the pH value was adjusted with saturated NaHCO.sub.3 to weakly basic, then the mixture was extracted with DCM (20 mL×2), the organic phase was combined, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to obtain a crude product, and the crude product was prepared to obtain (5-95% acetonitrile in water (containing 0.05% NH.sub.4HCO.sub.3)) the product A114. LCMS: m/z 405.2 (M+H).sup.+; .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.83 (s, 1H), 8.65 (s, 1H), 8.06-7.96 (m, 1H), 7.78 (s, 2H), 7.47 (d, J=10.7 Hz, 2H), 7.38 (dd, J=8.4, 6.3 Hz, 1H), 7.03-6.94 (m, 2H), 6.88 (td, J=8.6, 2.7 Hz, 1H), 4.18 (s, 2H), 2.16 (s, 3H).

Effect Embodiment

[0143] I. The Blocking Activity of the Compound of the Present Disclosure on Sodium Ion Channel 1.8 (NaV1.8)

[0144] 1. Test method: patch clamp technique was used to detect the influence of compounds on voltage-gated sodium channel (NaV) 1.1-1.8 subtype current

[0145] 2. Preparation and Analysis of Dosing Formulations

[0146] 2.1 Preparation Method of Dosing Formulation Storage Solution

[0147] Control: an appropriate volume of DMSO was weighted as a storage solution.

[0148] Test compound: an appropriate mass of the compound (actual amount=theoretical concentration*volume×molecular weight/purity) was weighed, the required DMSO volume according to the formula was calculated, and then the final required DMSO mass was obtained. Then the powder was dissolved with weighed DMSO. The actual storage solution concentration was calculated according to the final DMSO usage, generally, the actual storage solution concentration was slightly different from the theoretical concentration.

[0149] 2.2 Preparation Method and Concentration of the Working Solution for Dosing Formulations

[0150] Before the NaV channel current test, the control and test compound storage solutions were diluted into 10 mL of extracellular fluid as a working solution and were sonicated for 20 min.

[0151] 3. Experimental System

[0152] 3.1. Cell Culture

[0153] 1) The specific information of the CHO cell line stably expressing the Nav1.8 channel was as follows: SCN10A: NM_006514

[0154] 2) Cells were cultured in HAM'S/F-12 medium containing 10% fetal bovine serum and 10 μg/mL Blasticidin, 200 μg/mL Hygromycin B and 100 μg/mL Zeocin, culture temperature was 37° C. and the concentration of CO.sub.2 was 5%.

[0155] 3) Cell passage: the old medium was removed and the cells were washed with PBS once, then 1 mL of 0.25%-Trypsin-EDTA solution was added thereto, then incubated at 37° C. for 1.5 min. The cells were detached from the bottom of the dish, 5 mL of complete medium pre-warmed at 37° C. was added. The cell suspension was gently blown with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 min to collect cells. The culture was amplified or maintained, the cells were inoculated in a 6 cm cell culture dish, and the amount of cells inoculated in each cell culture dish was 2.5*10.sup.5 cells (final volume: 5 mL).

[0156] 4) In order to maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0157] 5) Patch clamp detection, before the experiment, the cells were separated with 0.25%—trypsin EDTA, inoculated into a 24 well plate with a density of 8*10.sup.3 cells per well (final volume: 500 μL), tetracycline was added thereto, and experimental test was performed on the next day.

[0158] 3.2. Electrophysiological Solution

[0159] 1) Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 2 mM CaCl.sub.2, 10 mM HEPES, 1.25 mM NaH.sub.2PO.sub.4, 1 mM MgCl.sub.2, 10 mM Glucose, pH=7.4 (NaOH).

[0160] 2) Intracellular fluid: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 20 mM EGTA, 60 mM CsF, pH=7.2 (CsOH).

[0161] 4. Test Method

[0162] 4.1. The Instrument was Shown in Table 3 Below

TABLE-US-00003 TABLE 3 Instrument supplier and model Name Supplier Model Amplifier HEKA (Germany) EPC 10 Micromanipulator Sutter Instruments (USA) MP285 Electrode drawing instrument Sutter Instruments (USA) P97 Microscope Olympus (Japan) IX71 Fur glass tube Sutter Instruments (USA) BF150-86-10 Data acquisition and HEKA (Germany) Patchmaster & analysis software IGOR

[0163] 4.2 Patch Clamp Detection

[0164] The voltage stimulation scheme of whole-cell patch clamp recording of Nav channel current was as follows: first the membrane potential of the cell was clamped at −130 mV, and then the voltage was stepped to −40 mV or −20 mV at 10 mv step intervals for 8 s. The clamping voltage was maintained at −120 mV, and data was collected repeatedly every 20 seconds. The peak amplitude of its inward current was measured to determine its half-inactivation voltage.

[0165] The cell clamping potential was set at −120 mV. The resting and half-inactivation inhibition of sodium current was measured using double pulse mode. The double pulse mode was completed by two 0 mV depolarization test pulses (TP1 and TP2) lasting 50 ms. The conditional voltage between the two depolarization pulses was set near the half-inactivation voltage (lasting 8 s). Before giving the second depolarization pulse, the cell membrane potential was clamped to −120 my for 20 ms to restore the channel that was not bounded to the compound and in an inactive state. The data acquisition was repeated at an interval of 20 s and the current peak was measured at the two test pulses.

[0166] The experimental data was collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software (software version: v2x73.2).

[0167] The capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode with a microelectrode drawing instrument (P97, Sutter Instruments). The microelectrode manipulator (MP285) was manipulated under an inverted microscope (IX71) to bring the recording electrode into contact with the cells, giving negative pressure suction to form a GΩ seal. After forming the GQ seal, fast capacitance compensation was performed, and then continued to give negative pressure to suck and break the cell membrane to form a whole-cell recording mode. Then slow capacitance compensation was performed, and the film capacitance and series resistance were recorded, no leakage compensation was given.

[0168] When the current of the Nav channel recorded by the whole cell was stable, the drug was administered, after each drug concentration was applied for 5 minutes (or the current was stable), the next concentration would be tested, and multiple concentrations would be tested for each test compound. The cover glass covered with cells was placed in the recording bath of an inverted microscope, the test compound and the external liquid without compound flowed through the recording chambers in turns from low concentration to high concentration by gravity perfusion, so as to act on the cells, in the recording, the liquid exchange was carried out by vacuum pump. The current detected in each cell in the compound-free external fluid served as its own control group. Multiple cells were detected independently and repeatedly. All electrophysiological experiments were performed at room temperature.

[0169] 4.3 Data Analysis

[0170] First, the current after the action of each drug concentration and the blank control current were normalized, and then the blocking rate corresponding to each drug concentration was calculated. The mean and standard error were calculated for each concentration, and all the above values were calculated by Microsoft Excel 2013. In addition, the half-inhibitory concentration of each compound was calculated by IGOR software with the following equation: retardation rate=1/[1+(IC.sub.50/c).sup.h].

[0171] The dose-dependent effect was nonlinearly fitted with the above equation, wherein, c refers to the drug concentration, IC.sub.50 was the half inhibitory concentration, and h refers to the Hill coefficient. The curve fitting and the calculation of IC.sub.50 were completed by IGOR software (software version: 6.0.1.0).

[0172] In this embodiment, the half blocking activity (IC.sub.50) of some compounds of the present disclosure against Nay 1.8 was measured, as shown in Table 4, and the blocking rate of some compounds to Nav1.8 at 100 nM was shown in Table 5. Wherein:

TABLE-US-00004 TABLE 4 The IC50 value (nM) of the blocking activity of the compounds of the present disclosure against NaV1.8 Number NaV1.8 IC.sub.50(nM) Number NaV1.8 IC.sub.50(nM) Number NaV1.8 IC.sub.50(nM) A5 7.4 A11 6.2 A19 10.0 A22 0.32 A27 0.64 A28 2.9 A33 4.6 A35 3.0 A37 3.2 A38 7.3 A41 1.3 A42 3.6 A46 3.1 A47 3.0 A51 2.7 A56 3.7 A57 1.8 A61 10.2 A67 6.7 A68 0.27 A69 2.0 A73 3.2 A74 3.5 A80 8.4 A85 1.7 A86 0.08 A106 3.0

TABLE-US-00005 TABLE 5 The blocking rate of the compounds of the present disclosure against NaV1.8 at a certain concentration Blocking Blocking Blocking Blocking rate (%) rate (%) rate (%) rate (%) Number @100 nM Number @100 nM Number @100 nM Number @100 nM A8 81.85 A10 78.17 A16 85.08 A18 96.02 A20 87.14 A21 98.02 A23 97.04 A24 91.28 A25 87.92 A26 79.32 A29 87.63 A31 88.88 A32 82.91 A34 90.16 A36 87.40 A39 97.82 A40 99.91 A43 76.10 A44 77.61 A45 78.46 A50 79.66 A52 80.75 A53 85.77 A54 94.99 A55 83.29 A58 82.55 A59 87.57 A62 89.79 A63 93.13 A65 93.18 A68 99.15 A72 85.63 A75 88.87 A78 96.55 A83 84.98 A84 99.14 A90 89.50 A91 92.81 A92 85.44 A95 93.84 A96 88.78 A97 86.65 A98 95.70 A100 97.60 A101 98.47 A102 82.71 A103 92.47 A104 97.93 A105 98.42 A107 95.60 A108 96.92 A109 88.79 A110 98.75 A111 99.42

[0173] It can be seen that the compound of the present disclosure has a significant blocking effect against NaV1.8 channel activity.

[0174] II. Pharmacokinetic Test Results of the Compound of the Present Disclosure

[0175] In this experimental embodiment, the in vivo pharmacokinetics of rat was evaluated by a single intravenous injection or oral administration by gavage.

[0176] Experimental methods and conditions: Male Sprague Dawley rats, all animals were fasted overnight, and the test compound was given 1 mg/Kg (intravenous injection, solvent 500 DMSO/1000 Solutol/85% Saline) and 10 mg/Kg (administrated by gavage) respectively, 5, 15, 30 min, 1, 2, 4, 6, 8 and 24 hr after administration, blood was collected through the submandibular vein, about 0.20 mL of each sample was collected, heparin sodium was used for anticoagulation, the samples were placed on ice after the collection, then centrifuged within 1 hour to separate the plasma for testing. The blood drug concentration in plasma was detected by liquid-phase tandem mass spectrometry (LC/MS/MS), and the pharmacokinetic parameters were calculated by the measured concentration. The results were shown in Table 6 and Table 7 below.

TABLE-US-00006 TABLE 6 Pharmacokinetics of intravenous administration (1 mg/kg) Number T.sub.1/2 (hr) AUC.sub.inf (ng*hr/mL) V.sub.Z (mL/kg) CL (mL/min/kg) A11 0.70 1462.27 699.19 11.44 A46 20.08 15625.27 1847.50 1.08 A56 13.09 9602.04 1969.82 1.74 A67 0.67 2400.69 441.48 7.61 A68 5.24 33349.32 228.44 0.50 A69 12.27 56697.73 311.95 0.30 A84 4.53 18823.37 354.87 0.91 A103 2.28 2758.59 1190.18 6.15

TABLE-US-00007 TABLE 7 Pharmacokinetics of intragastric injection (10 mg/kg) Number T.sub.1/2 (hr) C.sub.max (ng/mL) AUC.sub.inf (ng*hr/mL) F (%) A11 2.51 1326.67 10614.74 72.59 A46 914.98 2056.67 2934150.31 46.75 A56 27.88 3000.00 117018.94 68.16 A67 1.61 3543.33 12373.07 51.54 A68 5.72 9703.33 139330.03 41.78 A69 12.15 17100.00 398902.00 70.36 A84 5.75 4916.67 67173.65 35.69 A103 2.47 1713.33 13988.83 50.71

[0177] It can be seen that the compound of the present disclosure has good pharmacokinetic absorption in rats and has pharmacokinetic advantages.

[0178] All documents mentioned in the present disclosure are incorporated by reference in this application as if each document are individually incorporated by reference. It should also be understood that after reading the above teaching content of the present disclosure, a person skilled in the art may make various changes or modifications to the present disclosure, which in equivalent form likewise fall within the scope of the claims appended to this disclosure.