PROTAC SMALL MOLECULE COMPOUND AND USE THEREOF

Abstract

The present invention discloses a compound of general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof, a composition comprising the compound of general formula I, and use of the compound of general formula I, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof for preparing a medicament for treating a disease associated with the serine/threonine kinase family (MAP4Ks), and preferably for preparing a medicament for treating a disease associated with hematopoietic progenitor kinase 1 (HPK1).

##STR00001##

Claims

1. A compound of general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof: ##STR00145## wherein the MAP4Ks family inhibitor is selected from: a HPK1 inhibitor, an MAP4K2 inhibitor, an MAP4K3 inhibitor, an MAP4K4 inhibitor, an MAP4K5 inhibitor, and an MAP4K6 inhibitor; q is selected from integers between 1 and 5; the Cereblon protein ligand is a small molecular ligand of Cereblon protein in an E3 ubiquitin ligase complex; L is a linking group between the Cereblon protein ligand and the MAP4K family inhibitor; preferably, the L is -A.sub.1-A.sub.2 . . . -A.sub.t-, wherein A.sub.1, A.sub.2 . . . A.sub.t are independently selected from: CR.sup.L1R.sup.L2, O, S, S═O, S(═O).sub.2, S(O).sub.2O, OS(O).sub.2, OS(O).sub.2O, NR.sup.L3, S(═O).sub.2NR.sup.L3, S(═O)NR.sup.L3, C(═O)NR.sup.L3, OC(O)NR.sup.L3, NR.sup.L3C(═O), NR.sup.L3C(═O)NR.sup.L4, NR.sup.L3S(═O).sub.2NR.sup.L4, C(═O), CR.sup.L1═CR.sup.L2, C═C, C≡C, SiR.sup.L1R.sup.L2, P(═O)R.sup.L1, P(═O)OR.sup.L1, NR.sup.L3C(═N—CN)NR.sup.L4, NR.sup.L3C(═N—CN), NR.sup.L3C(═C—NO.sub.2)NR.sup.L4, C.sub.3-11 cyclohydrocarbyl, C.sub.3-11 heterocyclohydrocarbyl, succinimide, ##STR00146##  CH.sub.2CH.sub.2O—, —OCH.sub.2CH.sub.2—, ##STR00147##  or are absent, wherein any hydrogen atom of the cyclohydrocarbyl and the heterocyclohydrocarbyl may be substituted with 1-6 R.sup.L1 or R.sup.L2; when A.sub.1, A.sub.2 . . . A.sub.t are CR.sup.L1R.sup.L2 or SiR.sup.L1R.sup.L2, R.sup.L1 and R.sup.L2 may be independently linked to other A to form cyclohydrocarbyl or heterocyclohydrocarbyl, and preferably, the cyclohydrocarbyl or heterocyclohydrocarbyl is optionally substituted with 1-11 R.sup.L5 groups; R.sup.L1, R.sup.L2, R.sup.L3, R.sup.L4 and R.sup.L5 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cyclohydrocarbyl, C.sub.3-11 heterocyclohydrocarbyl, O(C.sub.1-8 cyclohydrocarbyl), S(C.sub.1-8 cyclohydrocarbyl), NH(C.sub.1-8 cyclohydrocarbyl), N(C.sub.1-8 cyclohydrocarbyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), P(═O)(OC.sub.1-8 alkyl)(C.sub.1-8 alkyl), P(═O)(OC.sub.1-8 alkyl).sub.2, C.sub.1-8 alkynyl, CH═CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)═CH(C.sub.1-8 alkyl), C(C.sub.1-8alkyl)═C(C.sub.1-8alkyl).sub.2, Si(OH).sub.3, Si(C.sub.1-8 alkyl).sub.3, Si(OH)(C.sub.1-8 alkyl).sub.2, C(═O)(C.sub.1-8 alkyl), CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, SF.sub.5, SO.sub.2NH(C.sub.1-8 alkyl), SO.sub.2N(C.sub.1-8 alkyl).sub.2, S(═O)N(C.sub.1-8 alkyl).sub.2, C(═O)NH(C.sub.1-8 alkyl), C(═O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(═O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(═O)N(C.sub.1-8 alkyl).sub.2, NHC(═O)NH(C.sub.1-8 alkyl), NHC(═O)N(C.sub.1-8 alkyl).sub.2, NHC(═O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), NHSO.sub.2N(C.sub.1-8 alkyl).sub.2 and NHSO.sub.2NH.sub.2; X.sup.3 is selected from O, S, —NR— and —CHR—; R is selected from H and C.sub.1-3 alkyl substituted with 1 or 2 —OH; i is selected from integers between 1 and 6; Y is selected from —O—, —S— and —NR—, or is absent; and t is selected from integers between 1 and 100, and preferably, t is selected from integers between 1 and 50.

2. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the MAP4K family inhibitor is selected from a HPK1 inhibitor.

3. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the linking group L is ##STR00148## wherein s is selected from integers between 1 and 6; CON is selected from ##STR00149##  or is absent; W.sub.1 and W.sub.2 are independently selected from ##STR00150## n is selected from integers between 1 and 10, and preferably from integers between 1 and 4; m is selected from integers between 0 and 10, and preferably from integers between 2 and 7; X.sup.1 is selected from O, S and —NR—; and X.sup.2 is selected from O, S, —NR—, —S(O)—, —S(O).sub.2O—, —OS(O).sub.2— and —OS(O).sub.2O—.

4. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the linking group L is selected from ##STR00151## ##STR00152## ##STR00153## ##STR00154## Ar is selected from N-containing six-membered aryl; g is selected from 0 and 1; k is selected from integers between 1 and 10, and preferably from integers between 1 and 4; and p is selected from integers between 1 and 10, and preferably from integers between 1 and 2.

5. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the Cereblon protein ligand is selected from: an amide compound, a phthalimide compound, thalidomide and a derivative thereof, lenalidomide and a derivative thereof, and pomalidomide and a derivative thereof, and preferably, the Cereblon protein ligand moiety has a general formula as follows: ##STR00155## wherein C.sub.1, C.sub.2, C.sub.3 and C.sub.4 are independently selected from C and N; T is selected from O and S; V is selected from —O—, —S—, wherein R′ and R″ ##STR00156##  are independently selected from C.sub.0-10 alkyl, cyclohydrocarbyl and heterocyclohydrocarbyl; G and Z are independently selected from H, —OH, C.sub.1-10 linear/branched alkyl, C.sub.3-10 cyclohydrocarbyl, O-containing heterocyclohydrocarbyl, N-containing heterocyclohydrocarbyl and S-containing heterocyclohydrocarbyl; and q is selected from integers between 1 and 3, such as 1, 2 or 3.

6. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 5, wherein C.sub.1, C.sub.2, C.sub.3 and C.sub.4 are C; or, when C.sub.1 is C, at least one of C.sub.2, C.sub.3 and C.sub.4 is N; or, when C.sub.2 is C, at least one of C.sub.1, C.sub.3 and C.sub.4 is N; or, when C.sub.3 is C, at least one of C.sub.1, C.sub.2 and C.sub.4 is N; or, when C.sub.4 is C, at least one of C.sub.1, C.sub.2 and C.sub.3 is N.

7. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 6, wherein C.sub.1, C.sub.2, C.sub.3 and C.sub.4 are C; T is O; V is selected from —CH.sub.2—, ##STR00157##  and —NH—; and G and Z are independently selected from H, —CH.sub.3 and —CH.sub.2CH.sub.3.

8. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 7, wherein the Cereblon protein ligand moiety has a structural formula as follows: ##STR00158##

9. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the linking group L has a structure as follows: ##STR00159## ##STR00160## ##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166##

10. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 9, wherein the L is ##STR00167## ##STR00168## ##STR00169##

11. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the HPK1 inhibitor moiety has a general formula as follows: ##STR00170## ##STR00171## ##STR00172## the general formula of HPK1 has 3, 2 or 1 attachment site(s) of Cereblon protein ligands, and may be optionally attached to 3, 2 or 1 Cereblon protein ligand(s), with the rest attachment sites being replaced with —R′″; preferably, a position {circle around (1)}, a position {circle around (2)} and a position {circle around (3)} in the HPK1 inhibitor are all attachment sites of the Cereblon protein ligands, or the position {circle around (1)} and the position {circle around (2)} are attachment sites of the Cereblon protein ligands while the position {circle around (3)} is attached to R′″, or the position {circle around (2)} and the position {circle around (3)} are attachment sites of the Cereblon protein ligands while the position {circle around (1)} is attached to R′″, or the position {circle around (1)} and the position {circle around (3)} are attachment sites of the Cereblon protein ligands while the position {circle around (2)} is attached to R′″, or the position {circle around (1)} is an attachment site of the Cereblon protein ligand while the position {circle around (2)} and the position {circle around (3)} are attached to R′″, or the position {circle around (2)} is an attachment site of the Cereblon protein ligand while the position {circle around (1)} and the position {circle around (3)} are attached to R′″, or the position {circle around (3)} is an attachment site of the Cereblon protein ligand while the position {circle around (1)} and the position {circle around (2)} are attached to R′″, or the position {circle around (1)} and the position {circle around (2)} are attachment sites of the Cereblon protein ligands, or the position {circle around (1)} is an attachment site of the Cereblon protein ligand while the position {circle around (22)} is attached to R′″, or the position {circle around (2)} is an attachment site of the Cereblon protein ligand while the position {circle around (1)} is attached to R′″; wherein R′″ is selected from —H, halogen, —NO.sub.2, —CN, C.sub.1-5 linear/branched alkyl, C.sub.3-10 cyclohydrocarbyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —CF.sub.3, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F and —OC.sub.0-10 alkyl; A is selected from C and N; B is selected from C and N; Q is selected from O and S; x and z are independently selected from integers between 0 and 6; y is selected from 0 and 1; R.sub.0 is independently selected from: —H, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl and C.sub.3-10 cyclohydrocarbyl; R.sub.1 is selected from —O heterocycloalkyl, —N heterocycloalkyl, C.sub.1-10 linear/branched alkyl, C.sub.3-10 cyclo alkyl, —OC.sub.0-10 alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —SO.sub.2(C.sub.0-10 alkyl), —O(C.sub.0-10 alkyl), —O-phenyl, —S(C.sub.0-10 alkyl), —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl, wherein H on a C atom or heteroatom may be substituted with C.sub.1-3 linear alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl) and —CF.sub.3; R.sub.2 is selected from: —H, halogen, —NO.sub.2, —CN, C.sub.1-5 linear/branched alkyl, C.sub.3-10 cyclohydrocarbyl, —N(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —CF.sub.3, —OCF.sub.3, —OCHF.sub.2, —OCH.sub.2F and —OC.sub.0-10 alkyl; when B is N, R.sub.3 is absent; when B is C, R.sub.3 is selected from: —H, halogen, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl) and C.sub.3-10 cyclohydrocarbyl; R.sub.4 is selected from: —H, halogen, —OC.sub.0-10 alkyl, —CN, C.sub.3-10 cyclohydrocarbyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —O heterocyclohydrocarbyl and —N heterocyclohydrocarbyl; R.sub.10 is selected from: H, C.sub.1-5 linear/branched alkyl, C.sub.3-19 cyclohydrocarbyl and ##STR00173## R.sub.11 and R.sub.12 are independently selected from: —H, —CF.sub.3, —CHF.sub.2H, —CH.sub.2F, C.sub.1-10 linear/branched alkyl, —CH═C(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —C≡C(C.sub.0-10 alkyl), C.sub.3-10 cyclohydrocarbyl, an aromatic five-membered cyclic group and an aromatic six-membered cyclic group, or R.sub.11 and R.sub.12, together with carbon atoms between Rif and R.sub.12, form C.sub.3-8 cyclohydrocarbyl or C.sub.3-8 heterocyclohydrocarbyl containing —O or —S, C.sub.9 fused cyclohydrocarbyl, C.sub.3-7 cyclolactam, C.sub.3-7 cyclic lactone, or C.sub.3-7 cyclic ketone, wherein H on a C atom may be substituted with alkyl or halogen; R.sub.5 is selected from: —H, halogen, —CN, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, heteroalkyl containing O and N, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), C.sub.3-10 cyclohydrocarbyl, —C≡C—R.sub.10, —O heterocyclohydrocarbyl and —N heterocyclohydrocarbyl, wherein H attached to a C atom may be substituted with the following groups: —SO.sub.2, —SO.sub.2N(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —N(C.sub.0-10alkyl), —CON(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)CO(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)COO(C.sub.0-10 alkyl), —OCON(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), halogen, —CN, —OCH.sub.2F, —OCHF.sub.2, —OCF.sub.3, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl, C.sub.3-10 cyclohydrocarbyl, —O heterocycloalkyl, —N heterocycloalkyl, —N heterocycloaryl, —0 heterocycloaryl and —S heterocycloaryl; R.sub.8 and R.sub.9 are independently selected from: —H, halogen and C.sub.1-10 linear/branched alkyl; A′ is selected from C and N; B.sub.1, B.sub.2, B.sub.3, B.sub.4 or B.sub.5 is independently selected from C and N; Q is selected from O and S; x′ and z′ are independently selected from integers between 0 and 6; y′ is selected from 0 and 1; R.sub.0′ is independently selected from: —H, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl and C.sub.3-10 cyclohydrocarbyl; R.sub.1′ is selected from: —O heterocycloalkyl, —N heterocycloalkyl, C.sub.1-10 linear/branched alkyl, C.sub.3-10 cyclohydrocarbyl, —OC.sub.0-10 alkyl, —N(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —SO.sub.2(C.sub.0-10 alkyl), —O(C.sub.0-10 alkyl), —O-phenyl, —S(C.sub.0-10 alkyl), —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl, wherein H attached to a C atom or heteroatom may be substituted with C.sub.1-3 linear alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl) or —CF.sub.3; R.sub.2′ is selected from: —H, halogen, —NO.sub.2, —CN, C.sub.1-5 linear/branched alkyl, C.sub.3-10 cyclohydrocarbyl, —N(C.sub.0-10 alkyl) (C.sub.0-10alkyl), —CF.sub.3, —OCHF.sub.2, —OCH.sub.2F and —OC.sub.0-10 alkyl; when B.sub.1, B.sub.2, B.sub.3, B.sub.4 or B.sub.5 is N, the corresponding R.sub.3′, R.sub.4′ and R.sub.5′ is absent; when B.sub.1, B.sub.2, B.sub.3, B.sub.4 or B.sub.5 is C, R.sub.3′, R.sub.4′ and R.sub.5′ are independently selected from: —H, halogen, —CN, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, heteroalkyl containing O and N, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), C.sub.3-10 cyclohydrocarbyl, —O heterocyclohydrocarbyl and —N heterocyclohydrocarbyl, or R.sub.5′ and R.sub.4′, or R.sub.4′ and R.sub.3′, together with carbon atoms therebetween, form C.sub.3-8 cyclohydrocarbyl or C.sub.3-8 heterocycloalkyl containing —O— and —S—, —N heterocycloaryl, —O heterocycloaryl or —S heterocycloaryl, or phenyl, wherein H attached to a C atom may be substituted with the following groups: —SO.sub.2, —SO.sub.2N(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)SO.sub.2(C.sub.0-10 alkyl), —CON(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)C.sub.0 (C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)COO(C.sub.0-10 alkyl), —OCON(C.sub.0-10alkyl)(C.sub.0-10 alkyl), halogen, —CN, —OCH.sub.2F, —OCHF.sub.2, —OCF.sub.3, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl, C.sub.3-10 cyclohydrocarbyl, —O heterocycloalkyl, —N heterocycloalkyl, —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl; R.sub.5′ and R.sub.9′ are independently selected from: —H, halogen and C.sub.1-10 linear/branched alkyl; R.sub.35, R.sub.36, R.sub.38 and R.sub.39 are selected from C.sub.1-10 linear/branched alkyl, —CON(C.sub.0-10 alkyl)-, —CO(C.sub.0-10 alkyl)-, C.sub.3-10 cyclohydrocarbyl, —O heterocycloalkyl, —N heterocycloalkyl, phenyl, —N heterocycloaryl and —O heterocycloaryl, and R.sub.37, together with an N atom attached thereto and a C atom adjacent to the N atom, forms 5-8 membered cyclolactam; and R.sub.13-R.sub.34 are independently selected from: —H, halogen, —CN, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), C.sub.3-10 cyclohydrocarbyl, —O heterocycloalkyl, —N heterocycloalkyl, —S heterocycloalkyl, phenyl, —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl.

12. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 11, wherein x and z are independently selected from integers between 0 and 2, such as 0, 1 or 2; the HPK1 inhibitor moiety has a structural formula as follows: ##STR00174##

13. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 12, wherein R.sub.0 is independently selected from: C.sub.1-5 linear/branched alkyl and —N(C.sub.0-10alkyl)(C.sub.0-10 alkyl); R.sub.1 is selected from: —O heterocycloalkyl and —N heterocycloalkyl, —SO.sub.2(C.sub.0-3 alkyl), —O-phenyl, —S(C.sub.0-4 alkyl), C.sub.3-6 cycloalkyl and C.sub.3-5 linear/branched alkyl, wherein H attached to a C atom or heteroatom may be substituted with —CH.sub.3, —NH.sub.2 or —CF.sub.3; R.sub.2 is selected from: —NO.sub.2, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl and —OCF.sub.3; R.sub.3 is selected from: —H, halogen, —OC.sub.0-10 alkyl and C.sub.1-10 linear/branched alkyl; R.sub.4 is selected from: —H, halogen, —OC.sub.0-10 alkyl, —CN, C.sub.3-19 cycloalkyl and —C≡C—R.sub.10; R.sub.11 and R.sub.12 are independently selected from: —H, —CF.sub.3, —CHF.sub.2H, —CH.sub.2F, C.sub.1-10 linear/branched alkyl, —CH═C(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), C.sub.3-10 cycloalkyl and an aromatic six-membered cyclic group, or R.sub.11 and R.sub.12, together with carbon atoms between R.sub.11 and R.sub.12, form C.sub.3-8 cycloalkyl, C.sub.4-7 fused cycloalkyl, C.sub.3-7 cyclolactam, C.sub.3-7 cyclic lactone, or C.sub.3-7 cyclic ketone, wherein H attached to a C atom may be substituted with alkyl or —F; R.sub.5 is selected from: —H, halogen, C.sub.3-6 cycloalkyl, —OC.sub.0-5 alkyl, C.sub.1-5 linear/branched alkyl and C.sub.1-5 linear/branched alkyl containing O and N, wherein H attached to a C atom may be substituted with —F; and R.sub.8 and R.sub.9 are independently selected from: —H and C.sub.1-10 linear/branched alkyl.

14. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 13, wherein R.sub.0 is independently selected from: —CH.sub.3, —CH.sub.2CH.sub.3 and —NH.sub.2; R.sub.1 is selected from: ##STR00175## R.sub.2 is selected from: —NH.sub.2 and —NO.sub.2; R.sub.3 is selected from: —H, —F and —OCH.sub.3; R.sub.4 is selected from: —H, —F, —Cl, —OCH.sub.3, —CN, ##STR00176##  and —C≡C—R.sub.10; R.sub.11 and R.sub.12 are independently selected from: —H, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —CH.sub.3, —CH.sub.2CH.sub.3, —CH═CH.sub.2, or ##STR00177## R.sub.11 and R.sub.12, together with carbon atoms between R.sub.11 and R.sub.12, form ##STR00178## R.sub.5 is selected from: —H, halogen, —OC.sub.0-3 alkyl, C.sub.1-3 linear/branched alkyl and C.sub.1-3 linear/branched alkyl containing N, wherein H attached to a C atom may be substituted with —F, and preferably, R.sub.5 is selected from: —H, —F, —Cl, —CH.sub.3, —CH.sub.2NH.sub.2, —CN and —OCH.sub.3; and R.sub.8 and R.sub.9 are independently selected from: —H and —CH.sub.3.

15. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 11, wherein B.sub.1, B.sub.2, B.sub.3, B.sub.4 or B.sub.5 is C, or, at least one of B.sub.1, B.sub.2, B.sub.3, B.sub.4 and B.sub.5 is N; preferably, B.sub.2 is C, at least one of B.sub.1, B.sub.3, B.sub.4 and B.sub.5 is N, or B.sub.2 is C, and B.sub.1 is N; B.sub.2 is C, and B.sub.3 is N; B.sub.2 is C, and B.sub.4 is N; B.sub.2 is C, and B.sub.5 is N, or B.sub.2 is C, B.sub.3 and B.sub.4 are N, or B.sub.3 and B.sub.5 are N; x′ and z′ are independently selected from integers between 0 and 2, such as 0, 1 or 2; the HPK1 inhibitor moiety has a structural formula as follows: ##STR00179## ##STR00180## R.sub.0′ is independently selected from: C.sub.1-5 linear/branched alkyl and —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl); R.sub.1′ is selected from: —O heterocycloalkyl and —N heterocycloalkyl, —SO.sub.2(C.sub.0-3 alkyl), —O-phenyl, —S(C.sub.0-4 alkyl), C.sub.3-6 cycloalkyl and C.sub.3-5 linear/branched alkyl, wherein H attached to a C atom or heteroatom may be substituted with —CH.sub.3, —NH.sub.2 or —CF.sub.3; R.sub.2′ is selected from: —NO.sub.2, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl and —OCF.sub.3; R.sub.3′ is selected from: —H, halogen, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl) and C.sub.3-10 cycloalkyl; R.sub.4′ is selected from: —H, halogen, —OC.sub.0-10 alkyl, —CN, C.sub.3-10 cycloalkyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —O heterocycloalkyl and —N heterocycloalkyl; R.sub.5′ is independently selected from: —H, halogen, —CN, —OC.sub.0-10 alkyl, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), C.sub.3-10 cycloalkyl, —O heterocycloalkyl and —N heterocycloalkyl, and C.sub.1-5 linear/branched alkyl containing 0 and N, wherein H attached to a C atom may be substituted with —F; R.sub.10′ is selected from: H, C.sub.1-5 linear/branched alkyl, C.sub.3-10 cycloalkyl and ##STR00181## R.sub.11′ and R.sub.12′ are independently selected from: —H, —CF.sub.3, —CHF.sub.2H, —CH.sub.2F, C.sub.1-10 linear/branched alkyl, —CH═C(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —C≡C(C.sub.0-10 alkyl), C.sub.3-10 cycloalkyl, an aromatic five-membered cyclic group and an aromatic six-membered cyclic group, or R.sub.11′ and R.sub.12′, together with carbon atoms between and R.sub.12′, form C.sub.3-8 cycloalkyl or C.sub.3-8 heterocycloalkyl containing —O and —S, C.sub.4-9 fused cycloalkyl, C.sub.5-10 spiro cycloalkyl, C.sub.4-9 bridged cycloalkyl, C.sub.3-7 cyclolactam, C.sub.3-7 cyclic lactone, or C.sub.3-7 cyclic ketone, wherein H attached to a C atom may be substituted with the following groups: —SO.sub.2, —SO.sub.2N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)SO.sub.2(C.sub.0-10 alkyl), —CON(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)CO(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)COO(C.sub.0-10 alkyl), —OCON(C.sub.0-10 alkyl) (C.sub.0-10 alkyl), halogen, —CN, —OCH.sub.2F, —OCHF.sub.2, —OCF.sub.3, C.sub.1-10 linear/branched alkyl, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl, C.sub.3-10 cycloalkyl, —O heterocycloalkyl, —N heterocycloalkyl, —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl, wherein the alkyl moieties may be optionally substituted with one or more of the following groups: —SO.sub.2, —SO.sub.2N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)SO.sub.2(C.sub.0-10 alkyl), —CON(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)CO(C.sub.0-10 alkyl), —N(C.sub.0-10 alkyl)COO(C.sub.0-10 alkyl), —OCON(C.sub.0-10alkyl)(C.sub.0-10 alkyl), halogen, —CN, —OCH.sub.2F, —OCHF.sub.2, —OCF.sub.3, —N(C.sub.0-10 alkyl)(C.sub.0-10 alkyl), —OC.sub.0-10 alkyl, —N heterocycloaryl, —O heterocycloaryl and —S heterocycloaryl; and R.sub.8′ and R.sub.9′ are independently selected from: —H and C.sub.1-10 linear/branched alkyl.

16. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 15, wherein R.sub.0′ is independently selected from: —CH.sub.3, —CH.sub.2CH.sub.3 and —NH.sub.2; R.sub.1′ is selected from: ##STR00182## R.sub.2′ is selected from: —NH.sub.2 and —NO.sub.2; R.sub.3′ is selected from: —H, halogen, —OC.sub.0-10 alkyl and C.sub.1-10 linear/branched alkyl; R.sub.4′ is selected from: —H, —F, —Cl, —OCH.sub.3, —CN, ##STR00183##  and —C≡C—R.sub.10′; R.sub.5′ is selected from: —H, —F, —Cl, —CH.sub.3, —CH.sub.2NH.sub.2, —CN and —OCH.sub.3; R.sub.11′ and R.sub.12′ are independently selected from: —H, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, —CH.sub.3, —CH.sub.2CH.sub.3, —CH═CH.sub.2, ##STR00184##  or R.sub.11′ and R.sub.12′, together with carbon atoms between R.sub.11 and R.sub.12′, form ##STR00185##  and R.sub.8′ and R.sub.9′ are independently selected from: —H and —CH.sub.3.

17. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 16, wherein R.sub.13-R.sub.34 are independently selected from: —H, halogen, —CN, C.sub.1-4 linear/branched alkyl, —N(C.sub.0-10alkyl)(C.sub.0-10alkyl) and C.sub.3-5 cycloalkyl, and preferably, R.sub.13-R.sub.34 are independently selected from: —H, —F, —Cl, —CN, —CH.sub.3, —CH.sub.2CH.sub.3, —NH.sub.2, ##STR00186##

18. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the HPK1 inhibitor moiety has a structure selected from: ##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196##

19. The compound, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, wherein the compound has a structural formula selected from: ##STR00197## ##STR00198## ##STR00199## ##STR00200##

20. A pharmaceutical composition, comprising the compound of general formula I, or the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1, and further comprising a pharmaceutically acceptable excipient.

21. Use of the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 for preparing a medicament for inhibiting the serine/threonine kinase family, and preferably for preparing a medicament for inhibiting hematopoietic progenitor kinase 1.

22. Use of the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 for preparing a medicament for treating a disease associated with hematopoietic progenitor kinase 1, wherein the disease associated with hematopoietic progenitor kinase 1 is selected from: inflammation, immune disease and cancer; the immune disease is selected from: lupus erythematosus, glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes; the cancer is selected from: lymphoma, blastoma, medulloblastoma, retinoblastoma, sarcoma, liposarcoma, synovial cell sarcoma, neuroendocrine tumor, carcinoid tumor, gastrinoma, islet cell carcinoma, mesothelioma, schwannoma, acoustic neuroma, meningioma, adenocarcinoma, melanoma, leukemia and lymphoid malignancy, squamous cell carcinoma, epithelial squamous cell carcinoma, lung carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, adenocarcinoma lung carcinoma, squamous lung carcinoma, peritoneal carcinoma, hepatocellular carcinoma, gastric carcinoma, intestinal carcinoma, pancreatic carcinoma, glioblastoma, cervical carcinoma, ovarian carcinoma, liver carcinoma, bladder carcinoma, liver carcinoma, breast carcinoma, metastatic breast carcinoma, colon carcinoma, rectal carcinoma, colorectal carcinoma, uterine carcinoma, salivary gland carcinoma, kidney carcinoma, prostate carcinoma, vulval carcinoma, thyroid carcinoma, liver carcinoma, anal carcinoma, penile carcinoma, Merkel cell carcinoma, esophageal carcinoma, biliary tract carcinoma, head and neck carcinoma, and hematological malignancies.

23. The use according to claim 21, wherein the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof are used alone or in combination with other pharmaceutical formulations and/or therapeutic methods; the other pharmaceutical formulations are selected from: PD-1, PD-L1, CTLA-4, TIM-3, TGF-β and receptors thereof, LAG3 antagonists and TLR4, TLR7, TLR8, TLR9, and STING agonists; the other therapeutic methods are selected from: radiotherapy and immunotherapy.

24. Use of the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 for preventing and/or treating cancer, immune disease and inflammation.

25. Use of the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 in cancer immunotherapy in combination with PD-1, PD-L1, CTLA-4, TIM-3, TGF-β and receptors thereof, LAG3 antagonists or TLR4, TLR7, TLR8, TLR9, and STING agonists.

26. Use of the compound of general formula I, and the pharmaceutically acceptable salt, the stereoisomer, the ester, the prodrug, the solvate and the deuterated compound thereof according to claim 1 in cancer immunotherapy in combination with CAR-T immunotherapy.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0154] FIG. 1 is a graph showing expression of HPK1 when treated with Compounds C.sub.1, C.sub.2 and C.sub.3.

DETAILED DESCRIPTION

[0155] The technical solutions in the examples of the present invention will be described clearly and completely below, and it is apparent that the examples described herein are only some examples of the present invention, but not all of them. Based on the examples of the present invention, all other examples obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present invention.

Example 1: Preparation of Compound C1

[0156] ##STR00068##

[0157] To a 250-mL round-bottom flask were added 3-hydroxyphthalic anhydride (2 g, 12.2 mmol, 1.0 equiv), 3-amino-2,6-piperidinedione hydrochloride (2 g, 12.2 mmol, 1.0 equiv) and an appropriate amount of toluene, and after thorough mixing, the resulting mixture was added with triethylamine (1860 uL, 13.4 mmol, 1.1 equiv), heated to reflux for 12 h, and then the heating was stopped. After the reaction system was returned to room temperature, toluene was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:40, v/v) to give a final product 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (1.9032 g, yield: 57%) in the form of a pale yellow solid.

[0158] NMR: .sup.1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 11.07 (s, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.29 (d, J=7.1 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.05 (dd, J=12.8, 5.1 Hz, 1H), 3.04-2.73 (m, 1H), 2.68-2.34 (m, 1H), 2.17-1.73 (m, 1H). .sup.13C NMR (100 MHz, DMSO) δ 173.28, 170.49, 167.50, 166.30, 155.94, 136.86, 133.63, 124.03, 114.84, 114.77, 49.11, 31.60, 22.80.

##STR00069##

[0159] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (100 mg, 0.4 mmol, 1.0 equiv), potassium iodide (6.1 mg, 0.03 mmol, 0.1 equiv) and sodium hydrogencarbonate (61.3 mg, 0.4 mmol, 2.0 equiv) were dissolved in DMF, 8-bromo-1-octanol (100.4 mg, 0.48 mmol, 1.2 equiv) was added to the reaction system, and then the reaction system was heated to 80° C. and reacted overnight. The heating was stopped, the reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (103.6 mg, yield: 64%); LC-MS: m/z=403.

##STR00070##

[0160] 2-1 (92.6 mg, 0.23 mmol, 1.0 equiv) and a Sarrett reagent PCC (99.2 mg, 0.46 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The resulting reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product 2-2 (91 mg, yield: 99%); LC-MS: m/z=401.

##STR00071##

[0161] 2-2 (54.3 mg, 0.14 mmol, 1.0 equiv) and potassium monopersulfate compound (Oxone) (83.4 mg, 0.14 mol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The resulting reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation to give a final product 2-3 (47.9 mg, yield: 82%); LC-MS: m/z=417.

##STR00072##

[0162] 2-3 (10 mg, 0.024 mmol, 1.1 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with benzotriazole-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU) (18.3 mg, 0.048 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (9.3 mg, 0.072 mmol, 3.0 equiv) and Compound 1 (10 mg, 0.022 mmol, 1.0 equiv), (for the preparation method of Compound 1, refer to patent application NOs. CN 201810945948.2 and CN 201810946081.2), then heated to room temperature, and stirred overnight. The resulting reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product 2-4 (17 mg, yield: 91.3%); LC-MS: m/z=847.

[0163] NMR: .sup.1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.89 (s, 1H), 7.85-7.72 (m, 2H), 7.63-7.46 (m, 3H), 7.41 (dd, J=16.7, 7.8 Hz, 2H), 7.34 (m, J=7.5 Hz, 2H), 6.10 (s, 2H), 5.48 (s, 1H), 5.22 (s, 2H), 5.09 (dd, J=12.8, 5.2 Hz, 1H), 4.43 (d, J=12.7 Hz, 1H), 4.19 (s, 2H), 3.93 (d, J=13.0 Hz, 1H), 3.20 (dt, J=24.9, 11.5 Hz, 2H), 3.01-2.80 (m, 1H), 2.72 (t, J=12.1 Hz, 1H), 2.66-2.43 (m, 2H), 2.33 (t, J=7.1 Hz, 2H), 2.04 (dd, J=21.1, 13.0 Hz, 3H), 1.85-1.70 (m, 2H), 1.69-1.58 (m, 1H), 1.58-1.49 (m, 4H), 1.47 (s, 6H), 1.32 (m, 4H), 1.24-1.11 (m, 1H). .sup.13C NMR (101 MHz, DMSO) δ 173.24, 171.83, 170.95, 170.42, 167.31, 165.77, 156.47, 151.49, 140.68, 137.66, 137.46, 137.09, 136.93, 135.88, 133.70, 131.14, 130.71, 129.25, 128.00, 123.19, 120.21, 116.67, 116.33, 115.56, 115.06, 96.78, 80.67, 69.25, 69.19, 64.07, 49.20, 45.10, 41.14, 33.07, 32.77, 32.40, 32.06, 31.44, 29.21, 28.99, 28.86, 25.70, 25.30, 22.48. 13C NMR (101 MHz, DMSO) δ 173.24, 171.83, 170.95, 170.42, 167.31, 165.77, 156.47, 151.49, 140.68, 137.66, 137.46, 137.09, 136.93, 135.88, 133.70, 131.14, 130.71, 129.25, 128.00, 123.19, 120.21, 116.67, 116.33, 115.56, 115.06, 96.78, 80.67, 69.25, 69.19, 64.07, 49.20, 45.10, 41.14, 33.07, 32.77, 32.40, 32.06, 31.44, 29.21, 28.99, 28.86, 25.70, 25.30, 22.48, 21.78, 14.55.

Example 2: Preparation of Compound C2

[0164] ##STR00073##

[0165] C1 (12 mg, 0.014 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, potassium carbonate (3.9 mg, 0.021 mmol, 1.5 equiv) and iodomethane (2.4 mg, 0.017 mmol, 1.2 equiv) were sequentially added, and the resulting mixture was stirred at room temperature overnight. When the reaction was completed, the resulting reaction system was diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funne, concentrated by rotary evaporation, and purified by silica gel column chromatography purification (methanol:dichloromethane=1:20, v/v) to give a final product 2-5 (8.2 mg, yield: 68%); LC-MS: m/z=861.

[0166] NMR: .sup.1H NMR (400 MHz, DMSO) δ 7.88 (s, 1H), 7.84-7.77 (m, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.56-7.48 (m, 3H), 7.45-7.36 (m, 2H), 7.36-7.30 (m, 2H), 6.09 (s, 2H), 5.46 (s, 1H), 5.21 (s, 2H), 5.15 (dd, J=13.0, 5.4 Hz, 1H), 4.42 (d, J=12.9 Hz, 1H), 4.20 (t, J=6.3 Hz, 2H), 3.93 (d, J=13.5 Hz, 1H), 3.29-3.09 (m, 3H), 2.98 (s, 3H), 2.96-2.87 (m, 1H), 2.81-2.65 (m, 2H), 2.62-2.51 (m, 2H), 2.33 (t, J=7.3 Hz, 2H), 2.12-1.97 (m, 3H), 1.83-1.69 (m, 2H), 1.69-1.56 (m, 1H), 1.57-1.47 (m, 3H), 1.45 (s, 6H), 1.44-1.40 (m, 1H), 1.30-1.15 (m, 3H). .sup.13C NMR (101 MHz, DMSO) δ 172.24, 171.87, 170.97, 170.17, 167.30, 165.78, 156.53, 151.50, 140.70, 137.68, 137.52, 137.08, 136.96, 135.89, 133.71, 131.15, 130.73, 129.27, 128.02, 123.20, 120.28, 116.68, 116.34, 115.60, 115.13, 96.80, 80.68, 69.29, 69.21, 64.08, 49.78, 45.11, 41.14, 33.08, 33.07, 32.77, 32.40, 32.07, 31.58, 29.20, 28.98, 28.86, 27.07, 25.71, 25.30, 21.68.

Example 3: Preparation of Compound C3

[0167] ##STR00074##

[0168] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (300 mg, 1.1 mmol, 1.0 equiv), potassium iodide (18.2 mg, 0.1 mmol, 0.1 equiv) and sodium bicarbonate (183.8 mg, 2.2 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 10-bromo-1-decanol (314 mg, 1.32 mmol, 1.2 equiv), heated to 80° C. and reacted overnight. The heating was stopped, the resulting reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (253.3 mg, yield: 53%); LC-MS: m/z=431.

##STR00075##

[0169] 3-1 (190 mg, 0.32 mmol, 1.0 equiv) and PCC (190 mg, 0.64 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The resulting reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product 3-2 (135.5 mg, yield: 99%); LC-MS: m/z=429.

##STR00076##

[0170] 3-2 (135.5 mg, 0.32 mmol, 1.0 equiv) and Oxone (197 mg, 0.32 mmol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The resulting reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product 3-3 (112.6 mg, yield: 79%); LC-MS: m/z=445.

##STR00077##

[0171] 3-3 (12.2 mg, 0.028 mmol, 1.1 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (19 mg, 0.05 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (9.7 mg, 0.075 mmol, 3.0 equiv) and Compound 1 (11 mg, 0.025 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The resulting reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product 3-4 (15.7 mg, yield: 72%); LC-MS: m/z=875.

[0172] NMR: .sup.1H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 7.89 (s, 1H), 7.84-7.77 (m, 1H), 7.76 (s, 1H), 7.53 (s, 2H), 7.47 (dd, J=25.3, 7.9 Hz, 2H), 7.42-7.36 (m, 1H), 7.34 (d, J=7.4 Hz, 2H), 6.11 (s, 2H), 5.49 (s, 1H), 5.22 (s, 2H), 5.09 (dd, J=12.9, 5.2 Hz, 1H), 4.43 (d, J=12.2 Hz, 1H), 4.19 (t, J=6.2 Hz, 2H), 3.93 (d, J=13.5 Hz, 1H), 3.30-3.11 (m, 4H), 2.99-2.78 (m, 2H), 2.78-2.65 (m, 1H), 2.64-2.53 (m, 2H), 2.35-2.25 (m, 2H), 2.14-1.92 (m, 4H), 1.83-1.48 (m, 6H), 1.47 (s, 6H), 1.43-1.32 (m, 3H), 1.24-1.15 (m, 4H). .sup.13C NMR (101 MHz, DMSO) δ 173.28, 171.84, 170.96, 170.44, 167.32, 165.77, 156.47, 151.49, 140.65, 137.67, 137.49, 137.08, 136.93, 135.89, 133.69, 131.13, 130.71, 129.26, 128.10, 128.02, 123.16, 120.21, 116.65, 116.29, 115.58, 115.06, 115.03, 96.77, 80.66, 69.22, 69.14, 64.06, 49.18, 45.11, 41.13, 33.08, 32.80, 32.42, 32.05, 31.42, 29.37, 29.27, 29.24, 29.09, 28.87, 25.73, 25.37, 22.46.

Example 4: Preparation of Compound C4

[0173] ##STR00078##

[0174] C3 (15.7 mg, 0.018 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, potassium carbonate (3.7 mg, 0.027 mmol, 1.5 equiv) and iodomethane (3.1 mg, 0.022 mmol, 1.2 equiv) were sequentially added, and the resulting mixture was stirred at room temperature overnight. When the reaction was completed, the resulting reaction system was diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, concentrated by rotary evaporation, and purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (10.4 mg, yield: 65%); LC-MS: m/z=889.

Example 5: Preparation of Compound C5

[0175] ##STR00079##

[0176] To a solution of triethylene glycol (5.9 g, 39 mmol, 5.0 equiv) in acetonitrile were added tert-butyl acrylate (1 g, 7.8 mmol, 1.0 equiv) and benzyltrimethylammonium hydroxide (Triton B) (121 mg, 0.29 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1, v/v) to give a target product 4-1 (1.6632 g, yield: 77%) in the form of an oily liquid.

##STR00080##

[0177] Triphenylphosphine (1007.2 mg, 3.84 mmol, 1.2 equiv), imidazole (261.4 mg, 3.84 mmol, 1.2 equiv) and iodine (1218.3 mg, 4.8 mmol, 1.5 equiv) were dissolved in tetrahydrofuran (extra dry) under argon atmosphere, after thorough mixing, the resulting mixture was added dropwise with 4-1 (900 mg, 3.2 mmol, 1.0 equiv), and stirred at room temperature for 3 h, followed by TLC detection and color development with KMnO.sub.4. After the reaction was completed, the white precipitate was removed by filtration, and the residue was concentrated on a rotary evaporator and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product 4-2 (1208.8 mg, yield: 97%) in the form of a brown oily liquid.

##STR00081##

[0178] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (181 mg, 0.66 mmol, 1.0 equiv) and cesium carbonate (644 mg, 1.98 mmol, 3.0 equiv) were dissolved in DMF, and the resulting mixture was added dropwise with 4-2 (307.5 mg, 0.79 mmol, 1.2 equiv), heated to 50° C. and stirred overnight. When the reaction was completed, the resulting reaction system was diluted with an appropriate amount of ethyl acetate, and sequentially extracted with a mixed solution of water and a saturated sodium bicarbonate solution (water:saturated sodium bicarbonate solution=1:5, v/v) and saturated saline. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, concentrated by rotary evaporation, and purified by silica gel column chromatography (acetone:petroleum ether=1:2, v/v) to give a final product 4-3 (194 mg, yield: 55%); LC-MS: m/z=535.

##STR00082##

[0179] 4-3 (40 mg, 0.075 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator, and the residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 4-4 (35.4 mg) which was used in the next step directly without further purification; LC-MS: m/z=479.

##STR00083##

[0180] 4-4 (23.7 mg, 0.05 mmol, 1.1 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and Compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (20.1 mg, yield: 51%); LC-MS: m/z=909.

[0181] NMR: .sup.1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.77 (s, 1H), 7.71-7.61 (m, 1H), 7.53 (s, 2H), 7.39 (m, 3H), 7.29 (dd, J=25.0, 7.8 Hz, 2H), 6.10 (s, 2H), 5.48 (s, 1H), 5.22 (s, 2H), 5.16 (dd, J=13.0, 5.3 Hz, 1H), 4.42 (d, J=13.2 Hz, 1H), 3.97 (d, J=13.1 Hz, 1H), 3.83 (m, 2H), 3.64 (t, J=6.6 Hz, 2H), 3.50 (d, J=6.0 Hz, 6H), 3.43 (t, J=6.6 Hz, 2H), 3.27-3.08 (m, 2H), 3.07-2.85 (m, 2H), 2.72 (dd, J=24.3, 12.1 Hz, 2H), 2.60 (m, 2H), 2.13-1.92 (m, 4H), 1.76-1.53 (m, 2H), 1.47 (s, 6H). .sup.13C NMR (101 MHz, DMSO) δ 171.98, 171.85, 170.00, 169.10, 167.44, 165.41, 156.04, 151.49, 148.07, 140.68, 137.89, 137.67, 137.10, 136.93, 136.85, 135.88, 133.59, 132.78, 131.13, 130.71, 130.11, 129.25, 128.01, 124.09, 123.18, 121.86, 118.15, 117.33, 116.33, 115.08, 114.79, 114.72, 96.78, 95.65, 88.52, 80.67, 70.24, 70.14, 70.07, 69.18, 67.36, 67.18, 64.07, 49.71, 33.28, 32.06, 31.59, 29.55, 29.49, 29.44, 22.56, 21.73.

Example 6: Preparation of Compound C6

[0182] ##STR00084##

[0183] C5 (10 mg, 0.011 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, potassium carbonate (2.3 mg, 0.017 mmol, 1.5 equiv) and iodomethane (2 mg, 0.013 mmol, 1.2 equiv) were sequentially added, and the resulting mixture was stirred at room temperature overnight. When the reaction was completed, the resulting reaction system was diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, concentrated by rotary evaporation, and purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (10.2 mg, yield: 81%); LC-MS: m/z=923.

[0184] NMR: 1H NMR (400 MHz, CDCl.sub.3) δ 7.83 (s, 1H), 7.72-7.65 (m, 1H), 7.64 (s, 1H), 7.50 (s, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.42-7.30 (m, 3H), 7.22 (d, J=8.5 Hz, 1H), 7.06 (d, J=1.4 Hz, 1H), 5.34 (t, J=4.7 Hz, 1H), 5.08 (s, 2H), 4.97 (dd, J=12.1, 5.7 Hz, 1H), 4.92 (s, 2H), 4.65 (d, J=13.3 Hz, 1H), 4.08-3.97 (m, 5H), 3.79 (t, J=6.8 Hz, 2H), 3.66-3.55 (m, 9H), 3.25-3.13 (m, 2H), 3.01-2.87 (m, 1H), 2.83-2.71 (m, 3H), 2.71-2.64 (m, 2H), 2.24-1.99 (m, 5H), 1.82-1.70 (m, 2H), 1.62 (s, 6H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.58, 171.10, 169.57, 168.71, 167.23, 166.12, 157.09, 150.22, 141.28, 137.24, 136.88, 136.73, 136.10, 135.78, 133.97, 131.83, 131.08, 130.05, 128.93, 127.62, 123.51, 118.09, 117.92, 117.20, 115.98, 115.24, 94.83, 81.61, 70.62, 70.12, 67.64, 67.58, 65.63, 56.51, 45.61, 41.50, 40.76, 39.42, 36.06, 33.78, 32.87, 32.11, 31.61, 29.46, 27.35, 25.67, 22.83, 22.12.

Example 7: Preparation of Compound C7

[0185] ##STR00085##

[0186] To a solution of tetraethylene glycol (5.9 g, 39 mmol, 5.0 equiv) in acetonitrile were added tert-butyl acrylate (1 g, 7.8 mmol, 1.0 equiv) and Triton B (121 mg, 0.29 mmol, 1.0 equiv, 40% aqueous solution), and the resulting was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=2:1, v/v) to give a target product (1.8954 g, yield: 75%) in the form of an oily liquid.

##STR00086##

[0187] Triphenylphosphine (879.7 mg, 3.4 mmol, 1.2 equiv), imidazole (228.3 mg, 3.4 mmol, 1.2 equiv) and iodine (1064 mg, 4.2 mmol, 1.5 equiv) were dissolved in tetrahydrofuran (extra dry) under argon atmosphere, after thorough mixing, the resulting mixture was added dropwise with 4-1 (900 mg, 2.8 mmol, 1.0 equiv), and stirred at room temperature for 3 h, followed by TLC detection and color development with KMnO.sub.4. After the reaction was completed, the white precipitate was removed by filtration, and the residue was concentrated on a rotary evaporator, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (1150.6 mg, yield: 95%) in the form of a brown oily liquid.

##STR00087##

[0188] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (470.7 mg, 1.7 mmol, 1.0 equiv) and cesium carbonate (1678 mg, 5.2 mmol, 3.0 equiv) were dissolved in DMF, and the resulting mixture was added dropwise with 5-2 (307.5 mg, 0.79 mmol, 1.2 equiv), heated to 50° C. and stirred overnight. When the reaction was completed, the resulting reaction system was diluted with an appropriate amount of ethyl acetate, and sequentially extracted with a mixed solution of water and a saturated sodium bicarbonate solution (water:saturated sodium bicarbonate solution=1:5, v/v) and saturated saline. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, concentrated by rotary evaporation, and purified by silica gel column chromatography (acetone:petroleum ether=1:2, v/v) to give a final product (463.1 mg, yield: 47%); LC-MS: m/z=579.

##STR00088##

[0189] 5-3 (40 mg, 0.084 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator, and the residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 5-4 (43.6 mg) which was used in the next step directly without further purification; LC-MS: m/z=523.

##STR00089##

[0190] 5-4 (26 mg, 0.05 mmol, 1.1 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The resulting reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation, and the crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product 5-5 (22.6 mg, yield: 44%); LC-MS: m/z=953.

[0191] NMR: .sup.1H NMR (400 MHz, DMSO) δ 7.91 (d, J=12.6 Hz, 1H), 7.77 (d, J=1.7 Hz, 1H), 7.70-7.60 (m, 1H), 7.54 (m, 2H), 7.47-7.32 (m, 3H), 7.27 (dd, J=22.9, 7.8 Hz, 2H), 6.10 (s, 2H), 5.22 (s, 2H), 5.16 (dd, J=13.0, 5.4 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H), 3.97 (d, J=13.4 Hz, 1H), 3.84 (m, 2H), 3.63 (t, J=6.7 Hz, 2H), 3.46-3.12 (m, 12H), 3.06-2.89 (m, 1H), 2.86-2.66 (m, 2H), 2.66-2.52 (m, 2H), 2.02 (dd, J=19.6, 16.5 Hz, 3H), 1.75-1.51 (m, 2H), 1.47 (s, 6H). .sup.13C NMR (101 MHz, DMSO) δ 172.03, 171.93, 170.02, 169.20, 167.50, 166.38, 156.38, 151.47, 140.70, 137.65, 137.07, 136.94, 136.85, 135.87, 133.58, 131.17, 130.70, 129.28, 128.02, 124.27, 123.18, 116.38, 115.09, 114.73, 114.56, 99.99, 96.76, 80.69, 70.24, 70.22, 70.14, 70.12, 70.06, 69.20, 67.34, 67.19, 64.10, 49.70, 45.21, 41.15, 39.11, 33.28, 32.97, 32.27, 32.04, 31.60, 21.73.

Example 8: Preparation of Compound C8

[0192] ##STR00090##

[0193] To a solution of 5-bromo-1-pentanol (260 mg, 0.78 mmol, 1.0 equiv) in acetonitrile were added tert-butyl acrylate (200 mg, 1.56 mmol, 2.0 equiv) and Triton B (10 mg, 0.09 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1, v/v) to give a target product (178 mg, yield: 77%) in the form of an oily liquid.

##STR00091##

[0194] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (150 mg, 0.55 mmol, 1.0 equiv), potassium iodide (9 mg, 0.054 mmol, 0.1 equiv) and sodium bicarbonate (92 mg, 1.1 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 6-1 (162 mg, 0.55 mmol, 1.2 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The resulting reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated brine for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:acetone=3:1, v/v) to give a final product 6-2 (164.7 mg, yield: 61%); LC-MS: m/z=489.

##STR00092##

[0195] 6-2 (164.7 mg, 0.34 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resulting residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 6-3 (145 mg) which was used in the next step directly without further purification; LC-MS: m/z=433.

##STR00093##

[0196] 6-3 (21.6 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (10.5 mg, yield: 27%); LC-MS: m/z=863.

[0197] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.82 (s, 1H), 7.71-7.59 (m, 2H), 7.51 (s, 1H), 7.46-7.38 (m, 2H), 7.35 (d, J=5.7 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 5.42-5.32 (m, 1H), 5.09 (s, 2H), 4.93 (d, J=9.7 Hz, 1H), 4.68 (t, J=5.7 Hz, 2H), 4.38-3.96 (m, 4H), 3.75 (t, J=6.6 Hz, 2H), 3.48 (d, J=8.1 Hz, 3H), 3.34-3.07 (m, 2H), 3.02-2.48 (m, 7H), 2.43-2.07 (m, 6H), 2.07-1.95 (m, 3H), 1.62 (s, 6H).

Example 9: Preparation of Compound C9

[0198] ##STR00094##

[0199] To a solution of 6-bromo-1-hexanol (260 mg, 0.78 mmol, 1.0 equiv) in acetonitrile were added tert-butyl acrylate (200 mg, 1.56 mmol, 2.0 equiv) and Triton B (10 mg, 0.09 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1, v/v) to give a target product 7-1 (174.4 mg, yield: 72%) in the form of an oily liquid.

##STR00095##

[0200] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (150 mg, 0.55 mmol, 1.0 equiv), potassium iodide (9 mg, 0.054 mmol, 0.1 equiv) and sodium bicarbonate (92 mg, 1.1 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 7-1 (169 mg, 0.55 mmol, 1.2 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The resulting reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated brine for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:acetone=3:1, v/v) to give a final product 7-2 (163 mg, yield: 59%); LC-MS: m/z=503.

##STR00096##

[0201] 7-2 (163 mg, 0.32 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 7-3 (144.5 mg) which was used in the next step directly without further purification; LC-MS: m/z=447.

##STR00097##

[0202] 7-3 (22.3 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (26 mg, yield: 65%); LC-MS: m/z=877.

[0203] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.76 (d, J=1.2 Hz, 1H), 7.69-7.58 (m, 2H), 7.46 (s, 1H), 7.43-7.35 (m, 2H), 7.35-7.28 (m, 2H), 7.16 (dd, J=8.5, 3.7 Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 5.52 (s, 1H), 5.03 (s, 2H), 4.98-4.84 (m, 1H), 4.65 (d, J=13.4 Hz, 1H), 4.12 (d, J=2.3 Hz, 3H), 3.99 (d, J=13.7 Hz, 1H), 3.84-3.62 (m, 2H), 3.54-3.37 (m, 4H), 3.18 (dd, J=27.3, 12.0 Hz, 2H), 2.98-2.52 (m, 7H), 2.11 (dd, J=20.1, 10.2 Hz, 3H), 1.93-1.65 (m, 3H), 1.61 (s, 6H), 1.54-1.29 (m, 5H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.64, 171.94, 169.76, 168.68, 167.16, 165.69, 156.59, 150.37, 141.22, 136.72, 136.44, 135.89, 135.64, 135.41, 133.79, 131.67, 130.90, 128.78, 127.46, 123.41, 118.90, 117.38, 117.08, 115.65, 115.06, 94.87, 81.41, 71.09, 70.02, 69.25, 67.14, 66.23, 65.40, 49.12, 45.63, 41.50, 40.56, 35.32, 33.70, 32.81, 32.12, 31.47, 29.47, 28.78, 25.76, 25.59, 22.66.

Example 10: Preparation of Compound C10

[0204] ##STR00098##

[0205] To a solution of 7-bromo-1-heptanol (260 mg, 0.78 mmol, 1.0 equiv) in acetonitrile were added tert-butyl acrylate (200 mg, 1.56 mmol, 2.0 equiv) and Triton B (10 mg, 0.09 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1, v/v) to give a target product 8-1 (258.6 mg, yield: 80%) in the form of an oily liquid.

##STR00099##

[0206] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (150 mg, 0.55 mmol, 1.0 equiv), potassium iodide (9 mg, 0.054 mmol, 0.1 equiv) and sodium bicarbonate (92 mg, 1.1 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 8-1 (177 mg, 0.55 mmol, 1.0 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated brine for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (petroleum ether:acetone=3:1, v/v) to give a final product 8-2 (179 mg, yield: 63%); LC-MS: m/z=517.

##STR00100##

[0207] 8-2 (179 mg, 0.35 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 8-3 (158.3 mg) which was used in the next step directly without further purification; LC-MS: m/z=461.

##STR00101##

[0208] 8-3 (23 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (28 mg, yield: 70%); LC-MS: m/z=891.

[0209] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.75 (s, 1H), 7.70-7.55 (m, 2H), 7.47 (s, 1H), 7.44-7.35 (m, 2H), 7.36-7.28 (m, 2H), 7.16 (dd, J=8.4, 5.1 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 5.68 (s, 2H), 5.04 (s, 2H), 4.97-4.87 (m, 2H), 4.66 (d, J=13.2 Hz, 1H), 4.28-4.05 (m, 3H), 4.00 (d, J=12.9 Hz, 1H), 3.82-3.62 (m, 3H), 3.54-3.35 (m, 4H), 3.31-3.08 (m, 2H), 2.91-2.45 (m, 9H), 2.32-1.95 (m, 4H), 1.90-1.63 (m, 5H), 1.61 (s, 6H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.76, 171.96, 169.74, 168.64, 167.15, 165.69, 156.61, 150.36, 141.31, 136.77, 136.44, 135.80, 135.29, 133.79, 131.70, 130.91, 128.79, 127.46, 123.43, 118.85, 117.27, 117.05, 115.64, 115.11, 94.89, 81.39, 71.20, 70.08, 69.36, 67.11, 66.15, 65.41, 49.10, 45.64, 41.48, 40.58, 35.27, 33.73, 32.78, 32.14, 31.46, 29.53, 29.37, 29.04, 28.78, 26.03, 25.78, 22.64.

Example 11: Preparation of Compound C11

[0210] ##STR00102##

[0211] To a solution of 8-bromo-1-octanol (260 mg, 0.78 mmol, 1.0 equiv) in acetonitrile were added tert-butyl acrylate (200 mg, 1.56 mmol, 2.0 equiv) and Triton B (10 mg, 0.09 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. Then the solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1, v/v) to give a target product 9-1 (198.4 mg, yield: 75%) in the form of an oily liquid.

##STR00103##

[0212] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (150 mg, 0.55 mmol, 1.0 equiv), potassium iodide (9 mg, 0.054 mmol, 0.1 equiv) and sodium bicarbonate (92 mg, 1.1 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 9-1 (184 mg, 0.55 mmol, 1.0 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated brine for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:acetone=3:1, v/v) to give a final product 9-2 (160.5 mg, yield: 55%); LC-MS: m/z=531.

##STR00104##

[0213] 9-2 (160.5 mg, 0.30 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 9-3 (143 mg) which was used in the next step directly without further purification; LC-MS: m/z=475.

##STR00105##

[0214] 9-3 (23.7 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (21.6 mg, yield: 53%); LC-MS: m/z=905.

[0215] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.12 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.78-7.59 (m, 2H), 7.50 (s, 1H), 7.46-7.39 (m, 2H), 7.38-7.30 (m, 2H), 7.20 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.4 Hz, 1H), 5.25 (s, 1H), 5.07 (s, 2H), 4.95 (dd, J=12.0, 5.2 Hz, 1H), 4.68 (d, J=13.4 Hz, 1H), 4.15 (t, J=6.4 Hz, 2H), 4.02 (d, J=13.5 Hz, 1H), 3.75 (dd, J=10.9, 6.6 Hz, 2H), 3.45 (t, J=6.6 Hz, 2H), 3.21 (dd, J=23.6, 11.8 Hz, 2H), 3.05-2.40 (m, 8H), 2.33-2.00 (m, 4H), 2.00-1.68 (m, 4H), 1.64 (s, 6H), 1.60-1.40 (m, 5H), 1.33 (s, 4H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.50, 171.98, 171.93, 169.67, 167.16, 165.70, 156.67, 150.28, 141.12, 136.74, 136.60, 136.41, 136.08, 135.97, 135.58, 133.82, 131.66, 130.89, 128.76, 127.43, 123.43, 118.92, 117.62, 117.12, 117.10, 115.64, 115.07, 94.86, 81.42, 71.30, 70.01, 69.39, 67.10, 65.34, 49.12, 45.60, 41.46, 40.61, 33.76, 32.80, 32.09, 31.46, 29.60, 29.23, 29.12, 28.83, 26.02, 25.68, 22.66.

Example 12: Preparation of Compound C12

[0216] ##STR00106##

[0217] To a solution of 9-bromo-1-nonanol (260 mg, 0.78 mmol, 1.0 equiv) in acetonitrile were added tert-butyl acrylate (200 mg, 1.56 mmol, 2.0 equiv) and Triton B (10 mg, 0.09 mmol, 1.0 equiv, 40% aqueous solution), and the resulting mixture was stirred at room temperature for 48 h. Color was developed with KMnO.sub.4 to determine whether the reaction was completed or not. The solvent was removed on a rotary evaporator. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1, v/v) to give a target product 10-1 (274 mg, yield: 73%) in the form of an oily liquid.

##STR00107##

[0218] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (150 mg, 0.55 mmol, 1.0 equiv), potassium iodide (9 mg, 0.054 mmol, 0.1 equiv) and sodium bicarbonate (92 mg, 1.1 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 10-1 (192 mg, 0.55 mmol, 1.0 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated brine for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:acetone=3:1, v/v) to give a final product 10-2 (176.7 mg, yield: 59%); LC-MS: m/z=545.

##STR00108##

[0219] 10-2 (176.7 mg, 0.32 mmol, 1.0 equiv) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product 10-3 (158.5 mg) which was used in the next step directly without further purification; LC-MS: m/z=489.

##STR00109##

[0220] 10-3 (24.2 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product 10-4 (27.7 mg, yield: 67%); LC-MS: m/z=919.

[0221] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.77 (s, 1H), 7.70-7.58 (m, 2H), 7.48 (s, 1H), 7.45-7.36 (m, 2H), 7.36-7.30 (m, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 5.72 (s, 2H), 5.06 (d, J=3.6 Hz, 2H), 5.01-4.87 (m, 2H), 4.66 (d, J=12.7 Hz, 1H), 4.12 (dd, J=12.1, 5.1 Hz, 4H), 4.01 (d, J=12.1 Hz, 1H), 3.73 (m, 3H), 3.45 (dd, J=12.5, 6.3 Hz, 3H), 3.34-3.07 (m, 2H), 2.76 (m, 11H), 2.27-1.96 (m, 5H), 1.91-1.66 (m, 5H), 1.62 (s, 6H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ 172.69, 171.92, 169.72, 168.68, 167.15, 165.69, 156.66, 150.46, 141.31, 136.77, 136.43, 135.83, 135.31, 133.78, 131.67, 130.86, 128.77, 127.40, 123.44, 118.93, 118.89, 117.21, 117.06, 115.62, 115.16, 94.95, 81.36, 71.30, 71.19, 70.07, 69.43, 69.39, 67.07, 66.11, 65.38, 65.35, 49.10, 45.59, 41.45, 40.53, 36.54, 35.21, 33.73, 32.75, 32.08, 31.46, 29.61, 29.49, 29.36, 29.29, 29.24, 29.12, 28.84, 26.07, 26.00, 25.73, 25.71, 22.63.

Example 13: Preparation of Compound C13

[0222] ##STR00110##

[0223] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (100 mg, 0.4 mmol, 1.0 equiv), potassium iodide (6.1 mg, 0.03 mmol, 0.1 equiv) and sodium bicarbonate (61.3 mg, 0.4 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 2-(4-bromobutoxy) tetrahydro-2H-pyran (113.8 mg, 0.48 mmol, 1.2 equiv), then heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (113.6 mg, yield: 66%); LC-MS: m/z=431.2.

##STR00111##

[0224] 11-1 (113.6 mg, 0.26 mmol) was weighed into a round-bottom flask, a 4 M dioxane hydrochloride solution was added, and the resulting mixture was stirred at room temperature until the reaction was completed. The redundant solvent was removed by rotary evaporation to give a final product (84 mg, yield: 93%); LC-MS: m/z=347.1.

##STR00112##

[0225] 11-2 (84 mg, 0.24 mmol, 1.0 equiv) and PCC (103.5 mg, 0.48 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (81 mg, yield: 98%); LC-MS: m/z=345.1.

##STR00113##

[0226] 11-3 (81 mg, 0.24 mmol, 1.0 equiv) and Oxone (140.1 mg, 0.24 mol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product (70.9 mg, yield: 82%); LC-MS: m/z=361.1.

##STR00114##

[0227] 11-4 (50 mg, 0.14 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (105.8 mg, 0.28 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (71.5 mg, 0.56 mmol, 4.0 equiv) and β-alanine tert-butyl ester hydrochloride (25.4 mg, 0.14 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to give a final product (44.4 mg, yield: 65%); LC-MS: m/z=488.2.

##STR00115##

[0228] 11-5 (44.4 mg, 0.09 mmol) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product (38.8 mg) which was used in the next step directly without further purification; LC-MS: m/z=432.1.

##STR00116##

[0229] 11-6 (10.8 mg, 25 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (17 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (8.6 mg, 0.065 mmol, 3.0 equiv) and compound 1 (10 mg, 0.023 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (7.9 mg, yield: 40%); LC-MS: m/z=862.3.

[0230] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (d, J=1.8 Hz, 1H), 7.76-7.64 (m, 2H), 7.54 (s, 1H), 7.51-7.42 (m, 2H), 7.41-7.35 (m, 2H), 7.24 (dd, J=8.4, 4.4 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 5.33 (s, 1H), 5.13 (s, 2H), 5.02-4.93 (m, 1H), 4.76-4.57 (m, 2H), 4.34-4.15 (m, 2H), 4.13-3.92 (m, 2H), 3.85-3.66 (m, 1H), 3.39-3.20 (m, 2H), 3.20-3.00 (m, 2H), 2.92-2.64 (m, 6H), 2.29-2.11 (m, 4H), 1.79-1.72 (m, 5H), 1.66 (s, 6H).

Example 14: Preparation of Compound C14

[0231] ##STR00117##

[0232] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (100 mg, 0.4 mmol, 1.0 equiv), potassium iodide (6.1 mg, 0.03 mmol, 0.1 equiv) and sodium bicarbonate (61.3 mg, 0.4 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 5-bromo-1-pentanol (80.2 mg, 0.48 mmol, 1.2 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (110.7 mg, yield: 64%); LC-MS: m/z=361.1.

##STR00118##

[0233] 12-1 (110.7 mg, 0.31 mmol, 1.0 equiv) and PCC (133.7 mg, 0.62 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (108.9 mg, yield: 98%); LC-MS: m/z=359.1.

##STR00119##

[0234] 12-2 (108.9 mg, 0.3 mmol, 1.0 equiv) and Oxone (175.1 mg, 0.3 mol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product (88.7 mg, yield: 79%); LC-MS: m/z=375.1.

##STR00120##

[0235] 12-3 (52.4 mg, 0.14 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (105.8 mg, 0.28 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (71.5 mg, 0.56 mmol, 4.0 equiv) and β-alanine tert-butyl ester hydrochloride (25.4 mg, 0.14 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation.

[0236] The resulting crude product was purified by silica gel column chromatography to give a final product (47 mg, yield: 67%); LC-MS: m/z=502.2.

##STR00121##

[0237] 12-4 (47 mg, 0.09 mmol) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product (40.1 mg) which was used in the next step directly without further purification; LC-MS: m/z=446.2.

##STR00122##

[0238] 12-5 (11.1 mg, 0.025 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (17 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (8.6 mg, 0.065 mmol, 3.0 equiv) and compound 1 (10 mg, 0.023 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (9.4 mg, yield: 43%); LC-MS: m/z=876.2.

[0239] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.86 (s, 1H), 7.75-7.63 (m, 2H), 7.54 (s, 1H), 7.51-7.42 (m, 2H), 7.42-7.34 (m, 2H), 7.24 (d, J=8.6 Hz, 1H), 7.12 (s, 1H), 5.46 (d, J=16.4 Hz, 1H), 5.12 (s, 2H), 5.04-4.94 (m, 1H), 4.68 (dd, J=33.0, 13.7 Hz, 2H), 4.31-4.16 (m, 2H), 4.00 (dd, J=26.4, 13.7 Hz, 2H), 3.83-3.68 (m, 1H), 3.35-3.19 (m, 2H), 3.18-3.03 (m, 1H), 3.01-2.65 (m, 6H), 2.51-2.30 (m, 3H), 2.26-2.10 (m, 4H), 1.80-1.74 (m, 5H), 1.65 (s, 6H).

Example 15: Preparation of Compound C15

[0240] ##STR00123##

[0241] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (100 mg, 0.4 mmol, 1.0 equiv), potassium iodide (6.1 mg, 0.03 mmol, 0.1 equiv) and sodium bicarbonate (61.3 mg, 0.4 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 6-bromo-1-hexanol (86.9 mg, 0.48 mmol, 1.2 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (120.4 mg, yield: 67%); LC-MS: m/z=375.2.

##STR00124##

[0242] 13-1 (120.4 mg, 0.32 mmol, 1.0 equiv) and PCC (138 mg, 0.64 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (118 mg, yield: 99%); LC-MS: m/z=373.1.

##STR00125##

[0243] 13-2 (118 mg, 0.32 mmol, 1.0 equiv) and Oxone (186.8 mg, 0.32 mol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product (100.7 mg, yield: 81%); LC-MS: m/z=389.1.

##STR00126##

[0244] 13-3 (54.4 mg, 0.14 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (105.8 mg, 0.28 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (71.5 mg, 0.56 mmol, 4.0 equiv) and β-alanine tert-butyl ester hydrochloride (25.4 mg, 0.14 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to give a final product (42.6 mg, yield: 59%); LC-MS: m/z=516.3.

##STR00127##

[0245] 13-4 (42.6 mg, 0.08 mmol) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product (36.8 mg) which was used in the next step directly without further purification; LC-MS: m/z=460.2.

##STR00128##

[0246] 13-5 (11.5 mg, 0.025 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, the resulting mixture was stirred at 0° C., added with HBTU (17 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (8.6 mg, 0.065 mmol, 3.0 equiv) and compound 1 (10 mg, 0.023 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum with a sand-core funnel. The redundant solvent was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (10.4 mg, yield: 51%); LC-MS: m/z=890.3.

[0247] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.87 (s, 1H), 7.76-7.63 (m, 2H), 7.53 (s, 1H), 7.49-7.41 (m, 2H), 7.41-7.33 (m, 2H), 7.24 (d, J=8.5 Hz, 1H), 7.10 (s, 1H), 5.32 (s, 1H), 5.24 (d, J=11.7 Hz, 1H), 5.11 (s, 2H), 5.05 (s, 1H), 5.02-4.91 (m, 1H), 4.75-4.57 (m, 2H), 4.26-4.15 (m, 2H), 4.00 (dd, J=27.7, 14.5 Hz, 2H), 3.84-3.64 (m, 1H), 3.34-3.20 (m, 2H), 3.17-3.05 (m, 1H), 2.96-2.63 (m, 6H), 2.45-2.31 (m, 3H), 2.30-2.09 (m, 4H), 1.91-1.71 (m, 9H), 1.65 (s, 6H).

Example 16: Preparation of Compound C16

[0248] ##STR00129##

[0249] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (100 mg, 0.4 mmol, 1.0 equiv), potassium iodide (6.1 mg, 0.03 mmol, 0.1 equiv) and sodium bicarbonate (61.3 mg, 0.4 mmol, 2.0 equiv) were dissolved in DMF, and the resulting mixture was added with 7-bromo-1-heptanol (93.6 mg, 0.48 mmol, 1.2 equiv), heated to 80° C. and reacted overnight, and then the heating was stopped. The reaction system was cooled to room temperature, diluted with an appropriate amount of ethyl acetate, and extracted with saturated saline for 5 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (113.7 mg, yield: 61%); LC-MS: m/z=389.1.

##STR00130##

[0250] 14-1 (113.7 mg, 0.29 mmol, 1.0 equiv) and PCC (125 mg, 0.58 mmol, 2.0 equiv) were dissolved in an appropriate amount of dichloromethane, and the resulting mixture was stirred at room temperature for 6 h. The reaction system was added with an appropriate amount of silica gel, concentrated by rotary evaporation, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:2, v/v) to give a final product (110.9 mg, yield: 99%); LC-MS: m/z=387.2.

##STR00131##

[0251] 14-2 (110.9 mg, 0.29 mmol, 1.0 equiv) and Oxone (180.6 mg, 0.29 mol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product (99.2 mg, yield: 85%); LC-MS: m/z=403.2.

##STR00132##

[0252] 14-3 (54.4 mg, 0.14 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (105.8 mg, 0.28 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (71.5 mg, 0.56 mmol, 4.0 equiv) and β-alanine tert-butyl ester hydrochloride (25.4 mg, 0.14 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to give a final product (47.5 mg, yield: 64%); LC-MS: m/z=530.3.

##STR00133##

[0253] 14-4 (47.5 mg, 0.09 mmol) was dissolved in an appropriate amount of dichloromethane, and the resulting mixture was added with 2-fold volume of trifluoroacetic acid at 0° C. and stirred for 2 h. After the reaction was completed as monitored by LC-MS, dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The residue was dried in a vacuum pump for 2 h to remove the residual solvent and acid to give a crude product (42.6 mg) which was used in the next step directly without further purification; LC-MS: m/z=474.2.

##STR00134##

[0254] 14-5 (11.8 mg, 0.025 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (17 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (8.6 mg, 0.065 mmol, 3.0 equiv) and compound 1 (10 mg, 0.023 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum with a sand-core funnel. The redundant solvent was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (8.1 mg, yield: 39%); LC-MS: m/z=904.3.

[0255] NMR: .sup.1H NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.55 (s, 1H), 7.52-7.43 (m, 2H), 7.42-7.35 (m, 3H), 7.30 (s, 1H), 5.37-5.31 (m, 2H), 5.20 (s, 2H), 5.08 (dd, J=12.1, 4.9 Hz, 2H), 4.61-4.51 (m, 2H), 4.42 (dd, J=9.7, 3.9 Hz, 1H), 4.25-4.19 (m, 2H), 4.05-3.98 (m, 1H), 3.81-3.72 (m, 2H), 3.64-3.56 (m, 3H), 3.50-3.45 (m, 2H), 2.87-2.62 (m, 6H), 2.60-2.52 (m, 2H), 2.49-2.41 (m, 2H), 2.15-2.03 (m, 5H), 1.56 (s, 6H).

Example 17: Preparation of Compound C17

[0256] ##STR00135##

[0257] 1-Boc-4-piperidineacetic acid (50.4 mg, 0.22 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (166.2 mg, 0.44 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (84.3 mg, 0.66 mmol, 3.0 equiv) and Compound 1 (100 mg, 0.22 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography to give a final product (117.2 mg, yield: 81%); LC-MS: m/z=660.3.

##STR00136##

[0258] 15-1 (117.2 mg, 0.18 mmol) was weighed into a round-bottom flask, a 4 M dioxane hydrochloride solution was added, and the resulting mixture was stirred at room temperature until the reaction was completed. The redundant solvent was removed by rotary evaporation to give a final product in the form of a hydrochloride salt as a yellow solid (103.1 mg, yield: 96%); LC-MS: m/z=560.3.

##STR00137##

[0259] 12-3 (9.4 mg, 0.025 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (17 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (8.6 mg, 0.065 mmol, 3.0 equiv) and 15-2 (13 mg, 0.023 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum with a sand-core funnel. The redundant solvent was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (7.4 mg, yield 35%); LC-MS: m/z=916.4.

[0260] NMR: .sup.1H NMR (400 MHz, MeOD) δ 7.75 (s, 1H), 7.73-7.66 (m, 2H), 7.55 (s, 1H), 7.51-7.45 (m, 1H), 7.41-7.33 (m, 4H), 7.29 (d, J=1.8 Hz, 1H), 5.20 (s, 2H), 5.09 (dd, J=12.9, 5.0 Hz, 1H), 4.58 (d, J=14.7 Hz, 1H), 4.25-4.15 (m, 2H), 4.04 (d, J=13.4 Hz, 1H), 3.49 (t, J=6.5 Hz, 2H), 3.31-3.19 (m, 5H), 2.92-2.65 (m, 6H), 2.65-2.54 (m, 2H), 2.34 (t, J=6.7 Hz, 2H), 2.21-2.07 (m, 5H), 1.91-1.80 (m, 4H), 1.79-1.61 (m, 3H), 1.56 (s, 6H).

Example 18: Preparation of Compound C18

[0261] ##STR00138##

[0262] 13-3 (11.7 mg, 0.03 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (22.7 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (11.9 mg, 0.065 mmol, 3.0 equiv) and 15-2 (17 mg, 0.03 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum with a sand-core funnel. The redundant solvent was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (14.2 mg, yield: 51%); LC-MS: m/z=930.3.

[0263] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.68 (d, J=59.9 Hz, 1H), 7.83 (s, 1H), 7.68-7.59 (m, 2H), 7.48 (s, 1H), 7.45-7.28 (m, 4H), 7.19 (d, J=8.5 Hz, 1H), 7.05 (s, 1H), 6.69 (t, J=6.1 Hz, 1H), 5.18 (d, J=8.2 Hz, 2H), 5.05 (s, 2H), 5.00-4.92 (m, 1H), 4.69-4.56 (m, 1H), 4.26-4.09 (m, 2H), 3.89 (d, J=13.8 Hz, 1H), 3.68-3.53 (m, 1H), 3.52-3.36 (m, 1H), 3.28-3.07 (m, 2H), 2.92-2.66 (m, 5H), 2.54 (t, J=5.5 Hz, 2H), 2.30-2.04 (m, 6H), 1.88-1.77 (m, 3H), 1.76-1.64 (m, 5H), 1.61 (s, 6H), 1.58-1.46 (m, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 173.24, 172.30, 172.19, 170.14, 169.08, 167.15, 165.92, 156.56, 150.34, 141.09, 136.88, 136.67, 136.48, 136.00, 135.72, 133.80, 131.66, 130.88, 128.79, 127.43, 123.43, 119.38, 117.61, 117.41, 115.89, 115.00, 94.86, 81.42, 69.99, 69.30, 65.40, 49.25, 45.14, 41.55, 40.55, 36.54, 35.05, 33.04, 32.76, 32.14, 31.58, 31.49, 28.23, 25.62, 25.09, 22.71.

Example 19: Preparation of Compound C19

[0264] ##STR00139##

[0265] 14-3 (12.1 mg, 0.03 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (22.7 mg, 0.045 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (11.9 mg, 0.065 mmol, 3.0 equiv) and 15-2 (17 mg, 0.03 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate, and extracted with water and saturated saline for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum with a sand-core funnel. The redundant solvent was removed on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:20, v/v) to give a final product (15.1 mg, yield: 53%); LC-MS: m/z=944.4.

[0266] NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ 10.93 (d, J=86.1 Hz, 2H), 7.79 (s, 1H), 7.69-7.55 (m, 2H), 7.44 (s, 1H), 7.42-7.27 (m, 4H), 7.16 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 6.92-6.77 (m, 1H), 5.20 (s, 2H), 5.02 (s, 2H), 4.99-4.92 (m, 1H), 4.61 (d, J=12.6 Hz, 1H), 4.23-4.05 (m, 2H), 3.83 (d, J=13.9 Hz, 1H), 3.62 (dt, J=13.0, 6.5 Hz, 4H), 3.53-3.44 (m, 1H), 3.22-3.01 (m, 5H), 2.87-2.70 (m, 4H), 2.61-2.42 (m, 3H), 2.20-2.02 (m, 5H), 1.87-1.74 (m, 2H), 1.73-1.61 (m, 3H), 1.58 (s, 6H), 1.53-1.51 (m, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3) δ 173.45, 172.27, 172.16, 170.26, 169.32, 167.16, 165.82, 156.59, 150.31, 141.09, 136.85, 136.66, 136.47, 136.04, 135.72, 133.82, 131.65, 130.85, 128.78, 127.44, 123.44, 119.03, 117.62, 117.18, 115.70, 114.97, 94.92, 81.39, 69.95, 69.25, 65.35, 49.21, 45.07, 41.59, 40.44, 35.94, 34.94, 32.98, 32.61, 32.07, 31.59, 31.49, 28.34, 28.20, 25.25, 25.01, 22.77.

Example 20: Preparation of Compound C20

[0267] ##STR00140##

[0268] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (200 mg, 0.73 mmol, 1.0 equiv) and sodium bicarbonate (184 mg, 2.19 mmol, 3.0 equiv) were dissolved in DMF, and the resulting mixture was added dropwise with 3-(2-iodoethoxy)prop-1-yne (184 mg, 0.88 mmol, 1.2 equiv), then heated to 80° C. and stirred overnight. When the reaction was completed, the reaction system was diluted with an appropriate amount of ethyl acetate, and sequentially extracted a mixed solution of water and a saturated sodium bicarbonate solution (water:saturated sodium bicarbonate solution=1:5, v/v) and saturated saline. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, concentrated by rotary evaporation, and purified by silica gel column chromatography (acetone:petroleum ether=1:2, v/v) to give a final product (156.1 mg, yield: 70%); LC-MS: m/z=357.2.

##STR00141##

[0269] Copper sulfate (14.4 mg, 0.09 mmol, 0.2 equiv) was dissolved in 6 mL of water. 16-1 (156.1 mg, 0.44 mmol, 1 equiv) and 2-azido-1,1-diethoxyethane (70 mg, 0.44 mmol, 1 equiv) were dissolved in 6 mL of tert-butanol, respectively, and sequentially added to the copper sulfate solution. Sodium ascorbate (35.6 mg, 0.18 mmol, 0.4 equiv) was dissolved in 6 mL of water and added to the reaction system, and the reaction system was stirred overnight at room temperature. After the reaction was completed as monitored, the reaction system was diluted with saturated saline and extracted twice with chloroform. The organic phases were combined, sequentially extracted with a saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The redundant solvent was removed on a rotary evaporator to give a crude product. The resulting crude product was purified by silica gel column chromatography to give a final product (102.1 mg, yield: 45%); LC-MS: m/z=516.2.

##STR00142##

[0270] 16-2 (100 mg, 0.19 mmol) was added to a 4 M dioxane hydrochloride solution, and the resulting mixture was added dropwise with a small amount of water and heated to 60° C. After the reaction was completed as monitored by TLC, the redundant solvent was removed by rotary evaporation. The reaction system was diluted with an appropriate amount of ethyl acetate, and extracted twice with saturated brine to give a final product (25.1 mg, yield: 30%); LC-MS: m/z=442.2.

##STR00143##

[0271] 16-3 (25 mg, 0.06 mmol, 1.0 equiv) and Oxone (37 mg, 0.32 mmol, 1.0 equiv) were dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at room temperature overnight. The reaction system was diluted with ethyl acetate and sequentially extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to give a final product (23 mg, yield: 83%); LC-MS: m/z=458.1.

##STR00144##

[0272] 16-4 (22.9 mg, 0.05 mmol, 1.0 equiv) was dissolved in an appropriate amount of DMF, and the resulting mixture was stirred at 0° C., added with HBTU (34 mg, 0.09 mmol, 2.0 equiv), after 5 min, sequentially added with DIEA (17.2 mg, 0.13 mmol, 3.0 equiv) and compound 1 (20 mg, 0.045 mmol, 1.0 equiv), then heated to room temperature, and stirred overnight. The reaction system was diluted with ethyl acetate and extracted with water and saturated brine for 3 times. The resulting organic phase was dried over anhydrous sodium sulfate, filtered under vacuum with a sand-core funnel, and concentrated by rotary evaporation. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane=1:10, v/v) to give a final product (16.0 mg, yield: 40%); LC-MS: m/z=888.3.

[0273] NMR: .sup.1H NMR (400 MHz, MeOD) δ 7.96 (d, J=3.8 Hz, 1H), 7.78 (d, J=1.8 Hz, 1H), 7.74-7.65 (m, 2H), 7.52 (s, 1H), 7.47 (d, J=7.3 Hz, 1H), 7.41-7.38 (m, 3H), 7.29 (dd, J=8.5, 1.7 Hz, 1H), 7.12 (d, J=1.8 Hz, 1H), 5.34 (p, J=16.3 Hz, 2H), 5.12 (s, 2H), 5.05-4.93 (m, 1H), 4.84 (q, J=12.7 Hz, 2H), 4.57 (d, J=13.4 Hz, 1H), 4.45-4.30 (m, 2H), 3.47-3.22 (m, 4H), 3.06-2.72 (m, 5H), 2.35-2.00 (m, 4H), 1.96-1.66 (m, 3H), 1.60 (s, 6H); .sup.13C NMR (101 MHz, MeOD) δ 171.84, 171.64, 168.66, 166.66, 165.35, 163.22, 155.72, 149.85, 144.35, 140.81, 136.11, 135.86, 135.65, 135.26, 133.01, 131.03, 130.12, 128.13, 126.74, 124.69, 123.01, 118.87, 116.71, 116.50, 115.50, 114.49, 94.15, 80.41, 69.45, 68.50, 67.50, 64.30, 64.02, 50.29, 44.44, 41.62, 39.57, 39.46, 31.64, 31.18, 30.72, 30.50, 22.02.

Example 21: Biological Experiment

[0274] S1: Jurkat cells were resuscitated, and then subjected to adherent culture for 12 h, compounds were added, the compound concentrations were fixed (treatment time was 0 h, 3 h, 6 h, 12 h, 24 h and 72 h) or the treatment time was fixed (compound concentrations were 0 nM, 1 nM, 10 nM, 100 nM and 1000 nM);

[0275] S2: the culture solution was poured out, the cells were washed with 3 mL of PBS pre-cooled at 4° C., then the washing solution was discarded, an appropriate amount of lysis solution containing PMSF (100×) was added according to the cell amount, the mixture was uniformly mixed, then placed on ice for lysis for 30 min, and centrifuged at 12000 rpm and at 4° C. for 5 min, (a centrifuge was started for pre-cooling in advance), and the centrifuged supernatant was transferred into a new centrifuge tube and prepared for quantification;

[0276] S3: an BCA quantitative reagent of Pierce™ BCA Protein Assay Kit (23225) was added at 200 uL/well, then 20 uL of BSA with known different concentrations was added to prepare a protein quantitative standard curve and a sample protein to be detected with avoiding generation of bubbles, the mixture was incubated for 30 min in the dark at 37° C., an OD value was measured at 562 nm, then an appropriate amount of SDS-PAGE loading buffer was added to the protein sample, and the reaction mixture was heated for 5 min in a boiling water bath to fully denature the protein, and stored at −20° C. for later use;

[0277] S4: an SDS-PAGE gel was prepared, wherein the voltage of a concentrated gel was 90 V, and the voltage of a separation gel was 120 V, a membrane was transferred for 1 h at 4° C. and at a voltage of 100 V, after the membrane was transferred, the protein membrane was immediately placed in a prepared 5% BSA solution, and the mixture was slowly shaken on a shaker, and sealed for 1 h at room temperature;

[0278] S5: the primary antibody was diluted according to an appropriate proportion according to the specifications of HPK1 Antibody (4472S CST), GLK (D1L4G) Rabbit mAb (92427S CST), SLP-76 (D1R1A) Rabbit mAb (70896S CST), Phospho-SLP-76 (Ser376) (D7S1K) XP® Rabbit mAb (92711T CST) and β-actin Mouse Monoclonal antibody (BE0021 easybio), then incubated overnight with slow shaking at 4° C., and washed 3 times with PBST for 10 min/time;

[0279] S6: Goat Anti-Rabbit IgG (H&L)-HRP Conjugated (BE0101 easybio) or Goat Anti-Mouse IgG (H&L)-HRP Conjugated (BE0102 easybio) was selected according to the primary antibody, and the secondary antibody was diluted according to an appropriate proportion according to the specification of the secondary antibody, then incubated for 1 h at room temperature with slow shaking, and washed 3 times with PBST for 10 min/time; and

[0280] S7: an ECL luminescence was added, the results were observed by a developing machine, Western results were quantified using Image J software, and the degradation rates (HPK1 and GLK) or inhibition rates (SLP76 Ser376 phosphorylation) were calculated by comparison with a control group to which no compounds were added, (degradation rate/inhibition rate=1−administration group/control group). The experimental results are shown in the tables below.

TABLE-US-00001 TABLE 1 Degradation Rates of HPK1 with Fixed Treatment Time of 12 h and Varying Treatment Concentrations of Compounds Degradation rate Degradation rate Compound (10 nM) (100 nM) C1 47% 68% C2 39% 33% C3 15% 75% C7 72% 68%

TABLE-US-00002 TABLE 2 Degradation Rates of HPK1 at Different Time Points with Treatment Concentration of Compound of 100 nM Degradation Degradation Degradation Degradation Degradation Degradation Com- rate rate rate rate rate rate pound (3 h) (6 h) (12 h) (24 h) (48 h) (72 h) C3 54% 52% 58%  3%   11% C7 58% 86% −40% −9%

TABLE-US-00003 TABLE 3 Maximum Degradation Rate of HPK1 and Maximum Inhibition Rate of SLP-76 Phosphorylation at Different Time Points with Treatment Concentration of Compound of 100 nM Maximum degradation Maximum inhibition rate of Compound rate of HPK1 SLP76 Ser376 phosphorylation C3 62% 81%

TABLE-US-00004 TABLE 4 Degradation Rates of HPK1 and GLK and Inhibition Rate of SLP-76 Phosphorylation with Treatment Time of 6 h and Treatment Concentration of Compound of 100 nM SLP76 HPK1 degradation GLK phosphorylation Compound rate degradation rate inhibition rate C8 66% 34% 51% C9 46% −34%   61% C19 48% −30%   C11 30% −36%   C12 30% 22% C13 38% 43%  4% C14 58% 60% 26% C15 −27%   38% −7% C16 49% 74% 24% C17 −7% 42% 22% C18 39% 71% 34% C19 −95%   34%  3% C20 −15% (12 h 41%) 15%  7%

[0281] Finally, it should be noted that, the above examples are only used to illustrate the technical solutions of the present invention, and should not limit the same; although the present invention has been described in detail with reference to the examples described above, it will be understood by those skilled in the art that, the technical solutions in the examples described above can still be modified, or some or all of the technical features can be equivalently replaced; and these modifications or replacements do not make the technical solutions corresponding thereto depart from the scope of the technical solutions in the examples of the present invention.