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AZAHETEROARYL COMPOUND AND APPLICATION THEREOF

20230002414 · 2023-01-05

    Inventors

    Cpc classification

    International classification

    Abstract

    Disclosed in the present disclosure are an azaheteroaryl compound, a pharmaceutically acceptable salt thereof, and a solvate thereof. The present disclosure also provides a method for preparing said compound, a composition containing said compound, and a use of said compound in the preparation of a drug for treating a disease or disorder related to the mechanism of action of an EED protein and/or a PRC2 protein complex. (Formula 1)

    ##STR00001##

    Claims

    1. A compound as shown in formula (I), a pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds: ##STR00596## wherein A is ##STR00597## R.sup.01, R.sup.02 and R.sup.03 are each independently hydrogen or halogen; n is 0 or 1; m is 1 or 2; X is C or N; R.sup.1 is ##STR00598## X.sup.1 and X.sup.5 are independently C or N; X.sup.2 is independently N or CR.sup.2; X.sup.3 is independently N or CR.sup.3; X.sup.4 is independently N or CR.sup.4; X.sup.6 is independently CR.sup.6, N, NR.sup.6, O or S; X.sup.7 is independently CR.sup.7, N, O or S; X.sup.8 is independently CR.sup.8, N, O or S; X.sup.9 is independently N or CR.sup.9; R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are independently H, halogen, —CN, R.sup.5-substituted or unsubstituted amino, R.sup.5-substituted or unsubstituted hydroxyl, R.sup.5-substituted or unsubstituted C.sub.1-4 alkyl, R.sup.5-substituted or unsubstituted C.sub.1-4 alkoxy, R.sup.5-substituted or unsubstituted C.sub.3-6 cycloalkyl, R.sup.5-substituted or unsubstituted C.sub.1-4 haloalkyl, —(C═O)R.sup.16, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, —SO.sub.2R.sup.16, —SO.sub.2NR.sup.16R.sup.17, —POR.sup.16R.sup.17, R.sup.5-substituted or unsubstituted C.sub.3-6 heterocycloalkyl, or C.sub.3-6 heterospirocycloalkyl; R.sup.5 is independently C.sub.1-4 alkoxy, —CN, C.sub.1-4 alkoxy substituted with 1, 2 or 3 hydroxyl groups, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, —NR.sup.a1R.sup.b1, halogen, hydroxyl, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.1-4 alkyl groups, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.3-6 heterocycloalkyl groups, C.sub.6-18 aryl, C.sub.1-15 heteroaryl, —C(═O)NR.sup.16aR.sup.17a, —CO.sub.2R.sup.16a, —O(C═O)R.sup.16a, —NH(C═O)R.sup.16a, or —(C═O)R.sup.16a; R.sup.a1 and R.sup.b1 are independently H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 —NR.sup.a2R.sup.b2 groups, C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups, or C.sub.1-4 alkoxy substituted with 1, 2 or 3 hydroxyl groups; R.sup.a2 and R.sup.b2 are independently H or C.sub.1-4 alkyl; each R.sup.16a and each R.sup.17a are independently H, C.sub.1-4 alkyl, or C.sub.3-6 heterocycloalkyl; the number of R.sup.5 is 1, 2, 3, 4, 5 or 6; R.sup.16 and R.sup.17 are independently H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 heterocycloalkyl; the heteroatom in the C.sub.3-6 heterocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.3-6 heterospirocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.1-15 heteroaryl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3, 4, 5 or 6.

    2. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein n is 1; or, X is N; or, A is ##STR00599## the moiety ##STR00600## is ##STR00601## or, the moiety ##STR00602## is ##STR00603## wherein X.sup.6 is independently CR.sup.6 or N; X.sup.7 is independently CR.sup.7 or N; or, the moiety ##STR00604## is ##STR00605## or, the moiety ##STR00606## is ##STR00607## or, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are independently H, halogen, —CN, —OH, —NR.sup.aR.sup.b, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5 groups, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkyl substituted with 1, 2 or 3 R.sup.5 groups, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy substituted with 1, 2 or 3 R.sup.5 groups, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 R.sup.5 groups, —(C═O)R.sup.16, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, —SO.sub.2R.sup.16, —SO.sub.2NR.sup.16R.sup.17, —POR.sup.16R.sup.17, or C.sub.3-6 heterospirocycloalkyl, wherein R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; R.sup.16 and R.sup.17 are independently H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 heterocycloalkyl; each R.sup.5 is independently —OH, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy substituted with 1, 2 or 3 hydroxyl groups, —NR.sup.a1R.sup.b1, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.1-4 alkyl groups, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.3-6 heterocycloalkyl groups, C.sub.6-18 aryl, C.sub.1-15 heteroaryl, —C(═O)NR.sup.16aR.sup.17a, —CO.sub.2R.sup.16a, —O(C═O)R.sup.16a, —NH(C═O)R.sup.16a, or —(C═O)R.sup.16a; R.sup.a1 and R.sup.b1 are independently H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 —NR.sup.a2R.sup.b2 groups, or C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups; R.sup.a2 and R.sup.b2 are independently H or C.sub.1-4 alkyl; each R.sup.16a and R.sup.17a are independently H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or C.sub.3-6 heterocycloalkyl; the heteroatom in the C.sub.3-6 heterocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.3-6 heterospirocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.1-15 heteroaryl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3, 4, 5 or 6; or, the isotope in the isotopically-labeled compound is selected from .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18F, .sup.31P, .sup.32P, .sup.35S, .sup.36Cl and .sup.125I.

    3. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein R.sup.1 is any one of the following structures: ##STR00608## ##STR00609## or, R.sup.2 is H, halogen, —CN, —NR.sup.aR.sup.b, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5 groups, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 R.sup.5 groups, C.sub.3-6 heterospirocycloalkyl, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, or —NR.sup.aR.sup.b; each R.sup.16 and R.sup.17 are independently H or C.sub.1-4 alkyl; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; each R.sup.5 is independently —OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy substituted with 1, 2 or 3 hydroxyl groups, —NR.sup.a1R.sup.b1, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.1-4 alkyl groups, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.3-6 heterocycloalkyl groups, or C.sub.1-15 heteroaryl; R.sup.a1 and R.sup.b1 are independently H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 —NR.sup.a2R.sup.b2 groups, or C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups; R.sup.a2 and R.sup.b2 are independently H or C.sub.1-4 alkyl; the heteroatom in the C.sub.3-6 heterocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.3-6 heterospirocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.1-15 heteroaryl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3, 4, 5 or 6; or, R.sup.3 is H, halogen, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, or —C(═O)NR.sup.16R.sup.17; or, R.sup.4 is H, halogen, or C.sub.1-4 alkyl; or, R.sup.6 is H, halogen, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5 groups, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, —(C═O)R.sup.16, SO.sub.2R.sup.16, or —POR.sup.16R.sup.17; each R.sup.16 and each R.sup.17 are independently H, C.sub.1-4 alkyl, or C.sub.3-6 heterocycloalkyl; each R.sup.5 is independently —OH, —CN, —NR.sup.a1R.sup.b1, C.sub.6-18 aryl, —C(═O)NR.sup.16aR.sup.17a, —CO.sub.2R.sup.16a, —O(C═O)R.sup.6a, —NH(C═O)R.sup.16a, or —(C═O)R.sup.16a; R.sup.a1 and R.sup.b1 are independently H or C.sub.1-4 alkyl; each R.sup.16a and R.sup.17a are independently H, C.sub.1-4 alkyl or C.sub.3-6 heterocycloalkyl; or, R.sup.7 is H, —OH, —NR.sup.aR.sup.b, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups, C.sub.1-4 haloalkyl, —CO.sub.2R.sup.16, or —C(═O)NR.sup.16R.sup.17; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; R.sup.16 and R.sup.17 are independently H, C.sub.1-4 alkyl or C.sub.1-4 haloalkyl; or, R.sup.8 is H or C.sub.1-4 alkyl; or, R.sup.9 is H, halogen, or C.sub.1-4 alkyl; or, R.sup.10 is H, halogen, C.sub.1-4 alkyl, or C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5 groups; each R.sup.5 is independently —NR.sup.a1R.sup.b1; R.sup.a1 and R.sup.b1 are independently H or C.sub.1-4 alkyl; or, R.sup.11 is H, halogen, or C.sub.1-4 alkyl; or, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are H.

    4. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein R.sup.1 is any one of the following structures: ##STR00610## ##STR00611##

    5. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 4, wherein in the moiety ##STR00612## (i) R.sup.2 is H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5-2-1 groups, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.3-6 heterocycloalkyl, C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 C.sub.1-4 alkyl groups, C.sub.3-6 heterospirocycloalkyl, or —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; each R.sup.5-2-1 is independently —OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkoxy substituted with 1, 2 or 3 hydroxyl groups, —NR.sup.a1R.sup.b1, C.sub.3-6 heterocycloalkyl, or C.sub.3-6 heterocycloalkyl substituted with 1, 2 or 3 R.sup.5-2-2 groups; R.sup.a1 and R.sup.b1 are independently H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 —NR.sup.a2R.sup.b2 groups, or C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups; R.sup.5-2-2 is C.sub.1-4 alkyl or C.sub.3-6 heterocycloalkyl; R.sup.a2 and R.sup.b2 are independently H or C.sub.1-4 alkyl; wherein the heteroatom in the C.sub.3-6 heterocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; the heteroatom in the C.sub.3-6 heterospirocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; or, (ii) when X.sup.3 is CR.sup.3, then R.sup.3 is H, halogen, C.sub.1-4 alkoxy, or —CN; or, (iii) R.sup.7 is H, C.sub.1-4 alkyl, or —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl.

    6. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 5, wherein in the moiety ##STR00613## (i) R.sup.2 is H, —CH.sub.3, —CF.sub.3, —OCH.sub.3, ##STR00614## —N(CH.sub.3).sub.2, ##STR00615## —CH.sub.2OCH.sub.2C(CH.sub.3).sub.2OH, —CH.sub.2N(CH.sub.3).sub.2, ##STR00616## —CH.sub.2NHCH.sub.2C(CH.sub.3).sub.2OH, ##STR00617## —CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, ##STR00618## —C(CH.sub.3).sub.2OH, or —CHF.sub.2; or, (ii) when X.sup.3 is CR.sup.3, then R.sup.3 is H, —OCH.sub.3, —F, or —CN; or, (iii) R.sup.7 is H, —NH(CH.sub.3), —N(CH.sub.3).sub.2, or —CH.sub.3.

    7. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 4, wherein in the moiety ##STR00619## (i) R.sup.2 is H, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5-2-3 groups, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, or —NR.sup.aR.sup.b, wherein each R.sup.16 and R.sup.17 are independently H or C.sub.1-4 alkyl; each R.sup.5-2-3 is independently —OH or —NR.sup.a1R.sup.b1; R.sup.a1 and R.sup.b1 are independently H or C.sub.1-4 alkyl; or, (ii) R.sup.3 is H, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, or —C(═O)NR.sup.16R.sup.17; R.sup.16 and R.sup.17 are independently H or C.sub.1-4 alkyl; or, (iii) R.sup.6 is H, halogen, —CN, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 R.sup.5-6-1 groups, —CO.sub.2R.sup.16, —C(═O)NR.sup.16R.sup.17, —(C═O)R.sup.16-1, —SO.sub.2R.sup.16, or —POR.sup.16R.sup.17; each R.sup.16 and each R.sup.17 are independently H or C.sub.1-4 alkyl; R.sup.16-1 is H, C.sub.1-4 alkyl or C.sub.3-6 heterocycloalkyl; each R.sup.5-6-1 is independently C.sub.6-8 aryl, —C(═O)NR.sup.16aR.sup.17a, —OH, —CN, —CO.sub.2R.sup.16a, —O(C═O)R.sup.16a, —NH(C═O)R.sup.16a, —(C═O)R.sup.16a1 or —NR.sup.a1R.sup.b1; R.sup.a1 and R.sup.b1 are independently H or C.sub.1-4 alkyl; each R.sup.16a and each R.sup.17a are independently H or C.sub.1-4 alkyl; R.sup.16a1 is C.sub.3-C.sub.6 heterocycloalkyl; for R.sup.16-1 and R.sup.16a1, the heteroatom in the C.sub.3-6 heterocycloalkyl is selected from N, O and S, and the number of the heteroatom is 1, 2, 3 or 4; or, (iv) R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 hydroxyl groups, C.sub.1-4 haloalkyl, —OH, —CO.sub.2R.sup.16, or —C(═O)NR.sup.16R.sup.17; R.sup.16 and R.sup.17 are independently H or C.sub.1-4 alkyl.

    8. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 7, wherein in the moiety ##STR00620## (i) R.sup.2 is H, —CH.sub.3, —CO.sub.2CH.sub.3, —CH.sub.2OH, —CON(CH.sub.3).sub.2, —CF.sub.3, —CH.sub.2N(CH.sub.3).sub.2, —OCH.sub.3, —N(CH.sub.3).sub.2, ##STR00621## or —CN; or, (ii) R.sup.3 is H, —F, —Cl, —CH.sub.3, —OCH.sub.3, —CONH.sub.2, —CONHCH.sub.3, or —CON(CH.sub.3).sub.2; or, (iii) R.sup.6 is H, —COOCH.sub.2CH.sub.3, —COOH, —CONH.sub.2, —CH.sub.3, —COCH.sub.3, ##STR00622## —CH.sub.2CH.sub.3, —F, —CN, —CH(CH.sub.3).sub.2, —CH.sub.2CONH.sub.2, —CH.sub.2CH.sub.2OH, —CH.sub.2OH, —CH.sub.2NH.sub.2, —CH.sub.2COOCH.sub.3, —CH.sub.2COOH, —CH.sub.2CON(CH.sub.3).sub.2, —CH.sub.2CH.sub.2OCOCH.sub.3, —CH.sub.2NHCOCH.sub.3, —CON(CH.sub.3).sub.2, —CN, ##STR00623## —CONH.sub.2, —CH.sub.2CN, —SO.sub.2Me, or —PO(CH.sub.3).sub.2; or, (iv) R.sup.7 is H, —CF.sub.3, —CH.sub.3, —OH, —CH.sub.2OH, —COOCH.sub.2CH.sub.3, —COOH, —CONH.sub.2, or —CON(CH.sub.3).sub.2.

    9. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 4, wherein in the moiety ##STR00624## R.sup.2 is H, halogen, C.sub.1-4 alkyl, or —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; R.sup.6 is H or C.sub.1-4 alkyl; or, in the moiety ##STR00625## R.sup.2 is C.sub.1-4 alkyl; or, in the moiety ##STR00626## X.sup.6 is N or CH; R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; or, in the moiety ##STR00627## X.sup.6 is NR.sup.6, O or S; R.sup.6 is C.sub.1-4 alkyl; R.sup.7 is H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, or —NR.sup.aR.sup.b; R.sup.a and R.sup.b are independently H or C.sub.1-4 alkyl; or, in the moiety ##STR00628## R.sup.3 is H or C.sub.1-4 haloalkyl; or, in the moiety ##STR00629## X.sup.8 is CR.sup.8 or N; R.sup.8 is H or C.sub.1-4 alkyl; or, in the moiety ##STR00630## R.sup.10 and R.sup.11 are independently H or halogen; or, in the moiety ##STR00631## R.sup.2 is H or halogen; R.sup.4 is H, halogen or C.sub.1-4 alkyl; R.sup.9 is H, halogen or C.sub.1-4 alkyl; R.sup.10 is H, C.sub.1-4 alkyl, C.sub.1-4 alkyl substituted with 1, 2 or 3 amino groups, or halogen; R.sup.11 is H, C.sub.1-4 alkyl, or halogen; or, in the moieties ##STR00632## R.sup.11 is independently H or C.sub.1-4 alkyl.

    10. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 9, wherein in the moiety ##STR00633## R.sup.2 is H, —Cl, —CH.sub.3, or —N(CH.sub.3).sub.2; R.sup.6 is H or —CH.sub.3; or, in the moiety ##STR00634## R.sup.2 is —CH.sub.3; or, in the moiety R ##STR00635## X.sup.6 is N or CH; R.sup.7 is H, —CH.sub.3, —NH.sub.2, or —CF.sub.3; or, in the moiety ##STR00636## X.sup.6 is —NCH.sub.3, O or S; R.sup.7 is H, —CH.sub.3, —NH.sub.2, or —CF.sub.3; or, in the moiety ##STR00637## R.sup.3 is H or —CF.sub.3; or, in the moiety ##STR00638## X.sup.8 is CH or N; or, in the moiety ##STR00639## R.sup.10 and R.sup.11 are independently H or —F; or, in the moiety ##STR00640## R.sup.2 is H or —F; R.sup.4 is H, —F or —CH.sub.3; R.sup.9 is H, F, —Cl, or —CH.sub.3; R.sup.10 is H, —CH.sub.3, —CH.sub.2CH.sub.2NH.sub.2, —F, or —Cl; R.sup.11 is H, —CH.sub.3, or —F; or, in the moieties ##STR00641## R.sup.11 is independently H or —CH.sub.3.

    11. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein R.sup.1 is ##STR00642## ##STR00643## ##STR00644## ##STR00645## ##STR00646## ##STR00647## ##STR00648## ##STR00649## ##STR00650## ##STR00651## ##STR00652## ##STR00653## or, R.sup.2 is H, —CH.sub.3, —CF.sub.3, —OCH.sub.3, ##STR00654## —N(CH.sub.3).sub.2, ##STR00655## —CH.sub.2OCH.sub.2C(CH.sub.3).sub.2OH, —CH.sub.2N(CH.sub.3).sub.2, ##STR00656## —CH.sub.2NHCH.sub.2C(CH.sub.3).sub.2OH, ##STR00657## —CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.2N(CH.sub.3).sub.2, ##STR00658## —C(CH.sub.3).sub.2OH, —CHF.sub.2, —CO.sub.2CH.sub.3, —CH.sub.2OH, —CON(CH.sub.3).sub.2, —CH.sub.2N(CH.sub.3).sub.2, —CN, or —Cl; or, R.sup.3 is H, —OCH.sub.3, —F, —CN, —Cl, —CH.sub.3, —CONH.sub.2, —CF.sub.3, —CONHCH.sub.3, or —CON(CH.sub.3).sub.2; or, R.sup.4 is H, —F, or —CH.sub.3; or, R.sup.6 is H, —COOCH.sub.2CH.sub.3, —COOH, —CONH.sub.2, —CH.sub.3, —COCH.sub.3, ##STR00659## —CH.sub.2CH.sub.3, —F, —CN, —CH(CH.sub.3).sub.2, —CH.sub.2CONH.sub.2, —CH.sub.2CH.sub.2OH, —CH.sub.2OH, —CH.sub.2NH.sub.2, —CH.sub.2COOCH.sub.3, —CH.sub.2COOH, —CH.sub.2CON(CH.sub.3).sub.2, —CH.sub.2CH.sub.2OCOCH.sub.3, —CH.sub.2NHCOCH.sub.3, —CON(CH.sub.3).sub.2, —CN, ##STR00660## —CONH.sub.2, —CH.sub.2CN, —SO.sub.2Me, or —PO(CH.sub.3).sub.2; or, R.sup.7 is H, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CH.sub.3, —CF.sub.3, —OH, —CH.sub.2OH, —COOCH.sub.2CH.sub.3, —COOH, —CONH.sub.2, —CON(CH.sub.3).sub.2, or —NH.sub.2; or, R.sup.8 is H; or, R.sup.9 is H, —F, —Cl, or —CH.sub.3; or, R.sup.10 is H, —CH.sub.3, —CH.sub.2CH.sub.2NH.sub.2, —F, or —Cl; or, R.sup.11 is H, —CH.sub.3, or —F; or, R.sup.12, R.sup.13, R.sup.14, and R.sup.15 are H.

    12. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein the compound as shown in formula (I) is selected from the compounds as shown below: ##STR00661## ##STR00662## ##STR00663## and in the compounds described above, the definitions of each letter and group are as defined above.

    13. The compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein the compound as shown in formula (I) is selected from any one of the following compounds: ##STR00664## ##STR00665## ##STR00666## ##STR00667## ##STR00668## ##STR00669## ##STR00670## ##STR00671## ##STR00672## ##STR00673## ##STR00674## ##STR00675## ##STR00676## ##STR00677## ##STR00678## ##STR00679## ##STR00680## ##STR00681## ##STR00682## ##STR00683## ##STR00684## ##STR00685## ##STR00686## ##STR00687## ##STR00688## ##STR00689##

    14. A method for preparing the compound as shown in formula (I) according to claim 1, comprising the step of: subjecting halo intermediate B.sub.0 and intermediate E.sub.0 to a coupling reaction so as to obtain the compound as shown in formula (I), ##STR00690## wherein W represents halogen; R.sup.x is —B(OH).sub.2 or ##STR00691## the definitions of A, R.sup.1, X, and n are as defined above.

    15. A method for preparing the compounds as shown in formulae I-A, (Ib) or (Ic), wherein the method for preparing the compound as shown in formula I-A includes the step of: subjecting halo intermediate compound B and intermediate E.sub.0 to a coupling reaction as shown below so as to obtain the compound as shown in formula I-A; ##STR00692## or, the method for preparing the compound as shown in formula I-A includes the step of: subjecting intermediate B-1 to a ring closure reaction as shown below so as to obtain the compound as shown in formula (Ib); ##STR00693## or, the method for preparing the compound as shown in formula (Ic) comprises the step of subjecting halo intermediate compound B and intermediate E.sub.01 to a coupling reaction as shown below so as to obtain the compound as shown in formula (Ic); ##STR00694## wherein in the compounds described above, W represents halogen; R.sup.x is —B(OH).sub.2 or ##STR00695## the definitions of A, R.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.6, and R.sup.7 are according to claim 1.

    16. (canceled)

    17. A method for treating cancer in a subject in need thereof, comprising: administrating the compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds according to claim 1 to the subject in need thereof; the compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer, and solvate thereof, or their isotopically-labeled compounds can be used alone or in combination with an additional drug; the additional drug is preferably an anti-cancer drug, an immuno-oncology drug, an antiallergic drug, an antiemetic, an analgesic, or a cell protective drug.

    18. The method according to claim 17, wherein the cancer is selected from lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, cerebroma including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial carcinoma, esophageal carcinoma, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine cancer, and soft tissue sarcoma, wherein the lymphoma is preferably diffuse large B-cell lymphoma, follicular lymphoma, or non-Hodgkin's lymphoma.

    19. A pharmaceutical composition, comprising the compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer thereof, and solvate thereof, or their isotopically-labeled compounds according to claim 1, and a pharmaceutically acceptable excipient.

    20. A pharmaceutical preparation, comprising the compound as shown in formula (I), the pharmaceutically acceptable salt, hydrate, stereoisomer thereof, and solvate thereof, or their isotopically-labeled compounds according to claim 1, wherein the pharmaceutical preparation is preferably in the form of tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, or solutions; the mode of administration of the pharmaceutical preparation is preferably oral administration, sublingual administration, subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, nasal administration, local topical administration, or rectal administration.

    Description

    DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

    [0244] The starting materials used in the following examples can be purchased from chemical vendors e.g., Aldrich, TCI, Alfa Aesar, Bide, and Energy Chemical, or can be synthesized by known methods.

    [0245] In the following examples, the ice bath refers to −5° C. to 0° C., the room temperature refers to 10° C. to 30° C., and the reflux temperature generally refers to the solvent reflux temperature under normal pressure. Overnight reaction refers to reaction for 8-15 hours. In the following examples, if the operating temperature is not specified, the operation is carried out at room temperature.

    [0246] In the following examples, the isolation and purification of the intermediates and final products are performed by normal phase or reversed-phase column chromatography or other suitable methods. For the normal phase Flash column chromatography, ethyl acetate and n-hexane or methanol and dichloromethane, etc. are used as mobile phases. For the reversed-phase preparative high-performance liquid chromatography (HPLC), a C18 column is used and UV 214 nm and 254 nm are used for detection, wherein the mobile phases are A (water and 0.1% formic acid) and B (acetonitrile), or A (water and 0.1% ammonium bicarbonate) and B (acetonitrile).

    [0247] In each example:

    [0248] LCMS instrument: Pump Agilent 1260 UV detector: Agilent 1260 DAD

    [0249] Mass Spectrometer API 3000

    [0250] Chromatography column: Waters sunfire C18, 4.6×50 mm, 5 um

    [0251] Mobile phase: A-H.sub.2O (0.1% HCOOH); B-acetonitrile

    [0252] NMR instrument: Bruker Ascend 400M (.sup.1H NMR: 400 MHz; .sup.13C NMR: 100 MHz).

    Example 1: 8-bromo-5-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (D)

    Step 1: 5-bromo-2-chloro-4-hydrazinopyrimidine (D-2)

    [0253] ##STR00329##

    [0254] Into a 50 mL single-necked flask, D-1 (2 g, 8.78 mmol) and ethanol (20 mL) were added, and hydrazine hydrate (1.72 g, 53.65 mmol) was slowly added dropwise in an ice bath. The suspension was stirred at 60° C. for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature to precipitate a light yellow solid. The solid was collected by filtration and the filter cake was washed with ethanol (5 mL) and dried to obtain a light yellow solid product D-2 (1.8 g, 92% yield).

    [0255] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) δ 8.06 (s, 1H), 7.85 (s, 1H), 4.34 (s, 2H) ppm.

    Step 2: 8-bromo-5-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (D)

    [0256] ##STR00330##

    [0257] Into a 50 mL single-necked flask, D-2 (1.2 g, 5.37 mmol), trimethylorthoformate (12 mL), and trifluoroacetic acid (1 drop) were added and the mixture was warmed to 100° C. and reacted for 10 h. Upon completion of the reaction, the reaction mixture was cooled to room temperature and trimethylorthoformate was removed by rotary evaporation. The concentrate was purified by silica gel column chromatography (PE:EA=20:1) to obtain a yellow solid product D (960 mg, 77% yield).

    [0258] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.03 (s, 1H), 8.05 (s, 1H) ppm; LCMS: m/z 232.9 [M+H].sup.+.

    Example 2: ((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methanamine (C1-a) and ((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methanamine (C1-b)

    Step 1: intermediate 2-bromo-6-(2-bromoethoxy)-3-fluorobenzaldehyde (C1-2)

    [0259] ##STR00331##

    [0260] Into a 250 mL single-necked flask, C1-1 (19 g, 86.7 mmol) was added, and then anhydrous DMF (90 mL) was added and dissolved with stirring. Potassium carbonate (24 g, 173.5 mmol) and 1,2-dibromoethane (24 g, 130.1 mmol) were added sequentially and the mixture was warmed to 64° C. and stirred for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted by adding ethyl acetate (400 mL) and stirred for 15 minutes. Insoluble salts were removed by filtration and the filter cake was washed once with ethyl acetate (100 mL). The filtrate was washed twice with saturated sodium chloride (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure. The crude was rapidly purified by short silica gel column chromatography (petroleum ether:ethyl acetate=50:1) to obtain an intermediate C1-2 (25 g, 88% yield) as a yellow solid.

    [0261] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.52-10.27 (m, 1H), 7.40-7.09 (m, 1H), 7.02-6.78 (m, 1H), 4.53-4.05 (m, 2H), 3.68 (t, J=6.0 Hz, 2H) ppm.

    Step 2: intermediate 2-bromo-3-fluoro-6-(ethenyloxy)benzaldehyde (C1-3)

    [0262] ##STR00332##

    [0263] Into a 1 L single-necked flask, C1-2 (10 g, 30.7 mmol) was added, and then anhydrous tetrahydrofuran (400 mL) was added and dissolved with stirring. The reaction mixture was cooled to −20° C. and then sodium tert-butoxide (4.4 g, 46.0 mmol) was slowly added in batches. At the end of the addition, the mixture was warmed to room temperature and stirred overnight. Upon completion of the reaction, the reaction mixture was cooled to −10° C. The reaction was quenched by slowly adding water dropwise (60 mL). The reaction mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum ether:ethyl acetate=80:1 to 30:1) to obtain C1-3 (5 g, 66% yield) as a light yellow solid.

    [0264] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.32 (d, J=9.8 Hz, 1H), 7.29 (dt, J=16.2, 8.3 Hz, 1H), 7.15-6.98 (m, 1H), 6.68-6.46 (m, 1H), 4.89-4.68 (m, 1H), 4.68-4.42 (m, 1H) ppm.

    Step 3: intermediate (E)-N′-(2-bromo-3-fluoro-6-(ethenyloxy)benzylidene)-4-methylbenzenesulfonohydrazide (C1-4)

    [0265] ##STR00333##

    [0266] Into a 250 mL single-necked flask, C1-3 (5 g, 20.4 mmol) was added, and then anhydrous methanol (100 mL) was added and resolved with stirring. p-Toluenesulfonyl hydrazide (4.2 g, 22.4 mmol) was slowly added at room temperature. The mixture was stirred at room temperature for 18 hours. Upon completion of the reaction, a large amount of white solid was precipitated. The reaction mixture was cooled to 0° C. The solid product was collected by filtration. The mother liquor was concentrated and the solid crude was slurried with the mixed solvents of petroleum ether and ethyl acetate (20:1). The solid product was collected and dried under reduced pressure to obtain C1-4 (7.5 g, 89% yield) as a white solid.

    [0267] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.81 (s, 1H), 7.97 (s, 1H), 7.76 (d, J=7.6 Hz, 2H), 7.42 (t, J=9.0 Hz, 2H), 7.16 (dd, J=9.1, 4.3 Hz, 1H), 6.67 (dd, J=13.6, 6.2 Hz, 1H), 4.49 (dd, J=21.4, 9.8 Hz, 3H), 2.35 (s, 3H) ppm; LCMS: m/z 414.1 [M+H].sup.+.

    Step 4: intermediate 6-bromo-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran (C1-5)

    [0268] ##STR00334##

    [0269] Into a 250 mL single-necked flask, C1-4 (3 g, 7.3 mmol) was added, and then toluene (100 mL) was added and dissolved with stirring. At room temperature, lithium tert-butoxide (639 mg, 7.9 mmol) and rhodium (II) octanoate dimer (56 mg, 72.6 μmol) were slowly added under nitrogen protection. The mixture was warmed to 100° C. and stirred for 3 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (50 mL) and the filtrate was concentrated under reduced pressure to obtain C1-5 (1.67 g, 100% yield) as a light yellow oil, which was directly used in the next reaction without further purification.

    [0270] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.03-6.81 (m, 2H), 4.97 (t, J=5.2 Hz, 1H), 2.84 (dt, J=9.0, 4.4 Hz, 1H), 1.26 (dt, J=8.0, 6.1 Hz, 1H), 0.55-0.37 (m, 1H) ppm.

    Step 5: intermediate 5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-carbonitrile (C1-6)

    [0271] ##STR00335##

    [0272] Into a 100 mL single-necked flask, C1-5 (1.9 g, 8.30 mmol), zinc cyanide (1.46 g, 12.4 mmol), palladium tetrakistriphenylphosphine (1.44 g, 1.24 mmol), and DMF (12 mL) were added. Under nitrogen protection, the mixture was warmed to 110° C. and stirred for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted by adding ethyl acetate (20 mL) and filtered. The filtrate was washed twice with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 20:1) to obtain C1-6 (1.35 g, 92% yield) as a white solid.

    [0273] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.03-6.84 (m, 2H), 4.97 (t, J=5.2 Hz, 1H), 2.84 (dt, J=9.0, 4.5 Hz, 1H), 1.33-1.20 (m, 1H), 0.52-0.40 (m, 1H) ppm.

    Step 6: intermediate tert-butyl ((5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)carbamate (C1-7)

    [0274] ##STR00336##

    [0275] Into a 100 mL single-necked flask, C1-6 (1.2 g, 6.8 mmol) was added, and then methanol (30 mL) was added and dissolved. Di-tert-butyldicarbonate (2.2 g, 10.3 mmol) was added at room temperature. The reaction mixture was cooled to −5° C. Nickel chloride hexahydrate (1.95 g, 8.22 mmol) was added slowly and solid sodium borohydride (778 mg, 20.5 mmol) was added in batches. The mixture was warmed to room temperature naturally and stirred for 2 hours. Upon completion of the reaction, the mixture was filtered through celite. The filter cake was washed with methanol (10 mL) and the filtrate was cooled to 0° C. The reaction was quenched with water (5 mL). The resulting mixture was concentrated under reduced pressure. Ethyl acetate (80 mL) was added to the crude. The organic phase was washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 40:1) to obtain C1-7 (1.2 g, 63% yield) as a white solid.

    [0276] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.76 (t, J=9.3 Hz, 1H), 6.64 (dd, J=8.6, 3.7 Hz, 1H), 4.90 (s, 1H), 4.82 (t, J=5.3 Hz, 1H), 4.48 (d, J=6.1 Hz, 1H), 4.46-4.33 (m, 1H), 2.85 (d, J=3.8 Hz, 1H), 1.44 (s, 9H), 1.05 (dd, J=14.6, 6.0 Hz, 1H), 0.32 (s, 1H) ppm; LCMS: m/z 224.1 [M−55].sup.+.

    Step 7: intermediate tert-butyl ((5-fluoro-1aR,6bR-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)carbamate (C1-7a) and ((5-fluoro-1aS,6bS-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)carbamate (C1-7b)

    [0277] ##STR00337##

    [0278] C1-7 (1.2 g, 4.3 mmol) was further purified by chiral SFC as follows: column: AD-H 20×250 mm, 10 μm (Daicel), flow rate: 80 g/min, mobile phase: 13% (0.2% ammonia in methanol/methanol), in CO.sub.2, detection: 214 nM, so as to obtain C1-7a (0.52 g, 43.3% yield) with Rt: 0.99 min; and C1-7b (0.57 g, 47.5% yield) with Rt: 0.71 min.

    [0279] C1-7a: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.76 (t, J=9.3 Hz, 1H), 6.64 (dd, J=8.6, 3.9 Hz, 1H), 4.98-4.73 (m, 2H), 4.45 (ddd, J=41.3, 14.0, 5.7 Hz, 2H), 2.84 (s, 1H), 1.45 (d, J=7.7 Hz, 9H), 1.05 (dd, J=14.8, 6.0 Hz, 1H), 0.31 (d, J=4.6 Hz, 1H) ppm; LCMS: m/z 224.1 [M−55].sup.+.

    [0280] C1-7b: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.76 (t, J=9.3 Hz, 1H), 6.64 (dd, J=8.6, 3.9 Hz, 1H), 4.98-4.73 (m, 2H), 4.45 (ddd, J=41.3, 14.0, 5.7 Hz, 2H), 2.84 (s, 1H), 1.45 (d, J=7.7 Hz, 9H), 1.05 (dd, J=14.8, 6.0 Hz, 1H), 0.31 (d, J=4.6 Hz, 1H) ppm; LCMS: m/z 224.1 [M−55].sup.+.

    Step 8: intermediate ((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methanamine (C1-a)

    [0281] ##STR00338##

    [0282] Into a 100 mL single-necked flask, compound C1-7a (1.2 g, 4.30 mmol) was added, and then dichloromethane (20 mL) was added and dissolved. Trifluoroacetic acid (4 mL, 52 mmol) was added at room temperature and stirred for 2 hours. Upon completion of the reaction, dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure to obtain the trifluoroacetate salt of C1-a (1.26 g, 100% yield) as a colorless solid. The product could be directly used in the next step.

    [0283] .sup.1H NMR (400 MHz, MeOD) δ 6.95 (t, J=9.5 Hz, 1H), 6.84 (dd, J=8.8, 4.0 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.31 (q, J=13.7 Hz, 2H), 2.92-2.77 (m, 1H), 1.26-1.11 (m, 1H), 0.38-0.21 (m, 1H) ppm; LCMS: m/z 180.1 [M+H].sup.+.

    [0284] Intermediate C1-7b was taken as the raw material to obtain the trifluoroacetate salt of C1-b using the method of step 8.

    ##STR00339##

    Example 3: intermediate 4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2)

    Step 1: intermediate 2-bromo-3,6-difluorobenzaldehyde (C2-2)

    [0285] ##STR00340##

    [0286] Into a dry 500 mL three-necked flask, C2-1 (22 g, 114 mmol) and dry THE (200 mL) were added and the mixture was cooled to −70° C. Lithium diisopropylamide (2 M, 68.4 mL) was slowly added dropwise into the reaction solution. The reaction solution was stirred at −70° C. for 45 minutes and then DMF (17.8 mL, 228 mmol) was added. The reaction solution was stirred at −70° C. for two hours and warmed to 0° C. Saturated ammonium chloride (200 mL) was added to the reaction solution. The reaction solution was extracted with EtOAc (200 mL×2). The combined organic phases were washed once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate=100:1) to obtain C2-2 (20 g, 79.4% yield) as a light yellow solid.

    [0287] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.34 (s, 1H), 7.34 (ddd, J=9.2, 7.4, 4.5 Hz, 1H), 7.16 (td, J=9.3, 4.0 Hz, 1H) ppm.

    Step 2: intermediate 2-bromo-3-fluoro-6-methoxybenzaldehyde (C2-3)

    [0288] ##STR00341##

    [0289] Into a 2 L three-necked flask, C2-2 (20 g, 90.5 mmol) was added and dissolved in anhydrous THE (1000 ml) and MeOH (200 ml) with stirring. Sodium methoxide (5.87 g, 108.6 mmol) was added and the reaction solution was stirred at 60° C. for 18 hours. Most of the solvent was removed by concentration under reduced pressure and 500 mL of water was added. The suspension was stirred for 30 minutes and filtered and the solid was collected. The solid was slurried with a mixed solution of petroleum ether and ethyl acetate (5:1) and filtered to obtain a solid, which was dried under reduced pressure to obtain C2-3 (18 g, 85% yield) as a yellow solid.

    [0290] LC-MS: m/z 233.1 [M+H].sup.+.

    Step 3: intermediate 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C2-4)

    [0291] ##STR00342##

    [0292] Into a 1 L single-necked flask, C2-3 (16.8 g, 72.1 mmol) and dichloromethane (300 mL) were added. At −78° C., boron tribromide (21.7 g, 86.5 mmol) was slowly added dropwise and the reaction solution was warmed to room temperature and stirred for 18 hours. The reaction solution was diluted with dichloromethane (300 mL) and saturated sodium hydrogen carbonate (300 mL) was slowly added. The organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate=50:1) to obtain C2-4 (10 g, 63.3% yield) as a light yellow solid.

    [0293] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.77 (s, 1H), 10.34 (s, 1H), 7.29 (dt, J=12.7, 6.3 Hz, 1H), 6.94 (dd, J=9.3, 4.1 Hz, 1H) ppm.

    Step 4: intermediate 4-bromo-5-fluoro-2,3-dihydrobenzofuran-3-ol (C2-5)

    [0294] ##STR00343##

    [0295] Into a dry 3-necked flask, trimethylsulfoxonium iodide (9.73 g, 44.2 mmol) and DMSO (50 ml) were added. In an ice-water bath, sodium tert-butoxide (4.25 g, 44.2 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and C2-4 (8.8 g, 40.2 mmol) was added. The reaction solution was stirred at room temperature for 18 hours, and then ethyl acetate (250 ml) and water (250 ml) were added. The resulting mixture was extracted with ethyl acetate (250 ml×2). The organic phase was washed once with water and brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate=10:1) to obtain C2-5 (6.2 g, 66.2% yield) as a white solid.

    [0296] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.03 (t, J=8.7 Hz, 1H), 6.76 (dd, J=8.8, 3.5 Hz, 1H), 5.51-5.40 (m, 1H), 4.58 (ddd, J=13.4, 10.8, 4.6 Hz, 2H), 2.33 (d, J=4.9 Hz, 1H) ppm.

    Step 5: intermediate 5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (C2-6)

    [0297] ##STR00344##

    [0298] Into a dry single-necked flask, C2-5 (2.7 g, 11.6 mmol), zinc cyanide (2.04 g, 17.4 mmol), DMF (50 ml), and palladium tetrakistriphenylphosphine (1.34 g, 1.16 mmol) were added sequentially. The reaction solution was warmed to 120° C. under nitrogen protection and stirred for 18 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate (200 mL×3) and water (200 ml). The organic phase was washed once with water and brine, respectively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on silica gel (petroleum ether:ethyl acetate=5:1) to obtain C2-6 (1.6 g, 77% yield) as a white solid.

    [0299] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.20-6.99 (m, 2H), 5.63 (dd, J=6.9, 2.9 Hz, 1H), 4.69 (dd, J=10.8, 7.1 Hz, 1H), 4.55 (dd, J=10.8, 3.1 Hz, 1H), 2.74 (s, 1H) ppm.

    Step 6: intermediate (5-fluoro-2,3-dihydrobenzofuran-4-yl)methanamine (C2)

    [0300] ##STR00345##

    [0301] Into a 100 mL single-necked flask, C2-6 (1.55 g, 8.65 mmol), trifluoroacetic acid (1.09 g, 8.65 mmol), methanol (20 mL), and 10% palladium on carbon (2 g, containing 50% water) were added sequentially. The reaction mixture was bubbled with hydrogen gas for 5 minutes, ventilated with a hydrogen balloon three times and stirred at 60° C. under a hydrogen balloon for 48 hours. The mixture was filtered through celite and then washed with methanol (50 mL×2). The filtrate was concentrated under reduced pressure and dioxane (10 mL) and 10 M aqueous sodium hydroxide solution (1 mL) were added. The resulting mixture was extracted with dioxane (10 mL×2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a compound C2 (1.4 g, 90% purity, 87% yield), which was directly used in the next step.

    [0302] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 3.27 (t, 2H), 3.77 (s, 2H), 4.56 (t, 2H), 6.59 (dd 1H), 6.81 (dd, 1H) ppm; LC-MS: m/z 168.1 [M+H].sup.+.

    Example 4: intermediate (6-fluorobenzodihydropyran-5-yl)methanamine (C3)

    Step 1: intermediate 2-bromo-1-fluoro-4-(prop-2-yn-1-yloxy)benzene (C3-2)

    [0303] ##STR00346##

    [0304] Into a dry 2 L single-necked flask, C3-1 (87 g, 455.5 mmol) and dry N,N-dimethylformamide (800 mL) were added at room temperature. Nitrogen gas was used to replace the air in the system three times. In an ice-water bath, 60% sodium hydride (20 g, 501 mmol) was added in batches over a period of 30 minutes. The reaction solution was stirred at room temperature for 15 minutes and then cooled with an ice-water bath. Then propargyl chloride (50.9 g, 683.3 mmol) was added. The reaction solution was stirred at room temperature for 18 hours. Upon completion of the reaction, water (1 L) was added and the resulting mixture was extracted with ethyl acetate (1 L) three times. The organic phase was washed once with saturated aqueous sodium chloride solution (500 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain a product C3-2 (80 g, 76.7% yield) as a yellow oily liquid.

    [0305] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.17 (dd, J=5.5, 3.0 Hz, 1H), 7.05 (dd, J=9.0, 8.1 Hz, 1H), 6.89 (ddd, J=9.1, 3.7, 3.2 Hz, 1H), 4.66 (d, J=2.4 Hz, 2H), 2.54 (t, J=2.4 Hz, 1H) ppm.

    Step 2: intermediate 5-bromo-6-fluoro-2H-chromene (C3-3)

    [0306] ##STR00347##

    [0307] Into a dry 20 mL microwave tube, C3-2 (2 g, 8.7 mmol) and N,N-diethylaniline (15 mL) were added. The reaction solution was warmed to 250° C. in a microwave synthesizer and reacted for 2.5 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate (100 mL) and washed with 2 N hydrochloric acid to remove N,N-diethylaniline. The organic phase was washed once with saturated aqueous sodium chloride solution (50 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to obtain a brown oily mixture of C3-3 and C3-3b (1.88 g, 94% yield).

    Step 3: intermediate 6-fluoro-2H-chromene-5-carbonitrile (C3-4)

    [0308] ##STR00348##

    [0309] Into a dry 500 mL three-necked flask, the brown oily mixture of C3-3 and C3-3b (20.2 g, 88.2 mmol), zinc cyanide (13.5 g, 115 mmol), anhydrous N,N dimethylformamide (250 mL), and palladium tetrakistriphenylphosphine (10.2 g, 8.8 mmol) were added sequentially. The reaction solution was stirred at 110° C. under nitrogen protection for 18 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature. 1 L of water was added and the resulting mixture was extracted with ethyl acetate (500 mL) three times. The organic phase was washed once with saturated aqueous sodium chloride solution (500 mL), then dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to obtain a product C3-4 (8.12 g, 52.6% yield) as a white solid. The conversion product of C3-3b was separated and removed.

    [0310] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.02-6.85 (m, 2H), 6.70 (dt, J=10.0, 1.8 Hz, 1H), 6.07 (dt, J=10.0, 3.6 Hz, 1H), 4.88 (dd, J=3.6, 2.0 Hz, 2H) ppm; LC-MS: m/z 176.1 [M+H].sup.+.

    Step 4: intermediate tert-butyl ((6-fluorobenzodihydropyran-5-yl)methyl)carbamate

    [0311] ##STR00349##

    [0312] Into a 500 mL single-necked flask, C3-4 (4.6 g, 26.3 mmol), BOC-anhydride (7.45 g, 34.1 mmol), methanol (200 mL), and 10% palladium on carbon (1.6 g, 50%) were added sequentially. The reaction solution was first bubbled with hydrogen gas for 5 minutes. Then the flask was fitted with a hydrogen balloon and ventilated with same three times. The reaction solution was heated to 60° C. in hydrogen gas and stirred overnight. Upon completion of the reaction, the reaction solution was cooled to room temperature, filtered and concentrated under reduced pressure to obtain a relatively pure product C3-5 (7.4 g, 100%), which was directly used in the next step.

    [0313] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 6.81 (t, J=9.1 Hz, 1H), 6.70 (dd, J=9.0, 4.9 Hz, 1H), 4.75 (s, 1H), 4.32 (d, J=5.2 Hz, 2H), 4.18-4.05 (m, 2H), 3.49 (d, J=1.8 Hz, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.10-1.91 (m, 2H), 1.45 (d, J=8.0 Hz, 9H) ppm; LC-MS: m/z 226.1 [M-tBu+H].sup.+.

    Step 5: intermediate (6-fluorobenzodihydropyran-5-yl)methanamine (C3)

    [0314] ##STR00350##

    [0315] Into a 50 mL single-necked flask, C3-5 (1.0 g, 3.55 mmol) and 10 mL of HCl/dioxane solution (4 M) were added sequentially and the mixture was stirred at room temperature for 4 hours. Upon completion of the reaction, the mixture was concentrated under reduced pressure to obtain a compound C3 (612 mg, 95% yield) as a white solid.

    [0316] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 6.98 (t, J=9.2 Hz, 1H), 6.86 (dd, J=9.1, 5.1 Hz, 1H), 4.28-4.07 (m, 4H), 2.89 (t, J=6.4 Hz, 2H), 2.14-2.01 (m, 2H) ppm; LC-MS: m/z 182.1 [M+H].sup.+.

    Example 5: 8-bromo-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (B1)

    [0317] ##STR00351##

    [0318] Into a 100 mL single-necked flask, the trifluoroacetate salt of compound C1-a (1.0 g, 3.41 mmol), compound D (0.95 g, 4.09 mmol), triethylamine (0.69 g, 6.82 mmol), and acetonitrile (20 mL) were added sequentially. The mixture was stirred at room temperature for 3 hours. Upon completion of the reaction, the reaction mixture was diluted by adding and dissolving ethyl acetate (80 mL). The organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: PE:EA=30:1 to PE:EA=10:1) to obtain a compound B1 (1.2 g, 94% yield).

    [0319] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (s, 1H), 8.87 (d, J=4.5 Hz, 1H), 7.85 (s, 1H), 6.94 (t, J=9.5 Hz, 1H), 6.77 (dd, J=8.7, 3.7 Hz, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.79 (p, J=9.7 Hz, 1H), 2.88 (dt, J=8.7, 4.5 Hz, 1H), 0.97 (dd, J=14.4, 5.7 Hz, 1H), 0.10 (s, 1H) ppm; LCMS: m/z 376.0 [M+H].sup.+.

    [0320] D was reacted with C1-b, C2 and C3, respectively using the method of example 5 to obtain intermediates B2, B3 and B4 as shown in Table 2.

    TABLE-US-00002 TABLE 2 Inter- mediates Chinese name Structural formula Analysis data B2 8-bromo-N-(((1aS,6bS)- 5-fluoro-1a,6b-dihydro- 1H-cyclopropa[b]benzo- furan-6-yl)methyl)- [1,2,4]triazolo[4,3-c]- pyrimidin-5-amine [00352]embedded image LCMS: m/z 376.0 [M + H].sup.+ B3 8-bromo-N-((5-fluoro- 2,3-dihydrobenzofuran- 4-yl)methyl)-[1,2,4]- triazolo[4,3-c]pyrimidin- 5-amine [00353]embedded image LCMS: m/z 364.0 [M + H].sup.+ B4 8-bromo-N-((6-fluoro- chroman-5-yl)methyl)- [1,2,4]triazolo[4,3-c]- pyrimidin-5-amine [00354]embedded image .sup.1HNMR (400 MHz, DMSO- d.sub.6) δ 9.35 (s, 1H), 8.57 (s, 1H), 7.50 (s, 1H), 6.91 (t, J = 9.2 Hz, 1H), 6.71 (dd, J = 9.0, 4.8 Hz, 1H), 4.63 (d, J = 4.6 Hz, 2H), 4.10- 3.97 (m, 2H), 2.85 (t, J = 6.4 Hz, 2H), 1.95-1.84 (m, 2H) ppm; LCMS: m/z 378.0 [M + H].sup.+

    Example 6: 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: [1,2,4]triazolo[1,5-a]pyridin-8-ylboronic acid (E1)

    [0321] ##STR00355##

    [0322] Into a dry 30 mL sealed tube, 8-bromo-[1,2,4]triazolo[1,5-a]pyridine (200 mg, 1.01 mmol) and bis(pinacolato)diboron (513 mg, 2.02 mmol) were added sequentially. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 0.05 mmol), and potassium acetate (198 mg, 2.02 mmol) dissolved in 10 ml of dry 1,4-dioxane were added. The reaction solution was bubbled with nitrogen gas for one minute and then warmed to 120 TC and stirred for 12 hours. The reaction solution was cooled to room temperature, and the raw materials were substantially converted to E1 (detected by LCMS). Then the reaction was not subjected to post-treatment, but was directly used in the next reaction by using a one-pot process.

    [0323] LCMS: m/z 164.0 [M+H].sup.+

    Step 2: 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0324] ##STR00356##

    [0325] Into the above-mentioned reaction solution of intermediate E1, intermediate B3 (100 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.03 mmol), potassium carbonate (76 mg, 0.54 mmol), and H.sub.2O (2 mL) were added sequentially. The resulting reaction solution was bubbled with nitrogen gas for one minute, warmed to 85° C. and stirred for 2 hours. The reaction solution was cooled to room temperature. The reaction system was slowly added dropwise into ice water (30 mL) and then extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography with a developing agent system (ethyl acetate:methanol=10:1) to obtain a crude product, which was then subjected to high-performance liquid chromatography to obtain the product 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (39 mg, 35% yield) as a white solid.

    [0326] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.56 (s, 1H), 9.51 (s, 1H), 9.19 (dd, J=7.6, 0.9 Hz, 1H), 8.98 (s, 1H), 8.93 (dd, J=6.7, 1.0 Hz, 1H), 8.63 (s, 1H), 7.43-7.38 (m, 1H), 7.01-6.95 (m, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.79 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.33 (d, J=8.8 Hz, 2H) ppm; LCMS: m/z 403.1 [M+H].sup.+.

    [0327] The following compound can be synthesized with 8-bromo-[1,2,4]triazolo[1,5-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 7: 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0328] ##STR00357##

    [0329] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.44 (s, 1H), 9.37 (s, 1H), 9.05 (d, J=7.4 Hz, 1H), 8.78 (d, J=6.6 Hz, 1H), 8.48 (s, 1H), 7.26 (t, J=7.2 Hz, 1H), 6.85-6.79 (m, 1H), 6.65 (dd, J=8.6, 3.8 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 4.79 (d, J=3.4 Hz, 2H), 3.04 (d, J=5.2 Hz, 1H), 2.83 (dd, J=9.2, 4.3 Hz, 1H), 1.10 (s, 1H), 0.92-0.82 (m, 1H) ppm; LCMS: m/z 414.8 [M+H].sup.+.

    [0330] The following compound can be synthesized with 8-bromoimidazo[1,2-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 8: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0331] ##STR00358##

    [0332] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.67 (s, 1H), 9.56 (s, 1H), 8.90 (s, 1H), 8.80 (d, J=6.7 Hz, 1H), 8.55 (d, J=5.8 Hz, 1H), 8.05 (d, J=1.0 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H), 7.08 (t, J=7.0 Hz, 1H), 7.02-6.93 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.78 (s, 2H), 4.55 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 401.7 [M+H].sup.+.

    [0333] The following compound can be synthesized with 8-bromoimidazo[1,2-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 9: N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8-(imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0334] ##STR00359##

    [0335] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (s, 1H), 9.42 (s, 1H), 8.86 (s, 1H), 8.64 (dd, J=7.3, 1.0 Hz, 1H), 8.42 (dd, J=6.7, 1.1 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H), 6.95 (t, J=7.0 Hz, 1H), 6.83 (dd, J=10.3, 8.8 Hz, 1H), 6.66 (dd, J=8.7, 3.9 Hz, 1H), 4.82 (dt, J=5.3, 2.7 Hz, 1H), 4.78 (s, 2H), 2.85 (dd, J=9.3, 4.5 Hz, 1H), 0.88 (dt, J=8.9, 6.0 Hz, 1H), 0.00 (ddd, J=6.0, 3.9, 1.9 Hz, 1H) ppm; LCMS: m/z 413.8 [M+H].sup.+.

    [0336] The following compound can be synthesized with 8-bromo-[1,2,4]triazolo[4,3-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 10: 8-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0337] ##STR00360##

    [0338] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.42 (s, 1H), 9.32 (s, 1H), 9.00 (d, J=7.4 Hz, 1H), 8.68 (d, J=6.6 Hz, 1H), 8.35 (s, 1H), 7.25 (t, J=7.2 Hz, 1H), 6.85-6.79 (m, 1H), 6.63 (dd, J=8.6, 3.8 Hz, 1H), 4.82 (d, J=6.1 Hz, 1H), 4.79 (d, J=3.4 Hz, 2H), 3.04 (d, J=5.2 Hz, 1H), 2.83 (dd, J=9.2, 4.3 Hz, 1H), 1.10 (s, 1H), 0.23-0.18 (m, 1H) ppm; LCMS: m/z 414.8 [M+H].sup.+.

    [0339] The following compound can be synthesized with 7-bromoimidazo[1,2-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 11: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-7-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0340] ##STR00361##

    [0341] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.84 (s, 1H), 8.69 (s, 1H), 8.59 (d, J=7.2 Hz, 1H), 8.32 (s, 1H), 7.95 (s, 1H), 7.66 (dd, J=7.3, 1.7 Hz, 1H), 7.60 (d, J=0.9 Hz, 1H), 7.02-6.89 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.75 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 401.8 [M+H].sup.+.

    [0342] The following compound can be synthesized with 6-bromoimidazo[1,2-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 12: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0343] ##STR00362##

    [0344] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (s, 1H), 9.52 (s, 1H), 8.79 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.90 (dd, J=9.6, 1.7 Hz, 1H), 7.65 (d, J=9.5 Hz, 1H), 7.60 (s, 1H), 7.04-6.91 (m, 1H), 6.71 (dd, J=8.8, 3.8 Hz, 1H), 4.74 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.26 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 401.8 [M+H].sup.+.

    [0345] The following compound can be synthesized with 6-bromopyrazolo[1,5-a]pyrimidine and intermediate B3 as the raw materials using the method of example 6:

    Example 13: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0346] ##STR00363##

    [0347] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.94 (s, 1H), 9.55 (s, 1H), 9.29 (d, J=2.0 Hz, 1H), 8.91 (s, 1H), 8.40 (s, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.02-6.92 (m, 1H), 6.80 (s, 1H), 6.72 (dd, J=8.7, 3.7 Hz, 1H), 4.76 (s, 2H), 4.56 (t, J=8.6 Hz, 2H), 2.06-1.90 (m, 2H) ppm; LCMS: m/z 402.8 [M+H].sup.+.

    [0348] The following compound can be synthesized with 6-bromo-[1,2,4]triazolo[4,3-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 14: 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0349] ##STR00364##

    [0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (s, 1H), 9.57 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H), 8.30 (s, 1H), 8.07 (dd, J=9.8, 1.3 Hz, 1H), 7.87 (d, J=9.7 Hz, 1H), 6.98-6.92 (m, 1H), 6.78 (dd, J=8.7, 3.8 Hz, 1H), 4.93 (t, J=4.5 Hz, 1H), 4.88 (t, J=9.2 Hz, 2H), 2.96-2.90 (m, 1H), 1.23 (s, 1H), 1.02-0.97 (m, 1H) ppm; LCMS: m/z 415.1 [M+H].sup.+.

    [0351] The following compound can be synthesized with 7-bromo-[1,2,4]triazolo[1,5-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 15: 8-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0352] ##STR00365##

    [0353] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 9.06 (s, 1H), 8.99 (d, J=7.3 Hz, 1H), 8.88 (s, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 8.01 (dd, J=7.4, 1.7 Hz, 1H), 7.02-6.92 (m, 1H), 6.78 (dd, J=8.7, 3.9 Hz, 1H), 4.94 (dd, J=5.4, 1.7 Hz, 1H), 4.91 (d, J=4.2 Hz, 2H), 2.97-2.90 (m, 1H), 1.23 (s, 1H), 1.00 (dd, J=5.7, 3.1 Hz, 1H) ppm; LCMS: m/z 415.1 [M+H].sup.+.

    [0354] The following compound can be synthesized with 6-bromoimidazo[1,2-a]pyrimidine and intermediate B3 as the raw materials using the method of example 6:

    Example 16: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0355] ##STR00366##

    [0356] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 9.52 (s, 1H), 9.20 (s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 6.96 (s, 1H), 6.72 (s, 1H), 4.65 (d, J=77.8 Hz, 4H), 3.57 (s, 2H) ppm; LCMS: m/z 402.8 [M+H].sup.+.

    [0357] The following compound can be synthesized with 6-bromopyrazolo[1,5-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 17: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0358] ##STR00367##

    [0359] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.78 (s, 1H), 9.54 (s, 1H), 8.82 (s, 1H), 8.29 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.92 (dd, J=9.5, 1.5 Hz, 1H), 7.79 (d, J=9.3 Hz, 1H), 7.01-6.92 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 6.65 (d, J=1.4 Hz, 1H), 4.75 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.31 (s, 2H) ppm; LCMS: m/z 401.8 [M+H].sup.+.

    [0360] The following compound can be synthesized with 3-bromopyrazolo[1,5-a]pyrimidine and intermediate B3 as the raw materials using the method of example 6:

    Example 18: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyrimidin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0361] ##STR00368##

    [0362] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.25-9.19 (m, 2H), 8.80 (s, 1H), 8.71 (dd, J=4.0, 1.7 Hz, 1H), 8.64 (s, 1H), 7.17 (dd, J=7.0, 4.1 Hz, 1H), 7.00-6.93 (m, 1H), 6.72 (s, 1H), 4.74 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (d, J=8.8 Hz, 2H) ppm; LCMS: m/z 402.8 [M+H].sup.+.

    [0363] The following compound can be synthesized with 7-bromobenzo[d]oxazole and intermediate B3 as the raw materials using the method of example 6:

    Example 19: 8-(benzo[d]oxazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0364] ##STR00369##

    [0365] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.49 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.01-6.93 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32-3.30 (m, 2H) ppm; LCMS: m/z 402.8 [M+H].sup.+.

    [0366] The following compound can be synthesized with 4-bromo-2-methylbenzo[d]oxazole and intermediate B3 as the raw materials using the method of example 6:

    Example 20: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylbenzo[d]oxazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0367] ##STR00370##

    [0368] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.97 (s, 1H), 8.56 (s, 1H), 8.24 (d, J=7.4 Hz, 1H), 7.54-7.38 (m, 2H), 6.88-6.75 (m, 1H), 6.61 (dd, J=8.7, 3.9 Hz, 1H), 6.47 (s, 1H), 4.72 (d, J=5.3 Hz, 2H), 4.57 (t, J=8.7 Hz, 2H), 3.37 (t, J=8.7 Hz, 2H), 2.66 (s, 3H) ppm; LCMS: m/z 416.8 [M+H].sup.+.

    Example 21: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: (2-amino-5-fluoropyridin-3-yl)boronic acid (E2)

    [0369] ##STR00371##

    [0370] Into a 25 mL microwave tube, 3-bromo-5-fluoropyridin-2-amine (0.3 g, 1.57 mmol), bis(pinacolato)diboron (598 mg, 2.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (115 mg, 0.157 mmol), bis(diphenylphosphino)ferrocene (87 mg, 0.157 mmol), potassium acetate (385 mg, 3.93 mmol), and 1,4-dioxane (10 mL) were added. Under nitrogen protection, the mixture was warmed to 110° C. in a microwave reactor and reacted for 4 hours. Upon completion of the reaction, the resulting reaction mixture was directly used in the next reaction without purification. LCMS: m/z 156.8 [M+H].sup.+.

    Step 2: 8-(2-amino-5-fluoropyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (E2-2)

    [0371] ##STR00372##

    [0372] Into the reaction solution obtained in the previous step, intermediate B3 (300 mg, 0.824 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (121 mg, 0.165 mmol), potassium carbonate (342 mg, 2.47 mmol), and dioxane-H.sub.2O (12 mL, 4:1) were added. Under nitrogen protection, the mixture was warmed to 80° C. in a microwave reactor and reacted for 1 hour. Upon completion of the reaction, the mixture was then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash chromatography (methanol:ethyl acetate=1:20) to obtain E2-2 (300 mg, 87% yield) as a yellowish brown solid.

    [0373] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.80 (s, 1H), 7.99 (d, J=2.9 Hz, 1H), 7.68 (s, 1H), 7.49 (d, J=9.0 Hz, 1H), 7.00-6.92 (m, 1H), 6.71 (dd, J=8.7, 3.8 Hz, 1H), 5.71 (s, 2H), 4.71 (s, 2H), 4.55 (s, 2H), 3.36 (s, 2H), LCMS: m/z 395.8 [M+H].sup.+.

    Step 3: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0374] ##STR00373##

    [0375] Into a 25 mL single-necked flask, E2-2 (80 mg, 0.2 mmol), 2-chloroacetaldehyde (159 mg, 2.0 mmol), potassium carbonate (28 mg, 0.2 mmol) and ethanol (5 mL) were added and the mixture was warmed to 90° C. and stirred for 5 hours. Upon completion of the reaction, the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash chromatography (methanol:ethyl acetate=1:50) to obtain N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (8 mg, 9.4% yield) as a light yellow solid.

    [0376] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 9.56 (s, 1H), 9.00 (s, 1H), 8.95 (dd, J=11.1, 2.3 Hz, 1H), 8.78-8.74 (m, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.00-6.94 (m, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.35 (s, 2H) ppm; LCMS: m/z 419.8[M+H].sup.+.

    [0377] The following compound can be synthesized with 3-chloro-1,1,1-trifluoropropan-2-one and intermediate E2-2 as the raw materials using the method in step 3 of example 21:

    Example 22: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0378] ##STR00374##

    [0379] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.66 (s, 1H), 9.57 (s, 1H), 9.09 (dd, J=11.1, 2.3 Hz, 2H), 8.80 (d, J=3.0 Hz, 1H), 8.63 (s, 1H), 7.02-6.96 (m, 1H), 6.73 (dd, J=8.7, 3.8 Hz, 1H), 4.82 (s, 2H), 4.54 (s, 2H), 3.29 (d, J=8.8 Hz, 2H) ppm; LCMS: m/z 487.7 [M+H].sup.+.

    [0380] The following compound can be synthesized with ethyl 2-chloro-3-oxopropanoate and intermediate E2-2 as the raw materials using the method in step 3 of example 21:

    Example 23: Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate

    [0381] ##STR00375##

    [0382] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.56 (s, 1H), 9.26-9.19 (m, 1H), 9.14-9.05 (m, 2H), 8.41 (s, 1H), 7.01-6.93 (m, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.80 (d, J=5.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.41 (q, J=7.1 Hz, 2H), 3.30 (s, 2H), 1.38 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 491.7 [M+H].sup.+.

    [0383] The following compound can be synthesized with ethyl 2-chloroacetoacetate and intermediate E2-2 as the raw materials using the method in step 3 of example 21:

    Example 24: Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridine-3-carboxylate

    [0384] ##STR00376##

    [0385] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 9.58 (s, 1H), 9.22 (s, 1H), 9.08 (d, J=10.8 Hz, 2H), 7.03-6.94 (m, 1H), 6.72 (dd, J=8.7, 3.8 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.27-3.29 (m, 2H), 2.68 (s, 3H), 1.39 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 505.8 [M+H].sup.+.

    [0386] The following compound can be synthesized with 3-bromo-5-chloropyridin-2-amine, dichloroacetaldehyde and intermediate B3 as the raw materials using the method of example 21:

    Example 25: 8-(6-chloroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0387] ##STR00377##

    [0388] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.80 (s, 1H), 9.55 (s, 1H), 9.07-8.91 (m, 2H), 8.83 (d, J=1.8 Hz, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.02-6.93 (m, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.78 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (s, 2H) ppm; LCMS: m/z 435.8 [M+H].sup.+.

    [0389] The following compound can be synthesized with 3-bromo-5-fluoropyridin-2-amine, 3-chloro-1,1,1-trifluoropropan-2-one and intermediate B3 as the raw materials using the method of example 21:

    Example 26: 8-(6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0390] ##STR00378##

    [0391] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.90 (s, 1H), 9.60 (s, 1H), 9.09 (d, J=2.0 Hz, 1H), 8.91 (s, 1H), 8.66 (s, 1H), 6.99-6.91 (m, 1H), 6.70 (dd, J=8.7, 3.8 Hz, 1H), 4.80 (s, 2H), 4.52 (t, J=8.7 Hz, 2H), 3.33 (s, 2H) ppm; LCMS: m/z 503.7 [M+H].sup.+.

    [0392] The following compound can be synthesized with 3-bromo-5-fluoropyridin-2-amine, chloracetone and intermediate B3 as the raw materials using the method of example 21:

    Example 27: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0393] ##STR00379##

    [0394] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.84 (s, 1H), 9.55 (s, 1H), 8.96 (s, 1H), 8.89 (dd, J=11.1, 2.3 Hz, 1H), 8.71-8.65 (m, 1H), 7.78 (s, 1H), 7.03-6.94 (m, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (t, J=8.9 Hz, 2H), 2.41 (s, 3H) ppm; LCMS: m/z 433.8 [M+H].sup.+.

    [0395] The following compound can be synthesized with 3-bromo-5-methylpyridin-2-amine, 2-chloroacetaldehyde and intermediate B3 as the raw materials using the method of example 21:

    Example 28: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0396] ##STR00380##

    [0397] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.73 (s, 1H), 9.62 (s, 1H), 8.96 (s, 1H), 8.75 (s, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.07-7.00 (m, 1H), 6.78 (dd, J=8.7, 3.9 Hz, 1H), 4.84 (s, 2H), 4.62 (t, J=8.7 Hz, 2H), 3.38 (s, 2H), 2.44 (s, 3H) ppm; LCMS: m/z 415.8 [M+H].sup.+.

    [0398] The following compound can be synthesized with 3-bromo-6-methylpyridin-2-amine, 2-chloropropanal and intermediate B3 as the raw materials using the method of example 21:

    Example 29: 8-(3,5-dimethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0399] ##STR00381##

    [0400] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.45 (s, 1H), 8.78 (s, 1H), 8.49 (d, J=7.3 Hz, 1H), 7.34 (s, 1H), 7.00-6.93 (m, 1H), 6.79-6.70 (m, 2H), 4.76 (d, J=3.4 Hz, 2H), 4.55 (s, 2H), 3.31 (s, 2H), 2.93 (s, 3H), 2.82 (s, 3H) ppm; LCMS: m/z 430.0 [M+H].sup.+.

    [0401] The following compound can be synthesized with 3-bromo-5-methylpyridin-2-amine, 3-chloro-1,1,1-trifluoropropan-2-one and intermediate B3 as the raw materials using the method of example 21:

    Example 30: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0402] ##STR00382##

    [0403] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (s, 1H), 9.47 (s, 1H), 8.99 (s, 1H), 8.82 (s, 1H), 8.56 (s, 1H), 8.39 (s, 1H), 7.02-6.93 (m, 1H), 6.72 (dd, J=8.7, 3.8 Hz, 1H), 4.80 (d, J=4.0 Hz, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.30 (d, J=8.7 Hz, 2H), 2.41 (s, 3H) ppm; LCMS: m/z 483.7 [M+H].sup.+.

    [0404] The following compound can be synthesized with 3-bromo-6-methylpyridin-2-amine, 2-chloropropanal and intermediate B3 as the raw materials using the method of example 21:

    Example 31: 8-(3,5-dimethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0405] ##STR00383##

    [0406] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.45 (s, 1H), 8.78 (s, 1H), 8.49 (d, J=7.3 Hz, 1H), 7.34 (s, 1H), 7.00-6.93 (m, 1H), 6.79-6.70 (m, 2H), 4.76 (d, J=3.4 Hz, 2H), 4.55 (s, 2H), 3.31 (s, 2H), 2.93 (s, 3H), 2.82 (s, 3H) ppm; LCMS: m/z 430.0 [M+H].sup.+.

    [0407] The following compound can be synthesized with 3-bromo-5-fluoropyridin-2-amine, 2-chloropropanal and intermediate B3 as the raw materials using the method of example 21:

    Example 32: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0408] ##STR00384##

    [0409] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.84 (s, 1H), 9.59 (s, 1H), 8.93 (dd, J=11.1, 2.4 Hz, 1H), 8.50 (dd, J=4.0, 2.4 Hz, 1H), 7.52 (d, J=1.0 Hz, 1H), 6.96 (dd, J=10.3, 8.7 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.78 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.34 (s, 6H), 3.32 (s, 4H) ppm; LCMS: m/z 434.1 [M+H].sup.+.

    [0410] The following compound can be synthesized with 3-bromo-6-methylpyridin-2-amine, 2-chlorobutanal and intermediate B3 as the raw materials using the method of example 21:

    Example 33: 8-(3-ethyl-5-methylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0411] ##STR00385##

    [0412] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (d, J=7.0 Hz, 1H), 9.45 (s, 1H), 8.77 (t, J=4.9 Hz, 1H), 8.48 (d, J=7.4 Hz, 1H), 7.38 (s, 1H), 7.01-6.92 (m, 1H), 6.78 (s, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 4.76 (d, J=4.7 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.34 (s, 2H), 3.30 (d, J=7.0 Hz, 2H), 2.92 (s, 3H), 1.35 (t, J=7.4 Hz, 3H) ppm; LCMS: m/z 444.0 [M+H].sup.+.

    Example 34: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: imidazo[1,2-a]pyridin-8-ylboronic acid (E3-2)

    [0413] ##STR00386##

    [0414] Into a 25 mL microwave tube, E3 (100 mg, 0.45 mmol), 3-chloro-1,1,1-trifluoropropan-2-one (100 mg, 0.68 mmol), and 1,4-dioxane (4 mL) were added and the mixture was warmed to 90° C. and stirred for 2 hours. The reaction of the raw materials was completed (detected by LCMS). The reaction solution was cooled to room temperature and then directly used in the next step without any treatment.

    [0415] LCMS: m/z 230.8 [M+H].sup.+.

    Step 2: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0416] ##STR00387##

    [0417] Into the reaction solution obtained in previous step, intermediate B3 (60 mg, 0.165 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (12 mg, 0.0165 mmol), potassium carbonate (45 mg, 0.33 mmol) and H.sub.2O (1 mL) were added. Under nitrogen protection, the mixture was warmed to 80° C. in a microwave reactor and reacted for 1 hour. Upon completion of the reaction, the reaction solution was extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash chromatography (100% ethyl acetate) to obtain N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (55 mg, 71% yield) as a brown solid.

    [0418] .sup.1H NMR (400 MHz, MeOD) δ 9.31 (s, 1H), 9.12 (s, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.26 (d, J=6.6 Hz, 1H), 8.09 (s, 1H), 7.12 (t, J=7.0 Hz, 1H), 6.85 (t, J=9.3 Hz, 1H), 6.67 (dd, J=8.6, 3.9 Hz, 1H), 4.63 (t, J=8.7 Hz, 2H), 4.12 (s, 2H), 3.42 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 469.8 [M+H].sup.+.

    Example 35: intermediate 8-(2-aminopyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (E3-3)

    [0419] ##STR00388##

    [0420] Into a 25 mL microwave tube, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1 mmol), intermediate B3 (300 mg, 0.824 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.136 mmol), potassium carbonate (342 mg, 2.47 mmol) and dioxane —H.sub.2O (12 mL, V/V=4:1) were added. Under nitrogen protection, the mixture was warmed to 80° C. in a microwave reactor and reacted for 1 hour. Upon completion of the reaction, the mixture was then extracted with ethyl acetate (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash chromatography (methanol:ethyl acetate=1:20) to obtain E3-3 (262 mg, 84% yield) as a yellowish brown solid.

    [0421] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.44 (s, 1H), 8.65 (d, J=4.7 Hz, 1H), 8.00 (dd, J=4.9, 1.6 Hz, 1H), 7.60 (s, 1H), 7.49-7.40 (m, 1H), 7.01-6.91 (m, 1H), 6.72 (dd, J=8.7, 3.8 Hz, 1H), 6.64 (dd, J=7.3, 4.9 Hz, 1H), 5.71 (s, 2H), 4.71 (d, J=4.8 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32-3.26 (m, 2H) ppm; LCMS: m/z 377.8 [M+H].sup.+.

    [0422] The following compound can be synthesized with intermediate E3-3 and chloracetone as the raw materials using the method in step 3 of example 21:

    Example 36: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0423] ##STR00389##

    [0424] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.65 (s, 1H), 9.55 (s, 1H), 8.85 (t, J=5.2 Hz, 1H), 8.73 (d, J=6.8 Hz, 1H), 8.44 (d, J=5.8 Hz, 1H), 7.77 (s, 1H), 7.03-6.93 (m, 2H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.79 (d, J=4.9 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.30 (d, J=8.8 Hz, 2H), 2.40 (s, 3H) ppm; LCMS: m/z 415.8 [M+H].sup.+.

    [0425] The following compound can be synthesized with intermediate E3-3 and 2-chloropropanal as the raw materials using the method in step 3 of example 21:

    Example 37: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0426] ##STR00390##

    [0427] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.65 (s, 1H), 9.56 (s, 1H), 8.89 (s, 1H), 8.79 (d, J=7.2 Hz, 1H), 8.25 (d, J=6.7 Hz, 1H), 7.45 (s, 1H), 7.13 (t, J=7.0 Hz, 1H), 7.01-6.93 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.78 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.33 (d, J=8.7 Hz, 2H), 2.51 (s, 3H) ppm; LCMS: m/z 415.8 [M+H].sup.+.

    [0428] The following compound can be synthesized with intermediate E3-3 and ethyl 2-chloro-3-oxopropanoate as the raw materials using the method in step 3 of example 21:

    Example 38: Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate

    [0429] ##STR00391##

    [0430] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.34 (d, J=6.6 Hz, 1H), 8.56 (s, 1H), 8.26 (d, J=7.1 Hz, 1H), 8.16 (s, 1H), 7.62 (s, 1H), 7.20 (t, J=7.1 Hz, 1H), 6.73 (t, J=9.4 Hz, 1H), 6.59 (dd, J=8.6, 3.9 Hz, 1H), 4.66 (d, J=4.6 Hz, 2H), 4.53 (t, J=8.7 Hz, 2H), 4.46 (q, J=7.1 Hz, 2H), 3.35 (t, J=8.7 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 473.8 [M+H].sup.+.

    [0431] The following compound can be synthesized with intermediate E3-3 and 2-chlorobutanal as the raw materials using the method in step 3 of example 21:

    Example 39: 8-(3-ethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0432] ##STR00392##

    [0433] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.72 (s, 1H), 9.35 (t, J=5.2 Hz, 1H), 8.83 (d, J=6.8 Hz, 1H), 8.22 (d, J=7.3 Hz, 1H), 8.12 (s, 1H), 8.05 (s, 1H), 7.63 (t, J=7.1 Hz, 1H), 6.97 (dd, J=10.3, 8.7 Hz, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.10-2.98 (m, 2H), 1.39 (t, J=7.4 Hz, 3H) ppm; LCMS: m/z 430.0 [M+H].sup.+.

    [0434] The following compound can be synthesized with intermediate E3-3 and 2-chloro-3-phenylpropanal as the raw materials using the method in step 3 of example 21:

    Example 40: 8-(3-phenylmethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0435] ##STR00393##

    [0436] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.52 (s, 1H), 8.84 (t, J=5.1 Hz, 1H), 8.75 (dd, J=7.4, 1.2 Hz, 1H), 8.20 (dd, J=6.8, 1.2 Hz, 1H), 7.50 (s, 1H), 7.39-7.16 (m, 5H), 7.07 (t, J=7.0 Hz, 1H), 7.01-6.92 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.78 (d, J=5.1 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.36 (s, 2H), 3.33 (s, 2H) ppm; LCMS: m/z 492.0 [M+H].sup.+.

    Example 41: Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate

    [0437] ##STR00394##

    [0438] Into a 25 mL sealed tube, intermediate E3-3 (60 mg, 0.16 mmol), ethyl 2-bromo-4,4,4-trifluoro-3-oxobutanoate (315 mg, 1.59 mmol), and anhydrous ethanol (6 mL) were added in one portion. The reaction system was warmed to 90° C. and stirred for 16 hours. Upon completion of the reaction, ethanol was removed by concentration under reduced pressure. The crude was purified by silica gel column chromatography to obtain methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-)[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-)trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (15 mg, 17% yield).

    [0439] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.28 (d, J=6.1 Hz, 2H), 9.02 (d, J=7.2 Hz, 1H), 7.56 (t, J=7.2 Hz, 1H), 6.97 (d, J=9.8 Hz, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.80 (d, J=4.8 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.45 (q, J=7.1 Hz, 2H), 3.34 (s, 2H), 3.30 (s, 3H), 3.17 (d, J=5.3 Hz, 1H), 1.37 (t, J=7.1 Hz, 3H), 1.23 (s, 2H) ppm; LCMS: m/z 541.9 [M+H].sup.+.

    Example 42: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylic acid

    [0440] ##STR00395##

    [0441] Into a 25 mL single-necked flask, ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate (47 mg, 0.1 mmol), methanol (10 mL) and water (5 mL) were added, and then potassium hydroxide (56 mg, 1.0 mmol) was added with stirring. The reaction was stirred overnight. The raw materials were fully reacted (monitored by a TLC plate). Then 2 N hydrochloric acid was added to adjust the PH value to 6. The solution was spin-dried and then purified by Flash chromatography (eluents:dichloromethane:methanol=3:1) to obtain a white solid, 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (35 mg, 79% yield).

    [0442] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 9.47 (d, J=7.8 Hz, 1H), 9.36 (s, 1H), 8.78 (d, J=7.3 Hz, 1H), 8.20 (s, 1H), 7.21 (t, J=7.1 Hz, 1H), 6.92-6.83 (m, 1H), 6.66 (dd, J=8.6, 3.8 Hz, 1H), 4.79 (s, 2H), 4.58 (t, J=8.7 Hz, 2H), 3.39 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 446.4 [M+H].sup.+.

    Example 43: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoroimidazo[1,2-a]pyridin-8-yl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0443] ##STR00396##

    [0444] Into a 25 ml single-necked flask, compound 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylic acid (55 mg, 0.123 mmol), potassium fluoride (36.5 mg, 0.628 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-2 tetrafluoroborate (111 mg, 0.314 mmol), dichloroethane (3 mL), and water (1 mL) were added sequentially. Under nitrogen protection, the mixture was refluxed at 70° C. for 16 hours. The reaction was completed (as detected) and then the resulting mixture was cooled to room temperature. The reaction was quenched by adding ice water (3 ml). The reaction mixture was extracted with ethyl acetate (3*5 ml) three times. The extraction liquid was extracted twice with saturated brine and purified water, respectively. The organic phase was dried over anhydrous sodium sulfate and the organic solvent was removed under reduced pressure. The crude product was subjected to purification by reverse phase column chromatography (0.05% aqueous formic acid solution:acetonitrile=2:3, volume ratio) to obtain an off-white solid compound, N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoroimidazo[1,2-a]pyridin-8-yl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (5 mg, 9.7% yield).

    [0445] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64-9.62 (m, 1H), 9.57 (s, 1H), 9.13 (s, 1H), 8.80 (dd, J=7.3, 1.1 Hz, 1H), 8.28 (dd, J=6.8, 1.1 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.96 (dd, J=10.3, 8.7 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 (d, J=8 Hz, 2H) ppm; LCMS: m/z 419.9 [M+H].sup.+.

    [0446] According to the method of example 42, the following compound can be obtained by hydrolyzing the raw material, ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylate:

    Example 44: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylic acid

    [0447] ##STR00397##

    [0448] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (s, 1H), 9.32 (s, 1H), 8.74 (d, J=7.3 Hz, 1H), 8.10 (s, 1H), 7.21 (t, J=7.1 Hz, 1H), 6.90-6.81 (m, 1H), 6.62 (dd, J=8.6, 3.8 Hz, 1H), 4.75 (s, 2H), 4.52 (t, J=8.7 Hz, 2H), 3.35 (t, J=8.7 Hz, 2H), 2.79 (d, J=6.8 Hz, 3H) ppm; LCMS: m/z 460.0 [M+H].sup.+.

    [0449] According to the method of example 43, the following compound can be obtained using intermediate 8-5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylic acid as the raw material:

    Example 45: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoro-5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0450] ##STR00398##

    [0451] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 9.44 (s, 1H), 9.02 (s, 1H), 8.60 (d, J=7.4 Hz, 1H), 7.42 (d, J=7.0 Hz, 1H), 6.96 (dd, J=10.3, 8.7 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 (d, J=8.8 Hz, 2H), 2.77 (d, J=6.8 Hz, 3H) ppm; LCMS: m/z 434.0 [M+H].sup.+.

    [0452] According to the method of example 43, the following compound can be obtained using intermediate 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidine-8-imidazo[1,2-a]pyridine-3-carboxylic acid as the raw material:

    Example 46: 8-(3,6-difluoroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0453] ##STR00399##

    [0454] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.75 (s, 1H), 9.56 (s, 1H), 9.05 (s, 1H), 8.93 (dd, J=11.3, 2.4 Hz, 1H), 8.58 (t, J=2.9 Hz, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.07-6.88 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.30 (s, 1H) ppm; LCMS: m/z 438.0 [M+H].sup.+.

    Example 47: Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate

    [0455] ##STR00400##

    [0456] Into a 25 mL sealed tube, E3-3 (150 mg, 0.40 mmol), diethyl 2-bromopropanedioate (475 mg, 1.99 mmol), and anhydrous ethanol (6 mL) were added in one portion. The reaction system was warmed to 90° C. and stirred for 16 hours. Upon completion of the reaction, ethanol was removed by concentration under reduced pressure. The crude was purified by HPLC to obtain methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate (8 mg, 4% yield).

    [0457] .sup.1H NMR (400 MHz, MeOD-d.sub.4) δ 9.59 (d, J=6.3 Hz, 1H), 9.38 (s, 1H), 8.03 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.44-7.36 (m, 1H), 6.93-6.85 (m, 1H), 6.67 (dd, J=8.6, 3.9 Hz, 1H), 4.87 (s, 2H), 4.61 (t, J=8.7 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.44 (t, J=8.7 Hz, 2H), 1.41 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 490.0 [M+H].sup.+.

    [0458] According to the method of example 47, the following compound can be obtained using intermediate E2-2 and diethyl 2-bromopropanedioate as the raw materials:

    Example 48: Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3-carboxylate

    [0459] ##STR00401##

    [0460] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (t, J=12.0 Hz, 1H), 8.96 (d, J=11.4 Hz, OH), 8.67 (s, OH), 6.96 (t, J=9.5 Hz, 1H), 6.70 (s, 1H), 6.06 (s, 5H), 4.77 (s, 1H), 4.53 (d, J=8.7 Hz, 1H), 4.47-4.27 (m, 1H), 3.30 (s, 3H) ppm; LCMS: m/z 508.0 [M+H].sup.+.

    Example 49: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile

    [0461] ##STR00402##

    [0462] Methoxyacrylonitrile (110 mg, 1.32 mmol) was dissolved in the mixed solvents of dioxane (6 mL) and water (2 mL). At 0° C., N-bromosuccinimide (235 mg, 1.32 mmol) was added with stirring. The reaction solution was stirred for another 30 minutes at 0° C. and then E3-3 (100 mg, 0.26 mmol) was added. The mixture was stirred at room temperature for 2 hours and then heated to 90° C. and the stirring was continued for 16 hours at this temperature. The reaction was completed and the solvents were removed by concentration under reduced pressure. The residue was purified by Flash column chromatography (dichloromethane:methanol=9:1, volume ratio) to obtain a compound 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile (12 mg, 11% yield).

    [0463] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.41 (s, 1H), 9.03-8.99 (m, 1H), 8.97 (t, J=5.2 Hz, 1H), 8.64 (dd, J=6.6, 1.0 Hz, 1H), 8.54 (s, 1H), 7.47-7.41 (m, 1H), 7.00-6.93 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.78 (d, J=5.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (s, 2H) ppm; LCMS: m/z 427.0 [M+H].sup.+.

    Example 50: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)benzo[c][1,2,5]thiadiazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: Intermediate E4-2 can be synthesized with 3-bromo-4-(trifluoromethyl)benzene-1,2-diamine and intermediate B3 as the raw materials using the method of example 21

    [0464] ##STR00403##

    [0465] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (d, J=16.9 Hz, 1H), 8.60 (dd, J=9.1, 4.5 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J=5.6 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 6.73 (d, J=4.4 Hz, 1H), 5.03 (s, 1H), 4.87 (s, 1H), 4.70 (dd, J=11.4, 4.8 Hz, 2H), 4.55 (q, J=8.9 Hz, 2H), 3.29 (dd, J=18.8, 10.2 Hz, 2H) ppm; LCMS: m/z 459.7 [M+H].sup.+.

    Step 2: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)benzo[c][1,2,5]thiadiazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0466] ##STR00404##

    [0467] Into a 25 mL single-necked flask, compound E4-2 (20 mg, 0.043 mmol), thionyl chloride (13.78 mg, 0.14 mmol), triethylamine (24.26 mg, 0.188 mmol), and dichloromethane (3 mL) were added sequentially and the mixture was reacted at 0° C. for 2 h. The reaction was completed and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase:ethyl acetate:methanol=15:1) to obtain a compound N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)benzo[c][1,2,5]thiadiazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (6 mg, 28.2% yield).

    [0468] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.56 (s, 1H), 9.26 (d, J=1.7 Hz, 1H), 9.20 (s, 1H), 9.07 (s, 1H), 8.56 (d, J=3.7 Hz, 1H), 6.98 (t, J=9.5 Hz, 1H), 6.73 (dd, J=8.6, 3.8 Hz, 1H), 4.81 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 2.10-1.91 (m, 2H) ppm; LCMS: m/z 487.4 [M+H].sup.+.

    Example 51: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-one

    [0469] ##STR00405##

    [0470] Into a 25 mL sealed tube, intermediate E3-3 (50 mg, 0.13 mmol), 3-chloropentane-2,4-dione (89 mg, 0.66 mmol), and anhydrous ethanol (6 mL) were added in one portion. The reaction system was warmed to 90° C. and stirred for 4 hours. Upon completion of the reaction, the resulting mixture was concentrated under reduced pressure to obtain a residue, which was purified by Flash silica gel column chromatography (eluents:methanol:ethyl acetate=1:20) to obtain a compound 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-one (4.8 mg, 8% yield).

    [0471] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.19 (s, 1H), 8.53 (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H), 7.46 (s, 1H), 6.99 (s, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.58 (s, 1H), 4.87 (d, J=6.3 Hz, 1H), 4.71 (s, 2H), 4.53 (d, J=7.7 Hz, 2H), 3.33 (d, J=7.0 Hz, 2H), 1.97 (d, J=6.7 Hz, 2H) ppm; LCMS: m/z 431.9 [M+H].sup.+.

    [0472] According to the method of example 51, the following compound can be obtained using intermediate E2-2 as the raw material:

    Example 52: 1-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-one

    [0473] ##STR00406##

    [0474] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.65 (dd, J=4.7, 2.6 Hz, 1H), 9.63 (s, 1H), 9.56 (s, 1H), 9.11 (dd, J=10.6, 2.5 Hz, 1H), 9.04 (s, 1H), 6.98 (t, J=9.4 Hz, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.81 (d, J=4.7 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (s, OH), 2.81 (s, 3H), 2.65 (s, 3H) ppm; LCMS: m/z 476.1 [M+H].sup.+.

    Example 53: 8-(2,3-dihydroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 2-((3-bromopyridin-2-yl)amino)ethan-1-ol E4-3

    [0475] ##STR00407##

    [0476] 3-bromo-2-chloropyridine (3.00 g, 15.6 mmol) and 2-aminoethan-1-ol (3.81 g, 62.4 mmol) were dissolved in pyridine (6 mL). The mixture was stirred at 180° C. for 90 minutes. Upon completion of the reaction, the mixture was cooled to room temperature and saturated sodium hydrogen carbonate solution was added into the reaction solution. The resulting mixture was then extracted with dichloromethane. The organic phases were mixed, dried, concentrated and purified by silica gel column chromatography to obtain intermediate E4-3 (3.18 g, 94% yield).

    [0477] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.03 (dd, J=4.8, 1.6 Hz, 1H), 7.73 (dq, J=7.7, 1.6 Hz, 1H), 6.57-6.45 (m, 1H), 6.12 (t, J=5.6 Hz, 1H), 4.80 (t, J=5.1 Hz, 1H), 3.57 (q, J=5.6, 4.5 Hz, 2H), 3.50-3.38 (m, 2H) ppm. LCMS: m/z 218.0 [M+H].sup.+.

    Step 2: (2-((2-hydroxyethyl)amino)pyridin-3-yl)boronic acid E4-4

    [0478] ##STR00408##

    [0479] In a 25 mL single-necked flask, E4-3 (300 mg, 1.38 mmol), bis(pinacolato)diboron (306 mg, 1.21 mmol), potassium acetate (118 mg, 1.21 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 0.05 mmol), and 1,4-dioxane (6 mL) were added sequentially. The reaction system was warmed to 90° C. and reacted under nitrogen atmosphere for 16 hours. The raw materials were substantially converted to E4-4 (monitored by TLC) and then the reaction solution was directly used in the next step without any treatment.

    Step 3: 2-((3-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)amino)ethan-1-ol E4-5

    [0480] ##STR00409##

    [0481] To the reaction solution obtained in the previous step, B3 (302 mg, 0.83 mmol), potassium carbonate (573 mg, 4.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (100 mg, 0.14 mmol) and water (3 mL) were added. The reaction system was warmed to 80° C. under nitrogen atmosphere and reacted for 5 hours. The reaction was completed (monitored by LCMS). The resulting mixture was cooled to room temperature and diluted and dissolved in ethyl acetate (30 mL). The organic phase was washed with water (5 mL*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by Flash silica gel column chromatography (mobile phase:ethyl acetate:methanol=10:1, volume ratio) to obtain a compound E4-5 (130 mg, 22% yield).

    [0482] LCMS: m/z 422.0 [M+H].sup.+.

    Step 4: 8-(2,3-dihydroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0483] ##STR00410##

    [0484] To a 25 mL eggplant-shaped flask, E4-5 (80 mg, 0.19 mmol) and xylene (5 mL) were added. In a stirring state, thionyl chloride (1.5 mL) was added dropwise and the reaction solution was stirred at 100° C. for 16 hours. The reaction was completed and the reaction solution was filtered to obtain a solid. The solid was dissolved in dichloromethane and then washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase was concentrated. The crude was purified by HPLC to obtain 8-(2,3-dihydroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (4 mg, 5% yield).

    [0485] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99 (s, 1H), 7.98 (s, 1H), 7.52 (d, J=6.8 Hz, 1H), 7.14 (d, J=6.3 Hz, 1H), 6.78-6.71 (m, 1H), 6.60 (dd, J=8.6, 3.8 Hz, 1H), 6.00 (t, J=6.7 Hz, 1H), 4.61-4.50 (m, 4H), 4.15 (t, J=10.3 Hz, 2H), 3.78 (t, J=10.4 Hz, 2H), 3.36 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 404.0 [M+H].sup.+.

    Example 54: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(quinolin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0486] ##STR00411##

    [0487] Into a 10 mL sealed tube, B3 (50 mg, 0.14 mmol), quinolin-8-ylboronic acid (24 mg, 0.20 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.1 mg, 0.014 mmol), potassium carbonate (58.5 mg, 0.423 mmol), anhydrous dioxane (2 mL) and water (0.5 mL) were added sequentially. The tube was sealed under nitrogen protection and the mixture was stirred in 80° C. oil bath for 2 hours. Upon completion of the reaction, the reaction solution was filtered and then spin-dried. The product in the residue was dissolved in 3 ml DMF and was then purified by prep-HPLC (0.05% aqueous trifluoroacetic acid solution:acetonitrile=3:7) to obtain a product N-((5-fluoro-1,3-dihydroisobenzofuran-4-yl)methyl)-8-(quinolin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (21 mg, 37.5% yield).

    [0488] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (s, 1H), 8.84 (dd, J=4.1, 1.8 Hz, 1H), 8.79 (s, 1H), 8.45 (dd, J=8.3, 1.8 Hz, 1H), 8.11 (dd, J=7.2, 1.5 Hz, 1H), 8.04 (dd, J=8.3, 1.5 Hz, 1H), 7.97 (s, 1H), 7.72 (dd, J=8.2, 7.2 Hz, 1H), 7.58 (dd, J=8.3, 4.1 Hz, 1H), 7.02-6.92 (m, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.76 (d, J=4.7 Hz, 2H), 4.57 (t, J=8.7 Hz, 2H), 3.39 (s, 5H) ppm; LCMS: m/z 413.0 [M+H].sup.+.

    Example 55: 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    Step 1: 5-bromobenzo[b]thiophene 1,1-dioxide (E5-2)

    [0489] ##STR00412##

    [0490] Into a 500 mL round-bottom flask, E5-1 (10 g, 46.9 mmol), dichloromethane (120 mL) and formic acid (85% aqueous solution, 10 mL) were added. Hydrogen peroxide (35% aqueous solution, 16.7 mL, 141 mmol) was then slowly added at room temperature. The reaction solution was stirred at room temperature overnight. Upon completion of the reaction, 200 mL of saturated brine was added and the resulting mixture was extracted with dichloromethane (200 mL*3). The organic layers were combined, then dried over anhydrous sodium sulfate, filtered and spin-dried to obtain a residue, which was purified by Flash chromatography (petroleum ether:ethyl acetate=10:1) to obtain a white solid E5-2 (9.9 g, 86% yield).

    [0491] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.68 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.18 (d, J=6.9 Hz, 1H), 6.77 (d, J=6.9 Hz, 1H) ppm; LCMS: m/z 244.9 [M+H].sup.+.

    Step 2: (1,1-dihydroxybenzo[b]thiophen-5-yl)boronic acid (E5-3)

    [0492] ##STR00413##

    [0493] Into a dry 30 mL sealed tube, E5-2 (130 mg, 0.53 mmol) and bis(pinacolato)diboron (188 mg, 0.74 mmol) were added sequentially. [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.032 mmol), and potassium acetate (156 mg, 1.59 mmol) dissolved in 5 ml of dry 1,4-dioxane were added. The reaction mixture was bubbled with nitrogen gas for one minute and then the reaction system was warmed to 90° C. and stirred for 12 hours. The reaction solution was cooled to room temperature, and the raw materials were substantially converted to E5-3 (detected by LCMS). Then the reaction was not subjected to post-treatment, but was directly used in the next reaction by using a one-pot process.

    [0494] LCMS: m/z 210.7 [M+H].sup.+.

    Step 3: 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0495] ##STR00414##

    [0496] Into the above-mentioned reaction solution of E5-3, intermediate B1 (100 mg, 0.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 0.03 mmol), potassium carbonate (76 mg, 0.54 mmol), and H.sub.2O (2 mL) were added sequentially. The resulting reaction solution was bubbled with nitrogen gas for one minute, then warmed to 85° C. and stirred for 2 hours. The reaction solution was cooled to room temperature. The reaction system was slowly added dropwise into ice water (30 mL) and then extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Flash chromatography (neat ethyl acetate) to obtain a product 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide (64 mg, 52% yield) as a white solid.

    [0497] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (s, 1H), 8.36-8.23 (m, 2H), 8.11 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.29 (d, J=6.6 Hz, 1H), 6.82 (t, J=9.4 Hz, 1H), 6.65 (d, J=6.3 Hz, 1H), 4.86-4.62 (m, 3H), 2.86-2.75 (m, 1H), 0.93-0.81 (m, 1H), 0.05-0.04 (m, 1H) ppm; LCMS: m/z 461.7 [M+H].sup.+.

    [0498] The following compound can be synthesized with intermediate B3 and 5-bromobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 56: 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0499] ##STR00415##

    [0500] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.11 (s, 1H), 8.47-8.36 (m, 2H), 8.25 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.72 (d, J=6.9 Hz, 1H), 7.42 (d, J=6.9 Hz, 1H), 7.00-6.92 (m, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.75 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.33-3.29 (m, 2H) ppm; LCMS: m/z 449.8 [M+H].sup.+.

    [0501] The following compound can be synthesized with intermediate B2 and 5-bromobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 57: 5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0502] ##STR00416##

    [0503] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (s, 1H), 8.36-8.23 (m, 2H), 8.11 (s, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.29 (d, J=6.6 Hz, 1H), 6.82 (t, J=9.4 Hz, 1H), 6.65 (d, J=6.3 Hz, 1H), 4.86-4.62 (m, 3H), 2.86-2.75 (m, 1H), 0.93-0.81 (m, 1H), 0.05-0.04 (m, 1H) ppm; LCMS: m/z 461.7 [M+H].sup.+.

    [0504] The following compound can be synthesized with intermediate B3 and 4-bromobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 58: 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0505] ##STR00417##

    [0506] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.49 (s, 1H), 8.87 (s, 1H), 7.96-7.66 (m, 4H), 7.44 (d, J=7.1 Hz, 1H), 7.34 (d, J=7.1 Hz, 1H), 6.97 (t, J=9.4 Hz, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.74 (d, J=4.5 Hz, 2H), 4.57 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 449.8 [M+H].sup.+.

    [0507] The following compound can be synthesized with intermediate B1 and 4-bromobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 59: 4-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0508] ##STR00418##

    [0509] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.34 (s, 1H), 8.82 (s, 1H), 7.76-7.51 (m, 4H), 7.26 (d, J=7.1 Hz, 1H), 7.17 (d, J=7.1 Hz, 1H), 6.85-6.74 (m, 1H), 6.62 (dd, J=8.7, 3.9 Hz, 1H), 4.84-4.67 (m, 3H), 0.96-0.80 (m, 1H), 0.00 (s, 1H) ppm; LCMS: m/z 461.7 [M+H].sup.+.

    [0510] The following compound can be synthesized with intermediate B3 and 5-bromo-6-methylbenzo[b]thiophene as the raw materials using the method of example 55:

    Example 60: 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylbenzo[b]thiophene 1,1-dioxide

    [0511] ##STR00419##

    [0512] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 8.78 (s, 1H), 7.85 (s, 1H), 7.69 (s, 1H), 7.62 (d, J=6.9 Hz, 1H), 7.58 (s, 1H), 7.34 (d, J=6.8 Hz, 1H), 6.97 (t, J=9.4 Hz, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.73 (d, J=4.0 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.35 (s, 2H), 2.31 (s, 3H) ppm; LCMS: m/z 463.7 [M+H].sup.+.

    [0513] The following compound can be synthesized with intermediate B3 and 5-bromo-7-fluorobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 61: 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0514] ##STR00420##

    [0515] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 9.07 (s, 1H), 8.44-8.31 (m, 3H), 7.75 (dd, J=6.8, 2.4 Hz, 1H), 7.50 (d, J=6.7 Hz, 1H), 7.02-6.89 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.55 (s, 2H) ppm; LCMS: m/z 467.7 [M+H].sup.+.

    [0516] The following compound can be synthesized with intermediate B2 and 2-(5-bromobenzo[b]thiophen-3-yl)ethylamine hydrochloride as the raw materials using the method of example 55:

    Example 62: 3-(2-aminoethyl)-5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0517] ##STR00421##

    [0518] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.67 (s, 1H), 9.29 (t, J=5.2 Hz, 1H), 8.56-8.40 (m, 2H), 8.35 (s, 1H), 8.10 (s, 3H), 7.96 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 6.94 (dd, J=10.3, 8.7 Hz, 1H), 6.77 (dd, J=8.7, 3.8 Hz, 1H), 5.01-4.82 (m, 3H), 3.22 (q, J=6.8 Hz, 2H), 3.08 (t, J=7.4 Hz, 2H), 2.98 (dt, J=9.1, 4.5 Hz, 1H), 0.95 (dt, J=9.1, 5.8 Hz, 1H), 0.09 (ddd, J=6.1, 4.0, 1.9 Hz, 1H) ppm; LCMS: m/z 504.7 [M+H].sup.+.

    [0519] The following compound can be synthesized with intermediate B3 and 5-bromobenzo[c]thiophene as the raw materials using the method of example 55:

    Example 63: 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide

    [0520] ##STR00422##

    [0521] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (s, 1H), 8.28 (s, 1H), 8.08 (d, J=6.8 Hz, 1H), 8.01 (s, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.31 (d, J=6.9 Hz, 1H), 6.90-6.82 (m, 1H), 6.75 (d, J=6.9 Hz, 1H), 6.68 (dd, J=8.6, 4.0 Hz, 1H), 6.17 (s, 1H), 4.84 (d, J=5.4 Hz, 2H), 4.64 (t, J=8.7 Hz, 2H), 3.42 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 449.7 [M+H].sup.+

    [0522] The following compound can be synthesized with intermediate B1 and 5-bromobenzo[c]thiophene as the raw materials using the method of example 55:

    Example 64: 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide

    [0523] ##STR00423##

    [0524] .sup.1H NMR (DMSO-d.sub.6) δ 9.55 (s, 1H), 9.06 (s, 1H), 8.45-8.36 (m, 2H), 8.25 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.71 (d, J=6.9 Hz, 1H), 7.41 (d, J=6.8 Hz, 1H), 6.98-6.90 (m, 1H), 6.78 (dd, J=8.7, 3.9 Hz, 1H), 4.93 (dd, J=12.5, 8.8 Hz, 2H), 2.98-2.89 (m, 1H), 2.03-1.93 (m, 1H), 0.99 (dt, J=9.0, 5.9 Hz, 1H), 0.13 (s, 1H).

    [0525] The following compound can be synthesized with intermediate B4 and 5-bromobenzo[c]thiophene as the raw materials using the method of example 55:

    Example 65: 5-(5-(((6-fluorochroman-5-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide

    [0526] ##STR00424##

    [0527] .sup.1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.38 (d, J=9.7 Hz, 1H), 7.34-7.26 (m, 1H), 7.22 (d, J=6.1 Hz, 1H), 7.00 (t, J=7.1 Hz, 1H), 6.58 (dd, J=6.9, 2.9 Hz, 1H), 6.06 (t, J=8.1 Hz, 1H), 6.03-5.90 (m, 2H), 4.51 (d, J=5.5 Hz, 1H), 4.04-3.91 (m, 2H), 3.38-3.28 (m, 2H), 2.17-2.04 (m, 2H), 1.27-1.14 (m, 2H) ppm; LCMS: m/z 463.7 [M+H].sup.+.

    Example 66: 6-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    Step 1: 6-bromo-2-methylbenzo[b]thiophene E6-2

    [0528] ##STR00425##

    [0529] Into a 25 mL three-necked flask, E6-1 (1 g, 4.69 mmol) and anhydrous tetrahydrofuran (10 mL) were added under nitrogen protection and the mixture was cooled to −70° C. Lithium diisopropylamide (2 M in THF, 3.52 mL, 7.04 mmol) was slowly added. The reaction continued for another 40 minutes at −70° C. Methyl iodide (1.33 g, 9.39 mmol) was slowly added and then the reaction solution was warmed to room temperature and reacted for 2 hours. Upon completion of the reaction, the reaction was quenched by adding ice water (5 mL). HCl (1 N) was used to adjust the pH to neutral. The resulting mixture was diluted with ethyl acetate (10 mL). The organic phase was washed with saturated sodium chloride solution (5 mL), then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude E6-2 (960 mg) as light yellow solid, which was directly used in the next step.

    Step 2: 6-bromo-2-methylbenzo[b]thiophene 1,1-dioxide (E6-3)

    [0530] ##STR00426##

    [0531] Into a 25 mL single-necked flask, intermediate E6-2 (960 mg, 4.23 mmol) was added. Acetic acid (10 mL) was added and dissolved with stirring. Then hydrogen peroxide (30% aqueous solution, 4.8 g, 42.27 mmol) was added. The mixture was warmed to 100° C. and reacted for 3 h. Upon completion of the reaction, The resulting mixture was cooled to room temperature. Ice water (8 mL) was added and the mixture was stirred for 5-10 minutes and then extracted twice with ethyl acetate (8 mL). The organic phase was washed once with water (5 mL) and saturated brine (5 mL), respectively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (mobile phase:petroleum ether to 10% petroleum ether/ethyl acetate) to obtain E6-3 (800 mg, 66% yield) as a white solid.

    [0532] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.83 (s, 1H), 7.65 (dd, J=8.0, 1.7 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), 2.21 (d, J=1.7 Hz, 3H) ppm; LCMS: m/z 278.7 [M+H].sup.+.

    [0533] Step 3: The following compound can be synthesized with intermediates B3 and E6-3 as the raw materials using the method of example 55:

    ##STR00427##

    [0534] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.50 (dd, J=8.0, 1.4 Hz, 1H), 8.32 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.01-6.92 (m, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.74 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32 (s, 2H), 2.24-2.09 (m, 3H) ppm; LCMS: m/z 463.7 [M+H].sup.+.

    [0535] The following compound can be synthesized with intermediate B1 and 5-bromo-benzothiophene as the raw materials using the method of example 66:

    Example 67: 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    [0536] ##STR00428##

    [0537] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.06 (s, 1H), 8.34 (d, J=6.6 Hz, 2H), 8.24 (s, 1H), 7.94 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.07-6.89 (m, 1H), 6.78 (dd, J=8.7, 3.9 Hz, 1H), 4.93 (td, J=5.3, 1.8 Hz, 1H), 4.89 (d, J=3.2 Hz, 2H), 3.00-2.87 (m, 1H), 2.16 (d, J=1.5 Hz, 3H), 0.99 (dt, J=8.9, 6.0 Hz, 1H), 0.13 (ddd, J=5.9, 3.9, 1.9 Hz, 1H) ppm; LCMS: m/z 475.7 [M+H].sup.+

    [0538] The following compound can be synthesized with intermediate B3 and 4-bromo-benzothiophene as the raw materials using the method of example 66:

    Example 68: 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    [0539] ##STR00429##

    [0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.50 (dd, J=8.0, 1.4 Hz, 1H), 8.32 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 7.00-6.90 (m, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.74 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32 (s, 2H), 2.27-2.08 (m, 3H) ppm; LCMS: m/z 463.7 [M+H].sup.+.

    [0541] The following compound can be synthesized with intermediate B3 and 5-bromo-7-chlorobenzothiophene as the raw materials using the method of example 66:

    Example 69: 7-chloro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    [0542] ##STR00430##

    [0543] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.58 (s, 1H), 8.81 (s, 1H), 8.12 (s, 1H), 8.03 (d, J=11.7 Hz, 2H), 6.91-6.75 (m, 2H), 6.71 (d, J=4.7 Hz, 1H), 4.93 (s, 2H), 4.85 (s, 1H), 2.93 (s, 1H), 2.59 (s, 1H), 2.25 (s, 3H), 1.04 (s, 1H).

    [0544] The following compound can be synthesized with intermediate B3 and 5-bromo-7-fluorobenzothiophene as the raw materials using the method of example 66:

    Example 70: 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2,3-dimethylbenzo[b]thiophene 1,1-dioxide

    [0545] ##STR00431##

    [0546] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 9.00 (t, J=4.9 Hz, 1H), 7.72 (s, 1H), 7.45 (s, 1H), 7.28 (s, 1H), 7.03-6.90 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.74 (d, J=4.8 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.33 (d, J=8.9 Hz, 2H), 2.17 (dd, J=7.2, 1.6 Hz, 6H) ppm; LCMS: m/z 495.7 [M+H].sup.+.

    Example 71: 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1-dioxide

    Step 1: 1-((4-bromophenyl)thio)propan-2-one (E7-2)

    [0547] ##STR00432##

    [0548] Into a 50 mL single-necked flask, compound E7-1 (800 mg, 4.23 mmol), bromoacetone (638 mg, 4.65 mmol), potassium carbonate (1.75 g, 12.7 mmol), and acetonitrile (15 mL) were added sequentially. The reaction mixture was warmed to 75° C., stirred for 3 hours and then cooled to room temperature. Water (30 mL) was added and the resulting mixture was extracted with ethyl acetate (50 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (ethyl acetate:methanol=5:1) to obtain the compound E7-2 (960 mg, 92% yield).

    [0549] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.55-7.45 (m, 2H), 7.32-7.20 (m, 2H), 4.05 (s, 2H), 2.21 (s, 3H). ppm; LCMS: m/z 244.8 [M+H].sup.+.

    Step 2: 5-bromo-3-methylbenzo[b]thiophene (E7-3)

    [0550] ##STR00433##

    [0551] Into a 50 mL eggplant-shaped flask, E7-2 (260 mg, 1.06 mmol), chlorobenzene (20 mL), and polyphosphoric acid (5 mL) were added sequentially. The reaction system was warmed to 135° C. and stirred for 20 hours. The reaction was completed (monitored by TLC) and the reaction solution was poured into ice water (30 mL). Then the resulting mixture was extracted with dichloromethane (40 mL*3). The organic phases were combined and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (eluents:ethyl acetate:methanol=5:1) to obtain the compound E7-3 (200 mg, 83% yield).

    [0552] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (d, J=1.6 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 2.33 (d, J=1.0 Hz, 3H) ppm.

    Step 3: 5-bromo-3-methylbenzo[b]thiophene 1,1-dioxide (E7-4)

    [0553] ##STR00434##

    [0554] Into a 50 mL single-necked flask, compound E7-3 (200 mg, 0.88 mmol), dichloromethane (4 mL), formic acid (1 mL, 85% aqueous solution), and hydrogen peroxide (0.5 mL, 35% aqueous solution) were added sequentially. The reaction system was stirred at room temperature overnight. Upon completion of the reaction, water (10 mL) was added into the reaction solution. The resulting mixture was extracted with dichloromethane (20 mL*2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the compound E7-4 (210 mg, 92% yield).

    [0555] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.89 (s, 1H), 7.87-7.76 (m, 2H), 7.21-7.16 (m, 1H), 2.37-2.19 (m, 3H) ppm; LCMS: m/z 260.7 [M+H].sup.+.

    [0556] Step 4: The following compound can be synthesized with intermediates B1 and E7-4 as the raw materials using the method of example 55:

    ##STR00435##

    [0557] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.43 (s, 1H), 8.96 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.23 (s, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 6.86-6.80 (m, 1H), 6.66 (dd, J=8.7, 3.9 Hz, 1H), 4.85-4.74 (m, 3H), 2.85-2.79 (m, 1H), 2.23 (s, 3H), 0.89-0.83 (m, 1H), −0.00 (s, 1H) ppm; LCMS: m/z 475.7 [M+H].sup.+.

    Example 72: 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    Step 1: 5-bromo-2-fluorobenzo[b]thiophene (E8-2)

    [0558] ##STR00436##

    [0559] Into a 25 mL three-necked flask, E8-1 (500 mg, 2.35 mmol) and anhydrous tetrahydrofuran (10 mL) were added under nitrogen protection and the mixture was cooled to −70° C. Lithium diisopropylamide (2M in THF, 1.5 mL, 3 mmol) was slowly added. The reaction continued for another 40 minutes at −70° C. N-fluorodibenzenesulfonimide (2.2 g, 2.35 mmol) was slowly added and the resulting mixture was warmed to room temperature and reacted overnight. Upon completion of the reaction, the reaction was quenched by adding ice water (30 mL). The mixture was then extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by Flash chromatography (eluents: 100% petroleum ether) to obtain a light yellow solid E8-2 (170 mg, 31% yield).

    [0560] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (d, J=1.8 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.6, 1.9 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H).

    [0561] The following compound can be synthesized with intermediates B1 and E8-2 as the raw materials using the method of example 55:

    ##STR00437##

    [0562] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.27 (s, 1H), 8.19 (s, 1H), 8.00 (dd, J=8.1, 1.4 Hz, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 6.74 (d, J=10.0 Hz, 1H), 6.65 (d, J=4.0 Hz, 1H), 6.59 (d, J=2.0 Hz, 1H), 4.92-4.84 (m, 2H), 4.81-4.77 (m, 1H), 2.87 (dd, J=9.2, 4.7 Hz, 1H), 1.01-0.99 (m, 1H), 0.32-0.26 (m, 1H) ppm; LCMS: m/z 479.7 [M+H].sup.+.

    Example 73: 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1-dioxide

    [0563] The following compound can be synthesized with intermediates B1 and E7-3 as the raw materials using the method of example 72:

    ##STR00438##

    [0564] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.88 (s, 1H), 8.21 (s, 1H), 8.11-8.03 (m, 1H), 8.02 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 6.87-6.77 (m, 1H), 6.71 (dd, J=8.7, 4.0 Hz, 1H), 6.18 (s, 1H), 5.00 (ddd, J=51.2, 14.3, 5.5 Hz, 2H), 4.88 (td, J=5.4, 1.9 Hz, 1H), 3.04-2.86 (m, 1H), 2.21 (d, J=3.2 Hz, 3H), 1.16-1.06 (m, 1H), 0.41-0.30 (m, 1H) ppm; LCMS: m/z 493.7 [M+H].sup.+.

    [0565] The following compound can be synthesized with intermediate B1 and 5-bromo-3-fluorobenzo[b]thiophene as the raw materials using the method of example 55:

    Example 74: 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide

    [0566] ##STR00439##

    [0567] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.13 (s, 1H), 8.56-8.38 (m, 2H), 8.26 (s, 1H), 7.97 (dd, J=8.2, 2.4 Hz, 1H), 7.43 (d, J=3.1 Hz, 1H), 6.91-6.77 (m, 1H), 6.66 (dd, J=8.7, 3.9 Hz, 1H), 4.85-4.80 (m, 1H), 4.78 (d, J=4.6 Hz, 2H), 2.94-2.79 (m, 1H), 0.92-0.80 (m, 1H), 0.00 (t, J=4.1 Hz, 1H) ppm; LCMS: m/z 479.6 [M+H].sup.+.

    [0568] The following compound can be synthesized with intermediate B1 and 5-bromo-3-fluorobenzo[b]thiophene as the raw materials using the method of example 66:

    Example 75: 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    [0569] ##STR00440##

    [0570] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.09 (s, 1H), 8.26-8.19 (m, 1H), 8.16 (s, 1H), 8.02 (s, 1H), 7.79 (dd, J=8.0, 2.3 Hz, 1H), 6.91 (s, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.69-6.57 (m, 1H), 4.97 (ddd, J=42.7, 14.3, 5.3 Hz, 2H), 4.84 (td, J=5.4, 1.8 Hz, 1H), 3.03-2.85 (m, 1H), 2.15 (s, 3H), 1.08 (dt, J=8.8, 6.2 Hz, 1H), 0.33 (ddd, J=6.1, 4.0, 1.9 Hz, 1H) ppm; LCMS: m/z 493.7 [M+H].sup.+.

    [0571] The following compound can be synthesized with intermediate B1 and 5-bromo-7-chlorobenzothiophene as the raw materials using the method of example 66:

    Example 76: 3-chloro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide

    [0572] ##STR00441##

    [0573] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.96 (s, 1H), 8.34-8.19 (m, 2H), 8.05 (s, 1H), 7.82 (d, J=7.9 Hz, 1H), 6.89-6.75 (m, 1H), 6.70 (dd, J=8.7, 4.0 Hz, 1H), 6.45 (s, 1H), 5.12-4.91 (m, 2H), 4.91-4.82 (m, 1H), 3.02-2.89 (m, 1H), 2.26 (s, 3H), 1.15-1.08 (m, 1H), 0.45-0.28 (m, 1H) ppm; LCMS: m/z 509.6 [M+H].sup.+.

    Example 77: Methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carboxylate

    Step 1: intermediate (2-amino-6-(methyloxycarbonyl)pyridin-3-yl)boronic acid E9-2

    [0574] ##STR00442##

    [0575] Into a 25 mL single-necked flask, compound E9-1 (200 mg, 0.87 mmol), bis(pinacolato)diboron (439 mg, 1.73 mmol), potassium acetate (212 mg, 2.16 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.09 mmol) and 1,4-dioxane (10 mL) were added sequentially. The reaction system was warmed to 90° C. and reacted under nitrogen atmosphere for 16 hours. The reaction was completed (monitored by LCMS) and the reaction solution was directly used in the next step.

    [0576] LCMS: m/z 196.9 [M+H].sup.+.

    [0577] Step 2: intermediate methyl 6-amino-5-(5-((((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)amino]-[1,2,4]triazole[4,3-c]pyrimidine-8-pyridylpicolinic acid E9-3

    ##STR00443##

    [0578] To the reaction solution obtained in the previous step, intermediate B3 (315 mg, 0.87 mmol), potassium carbonate (359 mg, 2.60 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (63 mg, 0.09 mmol) and water (3 mL) were added. The reaction system was warmed to 80° C. and reacted under nitrogen atmosphere for 5 h. The reaction was completed (as detected) and the reaction system was cooled to room temperature and diluted and dissolved in ethyl acetate (30 mL). The organic phase was washed with water (5 mL*2), then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (mobile phase:ethyl acetate:methanol=10:1) to obtain the compound E9-3 (260 mg, 69% yield).

    [0579] LCMS: m/z 436.1 [M+H].sup.+.

    [0580] Step 3: Methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carboxylate can be synthesized with intermediate E9-2 and 2-chloroacetaldehyde as the raw materials using the method in step 3 of example 21:

    ##STR00444##

    [0581] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.79 (s, 1H), 9.55 (s, 1H), 9.05 (s, 1H), 8.93 (d, J=7.9 Hz, 1H), 8.90 (d, J=1.3 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.86 (d, J=1.3 Hz, 1H), 6.98-6.94 (m, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.80 (s, 2H), 4.56 (t, J=8.6 Hz, 2H), 3.99 (s, 3H), 3.33 (s, 2H) ppm; LCMS: m/z 459.9 [M+H].sup.+.

    Example 78: (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-5-yl)methanol

    Step 1: intermediate (6-amino-5-(5-((((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl]amino)amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)pyridin-2-yl)methanol E9-4

    [0582] ##STR00445##

    [0583] E9-3 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (10 mL) and lithium aluminium hydride (22 mg, 0.57 mmol) was added at 0° C. The reaction solution was stirred at room temperature for 16 h. The reaction was completed and quenched by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (30 mL×2) and the organic phase was dried and concentrated to obtain the target compound E9-4 (35 mg, 76% yield).

    [0584] LCMS: m/z 408.1 [M+H].sup.+.

    [0585] Step 2: (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-5-yl)methanol can be synthesized with intermediate E9-4 and 2-chloroacetaldehyde as the raw materials using the method in step 3 of example 21:

    ##STR00446##

    [0586] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (d, J=1.1 Hz, 2H), 8.98 (s, 1H), 8.79 (d, J=7.4 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.72 (d, J=1.3 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.01-6.93 (m, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 5.78 (t, J=5.7 Hz, 1H), 4.82 (d, J=5.7 Hz, 2H), 4.77 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.28 (s, 2H) ppm; LCMS: m/z 432.0 [M+H].sup.+.

    [0587] Intermediate E10-1 can be synthesized with 3-bromo-6-methylpyridin-2-amine and intermediate B3 as the raw materials using the methods in steps 1 and 2 of example 21:

    ##STR00447##

    [0588] .sup.1H NMR (400 MHz, MeOD) δ 9.28 (s, 1H), 7.73 (s, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.39 (d, J=2.5 Hz, 1H), 6.85 (t, J=9.3 Hz, 1H), 6.71-6.62 (m, 2H), 4.77 (s, 2H), 4.63 (t, J=8.7 Hz, 2H), 4.00 (s, 2H), 3.38 (d, J=8.2 Hz, 2H), 2.43 (s, 3H) ppm; LCMS: m/z 392.1 [M+H].sup.+.

    [0589] The following compound can be synthesized with intermediate E10-1 and 2-chloro-3-methylbutanal as the raw materials using the method in step 3 of example 21:

    Example 79: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-isopropyl-5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0590] ##STR00448##

    [0591] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.85 (s, 1H), 9.56 (s, 1H), 9.00 (s, 1H), 8.95 (dd, J=11.1, 2.3 Hz, 1H), 8.78-8.74 (m, 1H), 8.05 (s, 1H), 7.72 (s, 1H), 7.00-6.94 (m, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.35 (s, 2H) ppm; LCMS: m/z 420.0 [M+H].sup.+.

    Example 80: Methyl 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetate

    Step 1: methyl 3-chloro-4-carbonylbutyrate E11-2

    [0592] ##STR00449##

    [0593] Into a dry 100 mL single-necked flask, E11-1 (290 mg, 2.5 mmol) and chloroform (9 mL) were added sequentially. In an ice bath, L-proline (57.57 mL, 0.5 mmol) and N-chlorosuccinimide (400 mg, 3 mmol) were added with stirring. The reaction temperature was raised to room temperature and the reaction solution was stirred and reacted at room temperature for 3 hours to obtain a chloroform solution of the crude E11-2. The reaction solution was directly used in the next step without any treatment.

    [0594] Step 2: Compound E11-3 as below can be synthesized with E11-2 and intermediate E10-1 as the raw materials using the method of example 21:

    ##STR00450##

    [0595] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.40 (s, 1H), 8.79 (t, J=4.9 Hz, 1H), 8.52 (d, J=7.4 Hz, 1H), 7.52 (s, 1H), 7.01-6.91 (m, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (d, J=4.6 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.42 (s, 2H), 3.69 (s, 3H), 3.31 (s, 2H), 2.78 (s, 3H) ppm; LCMS: m/z 488.0 [M+H].sup.+.

    Example 81: 2-(8-(5-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-ol E11-4

    [0596] ##STR00451##

    [0597] Into a dry 25 mL single-necked flask, E11-3 (30 mg, 0.06 mmol) and tetrahydrofuran (5 mL) were added sequentially. In an ice bath, lithium aluminium hydride (11.39 mg, 0.3 mmol) was added with stirring. The reaction temperature was raised to room temperature and the reaction solution was stirred and reacted at room temperature for 1 hour. Upon completion of the reaction, the reaction solution was cooled to 0° C. and the reaction was quenched with water. The resulting mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and finally purified by preparative high-performance liquid chromatography to obtain the compound E11-4 (15 mg, 54.4%).

    [0598] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (s, 1H), 9.42 (s, 1H), 8.76 (t, J=5.0 Hz, 1H), 8.47 (d, J=7.4 Hz, 1H), 7.43 (s, 1H), 6.95 (d, J=9.7 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.88 (t, J=5.2 Hz, 1H), 4.76 (d, J=4.9 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.79-3.75 (m, 2H), 3.41 (d, J=6.8 Hz, 2H), 3.31 (s, 2H), 2.91 (s, 3H) ppm; LCMS: m/z 460.0 [M+H].sup.+.

    Example 82: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)ethyl acetate

    [0599] ##STR00452##

    [0600] E11-4 (20 mg) was dissolved in pyridine (1 mL). 4-dimethylaminopyridine (2 mg) and acetic anhydride (10 mg) were added and the mixture was stirred at room temperature overnight. Dichloromethane (10 mL) and water (10 mL) were added into the reaction solution and the resulting mixture was extracted with dichloromethane (10 mL*3). The organic layer was dried over sodium sulfate and then spin-dried. The yellow solid obtained was washed with ethyl acetate (2 mL) under stirring to obtain a white solid, 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)ethyl acetate (13 mg, 59.5% yield).

    [0601] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H), 8.50 (d, J=7.3 Hz, 1H), 7.44 (s, 1H), 6.96 (t, J=9.4 Hz, 1H), 6.82 (d, J=7.5 Hz, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.76 (d, J=3.6 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.39 (t, J=6.7 Hz, 2H), 3.61 (t, J=6.7 Hz, 2H), 3.32-3.28 (m, 2H), 2.91 (s, 3H), 2.03 (s, 3H) ppm; LCMS: m/z 502.0 [M+H].sup.+.

    Example 83: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetamide

    [0602] ##STR00453##

    [0603] Into a 20 mL sealed tube, E11-3 (40 mg, 0.082 mmol) and a saturated solution of ammonia methanol (8 mL) were added. The mixture was stirred at 85° C. for 16 hours. Upon completion of the reaction, the reaction solution was cooled down and a white solid was precipitated out. The resulting reaction solution was filtered and washed with ethyl acetate to obtain the target compound 2-(8-(5-((((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetamide (26 mg, 67% yield).

    [0604] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (d, J=1.4 Hz, 1H), 9.41 (d, J=13.3 Hz, 1H), 8.50 (d, J=7.4 Hz, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.10 (s, 2H), 7.01-6.91 (m, 1H), 6.80 (d, J=7.3 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=3.9 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.07 (s, 2H), 3.32 (d, J=8.8 Hz, 2H), 2.85 (s, 3H). ppm; LCMS: m/z 473.1 [M+H].sup.+.

    Example 84: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide

    Step 1: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetic acid E11-5

    [0605] ##STR00454##

    [0606] Into a 25 mL single-necked flask, E11-3 (30 mg, 0.06 mmol) and methanol (3 mL) were added sequentially. A solution of sodium hydroxide (24 mg, 0.6 mmol) in water (1 mL) was added. The mixture was stirred and reacted at room temperature for 1 hour. Upon completion of the reaction, the PH was adjusted with 1M HCl to 7 and a white solid was precipitated out. The white solid was washed with water and methanol and then dried under vacuum to obtain a crude E11-5 (12 mg, 42.2%).

    [0607] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.43 (s, 1H), 8.79 (s, 1H), 8.49 (d, J=7.4 Hz, 1H), 7.42 (s, 1H), 7.01-6.92 (m, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.10 (s, 2H), 3.27-3.14 (m, 2H), 2.86 (s, 3H) ppm; LCMS: m/z 474.1 [M+H].sup.+.

    Step 2: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide

    [0608] ##STR00455##

    [0609] Into a dry 25 mL single-necked flask, E11-5 (20 mg, 0.04 mmol) and dimethylformamide (2 mL) were added sequentially. Then dimethylamine hydrochloride (2.16 mg, 0.05 mmol), 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluoniumhexafluorophosphate (20 mg, 0.05 mmol) and triethylamine (12.14 mg, 0.12 mmol) were added sequentially. The mixture was stirred and reacted at room temperature for 1 hour. Upon completion of the reaction, water (10 mL) was slowly added dropwise and a white solid was precipitated out. The white solid was washed with water and methanol to obtain a pure product 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide (5 mg, 25.7% yield).

    [0610] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.48 (s, 1H), 9.44 (s, 1H), 8.77 (s, 1H), 8.50 (d, J=7.4 Hz, 1H), 7.38 (s, 1H), 6.96 (t, J=9.4 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.71 (dd, J=8.6, 3.7 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.36 (s, 2H), 3.31-3.25 (m, 2H), 3.13 (s, 3H), 2.88 (d, J=9.9 Hz, 3H), 2.75 (s, 3H) ppm; LCMS: m/z 501.1 [M+H].sup.+.

    [0611] The following compound can be synthesized with 8-bromo-5-methyl[1,2,4]-triazolo[1,5-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 85: N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0612] ##STR00456##

    [0613] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.57 (s, 1H), 9.45 (s, 1H), 9.11 (d, J=7.7 Hz, 1H), 9.04 (s, 1H), 8.63 (s, 1H), 7.29 (dd, J=7.7, 1.1 Hz, 1H), 6.96 (dd, J=10.3, 8.7 Hz, 1H), 6.78 (dd, J=8.7, 3.9 Hz, 1H), 5.00-4.85 (m, 3H), 2.97 (dt, J=9.1, 4.5 Hz, 1H), 2.79 (s, 3H), 1.02 (dt, J=9.0, 5.9 Hz, 1H), 0.14 (ddd, J=6.1, 4.0, 1.9 Hz, 1H) ppm; LCMS: m/z 429.0 [M+H].sup.+.

    [0614] The following compound can be synthesized with 8-bromo-5-methyl[1,2,4]-triazolo[1,5-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 86: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0615] ##STR00457##

    [0616] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 9.45 (s, 1H), 9.11 (d, J=7.7 Hz, 1H), 8.90 (t, J=5.0 Hz, 1H), 8.64 (d, J=9.7 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 7.02-6.92 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.78 (d, J=4.9 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.35 (s, 2H), 2.79 (s, 3H) ppm; LCMS: m/z 417.0 [M+H].sup.+.

    [0617] The following compound can be synthesized with 8-bromo-5-methylimidazo[1,2-a]pyridine and intermediate B1 as the raw materials using the method of example 6:

    Example 87: N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8-(5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0618] ##STR00458##

    [0619] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.99 (d, J=7.0 Hz, 1H), 8.87 (d, J=6.1 Hz, 1H), 8.58 (d, J=7.5 Hz, 1H), 8.31 (d, J=3.7 Hz, 1H), 7.52 (t, J=5.2 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.73 (dd, J=10.0, 8.8 Hz, 1H), 6.64 (dd, J=8.7, 4.0 Hz, 1H), 4.95 (dd, J=14.2, 5.5 Hz, 1H), 4.89-4.74 (m, 2H), 3.08-2.96 (m, 1H), 2.83 (s, 3H), 1.08-1.00 (m, 1H), 0.28 (ddd, J=6.2, 4.0, 1.9 Hz, 1H) ppm; LCMS: m/z 428.1 [M+H].sup.+.

    [0620] The following compound can be synthesized with 2-chloroacetaldehyde and intermediate E10-1 as the raw materials using the method in step 3 of example 21:

    Example 88: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0621] ##STR00459##

    [0622] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.61 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.75 (d, J=7.4 Hz, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 6.97 (dd, J=13.0, 5.9 Hz, 2H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 2.67 (s, 3H), 2.33 (s, 2H) ppm; LCMS: m/z 416.0 [M+H].sup.+.

    [0623] The following compound can be synthesized with 3-acetamidopropanal and intermediate E10-1 as the raw materials using the method in step 3 of example 21:

    Example 89: N-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)methyl)acetamide

    [0624] ##STR00460##

    [0625] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.51 (s, 1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.55 (d, J=7.4 Hz, 1H), 8.38 (s, 1H), 7.57 (s, 1H), 7.00-6.94 (m, 1H), 6.87 (d, J=7.7 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.86-4.71 (m, 4H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (s, 2H), 2.86 (s, 3H), 1.86 (s, 3H) ppm; LCMS: m/z 487.0 [M+H].sup.+.

    [0626] Compound methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-2-carboxylate E12-1 can be synthesized with 3-acetamidopropanal and intermediate E10-1 as the raw materials using the method in step 3 of example 21:

    ##STR00461##

    [0627] .sup.1H NMR (400 MHz, MeOD) δ 9.74 (s, 1H), 8.51 (s, 1H), 8.26 (s, 1H), 8.05 (d, J=7.4 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 6.83 (t, J=9.4 Hz, 1H), 6.66 (dd, J=8.6, 3.8 Hz, 1H), 4.65 (d, J=8.7 Hz, 2H), 4.16 (s, 3H), 3.46 (t, J=8.7 Hz, 2H), 2.89 (s, 3H) ppm; LCMS: m/z 428.1 [M+H].sup.+.

    [0628] The following compound can be obtained by reducing the raw material E12-1 with lithium aluminium hydride using the method of example 81:

    Example 90: (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)methanol

    [0629] ##STR00462##

    [0630] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (s, 1H), 9.53 (s, 1H), 8.81 (s, 1H), 8.73 (d, J=7.4 Hz, 1H), 7.75 (s, 1H), 6.96 (dd, J=20.7, 8.6 Hz, 2H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 5.27 (t, J=5.6 Hz, 1H), 4.78 (s, 2H), 4.69 (d, J=5.7 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.29 (s, 2H), 2.64 (s, 3H) ppm; LCMS: m/z 446.0 [M+H].sup.+.

    Example 91: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2-a]pyridine-2-carboxamide

    [0631] ##STR00463##

    [0632] Into a dry 25 mL three-necked flask, dry tetrahydrofuran (2 mL) and a solution of dimethylamine in tetrahydrofuran (0.1 mL, 0.2 mmol) were added and in an ice-water bath, a solution of trimethylaluminum in toluene (0.07 mL, 0.14 mmol) was added. The mixture was stirred in an ice-water bath for 10 minutes and then E12-1 (47 mg, 0.1 mmol, dissolved in 2 mL of tetrahydrofuran) was added. The reaction solution was refluxed for 2 hours and cooled to room temperature. Ice water (5 mL) was slowly added and the resulting mixture was extracted with dichloromethane (10 mL*3). The organic layer was washed with brine (10 mL), then dried over anhydrous sodium sulfate and spin-dried to obtain a yellow solid. The yellow solid was washed with ethyl acetate to obtain a white pure product, 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2-a]pyridine-2-carboxamide (33 mg, 0.068 mmol, 68% yield).

    [0633] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.22 (s, 1H), 9.07 (s, 1H), 8.27 (s, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.57 (s, 2H), 6.89 (d, J=7.3 Hz, 1H), 6.77-6.66 (m, 1H), 6.62 (dd, J=8.7, 3.9 Hz, 1H), 4.83 (d, J=14.2 Hz, 1H), 4.74 (dd, J=11.1, 5.7 Hz, 2H), 3.11-3.02 (m, 1H), 2.69 (s, 3H), 1.00 (dt, J=8.9, 6.1 Hz, 1H), 0.24-0.15 (m, 1H) ppm; LCMS: m/z 487.1 [M+H].sup.+.

    [0634] The following compound can be synthesized with ethyl 2-chloro-3-oxopropanoate and intermediate E10-1 as the raw materials using the method in step 3 of example 21:

    Example 92: Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylate

    [0635] ##STR00464##

    [0636] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.21 (s, 1H), 8.87 (t, J=5.1 Hz, 1H), 8.76 (d, J=7.6 Hz, 1H), 8.32 (s, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.03-6.92 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.17 (d, J=5.3 Hz, 2H), 2.77 (s, 3H), 1.36 (t, J=7.1 Hz, 3H) ppm; LCMS: m/z 488.1 [M+H].sup.+.

    [0637] The following compound can be synthesized with a solution of dimethylamine in tetrahydrofuran, and ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylate (example 92) as the raw materials using the method of example 92:

    Example 93: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2-a]pyridine-3-carboxamide

    [0638] ##STR00465##

    [0639] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.96 (s, 1H), 8.92 (s, 1H), 8.41 (s, 1H), 7.93 (d, J=7.3 Hz, 1H), 7.64 (s, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.64 (t, J=9.3 Hz, 1H), 6.52 (dd, J=8.6, 3.9 Hz, 1H), 4.60 (d, J=4.7 Hz, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.37 (t, J=8.6 Hz, 2H), 3.24 (d, J=18.8 Hz, 6H), 2.58 (s, 3H) ppm; LCMS: m/z 487.1 [M+H].sup.+.

    [0640] The following compound can be synthesized with 4-bromo-1-methyl-1H-benzo[d]imidazole and intermediate B3 as the raw materials using the method of example 6:

    Example 94: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-benzo[d]imidazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0641] ##STR00466##

    [0642] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (s, 1H), 9.27 (s, 1H), 8.58 (d, J=7.5 Hz, 1H), 8.30 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.03-6.92 (m, 1H), 6.73 (dd, J=8.6, 3.8 Hz, 1H), 4.79 (s, 2H), 4.57 (t, J=8.7 Hz, 2H), 3.92 (s, 3H), 3.35 (d, J=8.7 Hz, 2H) ppm; LCMS: m/z 416.0 [M+H].sup.+.

    Example 95: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine-5-carboxamide

    Step 1: 6-amino-5-bromo-N,N-dimethyl methylpicolinamide E13-1

    [0643] ##STR00467##

    [0644] Into a 25 mL round-bottom flask, methyl 6-amino-5-bromopyridine-2-carboxylate (100 mg, 0.43 mmol) and dichloromethane (5 mL) were added. After the mixture was dissolved with stirring, magnesium dichloride (49 mg, 0.52 mmol) was added in an ice-water bath. The resulting suspension was stirred for another 5 minutes in an ice-water bath and then a solution of dimethylamine in dichloromethane (2 M, 0.35 mL) was added. After the resulting mixture was stirred at normal temperature for 6 hours, almost all the raw materials were converted into the desired product (monitored by LCMS). The reaction solution was spin-dried to obtain a white solid, which was washed with water to remove the inorganic substances. A white solid was obtained by filtration and the white solid was dried under high vacuum to obtain E13-1 (88 mg, 83.8% yield).

    [0645] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.73 (d, J=7.9 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 5.02 (s, 2H), 3.09 (s, 3H), 3.04 (s, 3H) ppm; LCMS: m/z 244.0 [M+1].sup.+.

    [0646] Step 2: The following compound can be synthesized with E13-1 and intermediate B3 as the raw materials using the method of example 21:

    8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine-5-carboxamide

    [0647] ##STR00468##

    [0648] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.14 (s, 1H), 8.86 (s, 1H), 8.58 (s, 1H), 8.00 (d, J=7.3 Hz, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.00 (d, J=7.3 Hz, 1H), 6.73 (t, J=9.3 Hz, 1H), 6.60 (dd, J=8.6, 3.7 Hz, 1H), 4.70 (s, 2H), 4.56 (t, J=8.6 Hz, 2H), 3.39 (t, J=8.6 Hz, 2H), 3.19 (d, J=35.5 Hz, 6H) ppm; LCMS: m/z 473.1 [M+H].sup.+.

    Example 96: 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile

    Step 1: (Z)-2-bromo-3-methoxyacrylonitrile E14-1

    [0649] ##STR00469##

    [0650] Into a 25 mL round-bottom flask, 3-methoxyacrylonitrile (2.0 g, 24.4 mmol), 1,4 dioxane (30 mL) and water (10 mL) were added. In an ice-water bath, N-bromosuccinimide (980 mg, 24.4 mmol) was added in batches over 15 minutes. The reaction solution was stirred in the ice-water bath for half an hour and then the ice-water bath war removed. Stirring of the reaction system was continued at normal temperature overnight to obtain a liquid of E14-1 in dioxane, which was directly used in the next step without any treatment.

    Step 2: 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile

    [0651] ##STR00470##

    [0652] Into the reaction solution obtained in the previous step, 8-(2-amino-5-fluoropyridin-3-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine E2-2 (780 mg, 2.0 mmol) was added and the reaction solution was refluxed for 10 hours. Then the resulting mixture was allowed to cool down and stand for 5 hours. A brown solid was precipitated out. The mixture was filtered to obtain the brown solid, which was washed with a small amount of cold methanol under stirring. The resulting mixture was filtered to obtain a yellow solid. The yellow solid was dried under vacuum to obtain 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile (490 mg, 55% yield).

    [0653] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.64 (s, 1H), 9.57 (s, 1H), 9.17 (dd, J=11.0, 2.2 Hz, 1H), 9.10 (t, J=4.9 Hz, 1H), 8.96-8.83 (m, 1H), 8.53 (s, 1H), 6.99-6.86 (m, 1H), 6.70 (dd, J=8.6, 3.8 Hz, 1H), 4.80 (d, J=4.8 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.35 (d, J=9.0 Hz, 2H) ppm; LCMS: m/z 445.1 [M+H].sup.+.

    [0654] The following compound can be synthesized with methyl 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetate E11-3 and morpholine as the raw materials using the method in step 2 of example 84:

    Example 97: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-1-morpholinoethan-1-one

    [0655] ##STR00471##

    [0656] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.43 (s, 1H), 8.77 (t, J=5.0 Hz, 1H), 8.51 (d, J=7.4 Hz, 1H), 7.40 (s, 1H), 7.01-6.93 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.40 (s, 2H), 3.65 (s, 2H), 3.60 (dd, J=9.5, 5.2 Hz, 4H), 3.50 (d, J=4.8 Hz, 2H), 3.31 (s, 2H), 2.75 (d, J=14.2 Hz, 3H) ppm; LCMS: m/z 544.0 [M+H].sup.+.

    [0657] The following compound can be synthesized with 3-bromo-6-(trifluoromethyl)pyridin-2-amine and intermediate B3 as the raw materials using the method of example 21:

    Example 98: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0658] ##STR00472##

    [0659] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.74 (s, 1H), 9.56 (s, 1H), 9.06 (s, 1H), 8.95 (d, J=7.8 Hz, 1H), 8.14 (s, 1H), 7.90 (d, J=1.3 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 6.98 (s, 1H), 6.74 (d, J=3.9 Hz, 1H), 4.80 (s, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.37 (s, 2H) ppm; LCMS: m/z 470.1 [M+H].sup.+.

    [0660] The following compound can be synthesized with morpholine and 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylic acid (example 44) as the raw materials using the method in step 2 of example 84:

    Example 99: (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)(morpholino)methanone

    [0661] ##STR00473##

    [0662] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.25 (s, 1H), 8.62 (s, 1H), 8.23 (s, 1H), 7.71 (s, 1H), 7.55-7.41 (m, 1H), 6.89-6.67 (m, 2H), 6.60 (dd, J=8.5, 3.7 Hz, 1H), 4.71 (s, 2H), 4.59 (t, J=8.7 Hz, 2H), 3.78 (d, J=31.2 Hz, 8H), 3.40 (t, J=7.8 Hz, 2H), 2.62 (s, 3H) ppm; LCMS: m/z 529.2 [M+H].sup.+.

    [0663] The following compound can be synthesized with 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine and intermediate B3 as the raw materials using the method of example 6:

    Example 100: 8-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0664] ##STR00474##

    [0665] .sup.1H NMR (400 MHz, MeOD) δ 9.40-9.30 (m, 1H), 9.25-9.19 (m, 1H), 8.88 (dd, J=9.3, 7.4 Hz, 1H), 8.53-8.47 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.84 (dd, J=17.3, 7.3 Hz, 1H), 6.70-6.64 (m, 1H), 4.82 (d, J=18.0 Hz, 1H), 4.63 (dd, J=20.5, 11.7 Hz, 1H), 3.45 (d, J=17.4 Hz, 2H) ppm; LCMS: m/z 437.0 [M+H].sup.+.

    [0666] The following compound can be synthesized by subjecting the raw materials, ammonia chloride and 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylic acid (example 44) to condensation using the method in step 2 of example 84:

    Example 101: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxamide

    [0667] ##STR00475##

    [0668] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.33 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.71 (d, J=7.5 Hz, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.01-6.92 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.35 (s, 2H), 2.69 (d, J=14.5 Hz, 3H) ppm; LCMS: m/z 459.1 [M+H].sup.+.

    Example 102: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carbonitrile

    [0669] ##STR00476##

    [0670] Into a 25 mL round-bottom flask, 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxamide (example 101) (30 mg, 0.07 mmol) and anhydrous tetrahydrofuran (2 ml) were added and in an ice-water bath, trifluoroacetic anhydride (29 mg, 0.14 mmol) and triethylamine (14 mg, 0.14 mmol) were added. The reaction system was stirred at normal temperature overnight. The reaction solution was spin-dried to obtain a yellow solid. The yellow solid was washed with methanol and the resulting mixture was filtered to obtain a white solid. The white solid was dried under vacuum to obtain pure 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carbonitrile (24 mg, 80%).

    [0671] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.23 (s, 1H), 8.91 (t, J=4.9 Hz, 1H), 8.81 (d, J=7.6 Hz, 1H), 8.56 (s, 1H), 7.21 (d, J=7.7 Hz, 1H), 7.00-6.92 (m, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.77 (d, J=4.9 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.35 (s, 2H), 2.99 (s, 3H) ppm; LCMS: m/z 441.1 [M+H].sup.+.

    Example 103: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: N-(3-bromo-6-(trifluoromethyl)pyridin-2-yl)-N′-hydroxycarboximide E15-1

    [0672] ##STR00477##

    [0673] To a mixture solution of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (400 mg, 1.46 mmol) in isopropanol (10 mL), N,N-dimethylformamide dimethylacetal (300 mg, 2.49 mmol) was added and under nitrogen, the mixture was stirred at 80° C. for 3 hours. All the raw materials were converted into intermediates (shown by LCMS). The reaction system was cooled to 50° C. Then hydroxylamine hydrochloride (173 mg, 2.49 mmol) was added and the resulting mixture was stirred at the temperature for 5 hours. The mixture was cooled to room temperature and subjected to rotary evaporation to remove the solvent. Water was added and then the resulting mixture was extracted with ethyl acetate (30 mL×3). The combined organic layer was concentrated and purified to obtain a yellow oil E15-1 (450 mg, 97% yield).

    [0674] LCMS: m/z 284.1 [M+H].sup.+.

    Step 2: 8-bromo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine E15-2

    [0675] ##STR00478##

    [0676] To a solution of E15-1 (450 mg, 1.59 mmol) in tetrahydrofuran, trifluoroacetic anhydride (0.66 g, 3.18 mmol) was added. The mixture was stirred at 100° C. for 16 hours. The reaction was completed (shown by LCMS). The reaction mixture was concentrated and purified to obtain a colorless oil E15-2 (400 mg, 95% yield).

    [0677] LCMS: m/z 266.1 [M+H].sup.+.

    Step 3: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine was obtained with E15-2 and intermediate B3 as the raw materials using the method of example 6

    [0678] ##STR00479##

    [0679] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.66 (d, J=2.6 Hz, 1H), 9.58 (s, 1H), 9.36 (d, J=7.9 Hz, 1H), 9.18 (t, J=4.9 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 6.97 (t, J=9.4 Hz, 1H), 6.72 (dd, J=8.6, 3.8 Hz, 1H), 4.81 (d, J=4.8 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32 (s, 2H) ppm; LCMS: m/z 471.1 [M+H].sup.+.

    Example 104: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetonitrile

    Step 1: 2-(8-(5-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetamide E16-1

    [0680] ##STR00480##

    [0681] Into a 25 mL round-bottom flask, 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)amino]-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetic acid (example 84) (100 mg, 0.21 mmol) and dimethylformamide (2 mL) were added. At room temperature, ammonium hydrogen carbonate (83 mg, 1.05 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluracilhexafluorophosphate (103 mg, 0.27 mmol) were added, respectively. The reaction mixture was stirred at normal temperature overnight to obtain a yellow turbid liquid. The reaction solution was quenched with water (10 ml) and extracted with ethyl acetate (10 ml*3). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash column chromatography (ethyl acetate:dichloromethane:methanol=(1:1:1) as the mobile phase) and eluted to obtain the target product E16-1 (90 mg, 90.7% yield) which was pure.

    Step 2: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetonitrile

    [0682] ##STR00481##

    [0683] Into a 25 mL round-bottom flask, E16-1 (90 mg, 0.19 mmol) and anhydrous tetrahydrofuran (2 ml) were added and in an ice-water bath, trifluoroacetic anhydride (80 mg, 0.38 mmol) and triethylamine (29 mg, 0.29 mmol) were added. The reaction system was stirred at normal temperature overnight. The reaction solution was spin-dried to obtain a yellow solid. The yellow solid was washed with methanol and the resulting mixture was filtered to obtain a white solid. The white solid was dried under vacuum to obtain pure 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetonitrile (30 mg, 35%).

    [0684] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (d, J=6.4 Hz, 1H), 9.36 (d, J=1.8 Hz, 1H), 8.86 (d, J=16.3 Hz, 1H), 8.56 (d, J=7.4 Hz, 1H), 7.62 (s, 1H), 6.96 (t, J=9.5 Hz, 1H), 6.90 (d, J=7.6 Hz, 1H), 6.71 (dd, J=8.7, 3.8 Hz, 1H), 4.81 (s, 2H), 4.77 (d, J=5.1 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 (d, J=8.9 Hz, 2H), 2.96 (s, 3H) ppm; LCMS: m/z 455.1 [M+H].sup.+

    Example 105: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methoxy-triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 8-bromo-5-methoxy-[1,2,4]triazolo[1,5-a]pyridine E17-1

    [0685] ##STR00482##

    [0686] Into a 25 mL round-bottom flask, 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine (150 mg, 0.65 mmol) and anhydrous methanol (5 ml) were added and then sodium methoxide (175.58 mg, 3.25 mmol) was added. The reaction system was stirred at 80° C. for 3 hours. The reaction solution was spin-dried and then purified by Flash silica gel column chromatography (eluents:petroleum ether:ethyl acetate=5:1) to obtain a pure E17-1 (0.11 g, 74.2%). LCMS: m/z 227.9, 229.9 [M+H].sup.+.

    [0687] Step 2: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methoxy-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine can be obtained with 8-bromo-5-methoxy-[1,2,4]triazolo[1,5-a]pyridine (E17-1) and intermediate B3 as the raw materials using the method of example 6.

    ##STR00483##

    [0688] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 9.33 (s, 1H), 9.17 (d, J=8.4 Hz, 1H), 8.83 (s, 1H), 8.59 (s, 1H), 6.99-6.93 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 4.20 (s, 3H), 3.30 (t, J=6.4 Hz, 2H) ppm; LCMS: m/z 433.1 [M+H].sup.+.

    [0689] The following compound can be synthesized with 4-bromobenzo[c][1,2,5]thiadiazole and intermediate B3 as the raw materials using the method of example 6:

    Example 106: 8-(benzo[c][1,2,5]thiadiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0690] ##STR00484##

    [0691] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (d, J=3.1 Hz, 1H), 8.95 (s, 1H), 8.92 (t, J=5.1 Hz, 1H), 8.83 (dd, J=7.1, 0.9 Hz, 1H), 8.08 (dd, J=8.7, 1.0 Hz, 1H), 7.88 (dd, J=8.7, 7.2 Hz, 1H), 7.00-6.94 (m, 1H), 6.73 (dd, J=8.6, 3.9 Hz, 1H), 4.79 (d, J=5.0 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.32 (s, 2H) ppm; LCMS: m/z 420.0 [M+H].sup.+.

    [0692] The following compound can be obtained by subjecting the raw material ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate (example 23) to hydrolysis, and then to condensation with dimethylamine hydrochloride using the method of example 84:

    Example 107: 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine-3-carboxamide

    [0693] ##STR00485##

    [0694] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.71 (s, 1H), 9.56 (s, 1H), 9.14-8.95 (m, 3H), 8.21 (s, 1H), 7.01-6.94 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.79 (d, J=4.9 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.34 (s, 2H), 3.20 (s, 6H) ppm; LCMS: m/z 491.0 [M+H].sup.+.

    [0695] The following compound can be obtained by subjecting the raw material ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate (example 23) to hydrolysis, and then to condensation with ammonium chloride using the method of example 84:

    Example 108: 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide

    [0696] ##STR00486##

    [0697] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.66 (d, J=6.7 Hz, 1H), 9.59-9.48 (m, 2H), 9.04 (dd, J=10.6, 2.6 Hz, 2H), 8.47 (d, J=4.3 Hz, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 7.02-6.94 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.80 (d, J=4.9 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.32 (d, J=9.0 Hz, 2H) ppm; LCMS: m/z 463.0 [M+H].sup.+.

    Example 109: 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 8-iodo-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-5-amine E18-1

    [0698] ##STR00487##

    [0699] To a solution of dimethylamine in tetrahydrofuran (4 mL, 2 M/L), 5-chloro-8-iodo-triazolo[1,5-a]pyridine (200 mg, 0.72 mmol) was added. The mixture was stirred at 90° C. for 16 h. The reaction was completed (shown by LCMS). The reaction mixture was concentrated and purified (petroleum ether:ethyl acetate=1:1) to obtain E18-1 (190 mg, 90%).

    [0700] LCMS: m/z 288.9 [M+H].sup.+.

    [0701] Step 2: The following compound can be synthesized with E18-1 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00488##

    [0702] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.34 (s, 1H), 8.63 (s, 1H), 8.31 (d, J=8.4 Hz, 2H), 6.85-6.72 (m, 1H), 6.61 (dd, J=8.6, 3.9 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H), 4.77 (s, 2H), 4.57 (t, J=8.7 Hz, 2H), 3.41 (t, J=8.7 Hz, 2H), 3.24 (s, 6H) ppm; LCMS: m/z 446.1 [M+H].sup.+.

    [0703] The following compound can be synthesized with 4-bromobenzothiazole and intermediate B3 as the raw materials using the method of example 6:

    Example 110: 8-(benzo[d]thiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0704] ##STR00489##

    [0705] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.43 (s, 1H), 8.78 (t, J=4.9 Hz, 1H), 8.49 (s, 1H), 8.32 (d, J=6.8 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.04-6.93 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=4.8 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.34 (s, 2H) ppm; LCMS: m/z 419.1 [M+H].sup.+.

    [0706] The following compound can be synthesized with 5-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine, morpholine and intermediate B3 as the raw materials using the method of example 109:

    Example 111: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-morpholino-triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0707] ##STR00490##

    [0708] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.32 (s, 1H), 9.10 (d, J=8.3 Hz, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 6.99-6.94 (m, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.92-3.81 (m, 4H), 3.56-3.46 (m, 4H), 3.35 (s, 2H) ppm; LCMS: m/z 488.1 [M+H].sup.+.

    [0709] The following compound can be synthesized with 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine, N-methylpiperazine and intermediate B3 as the raw materials using the method of example 109:

    Example 112: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0710] ##STR00491##

    [0711] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.31 (s, 1H), 9.08 (d, J=8.3 Hz, 1H), 8.80 (d, J=4.7 Hz, 1H), 8.58 (s, 1H), 6.99-6.92 (m, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (d, J=4.3 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.51 (s, 4H), 3.34 (d, J=7.4 Hz, 2H), 2.58 (s, 4H), 2.28 (s, 3H) ppm; LCMS: m/z 501.2 [M+H].sup.+.

    Example 113: 8-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0712] Step 1: (E)-N-(3-bromo-6-methylpyridin-2-yl)-N′-hydroxyacetamidine E19-1

    ##STR00492##

    [0713] To a mixture solution of 3-bromo-6-methylpyridin-2-amine (5.0 g, 26.7 mmol) in isopropanol (60 mL), 1,1-dimethoxy-N,N-dimethylethane-1-amine (5.3 g, 40.1 mmol) was added and the mixture was stirred under nitrogen at 80° C. for 3 hours. The reaction system was cooled to 50° C. Then hydroxylamine hydrochloride (3.7 g, 53.5 mmol) was added and the resulting mixture was stirred at this temperature for 5 hours. The reaction was substantially completed (shown by LCMS). The solvent was evaporated and water was added. Then the resulting mixture was extracted with ethyl acetate (50 mL substantially). The combined organic layer was concentrated and purified by Flash column chromatography (petroleum ether:ethyl acetate=5:1) to obtain E19-1 (5.3 g, 88%).

    [0714] LCMS: m/z 244.1 [M+H].sup.+.

    Step 2: 8-bromo-2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridine E19-2

    [0715] ##STR00493##

    [0716] To a solution of E19-1 (5.3 g, 21.7 mmol) in tetrahydrofuran, trifluoroacetic anhydride (6.84 g, 32.6 mmol) was added. The mixture was stirred at 100° C. for 16 hours. The reaction was completed (shown by LCMS). The resulting mixture was concentrated by Flash column chromatography (petroleum ether:ethyl acetate=2:1) to obtain E19-2 (2.9 g, 59%).

    [0717] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.88 (d, J=7.7 Hz, 1H), 7.07-6.88 (m, 1H), 2.66 (s, 3H), 2.52 (s, 3H) ppm; LCMS: m/z 226.0 [M+H].sup.+.

    [0718] Step 3: 8-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine can be obtained with E19-2 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00494##

    [0719] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.44 (s, 1H), 9.05 (d, J=7.7 Hz, 1H), 8.88 (t, J=5.1 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.03-6.92 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.79 (d, J=4.9 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.30 (d, J=8.8 Hz, 2H), 2.74 (s, 3H), 2.58 (s, 3H) ppm; LCMS: m/z 431.1 [M+H].sup.+.

    Example 114: 1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methoxy)-2-methylpropan-2-ol

    Step 1: 8-bromo-5-(bromomethyl)-[1,2,4]triazolo[1,5-a]pyridine E20-1

    [0720] ##STR00495##

    [0721] Into a 100 mL round-bottom flask, 8-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (2 g, 9.43 mmol) and carbon tetrachloride (20 ml) were added and in an ice-water bath bromosuccinimide (2 g, 11.3 mmol) and azobisisobutyronitrile (310 mg, 0.2 mmol) were added. Upon completion of the addition, the reaction system was raised from normal temperature to 80° C. and then reacted for 16 hours while the temperature was kept at 80° C. The reaction solution was washed with an aqueous solution of sodium sulfite and then spin-dried to obtain a reddish-brown solid. The solid was then purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=3:1) to obtain a reddish-brown solid. The reddish-brown solid was dried under vacuum to obtain pure E20-1 (1.7 g, 62% yield).

    [0722] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.48 (s, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 4.90 (s, 2H) ppm; LCMS: m/z 291.9 [M+H].sup.+.

    [0723] Step 2: 1-((8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methoxy)-2-methylpropan-2-ol E20-2

    ##STR00496##

    [0724] Into a 50 mL round-bottom flask, 2-methylpropane-1,2-diol (60 mg, 0.67 mmol) and anhydrous tetrahydrofuran (4 ml) were added and after the mixture was stirred in an ice-water bath for 5 minutes, potassium tert-butoxide (90 mg, 0.80 mmol) was added. The reaction solution was stirred in the ice-water bath for another 30 minutes and then warmed to room temperature and stirred for another 2 hours. E20-1 (97 mg, 0.34 mmol) was added and the stirring of the resulting mixture was continued overnight. 10 mL of water was added and the resulting mixture was extracted with ethyl acetate (10 ml*3). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=2:1) to obtain pure E20-2 (40 mg, 20% yield).

    [0725] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.42 (s, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 5.04 (s, 2H), 3.55 (s, 2H), 1.72 (s, 1H), 1.27 (s, 6H) ppm; LCMS: m/z 300.0, 302.0 [M+H].sup.+.

    [0726] Step 3: The following compound can be obtained with E20-2 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00497##

    [0727] .sup.1H NMR (400 MHz, MeOD) δ 9.35 (d, J=2.7 Hz, 1H), 9.08 (d, J=3.4 Hz, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.44 (s, 1H), 7.44 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 6.89-6.81 (m, 1H), 6.67 (dd, J=8.6, 3.9 Hz, 1H), 5.35 (t, J=4.6 Hz, 1H), 5.13 (s, 2H), 4.84 (s, 2H), 4.64 (t, J=8.7 Hz, 2H), 3.93 (s, 2H), 3.22 (s, 2H), 1.28 (s, 6H) ppm; LCMS: m/z 460.2 [M+H].sup.+.

    Example 115: 8-(5-((dimethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N, N-dimethylmethanamine E20-3

    [0728] ##STR00498##

    [0729] Into a 100 mL round-bottom flask, E20-1 (1 g, 3.44 mmol) and tetrahydrofuran (15 ml) were added and in an ice-water bath, a solution of 1 M dimethylamine in tetrahydrofuran (17 ml, 17.2 mmol) and potassium carbonate (0.59 g, 1.43 mmol) were added. Upon completion of the addition, the reaction system was raised from normal temperature to 80° C. and then reacted for 3 hours while the temperature was kept at 80° C. Upon completion of the reaction, the reaction solution was spin-dried to obtain a yellowish brown solid, which was eluted and purified by Flash column chromatography (petroleum ether:ethyl acetate=5:1) to obtain a yellow solid, E20-3 (0.6 g, 68.3% yield).

    [0730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.74-8.38 (m, 1H), 8.14-7.85 (m, 1H), 7.31-6.90 (m, 1H), 4.03-3.78 (m, 2H), 2.38-2.20 (m, 6H) ppm; LCMS: m/z 255.0, 257.0 [M+H].sup.+.

    [0731] Step 2: 8-(5-((dimethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine can be obtained with E20-3 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00499##

    [0732] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.46 (s, 1H), 9.18 (d, J=7.7 Hz, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 7.38 (d, J=7.7 Hz, 1H), 6.97 (dd, J=10.3, 8.7 Hz, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.78 (d, J=4.9 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 4.01 (s, 2H), 3.36 (t, 2H), 2.35 (s, 6H) ppm; LCMS: m/z 460.2 [M+H].sup.+.

    [0733] The following compound can be obtained with E20-1, N-methylmorpholine and intermediate B3 as the raw materials using the method of example 115:

    Example 116: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-((4-methylpiperazin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0734] ##STR00500##

    [0735] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.16 (d, J=7.7 Hz, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.02-6.92 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.78 (d, J=4.7 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 4.07 (s, 2H), 3.30 (s, 2H), 2.61 (s, 4H), 2.40 (s, 4H), 2.19 (s, 3H) ppm; LCMS: m/z 515.2 [M+H].sup.+.

    [0736] The following compound can be obtained with E20-1, 1-amino-2-methyl-2-propanol and intermediate B3 as the raw materials using the method of example 115:

    Example 117: 1-(((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)amino)-2-methylpropan-2-ol

    [0737] ##STR00501##

    [0738] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.16 (d, J=7.7 Hz, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 6.96 (d, J=10.1 Hz, 1H), 6.72 (dd, J=8.6, 4.0 Hz, 1H), 4.79 (d, J=4.9 Hz, 2H), 4.56 (s, 2H), 4.28 (s, 3H), 3.37 (s, 1H), 3.30 (s, 2H), 2.07 (s, 2H), 1.12 (s, 6H) ppm; LCMS: m/z 504.1 [M+H].sup.+.

    [0739] The following compound can be obtained with E20-1, morpholine and intermediate B3 as the raw materials using the method of example 115:

    Example 118: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(morpholinomethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0740] ##STR00502##

    [0741] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.45 (s, 1H), 9.17 (d, J=7.7 Hz, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 7.42 (d, J=7.8 Hz, 1H), 6.97 (t, J=9.4 Hz, 1H), 6.72 (dd, J=8.4, 3.6 Hz, 1H), 4.79 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 4.08 (s, 2H), 3.65 (s, 4H), 3.33 (s, 2H), 2.60 (s, 4H) ppm; LCMS: m/z 502.1 [M+H].sup.+.

    [0742] The following compound can be obtained with 7-boronic acid pinacol ester-2H-indazole and intermediate B3 as the raw materials using the method in step 2 of example 6:

    Example 119: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-indazol-7-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0743] ##STR00503##

    [0744] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H) 9.52 (s, 1H) 8.78 (t, J=5.0 Hz, 1H) 8.15 (d, J=1.3 Hz, 1H) 7.94 (s, 1H) 7.81 (d, J=8.0 Hz, 1H) 7.69 (d, J=7.1 Hz 1H) 7.22 (t, J=7.6 Hz, 1H) 7.04-6.90 (m, 1H) 6.72 (dd, J=8.6, 3.9 Hz, 1H) 4.76 (d, J=4.8 Hz, 2H) 4.57 (t, J=8.8 Hz, 2H) 3.38 (m, 2H) ppm; LCMS: m/z 402.1 [M+H].sup.+.

    Example 120: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyltetrazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 8-bromo-5-methyltetrazolo[1,5-a]pyridine E21-1

    [0745] ##STR00504##

    [0746] A mixture of 3-bromo-2-chloro-6-methylpyridine (1.00 g, 4.84 mmol), trimethylsilyl azide (1.12 g, 9.69 mmol), and tetrabutylammonium fluoride trihydrate (3.06 g, 9.69 mmol) was stirred at 85° C. for 16 hours. Upon completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted by adding dichloromethane (50 mL) and then the resulting mixture was washed with water (10 mL*4) and saturated brine (10 mL*2), respectively. The organic phases were mixed, dried, concentrated and purified by silica gel column chromatography to obtain E21-1 (0.50 g, 48% yield).

    [0747] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.80 (d, J=7.6 Hz, 1H), 6.91 (dd, J=7.6, 0.8 Hz, 1H), 2.92 (d, J=0.8 Hz, 3H) ppm; LCMS: m/z 214.9 [M+H].sup.+.

    [0748] Step 2: The following compound can be obtained with E21-1 and intermediate B3 as the raw materials using the method of example 6:

    N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyltetrazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0749] ##STR00505##

    [0750] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.58 (s, 1H), 9.40 (s, 1H), 9.29 (d, J=7.5 Hz, 1H), 9.06 (br s, 1H), 7.52-7.48 (m, 1H), 7.01-6.95 (m, 1H), 6.73 (dd, J=3.9, 8.7 Hz, 1H), 4.81 (br s, 2H), 4.57 (t, J=8.8 Hz, 2H), 3.32-3.32 (m, 2H), 2.93 (s, 3H) ppm; LCMS: m/z 418.1 [M+H].sup.+.

    Example 121: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-5-methoxyimidazo[1,2-a]pyridine-3-carbonitrile

    Step 1: 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carbonitrile E22-1

    [0751] ##STR00506##

    [0752] Into a 50 mL round-bottom flask, 3-ethoxyacrylonitrile (1.14 g, 11.79 mmol), dioxane (12 ml) and water (4 ml) were added. In an ice bath, N-bromosuccinimide (2.1 g, 11.79 mmol) was added in batches and the mixture was stirred for 30 minutes. Subsequently, the mixture was stirred at room temperature for another 2 hours and then 5-chloro-8-iodoimidazo[1,2-a]pyridine-3-carbonitrile (1 g, 3.93 mmol) was added to the reaction solution. Upon completion of the reaction (as detected by LCMS), water (10 mL) was added and the resulting mixture was extracted with ethyl acetate (10 mL*3). The organic layers were collected, dried over anhydrous sodium sulfate and spin-dried. The crude was purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=10:1) to obtain a yellow solid E22-1 (800 mg, 67% yield).

    [0753] LCMS: m/z 303.9 [M+H].sup.+.

    Step 2: 5-hydroxy-8-iodoimidazo[1,2-a]pyridine-3-carbonitrile E22-2

    [0754] ##STR00507##

    [0755] Into a 25 mL round-bottom flask, E22-1 (500 mg, 1.65 mmol) and methanol (5 ml) were added and in an ice bath, a sodium methoxide solution (0.5 ml) was added. The reaction was warmed to 80° C. and the mixture was reacted for 1 hour while the temperature was kept at 80° C. Upon completion of the reaction (as detected by LCMS), water (10 ml) was added and the resulting mixture was extracted with ethyl acetate (20 ml*3). The organic phases were combined, dried over anhydrous sodium sulfate and spin-dried. The crude obtained was purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=1:1) to obtain a white solid, E22-2 (300 mg, 60% yield).

    [0756] LCMS: m/z 299.9 [M+H].sup.+.

    [0757] Step 3: The following compound can be obtained with E22-2 and intermediate B3 as the raw materials using the method of example 6:

    8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methoxyimidazo[1,2-a]pyridine-3-carbonitrile

    [0758] ##STR00508##

    [0759] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.18 (s, 1H), 8.96 (d, J=8.3 Hz, 1H), 8.83 (s, 1H), 8.51 (s, 1H), 6.96 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.21 (s, 3H), 3.27-3.23 (m, 2H) ppm; LCMS: m/z 457.1 [M+H].sup.+.

    [0760] The following compound can be synthesized with 8-iodo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine, tetrahydropyrrole and intermediate B3 as the raw materials using the method of example 109:

    Example 122: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0761] ##STR00509##

    [0762] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.24 (s, 1H), 9.02 (d, J=8.4 Hz, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.00-6.91 (m, 1H), 6.71 (dd, J=8.6, 3.8 Hz, 1H), 6.41 (d, J=8.5 Hz, 1H), 4.75 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.82 (s, 4H), 3.31 (s, 2H), 2.00 (s, 4H) ppm; LCMS: m/z 472.1 [M+H].sup.+.

    [0763] The following compound can be synthesized with 8-iodo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine, 4-(piperidin-4-yl)morpholine and intermediate B3 as the raw materials using the method of example 109:

    Example 123: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-morpholinopiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0764] ##STR00510##

    [0765] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.31 (s, 1H), 9.07 (d, J=8.3 Hz, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 7.01-6.92 (m, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.7, 3.9 Hz, 1H), 4.76 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 4.12 (d, J=11.9 Hz, 2H), 3.72-3.50 (m, 4H), 3.32-3.28 (m, 2H), 2.91 (t, J=11.1 Hz, 2H), 2.58-2.51 (m, 4H), 2.43 (d, J=9.8 Hz, 1H), 1.96 (d, J=12.3 Hz, 2H), 1.66 (dd, J=20.5, 11.4 Hz, 2H) ppm; LCMS: m/z 571.2 [M+H].sup.+.

    [0766] The following compound can be synthesized with 8-iodo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine, 2-oxa-6-azaspiro[3.3]heptane and intermediate B3 as the raw materials using the method of example 109:

    Example 124: 8-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0767] ##STR00511##

    [0768] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.51 (s, 1H), 9.25 (s, 1H), 9.05 (d, J=8.3 Hz, 1H), 8.70 (s, 1H), 8.50 (s, 1H), 7.02-6.91 (m, 1H), 6.71 (dd, J=8.6, 3.9 Hz, 1H), 6.26 (d, J=8.4 Hz, 1H), 4.76 (d, J=11.0 Hz, 6H), 4.62-4.44 (m, 6H), 3.31 (d, J=8.8 Hz, 2H) ppm; LCMS: m/z 500.2 [M+H].sup.+.

    Example 125: 5-(dimethylamino)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile

    Step 1: 5-(dimethylamino)-8-iodoimidazo[1,2-a]pyridine-3-carbonitrile E22-3

    [0769] ##STR00512##

    [0770] Into a 25 mL round-bottom flask, E22-1 (100 mg, 0.329 mmol) and N,N-dimethylformamide (3 ml) were added. In an ice bath, solid dimethylamine hydrochloride (80 mg, 0.99 mmol) and potassium carbonate (140 mg, 0.99 mmol) were added. The reaction system was warmed to 110° C. and stirred overnight while the temperature was kept at 110° C. Upon completion of the reaction (as detected by LCMS), water (5 mL) was added and the resulting mixture was extracted with ethyl acetate (10 mL*3). The organic layers were collected, dried over anhydrous sodium sulfate and spin-dried. The crude was purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=12:1) to obtain a white solid E22-3 (80 mg, 77.6% yield).

    [0771] LCMS: m/z 313.0 [M+H].sup.+.

    [0772] Step 2: The following compound can be obtained with E22-3 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00513##

    [0773] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.19 (s, 1H), 8.87 (d, J=8.0 Hz, 1H), 8.86 (s, 1H), 8.53 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 7.02-6.92 (m, 1H), 6.72 (dd, J=8.6, 3.9 Hz, 1H), 4.77 (d, J=4.3 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31 (s, 2H), 2.86 (s, 6H) ppm; LCMS: m/z 470.1 [M+H].sup.+.

    [0774] The following compound can be obtained with E22-1, morpholine and intermediate B3 as the raw materials using the method of example 125:

    Example 126: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-5-morpholinoimidazo[1,2-a]pyridine-3-carbonitrile

    [0775] ##STR00514##

    [0776] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (s, 1H), 9.19 (s, 1H), 8.88 (d, J=8.0 Hz, 2H), 8.54 (s, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.01-6.93 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.76 (s, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.93 (d, J=12.5 Hz, 4H), 3.33 (s, 2H), 3.28 (s, 2H), 3.04 (dd, J=16.6, 5.9 Hz, 2H) ppm; LCMS: m/z 512.2 [M+H].sup.+.

    [0777] The following compound can be synthesized with 4-bromo-2H-benzo[d][1,2,3]triazole and intermediate B3 as the raw materials using the method of example 6:

    Example 127: 8-(1H-benzo[d][1,2,3]triazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0778] ##STR00515##

    [0779] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.67 (s, 1H) 9.11 (br s, 1H) 8.99 (br s, 1H) 8.47 (d, J=7.1 Hz, 1H) 7.84 (d, J=8.3 Hz, 1H) 7.55-7.65 (m, 1H) 6.95-7.00 (m, 1H) 6.71 (dd, J=8.6, 3.9 Hz, 1H) 4.79 (br s, 2H) 4.55 (t, J=8.7 Hz, 2H) 3.36 (t, J=8.7 Hz, 2H) ppm; LCMS: m/z 403.1 [M+H].sup.+.

    [0780] The following compound can be obtained with E20-1, N1,N1,N2-trimethylethane-1,2-diamine and intermediate B3 as the raw materials using the method of example 115:

    Example 128: N1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)-N1,N2,N2-trimethylethane-1,2-diamine

    [0781] ##STR00516##

    [0782] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 9.43 (s, 1H), 9.14 (d, J=7.7 Hz, 1H), 8.94 (s, 1H), 8.62 (s, 1H), 7.40 (d, J=7.7 Hz, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.72 (dd, J=8.5, 3.7 Hz, 1H), 4.78 (s, 2H), 4.56 (s, 2H), 4.11 (s, 2H), 3.35 (d, J=8.6 Hz, 2H), 2.64 (d, J=7.0 Hz, 2H), 2.46 (d, J=6.9 Hz, 2H), 2.36 (s, 3H), 2.15 (s, 6H) ppm; LCMS: m/z 517.2 [M+H].sup.m.

    [0783] The following compound can be synthesized with 8-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine, 2-methylmorpholine and intermediate B3 as the raw materials using the method of example 109:

    Example 129: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-methylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0784] ##STR00517##

    [0785] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.32 (s, 1H), 9.09 (d, J=8.2 Hz, 1H), 8.81 (s, 1H), 8.60 (s, 1H), 6.97 (s, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.67 (m, 1H), 4.77 (d, J=4.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.99 (d, J=11.3 Hz, 3H), 3.82 (dd, J=19.0, 9.7 Hz, 2H), 3.31 (s, 2H), 2.96 (dd, J=11.6, 8.7 Hz, 1H), 2.70 (d, J=10.6 Hz, 1H), 1.19 (d, J=6.2 Hz, 3H) ppm; LCMS: m/z 502.2 [M+H].sup.m.

    Example 130: 5-((dimethylamino)methyl)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile

    Step 1: 8-bromo-5-methylimidazo[1,2-a]pyridine-3-carbonitrile E23-1

    [0786] ##STR00518##

    [0787] At 02, to a solution of 3-ethoxyprop-2-enenitrile (2.6 g, 25.7 mmol) in 1,4dioxane (30 mL) and water (10 mL), N-bromosuccinimide (3.81 g, 16.1 mmol) was added. The mixture was stirred at 0 for 2 hours. Then compound 3-bromo-6-methylpyridin-2-amine (1 g, 5.35 mmol) was added into the mixture. The reaction system was warmed to room temperature and stirred for 2 h. Subsequently, the reaction system was stirred at 90° C. for 16 hours. The reaction was completed (detected by LCMS). Water (30 mL) was added into the reaction system and the reaction mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined and concentrated. The crude product was purified by Flash column chromatography (eluents:petroleum ether:ethyl acetate=1:1) to obtain E23-1 (600 mg, 47% yield).

    [0788] LCMS: m/z 236.1 [M+H].sup.+.

    Step 2: 8-bromo-5-(bromomethyl)imidazo[1,2-a]pyridine-3-carbonitrile E23-2

    [0789] ##STR00519##

    [0790] To a solution of compound E23-1 (450 mg, 1.91 mmol) in carbon tetrachloride (10 mL), N-bromosuccinimide (407 mg, 2.29 mmol) and azobisisobutyronitrile (47 mg, 0.29 mmol) were added and the mixture was stirred under nitrogen at 80° C. for 16 h. The reaction was successfully carried out (as shown by LCMS). The mixture was concentrated and purified by Flash column chromatography (petroleum ether:ethyl acetate=2:1) to obtain E23-2 (350 mg, 58% yield).

    [0791] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.66 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 5.28 (s, 2H). LCMS: m/z 313.9 [M+H].sup.+.

    Step 3: 8-bromo-5-((dimethylamino)methyl)imidazo[1,2-a]pyridine-3-carbonitrile E23-3

    [0792] ##STR00520##

    [0793] Into a 25 mL reaction vial, E23-2 (100 mg, 0.32 mmol) and a solution of dimethylamine in tetrahydrofuran (2 M, 10 ml) were added. The reaction system was stirred at 70° C. for 15 hours. The reaction solution was spin-dried and then extracted with ethyl acetate and water. The organic layer was spin-dried and then purified by Flash column chromatography (petroleum ether:ethyl acetate=2:1) to obtain E23-3 (70 mg, 78.4% yield).

    [0794] LCMS: m/z 279.0, 281.0 [M+H].sup.+.

    [0795] Step 4: The following compound can be obtained with E23-3 and intermediate B3 as the raw materials using the method of example 6:

    N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-methylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0796] ##STR00521##

    [0797] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.47 (s, 1H), 9.19 (s, 1H), 8.89 (s, 1H), 8.76 (d, J=7.6 Hz, 1H), 8.47 (s, 1H), 7.25 (d, J=7.7 Hz, 1H), 6.93-6.87 (m, 1H), 6.65 (dd, J=8.6, 3.8 Hz, 1H), 4.71 (s, 2H), 4.50 (d, J=8.7 Hz, 2H), 3.86 (s, 2H), 3.24 (s, 2H), 2.14 (s, 6H) ppm; LCMS: m/z 484.1 [M+H].sup.+.

    Example 131: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 3-bromo-5-fluoro-6-methylpyridin-2-amine E24-1

    [0798] ##STR00522##

    [0799] At 0° C., to a solution of 5-fluoro-6-methylpyridin-2-amine (4.50 g, 35.7 mmol) in acetonitrile (50 mL), N-bromosuccinimide (7.62 g, 42.8 mmol) was added in batches. The mixture was slowly warmed to room temperature and stirred and reacted at room temperature for 12 hours. Upon completion of the reaction, the mixture was diluted by adding ethyl acetate (100 mL) and then washed with a saturated aqueous sodium carbonate solution (50 mL*3) and saturated brine (80 mL), respectively. The organic phase was dried and concentrated to obtain a crude E24-1 (7.40 g, 60% yield), which was directly used in the next step.

    [0800] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.38 (d, J=8.0 Hz, 1H), 4.76 (br s, 2H), 2.31 (d, J=2.8 Hz, 3H) ppm; LCMS: m/z 204.9 [M+H].sup.+.

    Step 2: (E)-N′-(3-bromo-5-fluoro-6-methylpyridin-2-yl)-N,N-dimethylformamidine E24-2

    [0801] ##STR00523##

    [0802] Into a 250 mL single-necked flask, E24-1 (3.00 g, 14.6 mmol), N,N-dimethylformamide dimethylacetal (3.49 g, 29.3 mmol), and toluene (100 mL) were added sequentially. The reaction system was warmed to 110° C. and reacted for 12 hours. No raw material was left (as detected by LCMS) and the reaction solution was concentrated to obtain a crude E24-2 (3.80 g), which was directly used in the next step.

    [0803] LCMS: m/z 261.9 [M+H].sup.+.

    Step 3: (E)-N-(3-bromo-5-fluoro-6-methylpyridin-2-yl)-N′-hydroxyformamidine E24-3

    [0804] ##STR00524##

    [0805] Into a 250 mL single-necked flask, E24-2 (3.80 g, 14.6 mmol), hydroxylamine hydrochloride (2.03 g, 29.2 mmol), sodium acetate (2.40 g, 29.2 mmol) and ethanol (60 mL) were added sequentially. The reaction system was warmed to 55° C. under nitrogen atmosphere and reacted for 12 hours. The reaction was completed (monitored by LCMS). The reaction system was cooled to room temperature. Ethanol was removed from the reaction mixture by concentration under reduced pressure so as to obtain a crude, (E)-N-(3-bromo-5-fluoro-6-methylpyridin-2-yl)-N′-hydroxyformamidine. The crude was slurried with water (50 mL) and the solid was collected and dried to obtain a brown solid product E24-3 (3.08 g, 85.0% yield).

    [0806] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.26 (br s, 1H), 8.08 (s, 2H), 7.50 (d, J=7.6 Hz, 1H), 2.39 (d, J=2.8 Hz, 3H) ppm; LCMS: m/z 247.9 [M+H].sup.+.

    Step 4: 8-bromo-6-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine E24-4

    [0807] ##STR00525##

    [0808] At 0° C., to a solution of E24-3 (3.08 g, 12.4 mmol) in tetrahydrofuran (30 mL), trifluoroacetic anhydride (7.82 g, 37.3 mmol) was added dropwise. The mixture was slowly warmed to room temperature and then stirred and reacted at room temperature for 12 hours. Upon completion of the reaction, the reaction was quenched by adding saturated aqueous sodium hydrogen carbonate solution (50 mL) to the mixture at 0° C. The mixture was diluted by adding water (50 mL) and then extracted with dichloromethane (100 mL*3). The combined organic phase was washed with saturated brine (30 mL*2), dried and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a yellow solid product E24-4 (2.10 g, 73.5% yield).

    [0809] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.41 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 2.74 (d, J=2.8 Hz, 3H) ppm; LCMS: m/z 229.8 [M+H].sup.+.

    [0810] Step 5: The following compound can be obtained with E24-4 and intermediate B3 as the raw materials using the method of example 6:

    N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0811] ##STR00526##

    [0812] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (s, 1H), 9.57 (s, 1H), 9.32 (d, J=11.5 Hz, 1H), 9.09-9.04 (m, 1H), 8.70 (s, 1H), 6.98 (t, J=9.5 Hz, 1H), 6.73 (dd, J=3.9, 8.6 Hz, 1H), 4.80 (d, J=3.4 Hz, 2H), 4.56 (t, J=8.7 Hz, 2H), 3.64-3.58 (m, 1H), 3.32-3.30 (m, 2H), 2.76 (d, J=2.5 Hz, 3H) ppm; LCMS: m/z 435.1 [M+H].sup.+.

    [0813] The following compound can be obtained with E20-1, imidazole and intermediate B3 as the raw materials using the method of example 115:

    Example 132: 8-(5-((1H-imidazol-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0814] ##STR00527##

    [0815] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54-9.51 (m, 1H), 9.44 (s, 1H), 9.12 (d, J=7.8 Hz, 1H), 8.72 (s, 1H), 7.90 (s, 1H), 7.35 (s, 1H), 7.07 (d, J=7.9 Hz, 1H), 6.96 (s, 1H), 6.72 (s, 1H), 5.81 (s, 2H), 4.78 (s, 2H), 4.55 (s, 2H), 3.17-3.15 (m, 2H) ppm; LCMS: m/z 483.1 [M+H].sup.+.

    Example 133: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-triazolo[4,3-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 3-bromo-2-hydrazino-6-methylpyridine E25-1

    [0816] ##STR00528##

    [0817] 3-bromo-2-chloro-6-methylpyridine (4.50 g, 21.80 mmol) was dissolved in N-methylpyrrolidone (12 mL). At 25° C., hydrazine hydrate (4.32 mL, 87.18 mmol) was added into the mixture. In a hydrothermal synthesis reactor, the reaction mixture was reacted at 110° C. for 16 hours. After completion of the reaction, water (100 mL) was added into the reaction solution and then the resulting mixture was extracted with ethyl acetate. The organic phases were mixed, dried and concentrated to obtain a crude E25-1 (3.50 g, 79.5% yield) and the crude was directly used in the next step.

    [0818] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.59 (d, J=7.8 Hz, 1H) 7.24 (s, 1H) 6.43 (d, J=7.6 Hz, 1H) 4.21 (s, 2H) 2.32 (s, 3H) ppm; LCMS: m/z 203.9 [M+H].sup.+.

    Step 2: 8-bromo-5-methyl-[1,2,4]triazole[4,3-a]pyridine E25-2

    [0819] ##STR00529##

    [0820] Into a 100 mL single-necked flask, E25-1 (3.5 g, 17.0 mmol), trimethylorthoformate (33.0 g, 311 mmol) and trifluoroacetic acid (39.5 mg, 0.35 mmol) were added sequentially. The reaction solution was warmed to 100° C. and reacted under nitrogen atmosphere for 10 hours. No raw material was left (as detected by TLC) and after the reaction solution was spin-dried, the crude was slurried with methyl tert-butyl ether (20 mL) and then filtered. The resulting solid was dried under vacuum to obtain E25-2 (3 g, 81.6% yield).

    [0821] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.84 (s, 1H) 7.48 (d, J=7.1 Hz, 1H) 6.57 (dd, J=7.2, 0.8 Hz, 1H) 2.66 (d, J=0.6 Hz, 3H) ppm; LCMS: m/z 211.8 [M+H].sup.+.

    [0822] Step 3: The following compound can be obtained with E25-2 and intermediate B3 as the raw materials using the method of example 6:

    N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0823] ##STR00530##

    [0824] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.63 (s, 1H), 9.55 (s, 1H), 9.39 (s, 1H), 8.96 (d, J=7.3 Hz, 1H), 8.92 (s, 1H), 7.02 (d, J=7.3 Hz, 1H), 6.97 (t, J=9.4 Hz, 1H), 6.72 (dd, J=3.8, 8.8 Hz, 1H), 4.79 (br d, J=4.4 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.37-3.40 (m, 2H), 2.72 (s, 3H) ppm; LCMS: m/z 417.0 [M+H].sup.+.

    Example 134: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-triazolo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 5-bromo-4-amino-2-methylpyrimidine E26-1

    [0825] ##STR00531##

    [0826] 5-bromo-4-chloro-2-methylpyrimidine (1.9 g, 9.16 mmol) and ammonia water (7.28 g, 58.16 mmol, 28% purity) were dissolved in N-methylpyrrolidone (12 mL). In a hydrothermal synthesis reactor, the mixture was reacted at 110° C. for 4 hours. After completion of the reaction, water (20 mL) was added into the reaction solution and then the resulting mixture was extracted with ethyl acetate. The organic phases were mixed, dried and concentrated. The crude was separated by column chromatography (mobile phase:petroleum ether/ethyl acetate=1:1) to obtain E26-1 (800 mg, 46.4% yield).

    [0827] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.27 (s, 1H) 5.56 (br s, 2H) 2.47 (s, 3H) ppm; LCMS: m/z 187.8 [M+H].sup.+.

    Step 2: (E)-N′-(5-bromo-2-methylpyrimidin-4-yl)-N,N-dimethylformamidine E26-2

    [0828] ##STR00532##

    [0829] E26-1 (0.5 g, 2.66 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (633 mg, 5.32 mmol) were dissolved in toluene (10 mL). The reaction solution was reacted at 100° C. under nitrogen atmosphere for 10 hours. The reaction was completed (monitored by LCMS). The reaction solution was concentrated to dryness to obtain E26-2 (0.65 g, 100% yield).

    [0830] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.61 (s, 1H) 8.45 (s, 1H) 3.20 (s, 3H), 3.18 (s, 3H), 2.53 (s, 3H) ppm; LCMS: m/z 243.1 [M+H].sup.+.

    Step 3: (E)-N-(5-bromo-2-methylpyrimidin-4-yl)-N′-hydroxyformamidine E26-3

    [0831] ##STR00533##

    [0832] E26-2 (0.646 g, 2.66 mmol), hydroxylamine hydrochloride (369 mg, 5.31 mmol) and anhydrous sodium acetate (479 mg, 5.85 mmol) were dissolved in anhydrous ethanol (10 mL). The reaction solution was reacted at 50° C. under nitrogen atmosphere for 4 hours. The reaction was completed (detected by TLC). The reaction solution was filtered and the filter cake was rinsed with water and dried to obtain E26-3 (400 mg, 65.1% yield).

    [0833] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.08 (br s, 1H) 8.59 (s, 1H) 8.24 (br s, 1H) 7.96 (s, 1H) 2.47 (s, 3H) ppm; LCMS: m/z 231.0 [M+H].sup.+.

    Step 4: 8-bromo-5-methyl-[1,2,4]triazole[1,5-c]pyrimidine E26-4

    [0834] ##STR00534##

    [0835] At 0° C., to a solution of E26-3 (750 mg, 3.25 mmol) in anhydrous tetrahydrofuran (25 mL), trifluoroacetic anhydride (2.05 g, 9.74 mmol) was added dropwise. The reaction mixture was warmed to 25° C. naturally and reacted for 12 hours. The reaction was completed (detected by TLC). After the reaction solution was spin-dried, saturated sodium hydrogen carbonate solution (20 mL) was added and the mixture was extracted with dichloromethane/methanol (100 mL, V/V=10:1). After the organic phase was dried and concentrated, the resulting crude was separated by Flash silica gel column chromatography to obtain E26-4 (320 mg, 46.2% yield).

    [0836] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.72 (s, 1H) 8.47 (s, 1H) 2.86 (s, 3H) ppm; LCMS: m/z 212.8 [M+H].sup.+.

    [0837] Step 5: The following compound can be obtained with E26-4 and intermediate B3 as the raw materials using the method of example 6:

    N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0838] ##STR00535##

    [0839] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.68 (s, 1H), 9.55 (s, 1H), 9.38 (s, 1H), 9.02 (br t, J=5.1 Hz, 1H), 8.78 (s, 1H), 7.00-6.93 (m, 1H), 6.72 (dd, J=3.9, 8.6 Hz, 1H), 4.78 (d, J=4.9 Hz, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.32-3.30 (m, 2H), 2.96 (s, 3H) ppm; LCMS: m/z 418.0 [M+H].sup.+.

    Example 135: 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-2-ol

    Step 1: (E)-5-bromo-6-(((dimethylamino)methylene)amino)-pyridine-2-carboxylic acid methyl ester E27-1

    [0840] ##STR00536##

    [0841] (E)-5-bromo-6-(((dimethylamino)methylene)amino)-pyridine-2-carboxylic acid methyl ester (5.0 g, 21.6 mmol) and 1,1-dimethoxy-N,N-dimethyl methanamine (5.16 g, 43.3 mmol) were dissolved in toluene (100 mL). The reaction solution was warmed to 110° C. and reacted for 4 hours. No raw material was left (as detected by TLC) and the reaction solution was concentrated to obtain a crude E27-1 (6.00 g).

    [0842] LCMS: m/z 285.7 [M+H].sup.+.

    Step 2: (E)-5-bromo-6-(((hydroxyamino)methylene)amino)-pyridine-2-carboxylic acid methyl ester E27-2

    [0843] ##STR00537##

    [0844] Into a reaction vial, E27-1 (6.0 g, 20.97 mmol), hydroxylamine hydrochloride (2.91 g, 41.94 mmol), sodium acetate (3.44 g, 41.9 mmol) and ethanol (60 mL) were added sequentially. The reaction solution was warmed to 50° C. under nitrogen atmosphere and reacted for 4 hours. The reaction was completed (monitored by LCMS) and the reaction mixture was cooled to room temperature and filtered to obtain E27-2 (5.9 g, 85.0% yield).

    [0845] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.41-8.29 (m, 1H), 8.26-8.19 (m, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.57 (d, J=7.9 Hz, 1H), 3.97 (s, 3H) ppm; LCMS: m/z 273.7[M+H].sup.+.

    Step 3: 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester E27-3

    [0846] ##STR00538##

    [0847] At room temperature, to a solution of E27-2 (10 g, 36.49 mmol) in tetrahydrofuran (100 mL), trifluoroacetic anhydride (23.0 g, 109 mmol) was added dropwise. Then the reaction system was slowly warmed to 75° C. and then stirred and reacted for 3 hours. Upon completion of the reaction, at 0° C., aqueous saturated sodium hydrogen carbonate solution (100 mL) was added to the mixture to quench the reaction. The mixture was extracted with ethyl acetate (100 mL*3). The combined organic phase was dried and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1 to 4:1) to obtain a white solid, E27-3 (5.00 g, 53.5% yield).

    [0848] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.52 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 4.08 (s, 3H) ppm; LCMS: m/z 256.0[M+H].sup.+.

    Step 4: 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-2-ol E27-4

    [0849] ##STR00539##

    [0850] At −30° C., to a solution of E27-3 (500 mg, 1.95 mmol) in tetrahydrofuran (10 mL), methylmagnesium bromide (3 M, 2.60 mL) was added dropwise and at this temperature, the mixture was stirred for three hours. Upon completion of the reaction, the reaction was quenched by adding water (10 mL) to the reaction solution. The resulting mixture was extracted with ethyl acetate (10 mL*3). The combined organic phase was dried, concentrated and then purified by Flash silica gel column chromatography to obtain E27-4 (400 mg, 80.0% yield).

    [0851] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.61 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 5.91 (s, 1H), 1.72 (s, 6H) ppm; LCMS: m/z 255.9 [M+H].sup.+.

    [0852] Step 5: The following compound can be obtained with E27-4 and intermediate B3 as the raw materials using the method of example 6:

    2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-2-ol

    [0853] ##STR00540##

    [0854] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.39 (s, 1H), 9.12 (d, J=7.9 Hz, 1H), 8.96-8.90 (m, 1H), 8.66 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 6.99-6.94 (m, 1H), 6.73-6.70 (m, 1H), 5.87 (s, 1H), 4.78 (d J=4.4 Hz, 2H), 4.58-4.53 (m, 2H), 3.40-3.35 (m, 2H) 1.78 (s, 6H) ppm; LCMS: m/z 461.2 [M+H].sup.+.

    [0855] The following compound can be obtained with 3-bromo-5-methoxypyridin-2-amine and intermediate B3 as the raw materials using the method of example 96:

    Example 136: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carbonitrile

    [0856] ##STR00541##

    [0857] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.77 (s, 1H), 9.50 (s, 1H), 9.40 (s, 1H), 8.88 (d, J=2.3 Hz, 1H), 8.46 (s, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.00-6.91 (m, 1H), 6.70 (dd, J=8.7, 3.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.54 (t, J=8.7 Hz, 2H), 3.97 (s, 3H), 3.17 (d, J=5.3 Hz, 2H) ppm; LCMS: m/z 456.0 [M+H].sup.+.

    [0858] The following compound can be synthesized with 3-bromo-5-methoxypyridin-2-amine and intermediate B3 as the raw materials using the method of example 103:

    Example 137: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0859] ##STR00542##

    [0860] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.59 (s, 1H), 9.55 (s, 1H), 9.05 (d, J=2.3 Hz, 1H), 9.01 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.53 (s, 1H), 7.00-6.94 (m, 1H), 6.72 (dd, J=8.7, 3.9 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.93 (s, 3H), 3.31 (s, 2H) ppm; LCMS: m/z 433.1 [M+H].sup.+.

    Example 138: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carbonitrile

    Step 1: 6-amino-5-bromo-pyridine-2-carboxamide E28-1

    [0861] ##STR00543##

    [0862] Into a hydrothermal synthesis reactor, methyl-6-bromo-5-pyridine-2-carboxylate (5.00 g, 21.6 mmol), ammonia water (18.20 g, 145.41 mmol) and N-methylpyrrolidone (20 mL) were added sequentially and the mixture was stirred at 110° C. for 3 hours. Upon completion of the reaction (as monitored by LCMS), 100 mL of saturated brine was added to the mixture. Then the resulting mixture was filtered and the filter cake was washed with 100 mL of water to obtain a white solid, which was dried under vacuum to obtain pure E28-1 (3.00 g, 64.2% yield).

    [0863] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.80 (d, J=8.0 Hz, 1H), 7.57 (br s, 1H), 7.44 (d, J=8.0 Hz, 1H), 5.64 (br s, 1H), 4.99 (br s, 2H) ppm; LCMS: m/z 215.9 [M+H].sup.+.

    Step 2: 6-amino-5-bromo-pyridine-2-carbonitrile E28-2

    [0864] ##STR00544##

    [0865] Under nitrogen atmosphere and at 0° C., to a solution of E28-1 (2.00 g, 9.26 mmol) and pyridine (3.66 g, 46.3 mmol) in dichloromethane (20 mL), trifluoromethanesulfonic anhydride (7.84 g, 27.77 mmol) was added dropwise. The reaction solution was warmed to 25° C. and stirred for 12 hours. The reaction was completed (monitored by LCMS) and in an ice bath, 100 mL of saturated sodium hydrogen carbonate was added to quench the reaction. Subsequently, the mixture was extracted with dichloromethane (50 mL*3) and the combined organic phase was washed with saturated brine (50 mL), dried and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0) to obtain a yellow solid E28-2 (1.00 g, 54.5% yield).

    [0866] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.27 (br s, 2H) ppm; LCMS: m/z 294.0 [M+H].sup.+.

    Step 3: 8-bromo-imidazo[1,2-a]pyridine-5-carbonitrile E28-3

    [0867] ##STR00545##

    [0868] E28-2 (1.00 g, 5.05 mmol), 2-chloroacetaldehyde (5.44 g, 69.3 mmol) and sodium hydrogen carbonate (458 mg, 5.45 mmol) were dissolved in tert-amyl alcohol (20 mL). The reaction system was warmed to 140° C. under nitrogen atmosphere and reacted under microwave for 2 hours. The reaction was completed (monitored by LCMS). The reaction mixture was diluted with dichloromethane (100 mL). The resulting mixture was washed with saturated brine (100 mL*3), dried and concentrated. The concentrate was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 3:1) to obtain a yellow solid E28-3 (400 mg, 35.7% yield).

    [0869] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.04 (d, J=1.1 Hz, 1H), 7.92 (d, J=1.1 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H) ppm; LCMS: m/z 222.0 [M+H].sup.+.

    [0870] Step 4: The following compound can be obtained with E28-3 and intermediate B3 as the raw materials using the method of example 6:

    8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carbonitrile

    [0871] ##STR00546##

    [0872] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.88 (s, 1H), 9.42 (br s, 1H), 9.13 (br s, 1H), 8.96 (d, J=7.9 Hz, 1H), 8.20 (s, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.88 (d, J=1.0 Hz, 1H), 6.95 (t, J=9.5 Hz, 1H), 6.70 (dd, J=3.9, 8.6 Hz, 1H), 4.79 (s, 2H), 4.54 (t, J=8.8 Hz, 2H), 3.32-3.31 (m, 2H) ppm; LCMS: m/z 427.3 [M+H].sup.+.

    Example 139: 8-(2-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: Ethyl N-[(3-bromo-5fluoro-2pyridyl)aminothioacyl]amino carboxylate E29-1

    [0873] ##STR00547##

    [0874] 3-bromo-5-fluoropyridin-2-amine (2.30 g, 12.0 mmol) and ethoxycarbonyl isothiocyanate (1.66 g, 12.6 mmol) were dissolved in 1,4-dioxane (25 mL). After the reaction system was vacuumed and replaced with nitrogen 3 times, the reaction mixture was stirred and reacted at 20° C. for 4 hours. Upon completion of the reaction (as monitored by TLC), the reaction solution was concentrated to obtain a crude E29-1 (4.0 g, 11.9 mmol, 98.7% yield).

    [0875] LCMS: m/z 321.9/323.9 [M+H].sup.+.

    Step 2: 8-bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine E29-2

    [0876] ##STR00548##

    [0877] E29-1(4.0 g, 11.9 mmol), hydroxylamine hydrochloride (4.31 g, 62.1 mmol) and N,N-diisopropylethylamine (4.81 g, 37.2 mmol) were dissolved in methanol (30 mL) and ethanol (30 mL). After the reaction system was vacuumed and replaced with nitrogen 3 times, the reaction mixture was reacted at 70° C. for 12 hours. The reaction was completed (monitored by LCMS). The reaction solution was diluted by adding water (50 mL) and a white solid was precipitated out. The solid was collected by filtration and then dried under vacuum to obtain E29-2 (1.50 g, 6.49 mmol, 52.3% yield).

    [0878] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.98 (dd, J=2.3, 4.1 Hz, 1H), 8.00 (dd, J=2.3, 8.5 Hz, 1H), 6.30 (s, 2H) ppm; LCMS: m/z 231.7/233.7 [M+H].sup.+.

    Step 3: 8-bromo-6-fluoro-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine E29-3

    [0879] ##STR00549##

    [0880] At 0° C., to a solution of E29-2 (1.50 g, 6.49 mmol) in N,N-dimethylformamide (20 mL), sodium hydride (779 mg, 19.5 mmol, 60% content) was added. The reaction solution was reacted at 20° C. for 0.5 hours. Methyl iodide (3.69 g, 26.0 mmol) was added into the reaction solution and the reaction was continued at 20° C. for 4 hours. Upon completion of the reaction (as monitored by TLC), saturated ammonium chloride solution was added to quench the reaction and then the reaction mixture was extracted with dichloromethane. The organic phase was dried, concentrated and purified by silica gel column chromatography to obtain E29-3 (720 mg, 2.78 mmol, 42.8% yield).

    [0881] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.09 (dd, J=2.4, 4.0 Hz, 1H), 8.06 (dd, J=2.4, 8.4 Hz, 1H), 3.04 (s, 6H) ppm; LCMS: m/z 258.7/260.7 [M+H].sup.+

    [0882] Step 4: The following compound can be obtained with E29-3 and intermediate B3 as the raw materials using the method of example 6:

    8-(2-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0883] ##STR00550##

    [0884] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.62 (s, 1H), 9.55 (s, 1H), 9.18 (dd, J=2.3, 11.3 Hz, 1H), 8.98-8.90 (m, 2H), 6.98 (t, J=9.5 Hz, 1H), 6.73 (dd, J=3.9, 8.6 Hz, 1H), 4.80 (d, J=4.8 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.31-3.28 (m, 2H), 3.10 (s, 6H) ppm; LCMS: m/z 464.3 [M+H].sup.+.

    Example 140: 8-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0885] Step 1: Intermediate E30-1 can be obtained with 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-amine as the raw material using the method in step 3 of example 139.

    ##STR00551##

    [0886] LCMS: m/z 243.0, 229.0 [M+H].sup.+.

    [0887] Step 2: The following compound can be obtained with E30-1 and intermediate B3 as the raw materials using the method of example 6:

    8-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0888] ##STR00552##

    [0889] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (s, 1H), 9.50 (s, 1H), 9.07 (dd, J=7.7, 1.2 Hz, 1H), 8.82 (s, 1H), 8.61 (dd, J=6.6, 1.2 Hz, 1H), 7.10 (dd, J=7.7, 6.6 Hz, 1H), 6.98 (dd, J=10.3, 8.7 Hz, 1H), 6.73 (dd, J=8.7, 3.9 Hz, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.30 (d, J=8.8 Hz, 2H), 3.10 (s, 6H) ppm; LCMS: m/z 446.1 [M+H].sup.+.

    Example 141: 8-(5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-methanol E31-1

    [0890] ##STR00553##

    [0891] At 0° C., to a solution of E27-3 (3.5 g, 13.6 mmol) in tetrahydrofuran (30 mL), lithium borohydride (893 mg, 41.0 mmol) and calcium chloride (4.55 g, 14.0 mmol) were slowly added and the mixture was stirred at this temperature for 2 hours. Upon completion of the reaction, the reaction solution was added dropwise into ice water to quench the reaction. The resulting reaction mixture was extracted with ethyl acetate (100 mL*3). The organic phase was dried over anhydrous sodium sulfate and the concentrate obtained was purified by silica gel column chromatography to obtain a white solid E31-1 (1.3 g, 5.70 mmol, 41.7% yield).

    [0892] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.59 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 5.93 (br t, J=5.6 Hz, 1H), 4.90 (br d, J=5.0 Hz, 2H) ppm; LCMS: m/z 228.1 [M+H].sup.+.

    Step 2: 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-5-carbaldehyde E31-2

    [0893] ##STR00554##

    [0894] At 0° C., to a solution of E31-1 (400 mg, 1.75 mmol) in dichloromethane (16 mL) and N,N-dimethylformamide (8 mL), Dess-Martin periodinane (1.12 g, 2.63 mmol) was slowly added and the mixture was stirred at 25° C. for 2 hours. Upon completion of the reaction, the reaction solution was added dropwise into saturated aqueous sodium hydrogen carbonate solution to quench the reaction. The resulting reaction mixture was extracted with dichloromethane (60 mL*3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a white solid E31-2 (300 mg, crude).

    [0895] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.51 (s, 1H), 8.75 (s, 1H), 8.18 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H) ppm.

    Step 3: 8-bromo-5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine E31-3

    [0896] ##STR00555##

    [0897] At 0° C., to a solution of E31-2 (280 mg, 1.24 mmol) in dichloromethane (40 mL), diethylaminosulfur trifluoride (399 mg, 2.48 mmol) was slowly added and the mixture was stirred at 25° C. for 12 hours. Upon completion of the reaction, the reaction solution was added dropwise into saturated aqueous sodium hydrogen carbonate solution to quench the reaction. The resulting reaction mixture was extracted with dichloromethane (20 mL*3). The combined organic phase was dried and concentrated. The concentrate was purified by silica gel column chromatography to obtain a white solid E31-3 (270 mg, 1.09 mmol, 87.8% yield).

    [0898] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.73 (s, 1H), 8.16 (d, J=7.8 Hz, 1H), 7.57 (t, J=52.4 Hz), 7.50 (d, J=7.8 Hz, 1H); LCMS: m/z 249.7 [M+H].sup.+.

    [0899] Step 4: The following two compounds can be obtained with E31-3 and intermediate B3 as the raw materials using the method of example 6:

    ##STR00556##

    [0900] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.60 (s, 1H), 9.57 (s, 1H), 9.33 (br d, J=7.6 Hz, 1H), 9.09 (br s, 1H), 8.77 (s, 1H), 7.78 (br s, 1H), 7.65 (t, J=52.8 Hz, 1H), 6.98 (br t, J=9.5 Hz, 1H), 6.73 (br dd, J=3.4, 8.5 Hz, 1H), 4.81 (br d, J=3.4 Hz, 2H), 4.56 (t, J=8.5 Hz, 2H), 3.31-3.23 (m, 2H) ppm; LCMS: m/z 453.3 [M+H].sup.+.

    Example 142: 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 5-bromo-N2,N2-dimethylpyrimidine-2,4-diamine E32-1

    [0901] ##STR00557##

    [0902] In a hydrothermal synthesis reactor, 5-bromo-2chloropyrimidin-4-amine (3.0 g, 14.4 mmol) was added into aqueous dimethylamine solution (70 mL, 40%) and the reaction solution was reacted at 100° C. for 12 hours. It was found by LCMS monitoring that the reaction was completed. The reaction solution was extracted with ethyl acetate (100 mL*3). The organic phase was then washed with brine, subsequently dried over anhydrous sodium sulfate and concentrated to obtain E32-1 (3.33 g, crude), which was directly used in the next step.

    [0903] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.96 (s, 1H), 6.70 (br s, 2H), 3.07 (s, 6H) ppm; LCMS: m/z 217.1 [M+H].sup.+.

    Step 2: (E)-N′-(5-bromo-2-(dimethylamino)pyrimidin-4-yl)-N,N-dimethylformamidine E32-2

    [0904] ##STR00558##

    [0905] E32-1 (2.5 g, 11.5 mmol) was dissolved in toluene (30 mL) and N,N-dimethylformamide dimethyl acetal (2.74 g, 23.0 mmol) was added into the solution. The mixture was stirred at 110° C. for 8 hours and it was found by LCMS monitoring that the reaction was completed. Water was added to the reaction solution to quench the reaction. The resulting reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, then dried and concentrated to obtain E32-2 (3.0 g, crude), which was directly used in the next step.

    [0906] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.58 (s, 1H), 8.18 (s, 1H), 3.18 (s, 3H), 3.15 (s, 3H), 3.13 (s, 6H) ppm; LCMS: m/z 272.2 [M+H].sup.+.

    Step 3: (E)-N-(5-bromo-2-(dimethylamino)pyrimidin-4-yl)-N′-hydroxyformamidine E32-3

    [0907] ##STR00559##

    [0908] E32-2 (3 g, 11.0 mmol) was dissolved in ethanol (40 mL). Hydroxylamine hydrochloride (1.53 g, 22.0 mmol) and sodium acetate (1.81 g, 22.0 mmol) were added into the reaction solution. The well-mixed reaction solution was reacted at 60° C. for 4 hours. It was found by LCMS detection that the reaction was completed. The reaction solution was concentrated. The residue was slurried by adding water, and the resulting slurry was filtered and the solid was collected and dried to obtain E32-3 (2.8 g, 94.5% yield).

    [0909] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.92 (s, 1H), 8.21 (s, 1H), 8.09-8.02 (m, 1H), 8.01-7.94 (m, 1H), 3.08 (s, 6H) ppm; LCMS: m/z 262.1 [M+H].sup.+.

    Step 4: 8-bromo-N,N-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine E32-4

    [0910] ##STR00560##

    [0911] E32-3 (2.8 g, 10.8 mmol) was dissolved in tetrahydrofuran (30 mL). At 0° C., trifluoroacetic anhydride (11.3 g, 53.8 mmol) was added dropwise into the reaction solution. After the dropwise addition was complete, the resulting mixture was reacted at 25° C. for 14 hours. It was found by LCMS monitoring that the reaction was completed. After ice water was added into the reaction solution to quench the reaction, the resulting mixture was extracted with ethyl acetate (150 mL*3). The organic phase was sequentially washed with saturated sodium hydrogen carbonate solution and saturated brine, then dried and concentrated. The crude was separated by Flash silica gel column chromatography to obtain E32-4 (2.0 g, 76.7% yield).

    [0912] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.25 (s, 1H), 7.99 (s, 1H), 3.49 (s, 6H) ppm; LCMS: m/z 244.1 [M+H].sup.+.

    Step 5: 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-N-((5-fluoro-2,3,-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0913] ##STR00561##

    [0914] E32-4 (600 mg, 1.65 mmol), 8-bromo-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine B3 (800 mg, 3.30 mmol), hexabutylditin (1.49 g, 2.57 mmol) and tris(dibenzylideneacetone)dipalladium (473 mg, 517 umol) were dissolved in dioxane (4 mL) and N,N-dimethylformamide (4 mL). The reaction system was warmed to 100° C. under nitrogen atmosphere and stirred for 12 hours. A product was produced as detected by LCMS. The reaction solution was filtered and concentrated. The crude was separated through Flash silica gel column chromatography to obtain a crude product, which was separated by HPLC and basified to obtain 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-N-((5-fluoro-2,3,-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (20 mg, 3.12% yield).

    [0915] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (br s, 1H), 9.35 (s, 1H), 9.07 (s, 1H), 8.59 (s, 1H), 6.93 (t, J=9.2 Hz, 1H), 6.68 (dd, J=4.0, 8.8 Hz, 1H), 4.73 (s, 2H), 4.53 (t, J=8.8 Hz, 2H), 3.44 (s, 6H), 3.32-3.28 (m, 2H) ppm; LCMS: m/z 447.3 [M+H].sup.+.

    Example 143: 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethan-1-ol

    Step 1: 1-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethanol E31-7

    [0916] ##STR00562##

    [0917] At −30° C., to a solution of E31-2 (300 mg, 1.33 mmol) in tetrahydrofuran (10 mL), a solution of methylmagnesium bromide (3 M, 1.33 mL) was added dropwise and the mixture was stirred at this temperature for 2 hours. Upon completion of the reaction, saturated aqueous ammonium chloride solution was used to quench the reaction. The resulting mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried, concentrated and then purified by Flash silica gel column chromatography to obtain E31-7 (270 mg, 84.0% yield).

    [0918] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.43 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 5.40-5.37 (m, 1H), 4.01 (d, J=5.4 Hz, 1H), 1.74 (d, J=6.5 Hz, 3H) ppm; LCMS: 242.1 m/z [M+H].sup.+.

    [0919] Step 2: The following compound can be obtained with E31-7 and intermediate B3 as the raw materials using the method of example 6:

    1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)ethan-1-ol

    [0920] ##STR00563##

    [0921] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.19-9.17 (d, J=8.0 Hz, 1H), 8.93 (s, 1H), 8.64 (s, 1H), 7.44-7.42 (d, J=8.0 Hz, 1H), 6.99-6.94 (m, 1H), 6.73-6.70 (m, 1H), 5.90-5.89 (d, J=4.0 Hz, 1H), 5.43-5.40 (m, 1H), 4.78 (s, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.34-3.27 (m, 2H), 1.56-1.54 (d, J=8.0 Hz, 3H) ppm; LCMS: 447.3 m/z [M+H].sup.+.

    Example 144: 8-(5-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: tert-butyl (6-chloro-5-fluoropyridin-2-yl)-carbamate E33-1

    [0922] ##STR00564##

    [0923] 6-chloro-5-fluoropyridine-2-carboxylic acid (9.5 g, 54.1 mmol), tert-butanol (44.2 g, 596 mmol), 4 A molecular sieves (5 g), diphenyl phosphorazidate (19.4 g, 70.4 mmol) and N,N-diisopropylethylamine (21.0 g, 162 mmol) were dissolved in toluene (150 mL). The mixture was stirred at 85° C. for 2 hours. The reaction was completed (detected by LCMS). Upon completion of the reaction, the reaction solution was cooled to room temperature and subjected to rotary evaporation under reduced pressure to obtain a solid. Then the solid was extracted with ethyl acetate (250 mL*3). The organic phases were mixed, dried, concentrated and purified by silica gel column chromatography to obtain E33-1 (6.0 g, 45% yield).

    [0924] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.20 (s, 1H), 7.91-7.85 (m, 1H), 7.82-7.77 (m, 1H), 1.46 (s, 9H) ppm; LCMS: m/z 190.8 [M−55].sup.+.

    Step 2: 6-chloro-5-fluoropyridin-2-amine E33-2

    [0925] ##STR00565##

    [0926] E33-1 (6 g, 24.3 mmol) was dissolved in hydrochloric acid/ethyl acetate (35 mL). At 25° C., the mixture was reacted for 12 hours. The reaction was completed (detected by LCMS). The reaction mixture was diluted by adding water and filtered. The resulting solid was slurried and then dried to obtain E33-2 (3.5 g, 98% yield).

    [0927] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.49 (t, J=8.6 Hz, 1H), 6.42 (dd, J=2.7, 8.8 Hz, 1H) ppm; LCMS: m/z 147.2 [M+H].sup.+.

    Step 3: 3-bromo-6-chloro-5-fluoropyridin-2-amine E33-3

    [0928] ##STR00566##

    [0929] E33-2 (3.50 g, 24.0 mmol), N-bromosuccinimide (4.70 g, 26.3 mmol), and potassium carbonate (3.63 g, 26.3 mmol) were dissolved in dichloromethane (20 ml) and N,N-dimethylformamide (2 ml). At 25° C., the mixture was reacted for 30 minutes. No raw material was left (as detected by TLC). Sodium sulfite solution was added to quench the reaction and then the resulting mixture was extracted with ethyl acetate. The organic phases were mixed, dried and concentrated to obtain a crude E33-3 (5.3 g, 98% yield).

    [0930] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.05 (d, J=7.6 Hz, 1H), 6.59 (s, 2H) ppm; LCMS: m/z 227.0 [M+H].sup.+.

    Step 4: (E)-N′-(3-bromo-6-chloro-5-fluoropyridin-2-yl)-N,N-dimethylformamidine E33-4

    [0931] ##STR00567##

    [0932] E33-3 (5.30 g, 24 mmol) and N,N-dimethylformamide dimethylacetal (14.0 g, 118 mmol) were dissolved in toluene (45 ml). The reaction mixture was warmed to 100° C. and reacted for 5 hours. The reaction was completed (monitored by LCMS) and the reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude E33-4 (5.80 g, crude).

    [0933] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 8.19 (d, J=7.8 Hz, 1H), 3.14 (s, 3H), 3.04 (s, 3H) ppm; LCMS: m/z 282.0 [M+H].sup.+.

    Step 5: (E)-N-(3-bromo-6-chloro-5-fluoropyridin-2-yl)-N′-hydroxyformamidine E33-5

    [0934] ##STR00568##

    [0935] E33-4 (5.80 g, crude), hydroxylamine hydrochloride (2.90 g, 41.4 mmol) and sodium acetate (3.70 g, 45.5 mmol) were dissolved in ethyl acetate (50 ml) and the mixture was warmed to 50° C. and reacted for 1 hour. The reaction was completed (monitored by LCMS). The mixture was cooled to room temperature. Water was added. The resulting mixture was filtered and a solid was collected, namely, E33-5 (7.88 g, crude) was obtained.

    [0936] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.85 (br s, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.30-7.83 (m, 1H), 7.75 (s, 1H) ppm; LCMS: m/z 270.0 [M+H].sup.+.

    Step 6: 8-bromo-5-chloro-6-fluoro-[1,2,4]triazolo[1,5-a]pyridine E33-6

    [0937] ##STR00569##

    [0938] E33-5 (7.0, crude) was dissolved in polyphosphoric acid (70 ml). The temperature was raised to 80° C. and the reaction lasted for 2 hours. The reaction was completed (monitored by LCMS) and the reaction mixture was cooled to room temperature. Saturated sodium hydrogen carbonate solution was added to quench the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried and concentrated to obtain E33-6 (3.80 g, 58% yield).

    [0939] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.71 (s, 1H), 8.52 (d, J=8.6 Hz, 1H) ppm; LCMS: m/z 251.8 [M+H].sup.+.

    Step 7: 8-bromo-6-fluoro-N,N-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-5-amine E33-7

    [0940] ##STR00570##

    [0941] E33-6 (500 mg, 2.0 mmol), dimethylamine hydrochloride (814 mg, 10 mmol), and N,N-diisopropylethylamine (3.60 g, 28 mmol) were dissolved in N,N-dimethylformamide (3 ml). The mixture was warmed to 100° C. and reacted for 6 hours. The reaction was completed (monitored by LCMS) and the mixture was diluted by adding water and then extracted with ethyl acetate. The organic phase was washed, dried and concentrated. The resulting crude was purified by Flash silica gel column chromatography to obtain E33-7 (420 mg, 81.2% yield).

    [0942] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.53 (s, 1H), 8.18 (d, J=11.5 Hz, 1H), 3.09 (d, J=3.0 Hz, 6H) ppm; LCMS: m/z 258.9 [M+H].sup.+.

    [0943] Step 8: The following compound can be obtained with E33-7 and intermediate B3 as the raw materials using the method of example 6:

    8-(5-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0944] ##STR00571##

    [0945] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.54 (s, 1H), 9.49 (s, 1H), 9.25 (d, J=14.4 Hz, 1H), 8.95-8.90 (m, 1H), 8.62 (s, 1H), 6.97 (t, J=9.5 Hz, 1H), 6.72 (dd, J=4.1, 8.7 Hz, 1H), 4.77 (br d, J=4.0 Hz, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.27 (br d, J=5.1 Hz, 2H), 3.15 (d, J=2.8 Hz, 6H) ppm; LCMS m/z 464.1 [M+H].sup.+.

    Example 145: 8-(5-(dimethylamino)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: (E)-N′-(3-bromo-6-chloropyridin-2-yl)-N,N-dimethylacetamidine E34-1

    [0946] ##STR00572##

    [0947] 2-amine-3-bromo-6-chloropyridine (2.30 g, 11.1 mmol) was added into toluene (25 mL) and the reaction solution was reacted at 100° C. for 12 hours. It was found by LCMS monitoring that the reaction was completed. The reaction solution was directly concentrated to obtain E34-1 (3.00 g, crude).

    [0948] LCMS: m/z 277.7 [M+H].sup.+.

    Step 2: (E)-N′-(3-bromo-6-chloropyridine-2-yl)-N-hydroxyacetamidine E34-2

    [0949] ##STR00573##

    [0950] E34-1 (3.00 g, 10.8 mmol) was dissolved in ethanol (40 mL). Hydroxylamine hydrochloride (1.51 g, 21.7 mmol) and sodium acetate (1.78 g, 21.7 mmol) were then added into the solution. The mixture was stirred at 60° C. for 5 hours and it was found by LCMS monitoring that the reaction was completed. The reaction solution was dried and concentrated to obtain a crude. The crude was slurried with water (20 mL) at 25° C. for 2 hours. The mixture was filtered and the solid was collected and dried to obtain a product E34-2 (2.60 g, 87.1% yield).

    [0951] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.58 (s, 1H), 8.50 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 2.29 (s, 3H) ppm; LCMS: m/z 265.9 [M+H].sup.+.

    Step 3: 8-bromo-5-chloro-2-methyl-[,2,4]triazolo[1,5-a]pyridine E34-3

    [0952] ##STR00574##

    [0953] E34-2 (2.25 g, 8.51 mmol) was added into polyphosphoric acid (40 g). The well-mixed reaction solution was reacted at 95° C. for 4 hours. It was found by LCMS detection that the reaction was completed. The reaction solution was poured into a mixture of ice and water (200 mL). Sodium carbonate was directly added into the mixture until the pH of the mixture reached 7. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, then dried over anhydrous sodium sulfate and finally concentrated to obtain E34-3 (2.00 g, crude), which was directly used in the next step.

    [0954] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.69 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 2.69 (S, 3H) ppm; LCMS: m/z 248.1 [M+H].sup.+.

    Step 4: 8-bromo-5-dimethylamino-2-methyl-[1,2,4]triazolo[1,5-a]pyridine E34-4

    [0955] ##STR00575##

    [0956] E34-3 (2.15 g, 8.72 mmol) was dissolved in N,N-diisopropylethylamine (20 mL) and then dimethylamine hydrochloride was added. The reaction solution was reacted at 80° C. for 5 hours. It was found by LCMS monitoring that the reaction was completed. Saturated brine was added to the reaction solution to quench the reaction and then the resulting mixture was extracted with ethyl acetate. The organic phase was washed again with saturated brine, then dried and concentrated. The crude was separated by Flash silica gel column chromatography to obtain E34-4 (2.00 g, 76.7% yield).

    [0957] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.61 (d, J=8.0 Hz, 1H), 6.17 (d, J=8.0 Hz, 1H), 3.12 (s, 6H), 2.65 (s, 3H) ppm; LCMS: m/z 257.2 [M+H].sup.+.

    [0958] Step 5: The following compound can be obtained with E34-4 and intermediate B3 as the raw materials using the method of example 6:

    8-(5-(dimethylamino)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0959] ##STR00576##

    [0960] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.50 (s, 1H), 9.28 (s, 1H), 9.00 (d, J=8.4 Hz, 1H), 8.74 (d, J=1.2 Hz, 1H), 6.96 (t, J=9.6 Hz, 1H), 6.71 (dd, J=3.9, 8.8 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 4.76 (s, 2H), 4.54 (t, J=8.8 Hz, 2H), 3.31-3.27 (m, 2H), 3.13 (s, 6H), 2.55 (s, 3H) ppm; LCMS: m/z 460.3 [M+H].sup.+.

    Example 146: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile

    Step 1: Methyl 6-amino-5-bromonicotinate E35-1

    [0961] ##STR00577##

    [0962] Methyl 6-aminonicotinate (4.0 g, 26.3 mmol) and N-bromosuccinimide (5.15 g, 28.9 mmol) were dissolved in dichloromethane (100 mL). At 20° C., under nitrogen atmosphere, the mixture was reacted for 1 hour. The reaction was completed (monitored by LCMS) and the reaction solution was sequentially washed with sodium sulfite solution, sodium carbonate solution and water. The organic phase was dried and concentrated to obtain E35-1 (6.1 g, crude).

    [0963] LCMS: m/z 231.0 [M+H].sup.+.

    Step 2: (E) 5-bromo-6-(((dimethylamino)methylene)amino)nicotinic acid methyl ester E35-2

    [0964] ##STR00578##

    [0965] E35-1 (6.1 g, 26.4 mmol) and N, N-dimethylformamide dimethylacetal (6.3 g, 53 mmol) were dissolved in toluene (50 ml). The mixture was warmed to 100° C. and reacted under nitrogen atmosphere for 12 hours. The reaction was completed (monitored by LCMS) and the reaction solution was concentrated under reduced pressure to obtain E35-2 (7.6 g, crude).

    [0966] LCMS: m/z 285.7/287.7 [M+H].sup.+.

    Step 3: (E) 5-bromo-6-(N′-hydroxyformamidinyl)nicotinic acid methyl ester E35-3

    [0967] ##STR00579##

    [0968] E35-2 (5.0 g, 17.5 mmol), sodium acetate (3.2 g, 39 mmol) and hydroxylamine hydrochloride (2.4 g, 25 mmol) were dissolved in ethanol (50 mL). The mixture was warmed to 50° C. and reacted for 4 hours. The reaction was completed (monitored by LCMS) and water was added. The resulting mixture was filtered and a solid was collected, namely, E35-3 (4.0 g, 84% yield) was obtained.

    [0969] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.01 (s, 1H), 8.71 (d, J=1.9 Hz, 1H), 8.45 (d, J=9.4 Hz, 1H), 8.38 (d, J=1.9 Hz, 1H), 8.00 (s, 1H), 3.84 (s, 3H) ppm; LCMS: m/z 276.0 [M+H].sup.+.

    Step 4: 8-bromo-[1,2,4]triazolo[1,5,a]pyridine-6-carboxylic acid methyl ester E35-4

    [0970] ##STR00580##

    [0971] E35-3 (4.0 g, 15 mmol) was dissolved in polyphosphoric acid (20 mL). The temperature was raised to 100° C. and the reaction lasted 2 hours. The reaction was completed (monitored by LCMS) and the reaction mixture was cooled to room temperature. Saturated sodium hydrogen carbonate solution was added to quench the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried and concentrated to obtain E35-4 (2.8 g, 75% yield).

    [0972] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.53 (d, J=1.4 Hz, 1H), 8.74 (s, 1H), 8.29 (d, J=1.3 Hz, 1H), 3.92 (s, 3H) ppm; LCMS: m/z 257.7 [M+H].sup.+.

    Step 5: 8-bromo-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide E35-5

    [0973] ##STR00581##

    [0974] E35-4 (2.4 g, 9.4 mmol) and ammonia water (15 g, 103 mmol) were dissolved in ethanol (5 mL). The reaction system was warmed to 80° C. and the reaction mixture was reacted under nitrogen atmosphere for 2 hours. No raw material was left (as monitored by TLC) and the mixture was cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate. The organic phases were mixed, dried, concentrated and purified by Flash silica gel column chromatography to obtain E35-5 (830 mg, 37% yield).

    [0975] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.46 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.35 (d, J=1.3 Hz, 1H), 8.25 (br s, 1H), 7.79 (br s, 1H).

    Step 6: 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide E35-6

    [0976] ##STR00582##

    [0977] E35-5 (400 mg, 1.7 mmol), bis(pinacolato)diboron (506 mg, 2.0 mmol), potassium acetate (489 mg, 5.0 mmol), and a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (271 mg, 0.33 mmol) were dissolved in 1,4-dioxane (10 mL). The temperature was raised to 120° C. and the mixture was reacted under nitrogen atmosphere for 5 hours. No raw material was left (as detected by TLC) and the resulting reaction solution contained E35-6 and was directly used in the next step without any treatment.

    Step 7: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyridin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide E35-7

    [0978] ##STR00583##

    [0979] To the reaction solution obtained in the previous step, B3 (302 mg, 0.83 mmol), sodium carbonate (528 mg, 4.98 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (136 mg, 0.17 mmol) and water (2 mL) were added. The reaction system was warmed to 100° C. under nitrogen atmosphere and reacted for 2 hours. The reaction was completed (monitored by LCMS). The resulting mixture was cooled to room temperature and diluted and dissolved in ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude was purified by Flash silica gel column chromatography and then purified by HPLC to obtain E35-7 (34 mg, 4.6% yield).

    [0980] LCMS: m/z 446.1 [M+H].sup.+.

    Step 8: 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyridin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-cyan

    [0981] ##STR00584##

    [0982] At 0° C., to a solution of E35-7 (34 mg, 0.76 mmol) and triethylamine (31 mg, 0.31 mmol) in tetrahydrofuran (1.5), trifluoroacetic anhydride (48.1 mg, 0.23 mmol) was added. The mixture was reacted at 25° C. for 12 hours. The reaction was completed (monitored by LCMS) and saturated sodium hydrogen carbonate solution and water were added into the reaction solution. The resulting mixture was extracted with ethyl acetate. The organic phases were mixed, dried and concentrated. The resulting crude was purified by Flash silica gel column chromatography and then purified by HPLC to obtain the final compound 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyridin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-cyan (7.5 mg, 23% yield).

    [0983] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.81 (s, 1H), 9.59 (s, 1H), 9.57 (br s, 1H), 9.40 (s, 1H), 9.14 (br d, J=1.1 Hz, 1H), 8.86 (s, 1H), 6.97 (t, J=9.6 Hz, 1H), 6.72 (dd, J=3.9, 8.6 Hz, 1H), 4.80 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.25-3.22 (m, 2H) ppm; LCMS: m/z 428.0 [M+H].sup.+.

    Example 147: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-(methylsulfonyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0984] ##STR00585##

    Step 1: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine E36-1

    [0985] ##STR00586##

    [0986] Into a 25 mL round-bottom flask, N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (example 21) (600 mg, 1.43 mmol), anhydrous dichloromethane (10 ml) and glacial acetic acid (2 ml) were added and in an ice bath, iodosuccinimide (353.9 mg, 1.57 mmol) was added. The mixture was then stirred at room temperature for 1 hour. The reaction solution was poured into water. The resulting mixture was extracted with dichloromethane (50 mL*3), washed with brine and dried over anhydrous sodium sulfate, and then passed through a silica gel column (eluents:dichloromethane:methanol=20:1) and dried under vacuum to obtain pure E36-1 (0.39 g, 50.0% yield).

    [0987] LCMS: m/z 546.1 [M+H].sup.+.

    Step 2: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-(methylsulfonyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0988] ##STR00587##

    [0989] Into a sealed tube, E36-1 (100 mg, 0.18 mmol) and anhydrous dimethylsulfoxide (3 ml) were added and sodium methanesulfinate (55.13 mg, 0.54 mmol) and cuprous iodide (102.84 mg, 0.54 mmol) were added sequentially. The mixture was purged with nitrogen for five minutes, sealed and then reacted in a microwave reactor at 120° C. for 20 minutes and then reacted under microwave at 100° C. for another 3 hours. After the reaction mixture was cooled, dichloromethane (50 mL) was added and the resulting mixture was washed with water (30 mL) and saturated brine (30 mL). The organic layer was spin-dried and then subjected to preparative liquid chromatography to obtain N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-(methylsulfonyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (17 mg, 19.0% yield).

    [0990] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.70 (s, 1H), 9.26-9.21 (m, 1H), 8.97 (dd, J=10.7, 2.4 Hz, 1H), 8.86-8.83 (m, 1H), 8.72 (s, 1H), 8.33 (s, 1H), 6.90 (d, J=10.2 Hz, 1H), 6.69-6.65 (m, 1H), 4.81 (s, 2H), 4.52 (t, J=8.8 Hz, 2H), 3.50 (s, 3H), 3.31-3.29 (m, 2H) ppm; LCMS: m/z 498.1 [M+H].sup.+.

    Example 148: (6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-3-yl)dimethylphosphine oxide

    [0991] ##STR00588##

    [0992] Into a sealed tube, E36-1 (100 mg, 0.18 mmol) and anhydrous 1,4-dioxane (4 ml) were added. Dimethylphosphine oxide (42.15 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (16.48 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.42 mg, 0.02 mmol), and triethylamine (0.05 mL) were added sequentially. The mixture was purged with nitrogen for five minutes, sealed and then stirred at 100° C. for 15 hours. After the reaction mixture was cooled, dichloromethane (50 mL) was added and the resulting mixture was washed with water (30 mL) and saturated brine (30 mL). The organic layer was spin-dried and then purified by Flash column chromatography (eluents:dichloromethane:methanol=4:1) to obtain (6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-3-yl)dimethylphosphine oxide (55 mg, 61.68% yield).

    [0993] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.70 (s, 1H), 9.55 (s, 1H), 9.12-8.97 (m, 3H), 8.12 (s, 1H), 7.02-6.92 (m, 1H), 6.73 (s, 1H), 4.79 (s, 2H), 4.55 (t, J=8.7 Hz, 2H), 3.32 (d, J=8.9 Hz, 2H), 1.92 (s, 3H), 1.89 (s, 3H) ppm; LCMS: m/z 496.1 [M+H].sup.+.

    [0994] The following compound can be obtained with N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (example 88) as the raw material using the method of example 148:

    Example 149: N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-3-(methylsulfonyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [0995] ##STR00589##

    [0996] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.21 (s, 1H), 9.00 (t, J=5.7 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=7.6 Hz, 1H), 8.33 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 6.95-6.87 (m, 1H), 6.66 (dd, J=8.6, 3.8 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 4.52 (t, J=8.7 Hz, 2H), 3.65 (s, 3H), 3.30 (d, J=8.7 Hz, 2H), 3.07 (s, 3H) ppm; LCMS: m/z 494.1 [M+H].sup.+.

    Example 150: 8-(5-(dimethylamino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Step 1: 3-bromo-6-chloro-2-hydrazinopyridine E37-1

    [0997] ##STR00590##

    [0998] A solution of 3-bromo-6-chloro-2-fluoro-pyridine (1.00 g, 4.75 mmol) and hydrazine hydrate (4.10 mL) in N,N-dimethylformamide was stirred and reacted at 80° C. for 2 hours. Upon completion of the reaction (as monitored by LCMS), the mixture was concentrated to obtain a crude. Then the crude was slurried with water at 25° C. for 30 minutes, then filtered and dried under vacuum to obtain a brown solid E37-1 (1.00 g, 94.6% yield).

    [0999] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.55 (d, J=8.0 Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 6.32 (br s, 1H), 3.95 (br d, J=2.8 Hz, 2H) ppm; LCMS: m/z 224.0 [M+H].sup.+.

    Step 2: 8-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridine E37-2

    [1000] ##STR00591##

    [1001] A mixture of E37-1 (1.00 g, 4.49 mmol), trimethylorthoformate (9.68 g, 91.2 mmol) and trifluoroacetic acid (20 mg, 0.175 mmol) was reacted under nitrogen atmosphere at 100° C. for 12 hours. No raw material was left (as monitored by LCMS). The reaction solution was concentrated to obtain a crude and then the crude was slurried with methyl tert-butyl ether to obtain E37-2 (960 mg, 91.9% yield).

    [1002] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 9.03 (s, 1H), 7.53 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H) ppm; LCMS: m/z 234.0 [M+H].sup.+.

    Step 3: 8-bromo-N,N-methyl-[1,2,4]triazolo[4,3-a]pyridin-5-amine E37-3

    [1003] ##STR00592##

    [1004] E37-2 (960 mg, 4.13 mmol) and 40% aqueous dimethylamine solution (30 mL) were mixed and reacted at 100° C. for 12 hours. The reaction was completed (monitored by LCMS and TLC) and the mixture was cooled to room temperature and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried and concentrated to obtain a crude. Then the crude was slurried with ethyl acetate and a solid was collected, i.e., an off-white solid E37-3 (620 mg, 62.3% yield) was obtained.

    [1005] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.89 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 6.12 (d, J=7.6 Hz, 1H), 2.92 (s, 6H) ppm; LCMS: m/z 241.1 [M+H].sup.+.

    [1006] Step 4: The following compound can be obtained with E37-3 and intermediate B3 as the raw materials using the method of example 6:

    8-(5-(dimethylamino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [1007] ##STR00593##

    [1008] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.52 (d, J=8.0 Hz, 2H), 9.35 (s, 1H), 8.96 (d, J=8.0 Hz, 1H), 8.83 (br s, 1H), 7.01-6.92 (m, 1H), 6.71 (dd, J=8.4, 3.6 Hz, 1H), 6.60 (d, J=8.0 Hz, 1H), 4.77 (br d, J=3.6 Hz, 2H), 4.56 (t, J=8.8 Hz, 2H), 3.33-3.32 (m, 2H), 2.93 (s, 6H) ppm; LCMS: m/z 446.3 [M+H].sup.+.

    Example 151: 8-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazole[4,3-c]pyrimidin-5-amine

    Step 1: 8-bromo-3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridine E38-1

    [1009] ##STR00594##

    [1010] E25-1 (700 mg, 3.46 mmoL), trifluoroacetic acid (7.9 mg, 0.07 mmoL) and triethyl orthoacetate (10.1 g, 63.4 mmoL) were mixed. The mixture was warmed to 100° C. and reacted under nitrogen atmosphere for 10 hours. The reaction was completed (monitored by LCMS) and the reaction solution was cooled to room temperature, concentrated and slurried with methyl tert-butyl ether to obtain 8-bromo-3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridine E38-1 (600 mg, 76.6% yield).

    [1011] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 7.52 (d, J=7.1 Hz, 1H), 6.58 (dd, J=1.0, 7.3 Hz, 1H), 2.94 (s, 3H), 2.80 (s, 3H) ppm; LCMS: m/z 228.0 [M+H].sup.+.

    [1012] Step 2: The following compound can be obtained with E38-1 and intermediate B3 as the raw materials using the method of example 6:

    8-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazole[4,3-c]pyrimidin-5-amine

    [1013] ##STR00595##

    [1014] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.55 (s, 1H), 9.43 (s, 1H), 9.18 (d, J=7.9 Hz, 1H), 8.94 (br s, 1H), 8.65 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 6.97 (t, J=9.6 Hz, 1H), 6.72 (dd, J=3.8, 8.6 Hz, 1H), 5.90 (d, J=4.9 Hz, 1H), 5.47-5.38 (m, 1H), 4.78 (br s, 2H), 4.55 (t, J=8.8 Hz, 2H), 3.31-3.30 (m, 2H), 1.55 (d, J=6.4 Hz, 3H) ppm; LCMS: m/z 431.3 [M+H].sup.+.

    Pharmacology and Application

    [1015] Although EED, as one of the main components of the PRC2 protein complex, does not have an enzymatically catalytic activity, it plays an important role in the integral function of PRC2. The effect of EED on PRC2 is specifically embodied in two aspects: 1) EED directly binds to the trimethylated H3K27Me3, which enables the location of the PCR2 complex to the chromatin that needs to be modified; and 2) EED has strong allosteric potentiation effects on the enzymatically catalytic function of EZH2. Therefore, the development of target compounds for the allosteric protein EED provides a new strategy for inhibiting the enzymatic activity of EZH2. Moreover, such inhibitors have better or complementary advantages relative to catalytic site inhibitors of EZH2 enzymes, for example, when patients develop resistance to EZH2 enzyme inhibitors, EED inhibitors can also play a role in inhibiting the activity of EZH2 enzymes. The present disclosure discloses that the compounds can be used as EED target inhibitors and have therapeutic effects on diseases related to the mechanism of action of EED and/or PRC2.

    [1016] The biological functions of the compounds disclosed in the present disclosure have been demonstrated in tests at biochemical and cellular levels. For example, in biochemical tests, the compounds disclosed in the present disclosure can strongly compete for binding with the H3K27Me3 polypeptide that binds to the EED protein (IC.sub.50 can reach <0.2 nM). At the cellular level, the compounds disclosed in the present disclosure can not only inhibit the methylation level of histone H3K27 but also further inhibit the proliferation of cancer cells through this effect (IC.sub.50 can reach <1 nM). In comparison to the compound, N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine in US 20160176882 A1 and WO 2017219948 A1, the activity against cell proliferation of the compound of the present disclosure is increased by about 10-fold. When the compound disclosed in the present disclosure binds to an EED protein, the bicyclic structure outside the binding “pocket” enables the compound to have a better metabolic stability.

    Example 152: Evaluation of Effects of Compounds in Blocking the Binding of EED to H3K27Me3 with AlphaScreen (a-Screening) Method

    [1017] Firstly, compound solutions of different concentration gradients were prepared. Compound powder was dissolved in DMSO to prepare a mother liquor. 1.5 μl of the mother liquor of the compound was taken and added into 198.5 μl of a reaction buffer (25 mM HEPES (pH 8.0), 50 mM NaCl, 0.015% Tween 20, 0.5% BSA). The mixture was mixed uniformly. Then a 3-fold series dilution was carried out with the above-mentioned buffer containing 0.75% DMSO. 9 different test concentrations were provided for one same compound. 5 μL of compounds of different concentration gradients were taken and added into the ProxiPlate-384 Plus, White detection plate (PerkinElmer, 6008280) and two replicates in parallel were provided for each concentration gradient.

    [1018] Secondly, a reaction for blocking the binding was carried out. The above-mentioned buffer was used to dilute His6-tagged full-length EED protein (441 amino acids) to 60 nM and biotinylated polypeptide fragment H3K27me3 (amino acids at positions 19-33) (Biotinylated-H3K27me3) to 75 nM. 5 μl of the polypeptide fragment at the concentration of 75 nM and 5 l of the protein at the concentration of 60 nM were transferred to the detection wells containing the compound, respectively. The detection plate was sealed with the film and incubation was carried out at room temperature for 30 minutes.

    [1019] Finally, the detection was carried out with the AlphaScreen method. Prior use, nickel chelate receptor beads and streptavidin donor beads (at the ratio of 1:1, Perkin Elmer, product number 6760619M) were mixed with the above-mentioned reaction buffer. Then 5 μl of the above-mentioned pre-mixed detection solution was added to each of the detection wells. The donor beads and receptor beads were both at a final concentration of 5 μg/mL. The detection plate was covered and sealed with tinfoil and placed in the dark at room temperature for 1 hour. The signal was read using the AlphaScreen detector on the Spectra max i3. AlphaScreen signals were standardlized based on the readings obtained from positive controls (maximum signal controls) and negative controls (minimum signal controls) to give the inhibition rates for compounds at different concentrations, and afterwards non-linear regression analysis was carried out using GraphPad Prism 5, inhibition curves were made based on the Dose-Response equation of Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope)) and the IC.sub.50 values of each compound were obtained.

    [1020] To rule out the false positive results produced due to the interference with the AlphaScreen detection system by the compound, the compound was diluted using the same method, biotinylated polypeptide Biotinylated-(His).sub.6 was used to replace the EED and polypeptide H3K27me3 in the detection system, and after incubation was carried out for the same period of time, the signal values were read on the Spectra max i3. The data was processed using the same method.

    [1021] Table 3 below shows the IC.sub.50 values of part of the compounds of the present disclosure.

    TABLE-US-00003 TABLE 3 IC.sub.50 (μM), Compound name AlphaScreen N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0150 a]pyridin-7-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0424 a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0057 a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0042 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0045 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0049 a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0043 a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran- 0.0047 4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0044 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0040 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0035 yl)methyl)-8-(imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0095 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2- 0.0035 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-(6-chloroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0044 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro- 0.0096 2,3-dihydrobenzofuran-4-yl)methyl)-[1-1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2- 0.0049 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2- 0.0023 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[11,2,4]triazolo[4,3- c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4- 0.0221 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2- a]pyridine-3-carboxylate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0021 a]pyrimidin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4- 0.0452 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2- methylimidazo[1,2-a]pyridine-3-carboxylate Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0023 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0051 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylic acid N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2- 0.0030 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylimidazo[1,2- 0.0141 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2- 0.0092 methylbenzo[d]oxazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[d]oxazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0049 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methyl-2- 0.0157 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0035 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5- 0.0464 (trifluoromethyl)benzo[c][1,2,5]thiadiazol-4-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methylimidazo[1,2- 0.0046 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylimidazo[1,2- 0.0243 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,5-dimethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0051 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0048 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-one 8-(3-phenylmethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0012 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3-ethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0025 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0047 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0290 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-(trifluoromethyl)imidazo[1,2- a]pyridine-3-carboxylate 8-(3-ethyl-5-methylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0030 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0160 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-one N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3- 0.0074 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4- 0.0912 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2- hydroxyimidazo[1,2-a]pyridine-3-carboxylate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoroimidazo[1,2- 0.0092 a]pyridin-8-yl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,6-difluoroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0052 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0221 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3- carboxylate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0054 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3- carboxylic acid N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoro-5- 0.0058 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(quinolin-8-yl)- 0.0051 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0038 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0049 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0150 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0100 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0044 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0049 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2- methylbenzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0049 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3- methylbenzo[b]thiophene 1,1-dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.5660 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.1230 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0049 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0042 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0063 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0041 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1-dioxide 3-(2-aminoethyl)-5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H- 0.0054 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 3-chloro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0110 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 5-(5-(((6-fluorochroman-5-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0064 c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0045 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0041 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylbenzo[b]thiophene 1,1- dioxide 7-chloro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0039 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0020 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2,3-dimethylbenzo[b]thiophene 1,1- dioxide 1-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.1862 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0122 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 6-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0027 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 3-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0026 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 8-(2,3-dihydroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0052 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-isopropyl-5- 0.0028 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0080 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carboxylate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0118 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0099 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-ol Methyl 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0062 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0054 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetic acid (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0210 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-5-yl)methanol N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0035 yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)- [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0114 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)- N,N-dimethylacetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0062 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)ethyl acetate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylimidazo[1,2- 0.0058 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0083 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-2- yl)methanol N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl- 0.0089 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H- 0.0086 benzo[d]imidazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    Example 153: ELISA (H3K27 Trimethylation) Analysis

    [1022] 3-fold series dilution with DMSO was carried out on the representative compounds of the present disclosure; and 10 concentration gradients were detected for each compound, with the highest detection concentration of 10 μM. The compounds were diluted 200-fold into the G401 cells cultured in a 96-well plate (DMSO at a final concentration of 0.5%). After the cells, administered with the compound, were cultured for 72 hours, the trimethylation level of the histone H3K27 was detected using the ELISA method.

    [1023] Extraction of the histone: in a 96-well plate, the compound-treated cells were washed three times with 1×PBS (10×PBS buffer (80 g NaCl (Sigma, product number S3014), 2 g KCl (Sigma, product number 60128), 14.4 g Na.sub.2HPO.sub.4 (Sigma, product number S5136), and 2.4 g KH.sub.2PO.sub.4 (Sigma, product number P9791) in 1 L of water, adjusting the pH to 7.4)). 100 μL of 0.4 N HCl was added into each well. The plate was placed at 4° C. and gently agitated for 2 hours to lyse the cells. The cell lysate was then neutralized with 80 μL of neutralization buffer (0.5 M disodium hydrogen phosphate, pH 12.5, 2.5 mM DTT; 1% cocktail (Sigma, product number P8340)) (the cell lysate and the neutralization buffer were thoroughly mixed to uniformity).

    [1024] ELISA detection method: the cell lysate was transferred in parallel to two 384-well detection plates (PerkinElmer, OptiPlate-384HB, product number 6007290), wherein one of the plates was used to detect the H3K27 trimethylation level and the other plate was used to determine the level of H3. PBS was used to adjust the final volume to 50 μL/well. The plates were coated at 4° C. overnight. On the following day, the solution inside the wells was discarded and the plates were washed 5 times with TBST buffer (1×TBS (10×TBS: 24.2 g Tris (Sigma, product number T6066), 80 g NaCl (Sigma, product number S3014) in 1 L of water, adjusting the pH with HCl to 7.6), 0.1% Tween-20) and dried on an absorbent paper by inversion. 70 μL of blocking buffer (TBST, 5% BSA) was added into the coated reaction wells and the plates were incubated at room temperature for 1 hour. The blocking buffer was discarded and primary antibodies were added (30 μL/well). The desired primary antibodies were all diluted with a blocking buffer and the dilution factor was as follows: anti-H3K27me3 antibody (Cell Signaling Technology, product number 9733), 1:2000 dilution; anti-H3 antibody (Cell Signaling Technology, product number 4499), 1:10000 dilution. After the primary antibodies were added, the plates were placed at room temperature and incubated for 1 hour. After the plates were washed with TBST 5 times, the plates were dried by inversion. A secondary antibody (30 μL/well) was added to each of the reaction wells and the plates were incubated at room temperature for 1 hour. The secondary antibody (anti-rabbit antibody (Jackson ImmunoResearch, product number 111-035-003)) was diluted 2000-fold with a blocking buffer before use. After 1 hour, the plates were washed with TBST and dried by inversion. 30 μL of ECL substrate (Pierce, product number 34080) was added into each well and centrifuged at 2000 rpm for 30 seconds. The signal of each sample was detected using SpectraMax (Molecular Devices). Data processing: H3K27 methylation readings were first standardlized using H3 signals and 0.5% DMSO-treated samples was used as the control to calculate the inhibition percentage of the compounds. Data were fit to obtain Dose-Response curves using the GraphPad prism 5 program and the IC.sub.50 values of the test compounds were obtained.

    [1025] Table 4 below shows the IC.sub.50 values of part of the compounds of the present disclosure.

    TABLE-US-00004 TABLE 4 IC.sub.50 (μM), Compound name ELISA, G401 N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0056 a]pyridin-7-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0580 a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0180 a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0064 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0073 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0129 a]pyrimidin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0061 a]pyridin-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran- 0.0009 4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2- 0.0008 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0007 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0010 yl)methyl)-8-(imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b- 0.0074 dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2- 0.0024 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-(6-chloroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0085 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro- 0.0890 2,3-dihydrobenzofuran-4-yl)methyl)-[1-1,2,4]triazolo[4,3-c]pyrimidin-5- amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2- 0.0029 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2- 0.0171 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[11,2,4]triazolo[4,3- c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0470 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5- 0.0104 a]pyrimidin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0870 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridine-3- carboxylate Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0060 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.3290 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylic acid N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2- 0.0035 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylimidazo[1,2- 0.0030 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2- 0.0078 methylbenzo[d]oxazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[d]oxazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0130 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methyl-2- 0.0410 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0041 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5- 0.1700 (trifluoromethyl)benzo[c][1,2,5]thiadiazol-4-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methylimidazo[1,2- 0.0016 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylimidazo[1,2- 0.0140 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,5-dimethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0027 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0025 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-one 8-(3-phenylmethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0045 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3-ethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran- 0.0009 4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0032 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.2020 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-(trifluoromethyl)imidazo[1,2- a]pyridine-3-carboxylate 8-(3-ethyl-5-methylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0025 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0015 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-one N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3- 0.0057 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0910 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3- carboxylate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoroimidazo[1,2- 0.0035 a]pyridin-8-yl-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,6-difluoroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0077 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0680 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-hydroxyimidazo[1,2-a]pyridine-3- carboxylate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0040 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3- carboxylic acid N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-fluoro-5- 0.0061 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(quinolin-8-yl)- 0.0029 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0008 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0021 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0160 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0210 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0092 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0041 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2- methylbenzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0136 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3- methylbenzo[b]thiophene 1,1-dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.1600 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0780 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0003 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0058 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0006 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0220 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1-dioxide 3-(2-aminoethyl)-5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H- 0.0750 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 3-chloro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.127 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 5-(5-(((6-fluorochroman-5-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0020 c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0028 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0009 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methylbenzo[b]thiophene 1,1- dioxide 7-chloro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0260 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0140 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2,3-dimethylbenzo[b]thiophene 1,1- dioxide 1-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0750 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3- c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0036 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 6-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0079 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 3-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0073 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-isopropyl-5- 0.0007 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0035 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carboxylate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0030 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0016 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)ethan-1-ol Methyl 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0038 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0040 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetic acid (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0052 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-5-yl)methanol N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0024 yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)- [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0016 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)- N,N-dimethylacetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0010 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)ethyl acetate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylimidazo[1,2- 0.0013 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0012 yl)methyl)-8-(5-methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0024 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)methyl)acetamide (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0014 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-2- yl)methanol N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl- 0.0017 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H- 0.0013 benzo[d]imidazol-4-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0023 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2- a]pyridine-2-carboxamide 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0014 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2- a]pyridine-3-carboxamide 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0007 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine- 5-carboxamide 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0089 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0143 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)- 1-morpholinoethan-1-one N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5- 0.0106 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0024 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)(morpholino)methanone 8-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0330 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0035 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3- carboxamide 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0052 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3- carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)- 0.0069 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0070 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3- yl)acetonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methoxy- 0.0032 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[c][1,2,5]thiadiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0023 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0047 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine- 3-carboxamide 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0134 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-morpholino- 0.0011 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[d]thiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0047 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0010 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-methylpiperazin- 0.0041 1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5- amine 8-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0013 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0064 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5- yl)methoxy)-2-methylpropan-2-ol 8-(5-((dimethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5- 0.0006 fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-((4- 0.0011 methylpiperazin-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)- [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0022 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5- yl)methyl)amino)-2-methylpropan-2-ol N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5- 0.0011 (morpholinomethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-indazol-7-yl)- 0.0016 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5- 0.0024 methyltetrazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5- amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0039 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methoxyimidazo[1,2-a]pyridine-3- carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(pyrrolidin-1-yl)- 0.0027 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4- 0.0011 morpholinopiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)- [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)- 0.0017 N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 5-(dimethylamino)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4- 0.0009 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2- a]pyridine-3-carbonitrile 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0013 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-morpholinoimidazo[1,2-a]pyridine- 3-carbonitrile 8-(1H-benzo[d][1,2,3]triazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0007 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0112 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5- yl)methyl)-N1,N2,N2-trimethylethane-1,2-diamine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2- 0.0008 methylmorpholino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 5-((dimethylamino)methyl)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4- 0.0007 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2- a]pyridine-3-carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-5-methyl- 0.0036 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-((1H-imidazol-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5- 0.0006 fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl- 0.0002 [1,2,4]triazolo[4,3-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl- 0.0045 [1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5- amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0004 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5- yl)propan-2-ol 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0042 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-6-methoxyimidazo[1,2-a]pyridine-3- carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy- 0.0012 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0048 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carbonitrile 8-(2-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5- 0.0018 fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine 8-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0084 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(difluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0055 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-N-((5-fluoro- 0.0018 2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5- amine 8-(5-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5- 0.0028 fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine 8-(5-(dimethylamino)-2-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5- 0.0006 fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin- 5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0143 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridine-6- carbonitrile 8-(5-(dimethylamino)-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0078 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0023 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-3- yl)dimethylphosphine oxide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-3- 0.0880 (methylsulfonyl)imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3- c]pyrimidin-5-amine 8-(3,5-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(5-fluoro-2,3- 0.0008 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazole[4,3-c]pyrimidin-5-amine

    Example 154: Cell Proliferation Analysis

    [1026] Human B-cell non-Hodgkin lymphoma cells, KARPAS-422 S, were cultured in a culture flask using standard cell culture conditions. The medium contained 15% fetal bovine serum (FBS, Invitrogen, product number 10099-141) and 1% penicillin/streptomycin solution (P/S) RPMI-1640 (Invitrogen, product number 11875), and the culture flask was placed and cultured in a sterile incubator at the temperature of 37° C. and 500 CO.sub.2 with a relative humidity of 9500 To detect the effect of PRC2 inhibitors on cell proliferation, cells in exponential growth phase were taken and seeded into a 96-well plate (Corning, product number 3904) at a density of 1×10.sup.4 cells/well, and 100 μL of the medium was added into each well. Subsequently, the compounds at different concentrations disclosed in the present disclosure were added into the wells where cells had already been seeded (9 concentration gradients were provided for each compound, with the highest detection concentration at 10 μM, 3-fold gradient dilution) and two replicates in parallel were provided for each treatment concentration. DMSO was at a final concentration of 0.5%. Afterwards, viable cell numbers were determined using Vi-CELL (Beckman Coulter) every 3-4 days. Cells counted were seeded into a new 96-well plate at the same density (1×10.sup.4 cells/well) each time. The wells were supplemented with a fresh medium to 100 μL and at the same time, compounds at different concentrations were added. The cells were cultured to day 13. 100 μL of CellTiter-Glo (CellTiter-GloCellTiter-GloCellTiter-GloCTG) (Promega, product number G7573) was added into each well. The plate was placed in the dark at room temperature for 10-20 minutes and the luminescence signal was read using SpectraMax i3× (Molecular Devices). Data were fit to obtain Dose-Response curves using GraphPad prism 5 and hence the IC.sub.50 values of the test compounds were obtained.

    [1027] Table 5 below shows the IC.sub.50 values of part of the compounds of the present disclosure.

    TABLE-US-00005 TABLE 5 IC.sub.50 (μM), Compound name Karpas-422, 13 days N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-7-yl)- 0.0165 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)- 0.0941 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyrimidin-6-yl)- 0.0183 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0431 cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0077 cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyridin-6-yl)- 0.0154 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0014 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(imidazo[1,2-a]pyridin-8-yl)- 0.0015 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0019 cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8- 0.0006 (imidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-([1,2,4]triazolo[4,3-a]pyridin-8-yl)-N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H- 0.0048 cyclopropa[b]benzofuran-6-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-(trifluoromethyl)imidazo[1,2- 0.0017 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(6-chloroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0420 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoroimidazo[1,2-a]pyridin-8- 0.0020 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2- 0.0095 (trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)-[11,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(pyrazolo[1,5-a]pyrimidin-3-yl)- 0.0097 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0040 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxylate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-2-methylimidazo[1,2- 0.0013 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylimidazo[1,2-a]pyridin-8- 0.0024 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylbenzo[d]oxazol-4-yl)- 0.0042 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[d]oxazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0136 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0037 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-8- 0.0014 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methylimidazo[1,2-a]pyridin-8- 0.0116 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,5-dimethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0019 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0016 c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-one 8-(3-phenylmethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0036 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3-ethylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0009 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0035 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile 8-(3-ethyl-5-methylimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0022 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0011 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-one N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-3-methylimidazo[1,2- 0.0040 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(3,6-difluoroimidazo[1,2-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0075 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0007 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0007 c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0038 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0130 c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 4-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0115 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0125 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0243 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1- dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0790 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0970 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0004 c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 3-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0055 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1- dioxide 5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0008 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)benzo[c]thiophene 2,2-dioxide 2-fluoro-5-(5-((((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6- 0.0320 yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-3-methylbenzo[b]thiophene 1,1- dioxide 3-(2-aminoethyl)-5-(5-((((1aS,6bS)-5-fluoro-1a,6b-dihydro-1H- 0.0330 cyclopropa[b]benzofuran-6-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8- yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((6-fluorochroman-5-yl)methyl)amino)-[1,2,4]triazolo[4,3-c]pyrimidin-8- 0.0016 yl)benzo[c]thiophene 2,2-dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0005 c]pyrimidin-8-yl)benzo[b]thiophene 1,1-dioxide 5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0005 c]pyrimidin-8-yl)-6-methylbenzo[b]thiophene 1,1-dioxide 7-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0087 c]pyrimidin-8-yl)-2,3-dimethylbenzo[b]thiophene 1,1-dioxide 4-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0042 c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 6-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0088 c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide 3-fluoro-5-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0049 c]pyrimidin-8-yl)-2-methylbenzo[b]thiophene 1,1-dioxide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(3-isopropyl-5-methylimidazo[1,2- 0.0010 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine Methyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0051 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carboxylate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0032 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0024 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)ethan-1-ol Methyl 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0010 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetate 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0047 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetic acid (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0086 c]pyrimidin-8-yl)imidazo[1,2-a]pyridin-5-yl)methanol N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8-(5- 0.0044 methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0061 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylacetamide 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0017 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)ethyl acetate N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methylimidazo[1,2-a]pyridin-8- 0.0013 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-(((1aR,6bR)-5-fluoro-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-6-yl)methyl)-8-(5- 0.0009 methylimidazo[1,2-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0032 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)methyl)acetamide (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0033 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)methanol N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5- 0.0018 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1-methyl-1H-benzo[d]imidazol-4- 0.0016 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0028 c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2-a]pyridine-2-carboxamide Ethyl 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0047 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxylate 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0012 c]pyrimidin-8-yl)-N,N,5-trimethylimidazo[1,2-a]pyridine-3-carboxamide 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0013 c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine-5-carboxamide 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0083 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0057 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)-1-morpholinoethan-1-one N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)imidazo[1,2- 0.0070 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0011 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)(morpholino)methanone 8-(5-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4- 0.0180 yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0022 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carboxamide 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0030 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridine-3-carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(trifluoromethyl)- 0.0360 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0014 c]pyrimidin-8-yl)-5-methylimidazo[1,2-a]pyridin-3-yl)acetonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methoxy-[1,2,4]triazolo[1,5- 0.0011 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[c][1,2,5]thiadiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0140 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0024 c]pyrimidin-8-yl)-N,N-dimethylimidazo[1,2-a]pyridine-3-carboxamide 6-fluoro-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0046 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carboxamide N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-morpholino-[1,2,4]triazolo[1,5- 0.0007 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(benzo[d]thiazol-4-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0036 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0014 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-methylpiperazin-1-yl)- 0.0007 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(2,5-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3-dihydrobenzofuran- 0.0013 4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0012 c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methoxy)-2-methylpropan-2-ol 8-(5-((dimethylamino)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0005 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-((4-methylpiperazin-1- 0.0007 yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 1-(((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0021 c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)amino)-2-methylpropan-2-ol N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(morpholinomethyl)- 0.0011 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(1H-indazol-7-yl)- 0.0023 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyltetrazolo[1,5-a]pyridin-8- 0.0025 yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0062 c]pyrimidin-8-yl)-5-methoxyimidazo[1,2-a]pyridine-3-carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(pyrrolidin-1-yl)- 0.0032 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(4-morpholinopiperidin-1-yl)- 0.0008 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro- 0.0018 2,3-dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5-(dimethylamino)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0009 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0013 c]pyrimidin-8-yl)-5-morpholinoimidazo[1,2-a]pyridine-3-carbonitrile 8-(1H-benzo[d][1,2,3]triazol-7-yl)-N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)- 0.0012 [1,2,4]triazolo[4,3-c]pyrimidin-5-amine N1-((8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0035 c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)-N1,N2,N2-trimethylethane- 1,2-diamine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-(2-methylmorpholino)- 0.0005 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 5-((dimethylamino)methyl)-8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 0.0005 [1,2,4]triazolo[4,3-c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-3-carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-fluoro-5-methyl- 0.0047 [1,2,4]triazolo[1,5-a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-((1H-imidazol-1-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0009 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[4,3- 0.0002 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(5-methyl-[1,2,4]triazolo[1,5- 0.0025 c]pyrimidin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 2-(8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0002 c]pyrimidin-8-yl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)propan-2-ol 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0045 c]pyrimidin-8-yl)-6-methoxyimidazo[1,2-a]pyridine-3-carbonitrile N-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(6-methoxy-[1,2,4]triazolo[1,5- 0.0017 a]pyridin-8-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(5-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-[1,2,4]triazolo[4,3- 0.0036 c]pyrimidin-8-yl)imidazo[1,2-a]pyridine-5-carbonitrile 8-(2-(dimethylamino)-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0244 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine 8-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-N-((5-fluoro-2,3- 0.0054 dihydrobenzofuran-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine

    [1028] The compounds disclosed in the present disclosure can be used to treat cancer related to the mechanism of action of an EED protein and/or a PRC2 protein complex, including but not limited to lymphoma (such as diffuse large B-cell lymphoma, follicular lymphoma, non-Hodgkin's lymphoma), leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, cerebroma including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial carcinoma, esophageal carcinoma, head and neck cancer, lung cancer, nasopharyngeal carcinoma, ovarian cancer, pancreatic cancer, renal carcinoma, rectal cancer, thyroid cancer, parathyroid tumor, uterine cancer, and soft tissue sarcoma.

    [1029] Although the specific embodiments of the present disclosure have been described above, it will be understood by those of skill in the art that these are merely illustrative, and that various alterations or modifications can be made to these embodiments without departing from the principle and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is defined by the appended claims.