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BENZOFURAN ANALOGUE AS NS4B INHIBITOR

20170240519 · 2017-08-24

    Inventors

    Cpc classification

    International classification

    Abstract

    Provided is a benzofuran analogue having a structure represented by formula (I) and used as an NS4B inhibitor, or a pharmaceutically acceptable salt of the benzofuran analogue. The benzofuran analogue has anti-hepatitis C virus activity.

    Claims

    1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, ##STR00322## wherein, the moiety ##STR00323##  can be replaced by ##STR00324## none, one or two of T.sub.21-22 are selected from N, the rest of which are selected from C(R.sub.t); each of D.sub.21-22, L.sub.1-2 is independently selected from the group consisting of —[C(R.sub.d1)(R.sub.d2)].sub.0-2—, —C(═O)—, —C(═O)N(R.sub.d3)—, —N(R.sub.d4)—, —C(═NR.sub.d5)—, —S(═O).sub.2N(R.sub.d6)—, —S(═O)N(R.sub.d7)—, —O—, —S—, —C(═O)O—, —C(═S)—, —S(═O)—, —S(═O).sub.2— and —N(R.sub.d8)C(═O)N(R.sub.d9)—; m is selected from the group consisting of 1, 2, 3 and 4; R.sub.3 is selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2, CHO, COOH, C(═O)NH.sub.2, S(═O)NH.sub.2, and S(═O).sub.2NH.sub.2, or selected from the group, optionally substituted by none, one, two or three of R.sub.t, consisting of a C.sub.1-10alkyl or heteroalkyl, a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, and a C.sub.1-10 alkyl or heteroalkyl substituted by a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl; each of R.sub.11-13, R.sub.t, R.sub.d1, R.sub.d2 is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2, CHO, COOH, C(═O)NH.sub.2, or selected from the group, optionally substituted by none, one, two or three of R.sub.01, consisting of a C.sub.1-10alkyl or heteroalkyl, a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, a C.sub.1-10 alkyl or heteroalkyl substituted by a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl; R.sub.01 is selected from the group consisting of F, Cl, Br, I, CN, OH, SH, NH.sub.2, and R.sub.02; R.sub.02 is selected from the group consisting of a C.sub.1-10 alkyl, a C.sub.1-10 alkylamino, a N,N-bis(C.sub.1-10 alkyl)amino, a C.sub.1-10 alkoxyl, a C.sub.1-10 alkanoyl, a C.sub.1-10 alkoxycarbonyl, a C.sub.1-10 alkylsulfonyl, a C.sub.1-10 alkylsulfinyl, a C.sub.3-10 cycloalkyl, a C.sub.3-10 cycloalkylamino, a C.sub.3-10 heterocycloalkylamino, a C.sub.3-10 cycloalkoxyl, a C.sub.3-10 cycloalkanoyl, a C.sub.3-10 cycloalkoxycarbonyl, a C.sub.3-10 cycloalkylsulfonyl, and a C.sub.3-10 cycloalkylsulfinyl; the “hetero” represents a heteroatom or a heteroatomic group, which is selected from the group consisting of —C(═O)N(R.sub.d3)—, —N(R.sub.d4)—, —C(═NR.sub.d5)—, —S(═O).sub.2N(R.sub.d6)—, —S(═O)N(R.sub.d7)—, —O—, —S—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O).sub.2— and/or —N(R.sub.d8)C(═O)N(R.sub.d9)—; each of R.sub.d3-d9 is independently selected from the group consisting of H, OH, NH.sub.2, and R.sub.02; R.sub.02 is optionally substituted by R.sub.001; R.sub.001 is selected from the group consisting of F, Cl, Br, I, CN, OH, N(CH.sub.3).sub.2, NH(CH.sub.3), NH.sub.2, CHO, COOH, C(═O)NH.sub.2, trihalomethyl, dihalomethyl, monohalomethyl, aminomethyl, hydroxymethyl, methyl, methylamino, formyl, methoxycarbonyl, methylsulfonyl, and methylsulfinyl; the number of R.sub.01, R.sub.001, the heteroatom or the heteroatomic group is independently selected from the group consisting of 0, 1, 2 and 3; optionally, there is another linking bond (CH.sub.2).sub.1-3 between T.sub.21 and T.sub.22.

    2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein each of D.sub.21-22, L.sub.1-2 is independently selected from the group consisting of (CH.sub.2).sub.0-2, —C(═O)—, —C(═O)NH—, and —C(═O)N(Me)-.

    3. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the moiety ##STR00325## is selected from ##STR00326## each of R.sub.101-103 is independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2, CHO, COOH, C(═O)NH.sub.2, or selected from the group, optionally substituted by none, one, two or three of R.sub.01, consisting of a C.sub.1-10 alkyl or heteroalkyl, a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, and a C.sub.1-10 alkyl or heteroalkyl substituted by a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, R.sub.01 is defined as claims.

    4. The compound or the pharmaceutically acceptable salt thereof according to claim 3, wherein each of R.sub.101-103 is independently selected from the group consisting of F, Cl, Br, —CF.sub.3, —CHF.sub.2, CN, Me, ethyl, propyl, cyclopropyl and iso-propyl.

    5. The compound or the pharmaceutically acceptable salt thereof according to claim 3, wherein the moiety ##STR00327## is selected from the group consisting of ##STR00328## or the moiety ##STR00329##  is ##STR00330## or the moiety ##STR00331##  is ##STR00332##

    6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the moiety ##STR00333## is selected from the group consisting of ##STR00334##

    7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3 is selected from the group consisting of ##STR00335## —N(R.sub.33)(R.sub.34), and O(R.sub.35), or selected from the group, which is substituted by R.sub.001, consisting of a C.sub.1-3 alkyl, cyclopropyl, phenyl and pyridyl, wherein, each of T.sub.31-33 is dependently selected from the group consisting of N and C(R.sub.t); each of D.sub.31-35 is dependently selected from the group consisting of —[C(R.sub.d1)(R.sub.d2)].sub.0-2—, —C(═O)—, —C(═O)N(R.sub.d3)—, —N(R.sub.d4)—, —C(═NR.sub.d5)—, —S(═O).sub.2N(R.sub.d6)—, —S(═O)N(R.sub.d7)—, —O—, —S—, —C(═O)O—, —C(═S)—, —S(═O)— and —S(═O).sub.2—; each of R.sub.31-35 is dependently selected from the group consisting of H, F, Cl, Br, I, CN, OH, SH, NH.sub.2, CHO, COOH, and C(═O)NH.sub.2, or selected from the group consisting of a C.sub.1-10 alkyl or heteroalkyl optionally substituted by R.sub.01, a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, a C.sub.1-10 alkyl or heteroalkyl substituted by a C.sub.3-10 cyclohydrocarbyl or heterocyclohydrocarbyl; the definitions of R.sub.t, R.sub.d1-d7, R.sub.01 refer to that in claim 1; optionally, there is another linking bond (CH.sub.2).sub.1-3 between T.sub.31 and D.sub.31, D.sub.33 and D.sub.34, T.sub.33 and D.sub.35.

    8. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein each of D.sub.31-35 is dependently selected from the group consisting of —C(═O)—, —O—, methylene, —N(CH.sub.3)—, —CH(OH)—, and —CF.sub.2—; each of R.sub.31-34 is dependently selected from the group consisting of H, methyl, ethyl, n-propyl, and iso-propyl.

    9. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.3 is selected from the group consisting of ##STR00336## ##STR00337## ##STR00338##

    10. The compound or the pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of ##STR00339## ##STR00340## ##STR00341## ##STR00342## ##STR00343## ##STR00344## ##STR00345## ##STR00346## ##STR00347## ##STR00348## ##STR00349## ##STR00350## ##STR00351##

    Description

    DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

    [0085] The following examples further illustrate the present invention, but the present invention is not limited thereto.

    Reference 1: Fragment BB-1

    [0086] ##STR00048##

    [0087] Synthetic Route:

    ##STR00049##

    [0088] Step 1: Synthesis of Compound BB-1-2

    [0089] Compound BB-1-1 (6.0 g, 37 mmol) was dissolved in TFA (30 mL), then liquid bromine (5.91 g, 37 mmol) was added dropwise slowly, the reactants were stirred at r.t. for 2 hours. After the reaction was complete, EA (200 mL) was added, the organic phases were washed with brine (50 mL×2), saturated sodium carbonate (50 mL×2), brine (50 mL), dried over sodium sulfate, concentrated to deliver the target compound BB-1-2 (gray solid, 8.9 g, yield: 100%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 7.63 (s, 1H), 7.52 (d, J=8.8 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.09 (s, 1H).

    [0090] Step 2: Synthesis of Compound BB-1-4

    [0091] Compound BB-1-2 (1 g, 4.13 mmol) was dissolved in TFA (5 mL), then methenamine BB-1-3 (2.33 g, 16.6 mmol) was added. The reactants were heated to 90° C. in a stuffy can and stirred overnight. After cooling, water (20 mL) and 50% sulphuric acid (7 mL) were added, the mixture was further stirred for 1 hour, filtered, the solid was washed with water, dried to deliver the target compound BB-1-4 (gray solid, 0.60 g, yield 53.75%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 11.62 (s, 1H), 9.93 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H).

    [0092] Step 3: Synthesis of Compound BB-1-6

    [0093] Reactant BB-1-4 (0.60 g, 2.23 mmol) was dissolved in DMF (8 mL), then K.sub.2CO.sub.3 (0.925 g, 6.69 mmol), compound BB-1-5 (0.41 g, 2.45 mmol) were added. The reactants were heated to 100° C. and stirred for 2 hours. EA (50 mL) was added, the mixture was washed with brine (20 mL), dried, concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/3) to deliver the target compound BB-1-6 (yellow solid, 0.35 g, yield 46.5%). MS (ESI) m/z: 337 [M+H].sup.+, 339 [M+H+2].sup.+.

    [0094] Step 4: Synthesis of Compound BB-1-8 and BB-1-8a

    [0095] Compound BB-1-6 (0.34 g, 1.01 mmol) was dissolved in isopropanol (5 mL), then potassium isopropenyltrifluoroborate BB-1-7 (0.194 g, 1.31 mmol), TEA (0.510 g, 5.04 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium (0.074 g, 0.101 mmol) were added. The reaction mixture was reacted for 3 hours under nitrogen gas atmosphere. After cooling, EA (100 mL) was added, the mixture was washed with brine (20 mL), dried over sodium sulfate, concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-1-8 and BB-1-8a (yellow oil, 0.295 g, yield 98%). MS (ESI) m/z: 299 [M+H].sup.+.

    [0096] Step 5: Synthesis of Compound BB-1-9 and BB-1-9a

    [0097] Compound BB-1-8 and BB-1-8a (0.295 g, 0.989 mmol) were dissolved in EA (15 mL), 10% Pd/C (0.03 g) was added, the reactants were stirred under hydrogen gas atmosphere at a pressure of 20 Psi for 4 hours at r.t. The reaction mixture was evaporated to dry to deliver the target compound BB-1-9 and BB-1-9a, which were used for the next step directly (gray solid, 0.295 g, yield 99%). MS (ESI) m/z: 301 [M+H].sup.+.

    [0098] Step 6: Synthesis of Compound BB-1

    [0099] Compound BB-1-9 (0.105 g, 0.35 mmol) was dissolved in THF/H.sub.2O (3 mL, 2:1), lithium hydroxide hydrate (0.073 g, 1.75 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, pH was adjusted to 1 with 2 M hydrochloric acid, then the mixture was extracted with EA (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated to deliver the target compound BB-1 (gray solid, 0.093 g, yield 98%). MS (ESI) m/z: 273 [M+H].sup.+.

    Reference 2: Fragment BB-2

    [0100] ##STR00050##

    [0101] Synthetic Route:

    ##STR00051##

    [0102] Step 1: Synthesis of Compound BB-2-1

    [0103] Compound BB-1-6 (2 g, 5.93 mmol) was dissolved in toluene/H.sub.2O (30 mL, 2:1), then cyclopropylboronic acid (1.02 g, 11.86 mmol), Pd(OAC).sub.2 (0.133 g, 0.593 mmol), tricyclohexyl phosphate (0.183 g, 0.652 mmol), K.sub.3PO.sub.4 (3.78 g, 17.79 mmol) were added sequentially. The reaction mixture was stirred at 100° C. for 3 hours. After cooling, EA (100 mL) was added, the organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/10) to deliver the target compound BB-2-1 (yellow oil, 1.6 g, yield 90.4%). MS (ESI) m/z: 299 [M+H].sup.+.

    [0104] Step 2: Synthesis of Compound BB-2-2

    [0105] Compound BB-2-1 (1.6 g, 5.36 mmol) was dissolved in n-hexane (30 mL), then bis(pinacolato)diboron (1.497 g, 5.896 mmol), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (0.216 g, 0.32 mmol), 4,4′-di-tert-butyl-2,2′-dipyridine (0.144 g, 0.536 mmol) were added sequentially. The reactants were refluxed for 2 hours under nitrogen gas atmosphere. The reaction mixture was evaporated to dry, then purified by flash column chromatography (eluting agent, EA/PE=1/10) to deliver the target compound BB-2-2 (white solid, 2.1 g, yield 92%). MS (ESI) m/z: 343 [M−82+H].sup.+.

    [0106] Step 3: Synthesis of Compound BB-2-3

    [0107] Compound BB-2-2 (0.50 g, 1.18 mmol) was dissolved in methanol (8 mL), then CuCl.sub.2 (0.317 g, 2.36 mmol) was added. The reaction mixture was heated to 50° C. and reacted for 16 h. After cooling, the reaction mixture was evaporated to dry, then purified by flash column chromatography (eluting agent, EA/PE=1/10) to deliver the target compound BB-2-3 (white solid, 0.310 g, yield 79%). MS (ESI) m/z: 333 [M+H].sup.+.

    [0108] Step 4: Synthesis of Compound BB-2

    [0109] Compound BB-2-3 (0.31 g, 0.932 mmol) was dissolved in methanol/H.sub.2O (6 mL, 2:1), then lithium hydroxide hydrate (0.156 g, 3.73 mmol) was added. After the reaction was complete, pH was adjusted to 1 with 2N hydrochloric acid, then the mixture was extracted with DCM, the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to deliver the target compound BB-2, which was used for the next step directly (white solid, 0.270 g, yield 95%). MS (ESI) m/z: 305 [M+H].sup.+.

    Reference 3: Fragment BB-3

    [0110] ##STR00052##

    [0111] Synthetic Route:

    ##STR00053##

    [0112] Step 1: Synthesis of Compound BB-3-1

    [0113] Compound BB-1-9 (0.20 g, 0.666 mmol) was dissolved in n-hexane (3 mL), then bis(pinacolato)diboron (0.186 g, 0.763 mmol), di-μ-methoxobis(1,5-cyclooctadiene)diiridium(I) (0.028 g, 0.042 mmol), 4,4′-di-tert-butyl-2,2′-dipyridine (0.018 g, 0.067 mmol) were added sequentially, the reactants were refluxed for 16 hours under nitrogen gas atmosphere. After evaporated to dry, the mixture was purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-3-1 (white solid, 0.20 g, yield 70%). MS (ESI) m/z: 345 [M−82+H].sup.+.

    [0114] Step 2: Synthesis of Compound BB-3-2

    [0115] Compound BB-3-1 (0.20 g, 0.469 mmol) was dissolved in methanol (4 mL), then CuCl.sub.2 (0.126 g, 0.938 mmol) was added, the reaction mixture was heated to 50° C. and reacted for 16 hours. After cooling, the reaction mixture was evaporated to dry, then purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-3-2 (yellow solid, 0.140 g, yield 89%). MS (ESI) m/z: 335 [M+H].sup.+.

    [0116] Step 3: Synthesis of Compound BB-3

    [0117] Compound BB-3-2 (0.130 g, 0.388 mmol) was dissolved in methanol/H.sub.2O (5 mL, 2:1), then lithium hydroxide hydrate (0.081 g, 1.94 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, pH was adjusted to 1 with 2N hydrochloric acid. And then the mixture was extracted with EA (50 mL×2), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to deliver the compound compound BB-3 (white solid, crude product, 0.119 g, yield 100%), which was used for the next step directly. MS (ESI) m/z: 307 [M+H].sup.+.

    Reference 3a: Fragment BB-3a

    [0118] ##STR00054##

    [0119] Reference 3a (fragment BB-3a) was synthesized according to the process for preparing fragment BB-3 in Reference 3, but the starting material was compound BB-1-9a. MS (ESI) m/z: 307 [M+H].sup.+.

    Reference 4: Fragment BB-4

    [0120] ##STR00055##

    [0121] Synthetic Route:

    ##STR00056##

    [0122] Step 1: Synthesis of Compound BB-4-1

    [0123] Compound BB-2-2 (0.30 g, 0.707 mmol) was dissolved in methanol (8 mL), then CuBr.sub.2 (0.316 g, 1.41 mmol) was added, the reaction mixture was heated to 50° C. and reacted for 20 hours. After cooling, the reaction mixture was evaporated to dry to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/10) to deliver the target compound BB-4-1 (gray solid, 0.22 g, yield 82%). MS (ESI) m/z: 377[M+H].sup.+, 379[M+H+2].sup.+.

    [0124] Step 2: Synthesis of Compound BB-4

    [0125] Compound BB-4-1 (0.120 g, 0.318 mmol) was added into methanol/H.sub.2O (5 mL, 2:1), then lithium hydroxide monohydrate (0.089 g, 1.59 mmol) was added. After reacting for 2 hours at r.t., the reaction mixture was evaporated under reduced pressure, followed by adjusting pH to 1 with 2N hydrochloric acid, then the mixture was extracted with EA (25 mL×3), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to deliver the target compound BB-4 (gray solid, 0.105 g, yield 95%). MS (ESI) m/z: 349 [M+H].sup.+, 351 [M+H+2].sup.+.

    Reference 5: Fragment BB-5

    [0126] ##STR00057##

    [0127] Synthetic Route:

    ##STR00058##

    [0128] Step 1: Synthesis of Compound BB-5-1

    [0129] Compound BB-4-1 (0.100 g, 0.265 mmol) was dissolved in toluene/H.sub.2O (3 mL, 2:1), then methylboronic acid (0.032 g, 0.53 mmol), Pd(OAc).sub.2 (0.006 g, 0.0265 mmol), tricyclohexyl phosphate (0.008 g, 0.029 mmol), K.sub.3PO.sub.4 (0.169 g, 0.795 mmol) were added. The reactants were heated to 100° C. and stirred for 16 hours. The reaction mixture was cooled and EA (100 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product which was purified by thin silica gel plate (developing agent, EA/PE=1/6) to deliver the target compound BB-5-1 (gray solid, 0.075 g, yield 90.6%). MS (ESI) m/z: 313 [M+H].sup.+.

    [0130] Step 2: Synthesis of Compound BB-5

    [0131] Compound BB-5-1 (0.075 g, 0.24 mmol) was dissolved in methanol/H.sub.2O (3 mL, 2:1), then lithium hydroxide hydrate (0.040 g, 0.96 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, pH was adjusted to 1 with 2N hydrochloric acid, then the mixture was extracted with DCM (50 mL×2), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-5 (gray solid, 0.067 g, yield 98%) which was used for the next step directly. MS (ESI) m/z: 285 [M+H].sup.+.

    Reference 6: Fragment BB-6

    [0132] ##STR00059##

    [0133] Synthetic Route:

    ##STR00060##

    [0134] Step 1: Synthesis of Compound BB-6-1

    [0135] Compound BB-4-1 (0.160 g, 0.424 mmol) was dissolved in DMF (3 mL), then CuCN (0.152 g, 1.7 mmol) was added, the reaction mixture was reacted at 160° C. for 4 hours. After the mixture was cooling, EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product which was purified by thin silica gel plate (developing agent, EA/PE=1/3) to deliver the target compound BB-6-1 (gray solid, 0.040 g, yield 29%). MS (ESI) m/z: 324 [M+H].sup.+.

    [0136] Step 2: Synthesis of Compound BB-6

    [0137] Compound BB-6-1 (0.040 g, 0.124 mmol) was dissolved in THF/MeOH/H.sub.2O (3 mL, 1:1:1), then lithium hydroxide hydrate (0.021 g, 0.495 mmol) was added. The reaction mixture was stirred at r.t. and reacted for 2 hours. After the reaction was complete, pH was adjusted to 1 with 6N hydrochloric acid, then the mixture was extracted with EA (50 mL×2), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-6 (gray solid, 0.036 g, yield 98.6%) which was used for the next step directly. MS (ESI) m/z: 296 [M+H].sup.+.

    Reference 7: Fragment BB-7

    [0138] ##STR00061##

    [0139] Synthetic Route:

    ##STR00062## ##STR00063##

    [0140] Step 1: Synthesis of Compound BB-7-2

    [0141] Compound BB-7-1 (5 g, 26.18 mmol) was dissolved in TFA (5 mL), then under nitrogen gas atmosphere, compound BB-1-3 (7.34 g, 52.36 mmol) was added in portions. The reactants were stirred at r.t. for 20 minutes, then heated to 90° C. and reacted overnight. After cooling, H.sub.2O (30 mL) and 50% sulphuric acid (15 mL) were added, the mixture was stirred for 2 hours, filtered, and dried to deliver the target compound BB-7-2 (brown solid, 3.5 g, yield 61%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 10.85 (br. s., 1H), 9.84-9.89 (m, 1H), 7.45-7.53 (m, 2H).

    [0142] Step 2: Synthesis of Compound BB-7-3

    [0143] Compound BB-7-2 (1 g, 4.57 mmol) was dissolved in DMF (12 mL), then K.sub.2CO.sub.3 (1.89 g, 13.7 mmol), ethyl bromoacetate (0.838 g, 5.02 mmol) were added. The reaction mixture was heated to 100° C. and reacted for 2 hours. After cooling, EA (100 mL) was added. The organic phase was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product which was purified by flash column chromatography (eluting agent, EA/PE=1/3) to deliver the target compound BB-7-3 (yellow solid, 0.400 g, yield 30%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.61 (s, 1H), 7.48 (d, J=3.01 Hz, 1H), 7.34 (dd, J=9.54, 1.51 Hz, 1H), 4.46 (q, J=7.03 Hz, 2H), 1.43 (t, J=7.03 Hz, 3H).

    [0144] Step 3: Synthesis of Compound BB-7-4

    [0145] Compound BB-7-3 (0.287 g, 1 mmol) was dissolved in toluene/H.sub.2O (5 mL, 2:1), then cyclopropylboronic acid (0.172 g, 2 mmol), Pd(OAc).sub.2 (0.022 g, 0.1 mmol), tricyclohexyl phosphate (0.028 g, 0.1 mmol), K.sub.3PO.sub.4 (0.637 g, 3 mmol) were added. The reactants were heated to 100° C. and reacted for 4 hours. After cooling, EA (100 mL) was added, the organic phase was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-7-4 (gray solid, 0.240 g, yield 96.7%). MS (ESI) m/z: 249 [M+H].sup.+.

    [0146] Step 4: Synthesis of Compound BB-7-5

    [0147] Compound BB-7-4 (0.080 g, 0.322 mmol) was dissolved in n-hexane (3 mL), then (PinB).sub.2 (0.106 g, 0.419 mmol), di-g-methoxobis(1,5-cyclooctadiene)diiridium(I) (0.015 g, 0.022 mmol), 4,4′-di-tert-2,2′-bipyridine (0.009 g, 0.032 mmol) were added sequentially, the reactants were refluxed under nitrogen gas atmosphere for 16 hours. The reaction mixture was evaporated to dry, then purified by thin silica gel plate (developing agent, EA/PE=1/3) to deliver the target compound BB-7-5 (white solid, 0.070 g, yield 58%). MS (ESI) m/z: 293 [M−82+H].sup.+.

    [0148] Step 5: Synthesis of Compound BB-7-6

    [0149] Compound BB-7-5 (0.070 g, 0.187 mmol) was dissolved in methanol (3 mL), then CuCl.sub.2 (0.05 g, 0.374 mmol) was added, the reaction mixture was heated to 50° C. and reacted for 20 hours. After cooling, the reaction mixture was evaporated to dry, then EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-7-6 (gray solid, 0.052 g, yield 98%) which was used for the next step directly. MS (ESI) m/z: 283 [M+H].sup.+.

    [0150] Step 6: Synthesis of Compound BB-7

    [0151] Compound BB-7-6 (0.052 g, 0.184 mmol) was dissolved in THF/MeOH/H.sub.2O (4 mL, 2:1:1), then lithium hydroxide hydrate (0.039 g, 0.92 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, pH was adjusted to 1 with 2N hydrochloric acid, then the mixture was extracted with EA (50 mL×2), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-7 (gray solid, 0.045 g, yield 96%) which was used for the next step directly. MS (ESI) m/z: 255 [M+H].sup.+.

    Reference 8: Fragment BB-8

    [0152] ##STR00064##

    [0153] Synthetic Route:

    ##STR00065## ##STR00066##

    [0154] Step 1: Synthesis of Compound BB-8-2

    [0155] Compound BB-8-1 (5 g, 36.72 mmol) was dissolved in HOAc (30 mL), the mixture was cooled to 0° C., then liquid bromine (6.75 g, 42.23 mmol) was added dropwise, the resulting mixture was reacted at 0° C. for 2 hours. After the reaction was complete, H.sub.2O (100 mL) was added, the mixture was filtered, the solid was washed with H.sub.2O, and dried to deliver the target compound BB-8-2 (yellow solid, 7.5 g, yield 95%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 11.18 (s, 1H), 9.81 (s, 1H), 7.51-7.47 (m, 2H), 2.25 (s, 3H).

    [0156] Step 2: Synthesis of Compound BB-8-3

    [0157] Compound BB-8-2 (5.4 g, 25.11 mmol) was dissolved in DMF (70 mL), then K.sub.2CO.sub.3 (6.94 g, 50.22 mmol), ethyl bromoacetate (5.03 g, 30.13 mmol) were added. The reaction mixture was reacted at r.t. for 1 hour, then heated to 80° C. and reacted for 16 hours. After cooling, EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-8-3 (white solid, 4.2 g, yield 59%). MS (ESI) m/z: 283 [M+H].sup.+, 285[M+H+2].sup.+.

    [0158] Step 3: Synthesis of Compound BB-8-4

    [0159] Compound BB-8-3 (0.50 g, 1.77 mmol) was dissolved in CCl.sub.4 (7 mL), then NBS (0.377 g, 2.12 mmol), benzoperoxide (0.043 g, 0.177 mmol) were added. The reaction mixture was reacted at 80° C. for 16 h. The reaction mixture was concentrated to deliver a crude product, which is purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-8-4 (gray solid, 0.660 g, crude product). MS (ESI) m/z: 363 [M+H].sup.+, 361[M+H−2].sup.+, 365[M+H+2].sup.+.

    [0160] Step 4: Synthesis of Compound BB-8-5

    [0161] Compound BB-8-4 (0.30 g, 0.829 mmol) was dissolved in acetonitrile (10 mL), then N-methylmorpholine-N-oxide (0.970 g, 8.29 mmol) was added. The reaction mixture was stirred at r.t. for 4 hours, then evaporated to dry. EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-8-5 (white solid, 0.180 g, 73.11%). MS (ESI) m/z: 297 [M+H].sup.+, 299[M+H+2].sup.+.

    [0162] Step 5: Synthesis of Compound BB-8-6

    [0163] Compound BB-8-5 (0.170 g, 0.572 mmol) was dissolved in toluene (2 mL), then diethylaminosulphur trifluoride (0.185 g, 1.15 mmol) was added, the reactants were stirred at 25° C. for 16 hours under nitrogen gas atmosphere. After the reaction was complete, EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-8-6 (gray solid, 0.175 g, 95.84%). MS (ESI) m/z: 319 [M+H].sup.+, 321[M+H+2].sup.+.

    [0164] Step 6: Synthesis of Compound BB-8-7

    [0165] Compound BB-8-6 (0.170 g, 0.533 mmol) was dissolved in toluene (3 mL) and H.sub.2O (1 mL), then tricyclohexyl phosphate (0.015 g, 0.053 mmol), cyclopropylboronic acid (0.10 g, 1.16 mmol), Pd(OAc).sub.2 (0.012 g, 0.053 mmol) were added, the reactants were heated to 110° C. and stirred for 5 hours under nitrogen gas atmosphere. After cooling, EA (50 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-8-7 (yellow solid, 0.132 g, 88.40%). MS (ESI) m/z: 281 [M+H].sup.+.

    [0166] Step 7: Synthesis of Compound BB-8-8

    [0167] Compound BB-8-7 (0.132 g, 0.471 mmol) was dissolved in n-hexane (3 mL), then (PinB).sub.2 (0.145 g, 0.571 mmol), 4,4′-di-tert-2,2′-bipyridine (0.013 g, 0.048 mmol), di-g-methoxobis(1,5-cyclooctadiene)diiridium(I) (0.019 g, 0.029 mmol) were added sequentially, the reactants were refluxed under nitrogen gas atmosphere for 16 hours. The reaction mixture was evaporated to dry, purified by flash column chromatography (eluting agent, EA/PE=1/5) to deliver the target compound BB-8-8 (white solid, 0.10 g, 52.27%). MS (ESI) m/z: 325 [M−82+H].sup.+.

    [0168] Step 8: Synthesis of Compound BB-8-9

    [0169] Compound BB-8-8 (0.095 g, 0.234 mmol) was dissolved in methanol (4 mL), then CuCl.sub.2 (0.063 g, 0.468 mmol) was added, the reaction mixture was heated to 50° C. and reacted for 16 hours. After cooling, the reaction mixture was evaporated to dry, then EA (50 mL) was added. The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-8-9 (white solid, 0.073 g, 99.19%), which was used for the next step directly. MS (ESI) m/z: 315 [M+H].sup.+.

    [0170] Step 9: Synthesis of Compound BB-8

    [0171] Compound BB-8-9 (0.070 g, 0.222 mmol) was dissolved in methanol (2 mL) and H.sub.2O (2 mL), then lithium hydroxide hydrate (0.050 g, 1.19 mmol) was added, the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, pH was adjusted to 1 with 3N hydrochloric acid, then the mixture was extracted with EA (50 mL×2), the combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-8 (white solid, 0.063 g, 98.81%), which was used for the next step directly. MS (ESI) m/z: 287 [M+H].sup.+.

    Reference 9: Fragment BB-9

    [0172] ##STR00067##

    [0173] Synthetic Route:

    ##STR00068##

    [0174] Step 1: Synthesis of Compound BB-9-2

    [0175] Compound BB-2 (0.30 g, 0.98 mmol), compound BB-9-1 (0.141 g, 0.98 mmol), HATU (0.449 g, 1.18 mmol) and DIPEA (0.382 g, 2.95 mmol) were dissolved in anhydrous DMF (3 mL), stirred at 20° C. for 6 hours, H.sub.2O was added, the mixture was extracted with EA (20 mL×2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to deliver compound BB-9-2 (yellow oil, 0.460 g, yield 100%), which was used for the next step directly without purification. MS (ESI) m/z: 430.2 [M+H].sup.+.

    [0176] Step 2: Synthesis of Compound BB-9

    [0177] Compound BB-9-2 (0.460 g, 1.07 mmol) was dissolved in THF:methanol:H.sub.2O=2:2:1 (10 mL), lithium hydroxide monohydrate (0.135 g, 3.21 mmol) was added. The reaction mixture was stirred at 18° C. for 2 hours, the solvent was removed under reduced pressure, the residue was dissolved in H.sub.2O again, pH was adjusted to about 2-3 with 2N aqueous hydrochloric acid solution, the solid was collected to deliver the compound BB-9 (white solid, 0.380 g, yield 85.4%) which was used for the next step directly without purification. MS (ESI) m/z: 416 [M+H].sup.+.

    Reference 9a: Fragment BB-9a

    [0178] ##STR00069##

    [0179] Synthetic Route:

    ##STR00070##

    [0180] Step 1: Synthesis of Compound BB-9a-2

    [0181] Compound BB-2 (0.147 g, 0.483 mmol), compound BB-9a-1 (0.100 g, 0.483 mmol) were dissolved in DMF (1 mL), DIPEA (0.187 g, 1.45 mmol) and HATU (0.275 g, 0.724 mmol) were added. The reaction mixture was stirred at 18° C. for 2 hours, H.sub.2O (3 mL) was added, the mixture was extracted with EA (20 mL×3). The organic phases were combined, washed with H.sub.2O (20 mL×2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver compound BB-9a-2 (yellow solid, 0.220 g, yield 99.58%). MS (ESI) m/z: 458 [M+H].sup.+.

    [0182] Step 2: Synthesis of Compound BB-9a

    [0183] Compound BB-9a-2 (0.220 g, 0.480 mmol) was dissolved in methanol (5 mL), lithium hydroxide monohydrate (0.101 g, 2.40 mmol) and H.sub.2O (1 mL) were added. The reaction mixture was stirred at 25° C. for 16 hours, then the solvent was removed under reduced pressure, the residue was dissolved in H.sub.2O again, pH was adjusted to 3 with conc. hydrochloric acid. The mixture was filtered, the cake was dissolved in DCM (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver compound BB-9a (yellow solid, 0.150 g, yield 72.63%). MS (ESI) m/z: 430 [M+H].sup.+.

    Reference 10: Fragment BB-10

    [0184] ##STR00071##

    [0185] Synthetic Route:

    ##STR00072##

    [0186] Step 1: Synthesis of Compound BB-10-2

    [0187] Compound BB-10-1 (10.0 g, 52.85 mmol) was dissolved in DMF (120 mL), allyl bromide (7.67 g, 63.42 mmol) was added, and then NaH (3.17 g, 79.28 mmol, 60%) was added in portions at 0° C., the reaction mixture was stirred at 0° C. for 2 hours. After the reaction was complete, it was quenched with H.sub.2O. The mixture was extracted with EA (50 mL×2), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-10-2 (gray solid, 9.3 g, yield 76.7%). MS (ESI) m/z: 230 [M+H].sup.+.

    [0188] Step 2: Synthesis of Compound BB-10-3

    [0189] Compound BB-10-2 (9 g, 39.25 mmol) was dissolved in methanol (200 mL), cooled to −78° C., O.sub.3 was introduced until the reaction mixture became blue, then N.sub.2 was introduced until the reaction mixture became colorless, Me.sub.2S (15 mL, 203 mmol) was then added, the mixture was reacted at r.t. overnight. After the reaction was complete, the mixture was concentrated, EA (150 mL) was added, the organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-10-3 (yellow oil, 9.1 g, yield 100%). MS (ESI) m/z: 232 [M+H].sup.+.

    [0190] Step 3: Synthesis of Compound BB-10-5

    [0191] Compound BB-10-3 (6.35 g, 27.46 mmol) was dissolved in methanol (100 mL), then BB-10-4 (5.0 g, 32.95 mmol), DIPEA (4.26 g, 32.95 mmol), Na.sub.2SO.sub.4 (20 g) were added, the reaction mixture was stirred at r.t. for 1 hour, then NaBH.sub.4 (1.25 g, 32.95 mmol) was added, the reaction mixture was stirred at r.t. for 2 hours. Then NaH (2.2 g, 54.92 mmol, 60%) was added in portions, the reaction mixture was stirred at r.t. for 1 hour. The reaction mixture was concentrated, EA (200 mL) was added, the organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver a crude product which was then recrystallized (EA/PE=1/5) to deliver the target compound BB-10-5 (yellow solid, 5.58 g, yield 67%). MS (ESI) m/z: 299 [M+H].sup.+.

    [0192] Step 4: Synthesis of Compound BB-10

    [0193] Compound BB-10-5 (5.5 g, 18.43 mmol) was dissolved in DCM (20 mL), then hydrochloric acid/dioxane (50 mL, 4 N) was added. The reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, the mixture was concentrated to deliver the target compound BB-10 (yellow solid, 4.4 g, yield 100%). MS (ESI) m/z: 199 [M+H].sup.+.

    Reference 11: Fragment BB-11

    [0194] ##STR00073##

    [0195] Synthetic Route:

    ##STR00074##

    [0196] Step 1: Synthesis of Compound BB-11-1

    [0197] Compound BB-10-3 (0.450 g, 1.95 mmol) was dissolved in methanol (5 mL), then benzyl carbazate (0.356 g, 2.14 mmol), Na.sub.2SO.sub.4 (0.50 g) were added, the reactants were stirred at r.t. for 2 hours. The reaction mixture was filtered, the filtrate was concentrated to deliver the target compound BB-11-1 (gray solid, 0.740 g, yield 100%). MS (ESI) m/z: 402 [M+Na].sup.+.

    [0198] Step 2: Synthesis of Compound BB-11-2

    [0199] Compound BB-11-1 (0.22 g, 0.58 mmol) was dissolved in methanol (10 mL), then Pd(OH).sub.2/C (0.020 g) was added, the reactants were stirred at r.t. for 3 hours under hydrogen gas atmosphere (15 Psi). The reaction mixture was filtered, the filtrate was concentrated to deliver the target compound BB-11-2 (gray solid, 0.110 g, yield 76.7%).

    [0200] Step 3: Synthesis of Compound BB-11-3

    [0201] Compound BB-11-2 (0.110 g, 0.445 mmol) was dissolved in methanol (3 mL), then MeONa (0.048 g, 0.889 mmol) was added, the reactants were stirred at r.t. for 2 hours. After the reaction was complete, it was quenched by adding H.sub.2O dropwise, the mixture was extracted with EA (50 mL×2), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-11-3 (yellow oil, 0.090 g, yield 94%). MS (ESI) m/z: 160 [M−.sup.tBu+H].sup.+.

    [0202] Step 4: Synthesis of Compound BB-11-4

    [0203] Compound BB-11-3 (0.090 g, 0.418 mmol) was dissolved in DCM (3 mL), then 2-chloroethyl chloroformate (0.072 g, 0.502 mmol), DIPEA (0.162 g, 1.25 mmol) were added, the reactants were stirred at 0° C. for 3 hours. After the reaction was complete, DCM (100 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-11-4 (yellow solid, 0.110 g, yield 74.3%). MS (ESI) m/z: 322 [M+H].sup.+.

    [0204] Step 5: Synthesis of Compound BB-11-5

    [0205] Compound BB-11-4 (0.100 g, 0.31 mmol) was dissolved in DMF (3 mL), then NaH (0.025 g, 0.62 mmol) was added, the reactants were stirred at r.t. for 2 hours. After the reaction was complete, it was quenched by adding H.sub.2O dropwise, the mixture was extracted with EA (50 mL×2), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-11-5 (yellow oil, 0.080 g, yield 90.2%). MS (ESI) m/z: 308 [M+Na].sup.+.

    [0206] Step 6: Synthesis of Compound BB-11

    [0207] Compound BB-11-5 (0.080 g, 0.28 mmol) was dissolved in DCM (2 mL), then hydrochloric acid/dioxane (3 mL, 4 N) was added, the reactants were stirred at r.t. for 2 hours. The reaction mixture was concentrated to deliver the target compound BB-11 which was used for the next step directly (gray solid, 0.064 g, yield 100%). MS (ESI) m/z: 186 [M+H].sup.+.

    Reference 12: Fragment BB-12

    [0208] ##STR00075##

    [0209] Synthetic Route:

    ##STR00076##

    [0210] Step 1: Synthesis of Compound BB-12-2

    [0211] Compound BB-12-1 (15.0 g, 67.20 mmol) was dissolved in DMF (170 mL), allyl bromide (9.76 g, 80.64 mmol) was added, and then at 0° C., NaH (3.23 g, 80.64 mmol, 60%) was added in portions, the reaction mixture was stirred at 0° C. for 2 hours. After the reaction was complete, it was quenched by adding H.sub.2O, the mixture was extracted with EA (150 mL×2), the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-12-2 (gray solid, 12.0 g, yield 67.83%). MS (ESI) m/z: 264 [M+H].sup.+.

    [0212] Step 2: Synthesis of Compound BB-12-3

    [0213] Compound BB-12-2 (12 g, 45.58 mmol) was dissolved in methanol (250 mL), cooled to −78° C., O.sub.3 was introduced until the reaction mixture became blue, then N.sub.2 was introduced until the reaction mixture became colorless, Me.sub.2S (15 mL, 203 mmol) was then added, the reaction mixture was stirred overnight. After the reaction was complete, the mixture was concentrated, EA (250 mL) was added, the organic phase was washed with brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-12-3 (yellow oil, 12 g, yield 99.26%). MS (ESI) m/z: 266 [M+H].sup.+.

    [0214] Step 3: Synthesis of Compound BB-12-5

    [0215] Compound BB-12-4 (supplier: TCI, 0.1 g, 0.66 mmol) and compound BB-12-3 (0.175 g, 0.66 mmol) were dissolved in anhydrous methanol (10 mL), the reactants were stirred at r.t. overnight, then the solvent was removed under reduced pressure to deliver compound BB-12-5 (yellow oil, 0.239 g, yield 100%) which was used for the next step directly without purification. MS (ESI) m/z: 363.0 [M+H].sup.+.

    [0216] Step 4: Synthesis of Compound BB-12-6

    [0217] Compound BB-12-5 (0.239 g, 0.66 mmol) was dissolved in HOAc: H.sub.2O=1:1 (3 mL), then NaBH.sub.3CN (0.041 g, 0.66 mmol) was added. The reaction mixture was stirred at r.t. for 3 hours, pH was adjusted to 6-7 with 1N aqueous NaOH solution, and then the mixture was extracted with EA (20 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to deliver compound BB-12-6 (slight yellow oil, 0.240 g, yield 100%) which was used for the next step directly without purification. MS (ESI) m/z: 365.1 [M+H].sup.+.

    [0218] Step 5: Synthesis of Compound BB-12-7

    [0219] Compound BB-12-6 (0.190 g, 0.52 mmol) was dissolved in THF:methanol:H.sub.2O=2:2:1 (5 mL), lithium hydroxide monohydrate (0.109 g, 2.61 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours, the solvent was removed under reduced pressure, the residue was dissolved in H.sub.2O again, pH was adjusted to about 2-3 with 2N aqueous hydrochloric acid solution, the mixture was extracted with DCM:methanol=10:1 (10 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to deliver compound BB-12-7 (yellow oil, 0.120 g, yield 65.7%) which was used for the next step directly without purification.

    [0220] Step 6: Synthesis of Compound BB-12-8

    [0221] Compound BB-12-7 (0.183 g, 0.52 mmol), HATU (0.238 g, 0.63 mmol) and DIPEA (0.338 g, 2.61 mmol) were dissolved in dry DMF (3 mL). The reaction mixture was stirred at r.t. overnight, purified by preparative chromatography (column: Agela DuraShell C18 150*25*5 m, eluting agent: MeCN+0.075% TFA, H.sub.2O+0.075% TFA) to deliver the target compound BB-12-8 (slight yellow oil, 0.040 g, yield 23%). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.42-7.35 (m, 5H), 5.19 (s, 2H), 4.28-3.72 (m, 8H).

    [0222] Step 7: Synthesis of Compound BB-12

    [0223] Compound BB-12-8 (0.040 g, 0.12 mmol) was dissolved in dry methanol (5 mL), Pd/C (0.010 g, 10%) was added, under hydrogen gas atmosphere (15 Psi), the reaction mixture was stirred at r.t. for 2 hours, filtered, the filtrate was evaporated under reduced pressure to deliver compound BB-12 (white solid, 0.030 g, yield 100%) which was used for the next step directly without purification.

    Reference 13: Fragment BB-13

    [0224] ##STR00077##

    [0225] Synthetic Route:

    ##STR00078##

    [0226] Step 1: Synthesis of Compound BB-13-2

    [0227] Compound BB-13-1 (1.00 g, 4.71 mol) was dissolved in tert-BuOH (15 mL), then TEA (0.572 g, 5.65 mol), di-tert-butyl dicarbonate (3.70 g, 17.0 mmol) were added, then DPPA (1.56 g, 5.65 mmol) was added dropwise slowly. The reactants were stirred at 28° C. for 5 hours, then heated to reflux for 16 hours. After the reaction was complete, the solvent was evaporated, the residue was dissolved in MTBE (50 mL), washed with saturated NaHCO.sub.3 solution (20 mL), the aqueous phase was extracted with MTBE (50 mL×2), the combined organic phase was washed with saturated brine (20 mL), dried, filtered, and concentrated to deliver the crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/6) to deliver the target compound BB-13-2 (white solid, 0.67 g, yield 50%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 3.65 (s, 3H), 1.89 (s, 12H), 1.41 (s, 9H).

    [0228] Step 2: Synthesis of Compound BB-13-3

    [0229] Compound BB-13-2 (0.056 g, 0.2 mmol) was dissolved in methanol (2.0 mL), then lithium hydroxide (2N, 2 mL) was added, pH of the reactants was adjusted to 4-5 with 1N hydrochloric acid, the mixture was extracted with EA (20 mL×3), washed with H.sub.2O, dried over sodium sulfate, and evaporated to deliver the target compound BB-13-3 (white solid, 0.040 g, yield 80%). MS (ESI) m/z: 214 [M+H−56].sup.+.

    [0230] Step 3: Synthesis of Compound BB-13-4

    [0231] The reactant BB-13-3 (2.00 g, 7.43 mmol) was dissolved in DMF (20 mL), then benzyl carbazate (1.23 g, 7.43 mmol), DIPEA (2.88 g, 22.3 mmol), HATU (4.24 g, 11.1 mmol) were added. The reactants were stirred at 26° C. for 16 hours. H.sub.2O (40 mL) was added, filtered, the cake was dissolved in DCM (50 mL), dried, filtered, and concentrated to deliver the target compound BB-13-4 (white solid, 2.5 g, yield 81%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 7.55 (m, 5H), 5.16 (s, 2H), 1.69 (s, 12H), 1.43 (s, 9H).

    [0232] Step 4: Synthesis of Compound BB-13-5

    [0233] Compound BB-13-4 (1.00 g, 2.40 mmol) was dissolved in methanol (20 mL), then wet Pd/C (0.2 g) was added. The reaction mixture was stirred at 26° C. for 16 hours under nitrogen gas atmosphere (15 Psi). The reaction mixture was filtered with celite, washed with methanol (50 mL), the filtrate was concentrated to deliver the target compound BB-13-5 (gray solid, 0.665 g, yield 98%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.37 (br, 1H), 1.90-1.80 (m, 12H), 1.42 (s, 9H).

    [0234] Step 5: Synthesis of Compound BB-13-6

    [0235] Compound BB-13-5 (0.665 g, 2.35 mmol) was dissolved in triethyl orthoformate (5 mL), p-TsOH (0.040 g, 0.235 mmol) was added, the reactants were stirred at 90° C. for 2 hours. The reaction mixture was concentrated to deliver the crude product which was purified by flash column chromatography (eluting agent, EA/PE=1/2) to deliver the target compound BB-13-6 (white solid, 0.560 g, yield 81%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.31 (s, 1H), 4.40 (br, 1H), 2.10-1.96 (m, 12H), 1.44 (s, 9H).

    [0236] Step 6: Synthesis of Compound BB-13

    [0237] Compound BB-13-6 (0.560 g, 1.91 mmol) was dissolved in DCM (20 mL), TFA (4 mL) was added. The reaction mixture was stirred at 26° C. for 2 hours. After the reaction was complete, the mixture was washed with H.sub.2O (30 mL), pH of the aqueous phase was adjusted to 9 with Na.sub.2CO.sub.3, then the mixture was extracted with DCM (20 mL×5), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-13 (white solid, 0.200 g, yield 54%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.31 (s, 1H), 2.08-2.04 (br, 6H), 1.71-1.68 (m, 6H).

    Reference 14: Fragment BB-14

    [0238] ##STR00079##

    [0239] Synthetic Route:

    ##STR00080##

    [0240] Step 1: Synthesis of Compound BB-14-1

    [0241] Compound BB-13-3 (1.65 g, 6.13 mmol) was dissolved in DMF (20 mL), then acethydrazide (0.499 g, 6.74 mmol), DIPEA (2.37 g, 18.38 mmol), HATU (3.03 g, 7.96 mmol) were added, the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, H.sub.2O was added, then the mixture was extracted with EA (50 mL×3), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product which was purified by flash column chromatography (eluting agent, EA/PE=4/1) to deliver the target compound BB-14-1 (white solid, 1.6 g, yield 80%). MS (ESI) m/z: 326 [M+H].sup.+.

    [0242] Step 2: Synthesis of Compound BB-14-2

    [0243] Compound BB-14-1 (0.500 g, 1.54 mmol) was dissolved in DCM (8 mL), then TEA (0.311 g, 3.07 mmol), p-TsCl (0.469 g, 2.46 mmol) were added, the reaction mixture was stirred at r.t. for 4 hours. After the reaction was complete, DCM (100 mL) was added, the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product, which was purified by flash column chromatography (eluting agent, EA/PE=1/1) to deliver the target compound BB-14-2 (white solid, 0.330 g, yield 70%). MS (ESI) m/z: 308 [M+H].sup.+.

    [0244] Step 3: Synthesis of Compound BB-14

    [0245] Compound BB-14-2 (0.320 g, 1.04 mmol) was dissolved in DCM (4 mL), then TFA (1 mL) was added, the reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, DCM (100 mL) was added, the organic phase was washed with saturated aqueous Na.sub.2CO.sub.3 solution, brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-14 (white solid, 0.205 g, yield 95%). MS (ESI) m/z: 208 [M+H].sup.+.

    Reference 15: Fragment BB-15

    [0246] ##STR00081##

    [0247] Synthetic Route:

    ##STR00082##

    [0248] Step 1: Synthesis of Compound BB-15-2

    [0249] Glycine (1.51 g, 20.1 mmol) was suspended in H.sub.2O (5 mL), aqueous NaOH solution (1 M, 10 mL) was added dropwise, compound BB-15-1 (6.20 g, 28.0 mmol) was added, NaOH (1M, 20 mL) was added dropwise in portions, pH was kept greater than 9. After the addition, the reactants were stirred at r.t. for further 30 minutes. The reaction mixture was filtered, the filtrate was adjusted to be acidic with aqueous hydrochloric acid solution (5 M), and the precipitated solid was filtered out to deliver the target compound BB-15-2 (yellow solid, 2.4 g, yield 33%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.31 (d, J=8.8 Hz, 2H), 8.03 (d, J=8.8 Hz, 2H), 3.78 (s, 2H).

    [0250] Step 2: Synthesis of Compound BB-15-4

    [0251] Compound BB-15-3 (supplier: Aroma Circle Corp., 0.050 g, 0.417 mmol) was added into 1.5 mL DMF, then compound BB-15-2 (0.108 g, 0.417 mmol), HOBt (0.062 g, 0.459 mmol), DIPEA (0.161 g, 1.25 mmol), EDC HCl (0.088 g, 0.459 mmol) were added. After stirring at r.t. for 5 hours, the organic phase was poured into H.sub.2O, extracted with EA (25 mL), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the resulting residue was purified by flash column chromatography (eluting agent, EA/PE=1/3) to deliver the target compound BB-15-4 (yellow solid, 0.075 g, yield 55.6%). MS (ESI) m/z: 326 [M+H].sup.+.

    [0252] Step 3: Synthesis of Compound BB-15-5

    [0253] Compound BB-15-4 (0.100 g, 0.308 mmol) was added into 3 mL DMF, then dibromoethane (0.348 g, 1.85 mmol), CsCO.sub.3 (0.401 g, 1.23 mmol) were added. After stirring at r.t. for 16 hours, the reaction was quenched with H.sub.2O, dried over anhydrous sodium sulfate, the mixture was evaporated under reduced pressure to deliver the target compound BB-15-5 (yellow solid, 0.080 g, yield 80%). MS (ESI) m/z: 352 [M+H].sup.+.

    [0254] Step 4: Synthesis of Compound BB-15

    [0255] Compound BB-15-5 (0.080 g, 0.228 mmol) was added into 2 mL MeCN, then PhSH (0.075 g, 0.684 mmol) was added. After stirring at r.t. for 16 hours under nitrogen gas atmosphere, the organic phase was poured into DCM, filtered, the mixture was evaporated under reduced pressure to deliver the target compound BB-15 (yellow oil, 0.025 g, yield 65.8%). MS (ESI) m/z: 167 [M+H].sup.+.

    Reference 16: Fragment BB-16

    [0256] ##STR00083##

    [0257] Synthetic Route:

    ##STR00084##

    [0258] Step 1: Synthesis of Compound BB-16-2

    [0259] Compound BB-16-1 (supplier: Shanghai SHUYA, 0.50 g, 3.24 mmol), di-tert-butyl dicarbonate (2.5 g, 11.67 mmol) and TEA (0.393 g, 3.89 mmol) were dissolved in tert-butanol (20 mL), DPPA (1.07 g, 3.89 mmol) was added slowly under nitrogen gas atmosphere, then reaction mixture was stirred at r.t. for about 8 hours, followed by heating to reflux for 16 hours, the solvent was removed under reduced pressure, the residue was extracted with MTBE (150 mL×3), dried over anhydrous sodium sulfate, the mixture was evaporated under reduced pressure, the resulting residue was purified by flash preparative chromatography (eluting agent: PE/EA=30:1) to deliver the target compound BB-16-2 (white solid, 0.30 g, yield 41%), which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.27-4.13 (br, 1H), 1.77-1.63 (m, 6H), 1.62-1.51 (m, 6H), 1.50-1.45 (m, 1H), 1.35 (s, 9H).

    [0260] Step 2: Synthesis of Compound BB-16-3

    [0261] Compound BB-16-2 (0.300 g, 1.33 mmol) was added into 5 mL DCM, then hydrochloric acid/dioxane (5 mL) was added. After stirring at r.t. for 16 hours, the mixture was evaporated under reduced pressure to deliver the target compound BB-16-3 (white solid, 0.200 g, yield 100%). MS (ESI) m/z: 126 [M+H].sup.+.

    [0262] Step 3: Synthesis of Compound BB-16-4

    [0263] Compound BB-16-3 (0.200 g, 1.242 mmol) was added into 5 mL DMF, then compound BB-15-2 (0.324 g, 1.242 mmol), HOBt (0.184 g, 1.366 mmol), EDC HCl (0.262 g, 1.366 mmol), DIPEA (0.480 g, 3.72 mmol) were added. After stirring at r.t. for 5 hours, the organic phase was poured into H.sub.2O, the mixture was extracted with EA (50 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, the resulting residue was purified by flash column chromatography (eluting agent, EA/PE=1/3) to deliver the target compound BB-16-4 (yellow oil, 0.200 g, yield 43.8%). MS (ESI) m/z: 368 [M+H].sup.+.

    [0264] Step 4: Synthesis of Compound BB-16-5

    [0265] Compound BB-16-4 (0.150 g, 0.408 mmol) was added into 5 mL DMF, then compound 1,2-dibromoethane (0.462 g, 2.451 mmol), CsCO.sub.3 (0.531 g, 1.632 mmol) were added. After stirring at 60° C. for 16 hours, the reaction was quenched with H.sub.2O, the mixture was dried over anhydrous sodium sulfate, evaporated under reduced pressure to deliver the target compound BB-16-5 (yellow solid, 0.100 g, yield 80%). MS (ESI) m/z: 394 [M+H].sup.+.

    [0266] Step 5: Synthesis of Compound BB-16

    [0267] Compound BB-16-5 (0.100 g, 0.487 mmol) was added into 5 mL MeCN, then PhSH (0.429 g, 3.9 mmol), K.sub.2CO.sub.3 (0.269 g, 1.95 mmol) were added. After stirring at r.t. for 16 hours under nitrogen gas atmosphere, the organic phase was poured into DCM, filtered, the mixture was evaporated under reduced pressure to deliver the target compound BB-16 (yellow oil, 0.025 g, yield 24.6%). MS (ESI) m/z: 209 [M+H].sup.+.

    Reference 17: Fragment BB-17

    [0268] ##STR00085##

    [0269] Synthetic Route:

    ##STR00086##

    [0270] Step 1: Synthesis of Compound BB-17-2

    [0271] Compound BB-17-1 (7.0 g, 31.78 mmol) was dissolved in dilute hydrochloric acid (6M, 150 mL) and the mixture was stirred to be uniform, NaNO.sub.2 solution (4N, 30 mL) was added dropwise slowly under nitrogen gas atmosphere, then the mixture was stirred at r.t. for about 1 hour, 100 mL H.sub.2O was added, the mixture was extracted with EA (100 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to deliver the target compound BB-17-2 (7.5 g, yield 66%), which was used for the next step directly without purification. MS (ESI) m/z: 250 [M+H].sup.+.

    [0272] Step 2: Synthesis of Compound BB-17-3

    [0273] Compound BB-17-2 (4.0 g, 16 mmol), zinc powder (6.2 g, 96 mmol) and NH.sub.4Cl (10 g, 192 mmol) were dissolved in methanol (80 mL), the mixture was stirred at r.t. for 10 minutes, then heated to 45° C. and stirred for 2 hours, filtered under reduced pressure, the cake was washed with methanol, the filtrate was concentrated to dry under reduced pressure, DCM was added into the residue and the mixture was stirred for 1 hour, the filtrate was concentrated to dry under reduced pressure to deliver the target compound BB-17-3 (3.5 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 236 [M+H].sup.+.

    [0274] Step 3: Synthesis of Compound BB-17-4

    [0275] Compound BB-17-3 (3.5 g crude product) and DIPEA (3.81 g, 29.6 mmol) were dissolved in DCM (100 mL), under an ice-bath, 2-chloroethyl chloroformate (2.55 g, 18 mmol) was added dropwise slowly under nitrogen gas atmosphere, then the reaction mixture was stirred at r.t. for about 2 hours, followed by diluting with H.sub.2O (80 mL), the mixture was extracted with DCM (100 mL) (60 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to deliver the compound BB-17-4 (5.0 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 342 [M+H].sup.+.

    [0276] Step 4: Synthesis of Compound BB-17-5

    [0277] Compound BB-17-4 (5.0 g crude product) was dissolved in DMF (100 mL), under an ice-water bath, NaH (60%, 2.0 g) was added under nitrogen gas atmosphere, then the mixture was stirred at r.t. for about 2 hours, the reaction was quenched by adding H.sub.2O (100 mL), the mixture was extracted with EA (300 mL), the organic phase was washed with saturated brine (30 mL×5), dried over anhydrous sodium sulfate, and evaporated under reduced pressure, the residue was purified by flash preparative chromatography (eluting agent: PE/EA=1:10) to deliver the target compound BB-17-5 (2.4 g). MS (ESI) m/z: 306 [M+H].sup.+.

    [0278] Step 4: Synthesis of Compound BB-17

    [0279] Compound BB-17-5 (2.4 g 7.86 mmol) was dissolved in methanol (80 mL), then Pd/C (0.400 g) was added, the reaction mixture was stirred at r.t. overnight under hydrogen gas atmosphere (15 Psi), and then Pd/C was filtered off, the filtrate was concentrated to dry under reduced pressure to deliver the target compound BB-17 (1.2 g, yield 89%), which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.30 (t, J=7.8 Hz, 2H), 3.62 (t, J=7.8 Hz, 2H), 3.03-2.87 (m, 8H).

    Reference 18: Fragment BB-18

    [0280] ##STR00087##

    [0281] Synthetic Route:

    ##STR00088##

    [0282] Step 1: Synthesis of Compound BB-18-2

    [0283] Compound BB-18-1 (2.0 g, 10 mmol) and TEA (2.02 g, 20 mmol) was dissolved in DCM (40 mL), under an ice-water bath, benzyl chloroformate (2.0 g, 11 mmol) was added slowly under nitrogen gas atmosphere, then the mixture was stirred at r.t. for 24 hours, dilute hydrochloric acid (1N, 30 mL) was added, the mixture was extracted with EA (80 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to deliver the target compound BB-18-2 (2.6 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 279 [M+H−56].sup.+.

    [0284] Step 2: Synthesis of Compound BB-18-3

    [0285] Compound BB-18-2 (2.6 g crude product) was dissolved in HCl/dioxane (4M, 25 mL) and the mixture was stirred to be uniform, then the reaction mixture was stirred at r.t. for 2 hours, then concentrated to deliver the target compound BB-18-3 (1.8 g crude product), which was used directly for the next step without purification. MS (ESI) m/z: 235 [M+H].sup.+.

    [0286] Step 3: Synthesis of Compound BB-18-4

    [0287] Compound BB-18-3 (1.8 g crude product) was dissolved in dilute hydrochloric acid (6M, 40 mL) and the mixture was stirred to be uniform, NaNO.sub.2 solution (2N, 17 mL) was added dropwise slowly under nitrogen gas atmosphere, then the reaction mixture was stirred at r.t. for 1 hour, 50 mL H.sub.2O was added, the mixture was extracted with EA (60 mL×3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to remove the solvent thereby delivering the target compound BB-18-4 (2 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 264 [M+H].sup.+.

    [0288] Step 4: Synthesis of Compound BB-18-5

    [0289] Compound BB-18-4 (2 g crude product), zinc powder (2.73 g, 42 mmol) and NH.sub.4Cl (4.45 g, 84 mmol) were dissolved in methanol (50 mL), the mixture was stirred at r.t. for 10 minutes, then heated to 45° C. and stirred for 2 hours, the mixture was filtered under reduced pressure, the cake was washed with methanol, the filtrate was concentrated to dry under reduced pressure, DCM (100 mL) was added into the residue, and the mixture was stirred for 1 hour, the insolubles were filtered off, the filtrate was concentrated to dry under reduced pressure to deliver the target compound BB-18-5 (1.8 g crude product), which was used for the next step without purification. MS (ESI) m/z: 250 [M+H].sup.+.

    [0290] Step 5: Synthesis of Compound BB-18-6

    [0291] Compound BB-18-5 (1.8 g crude product) and DIPEA (1.85 g, 14.4 mmol) were dissolved in DCM (40 mL), under an ice-water bath, compound 2-chloroethyl chloroformate (1.36 g, 9.6 mmol) was added dropwise slowly under nitrogen gas atmosphere, then the mixture was stirred at r.t. for 2 hours, diluted by H.sub.2O (50 mL), extracted with DCM (50 mL×3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to remove the solvent thereby delivering the target compound BB-18-6 (2.5 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 356 [M+H].sup.+.

    [0292] Step 6: Synthesis of Compound BB-18-7

    [0293] Compound BB-18-6 (0.710 g crude product) was dissolved in DMF (15 mL), under an ice-water bath, NaH (60%, 0.320 g) was added under nitrogen gas atmosphere, then the mixture was stirred at r.t. for about 2 hours, then quenched by adding H.sub.2O (50 mL), the mixture was extracted with EA (200 mL), the organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, evaporated under reduced pressure, the resulting residue was purified by flash preparative chromatography (eluting agent: PE/EA=1:10) to deliver the target compound BB-18-7 (0.300 g, yield 47%). MS (ESI) m/z: 320 [M+H].sup.+.

    [0294] Step 7: Synthesis of Compound BB-18

    [0295] Compound BB-18-7 (0.300 g, 0.94 mmol) was dissolved in methanol (5 mL), then Pd/C (0.020 g) was added, the mixture was stirred at r.t. overnight under hydrogen gas atmosphere (15 Psi), Pd/C was filtered off, the filtrate was concentrated to dry under reduced pressure to deliver the target compound BB-18 (0.170 g, yield 97.7%), which was used for the next step directly.

    Reference 19: Fragment BB-19

    [0296] ##STR00089##

    [0297] Synthetic Route:

    ##STR00090##

    [0298] Step 1: Synthesis of Compound BB-19-2

    [0299] Compound BB-17-3 (1.0 g, 4.2 mmol) and TEA (0.860 g, 8.5 mmol) were dissolved in DCM (20 mL), compound BB-19-1 (0.680 g, 6.3 mmol) was added dropwise slowly at −10° C. under nitrogen gas atmosphere, then the mixture was stirred at r.t. for 2 hours, diluted by adding H.sub.2O (50 mL), extracted with DCM (50 mL×3). The organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to remove the solvent thereby delivering the compound BB-19-2 (1.3 g crude product), which was used for the next step directly without purification. MS (ESI) m/z: 308 [M+H].sup.+.

    [0300] Step 2: Synthesis of Compound BB-19

    [0301] Compound BB-19-2 (0.100 g, 0.32 mmol) was dissolved in methanol (10 mL), then Pd/C (0.020 g) was added, the mixture was stirred at r.t. overnight under the protection of hydrogen gas balloon (15 Psi), Pd/C was filtered off, the filtrate was concentrated to dry under reduced pressure to deliver the target compound BB-19 (0.056 g, yield 99.4%) which was used for the next step directly. MS (ESI) m/z: 174 [M+H].sup.+.

    Reference 20: Fragment BB-20

    [0302] ##STR00091##

    [0303] Synthetic Route:

    ##STR00092##

    [0304] Step 1: Synthesis of Compound BB-20-2

    [0305] Compound BB-20-1 (1 g, 7.6 mmol) was dissolved in THF (10 mL), benzaldehyde (0.77 mL, 7.6 mmol) was added. The reaction mixture was stirred at r.t. for 4 hours, then concentrated. The resulting solid (1.3 g, 7.6 mmol) was then dissolved in THF (15 mL) again, AcOH (9 mL) and NaBH.sub.3CN (1.05 g, 16.7 mmol) were added, the reaction mixture was stirred at r.t. overnight. pH was adjusted to 9-10 with 1M aqueous NaOH solution, the mixture was extracted with EA (50 mL×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to deliver 1.5 g solid. Then the resulting solid (1.5 g, 7.6 mmol) was dissolved in methanol (10 mL) again, 1M aqueous NaOH solution (10 mL) was added. The reaction was stirred at r.t. for 2 hours, concentrated, and extracted with DCM (50 mL×3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product BB-20-2 (white solid, 1.37 g, 81.45%) which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.28-7.33 (m., 4H), 4.02 (s, 2H), 1.45 (s, 9H). MS (ESI) m/z: 167.0 [M+H−56].sup.+.

    [0306] Step 2: Synthesis of Compound BB-20-4

    [0307] Compound BB-20-3 (0.833 g, 7.5 mmol) was dissolved in DCM (20 mL), compound BB-20-2 (1.1 g, 5 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours, then quenched by adding H.sub.2O, extracted with DCM (100 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated, the crude product was purified by preparative HPLC (column: Phenomenex Gemini C18 250*50 mm*5 μm, eluting agent: MeCN+0.05% NH.sub.3.H.sub.2O, H.sub.2O+0.05% NH.sub.3.H.sub.2O) to deliver BB-20-4 (yellow solid, 0.730 g, yield 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.24-7.29 (m, 5H), 6.10 (br, s, 5H), 3.92 (s, 2H), 1.73-1.77 (m, 8H), 1.45 (s, 9H). MS (ESI) m/z: 304.0 [M+H].sup.+.

    [0308] Step 3: Synthesis of Compound BB-20-5

    [0309] Compound BB-20-4 (0.600 g, 1.80 mmol) and 1,2-dibromoethane (0.507 g, 2.70 mmol) were dissolved in DMF (10 mL), CsCO.sub.3 (1.76 g, 5.40 mmol) was added. The reaction mixture was stirred at r.t. for 10 minutes under nitrogen gas atmosphere, then heated to 40° C., stirred for 48 hours. The reaction mixture was cooled to r.t., and poured into 50 mL H.sub.2O. The aqueous phase was extracted with EA (100 mL×3). The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash silica gel column (eluting agent: EA/PE=1/1) to deliver BB-20-5 (yellow oil, 0.140 g, yield 22%). MS (ESI) m/z: 382.2 [M+Na].sup.+.

    [0310] Step 4: Synthesis of Compound BB-20-6

    [0311] Compound BB-20-5 (0.200 g, 0.556 mmol) was dissolved in methanol (20 mL), Pd(OH).sub.2/C (20%, 0.020 g) was added under argon gas atmosphere. The reaction mixture was swept by hydrogen gas for 3 times, followed by adjusting the pressure of hydrogen gas (50 psi) at 50° C., the reaction mixture was stirred for 48 hours, then filtered, and concentrated to deliver the crude product BB-20-6 (gray solid, 0.180 g, crude product), which was used for the next step directly. MS (ESI) m/z: 270 [M+H].sup.+.

    [0312] Step 5: Synthesis of Compound BB-20

    [0313] Compound BB-20-6 (0.180 g, crude product) was dissolved in HCl/dioxane (3 mL, 4M), the reaction mixture was stirred at r.t. for 1 hour, then concentrated to deliver the crude product of compound BB-20 hydrochloride (yellow solid, 0.140 g, 100%), which was used for the next step directly. MS (ESI) m/z: 170 [M+H].sup.+.

    Reference 21: Fragment BB-21

    [0314] ##STR00093##

    [0315] Synthetic Route:

    ##STR00094##

    [0316] Step 1: Synthesis of Compound BB-21-2

    [0317] Compound BB-21-1 (42.0 g, 259 mmol) was dissolved in DMF (400 mL), then NBS (46.1 g, 259 mmol) was added. The reactants were stirred at 20° C. for 2 hours. The reaction mixture was poured into a mixture of 5% NaHSO.sub.3 and H.sub.2O (10:1) while stirring, the precipitate was filtered out, washed with H.sub.2O, dissolved in DCM (500 mL), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-20-2 (yellow solid, 51.0 g, yield 89.7%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 8.27 (s, 1H), 7.80 (s, 1H), 5.02 (br, 2H). MS (ESI) m/z: 241 [M+H].sup.+, 243 [M+H+2].sup.+.

    [0318] Step 2: Synthesis of Compound BB-21-3

    [0319] Compound BB-21-2 (51.0 g, 212 mmol) was dissolved in DMF (500 mL), then ethyl bromopyruvate (82.5 g, 423 mmol) was added. The reactants were stirred at 50° C. for 16 hours. The reaction mixture was cooled to r.t., poured into a mixture of ice and water (1 L) and stirred for 20 minutes, the precipitate was filtered out, the cake was dissolved in EA (500 mL), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-21-3 (yellow solid, 71.0 g, yield 99.5%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.49 (s, 1H), 8.25 (s, 1H), 7.69 (s, 1H), 4.47 (q, J=6.8 Hz, 2H), 1.43 (t, J=6.8 Hz, 3H). MS (ESI) m/z: 337 [M+H].sup.+, 339 [M+H+2].sup.+.

    [0320] Step 3: Synthesis of Compound BB-21-4

    [0321] Compound BB-21-3 (55.0 g, 163 mmol) and cyclopropylboronic acid (15.4 g, 179 mmol) were dissolved in dioxane (500 mL), then K.sub.3PO.sub.4 (103.9 g, 489 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.70 g, 3.26 mmol) were added under nitrogen gas atmosphere. The reactants were stirred at 90° C. for 16 hours. The reaction mixture was cooled to r.t., filtered with celite, the filtrate was concentrated to deliver the crude product, which was purified by flash column chromatography (eluting agent: EA/PE=1/4) to deliver the target compound BB-21-4 (yellow solid, 24.0 g, yield 49.3%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.18 (s, 1H), 8.06 (s, 1H), 7.38 (s, 1H), 4.46 (q, J=7.2 Hz, 2H), 1.98 (m, 1H), 1.43 (t, J=7.2 Hz, 3H), 1.07 (m, 2H), 0.76 (m, 2H). MS (ESI) m/z: 299 [M+H].sup.+.

    [0322] Step 4: Synthesis of Compound BB-21-5

    [0323] Compound BB-21-4 (28.0 g, 93.9 mmol) was dissolved in DMF (250 mL), NCS (12.5 g, 93.9 mmol) was added. The reactants were stirred at 40° C. for 16 hours. The reaction mixture was cooled to r.t., and poured into H.sub.2O (500 mL), stirred for 20 minutes, the precipitate was filtered out, dried to deliver the target compound BB-21-5 (white solid, 31.0 g, yield 99.3%). MS (ESI) m/z: 333 [M+H]+.

    [0324] Step 5: Synthesis of Compound BB-21-6

    [0325] Compound BB-21-5 (31.0 g, 93.2 mmol) was dissolved in methanol (400 mL), compound lithium hydroxide monohydrate (19.6 g, 466 mmol) and H.sub.2O (100 mL) were added. The reactants were stirred at 20° C. for 2 hours. The reaction mixture was concentrated, pH of the residue was adjusted below 3 with conc. hydrochloric acid, the mixture was extracted with EA (400 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-21-6 (white solid, 27.3 g, yield 89.6%). .sup.1HNMR (400 MHz, CDCl.sub.3): δ 8.05 (s, 1H), 7.42 (s, 1H), 2.02 (m, 1H), 1.08 (m, 2H), 0.76 (m, 2H). MS (ESI) m/z: 305 [M+H].sup.+.

    Reference 22: Fragment BB-22

    [0326] ##STR00095##

    [0327] Synthetic Route:

    ##STR00096##

    [0328] Step 1: Synthesis of Compound BB-22-2

    [0329] Compound BB-22-1 (0.1 g, 0.584 mmol) was dissolved in DCM (1 mL), dimethylamine hydrochloride (0.072 g, 0.876 mmol) was added. The reaction mixture was stirred at r.t. for 2 hours, NaBH.sub.3CN (0.055 g, 0.876 mmol) was added, then the mixture was stirred at r.t. overnight. After the reaction was complete, the reaction mixture was poured into 20 mL H.sub.2O, extracted with DCM/methanol (10/1) (30 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product of the target compound BB-22-2 (yellow oil, 0.12 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.10-4.21 (m, 2H), 3.87-3.95 (m, 2H), 3.81 (d, J=4.41 Hz, 1H), 2.16 (s, 6H), 1.43-1.44 (m, 9H).

    [0330] Step 2: Synthesis of Compound BB-22

    [0331] Compound BB-22-2 (0.11 g, 0.549 mmol) was dissolved in DCM (2 mL), HCl/dioxane solution (1 mL, 4M) was added, the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, the mixture was concentrated to deliver the target compound BB-22 hydrochloride (yellow solid, 0.075 g, crude product), which was used for the next step directly without purification.

    Reference 23: Fragment BB-23

    [0332] ##STR00097##

    [0333] Synthetic Route:

    ##STR00098##

    [0334] Step 1: Synthesis of Compound BB-23-1

    [0335] Compound BB-22-1 (0.4 g, 2.34 mmol) was dissolved in anhydrous THF (5 mL), the reaction mixture was cooled to 0° C., and methyl magnesium bromide in THF solution (3M, 1.00 mL) was added dropwise under nitrogen gas atmosphere. Then the reaction mixture was warmed to r.t., stirred for 1 hour, 1M aqueous NH.sub.4Cl solution (10 mL) was added. The reaction mixture was extracted with EA (30 mL×3), the organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product of the target compound BB-23-1 (yellow solid, 0.47 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 4.07-4.17 (m, 1H), 3.79-3.88 (m, 4H), 1.51 (s, 3H), 1.43 (s, 9H).

    [0336] Step 2: Synthesis of Compound BB-23

    [0337] Compound BB-23-1 (0.15 g, 0.80 mmol) was dissolved in DCM (2 mL), HCl/dioxane solution (1 mL, 4M) was added, and the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, the mixture was concentrated to deliver the target compound BB-23 hydrochloride (yellow solid, 0.099 g, crude product), which was used for the next step directly without purification.

    Reference 24: Fragment BB-24

    [0338] ##STR00099##

    [0339] Synthetic Route:

    ##STR00100##

    [0340] Step 1: Synthesis of Compound BB-24-1

    [0341] Compound BB-23-1 (0.2 g, 1.07 mmol) was dissolved in anhydrous THF (5 mL), NaH (0.17 g, 4.30 mmol, 60%) was added at r.t. The reaction mixture was stirred for 10 mins, MeI (1.14 g, 8.03 mmol) was added, and the reaction mixture was stirred at r.t. overnight. After the reaction was complete, it was quenched by adding 20 mL H.sub.2O, the mixture was extracted with EA (50 mL×3), the organic phases were combined and washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product of the target compound BB-23-1 (yellow oil, 0.26 g). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.90 (d, J=9.04 Hz, 2H), 3.66 (d, J=9.04 Hz, 2H), 3.19-3.29 (m, 3H), 1.45 (s, 3H), 1.44 (s, 9H).

    [0342] Step 2: Synthesis of Compound BB-24

    [0343] Compound BB-23-1 (0.14 g, 0.70 mmol) was dissolved in DCM (2 mL), HCl/dioxane solution (1 mL, 4M) was added, the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, the mixture was concentrated to deliver the target compound BB-24 hydrochloride (white solid, 0.095 g), the crude was used for the next step directly without purification.

    Reference 25: Fragment BB-25

    [0344] ##STR00101##

    [0345] Synthetic Route:

    ##STR00102##

    [0346] Step 1: Synthesis of Compound BB-25-2

    [0347] Compound BB-25-1 (0.1 g, 0.46 mmol) and NH.sub.4OAc (0.035 g, 0.046 mmol) were dissolved in DMF (2 mL), then HATU (0.265 g, 0.697 mmol) and DIPEA (0.18 g, 1.39 mmol) were added, the reactants were stirred at r.t. for 16 hours. After the reaction was complete, EA was added, the organic phase was washed with aqueous NaHCO.sub.3 solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove the solvent thereby delivering the target compound BB-25-2 (white solid, 0.05 g, crude product), the crude was used for the next step directly without purification. MS (ESI) m/z: 237 [M+Na].sup.+.

    [0348] Step 2: Synthesis of Compound BB-25-3

    [0349] Compound BB-25-2 (0.05 g, crude product) was dissolved in THF (1.5 mL), then HCl/dioxane solution (1.5 mL, 4M) was added, the reactants were stirred at r.t. for 1.5 hours, then the mixture was concentrated under reduced pressure to remove the solvent thereby delivering the target compound BB-25 (white solid, 0.025 g, crude product).

    Reference 26: Fragment BB-26

    [0350] ##STR00103##

    [0351] Synthetic Route:

    ##STR00104##

    [0352] Step 1: Synthesis of Compound BB-26

    [0353] Compound BB-26-1 (0.100 g, 0.534 mmol) was dissolved in DCM (2 mL), then HCl/dioxane solution (1 mL, 4M) was added. The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated to deliver the target compound BB-26 (white solid, 0.060 g, yield 90.91%).

    Reference 27: Fragment BB-27

    [0354] ##STR00105##

    [0355] Synthetic Route:

    ##STR00106##

    [0356] Step 1: Synthesis of Compound BB-27-2

    [0357] Compound BB-27-1 (0.10 g, 0.411 mmol) was dissolved in DMF (3 mL), then dimethyl amine hydrochloride (0.070 g, 0.858 mmol), DIPEA (0.210 g, 1.62 mmol), HATU (0.184 g, 0.484 mmol) were added, the reactants were stirred at r.t. for 2 hours. After the reaction was complete, EA was added, the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent thereby delivering the target compound BB-27-2 (light yellow oil, 0.111 g, yield 99.89%). MS (ESI) m/z: 293 [M+Na].sup.+.

    [0358] Step 2: Synthesis of Compound BB-27-3

    [0359] Compound BB-27-2 (0.111 g, 0.411 mmol) was dissolved in DCM (3 mL), then HCl/dioxane solution (3 mL, 4M, 12.00 mmol) was added, the reactants were stirred at r.t. for 2 hours. After the reaction was complete, the mixture was concentrated to deliver the target compound BB-27 directly, which was used for the next step (yellow solid, 0.085 g, crude product).

    Reference 28: Fragment BB-28

    [0360] ##STR00107##

    [0361] Synthetic Route:

    ##STR00108##

    [0362] Step 1: Synthesis of Compound BB-28-2

    [0363] Compound BB-28-1 (10 g, 85.36 mmol), di-tert-butyl dicarbonate (18.6 g, 85.36 mmol) were dissolved in Et.sub.2O (100 mL), then Na.sub.2CO.sub.3 (18.1 g, 170.73 mmol) was formulated to a saturated solution and added into the reaction mixture, the reactants were stirred at 25° C. overnight. After the reaction was complete, the solid was removed by filtration, the filtrate was concentrated to deliver the target compound BB-28-2 (yellow solid, 14 g, crude product). MS (ESI) m/z: 240[M+Na].sup.+.

    [0364] Step 2: Synthesis of Compound BB-28-3

    [0365] Compound BB-28-1 (6 g, 27.6 mmol) and allyl bromide (4 g, 33.1 mmol) were dissolved in DMF (60 mL), then NaH (1.7 g, 41.4 mmol, 60%) was added in portions at 0° C., the reaction mixture was stirred at 0° C. for 3 hours. After the reaction was complete, the reaction was quenched by adding H.sub.2O, the mixture was extracted with EA, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the crude product which was purified by flash column chromatography (eluting agent: EA/PE=1/10) to deliver the target compound BB-28-3 (yellow oil, 2 g, crude product). MS (ESI) m/z: 158[M-Boc+H].sup.+.

    [0366] Step 3: Synthesis of Compound BB-28-4

    [0367] Compound BB-28-3 (2 g, 7.8 mmol) was dissolved in methanol (20 mL), the mixture was cooled to −78° C., O.sub.3 was introduced until the reaction mixture became blue, then N.sub.2 was introduced until the reaction mixture became colorless, Me.sub.2S (12.4 g, 38.8 mmol) was then added, reacted at 25° C. overnight. After the reaction was complete, the mixture was concentrated, EA was added, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to deliver the target compound BB-28-4 (yellow oil, 1.8 g, crude product). MS (ESI) m/z: 160[M-Boc+H].sup.+.

    [0368] Step 4: Synthesis of Compound BB-28-5

    [0369] Compound BB-28-4 (0.5 g, 1.93 mmol), cyclopentyl amine (0.197 g, 2.31 mmol), DIPEA (0.29 g, 1.93 mmol) and anhydrous Na.sub.2SO.sub.4 (0.197 g, 2.31 mmol) were dissolved in dry methanol (5 mL), the reactants were stirred at r.t. for 2 hours, NaBH.sub.4 (0.088 g, 2.31 mmol) was added slowly, then the mixture was stirred at r.t. for 2 hours. The reaction was quenched with aqueous NH.sub.4Cl solution, the mixture was extracted with EA, washed with H.sub.2O, dried over anhydrous sodium sulfate, and concentrated to deliver the crude product which was purified by flash column chromatography (eluting agent: methanol/DCM=1/10) to deliver the target compound BB-28-5 (yellow oil, 0.25 g, crude product). MS (ESI) m/z: 329[M+H].sup.+.

    [0370] Step 5: Synthesis of Compound BB-28-6

    [0371] Compound BB-28-5 (0.1 g, 0.3 mmol) was dissolved in THF (0.5 mL), then aqueous LiOH solution (1 mL, 2M) was added. The reaction mixture was stirred at 30° C. for 4 hours, then concentrated under reduced pressure to remove THF, followed by frozen drying to deliver compound BB-28-6 (yellow oil, 0.09 g, crude product), which was used for the next step directly without purification. MS (ESI) m/z: 301[M+H].sup.+.

    [0372] Step 6: Synthesis of Compound BB-28-7

    [0373] Compound BB-12-7 (0.09 g, 0.3 mmol), HATU (0.172 g, 0.45 mmol) and DIPEA (0.116 g, 0.9 mmol) were dissolved in dry DMF (2 mL). The reaction mixture was stirred at 20° C. for 4 hours, after the reaction was complete, the reaction mixture was poured into EA. The mixture was washed with brine, dried over sodium sulfate, and concentrated to deliver the crude product, which was isolated and purified by thin silica gel plate (developing agent: EA/PE=1/3) to deliver the compound BB-28-6 (yellow oil, 0.05 g, 55%). MS (ESI) m/z: 227 [M−56+H].sup.+.

    [0374] Step 7: Synthesis of Compound BB-28

    [0375] Compound BB-28-7 (0.05 g, 0.18 mmol) was dissolved in DCM (1 mL), HCl/dioxane solution (1 mL, 4M) was added, the reaction mixture was stirred at 20° C. for 1.5 hours, then concentrated under reduced pressure to deliver compound BB-28 (white solid, 0.030 g, crude product), which was used for the next step directly without purification. MS (ESI) m/z: 183[M+H].sup.+.

    Reference 29: Fragment BB-29

    [0376] ##STR00109##

    [0377] Synthetic Route:

    ##STR00110##

    [0378] Step 1: Synthesis of Compound BB-29-2

    [0379] Compound BB-29-1 (4.56 g, 43.37 mmol) was dissolved in toluene (24 mL), NaOH (2.19 g, 54.65 mmol) was dissolved in H.sub.2O (12 mL), then aqueous NaOH solution was added into the mixture slowly. Benzyl chloroformate (6.96 g, 40.77 mmol) was added dropwise slowly into the reaction mixture, the temperature of the reaction solution was kept at 10-20° C. After the addition, the reactants were stirred at r.t. for 16 hours. After the reaction was complete, the organic phase was separated, washed with brine (50 mL×2), dried over sodium sulfate, filtered, and concentrated to deliver the target compound BB-29-2 (yellow oil, 11 g, crude product), which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.38-7.27 (m, 5H), 5.1 (s, 2H), 4.38 (t, J=5.4 Hz, 1H), 3.38 (s, 6H), 3.35-3.32 (m, 2H).

    [0380] Step 2: Synthesis of Compound BB-29-3

    [0381] Compound BB-29-2 (5.62 g, 23.49 mmol), KOH (2.64 g, 46.98 mmol) and BTMA (0.088 g, 0.474 mmol) were suspended in toluene (20 mL), then a solution of 3-allyl bromide (5.68 g, 46.98 mmol) in toluene (6 mL) was slowly added, the temperature of the reactants was kept at 20-30° C. The reactants were stirred at r.t. for 16 hours, then at 30° C. for 24 hours. After the reaction was complete, 20 mL H.sub.2O was added, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to deliver the target compound BB-29-3 (yellow oil, 5.20 g, crude product). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.35-7.29 (m, 5H), 5.79-5.73 (m, 1H), 5.17-5.14 (m, 3H), 4.53-4.07 (m, 1H), 4.00-3.96 (m, 2H), 3.40-3.31 (m, 8H).

    [0382] Step 3: Synthesis of Compound BB-29-4

    [0383] The reactant BB-29-3 (2.00 g, 7.16 mmol) was dissolved in methanol/DCM (3:1, 40 mL), the mixture was cooled to −78° C., O.sub.2 was introduced for 5 minutes, then O.sub.3 was introduced until the solution became continuous blue, then O.sub.2 was introduced until the solution became colorless. Me.sub.2S (0.344 g, 7.16 mmol) was added into the reaction mixture, and the mixture was slowly warmed to r.t., then stirred at r.t. for 16 hours. The reaction mixture was concentrated under reduced pressure to deliver the compound BB-29-4 (yellow oil, 2.70 g, crude product), which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.37-7.28 (m, 5H), 5.18-5.12 (m, 2H), 4.45-4.34 (m, 1H), 3.47-3.45 (m, 2H), 3.42-3.40 (m, 2H), 3.39-3.30 (m, 3H), 3.09 (s, 1H).

    [0384] Step 4: Synthesis of Compound BB-29-5

    [0385] Compound BB-29-4 (0.500 g, 1.32 mmol) was dissolved in methanol (5 mL), then compound BB-12-4 (TCI, 0.199 g, 1.32 mmol) was added, the reaction mixture was stirred at r.t. for 16 hours. The reaction mixture was concentrated under reduced pressure to deliver the compound BB-29-5 (orange oil, 0.550 g, crude product), which was used for the next step directly.

    [0386] Step 5: Synthesis of Compound BB-29-6

    [0387] Compound BB-29-5 (0.450 g, 1.19 mmol) was suspended in formic acid (5 mL), NaBH.sub.3CN (0.150 g, 2.38 mmol) was added slowly, the reactants were stirred at r.t. for 20 hours under nitrogen gas atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was isolated and purified by HPLC (column: Phenomenex Gemini C18 150*25 mm*5 μm, eluting agent: MeCN, H.sub.2O) to deliver the target compound BB-29-6 (yellow oil, 0.040 g, yield 10%). MS (ESI) m/z: 301 [M+H].sup.+.

    [0388] Step 6: Synthesis of Compound BB-29

    [0389] Compound BB-29-6 (0.050 g, 0.157 mmol) was dissolved in methanol (5 mL), then Pd/C (0.010 g) was added, the reactants were stirred at r.t. for 1 hour under hydrogen gas atmosphere (15 Psi). The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to deliver the target compound BB-29 (yellow oil, 0.030 g, crude product). MS (ESI) m/z: 185 [M+H].sup.+.

    Reference 30: Fragment BB-30 and BB-30a

    [0390] ##STR00111##

    [0391] Synthetic Route:

    ##STR00112##

    [0392] Step 1: Synthesis of Compound BB-30 and BB-30a

    [0393] Compound BB-30-1 (0.200 g, 1.10 mmol) was dissolved in DCM (2 mL), then HCl/dioxane solution (1 mL, 4M) was added. The reaction mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated to deliver the target compound BB-30 and BB-30a (white solid, 0.130 g, yield 99%), which were not isolated and used for the next step directly. MS (ESI) m/z: 83 [M+H].sup.+. MS (ESI) m/z: 101 [M+H].sup.+.

    Reference 31: Fragment BB-31

    [0394] ##STR00113##

    [0395] Synthetic Route:

    ##STR00114##

    [0396] Step 1: Synthesis of Compound BB-31-3

    [0397] Compound BB-31-1 (0.5 g, 2.18 mmol) and BB-31-2 (0.239 g, 2.18 mmol) were dissolved in DMF (5 mL), then DIPEA (0.845 g, 6.54 mmol) and HATU (1.24 g, 3.27 mmol) were added. The reactants were stirred at 20° C. for 3 hours. H.sub.2O (10 mL) was added, the mixture was extracted with EA (20 mL×3). The combined organic phase was washed with H.sub.2O (20 mL×2), brine (20 mL), dried over sodium sulfate. The mixture was filtered and concentrated to deliver the target compound BB-31-3 (yellow oil, 0.6 g, yield 97%). MS (ESI) m/z: 307 [M+Na].sup.+.

    [0398] Step 2: Synthesis of Compound BB-31

    [0399] Compound BB-31-3 (0.1 g, 0.352 mmol) was dissolved in DCM (2 mL), then HCl/MeOH solution (1 mL, 4M) was added. The reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated to deliver the target compound BB-31 (white oil, 0.077 g, yield 99%). MS (ESI) m/z: 185 [M+H].sup.+.

    Reference 32: Fragment BB-32

    [0400] ##STR00115##

    [0401] Synthetic Route:

    ##STR00116## ##STR00117##

    [0402] Step 1: Synthesis of Compound BB-32-2

    [0403] Compound BB-32-1 (22 g, 134.9 mmol) and anhydrous K.sub.2CO.sub.3 (23 g, 161.9 mmol) were dissolved in anhydrous DMF (250 mL), then MeI (19 mL, 296.8 mmol) was added slowly. The reaction mixture was heated to 65° C. for 2 hours. Then the reaction mixture was diluted with H.sub.2O, extracted with PE/DCM 9:1 (3×200 mL). The organic phases were combined, washed with H.sub.2O (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to deliver the target compound BB-32-2 (yellow oil, 20 g, crude product), which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.50 (d, 1H), 7.30 (s, 1H), 6.90 (d, 1H). MS (ESI) m/z: 178.1 [M+H].sup.+.

    [0404] Step 2: Synthesis of Compound BB-32-4

    [0405] Ethyl O-methylsulphonylacetohydroxamate (50 g, 175.4 mmol) was dissolved in dioxane (48 mL, 561.3 mmol), the reaction mixture was cooled to 0° C. under nitrogen gas atmosphere. Then HClO.sub.4 (22 mL, 368.3 mmol) was added dropwise over 30 minutes, the reaction mixture was stirred at r.t. for 2 hours, 100 mL mixture of ice and water was added. The reaction mixture was extracted with DCM (3×200 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous K.sub.2CO.sub.3 solid, and concentrated at 30° C. to deliver 200 mL solution of compound BB-32-3 in DCM. MS (ESI) m/z: 216.1[M+H].sup.+. The compound BB-32-2 (20 g, 112.9 mmol) and the solution of compound BB-32-3 in DCM were mixed. The reaction mixture was stirred at r.t. for 15 hours, and concentrated to deliver the crude product, which was then dissolved in 200 mL MTBE and stirred for 10 minutes and the mixture was filtered to deliver compound BB-32-4 (light yellow solid, 15 g, yield 69%).

    [0406] Step 3: Synthesis of Compound BB-32-5

    [0407] Compound BB-32-4 (25 g, 129 mmol) and anhydrous K.sub.2CO.sub.3 (37.6 g, 272 mmol) were dissolved in DMF (250 mL), DMAD (28.9 mL, 229.3 mmol) was added dropwise slowly at 0° C. The reaction mixture was stirred at r.t. for 48 hours, then poured into 300 mL H.sub.2O, a large amount of solid was precipitated and filtered, the cake was preserved. The filtrate was extracted with PE/EA (3×300 mL), the organic phases were combined, washed with H.sub.2O (50 mL), saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product together with the cake obtained were purified by flash column instrument (eluting agent: DCM/PE=1/1) to deliver the target compound BB-32-5 (yellow solid, 4.8 g, yield 10%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.60 (s, 1H), 7.13 (s, 1H), 3.98-4.00 (s, 6H), 3.90-3.94 (s, 3H). MS (ESI) m/z: 333.0 [M+H].sup.+.

    [0408] Step 4: Synthesis of Compound BB-32-6

    [0409] Compound BB-32-5 (4.8 g, 14.5 mmol) was dissolved in a mixed solution of conc. sulphuric acid (25 mL, 450 mmol) and H.sub.2O (10 mL), the reaction mixture was heated to 120° C. and stirred for 16 hours. The reaction mixture was poured into 200 mL ice-water, a large amount of solid was precipitated and filtered. The filtrate was extracted with EA (100 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate directly, and concentrated to remove the solvent. The residue together with the cake obtained were dried to deliver the target compound BB-32-6 (yellow solid, 4.2 g, crude product), which was used for the next step directly without purification. MS (ESI) m/z: 247.0 [M+H].sup.+.

    [0410] Step 5: Synthesis of Compound BB-32-7

    [0411] Compound BB-32-6 (4.2 g, 17 mmol) was dissolved in methanol (50 mL), conc. sulphuric acid (5 mL) was added dropwise slowly, and the reaction was refluxed at 90° C. for 2 hours. The reaction mixture was concentrated, the residue was diluted with H.sub.2O (50 mL), then extracted with EA (3×50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was isolated and purified by fast chromatography column (eluting agent: methanol/DCM=1/10) to deliver the target compound BB-32-7 (yellow solid, 2.7 g, yield 61%). MS (ESI) m/z: 261.0 [M+H].sup.+.

    [0412] Step 6: Synthesis of Compound BB-32-8

    [0413] Compound BB-32-7 (1.2 g, 4.6 mmol) was dissolved in DCM (15 mL), DIPEA (1.19 g, 9.2 mmol) and N-(trifluoromethyl)benzenesulphonamide (3.2 g, 8.98 mmol) were added sequentially at r.t. The reaction mixture was stirred at r.t. for 3 hours, then N-(trifluoromethyl)benzenesulphonamide (1 g, 2.8 mmol) was further added, and concentrated to remove the solvent. The resulting solid was isolated and purified by fast chromatography column (eluting agent: PE/DCM=10/1) to deliver the target compound BB-32-8 (yellow solid, 1.2 g, yield 67%). .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.76 (s, 1H), 7.35 (s, 1H), 7.26-7.28 (m, 1H).

    [0414] Step 7: Synthesis of Compound BB-32-9

    [0415] Compound BB-32-8 (0.5 g, 1.27 mmol) was dissolved in dioxane (5 mL), cyclopropylboronic acid (0.219 g, 2.54 mmol), K.sub.3PO.sub.4 (0.812 g, 3.82 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.05 g, 0.06 mmol) were added sequentially. The reaction mixture was stirred at 90° C. and refluxed for 3 hours under nitrogen gas atmosphere, then cooled to r.t., filtered to remove the insolubles. The filtrate was poured into a mixture of EA (50 mL) and H.sub.2O (20 mL) and stationarily partitioned, the organic phase was dried over anhydrous sodium sulfate, and concentrated. The resulting solid was isolated and purified by preparative chromatography plate (developing agent: PE/EA=5/1) to deliver the target compound BB-32-9 (yellow oil, 0.041 g, yield 11%). MS (ESI) m/z: 285.0 [M+H].sup.+.

    [0416] Step 8: Synthesis of Compound BB-32-10

    [0417] Compound BB-32-9 (0.04 g, 0.14 mmol) was dissolved in DMF (0.5 mL), NCS (0.028 g, 0.21 mmol) was added. The reaction was stirred at 60° C. for 1 hour, then diluted with H.sub.2O, extracted with PE/DCM (3×20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was isolated and purified by preparative chromatography plate (eluting agent: PE/EA=10/1) to deliver the target compound BB-32-10 (yellow oil, 0.046 g, yield 100%). MS (ESI) m/z: 319.0 [M+H].sup.+.

    [0418] Step 9: Synthesis of Compound BB-32

    [0419] Compound BB-32-10 (0.046 g, 0.15 mmol) was dissolved in a mixed solution of methanol (2 mL) and H.sub.2O (0.4 mL), lithium hydroxide monohydrate (0.037 g, 0.75 mmol) was added. The reaction mixture was stirred at r.t. overnight, concentrated to remove methanol, then pH of the reaction mixture was adjusted to 1 with 1M dilute hydrochloric acid, the mixture was extracted with DCM (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to deliver the crude product of the target compound BB-32 (gray solid, 0.028 g, yield 62%), which was used for the next step directly without purification. MS (ESI) m/z: 305.0 [M+H].sup.+.

    References 33 to 41: Fragment BB-33 to 41

    [0420] The reference examples in the below table were synthesized according to the steps 1-5 in reference 20 (fragment BB-20).

    TABLE-US-00001 Examples Structure MS m/z Fragment 33 [00118]embedded image 144 [M + H].sup.+ BB-33 34 [00119]embedded image 172 [M + H].sup.+ BB-34 35 [00120]embedded image 166 [M + H].sup.+ BB-35 36 [00121]embedded image 200 [M + H].sup.+ BB-36 37 [00122]embedded image 220 [M + H].sup.+ BB-37 38 [00123]embedded image 192 [M + H].sup.+ BB-38 39 [00124]embedded image 158 [M + H].sup.+ BB-39 40 [00125]embedded image 184 [M + H].sup.+ BB-40 41 [00126]embedded image 142 [M + H].sup.+ BB-41

    Embodiment 1: Compound YD_0346

    [0421] ##STR00127##

    [0422] Synthetic Route:

    ##STR00128##

    [0423] Step 1: Synthesis of Compound YD_0346_2

    [0424] Compound BB-9 (0.035 g, 0.084 mmol) and compound YD_0346_1 (0.019 g, 0.093 mmol) were dissolved in DMF (2 mL), then HATU (0.048 g, 0.126 mmol) and DIPEA (0.032 g, 0.253 mmol) were added, the reaction mixture was stirred at r.t. for 3 hours. After the reaction was complete, EA was added, the organic phase was washed with H.sub.2O and saturated brine, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure to remove the solvent thereby delivering the crude product, the crude was isolated and purified by thin silica gel plate (developing agent: EA/PE=1/2) to deliver the target compound YD_0346_2 (white solid, 0.040 g, yield 83%). MS (ESI) m/z: 570[M+H].sup.+, 541 [M−56+H].sup.+.

    [0425] Step 2: Synthesis of Compound YD_0346

    [0426] Compound YD_0346_2 was dissolved in THF (1 mL), then HCl/1,4-dioxane (4M, 2 mL) was added, the reaction mixture was stirred at 20° C. for 2 hours. Then the mixture was concentrated under reduced pressure to remove the solvent, the residue was isolated and purified by preparative HPLC (column: Gemini 150*25 mm*5 m, eluting agent: MeCN+0.075% HCl, H.sub.2O+0.075% HCl), followed by frozen drying to deliver the target compound YD_0346 (white solid, 0.0155 g, yield 43.6%). .sup.1H NMR (400 MHz, MeOD)=7.68-7.60 (m, 1H), 7.60-7.54 (m, 1H), 4.74-4.54 (m, 2H), 4.33 (d, J=8.0 Hz, 2H), 4.23-4.12 (m, 1H), 4.00 (d, J=4.0 Hz, 2H), 3.86-3.78 (m, 1H), 3.76-3.68 (m, 1H), 3.64-3.35 (m, 1H), 3.20-2.99 (m, 1H), 2.80-2.61 (m, 1H), 2.25-2.14 (m, 1H), 2.06-1.66 (m, 4H), 1.19-1.07 (m, 2H), 0.89-0.77 (m, 2H). MS (ESI) m/z: 470 [M+H].sup.+.

    [0427] The embodiments in the table below were synthesized according to the steps 1-2 in embodiment 1 (compound YD_0346)

    TABLE-US-00002 Embo- Com- diment Structure Fragment 1 Fragment 2 MS m/z pound 2 [00129]embedded image [00130]embedded image BB-9 [00131]embedded image 443 [M + H].sup.+ YD_0273 3 [00132]embedded image [00133]embedded image BB-9 [00134]embedded image 471 [M + H].sup.+ YD_0302 4 [00135]embedded image [00136]embedded image BB-9 [00137]embedded image 471 [M + H].sup.+ YD_0303 5 [00138]embedded image [00139]embedded image BB-9 [00140]embedded image 457 [M + H].sup.+ YD_0304 6 [00141]embedded image [00142]embedded image BB-9 [00143]embedded image 498 [M + H].sup.+ YD_0305 7 [00144]embedded image [00145]embedded image BB-9 [00146]embedded image 499 [M + H].sup.+ YD_0311 8 [00147]embedded image [00148]embedded image BB-9 [00149]embedded image 455 [M + H].sup.+ YD_0313 9 [00150]embedded image [00151]embedded image BB-9a [00152]embedded image BB-31-2 485 [M + H].sup.+ YD_0318 10 [00153]embedded image [00154]embedded image BB-9 [00155]embedded image 498 [M + H].sup.+ YD_0322 11 [00156]embedded image [00157]embedded image BB-9 [00158]embedded image 499 [M + H].sup.+ YD_0323 12 [00159]embedded image [00160]embedded image BB-9 [00161]embedded image 481 [M + H].sup.+ YD_0324 13 [00162]embedded image [00163]embedded image BB-9 [00164]embedded image 498 [M + H].sup.+ YD_0326 14 [00165]embedded image [00166]embedded image BB-9 [00167]embedded image 485 [M + H].sup.+ YD_0340 15 [00168]embedded image [00169]embedded image BB-9 [00170]embedded image 473 [M + H].sup.+ YD_0342 16 [00171]embedded image [00172]embedded image BB-9 [00173]embedded image BB-22 498 [M + H].sup.+ YD_0343 17 [00174]embedded image [00175]embedded image BB-9 [00176]embedded image BB-24 499 [M + H].sup.+ YD_0344 18 [00177]embedded image [00178]embedded image BB-9 [00179]embedded image BB-23 485 [M + H].sup.+ YD_0345 19 [00180]embedded image [00181]embedded image BB-9 [00182]embedded image BB-25 512 [M + H].sup.+ YD_0348 20 [00183]embedded image [00184]embedded image BB-9 [00185]embedded image 491 [M + H].sup.+ YD_0349 21 [00186]embedded image [00187]embedded image BB-9 [00188]embedded image 469 [M + H].sup.+ YD_0350 22 [00189]embedded image [00190]embedded image BB-9 [00191]embedded image BB-30 480 [M + H].sup.+ YD_0352 23 [00192]embedded image [00193]embedded image BB-9 [00194]embedded image BB-30a 498 [M + H].sup.+ YD_0353 24 [00195]embedded image [00196]embedded image BB-9 [00197]embedded image BB-26 485 [M + H].sup.+ YD_0355

    Embodiment 25: YD_0327

    [0428] ##STR00198##

    [0429] Synthetic Route:

    ##STR00199##

    [0430] Step 1: Synthesis of Compound YD_0327-2

    [0431] Compound BB-9 (0.100 g, 0.241 mmol), compound YD_0327-1 (0.046 g, 0.361 mmol) were dissolved in DMF (1 mL), DIPEA (0.093 g, 0.722 mmol) and HATU (0.137 g, 0.361 mmol) were added, the reaction mixture was stirred at 25° C. for 5 hours, H.sub.2O (2 mL) was added. The solid was filtered out and collected, the cake was purified by thin-layer chromatography plate (developing agent, EA/PE=1/2) to deliver compound YD_0327-2 (yellow solid, 0.040 g, yield 31.60%). MS (ESI) m/z: 527 [M+H].sup.+.

    [0432] Step 2: Synthesis of Compound YD_0327

    [0433] Compound YD_0327-2 (0.040 g, 0.076 mmol) was dissolved in DMF (1 mL), NaH (0.006 g, 0.152 mmol, 60%) was added, the reaction mixture was stirred at 25° C. for 10 minutes, MeI (0.054 g, 0.380 mmol) was added. The reaction mixture was stirred at 25° C. for 2 hours, then quenched with H.sub.2O (0.5 mL), and isolated and purified by preparative HPLC (column: Phenomenex Gemini C18 150*25 mm*5 μm, eluting agent: MeCN+0.05% NH.sub.3.H.sub.2O, H.sub.2O+0.05% NH.sub.3.H.sub.2O) to deliver the target compound YD_0327 (yellow solid, 0.004 g, yield 9.74%). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.19 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 4.51 (d, J=13.2 Hz, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.80 (s, 3H), 3.40-3.30 (m, 1H), 3.15-3.10 (m, 1H), 2.70-2.65 (m, 1H), 2.15-2.05 (m, 3H), 1.95-1.80 (m, 2H), 1.10-1.05 (m, 2H), 0.85-0.75 (m, 2H). MS (ESI) m/z: 540 [M+H].sup.+.

    Embodiment 26: YD 0329

    [0434] ##STR00200##

    [0435] Step 1: Synthesis of Compound YD_0329

    [0436] Compound YD_0329 was synthesized according to the steps of 1-2 in embodiment 25 (compound YD_0327), except for that the starting materials were compound BB-9 and 2-amino-5-fluoropyridine. .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.17 (s, 1H), 8.10-8.05 (m, 1H), 7.80-7.75 (m, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 4.52 (d, J=13.2 Hz, 1H), 3.92 (d, J=13.2 Hz, 1H), 3.83 (s, 3H), 3.40-3.30 (m, 1H), 3.15-3.10 (m, 1H), 2.70-2.65 (m, 1H), 2.15-2.05 (m, 3H), 1.95-1.80 (m, 2H), 1.10-1.05 (m, 2H), 0.85-0.75 (m, 2H). MS (ESI) m/z: 524 [M+H].sup.+.

    Embodiment 27: YD_0321

    [0437] ##STR00201##

    [0438] Synthetic Route:

    ##STR00202##

    [0439] Step 1: Synthesis of Compound YD_0321

    [0440] Compound YD_0322 (0.065 g, 0.130 mmol) was added to 2 mL MeOH, then aqueous formaldehyde solution (0.008 g, 0.266 mmol), formic acid (22 mg, 0.458 mmol) were added. The reaction mixture was stirred at 70° C. for 24 hours. The reaction mixture was evaporated to dry under reduced pressure, then isolated by preparative HPLC (column: Phenomenex Gemini C18 150*25 mm*5 μm, eluting agent: MeCN+0.05% NH.sub.3.H.sub.2O, H.sub.2O+0.05% NH.sub.3.H.sub.2O) to deliver compound YD_0321 (0.008 g, yield 12%). MS-ESI: m/z: 512 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.49 (m, 1H), 7.42 (m, 1H), 4.61-4.75 (m, 2H), 4.03-4.09 (m, 1H), 3.45-3.61 (m, 2H), 3.20-3.27 (m, 1H), 2.91-3.09 (m, 2H), 2.68-2.83 (m, 3H), 2.26 (s, 3H), 2.01-2.09 (m, 2H), 1.86-2.04 (m, 3H), 1.39-1.40 (m, 1H), 1.22-1.26 (m, 2H), 1.05-1.10 (m, 2H), 0.77-0.79 (m, 2H).

    Embodiment 28: YD_0325

    [0441] ##STR00203##

    [0442] Step 1: Synthesis of Compound YD_0325

    [0443] Compound YD_0325 was synthesized according to the step 1 in embodiment 27 (compound YD_0321), except for that the starting material was compound YD_0326. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.62 (m, 1H), 7.49 (m, 1H), 4.55-4.63 (m, 1H), 4.31-4.46 (m, 1H), 4.02-4.11 (m, 1H), 3.58-3.80 (m, 1H), 3.12-3.43 (m, 2H), 2.79-3.10 (m, 4H), 2.49-2.56 (m, 1H), 2.31 (s, 3H), 2.01-2.11 (m, 2H), 1.72-1.96 (m, 4H), 1.12-1.21 (m, 2H), 0.77-0.79 (m, 2H). MS-ESI: m/z 512 [M+H].sup.+.

    Embodiment 29: YD_0351

    [0444] ##STR00204##

    [0445] Synthetic Route:

    ##STR00205##

    [0446] Step 1: Synthesis of Compound YD_0351-2

    [0447] Compound YD_0351-1 (0.090 g, 0.449 mmol) was dissolved in MeOH (5 mL), then conc. sulfuric acid (0.008 g, 0.081 mmol) was added, the reaction mixture was stirred at reflux for 5 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure to deliver the crude product YD_0351-2 (yellow oil, 0.090 g, crude product) which was used for the next step directly. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.19-5.14 (m, 1H), 4.18-4.12 (m, 1H), 3.99-3.94 (m, 1H), 3.71 (s, 3H), 2.86-2.82 (m, 1H), 2.75-2.69 (m, 1H).

    [0448] Step 2: Synthesis of Compound YD_0351-3

    [0449] Compound YD_0351-2 (0.031 g, 0.144 mmol) was dissolved in DMF (2 mL), then compound BB-9 (0.060 g, 0.144 mmol), DIPEA (0.093 g, 0.722 mmol) and HATU (0.066 g, 0.173 mmol) were added, the reaction mixture was stirred at r.t. for 6 hours. After the reaction was complete, H.sub.2O (5 mL) was added, the mixture was extracted with EA (10 mL×2). The organic phases were combined and dried over sodium sulfate, filtered, and concentrated to deliver the crude product YD_0351-3 (yellow oil, 0.130 g, crude product). MS (ESI) m/z: 513 [M+H].sup.+.

    [0450] Step 3: Synthesis of Compound YD_0351

    [0451] Compound YD_0351-3 (0.130 g, 0.253 mmol) was dissolved in MeOH (3 mL) and H.sub.2O (1 mL), then lithium hydroxide monohydrate (0.032 g, 0.760 mmol) was added, the reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, the solvent was removed by concentration under reduced pressure, the resulting residue was dissolved in H.sub.2O again and pH was adjusted to about 2-3 with 2N aqueous hydrochloric acid solution. The solid was collected to deliver the crude product, which was isolated and purified by preparative HPLC (column: Synergy 150*30 mm, eluting agent: MeCN+0.075% TFA, H.sub.2O+0.075% TFA) to deliver YD_0351 (white solid, 0.030 g, yield 24%). .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.64 (s, 1H), 7.56 (s, 1H), 5.15-5.11 (m, 0.5H), 4.71-4.75 (m, 0.5H), 4.61-4.57 (m, 1H), 4.36-4.29 (m, 1H), 4.01-3.96 (m, 2H), 3.39-3.34 (m, 0.5H), 3.14-3.03 (m, 0.5H), 3.02-2.85 (m, 0.5H), 2.75-2.73 (m, 2H), 2.59-2.52 (m, 0.5H), 2.21-2.16 (m, 2H), 1.83-1.80 (m, 4H), 1.14-1.09 (m, 2H), 0.84-0.82 (m, 2H). MS (ESI) m/z: 499 [M+H].sup.+.

    Embodiment 30: YD_0019

    [0452] ##STR00206##

    [0453] Synthetic Route:

    ##STR00207##

    [0454] Step 1: Synthesis of Compound YD_0019

    [0455] Compound BB-1 (0.035 g, 0.128 mmol) was dissolved in DMF (2 mL), then compound BB-14 (0.027 g, 0.128 mmol), DIPEA (0.050 g, 0.386 mmol) and HATU (0.063 g, 0.167 mmol) were added. The reaction mixture was stirred at r.t. for 2 hours. After the reaction was complete, EA (100 mL) was added, then the mixture was washed with brine, dried over anhydrous sodium sulfate, and concentrated to deliver the crude product, which was isolated by thick silica gel plate (developing agent: PE/EA=1/1) to deliver the target compound YD_0019 (white solid, 0.050 g, yield 84%). MS (ESI) m/z: 462 [M+H].sup.+. .sup.1H NMR (400 MHz, MeOD): δ 7.87 (s, 1H), 7.62 (s, 1H), 7.55 (s, 1H), 3.15-3.11 (m, 1H), 2.52 (s, 3H), 2.13-2.26 (m, 12H), 1.36 (d, J=7.2 Hz, 6H).

    [0456] The embodiments in the table below were synthesized according to the step 1 in embodiment 30 (compound YD_0019)

    TABLE-US-00003 Embodi- Com- ments Structure Fragment 1 Fragment 2 MS m/z pound 31 [00208]embedded image [00209]embedded image BB-1 [00210]embedded image BB-10 453 [M + H].sup.+ YD_0044 32 [00211]embedded image [00212]embedded image BB-2 [00213]embedded image BB-14 494 [M + H].sup.+ YD_0056 33 [00214]embedded image [00215]embedded image BB-4 [00216]embedded image BB-14 540 [M + H].sup.+ YD_0057 34 [00217]embedded image [00218]embedded image BB-5 [00219]embedded image BB-14 474 [M + H].sup.+ YD_0058 35 [00220]embedded image [00221]embedded image BB-3 [00222]embedded image BB-14 496 [M + H].sup.+ YD_0059 36 [00223]embedded image [00224]embedded image BB-3a [00225]embedded image BB-14 496 [M + H].sup.+ YD_0060 37 [00226]embedded image [00227]embedded image BB-2 [00228]embedded image BB-13 480 [M + H].sup.+ YD_0122 38 [00229]embedded image YD_0214 [00230]embedded image BB-2 [00231]embedded image BB-17 458 [M + H].sup.+ YD_0214 39 [00232]embedded image [00233]embedded image BB-3 [00234]embedded image BB-17 460 [M + H].sup.+ YD_0215 40 [00235]embedded image [00236]embedded image BB-3a [00237]embedded image BB-17 460 [M + H].sup.+ YD_0216 41 [00238]embedded image [00239]embedded image BB-8 [00240]embedded image BB-11 472 [M + H].sup.+ YD_0219 42 [00241]embedded image [00242]embedded image BB-7 [00243]embedded image BB-17 408 [M + H].sup.+ YD_0245 43 [00244]embedded image [00245]embedded image BB-6 [00246]embedded image BB-17 449 [M + H].sup.+ YD_0250 44 [00247]embedded image [00248]embedded image BB-2 [00249]embedded image BB-15 453 [M + H].sup.+ YD_0253 45 [00250]embedded image [00251]embedded image BB-2 [00252]embedded image BB-12 485 [M + H].sup.+ YD_0272 46 [00253]embedded image [00254]embedded image BB-8 [00255]embedded image BB-17 440 [M + H].sup.+ YD_0278 47 [00256]embedded image [00257]embedded image BB-3 [00258]embedded image BB-18 472 [M + H].sup.+ YD_0279 48 [00259]embedded image [00260]embedded image BB-2 [00261]embedded image BB-16 495 [M + H].sup.+ YD_0280 49 [00262]embedded image [00263]embedded image BB-2 [00264]embedded image BB-19 460 [M + H].sup.+ YD_0312 50 [00265]embedded image [00266]embedded image BB-2 [00267]embedded image BB-27 457 [M + H].sup.+ YD_0317 51 [00268]embedded image [00269]embedded image BB-2 [00270]embedded image BB-28 469 [M + H].sup.+ YD_0330 52 [00271]embedded image [00272]embedded image BB-2 [00273]embedded image BB-29 471 [M + H].sup.+ YD_0331 53 [00274]embedded image [00275]embedded image BB-21 [00276]embedded image BB-20 456 [M + H].sup.+ YA_0338 54 [00277]embedded image [00278]embedded image BB-6 [00279]embedded image BB-31 462 [M + H].sup.+ YD_0356 55 [00280]embedded image [00281]embedded image BB-2 [00282]embedded image BB-20 456 [M + H].sup.+ YD_0357 56 [00283]embedded image [00284]embedded image BB-21 [00285]embedded image BB-35 452 [M + H].sup.+ YA_0358 57 [00286]embedded image [00287]embedded image BB-21 [00288]embedded image BB-34 458 [M + H].sup.+ YA_0359 58 [00289]embedded image [00290]embedded image BB-21 [00291]embedded image BB-33 430 [M + H].sup.+ YA_0360 59 [00292]embedded image [00293]embedded image BB-21 [00294]embedded image BB-40 470 [M + H].sup.+ YA_0361 60 [00295]embedded image [00296]embedded image BB-21 [00297]embedded image BB-41 428 [M + H].sup.+ YA_0362 61 [00298]embedded image [00299]embedded image BB-21 [00300]embedded image BB-36 486 [M + H].sup.+ YA_0363 62 [00301]embedded image [00302]embedded image BB-2 [00303]embedded image BB-36 486 [M + H].sup.+ YD_0365 63 [00304]embedded image [00305]embedded image BB-21 [00306]embedded image BB-37 506 [M + H].sup.+ YA_0366 64 [00307]embedded image [00308]embedded image BB-21 [00309]embedded image BB-38 478 [M + H].sup.+ YA_0367 65 [00310]embedded image [00311]embedded image BB-21 [00312]embedded image BB-39 444 [M + H].sup.+ YA_0368 66 [00313]embedded image [00314]embedded image BB-32 [00315]embedded image BB-20 456 [M + H].sup.+ YH_0369 67 [00316]embedded image [00317]embedded image BB-32 [00318]embedded image BB-33 430 [M + H].sup.+ YH_0373 68 [00319]embedded image [00320]embedded image BB-2 [00321]embedded image BB-33 430 [M + H].sup.+ YD_0374

    [0457] Experiment 1: Assay In Vitro

    [0458] Experimental Objective:

    [0459] The EC.sub.50 and CC.sub.50 values of anti-HCV compounds were determined by HCV genotype 1a (HCV-1a) and 1b (HCV-1b) stable transfected replication (replicon) cells. The source of genotype 1a replicon is H77 clones containing K1691R, K2040R and S2204I adaptive mutations. The source of genotype 1b replicon is Con1 clones containing E1202G, T1280I and K1846T adaptive mutations.

    [0460] Background Introduction:

    [0461] HCV 1a (HCV-1a) and 1b (HCV-1b) gene subtype replicon system contains the related HCV gene subtype non-structural protein gene, G418 resistance gene NEO and luciferase gene, which results in that HCV related protein and luciferase can be stably expressed in cells. By detecting the level of expression of luciferase gene, the level of HCV replication can be determined. Therefore, the system is used as a model for screening the activity of anti-HCV compound in vitro.

    [0462] Experimental Materials:

    [0463] HCV replicon cell lines: HCV-1a and HCV-1b cells

    [0464] Cell culture medium: DMEM (Invitrogen, Cat. #11960077) medium, add 10% fetal bovine serum (FBS, Sigma, Cat. #12003C) and 1% penicillin-streptomycin (penicillin 5000 IU/mL, streptomycin 10 mg/mL, Hyclone, Cat. #SV30010)

    [0465] Trypsin (Invitrogen, Cat. #25200072)

    [0466] PBS (Invitrogen, Cat. #10010023)

    [0467] Trypan blue (Invitrogen, Cat. #15250061)

    [0468] Cell Titer-fluor (Promega, Cat. #G6082)

    [0469] Bright-Glo (Promega, Cat. #E2650)

    [0470] CO.sub.2 incubator, Thermo 240 I

    [0471] Multidrop, Thermo

    [0472] POD 810 Plate Assembler, Labcyte

    [0473] Scepter Handheld Automated Cell Counter, Millipore

    [0474] Microplate Spectrophotometer, Molecular Device.

    [0475] Experimental Procedure and Method:

    [0476] a) Preparation, Dilution and Addition of Compound Solution:

    [0477] The compound powder was dissolved in 100% DMSO. Then the compound was diluted 5 times with 6 points, and added into the cell plate with Echo liquid handler. Ensure the final concentration of DMSO was 0.5%. Each compound was tested in duplicate.

    [0478] b) Cell Culture (HCV-1a or HCV-1b Replicon Cell):

    [0479] 1) Absorbing the culture supernatant of the cell culture and washing the cells with 10 mL PBS.

    [0480] 2) Adding prewarmed trypsin to the washed cell culture flasks, rotating culture bottle to make the bottom of the culture bottle uniformly covered by trypsin, then placed into 37° C., 5% CO.sub.2 incubator to digest.

    [0481] 3) Suspending cells in each T150 tissue culture flask with 10-15 mL culture medium, absorbing 0.1 mL liquid and diluting 2 times by trypan blue solution as counted.

    [0482] 4) Diluting cells to 8×10.sup.4 cells/mL with the culture medium, adding the diluted cells into the compound-containing 96-well plate (Greiner, Cat. #655090) (100 μL/well, 8000 cells/well) with automatic liquid separator (Thermo Scientific). Then place into a 37° C., 5% CO.sub.2 incubator for 3 days. Cell control well: no compound, only containing 0.5% DMSO.

    [0483] 5) Adding fluorescence substrate Cell Titer-fluor to the cell well, after incubation for 30 minutes, detecting the signal by microplate reader Envison (Ex at 405 nm and read at 515 nm). The effect of the compounds on the cytotoxicity of HCV replicon cells was analyzed according to the fluorescence data, which was used to calculate the CC.sub.50 values.

    [0484] 6) Then adding luciferase substrate Bright-Glo, after incubation for 5 minutes, detecting the luciferase activity by microplate reader Envison (wavelength>700 nm); analyzing the anti-HCV inhibitory activity of the compounds according to luminescence data, which was used to calculate EC.sub.50 values.

    [0485] c) Data Processing and Analysis:

    [0486] The EC.sub.50 or CC.sub.50 values were obtained by nonlinear fitting regression on inhibition percentage (inh %) data with GraphPad Prism software.

    [0487] The results of the experiments were shown in Table 1:

    TABLE-US-00004 TABLE 1 Experimental results of EC.sub.50/CC.sub.50 of HCV replicon cells Embodiment Compound ID EC.sub.50(1b) EC.sub.50(1a) CC.sub.50 1 YD_0346 B B >3000 2 YD_0273 A A >3000 3 YD_0302 C B >3000 4 YD_0303 A A >3000 5 YD_0304 A B >3000 6 YD_0305 C B >3000 7 YD_0311 B B >3000 8 YD_0313 A A >3000 9 YD_0318 C B >3000 10 YD_0322 B B >3000 11 YD_0323 B B >3000 12 YD_0324 A A >3000 13 YD_0326 C B >3000 14 YD_0340 B B >3000 15 YD_0342 A A >3000 16 YD_0343 C B >3000 17 YD_0344 C B >3000 18 YD_0345 C B >3000 19 YD_0348 C B >3000 20 YD_0349 B B >3000 21 YD_0350 B B >3000 22 YD_0352 C B >3000 23 YD_0353 C B >3000 24 YD_0355 C B >3000 25 YD_0327 C B >3000 26 YD_0329 B B >3000 27 YD_0321 C B >3000 28 YD_0325 C B >3000 29 YD_0351 C B >3000 30 YD_0019 B N/A >3000 31 YD_0044 A N/A >3000 32 YD_0056 C N/A >3000 33 YD_0057 B N/A >3000 34 YD_0058 B N/A >3000 35 YD_0059 B A >3000 36 YD_0060 B N/A >3000 37 YD_0122 B A >3000 38 YD_0214 A A >3000 39 YD_0215 A A >3000 40 YD_0216 A A >3000 41 YD_0219 A A >3000 42 YD_0245 A A >3000 43 YD_0250 A A >3000 44 YD_0253 A B >3000 45 YD_0272 B B >3000 46 YD_0278 A A >3000 47 YD_0279 A A >3000 48 YD_0280 B B >3000 49 YD_0312 B B >3000 50 YD_0317 C B >3000 51 YD_0330 A B >3000 52 YD_0331 A A >3000 53 YA_0338 A A >3000 54 YD_0356 A A >3000 55 YD_0357 A A >3000 56 YA_0358 B B >3000 57 YA_0359 N/A N/A >3000 58 YA_0360 A A >3000 59 YA_0361 N/A N/A >3000 60 YA_0362 N/A N/A >3000 61 YA_0363 A A >3000 62 YD_0365 A A >3000 63 YA_0366 A A >3000 64 YA_0367 A A >3000 65 YA_0368 B A >3000 66 YH_0369 C B >3000 67 YH_0373 A A >3000 68 YD_0374 A A >3000 Note: A (0.1 nM-100 nM); B (100.01 nM-1000 nM); C (1000.01 nM-5000 nM). Conclusion: the compounds of the present invention have excellent anti-HCV activity in vitro.