AROMATIC COMPOUND AND USE THEREOF

Abstract

A compound of the following formula

##STR00001##

capable of binding to a tripartite motif (TRIM) protein E3 ubiquitin ligase (TRIM21). This application also provides a method for treating a disease associated with abnormal cell proliferation with the compound of formula (I). This application further provides a method for preparing a drug for targeted protein degradation with such compound as an intermediate.

Claims

1. A compound of formula (I), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof: ##STR00095## wherein: A ring is selected from the group consisting of 6 to 10-membered aromatic ring, 5 to 10-membered heteroaromatic ring, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic ring, wherein aromatic ring, heteroaromatic ring, cycloalkyl and heterocyclic ring are independently unsubstituted or substituted with one, two, three or four R.sup.1; each R.sup.1 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, hydroxy-substituted C.sub.1-6 alkyl, C.sub.0-4 alkylene-OR.sup.12, C.sub.0-4 alkylene-OC(O)R.sup.12, C.sub.0-4 alkylene-SR.sup.12, C.sub.0-4 alkylene-S(O).sub.2R.sup.12, C.sub.0-4 alkylene-S(O)R.sup.12, C.sub.0-4 alkylene-S(O).sub.2NR.sup.12R.sup.13, C.sub.0-4 alkylene-S(O)NR.sup.12R.sup.13, C.sub.0-4 alkylene-C(O)R.sup.12, C.sub.0-4 alkylene-C(O)OR.sup.12, C.sub.0-4 alkylene-C(O)NR.sup.12R.sup.13, C.sub.0-4 alkylene-NR.sup.12R.sup.13, C.sub.0-4 alkylene-NR.sup.12C(O)R.sup.13, C.sub.0-4 alkylene-NR.sup.12S(O).sub.2R.sup.13, C.sub.0-4 alkylene-NR.sup.12S(O)R.sup.13, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); R.sup.12 and R.sup.13 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.14; each R.sup.14 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; each R.sup.2 is independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.22, C.sub.0-4 alkylene-OC(O)R.sup.22, C.sub.0-4 alkylene-SR.sup.22, C.sub.0-4 alkylene-S(O).sub.2R.sup.22, C.sub.0-4 alkylene-S(O)R.sup.22, C.sub.0-4 alkylene-S(O).sub.2NR.sup.22R.sup.23, C.sub.0-4 alkylene-S(O)NR.sup.22R.sup.23, C.sub.0-4 alkylene-C(O)R.sup.22, C.sub.0-4 alkylene-C(O)OR.sup.22, C.sub.0-4 alkylene-C(O)NR.sup.22R.sup.23, C.sub.0-4 alkylene-NR.sup.22R.sup.23, C.sub.0-4 alkylene-NR.sup.22C(O)R.sup.23, C.sub.0-4 alkylene-NR.sup.22S(O).sub.2R.sup.23, C.sub.0-4 alkylene-NR.sup.22S(O)R.sup.23, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); R.sup.22 and R.sup.23 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.24; each R.sup.24 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.34, C.sub.0-4 alkylene-OC(O)R.sup.34, C.sub.0-4 alkylene-SR.sup.34, C.sub.0-4 alkylene-S(O).sub.2R.sup.34, C.sub.0-4 alkylene-S(O)R.sup.34, C.sub.0-4 alkylene-S(O).sub.2NR.sup.34R.sup.35, C.sub.0-4 alkylene-S(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-C(O)R.sup.34, C.sub.0-4 alkylene-C(O)OR.sup.34, C.sub.0-4 alkylene-C(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34C(O)R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O).sub.2R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O)R.sup.35, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.36; each R.sup.36 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.34, C.sub.0-4 alkylene-OC(O)R.sup.34, C.sub.0-4 alkylene-SR.sup.34, C.sub.0-4 alkylene-S(O).sub.2R.sup.34, C.sub.0-4 alkylene-S(O)R.sup.34, C.sub.0-4 alkylene-S(O).sub.2NR.sup.34R.sup.35, C.sub.0-4 alkylene-S(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-C(O)R.sup.34, C.sub.0-4 alkylene-C(O)OR.sup.34, C.sub.0-4 alkylene-C(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34C(O)R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O).sub.2R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O)R.sup.35, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.37; R.sup.34 and R.sup.35 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; and each R.sup.37 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl.

2. The compound of claim 1, wherein the compound is represented by formula (IIA): ##STR00096## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are defined as in claim 1.

3. The compound of claim 1, wherein the A ring is selected from the group consisting of 6-membered aromatic ring, 6-membered cycloalkyl, 9-membered heterocycloalkyl, 6-membered heteroaromatic ring and 9-membered heteroaromatic ring, wherein aromatic ring, cycloalkyl, heterocycloalkyl and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.1; each R.sup.1 is independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, hydroxy-substituted C.sub.1-6 alkyl, C.sub.0-4 alkylene-OR.sup.12, C.sub.0-4 alkylene-OC(O)R.sup.12, C.sub.0-4 alkylene-SR.sup.12, C.sub.0-4 alkylene-NR.sup.12R.sup.13, C.sub.0-4 alkylene-(3 to 6-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 6-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); and R.sup.12 and R.sup.13 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and halogen-substituted C.sub.1-6 alkyl.

4. The compound of claim 3, wherein each R.sup.1 is independently selected from the group consisting of hydrogen, methylthio, halogen, methyl, ethyl, propyl, isopropyl, methoxy, trifluoromethyl, ##STR00097## cyclopropyl and ##STR00098##

5. The compound of claim 3, wherein the A ring is selected from the group consisting of ##STR00099##

6. The compound of claim 1, wherein R.sup.2 is C.sub.1-3 alkyl.

7. The compound of claim 1, wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.36; each R.sup.36 is independently selected from the group consisting of hydrogen, halogen, cyano group, O, C.sub.1-6 alkyl, halogen-substituted C.sub.1-6 alkyl, C.sub.0-4 alkylene-OR.sup.34, C.sub.0-4 alkylene-C(O)R.sup.34, C.sub.0-4 alkylene-C(O)OR.sup.34, C.sub.0-4 alkylene-C(O)NR.sup.4R.sup.35, C.sub.0-4 alkylene-NR.sup.34R.sup.35, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); and R.sup.34 and R.sup.35 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl.

8. The compound of claim 7, wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, amyl, hexyl, C.sub.0-2 alkylene-(3-membered cycloalkyl), C.sub.0-2 alkylene-(4-membered cycloalkyl), C.sub.0-2 alkylene-(5-membered cycloalkyl), C.sub.0-2 alkylene-(6-membered cycloalkyl), C.sub.0-2 alkylene-(4-membered heterocycloalkyl), C.sub.0-2 alkylene-(5-membered heterocycloalkyl), C.sub.0-2 alkylene-(6-membered heterocycloalkyl), C.sub.0-2 alkylene-(9-membered heterocycloalkyl), C.sub.0-2 alkylene-(6-membered aromatic ring), C.sub.0-2 alkylene-(5-membered heteroaromatic ring), C.sub.0-2 alkylene-(6-membered heteroaromatic ring) and C.sub.0-2 alkylene-(9-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.36; each R.sup.36 is independently selected from the group consisting of hydrogen, halogen, O, C.sub.1-3 alkyl, halogen-substituted C.sub.1-3 alkyl, OR.sup.34, C(O)R.sup.34 and NR.sup.34R.sup.35; and R.sup.34 and R.sup.35 are each independently selected from the group consisting of hydrogen and C.sub.1-3 alkyl.

9. The compound of claim 8, wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, amyl, hexyl, ##STR00100##

10. The compound of claim 1, wherein the compound is selected from the group consisting of: ##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109## ##STR00110## ##STR00111##

11. A compound of formula (V), or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof: ##STR00112## wherein: A ring is selected from the group consisting of 6 to 10-membered aromatic ring, 5 to 10-membered heteroaromatic ring, 3 to 10-membered cycloalkyl and 3 to 10-membered heterocyclic ring, wherein aromatic ring, heteroaromatic ring, cycloalkyl and heterocyclic ring are independently unsubstituted or substituted with one, two, three or four R.sup.1; each R.sup.1 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.12, C.sub.0-4 alkylene-OC(O)R.sup.12, C.sub.0-4 alkylene-SR.sup.12, C.sub.0-4 alkylene-S(O).sub.2R.sup.12, C.sub.0-4 alkylene-S(O)R.sup.12, C.sub.0-4 alkylene-S(O).sub.2NR.sup.12R.sup.13, C.sub.0-4 alkylene-S(O)NR.sup.12R.sup.13, C.sub.0-4 alkylene-C(O)R.sup.12, C.sub.0-4 alkylene-C(O)OR.sup.12, C.sub.0-4 alkylene-C(O)NR.sup.12R.sup.13, C.sub.0-4 alkylene-NR.sup.12R.sup.13, C.sub.0-4 alkylene-NR.sup.12C(O)R.sup.13, C.sub.0-4 alkylene-NR.sup.12S(O).sub.2R.sup.13, C.sub.0-4 alkylene-NR.sup.12S(O)R.sup.13, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); R.sup.12 and R.sup.13 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.14; each R.sup.14 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; each R.sup.2 is independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.22, C.sub.0-4 alkylene-OC(O)R.sup.22, C.sub.0-4 alkylene-SR.sup.22, C.sub.0-4 alkylene-S(O).sub.2R.sup.22, C.sub.0-4 alkylene-S(O)R.sup.22, C.sub.0-4 alkylene-S(O).sub.2NR.sup.22R.sup.23, C.sub.0-4 alkylene-S(O)NR.sup.22R.sup.23, C.sub.0-4 alkylene-C(O)R.sup.22, C.sub.0-4 alkylene-C(O)OR.sup.22, C.sub.0-4 alkylene-C(O)NR.sup.22R.sup.23, C.sub.0-4 alkylene-NR.sup.22R.sup.23, C.sub.0-4 alkylene-NR.sup.22C(O)R.sup.23, C.sub.0-4 alkylene-NR.sup.22S(O).sub.2R.sup.23, C.sub.0-4 alkylene-NR.sup.22S(O)R.sup.23, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); R.sup.22 and R.sup.23 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.24; each R.sup.24 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; R.sup.3 is independently selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.34, C.sub.0-4 alkylene-OC(O)R.sup.34, C.sub.0-4 alkylene-SR.sup.34, C.sub.0-4 alkylene-S(O).sub.2R.sup.34, C.sub.0-4 alkylene-S(O)R.sup.34, C.sub.0-4 alkylene-S(O).sub.2NR.sup.34R.sup.35, C.sub.0-4 alkylene-S(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-C(O)R.sup.34, C.sub.0-4 alkylene-C(O)OR.sup.34, C.sub.0-4 alkylene-C(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34C(O)R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O).sub.2R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O)R.sup.35, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.36; each R.sup.36 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.34, C.sub.0-4 alkylene-OC(O)R.sup.34, C.sub.0-4 alkylene-SR.sup.34, C.sub.0-4 alkylene-S(O).sub.2R.sup.34, C.sub.0-4 alkylene-S(O)R.sup.34, C.sub.0-4 alkylene-S(O).sub.2NR.sup.34R.sup.35, CO.sub.4 alkylene-S(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-C(O)R.sup.34, C.sub.0-4 alkylene-C(O)OR.sup.34, C.sub.0-4 alkylene-C(O)NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34R.sup.35, C.sub.0-4 alkylene-NR.sup.34C(O)R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O).sub.2R.sup.35, C.sub.0-4 alkylene-NR.sup.34S(O)R.sup.35, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.37; R.sup.34 and R.sup.35 are each independently selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; each R.sup.37 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl; T is -(L.sup.T).sub.q-; q is an integer selected from 1-50; each L.sup.T is independently selected from the group consisting of CR.sup.T2R.sup.T3, C(O), C(S), O, S, S(O), S(O).sub.2, NR.sup.T2, CR.sup.T2CR.sup.T3, CC, 3 to 12-membered cycloalkyl, 3 to 12-membered heterocycloalkyl, 6 to 10-membered aromatic ring, 5 to 10-membered heteroaromatic ring, 5 to 12-membered spiro cycle, 5 to 12-membered spiro heterocycle, 5 to 12-membered bridged ring, 5 to 12-membered bridged heterocycle and a combination thereof, wherein cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring, spiro cycle, spiro heterocycle, bridged ring and bridged heterocycle are independently unsubstituted or substituted with one, two, three or four R.sup.T1; each R.sup.T1 is independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, CR.sup.T2R.sup.T3, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-OR.sup.T2, C.sub.0-4 alkylene-OC(O)R.sup.T2, C.sub.0-4 alkylene-SR.sup.T2, C.sub.0-4 alkylene-S(O).sub.2R.sup.T2, C.sub.0-4 alkylene-S(O)R.sup.T2, C.sub.0-4 alkylene-S(O).sub.2NR.sup.T2R.sup.T3, C.sub.0-4 alkylene-S(O)NR.sup.T2R.sup.T3, C.sub.0-4 alkylene-C(O)R.sup.T2, C.sub.0-4 alkylene-C(O)OR.sup.T2, C.sub.0-4 alkylene-C(O)NR.sup.T2R.sup.T3, C.sub.0-4 alkylene-NR.sup.T2R.sup.T3, C.sub.0-4 alkylene-NR.sup.T2C(O)R.sup.T3, C.sub.0-4 alkylene-NR.sup.T2S(O).sub.2R.sup.T3, C.sub.0-4 alkylene-NR.sup.T2S(O)R.sup.T3, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring), wherein alkylene, cycloalkyl, heterocycloalkyl, aromatic ring and heteroaromatic ring are independently unsubstituted or substituted with one, two, three or four R.sup.T4; R.sup.T2, R.sup.T3 and R.sup.T4 are each independently selected from the group consisting of hydrogen, halogen, cyano group, nitro, O, S, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl, halogen-substituted C.sub.2-6 alkynyl, C.sub.0-4 alkylene-(3 to 10-membered cycloalkyl), C.sub.0-4 alkylene-(3 to 10-membered heterocycloalkyl), C.sub.0-4 alkylene-(6 to 10-membered aromatic ring) and C.sub.0-4 alkylene-(5 to 10-membered heteroaromatic ring); X.sup.2 is selected from the group consisting of NH.sub.2, NHR.sup.X21, OH, SH, ethynyl, ethenyl, C(O)H and C(O)OH; and R.sup.X21 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen-substituted C.sub.1-6 alkyl, halogen-substituted C.sub.2-6 alkenyl and halogen-substituted C.sub.2-6 alkynyl.

12. The compound of claim 11, wherein the compound is represented by formula (VIa): ##STR00113## wherein R.sup.1, R.sup.2, R.sup.3, T and X.sup.2 are defined as in claim 11.

13. The compound of claim 12, wherein T is selected from the group consisting of ##STR00114##

14. A method for treating a disease associated with abnormal cell proliferation in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the compound of claim 1, or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof.

15. The method of claim 14, wherein the disease is a cancer.

16. A drug for targeted protein degradation, comprising: the compound of claim 1, or a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof.

17. The drug of claim 16, wherein the drug is dependent on a tripartite motif protein 21 E3 ubiquitin ligase (TRIM21) for protein degradation.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0094] The disclosure will be further described in detail below with reference to the following examples. However, it should be understood that the scope of the present disclosure is not limited to the following exemplary embodiments. All embodiments implemented in light of the content disclosed herein shall fall within the scope of the present disclosure.

[0095] The known starting materials of the present disclosure can be synthesized according to the methods known in the prior art, or can be purchased from Energy Chemical Co., Ltd, Chengdu Kelong Chemical Co., Ltd, Accela ChemBio Co., Ltd, or J&K Scientific Co., Ltd.

[0096] Unless otherwise specified, reaction was carried out under a nitrogen atmosphere, a solution is an aqueous solution, a temperature of the reaction is room temperature, which is the most suitable temperature for the reaction (20 C. to 30 C.), and M represents mol/L.

[0097] Compounds are structurally characterized by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). The NMR shifts () is expressed in a unit of 10.sup.6 (ppm). The NMR spectra are obtained by using a Nuclear Magnetic Resonance Spectrometer (Bruker Avance III 400) and (Bruker Avance 600 spectrometer) with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3), or deuterated methanol (Methol-d.sub.4) as the solvent, and tetramethylsilane (TMS) as the internal standard. LC-MS is carried out using Shimadzu LC-MS 2020 (ESI). HPLC is performed using a Shimadzu High-Performance Liquid Chromatograph (Shimadzu LC-20A). MPLC (Medium-Pressure Preparative Liquid Chromatography) is performed on a Gilson GX-281 reversed phase preparative chromatograph. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin layer chromatography, and the product size used in the thin layer chromatography is 0.4 mm to 0.5 mm. Typically, 200-300 mesh silica gel (Yantai Huanghai silica gel) is used as the carrier in column chromatography.

[0098] Pd(dppf)Cl.sub.2: 1,1-bis(diphenylphosphino)ferrocene palladium(ii) dichloride; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate; DCE: dichloroethane; and DMF N,N-dimethylformamide.

Example 1 Preparation of Compound 1

##STR00033##

Synthesis of Compound S2

[0099] Under the protection of N.sub.2, substrate S1 (200 mg, 0.682 mmol), 2-(methylthio)phenylboronic acid (137.57 mg, 0.818 mmol), Pd(dppf)Cl.sub.2 (49.51 mg, 0.068 mmol), K.sub.2CO.sub.3 (282.89 mg, 2.05 mmol) and 2 mL of 1,4-dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and reacted under stirring at 100 C. for 2 h, where the reaction was monitored through liquid chromatography-mass spectrometry (LC-MS). The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a brown solid as substrate S2 (198 mg, 0.588 mmol, 86% yield). LCMS (ESI.sup.+) m/z: 337.0 [M+H].sup.+.

Synthesis of Compound S3

[0100] The substrate S2 (200 mg, 0.594 mmol) was added into a single-neck flask, to which 2 mL of MeOH was added. The reaction mixture was stirred for dissolution, added with a 2N NaOH solution (71.34 mg, 1.78 mmol), and reacted under stirring at 60 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, pH adjustment to 5-6 with a 3N HCl solution, freeze-drying, and purification through medium-pressure liquid chromatography to obtain a light reddish-brown oily liquid as substrate S3 (180 mg, 0.558 mmol, 93.92% yield). LCMS (ESI.sup.+) m/z: 321.1 [MH].sup..

Synthesis of Compound 1

[0101] The substrate S3 (30 mg, 0.093 mmol) and 3 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (120.26 mg, 0.93 mmol), cooled in an ice water bath, added with HATU (42.43 mg, 0.111 mmol), stirred at 0 C. for 5 min, added with methylamine (3.47 mg, 0.111 mmol), and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 1 (16 mg, 0.047 mmol, 50.90% yield, 99.3% purity). LCMS (ESI.sup.+) m/z: 336.1 [M+H].sup.+.

[0102] .sup.1H NMR (400 MHz, DMSO-d6) 8.63 (d, J=4.7 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.77 (dd, J=7.7, 1.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.50-7.38 (m, 2H), 7.28 (d, J=2.3 Hz, 1H), 6.04 (s, 1H), 3.41 (s, 3H), 2.77 (d, J=4.6 Hz, 3H), 2.42 (s, 3H).

Example 2 Preparation of Compound 2

##STR00034##

[0103] The substrate S3 (50 mg, 0.155 mmol) and 3 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (160.35 mg, 1.24 mmol, 216.10 L), cooled in an ice water bath, added with HATU (70.8 mg, 0.186 mmol), stirred at 0 C. for 5 min, added with N-methylcyclohexylmethanamine (23.7 mg, 0.186 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain an off-white solid as compound 2 (28.9 mg, 0.067 mmol, 43.2% yield, 99.0% purity). LCMS (ESI.sup.+) m/z: 432.1 [M+H].sup.+.

[0104] .sup.1H NMR (400 MHz, DMSO-d6) 7.94 (d, J=1.7 Hz, 1H), 7.80 (dt, J=7.8, 1.6 Hz, 1H), 7.58-7.38 (m, 3H), 7.31 (ddd, J=7.7, 6.6, 1.6 Hz, 2H), 3.28 (d, J=14.4 Hz, 3H), 2.89 (d, J=75.7 Hz, 3H), 2.42 (s, 3H), 1.70 (dq, J=48.1, 16.7, 13.4 Hz, 7H), 1.22 (q, J=9.9, 8.2 Hz, 4H), 1.00 (s, 2H).

Example 3 Preparation of Compound 3

##STR00035##

[0105] The substrate S3 (40 mg, 0.124 mol) and 3 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (160.35 mg, 1.24 mmol, 216.10 L), cooled in an ice water bath, added with HATU (42.43 mg, 0.111 mmol), stirred at 0 C. for 5 min, added with 3,4-methylenedioxybenzylamine (22.51 mg, 0.149 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 3-1 (46 mg, 0.093 mmol, 74.88% yield, 92.0% purity). LCMS (ESI.sup.+) m/z: 456.0 [M+H].sup.+.

[0106] A dried single-neck flask was added with NaH (5.27 mg, 0.132 mmol, 60% purity), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 3-1 (20 mg, 0.044 mmol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (20 mg, 0.143 mmol), reacted at 0 C. for 1 h and quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a white solid as compound 3 (13 mg, 0.026 mmol, 58.83% yield, 93.3% purity). LCMS (ESI.sup.+) m/z: 470.1 [M+H].sup.+.

[0107] .sup.1H NMR (400 MHz, DMSO-d6) 7.96 (t, J=2.2 Hz, 1H), 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (dd, J=7.8, 1.6 Hz, 1H), 7.49-7.39 (m, 2H), 7.35-7.25 (m, 2H), 6.97 (dd, J=7.1, 2.1 Hz, 1H), 6.89-6.84 (m, 2H), 6.07 (s, 2H), 4.86 (s, 1H), 4.50 (s, 1H), 3.33 (s, 3H), 3.31 (s, 3H), 2.42 (d, J=4.3 Hz, 3H).

Example 4 Preparation of Compound 4

##STR00036##

[0108] The substrate S3 (30 mg, 0.09 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (117 mg, 0.9 mmol), cooled in an ice water bath, added with HATU (42.5 mg, 0.11 mmol), stirred at 0 C. for 5 min, added with 3-(aminomethyl)thiophene (12.6 mg, 0.11 mmol), and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 4-1 (15.7 mg, 0.038 mmol, 42% yield). LCMS (ESI.sup.+) m/z: 418.1 [M+H].sup.+.

[0109] A dried single-neck flask was added with NaH (3.8 mg, 0.158 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 4-1 (8 mg, 0.019 mmol) was dissolved in 0.5 mL DMF and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (8.2 mg, 0.058 mmol), reacted at 0 C. for 1 h, and quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 4 (3.2 mg, 8.8 mol, 46% yield). LCMS (ESI.sup.+) m/z: 432.8 [M+H].sup.+.

[0110] .sup.1H NMR (400 MHz, DMSO-d6) 7.96 (t, J=1.8 Hz, 1H), 7.80 (ddd, J=20.0, 7.8, 1.8 Hz, 1H), 7.64 (dd, J=12.7, 7.8 Hz, 1H), 7.59-7.39 (m, 4H), 7.36-7.25 (m, 2H), 7.16 (ddd, J=23.2, 4.9, 1.3 Hz, 1H), 4.83-4.23 (m, 2H), 2.82 (d, J=69.3 Hz, 3H), 2.42 (d, J=6.8 Hz, 4H), 1.19 (d, 2H).

Example 5 Preparation of Compound 5

##STR00037##

[0111] The substrate S3 (16.1 mg, 0.05 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (65 mg, 0.5 mmol), cooled in an ice water bath, added with HATU (22.8 mg, 0.06 mmol), stirred at 0 C. for 5 min, added with 2,2-difluorocyclohexanemethanamine (11.1 mg, 0.06 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 5-1 (16 mg, 0.035 mmol, 71% yield). LCMS (ESI.sup.+) m/z: 454.1 [M+H].sup.+.

[0112] A dried single-neck flask was added with NaH (3.4 mg, 0.086 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF cooled in an ice water bath. The compound 5-1 (13 mg, 0.029 mmol) was dissolved in 0.5 mL DMF and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (20 mg, 0.143 mmol), reacted at 0 C. for 1 h and quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 5 (7.4 mg, 15.8 mol, 55% yield). LCMS (ESI.sup.+) m/z: 468.0 [M+H].sup.+.

[0113] .sup.1H NMR (400 MHz, DMSO-d6) 7.95 (d, J=1.8 Hz, 1H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.62-7.39 (m, 3H), 7.37-7.26 (m, 2H), 3.90-3.67 (m, 1H), 3.60-3.40 (m, 1H), 3.29 (s, 3H), 2.82 (s, 3H), 2.42 (s, 3H), 2.14-1.59 (m, 5H), 1.53-0.92 (m, 4H).

Example 6 Preparation of Compound 6

##STR00038##

[0114] The substrate S1 (100 mg, 0.34 mmol), 4 mL MeOH and 2 mL H.sub.2O were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with crushed NaOH (68.5 mg, 1.71 mmol) and subjected to backflow at 50 C. for 1 h, where the reaction was monitored by LC-MS. A 1M hydrochloric acid solution was added into the reaction solution until neutral, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a colorless oily compound 6-1 (46 mg, 0.20 mmol, 48% yield). LCMS (ESI.sup.+) m/z: 278.9 [M+H].sup.+.

[0115] A dried single-neck flask was added with 1-fluorocyclohexanemethanamine (26 mg, 0.19 mmol), 1.5 mL DMF and DIPEA (213 mg, 1.65 mmol), cooled in an ice water bath, added with HATU (69 mg, 0.18 mmol) and stirred in an ice water bath for 5 min. The compound 6-1 (46 mg, 0.20 mmol) was added into the single-neck flask and stirred in an ice water bath for 10 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 6-2 (40.6 mg, 0.10 mmol, 62% yield). LCMS (ESI.sup.+) m/z: 392.2 [M+H].sup.+.

[0116] A dried single-neck flask was added with NaH (4.9 mg, 0.20 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 6-2 (40.6 mg, 0.10 mmol) was dissolved in 0.5 mL DMF and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (29 mg, 0.20 mmol), and reacted at 0 C. for 1 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 6-3 (31 mg, 76.5 mol, 73% yield). LCMS (ESI.sup.+) m/z: 406.3 [M+H].sup.+.

[0117] The compound 6-3 (15 mg, 37 mol), 2 mL 1,4-dioxane and 0.2 mL H.sub.2O were added into a dried single-neck flask, added with 2-(methylthio)phenylboronic acid (7.5 mg, 44 mol), K.sub.2CO.sub.3 (15.4 mg, 111 mol) and Pd(dppf).sub.2Cl.sub.2 (3 mg, 3.7 mol), sealed, replaced with nitrogen three times, and subjected to backflow at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a green solid as compound 6 (15.5 mg, 34.5 mol, 93% yield). LCMS (ESI.sup.+) m/z: 450.0 [M+H].sup.+.

[0118] .sup.1H NMR (400 MHz, DMSO-d6) 7.96 (d, J=1.8 Hz, 1H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.50-7.39 (m, 2H), 7.36-7.26 (m, 2H), 3.29 (s, 3H), 2.88 (d, J=1.1 Hz, 3H), 2.42 (s, 3H), 1.86 (s, 2H), 1.56 (s, 9H).

Example 7 Preparation of Compound 7

##STR00039##

[0119] The substrate S3 (30 mg, 93 mol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (65 mg, 0.5 mmol), cooled in an ice water bath, added with HATU (42 mg, 0.11 mmol), stirred at 0 C. for 5 min, added with 4-(aminomethyl)isoxazole (15 mg, 0.11 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 7-1 (32 mg, 80 mol, 86% yield). LCMS (ESI.sup.+) m/z: 403.1 [M+H].sup.+.

[0120] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 9.36 (t, J=5.9 Hz, 1H), 8.88 (d, J=1.6 Hz, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.82 (dd, J=7.8, 1.8 Hz, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.53-7.38 (m, 2H), 7.36-7.24 (m, 2H), 6.67 (d, J=1.7 Hz, 1H), 4.56 (d, J=5.9 Hz, 2H), 3.44 (s, 3H), 2.42 (s, 3H).

[0121] A dried single-neck flask was added with NaH (7 mg, 0.186 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 7-1 (25 mg, 0.062 mmol) was dissolved in 0.5 mL DMF, dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (44 mg, 0.31 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 7 (20 mg, 48 mol, 77% yield). LCMS (ESI.sup.+) m/z: 417.0 [M+H].sup.+.

[0122] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.90 (d, J=1.7 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.51-7.39 (m, 2H), 7.36-7.28 (m, 2H), 6.68 (d, J=1.7 Hz, 1H), 4.44 (d, J=3.2 Hz, 2H), 3.33 (s, 3H), 2.81 (s, 3H), 2.42 (s, 3H).

Example 8 Preparation of Compound 8

##STR00040##

[0123] The substrate S3 (30 mg, 0.09 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (117 mg, 0.9 mmol), cooled in an ice water bath, added with HATU (42.5 mg, 0.11 mmol), stirred at 0 C. for 5 min, added with (2-ethylphenyl)methanamine (15.1 mg, 0.11 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 8-1 (15 mg, 0.034 mmol, 38% yield). LCMS (ESI.sup.+) m/z: 440.6 [M+H].sup.+.

[0124] A dried single-neck flask was added with NaH (5.46 mg, 0.136 mmol, 60% purity), sealed, replaced with nitrogen three times, added with 1 mL of DMF was added into the reactant, and cooled in an ice water bath. The compound 8-1 (20 mg, 0.046 mol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (12.92 mg, 0.091 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 8 (5 mg, 0.011 mmol, 24% yield, 99.0% purity). LCMS (ESI.sup.+) m/z: 454.2 [M+H].sup.+.

[0125] .sup.1H NMR (400 MHz, DMSO-d6) 7.96 (dd, J=14.4, 1.8 Hz, 1H), 7.84 (dd, J=7.8, 1.9 Hz, 1H), 7.68-7.58 (m, 1H), 7.42 (ddd, J=16.1, 13.6, 7.3 Hz, 4H), 7.35-7.30 (m, 1H), 7.29-7.23 (m, 3H), 5.03 (d, J=15.2 Hz, 1H), 4.48 (d, J=15.3 Hz, 1H), 3.34 (s, 3H), 2.72 (s, 2H), 2.42 (s, 3H), 1.21 (t, J=7.5 Hz, 3H).

Example 9 Preparation of Compound 9

##STR00041##

[0126] The substrate S3 (10.0 mg, 0.031 mmol) and 3 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (65 mg, 0.5 mmol), cooled in an ice water bath, added with HATU (14.2 mg, 0.037 mmol) and stirred at 0 C. for 5 min, added with cyclohexylamine (4.0 mg, 0.040 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 9-1 (11 mg, 0.027 mmol, 88% yield). LCMS (ESI.sup.+) m/z: 404.2 [M+H].sup.+.

[0127] A dried single-neck flask was added with NaH (3.2 mg, 60% wt, 0.081 mmol) under the protection of N.sub.2, added with 2 mL of DMF, and cooled in an ice water bath. The compound 9-1 (11 mg, 0.027 mmol) was dissolved in 1 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (18.9 mg, 0.135 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 9 (6 mg, 14.4 mol, 53% yield). LCMS (ESI.sup.+) m/z: 418.1 [M+H].sup.+.

[0128] .sup.1H NMR (400 MHz, Chloroform-d) 8.08 (dd, J=15.2, 1.8 Hz, 1H), 7.66 (dd, J=7.7, 1.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.27-7.22 (m, 1H), 7.19 (d, J=2.2 Hz, 1H), 7.16 (dd, J=6.7, 1.7 Hz, 1H), 3.22 (s, 3H), 2.68 (s, 3H), 2.33 (s, 3H), 2.03-1.87 (m, 1H), 1.85-1.59 (m, 4H), 1.57-1.34 (m, 4H), 1.11-0.91 (m, 2H).

Example 10 Preparation of Compound 10

##STR00042##

[0129] The substrate S3 (30 mg, 0.09 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture as added with DIPEA (117 mg, 0.9 mmol), cooled in an ice water bath, added with HATU (42.5 mg, 0.11 mmol), and stirred at 0 C. for 5 min. The reaction mixture was added with 3-aminopentane (11.4 mg, 0.11 mmol) and reacted at 0 C. for 20 min, where the reaction completion was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 10-1 (12.5 mg, 0.031 mmol, 34% yield). LCMS (ESI.sup.+) m/z: 406.6 [M+H].sup.+.

[0130] A dried single-neck flask was added with NaH (2.4 mg, 0.1 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 10-1 (8 mg, 0.029 mol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was stirred for 20 min, added with CH.sub.3I (8.4 mg, 0.059 mmol) and reacted at 0 C. for 1 h, where the reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 10 (4.4 mg, 10.5 mol, 36% yield). LCMS (ESI.sup.+) m/z: 420.6 [M+H].sup.+.

[0131] .sup.1H NMR (400 MHz, DMSO-d6) 7.94 (t, J=2.3 Hz, 1H), 7.86-7.75 (m, 1H), 7.58-7.39 (m, 3H), 7.37-7.26 (m, 2H), 3.13 (d, J=108.1 Hz, 2H), 2.78 (s, 3H), 2.41 (d, J=7.7 Hz, 3H), 1.81-1.04 (m, 7H), 0.90 (t, J=7.4 Hz, 5H), 0.68 (q, J=7.8 Hz, 2H).

Example 11 Preparation of Compound 11

##STR00043##

[0132] The substrate S3 (15 mg, 0.047 mmol) and 1 mL DMF were added into a dried single-neck flask to dissolve and cooled to 0 C. The reaction mixture was added with DIPEA (40 L, 0.23 mmol), reacted with 5 min, added with HATU (21.26 mg, 0.056 mmol) and reacted for 10 min. The reaction mixture was added with N-methyl-1-(1H-pyrrolidin-3-yl)methanamine (10.25 mg, 0.093 mmol) and reacted for 0.5 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The remnant was purified through high performance liquid chromatography (basic) to obtain a compound 11 (7.1 mg, 0.017 mmol). LCMS (ESI) m/z: 415.1 [M+H].sup.+. HPLC method B: R.sub.T=8.44 min, purity >99.9%.

[0133] .sup.1H NMR (600 MHz, DMSO-d.sub.6) 10.70 (d, J=28.8 Hz, 1H), 7.96-7.95 (m, 1H), 7.81-7.79 (m, 1H), 7.63-7.50 (m, 1H), 7.48-7.44 (m, 1H), 7.42-7.40 (m, 1H), 7.34-7.27 (m, 2H), 6.83-6.74 (m, 1H), 6.73-6.71 (m, 1H), 6.11-6.06 (m, 1H), 4.67-4.40 (m, 1H), 4.18-3.02 (m, 1H), 3.33 (s, 3H), 2.88-2.68 (m, 3H), 2.42 (d, J=5.4 Hz, 3H).

Example 12 Preparation of Compound 12

##STR00044##

[0134] The substrate S3 (20 mg, 0.062 mmol) and 1 mL DMF were added into a dried single-neck flask, and cooled to 0 C. The reaction mixture was added with DIPEA (40 L, 0.23 mmol), reacted for 5 min, added with HATU (28.3 mg, 0.074 mmol), and reacted for 10 min. The reaction mixture was added with N-methylaniline (8 mg, 0.074 mmol) and react for 0.5 h, where the reaction completion was monitored by LC-MS.

[0135] The reaction liquid was subjected to decompression concentration, and the remnant was purified through high performance liquid chromatography (basic) to obtain a compound 12 (2.0 mg, 4.9 mol, 8% yield). LCMS (ESI) m/z: 412.1 [M+H].sup.+.

[0136] .sup.1H NMR (400 MHz, DMSO-d6) 8.02-7.79 (m, 2H), 7.51-7.44 (m, 2H), 7.43-7.32 (m, 4H), 7.25 (tt, J=7.1, 6.0 Hz, 4H), 7.20-7.12 (m, 2H), 3.42 (d, J=6.5 Hz, 5.5H), 3.14 (s, 0.5H), 2.44-2.31 (m, 3H).

Example 13 Preparation of Compound 13

##STR00045##

[0137] The substrate S3 (30 mg, 0.093 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (117 mg, 0.9 mmol), cooled in an ice water bath, added with HATU (42.1 mg, 0.111 mmol), stirred at 0 C. for 5 min, added with 1-Boc-3-(aminomethyl)azetidine (20.7 mg, 0.111 mmol), and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 13-1 (11.0 mg, 0.023 mmol, 24% yield). LCMS (ESI.sup.+) m/z: 491.2 [M+H].sup.+.

[0138] A dried single-neck flask was added with NaH (2.8 mg, 0.115 mmol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 13-1 (11 mg, 0.023 mmol) was dissolved in 0.5 mL DMF, dropwise added into the single-neck flask, stirred for 20 min, added with CH.sub.3I (9.8 mg, 0.069 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated and purified through medium-pressure liquid chromatography to obtain a compound 13-2 (10.45 mg, 0.002 mmol, 90% yield). LCMS (ESI.sup.+) m/z: 505.2 [M+H].sup.+.

[0139] The compound 13-2 was dissolved in 2 mL DCM, slowly dropwise added with 1 mL of TFA, stirred for 20 min, and directly subjected to rotary evaporation in a high-temperature water bath to obtain a crude compound 13-3. The crude compound 13-3 can be subjected to subsequent reaction without purification.

[0140] The crude compound 13-3 (19 mg, 0.047 mmol) and 2 mL of DCM were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with an excess amount of acetic anhydride (7.2 mg, 0.071 mmol) and triethylamine (14.3 mg, 0.141 mmol) and reacted at a room temperature overnight, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a light yellow solid as compound 13 (4.15 mg, 9.3 mol, 20% yield). LCMS (ESI.sup.+) m/z: 447.1 [M+H].sup.+.

[0141] .sup.1H NMR (400 MHz, DMSO-d6) 7.98-7.92 (m, 1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 7.63-7.53 (m, 1H), 7.50-7.39 (m, 2H), 7.31 (q, J=3.4, 2.9 Hz, 2H), 4.23 (t, J=8.5 Hz, 1H), 3.95 (d, J=11.3 Hz, 2H), 3.64 (m, 1H), 3.28 (d, J=3.0 Hz, 4H), 2.98 (s, 2H), 2.79 (s, 3H), 2.40 (d, J=4.4 Hz, 3H), 1.77 (s, 3H).

Example 14 Preparation of Compound 14

##STR00046##

[0142] The substrate S3 (50 mg, 155 mol), 1 mL DMF and DIPEA (100 mg, 776 mol) were added into a dried single-neck flask, and then placed in an ice water bath. The reaction mixture was added with HATU (64.9 mg, 170 mol), stirred in an ice water bath for 5 min, added with (R)--methyl-cyclobutanemethylamine hydrochloride (21 mg, 155 mol), and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 14-1 (54 mg, 133.9 mol, 86.7% yield). LCMS (ESI.sup.+) m/z: 404.1 [M+H].sup.+.

[0143] .sup.1H NMR (400 MHz, DMSO-d6) 8.48 (d, J=8.5 Hz, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.79 (dd, J=7.7, 1.8 Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.50-7.38 (m, 2H), 7.35-7.23 (m, 2H), 3.96 (td, J=8.7, 6.6 Hz, 1H), 3.42 (s, 3H), 2.43 (s, 3H), 2.40-2.32 (m, 1H), 1.98 (dq, J=9.9, 3.5 Hz, 2H), 1.92-1.73 (m, 4H), 1.04 (d, J=6.6 Hz, 3H).

[0144] A dried single-neck flask was added with NaH (2.16 mg, 90.2 mol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 0.3 mL DMF, cooled in an ice water bath. The compound 14-1 (28 mg, 69.4 mol) was dissolved in 1 mL DMF, and then slowly added into the single-neck flask, stirred in an ice water bath for 20 min. CH.sub.3I (10.84 mg, 74.6 mol) was dissolved in 0.5 mL DMF, and then slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and filtered, and a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 14 (13.16 mg, 31.5 mol, 45.4% yield). LCMS (ESI.sup.+) m/z: 418.1 [M+H].sup.+.

[0145] .sup.1H NMR (400 MHz, DMSO-d6) 8.04-7.92 (m, 1H), 7.89-7.77 (m, 1H), 7.65-7.40 (m, 3H), 7.40-7.25 (m, 2H), 4.58 (dq, J=10.4, 6.7 Hz, 1H), 3.29 (d, J=12.4 Hz, 3H), 2.82 (s, 0.75H), 2.58 (d, J=14.6 Hz, 3H), 2.48 (s, 0.25H), 2.43 (d, J=4.1 Hz, 3H), 2.16-1.52 (m, 6H), 1.19-0.96 (m, 3H).

Example 15 Preparation of Compound 15

##STR00047##

[0146] The substrate S3 (30 mg, 93.1 mol) was dissolved in 1 mL DMF, dropwise added into DIPEA (60 mg, 465 mol) and placed in an ice water bath, added with HATU (38.9 mg, 102.4 mol), stirred in an ice water bath for 5 min. The reaction mixture was added with 3-(aminomethyl)tetrahydrofuran (10.4 mg, 102.4 mol) and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 15-1 (35 mg, 86.4 mol, 92.7% yield). LCMS (ESI.sup.+) m/z: 406.2 [M+H].sup.+.

[0147] A dried single-neck flask was added with NaH (2.1 mg, 86.6 mol), sealed, replaced with nitrogen three times, added with 0.3 mL DMF, and cooled in an ice water bath. The compound 15-1 (27 mg, 66.6 mol) was dissolved in 1 mL DMF, and slowly added into the single-neck flask, and stirred at the room temperature for 20 min. CH.sub.3I (11.3 mg, 80 mol) was dissolved 0.5 mL DMF, and then slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction completion was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 15 (7.12 mg, 16.9 mol, 25.4% yield). LCMS (ESI.sup.+) m/z: 420.0 [M+H].sup.+.

[0148] .sup.1H NMR (400 MHz, DMSO-d6) 7.95 (t, J=1.7 Hz, 1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 7.63-7.53 (m, 1H), 7.50-7.40 (m, 2H), 7.31 (pd, J=7.5, 6.9, 2.6 Hz, 2H), 3.88-3.76 (m, 1.61H), 3.73-3.63 (m, 1H), 3.61-3.42 (m, 3H), 3.30 (d, J=7.8 Hz, 3H), 3.10 (dd, J=10.2, 7.5 Hz, 0.52H), 3.02 (d, J=3.3 Hz, 0.75H), 2.82 (s, 2.31H), 2.73-2.55 (m, 1.27H), 2.42 (d, J=4.0 Hz, 3H), 1.96 (ddt, J=56.0, 13.6, 6.2 Hz, 1H), 1.78-1.44 (m, 1H).

Example 16 Preparation of Compound 16

##STR00048##

[0149] The substrate S3 (50 mg, 155 mol) and 1 mL DMF were added into a dried single-neck flask, slowly added with DIPEA (100 mg, 776 mol), and then placed in an ice water bath. The reaction mixture was added with HATU (64.9 mg, 170 mol), stirred in an ice water bath for 5 min, added with (2-methoxypyridin-4-yl)methanamine (23.6 mg, 170 mol) and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 16-1 (50 mg, 113 mol, 72.8% yield). LCMS (ESI.sup.+) m/z: 443.1 [M+H].sup.+.

[0150] NaH (3.5 mg, 147 mol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times. 0.5 mL DMF was added into the reactant, followed by cooling in an ice water bath. The compound 16-1 (50 mg, 113 mol) was dissolved in 1 mL DMF, and then slowly added into the single-neck flask, and stirred in an ice water bath for 20 min. CH.sub.3I (19.3 mg, 135 mol) was dissolved in 0.5 mL DMF, and then slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and filtered, and a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 16 (51 mg, 111 mol, 98.9% yield). LCMS (ESI.sup.+) m/z: 457.1 [M+H].sup.+.

[0151] .sup.1H NMR (400 MHz, DMSO-d6) 8.21-8.11 (m, 1H), 7.98 (dd, J=9.7, 1.8 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.66 (dd, J=30.1, 7.8 Hz, 1H), 7.51-7.38 (m, 2H), 7.37-7.24 (m, 2H), 7.03 (ddd, J=29.0, 5.3, 1.4 Hz, 1H), 6.94-6.78 (m, 1H), 4.34 (d, J=2.5 Hz, 2H), 3.86 (d, J=9.9 Hz, 3H), 3.35 (d, J=4.0 Hz, 3H), 2.86 (d, J=59.8 Hz, 3H), 2.42 (d, J=11.6 Hz, 3H).

Synthesis of Compound S4

##STR00049##

Synthesis of Compound S1-1

[0152] The substrate S1 (500 mg, 1.71 mmol) and 5 mL MeOH were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with a 2N NaOH solution (2 M, 8.53 mL), and stirred at 50 C. for 1 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, pH adjustment to 5-6 with a 3N HCl solution, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a compound S1-1 (463 mg, 1.66 mmol, 97.25% yield). LCMS (ESI.sup.+) m/z: 280.9 [M+H].sup.+.

Synthesis of Compound S4

[0153] The compound S1-1 (430 mg, 1.54 mmol) and 8 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (597.33 mg, 4.62 mmol), cooled in an ice water bath, added with HATU (702.95 mg, 1.85 mmol) and stirred at 0 C. for 5 min. The reaction mixture was added with N-methyl-1-cyclohexylmethanamine (235.21 mg, 1.85 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a compound S4 (380 mg, 978.58 mol, 63.52% yield). LCMS (ESI.sup.+) m/z: 389.2 [M+H].sup.+.

Example 17 Preparation of Compound 17

##STR00050##

[0154] The compound S4 (15 mg, 38.7 mol), 4-fluoro-2-(methylthio)phenylboronic acid (8.6 mg, 46.5 mol), Pd(dppf)Cl.sub.2 (1.4 mg, 1.93 mol) and K.sub.2CO.sub.3 (10.69 mg, 77.5 mol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times. 1 mL dioxane and 0.25 mL H.sub.2O were added into the single-neck flask, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 17 (12.37 mg, 27.5 mol, 71% yield). LCMS (ESI.sup.+) m/z: 450.5 [M+H].sup.+.

[0155] 1H NMR (600 MHz, DMSO-d6) 7.92 (d, J=1.8 Hz, 1H), 7.79 (dt, J=7.8, 1.5 Hz, 1H), 7.52 (dd, J=10.5, 7.8 Hz, 1H), 7.37 (ddd, J=11.5, 8.4, 6.0 Hz, 1H), 7.24 (dd, J=10.2, 2.6 Hz, 1H), 7.12 (td, J=8.4, 2.5 Hz, 1H), 3.54 (d, J=10.1 Hz, 1H), 3.28 (d, J=21.6 Hz, 3H), 3.09 (d, J=13.0 Hz, 1H), 2.99 (s, 0.86H), 2.95-2.82 (m, 1H), 2.79 (s, 2.2H), 2.46 (d, J=4.0 Hz, 3H), 1.86-1.54 (m, 6H), 1.29-1.16 (m, 3H), 1.08-0.65 (m, 2H).

Example 18 Preparation of Compound 18

##STR00051##

[0156] The compound 16 (25 mg, 54.8 mol), 2 mL MeCN and TMSI (43.8 mg, 219 mol) were added into a dried single-neck flask, followed by backflow stirring at 50 C. for 12 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a yellow solid as compound 18 (2.66 mg, 6 mol, 10.9% yield). LCMS (ESI.sup.+) m/z: 443.1 [M+H].sup.+.

[0157] .sup.1H NMR (400 MHz, DMSO-d6) 11.50 (s, 1H), 7.97 (dd, J=7.0, 1.8 Hz, 1H), 7.82 (ddd, J=30.3, 7.8, 1.8 Hz, 1H), 7.61 (dd, J=31.3, 7.8 Hz, 1H), 7.51-7.39 (m, 2H), 7.38-7.25 (m, 3H), 6.42-6.10 (m, 2H), 4.59-4.12 (m, 2H), 3.42 (d, J=3.7 Hz, 3H), 2.86 (d, J=65.2 Hz, 3H), 2.42 (d, J=8.6 Hz, 3H).

Example 19 Preparation of Compound 19

##STR00052##

[0158] The substrate S3 (20 mg, 62.03 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (24.05 mg, 186.10 mmol), cooled in an ice water bath, added with HATU (28.31 mg, 74.44 mol), stirred at 0 C. for 5 min, added with (R)-1-cyclopropylethylamine hydrochloride (7.54 mg, 62.03 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a compound 19-1 (24 mg, 61.61 mol, 99.32% yield). LCMS (ESI.sup.+) m/z: 390.1 [M+H].sup.+.

[0159] Under the protection of N.sub.2, NaH (2.96 mg, 73.94 mol, 60% purity) was added into a dried single-neck flask, dispersed in 1 mL DMF, cooled in an ice water bath. The compound 19-1 (24 mg, 61.61 mol) was slowly dropwise added into the reaction system, and reacted at 0 C. for 30 min. The reaction mixture was added with iodomethane (10.49 mg, 73.94 mol), heated to the room temperature, and stirred for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a white solid as compound 19 (14.8 mg, 36.16 mol, 58.69% yield, 98.6% purity). LCMS (ESI.sup.+) m/z: 404.1 [M+H].sup.+.

[0160] 1H NMR (400 MHz, DMSO-d.sub.6) 7.98-7.92 (m, 1H), 7.85-7.76 (m, 1H), 7.60-7.39 (m, 3H), 7.35-7.26 (m, 2H), 4.03-3.78 (m, 1H), 3.32-3.26 (m, 3H), 2.99 (d, J=9.3 Hz, 1H), 2.76 (d, J=9.0 Hz, 2H), 2.42 (s, 3H), 1.29-1.19 (m, 2H), 1.13 (dd, J=9.9, 6.7 Hz, 1H), 1.11-0.99 (m, 1H), 0.64-0.16 (m, 4H).

Example 20 Preparation of Compound 20

##STR00053##

[0161] The substrate S3 (20 mg, 62.03 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (24.05 mg, 186.10 mmol), cooled in an ice water bath, added with HATU (28.31 mg, 74.44 mol), stirred at 0 C. for 5 min, added with (R)-1-cyclopentylethylamine hydrochloride (11.14 mg, 74.44 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a compound 20-1 (25.5 mg, 61.07 mol, 98.44% yield). LCMS (ESI.sup.+) m/z: 418.2 [M+H].sup.+.

[0162] Under the protection of N.sub.2, NaH (2.93 mg, 73.28 mol, 60% purity) was added into a dried single-neck flask, dispersed in 1 mL DMF, and cooled in an ice water bath. The compound 20-1 (25.5 mg, 61.07 mol) was slowly dropwise added into the reaction system to react at 0 C. for 30 min. The reaction mixture was added with iodomethane (10.40 mg, 73.28 mol), heated to the room temperature, and stirred for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a white solid as compound 20 (16.7 mg, 38.69 mol, 63.36% yield, 100% purity). LCMS (ESI.sup.+) m/z: 432.1 [M+H].sup.+.

[0163] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.00-7.91 (m, 1H), 7.81 (d, J=6.9 Hz, 1H), 7.54-7.39 (m, 3H), 7.36-7.26 (m, 2H), 4.47-4.26 (m, 1H), 3.29 (d, J=12.0 Hz, 3H), 2.94-2.61 (m, 3H), 2.42 (s, 3H), 2.10-1.99 (m, 1H), 1.86-1.69 (m, 2H), 1.68-1.47 (m, 4H), 1.45-1.20 (m, 3H), 1.14 (d, J=6.9 Hz, 2H).

Example 21 Preparation of Compound 21

##STR00054##

[0164] The substrate S3 (280 mg, 0.87 mmol) and 3.0 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with EDCI (176 mg, 1.3 mmol), HOBt (249 mg, 1.3 mmol), DIPEA (0.45 mL, 2.61 mmol) and 2-(methylamino)ethanol (78.3 mg, 1.04 mmol), and stirred at the room temperature for 16 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 21-1 (250 mg, 0.66 mmol, 75% yield).

[0165] The compound 21-1 (100 mg, 0.26 mmol), 2 mL CH.sub.2Cl.sub.2 and DIPEA (0.14 mL, 0.78 mmol) were added into a dried single-neck flask, cooled in an ice water bath, added with MsCl (90 mg, 0.78 mmol), heated to the room temperature and stirred for 30 min, where the reaction was monitored by TLC (thin-layer chromatography). The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 21-2 (80 mg, 0.17 mmol, 66% yield).

[0166] The compound 21-2 (33 mg, 0.07 mmol) was added into a 25 mL single-neck flask, dissolved in 3 mL acetonitrile, added with K.sub.2CO.sub.3 (30 mg, 0.21 mmol) and morpholine (7.5 mg, 0.08 mmol), heated to 60 C. and reacted for 2 h, where the completion was monitored by LCMS (liquid chromatography-mass spectrometry). The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, and a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 21 (18 mg, 0.04 mmol, 55% yield). LCMS (ESI.sup.+) m/z: 449.5 [M+H].sup.+.

[0167] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (d, J=1.8 Hz, 0.6H), 7.92 (d, J=1.8 Hz, 0.4H), 7.81 (ddd, J=8.6, 7.8, 1.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 0.4H), 7.53 (d, J=7.8 Hz, 0.6H), 7.50-7.38 (m, 2H), 7.35-7.25 (m, 2H), 3.82-3.38 (m, 5.2H), 3.30 (s, 1.8H), 3.28 (s, 1.2H), 3.26-3.05 (m, 0.8H), 3.03 (s, 1.2H), 2.83 (s, 1.8H), 2.71-2.57 (m, 0.5H), 2.50-2.30 (m, 7H), 2.22 (t, J=4.7 Hz, 1.5H).

Example 22 Preparation of Compound 22

##STR00055##

[0168] The compound 21-2 (40 mg, 0.087 mmol) was added into the 25 mL single-neck flask, dissolved in 3 mL acetonitrile, added with K.sub.2CO.sub.3 (36 mg, 0.26 mmol) and piperidine (9 mg, 0.10 mmol), heated to 60 C. and reacted for 2 h, where the reaction was monitored by LCMS. The reaction mixture was quenched with water, followed by extraction followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate and filtered, and a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 22 (32.2 mg, 0.072 mmol, 82% yield). LCMS (ESI.sup.+) m/z: 447.1 [M+H].sup.+.

[0169] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.94 (d, J=1.8 Hz, 0.6H), 7.92 (d, J=1.8 Hz, 0.4H), 7.81 (ddd, J=11.3, 7.7, 1.8 Hz, 1H), 7.63-7.50 (m, 1H), 7.49-7.36 (m, 2H), 7.36-7.25 (m, 2H), 3.76-3.39 (m, 1.2H), 3.31 (s, 1.8H), 3.28 (s, 1.2H), 3.22-3.04 (m, 0.8H), 3.02 (s, 1.2H), 2.83 (s, 1.8H), 2.65-2.35 (m, 7.5H), 2.26-2.09 (m, 1.5H), 1.61-1.28 (m, 6H).

Example 23 Preparation of Compound 23

##STR00056##

[0170] The substrate S3 (30 mg, 0.093 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (60.13 mg, 0.465 mmol), cooled in an ice water bath, added with HATU (42.43 mg, 0.112 mmol) and stirred at 0 C. for 5 min. The reaction mixture was added with N-methyltetrahydropyran (12.86 mg, 0.111 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 23-1 (35 mg, 0.0083 mmol, 89.65% yield). LCMS (ESI.sup.+) m/z: 420.2 [M+H].sup.+.

[0171] A dried single-neck flask was added with NaH (2.86 mg, 0.07 mmol, 60% purity) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL of DMF was added into the reaction system, and cooled in an ice water bath. The compound 23-1 (15 mg, 0.036 mmol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The temperature was kept and the reaction mixture was stirred for 20 min, added with CH.sub.3I (15.22 mg, 0.107 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a white solid as compound 23 (6 mg, 0.014 mmol, 38.51% yield, 99.5% purity). LCMS (ESI.sup.+) m/z: 434.2 [M+H].sup.+.

[0172] .sup.1H NMR (400 MHz, DMSO-d6) 7.94 (d, J=1.7 Hz, 1H), 7.80 (ddd, J=7.8, 5.0, 1.8 Hz, 1H), 7.55 (dd, J=7.8, 6.7 Hz, 1H), 7.50-7.39 (m, 2H), 7.37-7.25 (m, 2H), 3.88 (ddd, J=11.3, 4.5, 2.0 Hz, 2H), 3.78 (s, 1H), 3.48 (d, J=9.0 Hz, 1H), 3.32-3.30 (m, 1H), 3.30 (s, 2H), 3.26 (s, 1H), 3.22 (dd, J=11.4, 2.3 Hz, 1H), 3.00 (s, 1H), 2.81 (s, 2H), 2.42 (d, J=3.1 Hz, 3H), 2.03 (s, 1H), 1.69 (s, 2H), 1.26 (d, J=13.4 Hz, 2H).

##STR00057##

Synthesis of Compound S5

[0173] Under the protection of N.sub.2, the substrate S1 (1 g, 3.41 mmol), 2-methoxyphenylboronic acid (605.90 mg, 4.09 mmol), Pd(dppf)Cl.sub.2 (248.92 mg, 0.341 mmol), K.sub.2CO.sub.3 (1.41 g, 10.23 mmol) and 2 mL of 1, dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored through LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a brown solid as compound S5 (1.2 g, crude). LCMS (ESI.sup.+) m/z: 321.1 [M+H].sup.+.

Synthesis of Compound S6

[0174] The compound S5 (1.2 g, 3.75 mmol) and 5 mL MeOH were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with a 2N NaOH solution (449.49 mg, 11.24 mmol) and reacted under stirring at 60 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, pH adjustment to 5-6 with a 3N HCl solution, freeze-drying and purification through medium-pressure liquid chromatography to obtain a light reddish-brown oily solid as compound S6 (730 mg, 2.38 mmol, 63.62% yield). LCMS (ESI.sup.) m/z: 305.2 [MH].sup..

Example 24 Preparation of Compound 24

##STR00058##

[0175] The compound S6 (30 mg, 98 mol), 1 mL DMF and DIPEA (63.2 mg, 490 mol) were added into a dried single-neck flask, and placed in an ice water bath. The reaction mixture was added with HATU (40.9 mg, 107.8 mol), stirred in an ice water bath for 5 min, added with (R)-ALPHA-cyclobutylethylamine hydrochloride (14.6 mg, 107.8 mol), and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 24-1 (31 mg, 80 mol, 81.6% yield). LCMS (ESI.sup.+) m/z: 388.3 [M+H].sup.+.

[0176] A dried single-neck flask was added with NaH (2.5 mg, 104 mol), sealed, replaced with nitrogen three times, added with 0.3 mL DMF, and cooled in an ice water bath. The compound 24-1 (31 mg, 80 mol) was dissolved in 1 mL DMF, and slowly added into the reaction system, and stirred in an ice water bath for 20 min. CH.sub.3I (12.5 mg, 88 mol) was dissolved in 0.5 mL DMF, and slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 24 (10.18 mg, 25.3 mol, 31.6% yield). LCMS (ESI.sup.+) m/z: 402.0 [M+H].sup.+.

[0177] .sup.1H NMR (400 MHz, DMSO-d6) 8.16-8.01 (m, 1H), 8.00-7.85 (m, 1H), 7.62-7.34 (m, 3H), 7.26-7.15 (m, 1H), 7.14-7.04 (m, 1H), 4.58 (dq, J=10.4, 6.7 Hz, 0.73H), 3.82 (d, J=6.1 Hz, 3H), 3.51-3.39 (m, 0.31H), 3.33-3.25 (m, 3H), 2.82 (s, 0.85H), 2.58 (d, J=14.7 Hz, 2.75H), 2.15-1.49 (m, 6H), 1.16-0.97 (m, 3H).

Example 25 Preparation of Compound 25

##STR00059##

[0178] The compound S6 (30 mg, 98 mol), 1 mL DMF and DIPEA (63.2 mg, 490 mol) were added into a dried single-neck flask, and placed in an ice water bath. The reaction mixture was added with HATU (40.9 mg, 107.8 mol), stirred in an ice water bath for 5 min, added with (tetrahydrofuran-3-yl)methanamine (10.9 mg, 107.8 mol) and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 25-1 (36.8 mg, 94.5 mol, 96.4% yield). LCMS (ESI.sup.+) m/z: 390.2 [M+H].sup.+.

[0179] A dried single-neck flask was added with NaH (1.9 mg, 80.1 mol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 0.3 mL DMF was added into the reaction system, and cooled in an ice water bath. The compound 25-1 (24 mg, 61.6 mol) was dissolved in 1 mL DMF, and slowly added into the single-neck flask, and stirred in an ice water bath for 20 min. CH.sub.3I (12.5 mg, 88 mol) was dissolved in 0.5 mL DMF, slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 25 (15.9 mg, 39.4 mol, 63.9% yield). LCMS (ESI.sup.+) m/z: 404.0 [M+H].sup.+.

[0180] .sup.1H NMR (400 MHz, DMSO-d6) 8.06 (dd, J=6.7, 1.7 Hz, 1H), 7.91 (dd, J=7.9, 1.8 Hz, 1H), 7.57-7.49 (m, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.23-7.16 (m, 1H), 7.10 (td, J=7.5, 1.0 Hz, 1H), 3.87-3.76 (m, 4.75H), 3.74-3.62 (m, 1H), 3.53 (dt, J=19.2, 8.6 Hz, 3H), 3.31 (s, 3H), 3.16-3.06 (m, 0.52H), 3.01 (d, J=3.3 Hz, 0.76H), 2.83 (s, 2.4H), 2.73-2.55 (m, 1H), 2.12-1.84 (m, 1H), 1.79-1.43 (m, 1H).

Example 26 Preparation of Compound 26

##STR00060##

[0181] The compound S6 (35 mg, 114 mol), 2 mL DMF and DIPEA (73.7 mg, 571 mol) were added into a dried single-neck flask, and placed in an ice water bath. The reaction mixture was added with HATU (47.8 mg, 125 mol), stirred in an ice water bath for 5 min, added with 1-Boc-3-(aminomethyl)azetidine (21.2 mg, 114 mol) and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS.

[0182] The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 26-1 (50 mg, 105 mol, 92.2% yield). LCMS (ESI.sup.+) m/z: 473.2 [M+H].sup.+.

[0183] A dried single-neck flask was added with NaH (3.3 mg, 137 mol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 0.5 mL DMF and cooled in an ice water bath. The compound 26-1 (50 mg, 105 mol) was dissolved in 1 mL DMF, and slowly added into the single-neck flask, and stirred in an ice water bath for 20 min. CH.sub.3I (17.9 mg, 126 mol) was dissolved in 0.5 mL DMF, and slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 26-2 (40 mg, 81.9 mol, 77.7% yield). LCMS (ESI.sup.) m/z: 487.2 [MH].sup..

[0184] The compound 26-2 (40 mg, 81.9 mol), 1 mL DCM and 1 mL TFA were added into a dried single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, added with water and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, and filtered to obtain a crude compound 26-3 (60 mg). The crude compound 26-3 can be directly subjected to the subsequent reaction without purification. LCMS (ESI.sup.+) m/z: 389.2 [M+H].sup.+.

[0185] The crude compound 26-3 (60 mg), 2 mL DCM, TEA (24.8 mg, 245 mol) and acetic anhydride (12.5 mg, 122 mol) were added into a dried single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 26 ((25.7 mg, 59.7 mol, 72.9% yield). LCMS (ESI.sup.+) m/z: 431.1 [M+H].sup.+.

[0186] .sup.1H NMR (600 MHz, DMSO-d6) 8.12 (dd, J=18.7, 1.7 Hz, 1H), 7.97 (dd, J=7.8, 1.9 Hz, 1H), 7.64-7.54 (m, 1H), 7.50 (td, J=7.9, 3.6 Hz, 2H), 7.24 (d, J=8.2 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 4.34-4.13 (m, 1H), 4.01 (ddt, J=25.5, 14.3, 7.0 Hz, 2H), 3.87 (s, 3H), 3.85-3.58 (m, 2H), 3.53-3.45 (m, 0.75H), 3.35 (d, J=3.7 Hz, 3H), 3.09-3.04 (m, 0.58H), 3.01-2.94 (m, 0.27H), 2.85 (s, 2.48H), 1.81 (s, 3H), 1.44-0.79 (m, 1H).

Example 27 Preparation of Compound 27

##STR00061##

[0187] The compound S6 (30 mg, 98 mol), 1 mL DMF and DIPEA (63.2 mg, 490 mol) were added into a dried single-neck flask, and placed in an ice water bath.

[0188] The reaction mixture was added with HATU (40.9 mg, 107 mol) was added into the reaction system, stirred in an ice water bath for 5 min, added with (2-methoxypyridin-4-yl)methanamine (14.9 mg, 107 mol) and stirred in an ice water bath for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 27-1 (40 mg, 93.8 mol, 95.7% yield). LCMS (ESI.sup.+) m/z: 427.1 [M+H].sup.+.

[0189] A dried single-neck flask was added with NaH (2.9 mg, 122 mol) was added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 0.5 mL DMF and cooled in an ice water bath. The compound 27-1 (40 mg, 93.8 mol) was dissolved in 1 mL DMF, slowly added into the single-neck flask, and stirred in an ice water bath for 20 min. CH.sub.3I (15.9 mg, 112 mol) was dissolved in 0.5 mL DMF, slowly added into the single-neck flask, and stirred at the room temperature for 30 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 27 (39 mg, 88.6 mol, 94.3% yield). LCMS (ESI.sup.+) m/z: 441.4 [M+H].sup.+.

[0190] .sup.1H NMR (400 MHz, DMSO-d6) 8.19-8.06 (m, 2H), 7.90 (ddd, J=36.9, 7.9, 1.8 Hz, 1H), 7.61 (dd, J=26.8, 7.9 Hz, 1H), 7.43 (tdd, J=10.9, 5.1, 2.3 Hz, 2H), 7.33-7.14 (m, 2H), 7.14-6.95 (m, 2H), 6.86 (d, J=45.6 Hz, 1H), 4.35 (d, J=7.8 Hz, 2H), 3.83 (dd, J=20.9, 12.2 Hz, 6H), 3.35 (d, J=2.9 Hz, 3H), 2.85 (d, J=54.8 Hz, 3H).

Example 28 Preparation of Compound 28

##STR00062##

[0191] The compound 27 (25 mg, 56.8 mol), 2 mL MeCN and TMSI (45.4 mg, 227 mol) were added into a dried single-neck flask, and subjected to backflow stirring at 50 C. for 12 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a yellow solid as compound 28 (18.3 mg, 42.9 mol, 75.6% yield). LCMS (ESI.sup.+) m/z: 427.4 [M+H].sup.+.

[0192] .sup.1H NMR (400 MHz, DMSO-d6) 8.14 (dd, J=4.8, 1.7 Hz, 1H), 7.97 (ddd, J=30.2, 7.8, 1.7 Hz, 1H), 7.63 (dd, J=35.2, 7.9 Hz, 1H), 7.55-7.38 (m, 3H), 7.27-7.11 (m, 2H), 6.53-6.24 (m, 2H), 4.68-4.18 (m, 2H), 3.87 (d, J=9.5 Hz, 3H), 3.39 (s, 3H), 2.92 (d, J=59.0 Hz, 3H).

Example 29 Preparation of Compound 29

##STR00063##

[0193] Pyrrole-3-carbaldehyde (190.2 mg, 2 mmol) and methylamine hydrochloride (162 mg, 2.4 mmol) were dissolved in 5 mL methyl alcohol, added with DIPEA (1.25 mL, 7.2 mmol), reacted at the room temperature for 2 h, cooled to 0 C., added with sodium borohydride (379.5 mg, 10 mmol) and reacted at 0 C. for 1 h, where the reaction was monitored by LC-MS. The reaction mixture was added with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered and subjected to decompression concentration to obtain a compound 29-1 (150 mg, crude product), and the compound 29-1 can be directly used in subsequent reaction. LCMS (ESI.sup.+) m/z: 111.2 [M+H].sup.+.

[0194] The compound S6 (15 mg, 0.048 mmol) was added into a dried single-neck flask, dissolved in 1 mL DMF, cooled to 0 C., added with DIPEA (41 L, 0.24 mmol), reacted for 5 min, added with HATU (21.66 mg, 0.057 mmol) and reacted for 10 min. The compound 29-1 (10.44 mg, 0.095 mmol) was added into the single-neck flask and reacted for 0.5 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to decompression concentration, and the remnant was purified through high performance liquid chromatography (basic) to obtain a white solid as compound 29 (10.1 mg, 0.025 mmol, 52.0% yield). LCMS (ESI.sup.+) m/z: 399.2 [M+H].sup.+. HPLC method B: RT=7.14 min, purity >99.9%.

[0195] .sup.1H NMR (600 MHz, DMSO-d6) 10.69 (d, J=26.4 Hz, 1H), 8.06-8.05 (m, 1H), 7.91-7.88 (m, 1H), 7.59-7.45 (m, 1H), 7.44-7.41 (m, 2H), 7.20-7.16 (m, 1H), 7.11-7.07 (m, 1H), 6.83-6.73 (m, 1H), 6.73-6.69 (m, 1H), 6.11-6.04 (m, 1H), 4.66-4.38 (m, 1H), 4.05-3.80 (m, 1H), 3.81 (d, J=3.0 Hz, 3H), 3.34 (s, 3H), 2.87-2.68 (m, 3H).

Example 30 Preparation of Compound 30

##STR00064##

[0196] The substrate S3 (20 mg, 0.065 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (0.11 mL, 0.65 mmol), cooled in an ice water bath, added with HATU (30 mg, 0.078 mmol), stirred at 0 C. for 5 min, added with 3-(aminomethyl)oxetane (6.8 mg, 0.078 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 30-1 (24 mg, 0.064 mmol, 99% yield). LCMS (ESI.sup.+) m/z: 376.1 [M+H].sup.+.

[0197] A dried single-neck flask was added with NaH (8 mg, 0.2 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 30-1 (24 mg, 0.064 mmol) was dissolved in 0.5 mL DMF, and dropwise added into the. The temperature was kept and the reaction mixture was stirred for 20 min. CH.sub.3I (28 mg, 0.2 mmol) was added into the single-neck flask and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 30 (14 mg, 36 mol, 56% yield). LCMS (ESI.sup.+) m/z: 390.1 [M+H].sup.+.

[0198] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.07 (d, J=1.8 Hz, 0.24H), 8.02 (d, J=1.8 Hz, 0.71H), 7.92-7.85 (m, 1H), 7.57-7.33 (m, 3H), 7.21-7.12 (m, 1H), 7.13-7.04 (m, 1H), 4.68 (dd, J=7.9, 6.1 Hz, 1.58H), 4.62-4.51 (m, 0.57H), 4.53-4.35 (m, 1.56H), 4.23-4.12 (m, 0.64H), 4.08-3.95 (m, 0.72H), 3.78 (s, 0.79H), 3.77 (s, 2.21H), 3.66-3.52 (m, 0.72H), 3.46-3.26 (m, 1.64H), 3.23 (s, 3H), 2.89 (s, 0.76H), 2.72 (s, 2.24H).

Example 31 Preparation of Compound 31

##STR00065##

[0199] The substrate S3 (20 mg, 0.062 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (117 mg, 0.9 mmol), cooled in an ice water bath, added with HATU (28.3 mg, 0.074 mmol), stirred at 0 C. for 5 min, added with 1-(oxetan-3-yl)ethan-1-amine (7.5 mg, 0.074 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 31-1 (15.6 mg, 0.04 mmol, 65% yield). LCMS (ESI.sup.+) m/z: 390.5 [M+H].sup.+.

[0200] A dried single-neck flask was added with NaH (1.8 mg, 0.077 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 31-1 (6 mg, 0.015 mmol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was subjected to temperature keeping, stirred for 20 min, added with CH.sub.3I (6.6 mg, 0.046 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 31 (2.34 mg, 5.8 mol, 39% yield). LCMS (ESI.sup.+) m/z: 404.4 [M+H].sup.+.

[0201] .sup.1H NMR (400 MHz, DMSO-d6) 8.02 (d, J=1.8 Hz, 1H), 8.00-7.84 (m, 1H), 7.62-7.35 (m, 3H), 7.16 (t, J=7.1 Hz, 1H), 7.13-7.05 (m, 1H), 4.94 (t, J=8.3 Hz, 1H), 4.78-4.14 (m, 4H), 3.78 (d, J=8.9 Hz, 3H), 3.29-3.12 (m, 4H), 2.75 (s, 1H), 1.23-1.01 (m, 4H).

Example 32 Preparation of Compound 32

##STR00066##

[0202] The compound S6 (20 mg, 65.29 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (25.31 mg, 195.87 mmol), cooled in an ice water bath, added with HATU (29.79 mg, 78.35 mol), stirred at 0 C. for 5 min, added with (R)-1-cyclopropylethylamine hydrochloride (9.53 mg, 78.35 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a compound 32-1 (21 mg, 56.23 mol, 86.13% yield). LCMS (ESI.sup.+) m/z: 374.2 [M+H].sup.+.

[0203] Under the protection of N.sub.2, NaH (1.93 mg, 48.20 mol, 60% purity) was dispersed in 1 mL DMF, and cooled in an ice water bath. The compound 32-1 (15 mg, 40.16 mol) was slowly dropwise added into the single-neck flask and reacted at 0 C. for 30 min. The reaction mixture was added with iodomethane (6.84 mg, 48.20 mol), heated to the room temperature and stirred for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a white solid as compound 32 (5.03 mg, 12.98 mol, 32.32% yield, 100% purity). LCMS (ESI.sup.+) m/z: 388.1 [M+H].sup.+.

[0204] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.87-7.80 (m, 1H), 7.70-7.62 (m, 1H), 7.32-7.17 (m, 3H), 7.01-6.93 (m, 1H), 6.91-6.84 (m, 1H), 3.78-3.61 (m, 1H), 3.59 (s, 3H), 3.09-3.03 (m, 3H), 2.75 (d, J=9.2 Hz, 1H), 2.54 (d, J=9.6 Hz, 2H), 1.07-0.95 (m, 3H), 0.93-0.86 (m, 1H), 0.41-0.05 (m, 4H).

Example 33 Preparation of Compound 33

##STR00067##

[0205] The compound S6 (20 mg, 65.29 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (25.31 mg, 195.87 mmol), cooled in an ice water bath, added with HATU (29.79 mg, 78.35 mol), stirred at 0 C. for 5 min, added with (R)-1-cyclopentylethylamine hydrochloride (11.73 mg, 78.35 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a compound 33-1 (23 mg, 57.28 mol, 87.74% yield). LCMS (ESI.sup.+) m/z: 402.2 [M+H].sup.+.

[0206] Under the protection of N.sub.2, NaH (1.79 mg, 44.83 mol, 60% purity) was dispersed in 1 mL DMF and cooled in an ice water bath. The compound 33-1 (15 mg, 37.36 mol) was slowly dropwise added into the reaction mixture and reacted at 0 C. for 30 min. The reaction mixture was added with iodomethane (6.36 mg, 44.83 mol), heated to the room temperature and stirred for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through column chromatography to obtain a white solid as compound 33 (6.3 mg, 15.16 mol, 40.58% yield, 100% purity). LCMS (ESI.sup.+) m/z: 416.1 [M+H].sup.+.

[0207] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.18-8.08 (m, 1H), 8.01-7.92 (m, 1H), 7.53-7.44 (m, 3H), 7.25 (d, J=7.9 Hz, 1H), 7.20-7.12 (m, 1H), 4.50-4.33 (m, 1H), 3.88 (s, 3H), 3.36 (s, 3H), 2.94-2.69 (m, 3H), 2.23-2.02 (m, 1H), 1.91-1.53 (m, 6H), 1.38-1.17 (m, 5H).

Example 34 Preparation of Compound 34

##STR00068##

[0208] The substrate S1 (50 mg, 0.179 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (115.76 mg, 0.896 mmol), cooled in an ice water bath, added with HATU (70.92 mg, 0.215 mmol), stirred at 0 C. for 5 min, added with 4-(aminomethyl)tetrahydropyran (20.63 mg, 0.179 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, purified through medium-pressure liquid chromatography to obtain a white solid as compound 34-1 (50 mg, 0.134 mmol, 74.18% yield). LCMS (ESI.sup.+) m/z: 377.9 [M+H].sup.+.

[0209] Under the protection of N.sub.2, the compound 34-1 (50 mg, 0.134 mmol), 2-methoxyphenylboronic acid (24.36 mg, 0.160 mmol), Pd(dppf)Cl.sub.2 (9.75 mg, 0.013 mmol), K.sub.2CO.sub.3 (55.39 mg, 0.400 mmol) and 2 mL of 1, dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored through LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a brown solid as compound 34-2 (50 mg, 0.124 mmol, 92.76% yield). LCMS (ESI.sup.+) m/z: 404.1 [M+H].sup.+.

[0210] A dried single-neck flask was added with NaH (5.98 mg, 0.149 mmol, 60% purity), sealed, replaced with nitrogen three times, added with 1 mL DMF and cooled in an ice water bath. The compound 34-2 (20.10 mg, 0.050 mmol) was dissolved in 0.5 mL DMF, dropwise added into the single-neck flask, subjected to temperature keeping, stirred for 20 min, added with CH.sub.3I (14.14 mg, 0.100 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 34 (10 mg, 0.023 mmol, 46.50% yield, 96.7% purity). LCMS (ESI.sup.+) m/z: 418.3 [M+H].sup.+.

[0211] .sup.1H NMR (400 MHz, DMSO-d6) 8.05 (dd, J=6.0, 1.8 Hz, 1H), 7.89 (dd, J=7.9, 1.8 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.43 (dd, J=9.0, 7.0 Hz, 2H), 7.18 (d, J=8.2 Hz, 1H), 7.14-7.05 (m, 1H), 3.88 (ddd, J=11.3, 4.5, 2.0 Hz, 2H), 3.81 (d, J=2.0 Hz, 3H), 3.48 (d, J=9.3 Hz, 1H), 3.32-3.18 (m, 6H), 3.00 (s, 1H), 2.82 (s, 2H), 2.02 (s, 1H), 1.69 (s, 2H), 1.39-1.16 (m, 2H).

Example 35 Preparation of Compound 35

##STR00069##

[0212] The compound S6 (40 mg, 0.131 mmol) and 1 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (84.38 mg, 0.653 mmol), cooled in an ice water bath, added with HATU (59.54 mg, 0.157 mmol), stirred at 0 C. for 5 min, added with 4-(aminomethyl)cyclohexanol (20.24 mg, 0.157 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 35-1 (40 mg, 0.096 mmol, 73.37% yield). LCMS (ESI.sup.+) m/z: 418.1 [M+H].sup.+.

[0213] The compound 35-1 (20 mg, 0.048 mmol) and 3 mL DCM were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with acetic anhydride (24.45 mg, 0.240 mmol) and DMAP (5.85 mg, 0.048 mmol) and stirred at 25 C. for 0.5 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 35-2 (22 mg, 0.048 mmol, 99.94% yield). LCMS (ESI.sup.+) m/z: 460.1 [M+H].sup.+.

[0214] A dried single-neck flask was added with NaH (3.83 mg, 0.096 mmol, 60% purity), sealed, replaced with nitrogen three times, added with 1 mL DMF and cooled in an ice water bath. The compound 35-2 (22 mg, 0.048 mmol) was dissolved in 0.5 mL DMF dropwise added into the single-neck flask, subjected to temperature keeping, stirred for 20 min, added with CH.sub.3I (20.38 mg, 0.144 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 35-3 (20 mg, 0.042 mmol, 88.22% yield). LCMS (ESI.sup.+) m/z: 474.1 [M+H].sup.+.

[0215] The compound 35-3 (20 mg, 0.042 mmol) and 3 mL MeOH were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with potassium carbonate anhydrous (17.51 mg, 0.127 mmol) and stirred at 25 C. for 1 h, where the reaction was monitored by LC-MS. The reaction mixture was filtered, subjected to rotary evaporation, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 35 (10 mg, 0.023 mmol, 54.32% yield, 99.0% purity). LCMS (ESI.sup.+) m/z: 432.1 [M+H].sup.+.

[0216] .sup.1H NMR (400 MHz, DMSO-d6) 8.05 (d, J=4.8 Hz, 1H), 7.93-7.85 (m, 1H), 7.53-7.35 (m, 3H), 7.17 (d, J=8.3 Hz, 1H), 7.09 (t, J=7.4 Hz, 1H), 4.52 (s, 1H), 3.81 (s, 3H), 3.30-3.24 (m, 3H), 2.97 (d, J=2.4 Hz, 1H), 2.79 (d, J=2.3 Hz, 2H), 1.91-1.74 (m, 3H), 1.66 (dtd, J=17.8, 9.4, 8.2, 3.7 Hz, 1H), 1.46 (s, 1H), 1.22-1.06 (m, 2H), 1.01 (s, 1H).

Example 36 Preparation of Compound 36

##STR00070##

[0217] The substrate S1 (147 mg, 0.5 mmol), cyclohex-1-ene-1-boronic acid pinacol ester (125 mg, 0.6 mmol), Pd(dppf)Cl.sub.2 (36 mg, 0.05 mmol), K.sub.2CO.sub.3 (276 mg, 2 mmol), 4 mL 1,4-dioxane and 1 mL water were added into a dried single-neck flask, sealed, replaced with nitrogen three times, heated to 100 C. and stirred overnight. The reaction mixture was cooled to the room temperature, added with EtOAc and water, and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, filtered and concentrated to obtain a crude product. The crude product was purified through column chromatography to obtain a compound 36-1 (102 mg, 0.35 mmol, 70% yield). LCMS (ESI.sup.+) m/z: 295.0 [M+H].sup.+.

[0218] A dried single-neck flask was added with the compound 36-1 (60 mg, 0.20 mmol), 4 mL MeOH and Pd/C (10%, 22 mg), replaced with hydrogen three times through a hydrogen balloon, and stirred at the room temperature for 16 h, where the reaction was monitored by LC-MS. The reaction mixture was filtered, and the filtrate was subjected to decompression concentration to obtain a compound 36-2 (62 mg, crude). The compound 36-2 can be directly used in the subsequent reaction. LCMS (ESI.sup.+) m/z: 297.0 [M+H].sup.+.

[0219] The compound 36-2 (62 mg, 0.20 mml) was dissolved in a MeOH (4 mL) and H.sub.2O (1 mL) mixed solution, and added with NaOH (80 mg, 2 mmol), followed by reaction at 70 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was cooled to the room temperature, subjected to pH adjustment to around 5 with a 2N HCl solution, extracted with ethyl acetate and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried and concentrated to obtain a compound 36-3 (60 mg, crude), and the compound 36-3 can be directly used in the subsequent reaction.

[0220] The compound 36-3 (60 mg, 0.2 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (0.35 mL, 2 mmol), cooled in an ice water bath, added with HATU (91 mg, 0.24 mmol), stirred at 0 C. for 5 min, added with cyclohexylmethylamine (34 mg, 0.3 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 36-4 (58 mg, 0.15 mmol, 77% yield). LCMS (ESI.sup.+) m/z: 378.2 [M+H].sup.+.

[0221] A dried single-neck flask was added with NaH (6 mg, 0.16 mmol), sealed, replaced with nitrogen three times, added with 1 mL DMF and cooled in an ice water bath. The compound 36-4 (20 mg, 0.053 mmol) was dissolved in 0.5 mL DMF, and dropwise added into the single-neck flask. The reaction mixture was held at 0 C., stirred for 20 min, added with CH.sub.3I (38 mg, 0.159 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 36 (15 mg, 38 mol, 72% yield). LCMS (ESI.sup.+) m/z: 392.2 [M+H].sup.+.

[0222] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.78 (s, 1H), 7.70-7.62 (m, 1H), 7.39-7.28 (m, 1H), 3.55-3.40 (m, 0.7H), 3.23 (s, 2.1H), 3.20 (s, 0.9H), 3.12-3.01 (m, 0.7H), 2.95 (s, 0.9H), 2.92-2.74 (m, 0.6H), 2.72 (s, 2.1H), 2.72-2.60 (m, 1H), 1.89-1.51 (m, 11H), 1.50-1.33 (m, 4H), 1.31-0.88 (m, 5.4H), 0.76-0.54 (m, 0.6H).

Example 37 Preparation of Compound 37

##STR00071##

[0223] The compound S4 (30 mg, 77.5 mol), 2-methoxyphenylboronic acid (14.14 mg, 93 mol), Pd(dppf)Cl.sub.2 (2.81 mg, 3.87 mol) and K.sub.2CO.sub.3 (21.39 mg, 155 mol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL dioxane and 0.25 mL H.sub.2O and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 37 (10.96 mg, 26.3 mol, 30% yield). LCMS (ESI.sup.+) m/z: 416.2 [M+H].sup.+.

[0224] .sup.1H NMR (400 MHz, DMSO-d6) 8.06 (dd, J=5.1, 1.8 Hz, 1H), 7.90 (ddd, J=7.9, 4.2, 1.8 Hz, 1H), 7.53-7.39 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 7.10 (t, J=7.3 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 0.75H), 3.28 (d, J=14.1 Hz, 3H), 3.09 (s, 0.79H), 2.98 (s, 0.82H), 2.90 (t, J=7.2 Hz, 0.53H), 2.80 (s, 2.2H), 1.84-1.54 (m, 6H), 1.32-0.64 (m, 5H).

Example 38 Preparation of Compound 38

##STR00072##

[0225] The compound S4 (30 mg, 77.5 mol), 2-methylphenylboronic acid (12.65 mg, 93 mol), Pd(dppf)Cl.sub.2 (2.81 mg, 3.87 mol) and K.sub.2CO.sub.3 (21.39 mg, 155 mol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL dioxane and 0.25 mL H.sub.2O and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 38 (8.12 mg, 23.9 mol, 26.2% yield). LCMS (ESI.sup.+) m/z: 400.1 [M+H].sup.+.

[0226] .sup.1H NMR (400 MHz, DMSO-d6) 7.86 (t, J=1.8 Hz, 1H), 7.79 (ddd, J=7.7, 4.0, 1.8 Hz, 1H), 7.50 (dd, J=7.8, 5.7 Hz, 1H), 7.34 (ddt, J=15.7, 4.7, 2.5 Hz, 4H), 3.55 (s, 0.75H), 3.30 (d, J=13.5 Hz, 3H), 3.11 (s, 0.75H), 2.98 (s, 0.87H), 2.89 (dd, J=11.4, 7.1 Hz, 0.52H), 2.80 (s, 2.22H), 2.27 (d, J=2.7 Hz, 3H), 1.81-1.53 (m, 6H), 1.30-0.65 (m, 5H).

Example 39 Preparation of Compound 39

##STR00073##

[0227] The compound S4 (15 mg, 38.7 mol), 2-(trifluoromethyl)phenylboronic acid (8.1 mg, 42.6 mol), Pd(dppf)Cl.sub.2 (1.4 mg, 1.9 mol) and K.sub.2CO.sub.3 (10.69 mg, 77.5 mol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL dioxane and 0.25 mL H.sub.2O and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 39 (13.35 mg, 29.4 mol, 76% yield). LCMS (ESI.sup.+) m/z: 454.1 [M+H].sup.+.

[0228] .sup.1H NMR (400 MHz, DMSO-d6) 7.94-7.85 (m, 2H), 7.84-7.74 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.61-7.51 (m, 2H), 3.55 (s, 0.64H), 3.28 (d, J=13.6 Hz, 3H), 3.16-3.04 (m, 0.67H), 2.99 (s, 1H), 2.95-2.82 (m, 0.5H), 2.78 (s, 2.19H), 1.87-1.53 (m, 6H), 1.33-0.61 (m, 5H).

Example 40 Preparation of Compound 40

##STR00074##

[0229] The compound S4 (15 mg, 38.7 mol), 2-(dimethylamino)phenylboronic acid (6.39 mg, 42.6 mol), Pd(dppf)Cl.sub.2 (1.4 mg, 1.9 mol) and K.sub.2CO.sub.3 (10.69 mg, 77.5 mol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1 mL dioxane and 0.25 mL H.sub.2O and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, filtered, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 40 (11.83 mg, 27.6 mol, 71.2% yield). LCMS (ESI.sup.+) m/z: 429.1 [M+H].sup.+.

[0230] .sup.1H NMR (400 MHz, DMSO-d6) 8.12 (dd, J=10.3, 1.7 Hz, 1H), 7.96 (ddd, J=7.6, 5.4, 1.7 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.38-7.26 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.08 (t, J=7.4 Hz, 1H), 3.54 (d, J=11.0 Hz, 0.69H), 3.27 (d, J=13.8 Hz, 3H), 3.07 (d, J=13.2 Hz, 0.68H), 2.98 (s, 0.94H), 2.95-2.83 (m, 0.65H), 2.79 (s, 2.10H), 2.50 (d, J=3.7 Hz, 3H), 1.85-1.52 (m, 6H), 1.31-0.62 (m, 5H).

Example 41 Preparation of Compound 41

##STR00075##

[0231] The compound S4 (20 mg, 0.051 mmol), 2-(2-cyclopropyl-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16 mg, 0.06 mmol), Pd(dppf)Cl.sub.2 (7.3 mg, 0.01 mmol) and K.sub.2CO.sub.3 (14 mg, 0.1 mmol) were added into a dried single-neck flask, sealed, replaced with nitrogen three times, added with 1.6 mL 1,4-dioxane and 0.4 mL H.sub.2O and stirred at 100 C. overnight. The reaction mixture was cooled to the room temperature, added with EtOAc and water, and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, filtered and concentrated to obtain a crude product. The crude product was purified through medium-pressure liquid chromatography to obtain a white solid as compound 41 (7.6 mg, 17.07 mol, 33% yield). LCMS (ESI.sup.+) m/z: 444.0 [M+H].sup.+.

[0232] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.98 (d, J=1.9 Hz, 2H), 7.91 (d, J=49.0 Hz, OH), 7.86-7.83 (m, OH), 7.83 (dd, J=7.8, 1.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.42-7.31 (m, 1H), 7.18-7.06 (m, 1H), 6.96-6.82 (m, 1H), 3.54 (d, J=10.1 Hz, 1H), 3.31 (s, 4H), 3.27 (s, 1H), 3.11 (d, J=17.1 Hz, 2H), 2.98 (s, 2H), 2.95-2.83 (m, 1H), 2.80 (s, 4H), 1.87-1.48 (m, 13H), 1.33-1.10 (m, 4H), 1.07-0.60 (m, 13H).

Example 42 Preparation of Compound 42

##STR00076##

[0233] A dried single-neck flask was added with methyl 2-bromobenzoate (500 mg, 2.32 mmol), 10 mL of tetrahydrofuran, cooled to 0 C. under the protection of N.sub.2, added with methylmagnesium bromide (11.6 mL, 11.6 mmol, 1M in THF) and reacted at the room temperature for 16 h, where the reaction was monitored by TLC. The reaction mixture was added with a saturated ammonium chloride solution and extracted with ethyl acetate three times. The resultant organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and a filtrate was collected, concentrated, and purified through column chromatography to obtain a compound 42-1 (200 mg, 0.93 mmol). LCMS (ESI.sup.+) m/z: 215.1 [M+H].sup.+.

[0234] The compound 42-1 (50 mg, 0.23 mmol), bis(pinacolato)diboron (118 mg, 0.46 mmol), Pd(dppf)Cl.sub.2 (17 mg, 0.023 mmol) and potassium acetate (68 mg, 0.69 mmol) were added into a dried single-neck flask, and dissolved in 1,4-dioxane, and reacted at 100 C. under the protection of N.sub.2 for 2 h, where the reaction completion was monitored by LC-MS. The reaction mixture was cooled to the room temperature, filtered, and subjected to decompression concentration to obtain a compound 42-2 (80 mg, crude). The compound 42-2 can be directly used in the subsequent reaction. LCMS (ESI.sup.+) m/z: 263.2 [M+H].sup.+.

[0235] The compound 42-2 (80 mg, 0.23 mmol), the compound S4 (50 mg, 0.13 mmol), Pd(dppf)Cl.sub.2 (9.4 mg, 0.013 mmol) and K.sub.2CO.sub.3 (53.3 mg, 0.39 mmol) were added into a dried single-neck flask, dissolved in 1.5 mL 1,4-dioxane and 0.5 mL H.sub.2O, and reacted at 100 C. under the protection of N.sub.2 for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was cooled to the room temperature, filtered, and subjected to decompression concentration, and the remnant was purified through high performance liquid chromatography (basic) to obtain a white solid as compound 42 (12.9 mg, 0.029 mmol, 22.3% yield). LCMS (ESI.sup.+) m/z: 444.1 [M+H].sup.+. HPLC method B: R.sub.T=8.37 min, purity >99.1%.

[0236] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.84-7.76 (m, 1H), 7.75-7.62 (m, 2H), 7.62-7.44 (m, 1.2H), 7.44-7.36 (m, 1.5H), 7.34-7.24 (m, 0.8H), 7.11-7.01 (m, 0.7H), 4.91-4.86 (m, 1H), 3.56 (s, 0.7H), 3.30-3.20 (m, 3.2H), 3.09 (s, 0.7H), 3.01-2.72 (m, 3.7H), 2.48-2.22 (m, 1H), 1.87-1.51 (m, 6H), 1.40-1.15 (m, 7H), 1.15-0.53 (m, 3H).

Example 43 Preparation of Compound 43

##STR00077##

[0237] The compound S4 (31 mg, 0.08 mmol), 3-methoxy-4-pyridineboronic acid (24.4 mg, 0.16 mmol), Pd(dppf)Cl.sub.2 (5.8 mg, 8 mol), Cs.sub.2CO.sub.3 (52 mg, 0.16 mmol), and CuI (15.2 mg, 0.08 mmol) were added into a dried single-neck flask. The reaction mixture was added with 1.5 mL DMF, sealed, replaced with nitrogen three times, stirred at 100 C. for 2 h, cooled to the room temperature, added with EtOAc and water, and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, filtered and concentrated to obtain a crude product. The crude product was purified through medium-pressure liquid chromatography to obtain a white solid as compound 43 (9.3 mg, 22.3 mol, 28% yield). LCMS (ESI.sup.+) m/z: 417.1 [M+H].sup.+.

[0238] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.92-8.21 (m, 2H), 8.14 (d, J=1.7 Hz, 1H), 8.04-7.92 (m, 1H), 7.62-7.39 (m, 2H), 3.95 (s, 3H), 3.58-3.47 (m, 0.7H), 3.30 (s, 2.1H), 3.27 (s, 0.9H) 3.14-3.04 (m, 0.7H), 2.97 (s, 0.9H), 2.95-2.81 (m, 0.6H), 2.79 (s, 2.1H), 1.91-1.48 (m, 6.3H), 1.31-1.10 (m, 2.4H), 1.10-0.87 (m, 1.7H), 0.77-0.61 (m, 0.6H).

Example 44 Preparation of Compound 44

##STR00078##

[0239] Under the protection of N.sub.2, the compound S4 (25 mg, 64.38 mol), 3-methylphenylboronic acid (10.50 mg, 77.26 mol), Pd(dppf)Cl.sub.2 (2.34 mg, 3.22 mol), K.sub.2CO.sub.3 (17.80 mg, 128.76 mol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 44 (13.3 mg, 33.29 mol, 51.71% yield, 100% purity). LCMS (ESI.sup.+) m/z: 400.2 [M+H].sup.+.

[0240] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.17-8.12 (m, 1H), 8.10-8.03 (m, 1H), 7.62-7.49 (m, 3H), 7.45-7.40 (m, 1H), 7.28 (d, J=7.6 Hz, 1H), 3.60-3.50 (m, 1H), 3.30 (d, J=12.6 Hz, 3H), 3.15-3.04 (m, 1H), 2.97 (s, 1H), 2.94-2.84 (m, 1H), 2.78 (s, 2H), 2.41 (s, 3H), 1.85-1.70 (m, 4H), 1.67-1.55 (m, 2H), 1.29-1.06 (m, 4H).

Example 45 Preparation of Compound 45

##STR00079##

[0241] Under the protection of N.sub.2, the substrate S3 (25 mg, 64.38 mol), 2-fluorophenylboronic acid (10.81 mg, 77.26 mol), Pd(dppf)Cl.sub.2 (2.34 mg, 3.22 mol), K.sub.2CO.sub.3 (17.80 mg, 128.76 mol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 45 (17 mg, 41.58 mol, 64.59% yield, 98.7% purity). LCMS (ESI.sup.+) m/z: 404.2 [M+H].sup.+.

[0242] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.10 (s, 1H), 8.02-7.95 (m, 1H), 7.74-7.64 (m, 1H), 7.59-7.48 (m, 2H), 7.44-7.35 (m, 2H), 3.62-3.45 (m, 1H), 3.30 (d, J=14.0 Hz, 3H), 3.20-3.00 (m, 1H), 2.98 (s, 1H), 2.96-2.82 (m, 1H), 2.79 (s, 2H), 1.91-1.69 (m, 4H), 1.67-1.50 (m, 2H), 1.29-0.99 (m, 4H).

Example 46 Preparation of Compound 46

##STR00080##

[0243] Under the protection of N.sub.2, the compound S4 (25 mg, 64.38 mol), 2-isopropylphenylboronic acid (12.67 mg, 77.26 mol), Pd(dppf)Cl.sub.2 (2.34 mg, 3.22 mol), K.sub.2CO.sub.3 (17.80 mg, 128.76 mol), and 1 mL dioxane/H2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 46 (17.6 mg, 41.16 mol, 63.93% yield, 100% purity). LCMS (ESI.sup.+) m/z: 428.2 [M+H].sup.+.

[0244] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 7.89-7.78 (m, 1H), 7.79-7.68 (m, 1H), 7.62-7.47 (m, 2H), 7.46-7.36 (m, 1H), 7.36-7.17 (m, 2H), 3.56-3.52 (m, 1H), 3.29 (d, J=14.1 Hz, 3H), 3.14-3.04 (m, 1H), 2.99 (s, 1H), 2.96-2.84 (m, 2H), 2.81 (s, 2H), 1.85-1.69 (m, 4H), 1.68-1.57 (m, 2H), 1.27-1.12 (m, 10H).

Example 47 Preparation of Compound 47

##STR00081##

[0245] Under the protection of N.sub.2, the compound S4 (15 mg, 38.63 mol), benzofuran-4-ylboronic acid (7.51 mg, 46.35 mol), Pd(dppf)Cl.sub.2 (1.40 mg, 1.93 mol), K.sub.2CO.sub.3 (10.68 mg, 77.26 mol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 47 (10.0 mg, 23.50 mol, 60.84% yield, 100% purity). LCMS (ESI.sup.+) m/z: 426.3 [M+H].sup.+.

[0246] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.50-8.42 (m, 1H), 8.34-8.24 (m, 1H), 8.18-8.11 (m, 1H), 7.77 (d, J=7.7, 1.2 Hz, 1H), 7.71-7.64 (m, 1H), 7.64-7.57 (m, 1H), 7.46-7.38 (m, 1H), 7.11 (d, J=2.2 Hz, 1H), 3.65-3.45 (m, 1H), 3.33 (s, 2H), 3.30 (s, 1H), 3.19-3.04 (m, 1H), 2.99 (s, 1H), 2.81 (s, 2H), 1.87-1.69 (m, 4H), 1.68-1.53 (m, 2H), 1.31-1.11 (m, 3H), 1.00 (d, J=12.5 Hz, 2H).

Example 48 Preparation of Compound 48

##STR00082##

[0247] Under the protection of N.sub.2, the compound S4 (15 mg, 38.63 mol), benzofuran-4-boronic acid pinacol ester (11.31 mg, 46.35 mol), Pd(dppf)Cl.sub.2 (1.40 mg, 1.93 mol), K.sub.2CO.sub.3 (10.68 mg, 77.26 mol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 48 (9.26 mg, 21.76 mol, 56.33% yield, 94.5% purity). LCMS (ESI.sup.+) m/z: 426.3 [M+H].sup.+.

[0248] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.23-8.13 (m, 2H), 8.10-8.04 (m, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.42 (m, 2H), 7.20-7.14 (m, 1H), 3.65-3.48 (m, 1H), 3.37 (s, 3H), 3.17-3.02 (m, 1H), 2.99 (s, 1H), 2.82 (s, 2H), 1.86-1.70 (m, 4H), 1.68-1.55 (m, 2H), 1.30-1.13 (m, 3H), 1.11-0.81 (m, 2H).

Example 49 Preparation of Compound 49

##STR00083##

[0249] Under the protection of N.sub.2, the compound S4 (15 mg, 38.63 mol), 2-isopropylphenylboronic acid (7.51 mg, 46.35 mol), Pd(dppf)Cl.sub.2 (1.40 mg, 1.93 mol), K.sub.2CO.sub.3 (10.68 mg, 77.26 mol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and subjected to decompression concentration, and the remnant was purified through medium-pressure liquid chromatography to obtain a white solid as compound 49 (6.4 mg, 14.66 mol, 37.96% yield, 97.5% purity). LCMS (ESI.sup.+) m/z: 426.6 [M+H].sup.+.

[0250] .sup.1H NMR (600 MHz, DMSO-d.sub.6) 8.07 (d, J=3.6 Hz, 1H), 8.03-7.96 (m, 1H), 7.48-7.41 (m, 2H), 7.41-7.36 (m, 1H), 7.36-7.31 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 3.46 (t, J=10.2 Hz, 1H), 3.24 (d, J=19.1 Hz, 3H), 3.02 (t, 1H), 2.90 (s, 1H), 2.71 (s, 2H), 2.01-1.94 (m, 1H), 1.76-1.68 (m, 2H), 1.67-1.61 (m, 2H), 1.60-1.48 (m, 2H), 1.23-1.06 (m, 3H), 1.02-0.85 (m, 4H), 0.74-0.68 (m, 2H).

Example 50 Preparation of Compound 50

##STR00084##

[0251] Under the protection of N.sub.2, the compound S4 (40 mg, 0.103 mmol), 1-indol-4-bromophenylboronic acid (19.90 mg, 0.124 mmol), Pd(dppf)Cl.sub.2 (7.52 mg, 0.010 mmol), K.sub.2CO.sub.3 (42.71 mg, 0.309 mmol), and 1 mL dioxane/H.sub.2O (v:v=4:1) were added into a microwave tube, and stirred at 90 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 50 (16 mg, 0.036 mmol, 34.68% yield, 94.8% purity). LCMS (ESI.sup.+) m/z: 425.2 [M+H].sup.+.

[0252] .sup.1H NMR (400 MHz, DMSO-d6) 11.19 (s, 1H), 8.13 (d, J=1.7 Hz, 1H), 8.01 (dt, J=7.8, 2.1 Hz, 1H), 7.64 (dd, J=7.7, 1.2 Hz, 1H), 7.56 (dd, J=11.4, 7.8 Hz, 1H), 7.41 (dt, J=5.6, 2.7 Hz, 1H), 7.26-7.09 (m, 2H), 6.58 (dt, J=3.2, 1.7 Hz, 1H), 3.55 (d, J=7.5 Hz, 1H), 3.37 (s, 2H), 3.34 (s, 1H), 3.10 (dd, J=12.8, 6.0 Hz, 1H), 2.99 (s, 1H), 2.84 (s, 2H), 1.80 (d, J=6.8 Hz, 2H), 1.73 (dd, J=13.5, 3.8 Hz, 2H), 1.68-1.52 (m, 2H), 1.23 (d, J=9.7 Hz, 3H), 1.01 (s, 2H).

Example 51 Preparation of Compound 51

##STR00085##

[0253] Under the protection of N.sub.2, the compound S4 (20 mg, 0.052 mmol), 7-indoleboronic acid pinacol ester (15.03 mg, 0.062 mmol), K.sub.2CO.sub.3 (21.36 mg, 0.155 mmol), Pd(dppf)Cl.sub.2 (3.76 mg, 0.005 mmol), and 2 mL dioxane/H2O (v:v=3:1) were added into a microwave tube, and stirred at 90 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 51 (16 mg, 0.038 mmol, 73.17% yield, 100% purity). LCMS (ESI.sup.+) m/z: 425.1 [M+H].sup.+.

[0254] .sup.1H NMR (400 MHz, DMSO-d6) 11.19 (s, 1H), 8.13 (d, J=1.7 Hz, 1H), 8.01 (dt, J=7.8, 2.1 Hz, 1H), 7.64 (dd, J=7.7, 1.2 Hz, 1H), 7.56 (dd, J=11.4, 7.8 Hz, 1H), 7.41 (q, J=2.8, 2.3 Hz, 1H), 7.26-7.09 (m, 2H), 6.58 (dt, J=3.2, 1.7 Hz, 1H), 3.55 (d, J=7.5 Hz, 1H), 3.37 (s, 3H), 3.34 (s, 1H), 3.10 (dd, J=13.0, 5.9 Hz, 1H), 2.99 (s, 1H), 2.84 (s, 2H), 1.88-1.77 (m, 2H), 1.73 (dd, J=13.5, 3.8 Hz, 2H), 1.63 (d, J=22.6 Hz, 2H), 1.33-1.12 (m, 3H), 1.01 (s, 2H).

Example 52 Preparation of Compound 52

##STR00086##

[0255] Under the protection of N.sub.2, the compound S4 (50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (24.3 mg, 0.143 mmol), K.sub.2CO.sub.3 (53.8 mg, 0.39 mmol), Pd(dppf)Cl.sub.2 (11.2 mg, 0.013 mmol), and 2 mL dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and stirred at 90 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 52 (22.6 mg, 0.052 mmol, 40% yield, 94.9% purity). LCMS (ESI.sup.+) m/z: 434.1 [M+H].sup.+.

[0256] .sup.1H NMR (400 MHz, DMSO-d6) 8.00 (dd, J=3.5, 1.8 Hz, 1H), 7.86 (dd, J=7.9, 1.8 Hz, 1H), 7.44 (ddt, J=8.3, 6.8, 3.7 Hz, 2H), 7.04 (dd, J=11.4, 2.5 Hz, 1H), 6.91 (tdd, J=8.4, 2.5, 1.1 Hz, 1H), 3.79 (d, J=1.3 Hz, 3H), 3.47 (s, 1H), 3.21 (s, 1H), 3.08 (d, J=9.1 Hz, 1H), 2.95 (s, 1H), 2.76 (s, 2H), 1.85-1.48 (m, 7H), 1.19-1.09 (m, 3H), 0.95 (d, J=12.1 Hz, 2H), 0.86-0.59 (m, 1H).

Example 53 Preparation of Compound 53

##STR00087##

[0257] Under the protection of N.sub.2, the compound S4 (10 mg, 0.026 mmol), 2-ethylphenylboronic acid (4.3 mg, 0.028 mmol), K.sub.2CO.sub.3 (10.8 mg, 0.078 mmol), Pd(dppf)Cl.sub.2 (2.6 mg, 0.003 mmol), and 2 mL dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and stirred at 90 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 53 (3.43 mg, 0.008 mmol, 31.8% yield, 97.5% purity). LCMS (ESI.sup.+) m/z: 414.2 [M+H].sup.+.

[0258] 1H NMR (400 MHz, DMSO-d6) 7.84 (d, J=1.8 Hz, 1H), 7.76 (ddd, J=7.6, 5.5, 1.9 Hz, 1H), 7.51 (dd, J=7.8, 3.1 Hz, 1H), 7.43-7.37 (m, 2H), 7.36-7.24 (m, 2H), 3.55 (s, 1H), 3.29 (d, J=8.2 Hz, 3H), 3.10 (s, 1H), 2.99 (s, 1H), 2.80 (s, 2H), 1.86-1.53 (m, 7H), 1.33-1.12 (m, 4H), 1.06 (dt, J=17.9, 7.5 Hz, 5H).

Example 54 Preparation of Compound 54

##STR00088##

[0259] Under the protection of N.sub.2, the compound S4 (10 mg, 0.026 mmol), 4-fluorophenylboronic acid (3.9 mg, 0.028 mmol), K.sub.2CO.sub.3 (10.8 mg, 0.078 mmol), Pd(dppf)Cl.sub.2 (2.6 mg, 0.003 mmol), and 2 mL dioxane/H.sub.2O (v:v=3:1) were added into a microwave tube, and stirred at 90 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 54 (5.12 mg, 0.012 mmol, 48.8% yield, 99.3% purity). LCMS (ESI.sup.+) m/z: 404.1 [M+H].sup.+.

[0260] .sup.1H NMR (600 MHz, DMSO-d6) 8.14 (dd, J=3.6, 1.8 Hz, 1H), 8.07 (ddd, J=14.8, 7.9, 2.0 Hz, 1H), 7.84 (ddd, J=16.5, 8.7, 5.5 Hz, 2H), 7.52 (dd, J=12.7, 7.9 Hz, 1H), 7.38 (td, J=8.8, 1.9 Hz, 2H), 3.53 (d, J=10.3 Hz, 1H), 3.32 (s, 2H), 3.29 (s, 1H), 3.09 (s, 1H), 2.98 (s, 1H), 2.79 (s, 2H), 1.84-1.54 (m, 7H), 1.21-1.12 (m, 2H), 1.00 (d, J=10.6 Hz, 2H).

##STR00089##

Synthesis of Compound S7

[0261] The substrate S1 (150 mg, 0.51 mmol), 4-fluoro-2-(methylthio)phenylboronic acid (112 mg, 0.6 mmol), Pd(dppf)Cl.sub.2 (36 mg, 0.05 mmol), K.sub.2CO.sub.3 (276 mg, 2 mmol), 4 mL 1,4-dioxane and 1 mL water were added into a dried single-neck flask, sealed, replaced with nitrogen three times, heated to 100 C. and stirred overnight. The reaction mixture was cooled to the room temperature, added with EtOAc and water, and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, filtered and concentrated to obtain a crude product. The crude product was purified through column chromatography to obtain a compound S7 (175 mg, 0.49 mmol, 96% yield).

Synthesis of Compound S8

[0262] The compound S7 (175 mg, 0.49 mmol) was dissolved in the MeOH/H2O mixed solution (v:v=4:1, 5 mL), added with NaOH (200 mg, 5 mmol), and reacted at 70 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was cooled to the room temperature, subjected to pH adjustment to around 5 with a 2N HCl solution, extraction with ethyl acetate and liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound S8 (160 mg, 0.47 mmol, 96% yield).

Example 55 Preparation of Compound 55

##STR00090##

[0263] The compound S8 (30.0 mg, 0.088 mmol) was added into a dried single-neck flask, dissolved in 1.0 mL DMF, and cooled to 0 C. The reaction mixture was added with DIPEA (153.0 L, 0.88 mmol), reacted for 5 min, added with HATU (40.1 mg, 0.106 mmol), reacted for 10 min, added with 4-(aminomethyl)tetrahydropyran (12.2 mg, 0.106 mmol) and reacted for 0.5 h, where the reaction was monitored by LC-MS.

[0264] The reaction mixture was subjected to vacuum concentration, and the remnant was purified through high performance liquid chromatography (basic) to obtain a compound 55-1 (28.0 mg, 0.064 mmol). LCMS (ESI.sup.+) m/z: 438.1 [M+H].sup.+.

[0265] A dried single-neck flask was added with NaH (5 mg, 0.128 mmol), cooled to 0 C. under the protection of N.sub.2, added with 1 mL of DMF, and reacted for 5 min. The compound 55-1 (28.0 mg, 0.064 mmol) was dissolved in 0.5 mL DMF, added into the reaction mixture and stirred for 0.5 h. The reaction mixture was added with methyl iodide (18.2 mg, 0.128 mmol) and reacted at the room temperature for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to vacuum concentration, and the remnant was purified through high performance liquid chromatography (basic) to obtain a compound 55 (8.4 mg, 0.019 mmol). LCMS (ESI.sup.+) m/z: 452.2 [M+H].sup.+. HPLC method B: R.sub.T=7.53 min, purity >98.8%.

[0266] .sup.1H NMR (600 MHz, DMSO-d.sub.6) 7.92 (d, J=1.8 Hz, 1H), 7.83-7.75 (m, 1H), 7.57-7.53 (m, 1H), 7.40-7.35 (m, 1H), 7.25-7.23 (m, 1H), 7.13-7.10 (m, 1H), 3.92-3.73 (m, 2H), 3.55-3.44 (m, 0.7H), 3.32-3.28 (m, 3.6H), 3.28-3.20 (m, 2H), 3.03-2.78 (m, 3.7H), 2.48-2.41 (m, 3H), 2.08-1.85 (m, 1H), 1.75-1.42 (m, 2H), 1.28-0.95 (m, 2H).

Example 56 Preparation of Compound 56

##STR00091##

[0267] The compound S8 (23 mg, 67.6 mol) was added into a dried single-neck flask, and dissolved in 1.5 mL DMF under stirring. The reaction mixture was added with DIPEA (59 L, 0.34 mmol), cooled in an ice water bath, added with HATU (31 mg, 81 mol), reacted at 0 C. under stirring for 5 min, added with 2-methoxy-4-(aminomethyl)pyridine (11.2 mg, 81 mol) and reacted at 0 C. for 20 minutes, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 56-1 (25 mg, 54.3 mol, 80% yield).

[0268] A dried single-neck flask was added with NaH (8 mg, 0.2 mmol), sealed, replaced with nitrogen three times, added with 1 mL DMF and cooled in an ice water bath. The compound 56-1 (25 mg, 54.3 mol) was dissolved in 0.5 mL DMF, dropwise added into the single-neck flask, subjected to temperature keeping, stirred for 20 min, added with CH.sub.3I (28 mg, 0.2 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 56-2 (22 mg, 46.3 mol, 85% yield). LCMS (ESI.sup.+) m/z: 475.0 [M+H].sup.+.

[0269] The compound 56-2 (17 mg, 36 mol) was added into the 25 mL single-neck flask, dissolved in 2 mL 1,4-dioxane and stirred, added with 1 mL of concentrated hydrochloric acid, heated and stirred at 90 C. for 16 h, where the reaction was monitored by LC-MS. The reaction mixture was adjusted to pH 8 with saturated NaHCO.sub.3, extracted with ethyl acetate, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, and a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 56 (10 mg, 21.7 mol, 60% yield). LCMS (ESI.sup.+) m/z: 461.1 [M+H].sup.+.

[0270] .sup.1H NMR (600 MHz, DMSO-d.sub.6) 11.49 (s, 1H), 7.96 (d, J=1.8 Hz, 0.7H), 7.94 (d, J=1.8 Hz, 0.3H), 7.83 (dd, J=7.8, 1.8 Hz, 0.7H), 7.76 (dd, J=7.8, 1.8 Hz, 0.3H), 7.65 (d, J=7.8 Hz, 0.7H), 7.57 (d, J=7.8 Hz, 0.3H), 7.40-7.31 (m, 2H), 7.27-7.20 (m, 1H), 7.15-7.07 (m, 1H), 6.37 (d, J=1.6 Hz, 0.7H), 6.27-6.21 (m, 1H), 6.15 (dd, J=6.8, 1.8 Hz, 0.3H), 4.54 (s, 1.4H), 4.14 (d, J=5.7 Hz, 0.6H), 3.33 (s, 3H), 2.93 (s, 0.9H), 2.77 (s, 2.1H), 2.47 (s, 2.1H), 2.45 (s, 0.9H).

##STR00092##

Synthesis of Compound S9

[0271] The substrate S1 (200 mg, 0.68 mmol), 4-fluoro-2-methoxyphenylboronic acid (140 mg, 0.82 mmol), Pd(dppf)Cl.sub.2 (58 mg, 0.068 mmol), K.sub.2CO.sub.3 (282 mg, 2.04 mmol) 4 mL 1,4-dioxane and 1 mL water were added into a dried single-neck flask, sealed, replaced with nitrogen three times, heated to 100 C. and stirred overnight. The reaction mixture was cooled to the room temperature, added with EtOAc and water, and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, filtered and concentrated to obtain a crude product. The crude product was purified through column chromatography to obtain a compound S9 (153 mg, 0.45 mmol, 66% yield).

Synthesis of Compound S10

[0272] The compound S9 (153 mg, 0.45 mmol) was dissolved in the MeOH/H.sub.2O mixed solution (v:v=4:1, 5 mL), added with NaOH (200 mg, 5 mmol), and reacted at 70 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was cooled to the room temperature, subjected to pH adjustment to around 5 with a 2N HCl solution, extraction with ethyl acetate and subjected to liquid separation. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried, concentrated, and purified through medium-pressure liquid chromatography to obtain a white solid as compound S10 (142.7 mg, 0.44 mmol, 97% yield).

Example 57 Preparation of Compound 57

##STR00093##

[0273] The compound S10 (50 mg, 0.154 mmol) and 1.5 mL DMF were added into a dried single-neck flask, followed by stirring for dissolution. The reaction mixture was added with DIPEA (118 L, 0.68 mmol) cooled in an ice water bath, added with HATU (70.4 mg, 0.185 mmol), stirred at 0 C. for 5 min, added with 2-methoxy-4-(aminomethyl)pyridine (25.5 mg, 0.185 mmol) and reacted at 0 C. for 20 min, where the reaction was monitored by LC-MS. The reaction mixture was quenched with water, followed by extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 57-1 (35 mg, 78.7 mol, 51% yield). LCMS (ESI.sup.+) m/z: 445.5 [M+H].sup.+.

[0274] A dried single-neck flask was added with NaH (16 mg, 0.4 mmol), sealed, replaced with nitrogen three times, added with 1 mL of DMF and cooled in an ice water bath. The compound 57-1 (40 mg, 90 mol) was dissolved in 0.5 mL DMF, dropwise added into the single-neck flask, subjected to temperature keeping, stirred for 20 min, added with CH.sub.3I (56 mg, 0.4 mmol) and reacted at 0 C. for 1 h. The reaction mixture was quenched with water, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and filtered, a filtrate was collected, concentrated, and purified through medium-pressure liquid chromatography to obtain a compound 57-2 (18.7 mg, 40.8 mol, 45% yield). LCMS (ESI.sup.+) m/z: 459.4 [M+H].sup.+.

[0275] The compound 57-2 (18.7 mg, 40.8 mol) was added into the 25 mL single-neck flask, dissolved in 2 mL of 1,4-dioxane through stirring, added with 1 mL of concentrated hydrochloric acid, heated and stirred at 90 C. for 16 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to pH adjustment to around 8 with saturated NaHCO.sub.3, extracted with ethyl acetate, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a white solid as compound 57 (5.12 mg, 11.5 mol, 28% yield). LCMS (ESI.sup.+) m/z: 445.1 [M+H].sup.+.

[0276] .sup.1H NMR (400 MHz, DMSO-d6) 11.51 (s, 1H), 8.04 (dd, J=5.2, 1.8 Hz, 1H), 7.88 (ddd, J=28.9, 7.9, 1.8 Hz, 1H), 7.64-7.43 (m, 2H), 7.35 (dd, J=14.4, 6.7 Hz, 1H), 7.10 (ddd, J=10.7, 8.0, 2.5 Hz, 1H), 7.03-6.87 (m, 1H), 6.40-6.12 (m, 2H), 4.53 (s, 1H), 4.24-4.12 (m, 1H), 3.83 (d, J=9.2 Hz, 3H), 3.33 (s, 3H), 2.93 (s, 1H), 2.77 (s, 2H).

Example 58 Preparation of Compound 58

##STR00094##

[0277] Under the protection of N.sub.2, the compound S4 (20 mg, 0.052 mmol), phenylboronic acid (7.54 mg, 0.062 mmol), Pd(dppf)Cl.sub.2 (3.76 mg, 0.0052 mmol), K.sub.2CO.sub.3 (21.36 mg, 0.155 mol), and 1 mL dioxane/H2O (v:v=3:1) were added into a microwave tube, and stirred at 100 C. for 2 h, where the reaction was monitored by LC-MS. The reaction mixture was subjected to rotary evaporation, and extraction with ethyl acetate three times. The resultant organic phases were combined, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified through medium-pressure liquid chromatography to obtain a brown solid as compound 58 (7 mg, 0.018 mmol, 35.25% yield, 100% purity). LCMS (ESI.sup.+) m/z: 386.1 [M+H].sup.+.

[0278] .sup.1H NMR (400 MHz, DMSO-d6) 8.16 (dd, J=2.7, 1.8 Hz, 1H), 8.08 (ddd, J=9.9, 7.9, 1.9 Hz, 1H), 7.82-7.72 (m, 2H), 7.54 (dd, J=8.2, 6.7 Hz, 3H), 7.50-7.43 (m, 1H), 3.52 (d, J=9.1 Hz, 1H), 3.32 (s, 2H), 3.29 (s, 1H), 3.08 (d, J=9.7 Hz, 1H), 2.97 (s, 1H), 2.78 (s, 2H), 1.87-1.66 (m, 4H), 1.68-1.51 (m, 2H), 1.31-1.11 (m, 3H), 0.99 (s, 2H).

[0279] Performances of compounds of the present disclosure were shown in the following test examples.

Test Example 1 Detection of SPR Binding Assays (Surface Plasmon Resonance Binding Assay) of TRIM21 Compounds

(1) Experimental Materials and Reagents

TABLE-US-00001 Biacore 8K Cytiva S series CM5 sensor chip Cytiva Cat#BR-1005-30 Twin Strep Tag Capture Kit IBA 2-4370-000 NaOH 50 Cytiva Cat#BR-1003-58 DMSO VETEC V900090 Na.sub.2HPO4 Sigma 795410 NaH.sub.2PO4 Sigma RDD007 NaCl Sangon Biotech A501218-0005 Tween-20 Sigma 93773 Amine Coupling Kit Cytiva Cat#BR100050 96-Well Plate Greener bio-one Cat#650201

(2) SPR Binding Assays

Preparation of Running Buffer

[0280] A protein fixation buffer included 7.6 mM NaH.sub.2OP.sub.4, 12.4 mM Na.sub.2HOP.sub.4, 150.0 mM NaCl, and 0.1% of Tween 20, and adjusted to pH 7.0. A running buffer A included 7.6 mM NaH.sub.2OP.sub.4, 12.4 mM Na.sub.2HOP.sub.4, 150.0 mM NaCl, and 0.1% Tween 20, and adjusted to pH 7.0. A running buffer B included 7.6 mM NaH.sub.2OP.sub.4, 12.4 mM Na.sub.2HOP.sub.4, 150.0 mM NaCl, 0.1% of Tween 20 and 1.00% of DMSO, and adjusted to pH 7.0. The protein fixation buffer, the running buffer A and the running buffer B were prepared and filtered through a 0.22 m membrane prior to use.

Strep-Tactin XT Fixation

[0281] A surface of a CM5 chip was washed for three times with 50 mM NaOH at a flow rate of 60.0 L/min and 60 seconds per wash. EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (75.00 mg/mL) and NHS (N-hydroxysuccinimide) (11.50 mg/mL) in the amine coupling kit were prepared as an activation reagent with a volume ratio of 1:1. The CM5 chip was activated for 420 s at a flow rate of 6.0 L/min. A strep tactin XT fixation buffer fixation built in the twin strep tag capture kit was used to prepare a 50.0 g/mL Strep tactin XT. The Strep tactin XT was injected at a flow rate of 5.0 L/min for 600 s. After injection of His antibody (anti-polyhistidine antibody), 1 M ethanolamine from the amine coupling kit was injected at a flow rate of 6.0 L/min for 7 min to close the surface of the CM5 chip. A final fixation amount of the Strep tactin XT was about 12000.0 RU.

TRIM21 Protein Fixation

[0282] The running buffer A was used as the protein fixation buffer. The protein fixation buffer and the TRIM21 protein were mixed to prepare a 40.0 g/mL mixed solution. The 40.0 g/mL mixed solution was injected at flow rate of 5.0 L/min for 600 s, and the TRIM21 protein was captured on the CM5 chip through Strep tactin XT.

[0283] A final fixation amount of the TRIM21 protein was about 2200.00 RU.

Compound Dilution

[0284] A compound to be tested was diluted with 100% DMSO to a concentration that was 100 times a required final concentration and mixed evenly, and 4.0 L of such solution was added into 396 L of the running buffer A, followed by centrifugation at 15,000 rpm for 5 min to obtain an X compound solution contained with 1% DMSO.

[0285] The X compound was subjected to 8-point, 2-fold serial dilutions with the running buffer B, starting from an initial concentration. The diluted X compound was transferred into the 96-well plate for sample injection.

Program Running

[0286] A Biacore 8K Control software was started, and tests were run in a 25 C. environment. During program running, the running buffer B was used at a flow rate of 30.0 L/min. The running buffer B was injected for three times to complete balance. The X compound was injected from a lower concentration to a higher concentration in sequence, where a binding time and dissociation time were both 60 s. An injection needle was cleaned with 50% DMSO after each injection. A solvent difference caused by DMSO was corrected by 0.50%, 0.75%, 1.00%, 1.25% and 1.50% DMSO.

(3) Data Analysis

[0287] A response value of binding of the X compound and the TRIM21 protein was corrected after deducting a reference channel and 0 concentration. A binding affinity Kd was matched by a steady state affinity model (1:1 binding model) through the Biacore Insight Evaluation Software.

[0288] The binding affinities between X compounds of the embodiments of the present disclosure were tested according the above method. Test results were shown in Table 1, where Kd values of the X compounds were classified according to instructions as follows: [0289] represented the Kd value>10 M; [0290] + represented 1 M

Table 1 Binding Affinity Kd Between the X Compounds and the TRIM421 Protein

TABLE-US-00002 Compound TRIM21 Kd Test Value 1 ++ 2 ++ 3 +++ 4 ++ 5 + 6 ++ 7 ++ 8 ++ 9 + 10 ++ 11 +++ 12 + 13 ++ 14 ++ 15 ++ 16 ++ 17 +++ 18 + 19 ++ 20 ++ 21 22 23 +++ 24 + 25 + 26 27 +++ 28 +++ 29 +++ 30 + 31 + 32 + 33 + 34 ++ 35 ++ 36 37 ++ 38 ++ 39 ++ 40 ++ 41 +++ 42 ++ 43 + 44 45 + 46 ++ 47 48 49 50 51 52 ++++ 53 ++ 54 + 55 ++++ 56 ++++ 57 ++++ 58

[0294] The experimental data indicated that the compounds of the present disclosure had a moderate to good binding affinities with the TRIM21 protein, and was considered promising in the preparation of a drug for treating TRIM21-associated diseases, such as tumors or autoimmune diseases. In addition, the compounds of the present disclosure may be also used as ligand or intermediate compounds for the development of TRIM21-based PROTACs.