PURINE DERIVATIVE AND MEDICAL USE THEREOF

Abstract

The present invention relates to a purine derivative and use thereof in medicine, and in particular to a pyrimidine derivative shown as general formula (I) or a stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof, a pharmaceutical composition comprising the same, and use of the compound or composition of the present invention in the field of preparation of a DNA-PK inhibitor, wherein the substituents in general formula (I) are defined in the same way as in the specification

##STR00001##

Claims

1. A compound shown as general formula (I) or all stereoisomers, solvates, prodrugs, metabolites, deuterides, pharmaceutically acceptable salts or cocrystals thereof: ##STR00082## wherein, A is absent or is selected from a 4-12 membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S; X.sub.1 and X.sub.2 are each independently selected from C, O, N and S, and when A is selected from a 4-12 membered heterocycle, X.sub.1 and X.sub.2 are part of ring A; B is selected from adamantyl; R.sub.0 and R.sub.1 are each independently selected from H, halogen, carboxyl, ═O, —OH, cyano, —NR.sup.a1R.sup.a2 C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, —C.sub.1-6 alkylene-NR.sup.a1R.sup.a2, C.sub.1-6 alkoxy, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.1-6 alkoxy are optionally further substituted with 1-3 substituents selected from D and halogen; or when n is selected from 2, 3 and 4, two R.sub.0, together with atoms to which they are attached, form a 3-8 membered ring, wherein the 3-8 membered ring optionally contains 1 to 3 heteroatoms selected from N, O and S, and is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl and amino; R.sub.2 is selected from H and C.sub.1-6 alkyl; R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R.sub.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl, wherein the C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl is optionally substituted with 1 or more substituents selected from —OH, D, halogen, cyano, carboxyl, —NH.sub.2, ═O, —C(═O)NH.sub.2, C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; or, R.sub.3 and R.sub.4, together with atoms to which they are attached, form a 4-12 membered heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S, and the 4-12 membered heterocycle is optionally substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, cyano, halogen, —O—R.sup.a1, —NR.sup.a1R.sup.a2 C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; R.sub.5 is selected from —OH, halogen, D, cyano, carboxyl, ═O, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —OC(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-12 cycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl are optionally further substituted with 1 to 3 substituents selected from OH, carboxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NR.sup.a1R.sup.a2 and ═O; R.sup.a1 and R.sup.a2 are each independently selected from H, C.sub.1-6 alkyl, —C(═O)R.sup.a3 and —C(═O)NR.sup.a4R.sup.a5, wherein the C.sub.1-6 alkyl is optionally further substituted with 1 or more substituents selected from OH, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl, C.sub.3

5. The compound or the stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof according to claim 1, wherein the compound is selected from one of the following structures: ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## ##STR00102## heterocycloalkyl and C.sub.4-12 heterocycloalkyl; or R.sup.a1 and R.sup.a2, together with a N atom form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; R.sup.a3 is selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.a4 and R.sup.a5 are each independently selected from H and C.sub.1-6 alkyl; or R.sup.a4 and R.sup.a5, together with a N atom, form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; W is selected from O and S; n, p and q are each independently selected from 0, 1, 2, 3 or 4; is a single bond or a double bond.

2. The compound or the stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof according to claim 1, wherein the compound is a compound shown as general formula (II): ##STR00103## wherein, A is absent or is selected from a 4-12 membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S; X.sub.1 and X.sub.2 are each independently selected from C and N, and when A is selected from a 4-12 membered heterocycle, X.sub.1 and X.sub.2 are part of ring A; B is selected from adamantyl; R.sub.0 and R.sub.1 are each independently selected from H, halogen, carboxyl, ═O, —OH, cyano, —NR.sup.a1R.sup.a2 C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, —C.sub.1-6 alkylene-NR.sup.a1R.sup.a2, C.sub.1-6 alkoxy, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.1-6 alkoxy are optionally further substituted with 1-3 substituents selected from D and halogen; or when n is selected from 2, 3 and 4, two R.sub.0, together with atoms to which they are attached, may form a 3-8 membered ring, wherein the 3-8 membered ring optionally contains 1 to 3 heteroatoms selected from N, O and S, and is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl and amino; R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R.sub.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl, wherein the C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl is optionally substituted with 1 or more substituents selected from —OH, D, halogen, cyano, carboxyl, —NH.sub.2, ═O, —C(═O)NH.sub.2, C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; R.sub.5 is selected from —OH, D, halogen, cyano, carboxyl, ═O, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —OC(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-12 cycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl are optionally further substituted with 1 to 3 substituents selected from OH, carboxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NR.sup.a1R.sup.a2 and ═O; R.sup.a1 and R.sup.a2 are each independently selected from H, C.sub.1-6 alkyl, —C(═O)R.sup.a3 and —C(═O)NR.sup.a4R.sup.a5, wherein the C.sub.1-6 alkyl is optionally further substituted with 1 or more substituents selected from OH, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl; or R.sup.a1 and R.sup.a2, together with a N atom form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; R.sup.a3 is selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.a4 and R.sup.a5 are each independently selected from H and C.sub.1-6 alkyl; or R.sup.a4 and R.sup.a5, together with a N atom, form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; n, p and q are each independently selected from 0, 1, 2, 3 or 4; is a single bond or a double bond.

3. The compound or the stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof according to claim 2, wherein the compound is selected from a compound shown as general formula (III), (IV), (V), (VI), (VII) or (VIII): ##STR00104## ##STR00105## R.sub.0, R.sub.1, R.sub.3, R.sub.4, R.sub.5, B, n, p and q are defined in the same way as in general formula (II).

4. The compound or the stereoisomer, solvate, metabolite, prodrug, deuteride, pharmaceutically acceptable salt or cocrystal thereof according to claim 3, wherein: A is absent or is selected from a 5 membered heterocycle containing 1 to 3 heteroatoms selected from N and O; X.sub.1 and X.sub.2 are each independently selected from C and N, and when A is selected from a 5 membered heterocycle, X.sub.1 and X.sub.2 are part of ring A; B is selected from adamantyl; R.sub.0 is selected from H; R.sub.1 is selected from H, halogen, C.sub.1-4 alkyl, cyano and —C(═O)NR.sup.a1R.sup.a2, wherein the C.sub.1-4 alkyl is optionally further substituted with 1-3 substituents selected from D and halogen; R.sub.3 is selected from H; R.sub.4 is selected from H and C.sub.1-4 alkyl; R.sub.5 is selected from —OH, D, cyano, —NR.sup.a1R.sup.a2, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, —C(═O)OC.sub.1-4 alkyl, carboxyl, halogen, ═O and —C(═O)NR.sup.a1R.sup.a2, wherein the C.sub.1-4 alkyl and C.sub.1-4 alkoxy are optionally further substituted with 1 to 3 substituents selected from OH and halogen; R.sup.a1 and R.sup.a2 are each independently selected from H and C.sub.1-4 alkyl; or R.sup.a1 and R.sup.a2, together with a N atom, form a 6 membered heterocycle, which contains 1 to 2 heteroatoms selected from N and 0; n is selected from 0 and 1; p is selected from 1, 2 and 3; q is selected from 1 and 2; is a single bond or a double bond.

6. An intermediate compound for preparing a compound of general formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIX) or (VX), wherein the intermediate compound R is selected from a compound shown as formula (I-A) or (I-B): ##STR00106## wherein, X is selected from halogen; B is selected from adamantyl; R.sub.x is selected from H and C.sub.1-6 alkyl; R.sub.4, R.sub.5 and q are defined in the same way as in claim 1.

7. The intermediate compound according to claim 6, wherein the intermediate compound is selected from one of the following structures: ##STR00107## ##STR00108## ##STR00109##

8. A pharmaceutical composition, comprising: (1) the compound or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof according to claim 1; (2) optionally one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and/or excipient.

9. A method for inhibiting DNA-PK or treating a disease associated with DNA-PK, comprising contacting a compound or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof or a pharmaceutical composition with a subject in need thereof or administering to said subject a compound or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof or a pharmaceutical composition; the compound is shown as general formula (I) or all stereoisomers, solvates, prodrugs, metabolites, deuterides, pharmaceutically acceptable salts or cocrystals thereof: ##STR00110## wherein, A is absent or is selected from a 4-12 membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S; X.sub.1 and X.sub.2 are each independently selected from C, O, N and S, and when A is selected from a 4-12 membered heterocycle, X.sub.1 and X.sub.2 are part of ring A; B is selected from adamantyl; R.sub.0 and R.sub.1 are each independently selected from H, halogen, carboxyl, ═O, —OH, cyano, —NR.sup.a1R.sup.a2 C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, —C.sub.1-6 alkylene-NR.sup.a1R.sup.a2, C.sub.1-6 alkoxy, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.1-6 alkoxy are optionally further substituted with 1-3 substituents selected from D and halogen; or when n is selected from 2, 3 and 4, two R.sub.0, together with atoms to which they are attached, form a 3-8 membered ring, wherein the 3-8 membered ring optionally contains 1 to 3 heteroatoms selected from N, O and S, and is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl and amino; R.sub.2 is selected from H and C.sub.1-6 alkyl; R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R.sub.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl, wherein the C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl is optionally substituted with 1 or more substituents selected from —OH, D, halogen, cyano, carboxyl, —NH.sub.2, ═O, —C(═O)NH.sub.2, C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; or, R.sub.3 and R.sub.4, together with atoms to which they are attached, form a 4-12 membered heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S, and the 4-12 membered heterocycle is optionally substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, cyano, halogen, —O—R.sup.a1, —NR.sup.a1R.sup.a2 C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; R.sub.5 is selected from —OH, halogen, D, cyano, carboxyl, ═O, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —OC(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-12 cycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl are optionally further substituted with 1 to 3 substituents selected from OH, carboxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NR.sup.a1R.sup.a2 and ═O; R.sup.a1 and R.sup.a2 are each independently selected from H, C.sub.1-6 alkyl, —C(═O)R.sup.a3 and —C(═O)NR.sup.a4R.sup.a5 wherein the C.sub.1-6 alkyl is optionally further substituted with 1 or more substituents selected from OH, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl; or R.sup.a1 and R.sup.a2, together with a N atom form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; R.sup.a3 is selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.a4 and R.sup.a5 are each independently selected from H and C.sub.1-6 alkyl; or R.sup.a4 and R.sup.a5, together with a N atom, form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; W is selected from O and S; n, p and q are each independently selected from 0, 1, 2, 3 or 4; is a single bond or a double bond, the pharmaceutical composition comprises: (1) the compound shown as general formula (I) or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug; (2) optionally one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and/or excipient.

10. A method for treating and preventing cancer, comprising administrating a compound or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug thereof or a pharmaceutical composition to a subject in need thereof; the compound is shown as general formula (I) or all stereoisomers, solvates, prodrugs, metabolites, deuterides, pharmaceutically acceptable salts or cocrystals thereof: ##STR00111## wherein, A is absent or is selected from a 4-12 membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S; X.sub.1 and X.sub.2 are each independently selected from C, O, N and S, and when A is selected from a 4-12 membered heterocycle, X.sub.1 and X.sub.2 are part of ring A; B is selected from adamantyl; R.sub.0 and R.sub.1 are each independently selected from H, halogen, carboxyl, ═O, —OH, cyano, —NR.sup.a1R.sup.a2 C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, —C.sub.1-6 alkylene-NR.sup.a1R.sup.a2, C.sub.1-6 alkoxy, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkylene and C.sub.1-6 alkoxy are optionally further substituted with 1-3 substituents selected from D and halogen; or when n is selected from 2, 3 and 4, two R.sub.0, together with atoms to which they are attached, form a 3-8 membered ring, wherein the 3-8 membered ring optionally contains 1 to 3 heteroatoms selected from N, O and S, and is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl and amino; R.sub.2 is selected from H and C.sub.1-6 alkyl; R.sub.3 is selected from H, halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R.sub.4 is selected from H, C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl, wherein the C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl contains 1 to 3 heteroatoms selected from N, O and S, and the C.sub.1-6 alkyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl or C.sub.4-12 heterocycloalkyl is optionally substituted with 1 or more substituents selected from —OH, D, halogen, cyano, carboxyl, —NH.sub.2, ═O, —C(═O)NH.sub.2, C.sub.1-6 alkyl, —C.sub.1-6 alkylene-OH, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; or, R.sub.3 and R.sub.4, together with atoms to which they are attached, form a 4-12 membered heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from N, O and S, and the 4-12 membered heterocycle is optionally substituted with 1 or more substituents selected from —OH, carboxyl, halogen, cyano, ═O, C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl is optionally further substituted with 1 or more substituents selected from —OH, carboxyl, cyano, halogen, —O—R.sup.a1, —NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl; R.sub.5 is selected from —OH, halogen, D, cyano, carboxyl, ═O, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, —NR.sup.a1R.sup.a2, —C(═O)OC.sub.1-6 alkyl, —OC(═O)C.sub.1-6 alkyl, —C(═O)NR.sup.a1R.sup.a2, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl, wherein the C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-12 cycloalkyl, C.sub.4-12 heterocycloalkyl, C.sub.6-12 aryl and C.sub.5-12 heteroaryl are optionally further substituted with 1 to 3 substituents selected from OH, carboxyl, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, —NR.sup.a1R.sup.a2 and ═O; R.sup.a1 and R.sup.a2 are each independently selected from H, C.sub.1-6 alkyl, —C(═O)R.sup.a3 and —C(═O)NR.sup.a4R.sup.a5, wherein the C.sub.1-6 alkyl is optionally further substituted with 1 or more substituents selected from OH, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.6-12 aryl, C.sub.5-12 heteroaryl, C.sub.3-12 cycloalkyl, C.sub.3 heterocycloalkyl and C.sub.4-12 heterocycloalkyl; or R.sup.a1 and R.sup.2, together with a N atom form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; R.sup.a3 is selected from C.sub.1-6 alkyl, C.sub.1-6 alkoxy and C.sub.6-12 aryl; R.sup.a4 and R.sup.a5 are each independently selected from H and C.sub.1-6 alkyl; or R.sup.a4 and R.sup.a5, together with a N atom, form a 3-12 membered heterocycle, which contains 1 to 4 heteroatoms selected from N, O and S; W is selected from O and S; n, p and q are each independently selected from 0, 1, 2, 3 or 4; is a single bond or a double bond, the pharmaceutical composition comprises: (1) the compound shown as general formula (I) or the stereoisomer, solvate, metabolite, deuteride, pharmaceutically acceptable salt, cocrystal or prodrug; (2) optionally one or more other active ingredients; and (3) a pharmaceutically acceptable carrier and/or excipient.

Description

DETAILED DESCRIPTION

[0100] The following examples illustrate the technical schemes of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.

[0101] The structure of a compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are expressed in 10.sup.−6 (ppm). NMR determination is performed using NMR spectrometers (Bruker Avance III 400 and Bruker Avance 300), with deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3) and deuterated methanol (CD.sub.3OD) as solvents and tetramethylsilane (TMS) as an internal standard; MS determination is performed using Agilent 6120B (ESI) and Agilent 6120B (APCI);

[0102] HPLC determination is performed using Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0103] Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate is used as a thin layer chromatography (TLC) silica gel plate. The specification of the silica gel plate for TLC is 0.15-0.20 mm, and that for TLC separation and purification of products is 0.4-0.5 mm;

[0104] Yantai Yellow Sea silica gel of 200-300 mesh is generally used as a carrier in column chromatography;

[0105] known starting materials of the present invention can be synthesized by methods known in the art or can be purchased from companies such as Shanghai Titan Scientific, Energy Chemical, Shanghai DEMO Medical, Chengdu Kelong Chemical, Accela ChemBio, and J&K Scientific; nitrogen atmosphere means that a reaction flask is connected with a nitrogen balloon with a volume of about 1 L;

[0106] hydrogen atmosphere means that a reaction flask is connected with a nitrogen balloon with a volume of about 1 L;

[0107] in hydrogenation reaction, the operation of vacuumizing and introducing hydrogen is usually performed, and repeated 3 times;

[0108] reactions are performed under nitrogen atmosphere if not otherwise specified in examples;

[0109] a solution is an aqueous solution if not otherwise specified in examples;

[0110] reaction temperature is room temperature and the optimum reaction temperature of room temperature is 20-30° C. if not otherwise specified in examples;

[0111] DCM: dichloromethane;

[0112] EA: ethyl acetate;

[0113] HCl: hydrochloric acid;

[0114] THF: tetrahydrofuran;

[0115] DMF: N,N-dimethylformamide;

[0116] PE: petroleum ether;

[0117] TLC: thin layer chromatography;

[0118] SFC: supercritical fluid chromatography;

[0119] NCS: N-chlorosuccinimide;

[0120] Pd(dppf)Cl.sub.2: [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride;

[0121] DMSO: dimethyl sulfoxide;

[0122] DTT: dithiothreitol;

[0123] ATP: adenosine triphosphate;

[0124] DNA: deoxyribonucleic acid.

[0125] IC.sub.50: refers to the concentration of a compound at which the activity of DNA-PK kinase is 50% inhibited.

EXAMPLES

Example 1

9-(3-hydroxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 1)

[0126] ##STR00040## ##STR00041##

Step 1

(E)-N,N-dimethyl-N-(4-methyl-5-nitropyridin-2-yl)formimidamide (1b)

[0127] Compound 1a (30 g, 195.9 mmol) was dissolved in toluene (300 mL), and N,N-dimethylformamide dimethyl acetal (90 mL, 587.7 mmol) was added at room temperature. The reaction mixture was allowed to react at 100° C. for 2 h. After the reaction was completed, the reaction mixture was directly concentrated to give the title compound 1b (yellow solid, 40.79 g, 100% yield).

[0128] .sup.1H NMR (400 MHz DMSO) δ 8.85 (s, 1H), 8.66 (s, 1H), 6.78 (s, 1H), 3.32 (s, 1H), 3.15 (s, 3H), 3.04 (s, 3H), 2.45 (s, 3H).

Step 2

(E)-N-hydroxy-N-(4-methyl-5-nitropyridin-2-yl)formimidamide (1c)

[0129] Compound 1b (40.79 g, 195.90 mmol) was dissolved in methanol (300 mL), and hydroxylamine hydrochloride (27.22 g, 391.80 mmol) was added at room temperature. The reaction mixture was allowed to react at 65° C. for 1 h. The reaction mixture was cooled to room temperature and directly concentrated to give the title compound 1c (yellow solid, 38 g, 100% yield).

[0130] .sup.1H NMR (400 MHz DMSO) δ 10.56 (s, 1H), 10.13 (d, 1H), 8.87 (s, 1H), 7.88 (d, 1H), 7.03 (s, 1H), 2.50 (s, 3H).

Step 3

7-Methyl-6-nitro-[1,2,4]triazolo[1,5-a]pyridine (1d)

[0131] 2,2,2-trifluoroacetic anhydride (41 mL, 290.56 mmol) was added to a solution of compound 1c (38 g, 193.71 mmol) in tetrahydrofuran (400 mL) at 0° C. The reaction mixture was allowed to react at 80° C. for 1 h and concentrated. The resulting solid was slurried with a saturated solution of sodium bicarbonate (100 mL×3), followed by filtration and drying to give the title compound 1d (red solid, 30 g, 100% yield).

[0132] .sup.1H NMR (400 MHz DMSO) δ 9.98 (s, 1H), 8.73 (s, 1H), 7.95 (s, 1H), 2.66 (s, 3H).

Step 4

7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (1e)

[0133] Pd/C (10%, wet support) (0.8 g) was added to a solution of compound 1d (8 g, 44.91 mmol) in methanol (100 mL). The reaction mixture was allowed to react overnight at room temperature under hydrogen atmosphere. The catalyst was removed by filtration, followed by concentration to give a crude product, which was then recrystallized from methanol to give the title compound 1e (pale yellow pure product, 4 g, 60% yield).

[0134] .sup.1H NMR (400 MHz DMSO) δ 8.11 (s, 1H), 8.07 (s, 1H), 5.01 (s, 2H), 2.25 (s, 3H).

Step 5

Ethyl 2-chloro-4-((3-hydroxyadamantan-1-yl)amino)pyrimidine-5-carboxylate (1g)

[0135] Compound 1f (5 g, 22.6 mmol) and potassium carbonate (6.2 g, 44.8 mmol) were dissolved in acetonitrile (20 mL), and 3-aminoadamantan-1-ol (3.7 g, 22.1 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 20 h. 30 mL of water was added, and the solid that precipitated was isolated by filtration and washed with water 3 times at the time of filtration. The filtrate was concentrated to give the title compound 1g (white solid, 6.2 g, 78% yield).

[0136] .sup.1H NMR (400 MHz DMSO) δ 8.62 (s, 1H), 8.37 (s, 1H), 4.66 (s, 1H), 4.30 (s, 2H), 2.20 (s, 2H), 1.98 (s, 6H), 1.58-1.29 (m, 7H).

Step 6

2-Chloro-4-((3-hydroxyadamantan-1-yl)amino)pyrimidine-5-carboxylic acid (1h)

[0137] Compound 1g (6.2 g, 17.6 mmol) was dissolved in 10 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide (915 mg, 38.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Tetrahydrofuran was removed by rotary evaporation. The pH was adjusted to 4-5, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with petroleum ether/ethyl acetate (v/v=10/1) and dried after filtration to give the title compound 1h (white solid, 5 g, 81.9% yield).

Step 7

2-Chloro-9-(3-hydroxyadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (1i)

[0138] Compound 1h (2 g, 6.2 mmol) was dissolved in dimethylacetamide (20 mL), and triethylamine (750 mg, 7.4 mmol) and diphenylphosphoryl azide (1.87 g, 6.8 mmol) were added. The reaction mixture was then gradually warmed to 120° C. and stirred for 1.5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=5:1-1:10) to give the title compound 1i (white solid, 780 mg, 35% yield).

[0139] .sup.1H NMR (400 MHz DMSO) δ 8.08 (s, 1H), 4.71 (s, 1H), 2.40 (s, 4H), 2.43 (d, 2H), 2.25 (s, 2H), 1.66-1.46 (m, 7H).

Step 8

2-Chloro-9-(3-hydroxyadamantan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (1j)

[0140] Compound 1i (780 mg, 2.4 mmol) was dissolved in dimethylformamide (10 mL), and dimethyl sulfate (307 mg, 2.4 mmol) and cesium carbonate (1.5 g, 4.8 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 h. 20 mL of water was then added, followed by extraction with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated, and a solid precipitated. The solid was collected by filtration to give the title compound 1j (white solid, 397 mg, 49% yield).

[0141] .sup.1H NMR (400 MHz DMSO) δ 8.30 (s, 1H), 3.29 (s, 3H), 2.40 (s, 4H), 2.43 (d, 2H), 2.25 (s, 2H), 1.65-1.46 (m, 7H).

Step 9

9-(3-Hydroxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 1)

[0142] Compound 1j (372 mg, 0.14 mmol), compound 1e (132 mg, 0.1 mmol), cesium carbonate (130 mg, 0.4 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (50 mg, 0.08 mmol) were dissolved in dioxane, followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 1 (white solid, 12.6 mg, 2.5% yield).

[0143] .sup.1H NMR (400 MHz DMSO) δ 9.09 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 4.56 (s, 1H), 3.24 (s, 3H), 2.39 (d, 9H), 2.17 (s, 2H), 1.58-1.23 (m, 6H).

Example 2

9-(3-Hydroxyadamantan-1-yl)-7-methyl-2-((7-methylquinolin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 2)

[0144] ##STR00042##

[0145] Compound 1j (200 mg, 0.6 mmol), 7-methylquinolin-6-amine 2a (94.6 mg, 0.6 mmol), cesium carbonate (384.4 mg, 1.2 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (55 mg, 0.06 mmol) were dissolved in 2 mL of dioxane, followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=35/1) followed by preparative HPLC to give compound 2 (yellow solid, 45 mg, 35% yield).

[0146] .sup.1H NMR (400 MHz DMSO) δ 9.04 (d, 1H), 9.03 (s, 1H), 8.92 (t, 1H), 8.60 (s, 1H), 8.04 (s, 1H), 7.88 (q, 1H), 3.29 (s, 3H), 2.63 (s, 3H), 2.37-2.51 (m, 6H), 2.18 (s, 2H), 1.56 (q, 4H), 1.44 (q, 2H).

[0147] LC-MS m/z (ESI)=457.20 [M+1].

Example 3

tert-Butyl-3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate (Compound 3)

[0148] ##STR00043## ##STR00044##

Step 1

tert-Butyl 3-aminoadamantane-1-carboxylate (3b)

[0149] Compound 3a (10 g, 51.21 mmol) was dissolved in thionyl chloride (70 mL). The reaction mixture was refluxed at 90° C. for 1 h. The reaction mixture was directly concentrated, and the residue was re-dissolved in toluene (50 mL). The resulting solution was concentrated to remove excess thionyl chloride, and tert-butanol (60 mL) was added under an ice bath. The reaction mixture was then reacted at room temperature for 1 h, with the reaction monitored by TLC until its completion. The reaction mixture was directly concentrated, and the solid was collected to give the target compound 3b (white solid, 12 g, 93.22% yield).

[0150] LC-MS m/z (ESI)=252.20 [M+1].

Step 2

Ethyl 4-(((1s,3r,5R,7S)-3-(tert-butoxycarbonyl)adamantan-1-yl)amino)-2-chloropyrimidine-5-carboxylate (3c)

[0151] Compound 1f (12 g, 54.29 mmol), compound 3b (13.65 g, 54.29 mmol) and potassium carbonate (15.01 g, 108.58 mmol) were dissolved in acetonitrile (150 mL). The reaction mixture was allowed to react at room temperature for 16 h. The reaction was monitored by TLC until its completion. The reaction mixture was filtered, and the solid was washed with a small amount of acetonitrile. The filtrates were combined and concentrated. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to give the target compound 3c (white solid, 15 g, 63.38% yield).

[0152] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.63 (s, 1H), 8.36 (s, 1H), 4.30 (q, 2H), 2.00-2.18 (m, 8H), 1.61-1.73 (m, 6H), 1.38 (s, 9H), 1.31 (t, 3H).

Step 3

4-((3-(tert-Butoxycarbonyl)adamantan-1-yl)amino)-2-chloropyrimidine-5-carboxylic acid (3d)

[0153] Compound 3c (15 g, 34.41 mmol) was dissolved in 200 mL of tetrahydrofuran and 200 mL of water, and lithium hydroxide (1.65 g, 68.82 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated to remove tetrahydrofuran and adjusted to pH 5 with 6N hydrochloric acid, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with petroleum ether and collected to give the title compound 3d (white solid, 14 g, 99.75% yield).

[0154] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.65 (s, 1H), 8.58 (s, 1H), 2.01-2.17 (m, 8H), 1.57-1.77 (m, 6H), 1.38 (s, 9H).

[0155] LC-MS m/z (ESI)=408.10 [M+1].

Step 4

tert-Butyl-3-(2-chloro-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate (3e)

[0156] Compound 3d (15 g, 36.77 mmol) was dissolved in N,N-dimethylacetamide (150 mL), and diphenylphosphoryl azide (7.91 mL, 36.77 mmol) and triethylamine (5.11 mL, 36.77 mmol) were added under an ice bath. The reaction mixture was stirred at room temperature for 1 h, then warmed to 120° C., and allowed to react for another 3 h. The reaction was monitored by TLC (dichloromethane/methanol (v/v)=4/1) until its completion. The reaction mixture was allowed to naturally cool to room temperature and poured slowly into 600 mL of ice water, and a large amount of solid appeared. The solid was collected by filtration, triturated with ethyl acetate (150 mL), and dried in vacuo to give the target compound 3e (white solid, 7.0 g, 47.02% yield).

[0157] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.56 (s, 1H), 8.07 (s, 1H), 2.44-2.57 (m, 6H), 2.23 (s, 2H), 1.58-1.80 (m, 6H), 1.39 (s, 9H).

Step 5

tert-Butyl 3-(2-chloro-7-methyl-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate (3f)

[0158] Compound 3e (5 g, 12.35 mmol) was dissolved in dimethylformamide (40 mL), and cesium carbonate (6.04 g, 18.52 mL) and dimethyl sulfate (1.4 mL, 14.82 mmol) were added at 0° C. The reaction mixture was allowed to react at room temperature for 2 h. The reaction was monitored by TLC until its completion. 100 mL of water was added, and a solid precipitated. The solid was collected by filtration and dried to give the target compound 3f (white solid, 5.0 g, 96.64% yield).

[0159] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 3.29 (s, 3H), 2.43-2.56 (m, 6H), 2.24 (s, 2H), 1.54-1.80 (m, 6H), 1.38 (s, 9H).

Step 6

tert-Butyl 3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate (Compound 3)

[0160] Compound 1e (500 mg, 3.37 mmol), compound 3f (1.41 g, 3.37 mmol), cesium carbonate (2.31 g, 7.08 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (310 mg, 0.34 mmol) were dissolved in dioxane (10 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1) to give compound 3 (white solid, 1.4 g, 78.29% yield).

[0161] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.08 (s, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 3.24 (s, 3H), 2.33-2.61 (m, 6H), 2.14 (s, 2H), 1.51-1.67 (m, 6H), 1.32 (s, 9H).

[0162] LC-MS m/z (ESI)=531.3 [M+1].

Example 4

3-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylic Acid (Compound 4)

[0163] ##STR00045##

[0164] Compound 3 (1.4 g, 2.64 mmol) was dissolved in 4N dioxane hydrochloride solution (100 mL). The mixture was allowed to react at room temperature for 16 h and concentrated, and the residue was purified by preparative medium pressure liquid chromatography to give compound 4 (pale yellow solid, 1.4 g, 99% yield).

[0165] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.15 (s, 1H), 9.07 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 3.24 (s, 3H), 2.41-2.58 (m, 6H), 2.38 (s, 3H), 2.14 (s, 2H), 1.56-1.71 (m, 6H).

[0166] LC-MS m/z (ESI)=475.20 [M+1].

Example 5

3-(7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxamide (Compound 5)

[0167] ##STR00046##

[0168] Compound 4 (0.5 g, 1.05 mmol), ammonium chloride (0.56 g, 10.50 mmol) and triethylamine (0.73 mL, 5.25 mmol) were dissolved in N,N-dimethylformamide (15 mL), and HATU (0.6 g, 1.58 mmol) was added under an ice bath. The mixture was allowed to react at room temperature for 1 h, quenched with water (30 mL), and extracted with ethyl acetate (30 mL×3). The organic phase was dried and concentrated to give compound 5 (white solid, 0.14 g, 28.16% yield).

[0169] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.08 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.68 (s, 1H), 6.97 (s, 1H), 6.74 (s, 1H), 3.24 (s, 3H), 2.33-2.62 (m, 9H), 2.15 (s, 2H), 1.51-1.73 (m, 4H).

[0170] LC-MS m/z (ESI)=474.3 [M+1].

Example 6

3-(7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carbonitrile (Compound 6)

[0171] ##STR00047##

[0172] Compound 5 (130 mg, 0.27 mmol) was dissolved in dichloromethane (20 mL), and pyridine (90 mg, 1.08 mmol) and trifluoroacetic anhydride (170 mg, 0.81 mmol) were added under an ice bath. The reaction mixture was allowed to react for another hour with the temperature maintained. Methanol (20 mL) was added, and the crude product was concentrated. The crude product was re-dissolved in ethyl acetate (50 mL), and the resulting solution was washed successively with 15% NaHCO.sub.3 (50 mL) and saturated brine (50 mL), dried, and concentrated to give Compound 6 (pale yellow solid, 60 mg, 48.78% yield).

[0173] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.07 (s, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 3.25 (s, 3H), 2.75 (s, 2H), 2.44-2.51 (m, 4H), 2.38 (s, 3H), 2.15 (s, 2H), 1.91-1.94 (m, 4H), 1.53-1.62 (m, 2H).

[0174] LC-MS m/z (ESI)=456.2 [M+1].

Example 7

Ethyl-3-(7-methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-8-oxo-8,9-dihydro-7H-purin-9-yl)adamantane-1-carboxylate (Compound 7)

[0175] ##STR00048##

[0176] Compound 4 (0.5 g, 1.05 mmol) was dissolved in ethanol (20 mL), and 2 drops of concentrated sulfuric acid were added. The reaction mixture was directly heated to 90° C. and refluxed for 2 h. The reaction was monitored by LCMS until its completion. The reaction mixture was brought back to room temperature, and solid sodium carbonate was added until no bubble produced. The reaction mixture was filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by preparative medium pressure liquid chromatography (100% acetonitrile) to give compound 7 (white solid, 0.3 g, 56.85% yield).

[0177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.68 (s, 1H), 3.98 (q, 2H), 3.24 (s, 3H), 2.41-2.57 (m, 4H), 2.38 (s, 3H), 2.15 (s, 2H), 1.57-1.71 (m, 6H), 1.10 (t, 3H).

[0178] LC-MS m/z (ESI)=503.3 [M+1].

Example 8

7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-[3-(hydroxymethyl)adamantan-1-yl]-8,9-dihydro-7H-purin-8-one (Compound 8)

[0179] ##STR00049##

[0180] Compound 7 (200 mg, 0.4 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (0.8 mL, 0.8 mmol, 1 M) was added under an ice bath. The reaction mixture was allowed to react under the ice bath for 30 min. 30 μL of deionized water, 15% sodium hydroxide solution, 90 μL of deionized water and 1 g of anhydrous magnesium sulfate were successively added. The reaction mixture was stirred at room temperature for another 30 min and filtered, and the filtrate was concentrated to give a crude product, which was then purified by column chromatography to give compound 8 (white solid, 60 mg, 32.01% yield).

[0181] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 4.36 (t, 1H), 3.24 (s, 3H), 2.95 (d, 2H), 2.46 (s, 2H), 2.41 (s, 2H), 2.38 (s, 3H), 2.15 (s, 2H), 2.10 (s, 2H) 1.36-1.58 (m, 6H).

[0182] LC-MS m/z (ESI)=461.2 [M+1].

Example 9

7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-[3-(morpholine-4-carbonyl)adamantan-1-yl]-8,9-dihydro-7H-purin-8-one (Compound 9)

[0183] ##STR00050##

[0184] Compound 4 (50 mg, 0.11 mmol), morpholine (28.75 mg, 0.33 mmol) and triethylamine (55.65 mg, 0.55 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (209.13 mg, 0.55 mmol) was added under an ice bath. The reaction mixture was allowed to react at room temperature for another hour. The reaction was monitored by TLC until its completion. The reaction mixture was diluted with water (30 mL) and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by preparative medium pressure liquid chromatography to give compound 9 (white solid, 22 mg, 35.73% yield).

[0185] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.09 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 3.51 (d, 7H), 3.24 (s, 3H), 2.67 (d, 2H), 2.60 (s, 2H), 2.38 (s, 3H), 2.34 (d, 2H), 2.17 (s, 2H), 1.79-1.85 (m, 4H), 1.56-1.63 (m, 2H).

[0186] LC-MS m/z (ESI)=544.30 [M+1].

Example 10

7-Methyl-2-[(7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino]-9-[3-aminoadamantan-1-yl]—8,9-dihydro-7H-purin-8-one (Compound 10)

[0187] ##STR00051##

[0188] Compound 4 (50 mg, 0.11 mmol) was dissolved in tert-butanol (10 mL), and diphenylphosphoryl azide (42.39 mg, 0.11 mmol) and triethylamine (11.13 mg, 0.11 mmol) were added under an ice bath. The reaction mixture was allowed to react at room temperature for 1 h and then refluxed at 90° C. for 1 h. The reaction mixture was allowed to naturally cool to room temperature and slowly added to 2 mL of concentrated sulfuric acid. The resulting liquid was added dropwise to 50 mL of ice water, and the resulting liquid was concentrated to dryness. The residue was purified by preparative medium pressure liquid chromatography to give compound 10 (white solid, 4 mg, 7.92% yield).

[0189] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.12 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 8.11 (s, 1H), 7.71 (s, 1H), 3.25 (s, 3H), 2.32-2.44 (m, 9H), 2.15 (s, 2H), 1.86 (s, 2H), 1.41-1.53 (m, 6H).

[0190] LC-MS m/z (ESI)=446.20 [M+1].

Example 11

9-(3-Methoxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 11)

[0191] ##STR00052##

Step 1

2-Chloro-9-(3-methoxyadamantan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (11a)

[0192] Compound 1j (160 mg, 0.48 mmol) and sodium hydride (38.23 mg, 0.96 mmol) were dissolved in N,N-dimethylformamide (10 mL), followed by nitrogen purging, and iodomethane (101.75 mg, 0.72 mmol) was added dropwise under an ice bath. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 11a (white solid, 100 mg, 59.72% yield).

[0193] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.32 (s, 1H), 3.30 (s, 3H), 3.15 (s, 3H), 2.38-2.46 (m, 6H), 2.33 (s, 2H), 1.50-1.72 (m, 6H).

[0194] LC-MS m/z (ESI)=349.10 [M+1].

Step 2

9-(3-Methoxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 11)

[0195] Compound 11a (120 mg, 0.34 mmol), cesium carbonate (220 mg, 0.68 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (30 mg, 0.03 mmol) were dissolved in dioxane (5 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1) to give compound 11 (white solid, 12 mg, 7.66% yield).

[0196] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 9.04 (s, 1H), 8.60 (s, 1H), 8.37 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 3.24 (s, 3H), 2.92 (s, 3H), 2.36-2.38 (m, 9H), 2.22 (s, 2H), 1.60-1.42 (m, 6H).

[0197] LC-MS m/z (ESI)=461.2 [M+1].

Example 12

4-((9-3-Hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzonitrile (Compound 12)

[0198] ##STR00053##

[0199] Compound 12a (100 mg, 0.76 mmol), compound 1j (250 mg, 0.76 mmol), cesium carbonate (500 mg, 1.52 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (70 mg, 0.08 mmol) were dissolved in dioxane (10 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 12 (white solid, 60 mg, 17.61% yield).

[0200] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.54 (s, 1H), 8.16 (s, 1H), 8.07 (d, 1H), 7.62 (s, 1H), 7.58 (d, 1H), 4.66 (s, 1H), 3.26 (s, 3H), 2.37 (m, 9H), 2.24 (s, 2H), 1.46-1.66 (m, 6H).

[0201] LC-MS m/z (ESI)=431.20 [M+1].

Example 13

4-((9-(5-Hydroxyadamantan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzonitrile (Compound 13)

[0202] ##STR00054##

Step 1

4-Aminoadamantan-1-ol (13b)

[0203] Compound 13a (9 g, 54.2 mmol) was dissolved in methanol (50 mL), and 910 mg of 4A molecular sieve was added, followed by 10 mL of aminomethanol solution. The reaction mixture was stirred at room temperature for 20 h. The reaction was monitored by TLC until its completion. The reaction mixture was filtered, and the filtrate was concentrated to give compound 13b (white solid, 7.8 g, 85% yield).

[0204] .sup.1H NMR (400 MHz DMSO) δ 4.256 (m, 1H), 2.735 (d, 1H), 1.936 (m, 4H), 1.792 (m, 1H), 1.698 (s, 1H), 1.578 (m, 8H), 1.216 (m, 2H).

[0205] LC-MS m/z (ESI)=168.2 [M+1].

Step 2

Ethyl 2-chloro-4-((5-hydroxyadamantan-2-yl)amino)pyrimidine-5-carboxylate (13c)

[0206] Compound 1f (7.8 g, 46.7 mmol) and potassium carbonate (6.2 g, 44.8 mmol) were dissolved in acetonitrile (20 mL), and compound 13b (10.3 g, 46.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 20 h. 30 mL of water was added, and a white solid precipitated. The solid was collected by filtration to give compound 13c (white solid, 10 g, 92% yield).

[0207] .sup.1H NMR (400 MHz DMSO) δ 8.79 (t, 1H), 8.640 (d, 1H), 4.345 (m, 2H), 4.123 (m, 1H), 2.086 (s, 2H), 1.767 (m, 1H), 1.607 (m, 2H), 1.353 (m, 9H), 1.212 (m, 3H).

[0208] LC-MS m/z (ESI)=353.2 [M+1].

Step 3

2-Chloro-4-((5-hydroxyadamantan-2-yl)amino)pyrimidine-5-carboxylic Acid (13d)

[0209] Compound 13c (10 g, 28.4 mmol) was dissolved in 50 mL of tetrahydrofuran and 30 mL of water, and lithium hydroxide (2.4 g, 56.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until its completion. Tetrahydrofuran was removed by rotary evaporation. The pH was adjusted to 4-5, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with petroleum ether/ethyl acetate (v/v=10/1). The filtrate was concentrated to give compound 13d (white solid, 8.6 g, 83% yield), which was directly used in the next step.

[0210] .sup.1H NMR (400 MHz DMSO) δ 13.903 (S, 1H), 9.034 (d, 1H), 8.583 (d, 1H), 4.038 (m, 1H), 2.089 (m, 3H), 1.686 (m, 9H), 1.521 (m, 2H).

[0211] LC-MS m/z (ESI)=325.2 [M+1].

Step 4

2-Chloro-9-(5-hydroxyadamantan-2-yl)-7,9-dihydro-8H-purin-8-one (13e)

[0212] Compound 13d (4 g, 12.3 mmol) was dissolved in dimethylacetamide (10 mL), and triethylamine (1.2 g, 12.3 mmol) and diphenylphosphoryl azide (3.4 g, 12.3 mmol) were added. The reaction mixture was then gradually warmed to 120° C. and stirred for 1.5 h. The reaction was monitored by TLC until its completion. 30 mL of water was added, and a white solid precipitated. The solid was collected by filtration to give compound 13e (white solid, 1.36 g, 36% yield).

[0213] .sup.1H NMR (400 MHz DMSO) δ 11.606 (s, 1H), 8.098 (d, 1H), 4.446 (m, 1H), 4.223 (d, 1H), 2.999 (m, 2H), 2.128 (m, 3H), 1.780 (m, 6H), 1.460 (m, 2H).

[0214] LC-MS m/z (ESI)=321.2 [M+1].

Step 5

2-Chloro-9-(5-hydroxyadamantan-2-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (13f)

[0215] Compound 13e (1.36 g, 4.25 mmol) was dissolved in dimethylformamide (10 mL), and dimethyl sulfate (535.5 mg, 4.25 mmol) and cesium carbonate (923 mg, 7.8 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction was monitored by TLC until its completion. 10 mL of water was then added, followed by three extractions with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and a solid precipitated. The solid was collected by filtration to give compound 13f (white solid, 423 mg, 63% yield).

[0216] .sup.1H NMR (400 MHz DMSO) δ 8.327 (s, 1H), 4.489 (d, 1H), 4.203 (d, 1H), 3.330 (s, 3H), 2.989 (s, 2H), 20.79 (m, 3H), 1.730 (m, 6H), 1.455 (m, 2H).

[0217] LC-MS m/z (ESI)=335.2 [M+1].

Step 6

4-((9-(5-Hydroxyadamantan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzonitrile (Compound 13)

[0218] Compound 13f (314 mg, 1.0 mmol), compound 12a (132 mg, 1.0 mmol), cesium carbonate (977 mg, 3 mmol), tris(dibenzylideneacetone)dipalladium (146 mg, 0.16 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (90.6 mg, 0.1 mmol) were dissolved in dioxane, followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) followed by preparative HPLC to give compound 13 (i.e., compound 13-1 and compound 13-2) as two white solids: compound 13-1 (45 mg, 13% yield, RT=5.55, dr %: 99.56%), and compound 13-2 (30 mg, 9.8%, RT=5.70, dr %: 99.18%). Mobile phase: acetonitrile/0.01 mol/L NH.sub.4HCO.sub.3—H.sub.2=46/54; column temperature: 35° C.; column pressure: 80 bar; flow rate: 20 mL/min; diode array detector at a wavelength of 200-300 nm.

Compound 13-1

[0219] .sup.1H NMR (400 MHz DMSO) δ 8.57 (s, 1H), 8.15 (s, 1H), 7.97 (d, 1H), 7.62 (d, 1H), 7.56 (dd, 1H), 4.49 (s, 1H), 4.24 (s, 1H), 3.29 (s, 3H), 3.01 (d, 2H), 2.29 (s, 3H), 2.07 (d, 2H), 1.99 (s, 1H), 1.68-1.79 (d, 4H), 1.64 (S, 2H), 1.38 (d, 2H).

[0220] LC-MS m/z (ESI)=431.2 [M+1].

Compound 13-2

[0221] .sup.1H NMR (400 MHz DMSO) δ 8.54 (s, 1H), 8.16 (s, 1H), 8.02 (d, 1H), 7.61 (s, 1H), 7.57 (dd, 1H), 4.34 (s, 1H), 4.14 (s, 1H), 3.29 (s, 3H), 3.16 (s, 3H), 2.30 (s, 3H), 2.01-2.07 (m, 3H), 1.67-1.76 (m, 4H), 1.60 (s, 2H), 1.44 (d, 2H).

[0222] LC-MS m/z (ESI)=431.2 [M+1].

Example 14

4-((9-(3-Hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-3-methylbenzamide (Compound 14)

[0223] ##STR00055##

[0224] Compound 14a (100 mg, 0.76 mmol), compound 1j (270 mg, 0.8 mmol), cesium carbonate (440 mg, 1.34 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (61 mg, 0.08 mmol) were dissolved in dioxane (10 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 14 (white solid, 60 mg, 17.61% yield).

[0225] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.31 (s, 1H), 8.10 (s, 1H), 7.87 (d, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 7.67 (d, 1H), 7.15 (s, 1H), 4.63 (s, 1H), 3.25 (s, 3H), 2.40 (m, 6H), 2.30 (s, 3H), 2.23 (s, 2H), 1.45-1.65 (m, 6H).

[0226] LC-MS m/z (ESI)=449.20 [M+1].

Example 15

5-((9-(3-Hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-N,4-dimethylpicolinamide (Compound 15)

[0227] ##STR00056##

[0228] Compound 1j (190 mg, 0.6 mmol), compound 15a (100 mg, 0.6 mmol), cesium carbonate (391 mg, 1.2 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (55 mg, 0.06 mmol) were dissolved in 2 mL of dioxane, followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=35/1) followed by Pre-HPLC to give compound 15 (yellow solid, 86 mg, 89% yield).

[0229] .sup.1H NMR (400 MHz DMSO) δ 8.77 (s, 1H), 8.71 (s, 1H), 8.55 (m, 1H), 8.071 (s, 1H), 7.86 (s, 1H), 4.60 (S, 1H), 3.24 (S, 1H), 2.80 (d, 3H), 2.32-2.40 (s, 8H), 2.20 (m, 2H), 1.34-1.62 (m, 6H).

[0230] LC-MS m/z (ESI)=464.20 [M+1].

Example 16

9-((1R,2r,3S,5s,7s)-5-hydroxyadamantan-2-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 16)

[0231] ##STR00057##

[0232] CoCommpound 13f (200 mg, 0.59 mmol), compound 1e (88 mg, 0.59 mmol), cesium carbonate (576 mg, 1.77 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (54 mg, 0.059 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=35/1) followed by Pre-HPLC to give compound 16 (i.e., compound 16-1 and compound 16-2) as two white solids: compound 16-1 (39 mg, 15.1% yield, RT=3.53, dr %: 99.01%), and compound 16-2 (5 mg, 6.2% yield, RT=3.70, dr %: 99.21%). Pre-HPLC (OZ), mobile phase: acetonitrile/0.01 mol/L NH.sub.4HCO.sub.3—H.sub.2=45/55; column temperature: 35° C.; column pressure: 80 bar; flow rate: 20 mL/min; diode array detector at a wavelength of 200-300 nm.

Compound 16-1

[0233] .sup.1H NMR (400 MHz DMSO) δ 8.999 (s, 1H), 8.558 (s, 1H), 8.373 (s, 1H), 8.097 (s, 2H), 7.690 (s, 1H), 4.456 (s, 1H), 4.201 (s, 1H), 3.293 (s, 3H), 2.908 (s, 2H), 2.355 (s, 3H), 2.031 (d, 2H), 1.821 (s, 1H), 1.365 (dd, 3H), 1.551 (s, 1H), 1.225 (d, 2H).

[0234] LC-MS m/z (ESI)=447.2 [M+1].

Compound 16-2

[0235] .sup.1H NMR (400 MHz DMSO) δ 9.077 (s, 1H), 8.533 (s, 1H), 8.366 (s, 1H), 8.102 (s, 2H), 7.682 (s, 1H), 4.299 (s, 1H), 4.119 (s, 1H), 3.280 (s, 3H), 3.148 (s, 2H), 2.385 (s, 3H), 1.950 (m, 3H), 1.634 (m, 5H), 1.352 (d, 2H).

[0236] LC-MS m/z (ESI)=447.2 [M+1].

Example 17

2-Fluoro-4-(4-hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-5-methylbenzamide (Compound 17)

[0237] ##STR00058##

Step 1

Ethyl 2-chloro-4-(4-oxoadamantan-1-yl)amino)pyrimidine-5-carboxylate (17b)

[0238] Compound 1f (3.7 g, 16.7 mmol) and potassium carbonate (6.9 g, 50.1 mmol) were dissolved in acetonitrile (20 mL), and compound 17a (2.7 g, 16.7 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 20 h. Water (30 mL) was added, followed by extraction with ethyl acetate (60 mL×3). The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and mixed with silica gel to prepare a sample, which was then applied in the purification by silica gel column chromatography (n-hexane:ethyl acetate=10:1), followed by concentration to give compound 17b (white solid, 4 g, 69% yield).

[0239] .sup.1H NMR (400 MHz DMSO) δ 8.65 (s, 1H), 8.38 (s, 1H), 4.28-4.34 (m, 1H), 2.49-2.52 (m, 2H), 2.24-2.36 (m, 5H), 2.01-2.05 (m, 2H), 1.87-1.90 (m, 2H), 1.31 (t, 3H).

[0240] LC-MS m/z (ESI)=350.10 [M+1].

Step 2

2-Chloro-4-(4-oxoadamantan-1-yl)amino)pyrimidine-5-carboxylic acid (17c)

[0241] Compound 17b (4 g, 11.5 mmol) was dissolved in 5 mL of tetrahydrofuran and 5 mL of water, and lithium hydroxide (966 mg, 23 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. Tetrahydrofuran was removed by rotary evaporation. The pH was adjusted to 4-5, and a white solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with petroleum ether/ethyl acetate (v/v=10/1). The filtrate was concentrated to give compound 17c (white solid, 3.2 g, 99% yield).

[0242] .sup.1H NMR (400 MHz DMSO) δ 11.64 (s, 1H), 8.10 (s, 1H), 2.85-2.86 (m, 2H), 2.71-2.77 (m, 4H), 2.57-2.61 (m, 2H), 2.28-2.33 (m, 1H), 2.04-2.13 (m, 2H), 1.87-1.95 (m, 2H).

[0243] LC-MS m/z (ESI)=322.10 [M+1].

Step 3

2-Chloro-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (17d)

[0244] Compound 17c (3.7 g, 11.5 mmol) was dissolved in dimethylacetamide (10 mL), and triethylamine (1.1 g, 11.5 mmol) and diphenylphosphoryl azide (3.2 g, 11.5 mmol) were added. The reaction mixture was then gradually warmed to 110° C. and stirred for 1.5 h. The reaction mixture was concentrated, followed by addition of 30 mL of water, and a white solid precipitated. The solid was collected by filtration to give compound 17d (white solid, 3.3 g, 83% yield).

[0245] LC-MS m/z (ESI)=319.10 [M+1]

Step 4

2-Chloro-7-methyl-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (17e)

[0246] Compound 17d (3.3 g, 10.3 mmol) was dissolved in dimethylformamide (10 mL), and dimethyl sulfate (1.3 g, 10.3 mmol) and cesium carbonate (6.7 g, 20.6 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. 20 mL of water was then added, and a solid precipitated. The solid was collected by filtration to give compound 17e (white solid, 2.9 g, 86% yield).

[0247] 1H NMR (400 MHz DMSO) δ 8.34 (s, 1H), 3.31 (s, 3H), 2.96-2.99 (m, 2H), 2.72-2.88 (m, 4H), 2.62-2.67 (m, 2H), 2.30 (S, 2H), 2.06-2.14 (m, 2H), 1.88-1.93 (m, 2H).

[0248] LC-MS m/z (ESI)=333.10 [M+1]

Step 5

2-Chloro-9-(4-hydroxyadamantan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-oneile (17f)

[0249] Compound 17e (600 mg, 0.3 mmol) was dissolved in 5 mL of methanol, and sodium borohydride (23 mg, 0.6 mmol) was added in batches at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=40/1) to give compound 17f (white solid, 566 mg, 92% yield).

[0250] .sup.1H NMR (400 MHz DMSO) δ 8.31 (d, 1H), 3.68 (d, 1H), 3.03 (s, 3H), 2.76 (d, 1H), 2.61 (d, 1H), 2.38-2.49 (m, 4H), 1.97-2.07 (m, 4H), 1.76 (d, 1H), 1.40-1.62 (m, 2H).

[0251] LC-MS m/z (ESI)=335.10 [M+1].

Step 6

2-Fluoro-4-(4-hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-5-methylbenzamide (Compound 17)

[0252] Compound 17f (200 mg, 0.6 mmol), 4-amino-2-fluoro-5-methylbenzamide (201 mg, 1.2 mmol), cesium carbonate (586 mg, 1.8 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (54.4 mg, 0.06 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) followed by Pre-HPLC to give compound 17 (i.e., compound 17-1 and compound 17-2) as two white solids: compound 17-1 (27 mg, 31% yield, RT=6.26, dr %: 99.44%), and compound 17-2 (12 mg, 16% yield, RT=6.53, dr %: 99.50%). Pre-HPLC (OZ), mobile phase: acetonitrile/0.01 mol/L NH.sub.4HCO.sub.3—H.sub.2=46/54; column temperature: 34° C.; column pressure: 80 bar; flow rate: 20 mL/min; diode array detector at a wavelength of 200-300 nm.

Compound 17-1

[0253] .sup.1H NMR (400 MHz DMSO) δ 8.41 (s, 1H), 8.17 (s, 1H), 7.86 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 4.71 (s, 1H), 3.77 (m, 1H), 3.26 (s, 3H), 2.65 (m, 2H), 2.50-2.51 (m, 3H), 2.89 (s, 3H), 1.96-2.06 (m, 5H), 1.42 (m, 2H).

[0254] LC-MS m/z (ESI)=467.20 [M+1]

Compound 17-2

[0255] .sup.1H NMR (400 MHz DMSO) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.87 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 4.71 (d, 1H), 3.59 (m, 1H), 3.26 (s, 3H), 2.71 (m, 2H), 2.44-2.52 (m, 4H), 2.29 (s, 3H), 2.02 (s, 3H), 1.75-1.19 (m, 2H), 1.58-1.61 (m, 2H).

[0256] LC-MS m/z (ESI)=467.20 [M+1]

Example 18

9-(4-Hydroxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 18)

[0257] ##STR00059##

[0258] Compound 17f (200 mg, 0.6 mmol), compound 1e (88.8 mg, 0.6 mmol), cesium carbonate (586 mg, 1.8 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (54.4 mg, 0.06 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) followed by Pre-HPLC to give compound 18 (i.e., compound 18-1 and compound 18-2) as two white solids: compound 18-2 (44 mg, 36% yield, RT=6.03, dr %: 98.56%), and compound 17-1 (58 mg, 43% yield, RT=6.51, dr %: 98.98%). Pre-HPLC (OZ), mobile phase: acetonitrile/0.01 mol/L NH.sub.4HCO.sub.3—H.sub.2=43/57; column temperature: 34° C.; column pressure: 80 bar; flow rate: 20 mL/min; diode array detector at a wavelength of 200-300 nm.

Compound 18-1

[0259] .sup.1H NMR (400 MHz DMSO) δ 9.10 (s, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 4.64 (d, 1H), 3.70 (d, 1H), 3.24 (s, 3H), 2.62 (d, 2H), 2.42 (s, 3H), 2.39 (s, 4H), 1.97 (d, 2H), 1.90 (d, 3H), 1.29 (d, 2H).

[0260] LC-MS m/z (ESI)=447.20 [M+1]

Compound 18-2

[0261] .sup.1H NMR (400 MHz DMSO) δ 9.09 (s, 1H), 8.52 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 4.66 (d, 1H), 3.55 (d, 1H), 3.23 (s, 3H), 2.64 (d, 2H), 2.45 (s, 2H), 2.39 (s, 3H), 2.37 (s, 2H), 1.93 (d, 3H), 1.63 (d, 2H), 1.52 (d, 2H).

[0262] LC-MS m/z (ESI)=447.20 [M+1]

Example 19

7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (Compound 19)

[0263] ##STR00060##

[0264] Compound 17e (200 mg, 0.68 mmol), compound 1e (89 mg, 0.68 mmol), cesium carbonate (391 mg, 1.2 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (62 mg, 0.068 mmol) were dissolved in dioxane (3 mL), followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) followed by Pre-HPLC to give compound 19 (white solid, 68 mg, 22.4% yield).

[0265] .sup.1H NMR (400 MHz DMSO) δ 9.11 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 3.25 (s, 3H), 2.93-2.96 (m, 2H), 2.66-2.69 (m, 4H), 2.39 (s, 3H), 2.16-2.20 (m, 1H), 1.94-1.99 (m, 2H), 1.81-1.84 (m, 2H), 1.34-1.49 (m, 2H).

[0266] LC-MS m/z (ESI)=445.20 [M+1].

Example 20

9-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 20)

[0267] ##STR00061##

Step 1

2-Chloro-9-(4-hydroxyadamantan-1-yl-4-d)-7-methyl-7,9-dihydro-8H-purin-8-one (20a)

[0268] Compound 17e (600 mg, 1.8 mmol) was dissolved in 10 mL of tetrahydrofuran, and lithium aluminium hydride (76 mg, 1.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, with the reaction monitored by TLC until its completion. Water:10% aqueous sodium hydroxide solution:water=1:2:3 was added under an ice bath to quench the reaction, and a solid precipitated. The reaction mixture was filtered, and the filtrate was concentrated to give compound 20a (white solid, 511 mg, 83% yield).

[0269] .sup.1H NMR (400 MHz DMSO) δ 8.30 (d, 1H), 4.70 (d, 1H), 3.30 (s, 3H), 3.18 (d, 1H), 2.76 (d, 1H), 2.59-2.63 (m, 1H), 2.36-2.51 (m, 3H), 1.97-2.07 (m, 4H), 1.59-1.77 (m, 2H), 1.40-1.43 (m, 1H).

[0270] LC-MS m/z (ESI)=336.20 [M+1].

Step 2

9-(Hydroxyadamantan-1-yl-4-d)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 20)

[0271] Compound 20a (200 mg, 0.59 mmol), compound 1e (88 mg, 0.59 mmol), cesium carbonate (586 mg, 1.8 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (55 mg, 0.059 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) followed by Pre-HPLC to give compound 20 (i.e., compound 20-1 and compound 20-2) as two white solids: compound 20-1 (30 mg, 22% yield, RT=3.25, dr %: 98.74%), and compound 20-2 (64 mg, 44.1% yield, RT=4.66, dr %: 98.92%). Pre-HPLC (OZ), mobile phase: CO.sub.2/(0.3% ethylenediamine/ethanol)=75/25; column temperature: 35° C.; column pressure: 80 bar; flow rate: 1 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

Compound 20-1

[0272] .sup.1H NMR (400 MHz DMSO) δ 9.10 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 4.63 (s, 1H), 3.24 (s, 3H), 2.64-2.67 (m, 2H), 2.36-2.45 (m, 7H), 1.91-1.95 (m, 3H), 1.62-1.65 (m, 2H), 1.51-1.54 (m, 2H).

[0273] LC-MS m/z (ESI)=448.20 [M+1].

Compound 20-2

[0274] .sup.1H NMR (400 MHz DMSO) δ 9.10 (s, 1H), 8.54 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 4.61 (s, 1H), 3.24 (s, 3H), 2.59-2.67 (m, 2H), 2.32-2.42 (m, 7H), 1.88-1.99 (m, 5H), 1.23-1.40 (m, 2H).

[0275] LC-MS m/z (ESI)=448.20 [M+1].

Example 21

5-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-2-carbonitrile (Compound 21)

[0276] ##STR00062##

Step 1

5-(2-Chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-2-carbonitrile (21a)

[0277] Compound 17e (800 mg, 2.4 mmol), p-toluenesulfonylmethyl isocyanide (610 mg, 3.12 mmol) and potassium tert-butoxide (672 mg, 6 mmol) were dissolved in 16 mL of dioxane, and 3 mL of ethanol was added. The reaction mixture was stirred at room temperature for 6 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/dichloromethane (v/v)=10/1) to give compound 21a (white solid, 533 mg, 47% yield).

[0278] LC-MS m/z (ESI)=344.20 [M+1].

Step 2

5-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-2-carbonitrile (Compound 21)

[0279] Compound 21a (200 mg, 0.58 mmol), compound 1e (86.3 mg, 0.58 mmol), cesium carbonate (567 mg, 1.74 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (53 mg, 0.058 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) followed by Pre-HPLC to give compound 21 (i.e., compound 21-1 and compound 21-2) as two white solids: compound 21-1 (23 mg, 16% yield, RT=3.92, dr %: 99.32%), and compound 21-2 (28 mg, 17.2% yield, RT=5.16, dr %: 98.96%). Pre-HPLC (OZ), mobile phase: CO.sub.2/(50% isopropanol/acetonitrile solution with 0.3% ethylenediamine added)=60/40; column temperature: 35° C.; column pressure: 80 bar; flow rate: 1 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

Compound 21-1

[0280] .sup.1H NMR (400 MHz DMSO) δ 9.11 (s, 1H), 8.54 (s, 1H), 8.35 (d, 1H), 8.10 (d, 1H), 7.69 (s, 1H), 3.25 (d, 3H), 2.68-2.72 (m, 2H), 2.60-2.64 (m, 2H), 2.45-2.46 (m, 2H), 2.38 (s, 3H), 2.31 (s, 2H), 2.05 (s, 1H), 1.62-1.69 (m, 4H).

[0281] LC-MS m/z (ESI)=456.20 [M+1].

Compound 21-2

[0282] .sup.1H NMR (400 MHz DMSO) δ 9.13 (s, 1H), 8.60 (s, 1H), 8.38 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H), 3.25 (s, 3H), 3.15-3.18 (m, 1H), 2.68-2.71 (m, 2H), 2.48-2.52 (m, 5H), 2.40 (s, 3H), 2.30 (s, 2H), 2.10 (s, 1H), 1.83-1.86 (m, 2H), 1.62-1.65 (m, 2H).

[0283] LC-MS m/z (ESI)=456.20 [M+1].

Example 22

2-Fluoro-4-((9-(3-hydroxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-5-methylbenzamide (Compound 22)

[0284] ##STR00063##

[0285] Compound 1j (200 mg, 0.59 mmol), compound 22a (201 mg, 1.19 mmol), cesium carbonate (577 mg, 1.77 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′—tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (54 mg, 0.059 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) followed by Pre-HPLC to give compound 22 (white solid, 31.4 mg, 23% yield).

[0286] .sup.1H NMR (400 MHz DMSO) δ 8.37 (s, 1H), 8.16 (s, 1H), 7.86 (d, 1H), 7.55 (d, 1H), 7.42 (d, 2H), 4.62 (s, 1H), 3.27 (s, 3H), 2.45 (s, 3H), 2.40 (m, 3H), 2.25-2.29 (m, 5H), 1.56-1.68 (m, 5H), 1.47-1.50 (m, 1H).

[0287] LC-MS m/z (ESI)=467.20 [M+1].

Example 23

4-((9-(Adamantan-1-yl-4-d)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 23)

[0288] ##STR00064##

[0289] Compound 20a (200 mg, 0.58 mmol), compound 22a (200 mg, 1.19 mmol), cesium carbonate (567 mg, 1.74 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (53 mg, 0.058 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) followed by Pre-HPLC to give compound 23 (i.e., compound 23-1 and compound 23-2) as two white solids: compound 23-1 (25.4 mg, 18.3% yield, RT=3.71, dr %: 98.37%), and compound 23-2 (10.2 mg, 8.6% yield, RT=4.73, dr %: 98.66%). Pre-HPLC (OZ), mobile phase: CO.sub.2/(0.3% ethylenediamine/ethanol)=70/30; column temperature: 35° C.; column pressure: 80 bar; flow rate: 1 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

Compound 23-1

[0290] .sup.1H NMR (400 MHz DMSO) δ 8.36 (s, 1H), 8.16 (s, 1H), 7.88 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 4.68 (s, 1H), 3.27 (s, 3H), 2.66-2.73 (m, 2H), 2.52-2.53 (m, 2H), 2.44-2.49 (m, 2H), 2.29 (s, 3H), 2.02 (m, 3H), 1.76-1.79 (m, 2H), 1.59-1.62 (m, 2H).

[0291] LC-MS m/z (ESI)=468.20 [M+1].

Compound 23-2

[0292] .sup.1H NMR (400 MHz DMSO) δ 8.40 (s, 1H), 8.17 (s, 1H), 7.88 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 4.67 (s, 1H), 3.27 (s, 3H), 2.65-2.68 (s, 2H), 2.01-2.07 (m, 3H), 1.96 (m, 2H), 1.59-1.62 (m, 2H).

[0293] LC-MS m/z (ESI)=468.20 [M+1].

Example 24

4-((9-(4-Cyanoadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 24)

[0294] ##STR00065##

[0295] Compound 21a (200 mg, 0.58 mmol), compound 22a (194 mg, 1.16 mmol), cesium carbonate (567 mg, 1.74 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (53 mg, 0.058 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) followed by Pre-HPLC to give compound 24 (i.e., compound 24-1 and compound 24-2) as two white solids: compound 24-1 (5.5 mg, 5.6% yield, RT=4.97, dr %: 98.94%), and compound 24-2 (16.8 mg, 11.3% yield, RT=5.96, dr %: 99.04%). Pre-HPLC (OZ), mobile phase: CO.sub.2/ethanol=65/35; column temperature: 35° C.; column pressure: 80 bar; flow rate: 1 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

Compound 24-1

[0296] .sup.1H NMR (400 MHz DMSO) δ 8.47 (s, 1H), 8.19 (s, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 7.38 (d, 2H), 3.29 (s, 3H), 3.15-3.27 (m, 2H), 2.67-2.77 (m, 4H), 2.38 (s, 2H), 2.28 (s, 3H), 2.11-2.13 (m, 2H), 1.77-1.83 (m, 2H), 1.70-1.76 (m, 2H).

[0297] LC-MS m/z (ESI)=476.20 [M+1].

Compound 24-2

[0298] .sup.1H NMR (400 MHz DMSO) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.88 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 3.28 (s, 3H), 2.99-3.02 (m, 2H), 2.71-2.75 (m, 4H), 3.57 (s, 3H), 2.28-2.33 (m, 4H), 2.06-2.10 (m, 2H), 1.88-1.91 (m, 2H).

[0299] LC-MS m/z (ESI)=476.20 [M+1].

Example 25

2-Fluoro-5-methyl-4-((7-methyl-8-oxo-9-(4-oxoadamantan-1-yl)-8,9-dihydro-7H-purin-2-yl)amino)benzamide (Compound 25)

[0300] ##STR00066##

[0301] Compound 17e (200 mg, 0.68 mmol), compound 22a (101 mg, 0.68 mmol), cesium carbonate (391 mg, 1.2 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (62 mg, 0.068 mmol) were dissolved in dioxane (3 mL), followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) followed by Pre-HPLC to give compound 25 (white solid, 30 mg, 13.4% yield).

[0302] .sup.1H NMR (400 MHz DMSO) δ 8.47 (s, 1H), 8.19 (s, 1H), 7.82 (d, 1H), 7.54 (d, 1H), 7.41 (d, 2H), 3.28 (s, 3H), 2.99-3.02 (m, 2H), 2.71-2.75 (m, 4H), 2.27-2.34 (m, 5H), 2.06-2.10 (m, 2H), 1.88-1.91 (m, 2H).

[0303] LC-MS m/z (ESI)=465.20 [M+1].

Example 26

4-((9-(4,4-Dimethoxyadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 26)

[0304] ##STR00067##

[0305] Compound 25 (80 mg, 0.17 mmol) was dissolved in 3 mL of methanol and 5 mL of acetonitrile, and 0.5 mL of 2 M hydrochloric acid was added. The reaction mixture was let stand at room temperature for 30 min, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by Pre-HPLC to give compound 26 (white solid, 19.5 mg, 9.6% yield).

[0306] .sup.1H NMR (400 MHz DMSO) δ 8.38 (s, 1H), 8.17 (s, 1H), 7.87 (d, 1H), 7.55 (d, 1H), 7.40 (d, 2H), 3.27 (s, 3H), 3.08 (s, 3H), 3.07 (s, 3H), 2.65-2.69 (m, 2H), 2.43-2.44 (m, 2H), 2.29-2.34 (m, 3H), 2.24 (s, 2H), 2.04-2.07 (m, 1H), 1.77-1.80 (m, 2H), 1.59-1.62 (m, 2H).

[0307] LC-MS m/z (ESI)=465.20 [M+1].

Example 27

2-Fluoro-4-((9-(5-hydroxyadamantan-2-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-5-methylbenzamide (Compound 27)

[0308] ##STR00068##

[0309] Compound 13f (200 mg, 0.59 mmol), compound 22a (201 mg, 1.19 mmol), cesium carbonate (577 mg, 1.77 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (55 mg, 0.059 mmol) were dissolved in dioxane (4 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) followed by Pre-HPLC to give compound 27 (i.e., compound 27-1 and compound 27-2) as two white solids: compound 27-1 (10 mg, 10.2% yield, RT=4.18, dr %: 99.22%), and compound 27-2 (13 mg, 11.3% yield, RT=5.25, dr %: 99.34%). Pre-HPLC (OZ), mobile phase: CO.sub.2/(50% isopropanol/acetonitrile solution with 0.3% ethylenediamine added)=60/40; column temperature: 35° C.; column pressure: 80 bar; flow rate: 1 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

Compound 27-1

[0310] .sup.1H NMR (400 MHz DMSO) δ 8.39 (s, 1H), 8.19 (s, 1H), 7.87 (d, 2H), 7.54 (d, 2H), 7.40 (d, 2H), 4.35 (s, 1H), 4.17-4.19 (m, 1H), 3.31 (s, 3H), 3.22-3.23 (m, 2H), 2.28 (s, 3H), 2.04-2.10 (m, 3H), 1.69-1.80 (m, 4H), 1.61-1.62 (m, 2H), 1.15-1.52 (m, 2H).

[0311] LC-MS m/z (ESI)=467.20 [M+1].

Compound 27-2

[0312] .sup.1H NMR (400 MHz DMSO) δ 8.40 (s, 1H), 8.18 (s, 1H), 7.80 (d, 2H), 7.53 (d, 2H), 7.41 (d, 2H), 4.49 (s, 1H), 4.26-4.28 (m, 1H), 3.30 (s, 3H), 3.09-3.10 (m, 2H), 2.28 (s, 3H), 2.01-2.11 (m, 3H), 1.80-1.83 (m, 2H), 1.65-1.73 (m, 4H), 1.39-1.49 (m, 2H).

[0313] LC-MS m/z (ESI)=467.20 [M+1].

Example 28

4-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (Compound 28)

[0314] ##STR00069## ##STR00070## ##STR00071##

Step 1

tert-Butyl-4-oxoadamantane-1-carboxylate (28b)

[0315] Compound 28a (10 g, 51.49 mmol) was dissolved in dichloromethane (100 mL), and oxalyl chloride (7.84 g, 61.79 mmol) and N,N-dimethylformamide (0.38 g, 5.15 mmol) were added under an ice bath. The reaction mixture was allowed to react at room temperature for 1 h and concentrated, and the solid was collected. tert-Butanol (100 mL) was added under an ice bath, and the reaction mixture was allowed to react for another 12 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to give the target compound 28b (white solid, 8.4 g, 65.17% yield). 1H NMR (400 MHz, CDCl.sub.3) δ 2.57 (s, 2H), 1.96-2.19 (m, 11H), 1.43 (s, 9H).

Step 2

tert-Butyl-4-aminoadamantane-1-carboxylate (28c)

[0316] Compound 28b (8 g, 31.96 mmol) was dissolved in a solution of ammonia in methanol (100 mL, 7 M). The reaction mixture was allowed to react at room temperature for 12 h. Sodium borohydride (3.63 g, 95.88 mmol) was then added under an ice bath, and the reaction mixture was allowed to react for 1 h with the temperature maintained. 50 mL of sodium bicarbonate (1 M) was added to the reaction mixture, which was then allowed to react for another hour and concentrated. The resulting solid was dissolved in 100 mL of ethyl acetate, and the solution was washed successively with 50 mL of water and 50 mL of saturated brine, dried, and concentrated to give 28c (white solid, 8 g, 99.58% yield). 1H NMR (400 MHz, CDCl.sub.3) δ 2.90-2.94 (m, 1H), 1.54-2.03 (m, 12H), 1.38 (s, 9H).

[0317] LC-MS m/z (ESI)=m/z=252.10 [M+1].

Step 3

Ethyl 4-((5-(tert-butoxycarbonyl)adamantan-2-yl)amino)-2-chloropyrimidine-5-carboxylate (28d)

[0318] Compound 1f (8.0 g, 31.83 mmol) and compound 28c (8.44 g, 38.20 mmol) were dissolved in acetonitrile (80 mL), and potassium carbonate (20.74 g, 63.66 mmol) was added under an ice bath. The reaction mixture was allowed to react at room temperature for 12 h. The reaction was monitored by TLC until its completion. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (60 mL×3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=4:1) to give the target compound 28d (white solid, 9.3 g, 33.92% yield). 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.83 (d, 0.5H), 8.78 (d, 0.5H), 8.65 (s, 0.5H), 8.64 (s, 0.5H), 4.30-4.36 (m, 2H), 4.15-4.17 (m, 1H), 2.06-2.07 (m, 2H), 1.97 (s, 1H), 1.85-1.90 (m, 3H), 1.69-1.78 (m, 7H), 1.54-1.60 (m, 1H), 1.39 (s, 9H), 1.29-1.39 (m, 3H).

[0319] LC-MS m/z (ESI)=m/z=436.20 [M+1].

Step 4

4-((5-(tert-Butoxycarbonyl)adamantan-2-yl)amino)-2-chloropyrimidine-5-carboxylic Acid (28e)

[0320] Compound 28d (9.3 g, 21.33 mmol) was dissolved in 40 mL of tetrahydrofuran and 40 mL of water, and lithium hydroxide (1.02 g, 42.66 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC until its completion. The reaction mixture was concentrated to remove tetrahydrofuran and adjusted to pH 5 with 6N hydrochloric acid, and a solid precipitated. The reaction mixture was filtered, and the filter cake was washed twice with petroleum ether and collected to give the title compound 28e (white solid, 7.8 g, 89.65% yield), which was directly used in the next step. 1H NMR (400 MHz, DMSO-d.sub.6) δ 9.18-9.23 (m, 1H), 8.58 (s, 1H), 2.05 (s, 2H), 1.67-1.97 (m, 9H), 1.56-1.59 (m, 1H), 1.38-1.39 (d, 9H).

[0321] LC-MS m/z (ESI)=m/z=408.2 [M+1].

Step 5

tert-Butyl 4-(2-chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylate (28f)

[0322] Compound 28e (7.8 g, 119.12 mmol) was dissolved in N,N-dimethylacetamide (100 mL), and diphenylphosphoryl azide (1.93 g, 19.12 mmol) and triethylamine (7.37 g, 19.12 mmol) were added under an ice bath. The reaction mixture was stirred at room temperature for 2 h, then warmed to 90° C., and allowed to react for another 3 h. The reaction was monitored by TLC until its completion. The reaction mixture was allowed to naturally cool to room temperature, diluted with 40 mL of water, and then extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried, and concentrated to give compound 28f (grey solid, 7.8 g, 60.45% yield).

[0323] 1H NMR (400 MHz, DMSO-d.sub.6) δ 11.61-11.62 (d, 1H), 8.11 (s, 1H), 4.3 (s, 1H), 2.95 (s, 2H), 1.54-2.33 (m, 11H), 1.36-1.40 (m, 9H).

[0324] LC-MS m/z (ESI)=405.20 [M+1]

Step 6

tert-Butyl 4-(2-chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylate (28g)

[0325] Compound 28f (4.8 g, 11.86 mmol) was dissolved in dimethylformamide (40 mL), and cesium carbonate (7.73 g, 23.72 mmol) and dimethyl sulfate (1.12 mL, 11.86 mmol) were added at 0° C. The reaction mixture was allowed to react at room temperature for 2 h. 20 mL of water was then added, and a solid precipitated. The solid was collected by filtration and dried to give the target compound 28g (pale yellow solid, 2.0 g, 40.25% yield).

[0326] LC-MS m/z (ESI)=m/z=419.20 [M+1].

[0327] 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.34 (s, 1H), 4.32 (s, 1H), 3.33 (d, 3H), 2.94-2.96 (m, 2H), 2.28 (d, 1H), 2.17 (d, 1H), 1.91 (s, 3H), 1.79-1.84 (m, 4H), 1.69 (d, 1H), 1.54 (d, 1H), 1.35-1.40 (m, 9H).

Step 7

tert-Butyl-4-(7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylate (28h)

[0328] Compound 1e (300 mg, 2.02 mmol), compound 28g (850 mg, 2.02 mmol), cesium carbonate (1.3 g, 4.04 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (183.12 mg, 0.2 mmol) were dissolved in dioxane (10 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1) to give compound 28h (white solid, 500 mg, 13.96% yield).

[0329] 1H NMR (400 MHz, DMSO-d.sub.6) δ 9.03 (s, 0.5H), 9.02 (s, 0.5H), 8.57 (d, 1H), 8.36 (d, 1H), 8.11 (d, 1H), 7.69 (s, 0.5H), 7.68 (s, 0.5H), 4.26 (s, 0.5H), 4.21 (s, 0.5H), 3.28-3.34 (m, 3H), 2.99 (s, 1H), 2.86 (s, 1H), 2.36 (d, 3H), 2.13 (d, 2H), 1.71-1.94 (m, 8H), 1.52 (s, 0.5H), 1.49 (s, 0.5H), 1.38 (s, 4.5H), 1.28 (s, 4.5H).

[0330] LC-MS m/z (ESI)=531.3 [M+1].

Step 8

4-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylic Acid (28i)

[0331] Compound 28h (0.5 g, 0.94 mmol) was dissolved in 4N dioxane hydrochloride solution (50 mL). The mixture was allowed to react at room temperature for 16 h and concentrated to give crude compound 28i (pale yellow solid, 0.45 g, 99% yield).

[0332] LC-MS m/z (ESI)=475.20 [M+1].

Step 9

4-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxamide (28j)

[0333] Compound 28i (400 mg, 0.84 mmol), triethylamine (212.50 mg, 2.1 mmol) and ammonium chloride (224.66 mg, 4.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (239.54 mg, 0.63 mmol) was added at 0° C. The reaction mixture was allowed to react for 1 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, dried, and concentrated to give a crude product. The crude product was purified by preparative medium pressure liquid chromatography to give compound 28j (white solid, 100 mg, 25.14% yield). 1H NMR (400 MHz, Chloroform-d) δ 9.64 (s, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.58 (s, 2H), 4.53 (s, 1H), 3.41 (s, 3H), 3.02 (s, 2H), 2.51 (s, 3H), 2.35 (d, J=13.7 Hz, 2H), 2.22 (s, 2H), 2.10 (d, J=12.8 Hz, 2H), 1.97 (s, 3H), 1.64 (s, 2H).

[0334] LC-MS m/z (ESI)=474.20 [M+1].

Step 10

4-(7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (Compound 28-1 and Compound 28-2)

[0335] Compound 28j (150 mg, 0.32 mmol) was dissolved in dichloromethane (20 mL), and pyridine (100.23 mg, 1.27 mmol) and trifluoroacetic anhydride (199.59 mg, 0.95 mmol) were added under an ice bath. The reaction mixture was allowed to react for another hour with the temperature maintained. Methanol (20 mL) was added, and the crude product was concentrated. The crude product was re-dissolved in ethyl acetate (50 mL), and the resulting solution was washed successively with 15% NaHCO.sub.3 (50 mL) and saturated brine (50 mL), dried, and concentrated to give compound 28, which was subjected to Pre-HPLC separation to give two white solids (i.e. compound 28-1 and compound 28-2): compound 28-1 (50 mg, 34.30%, RT=2.637 min, dr %: 99.32%), and compound 28-2 (70 mg, 48.02%, RT=3.129 min, dr %: 99.43%). Pre-HPLC (OZ), mobile phase: acetonitrile/methanol=1/1; column temperature: 35° C.; column pressure: 100 bar; flow rate: 13.5 mL/min; detector signal channel: 215 nm@4.8 nm; diode array detector at a wavelength of 200-400 nm.

[0336] LC-MS m/z (ESI)=456.2 [M+1].

Compound 28-1

[0337] 1H NMR (401 MHz, DMSO-d.sub.6) δ 9.06 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.69 (s, 1H), 4.27 (s, 1H), 3.29 (s, 3H), 2.92 (s, 2H), 2.37 (s, 3H), 1.71-2.08 (m, 8H).

Compound 28-2

[0338] 1H NMR (400 MHz, Chloroform-d) δ 9.48 (s, 1H), 8.28 (s, 1H), 7.90 (s, 1H), 7.58 (s, 1H), 6.76 (s, 1H), 4.42 (s, 1H), 3.40 (s, 3H), 3.14 (s, 2H), 2.24-2.33 (m, 6H), 2.1 (s, 2H), 2.01-2.03 (m, 1H), 1.67 (d, 2H).

Example 29

9-(3-Hydroxyadamantan-1-yl)-2-((6-methoxy-4-methylpyridin-3-yl)amino)-7-methyl-7,9-dihydro-8H-purin-8-one (Compound 29)

[0339] ##STR00072##

[0340] Compound 1j (170 mg, 0.78 mmol), compound 29a (130 mg, 0.94 mmol), cesium carbonate (510 mg, 1.57 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (70 mg, 0.078 mmol) were dissolved in 1,4-dioxane (5 mL), followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to give compound 29 (white solid, 158 mg, 46.16% yield). 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.35 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 6.69 (s, 1H), 4.56 (s, 1H), 3.80 (s, 3H), 3.20 (s, 3H), 2.37-2.27 (m, 6H), 2.15 (s, 3H), 1.60-1.41 (m, 6H).

[0341] LC-MS m/z (ESI)=437.2 [M+1].

Example 30

7-Methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (Compound 30)

[0342] ##STR00073##

Step 1

1-Bromo-2-(2-bromoethoxy)-4-methylbenzene (30b)

[0343] 1,2-Dibromoethane was well mixed with acetonitrile (100 mL), and then 2-bromo-5-methylphenol 30a (25 g, 133.67 mmol) was added, followed by addition of potassium carbonate (55.42 g, 401.01 mmol). The reaction mixture was allowed to react at 80° C. for 5 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (pure petroleum ether) to give compound 30b (colorless liquid, 34 g, 86.51% yield).

Step 2

6-Methyl-2,3-dihydrobenzofuran (30c)

[0344] Compound 30b (34 g, 115.65 mmol) was added to a dry reaction flask and dissolved in dry tetrahydrofuran (160 mL), and n-butyllithium (55 mL, 138.78 mmol) was added dropwise at −78° C. After the dropwise addition was completed, the reaction mixture was allowed to react for another 1.5 h. After the reaction was completed, the reaction mixture was quenched by addition of water (20 mL), concentrated under reduced pressure to remove the organic solvent, and extracted twice with ethyl acetate. The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography (pure petroleum ether) to give compound 30c (colorless liquid, 10 g, 64.43% yield).

Step 3

6-Methyl-5-nitro-2,3-dihydrobenzofuran (30d)

[0345] Compound 30c (10 g, 74.53 mmol) was dissolved in acetic acid (50 mL), and nitric acid (11.8 mL, 178.87 mmol, 68% purity) was added dropwise at room temperature. After the addition was completed, the reaction mixture was allowed to react for another 10 min. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, followed by three extractions with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give compound 30d (yellow solid, 7.0 g, 52.43% yield).

Step 4

6-Methyl-2,3-dihydrobenzofuran-5-amine (30e)

[0346] Compound 30d (7.0 g, 39.07 mmol) was well mixed with 110 mL of ethanol/water (10/1), and iron powder (10.9 g, 195.33 mmol) was added, followed by addition of diluted hydrochloric acid (9.8 mL, 2 mol/L). The reaction mixture was allowed to react at 85° C. for 2 h. The reaction mixture was filtered to remove iron powder. The filtrate was concentrated, and then the pH was adjusted with saturated sodium bicarbonate solution until it is slightly basic, followed by three extractions with ethyl acetate. The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1) to give compound 30e (brown solid, 4.5 g, 77.05% yield).

[0347] .sup.1H NMR (400 MHz DMSO) δ 6.52 (s, 1H), 6.38 (s, 1H), 4.36-4.31 (t, 2H), 4.25 (s, 2H), 3.02-2.98 (t, 2H), 1.98 (s, 3H).

[0348] LC-MS m/z (ESI)=150.10 [M+1].

Step 5

7-Methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-9-(4-oxoadamantan-1-yl)-7,9-dihydro-8H-purin-8-one (Compound 30)

[0349] Compound 1j (200 mg, 0.60 mmol), compound 30e (178 mg, 1.2 mmol), cesium carbonate (579 mg, 1.8 mmol) and Brettphos G3 Pd (54 mg, 0.06 mmol) were added to a dry reaction flask, followed by addition of 1,4-dioxane (20 mL). The system was purged with nitrogen three times, and the reaction mixture was allowed to react at 110° C. for 2.5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give compound 30 (white solid, 40 mg, 14.97% yield).

[0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.26 (s, 1H), 6.60 (s, 1H), 4.59 (s, 1H), 4.47 (t, 2H), 3.21 (s, 3H), 3.12 (t, 2H), 2.38-2.32 (m, 4H), 2.17 (s, 2H), 2.13 (s, 3H), 1.62-1.51 (m, 4H), 1.50-1.40 (m, 2H).

[0351] LC-MS m/z (ESI)=446.20 [M+1].

Example 31

9-(4,4-Dimethoxyadamantan-1-yl)-7-methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 31)

[0352] ##STR00074##

[0353] Compound 30 (100 mg, 0.22 mmol) was dissolved in 3 mL of methanol and 5 mL of acetonitrile, and 0.5 mL of 2 M hydrochloric acid was added. The reaction mixture was let stand at room temperature for 30 min, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by Pre-HPLC to give compound 31 (white solid, 22.0 mg, 20.4% yield).

[0354] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.26 (s, 1H), 6.60 (s, 1H), 4.59 (s, 1H), 4.47 (t, 2H), 3.21 (s, 3H), 3.08 (s, 3H), 3.07 (s, 3H), 3.12 (t, 2H), 2.38-2.32 (m, 4H), 2.17 (s, 2H), 2.13 (s, 3H), 1.62-1.51 (m, 4H), 1.50-1.40 (m, 2H).

[0355] LC-MS m/z (ESI)=492.24 [M+1].

Example 32

9-(3-Hydroxyadamantan-1-yl)-7-methyl-2-((6-methyl-2,3-dihydrobenzofuran-5-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 32)

[0356] ##STR00075##

[0357] Compound 1j (200 mg, 0.60 mmol), compound 30e (178 mg, 1.2 mmol), cesium carbonate (579 mg, 1.8 mmol) and Brettphos G3 Pd (54 mg, 0.06 mmol) were added to a dry reaction flask, followed by addition of 1,4-dioxane (20 mL). The system was purged with nitrogen three times, and the reaction mixture was allowed to react at 110° C. for 2.5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give compound 32 (white solid, 40 mg, 14.97% yield).

[0358] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.07 (s, 1H), 7.96 (s, 1H), 7.26 (s, 1H), 6.60 (s, 1H), 4.59 (s, 1H), 4.47 (t, 2H), 3.21 (s, 3H), 3.12 (t, 2H), 2.38-2.32 (m, 6H), 2.17 (s, 2H), 2.13 (s, 3H), 1.62-1.51 (m, 4H), 1.50-1.40 (m, 2H).

[0359] LC-MS m/z (ESI)=448.20 [M+1].

Example 33

2-((6-Chloro-2,3-dihydrobenzofuran-5-yl)amino)-9-(3-hydroxyadamantan-1-yl)-7-methyl-7,9-dihydro-8H-purin-8-one (Compound 33)

[0360] ##STR00076##

Step 1

1-Bromo-2-(2-bromoethoxy)-4-chlorobenzene (3b)

[0361] 1,2-Dibromoethane (109.2 g, 581.28 mmol) was well mixed with acetonitrile (120 mL), and then compound 33a (30 g, 144.61 mmol) was added, followed by addition of potassium carbonate (60 g, 434.12 mmol). The reaction mixture was allowed to react at 80° C. for 5 h. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=200/1) to give compound 33b (white solid, 31 g, 68.19% yield).

Step 2

6-Chloro-2,3-dihydrobenzofuran (33c)

[0362] Compound 33b (31 g, 98.60 mmol) was added to a dry reaction flask and dissolved in dry tetrahydrofuran (160 mL), and n-butyllithium (45.5 mL, 118.32 mmol) was added dropwise at −78° C. After the dropwise addition was completed, the reaction mixture was allowed to react for another 1.5 h. After the reaction was completed, the reaction mixture was quenched by addition of water (20 mL), concentrated under reduced pressure to remove the organic solvent, and extracted twice with ethyl acetate. The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography (pure petroleum ether) to give compound 33c (colorless liquid, 15 g, 98.42% yield). 1H NMR (400 MHz CDCl.sub.3) δ 6.98-6.96 (dt, 1H), 6.72-6.69 (dd, 1H), 6.67 (d, 1H), 4.50-4.46 (t, 2H), 3.08-3.03 (t, 2H).

Step 3

6-Chloro-5-nitro-2,3-dihydrobenzofuran (33d)

[0363] Compound 33c (15 g, 97.03 mmol) was dissolved in acetic acid (110 mL), and nitric acid (15.5 mL, 232.87 mmol, 68% purity) was added dropwise at 70° C. After the addition was completed, the reaction mixture was allowed to react for another 30 min. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, followed by three extractions with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to give compound 33d (yellow solid, 12.5 g, 64.55% yield).

[0364] LC-MS m/z (ESI)=200.00 [M+1].

Step 4

6-Chloro-2,3-dihydrobenzofuran-5-amine (33e)

[0365] Compound 33d (12.5 g, 62.63 mmol) was well mixed with 110 mL of ethanol/water (10/1), and iron powder (17.8 g, 318.77 mmol) was added, followed by addition of diluted hydrochloric acid (16.5 mL, 2 mol/L). The reaction mixture was allowed to react at 85° C. for 2 h. The reaction mixture was filtered to remove iron powder. The filtrate was concentrated, and then the pH was adjusted with saturated sodium bicarbonate solution until it is slightly basic, followed by three extractions with ethyl acetate. The organic phases were combined, dried, and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=15/1) to give compound 33e (yellow solid, 7.0 g, 65.91% yield).

[0366] 1H NMR (400 MHz DMSO) δ 6.72 (s, 1H), 6.64 (s, 1H), 4.73 (s, 2H), 4.43-4.39 (t, 2H), 3.07-3.02 (t, 2H).

[0367] LC-MS m/z (ESI)=170.00 [M+1].

Step 5

[0368] Compound 1j (0.2 g, 1.18 mmol), compound 33e (0.197 g, 0.589 mmol), cesium carbonate (0.80 g, 0.088 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.384 g, 1.18 mmol) were dissolved in 1,4-dioxane (5 mL), followed by nitrogen purging. The reaction mixture was stirred at 110° C. for 4 h, with the reaction monitored by TLC until it was substantially completed. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20/1) to give compound 33 (white solid, 83 mg, 30.08% yield).

[0369] 1H NMR (400 MHz, DMSO-d.sub.6) δ 8.12 (s, 1H), 8.00 (s, 1H), 7.54 (s, 1H), 6.89 (s, 1H), 4.59 (s, 1H), 4.55 (t, 2H), 3.22 (s, 3H), 3.18 (t, 2H), 2.40-2.30 (m, 7H), 1.60-1.43 (m, 7H).

[0370] LC-MS m/z (ESI)=468.17 [M+1].

Example 34

4-((9-(3-Cyanoadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 34)

[0371] ##STR00077##

Step 1

3-(2-Chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylic Acid (34a)

[0372] Compound 3f (5.0 g, 11.9 mmol) was dissolved in 4N dioxane hydrochloride solution (100 mL). The mixture was allowed to react at 60° C. for 6 h and concentrated, and the residue was purified by preparative medium pressure liquid chromatography to give compound 34a (pale yellow solid, 4.3 g, 99% yield).

[0373] LCMS m/z (ESI)=363.2 [M+1].

Step 2

3-(2-Chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxamide (34b)

[0374] Compound 34a (4.3 g, 11.9 mmol), ammonium chloride (6.37 g, 119.0 mmol) and triethylamine (6.0 g, 59.5 mmol) were dissolved in tetrahydrofuran (50 mL), and HATU (9.05 g, 23.8 mmol) was added under an ice bath. The mixture was allowed to react at room temperature for 2 h, quenched by addition of water (100 mL), and concentrated by rotary evaporation under reduced pressure to remove tetrahydrofuran, and a large amount of solid precipitated. The mixture was filtered, and the filtrate was concentrated to dryness by rotary evaporation to give compound 34b (off-white solid, 4.0 g, 93.0% yield).

[0375] LCMS m/z (ESI)=362.2 [M+1].

Step 3

3-(2-Chloro-7-methyl-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (34c)

[0376] Compound 34b (4.0 g, 11.0 mmol) was dissolved in dichloromethane (40 mL), and pyridine (3.48 g, 44.0 mmol) and trifluoroacetic anhydride (6.93 g, 33.0 mmol) were added under an ice bath. The reaction mixture was allowed to react for another hour with the temperature maintained. Methanol (20 mL) was added, and the crude product was concentrated. The crude product was poured into saturated NaHCO.sub.3 solution (100 mL), and a large amount of solid precipitated. The mixture was filtered, and the filtrate was concentrated to dryness by rotary evaporation to give compound 34c (pale yellow solid, 3.3 g, 87.3% yield).

[0377] LCMS m/z (ESI)=344.2 [M+1].

Step 4

4-((9-(3-Cyanoadamantan-1-yl)-7-methyl-8-oxo-8,9-dihydro-7H-purin-2-yl)amino)-2-fluoro-5-methylbenzamide (Compound 34)

[0378] Compound 34c (2.0 g, 5.82 mmol), compound 21a (1.96 g, 11.64 mmol), cesium carbonate (3.80 g, 11.64 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (528 mg, 0.582 mmol) were dissolved in dioxane (30 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1) to give compound 34 (white solid, 1.0 g, 36.1% yield).

[0379] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (s, 1H), 8.18 (s, 1H), 7.80 (d, 1H), 7.54 (d, 1H), 7.48 (s, 1H), 7.32 (d, 1H), 3.27 (s, 3H), 2.82 (s, 2H), 2.61-2.52 (m, 4H), 2.28 (s, 3H), 2.23 (q, 2H), 2.06-1.94 (m, 4H), 1.68 (s, 2H).

[0380] LCMS m/z (ESI)=476.2 [M+1].

[0381] .sup.19F NMR (377 MHz, DMSO-d.sub.6) δ −115.48.

Example 35

3-(2-((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (Compound 35)

[0382] ##STR00078##

Step 1

3-(2-Chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxylic acid (35a)

[0383] Compound 1e (3.2 g, 7.90 mmol) was dissolved in 4N dioxane hydrochloride solution (100 mL). The mixture was allowed to react at 60° C. for 6 h and concentrated, and the residue was purified by preparative medium pressure liquid chromatography to give compound 35a (pale yellow solid, 2.75 g, 100% yield).

[0384] LCMS m/z (ESI)=349.2 [M+1].

Step 2

3-(2-Chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carboxamide (35b)

[0385] Compound 35a (2.75 g, 7.90 mmol), ammonium chloride (4.23 g, 79.0 mmol) and triethylamine (3.99 g, 39.5 mmol) were dissolved in tetrahydrofuran (40 mL), and HATU (6.01 g, 15.80 mmol) was added under an ice bath. The mixture was allowed to react at room temperature for 2 h, quenched by addition of water (100 mL), and concentrated by rotary evaporation under reduced pressure to remove tetrahydrofuran, and a large amount of solid precipitated. The mixture was filtered, and the filtrate was concentrated to dryness by rotary evaporation to give compound 35b (off-white solid, 2.4 g, 87.5% yield).

[0386] LCMS m/z (ESI)=348.2 [M+1].

Step 3

3-(2-Chloro-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (35c)

[0387] Compound 35b (2.4 g, 6.91 mmol) was dissolved in dichloromethane (40 mL), and pyridine (2.19 g, 27.63 mmol) and trifluoroacetic anhydride (4.35 g, 20.73 mmol) were added under an ice bath. The reaction mixture was allowed to react for another hour with the temperature maintained. Methanol (20 mL) was added, and the crude product was concentrated. The crude product was poured into saturated NaHCO.sub.3 solution (100 mL), and a large amount of solid precipitated. The mixture was filtered, and the filtrate was concentrated to dryness by rotary evaporation to give compound 35c (pale yellow solid, 1.4 g, 61.4% yield).

[0388] LCMS m/z (ESI)=330.2 [M+1].

Step 4

3-(2-((7-Methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-8-oxo-7,8-dihydro-9H-purin-9-yl)adamantane-1-carbonitrile (Compound 35)

[0389] Compound 35c (1.4 g, 4.24 mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine 1e (624 mg, 4.24 mmol), cesium carbonate (2.70 g, 8.28 mmol) and methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (385 mg, 0.424 mmol) were dissolved in dioxane (30 mL), followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction was monitored by TLC until its completion. The reaction mixture was poured into ice water, and the solid was collected and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=100/1) to give compound 35 (white solid, 286 mg, 15.3% yield).

[0390] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.95 (s, 1H), 9.06 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 2.75 (s, 2H), 2.49-2.44 (m, 4H), 2.37 (s, 3H), 2.14 (s, 2H), 1.90 (d, 4H), 1.61-1.53 (m, 2H).

[0391] LCMS m/z (ESI)=442.2 [M+1].

Example 36

9-(3-Hydroxyadamantan-1-yl)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 36)

[0392] ##STR00079##

[0393] Compound 1i (128 mg, 0.4 mmol), compound 1e (132 mg, 0.3 mmol), cesium carbonate (1 g, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (915 mg, 0.04 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (622 mg, 0.08 mmol) were dissolved in dioxane, followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 36 (white solid, 30.0 mg, 17.5% yield).

[0394] .sup.1H NMR (400 MHz DMSO) δ 10.86 (s, 1H), 9.09 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 7.87 (s, 1H), 7.69 (s, 1H), 4.55 (s, 1H), 2.50-2.52 (m, 9H), 1.50-1.58 (M, 4H), 1.41-1.44 (m, 2H).

[0395] LC-MS m/z (ESI)=433.20 [M+1].

Example 37

9-(3-Hydroxyadamantan-1-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 37)

[0396] ##STR00080##

Step 1

2-Chloro-9-((3-hydroxyadamantan-1-yl)-7-(methyl-d3)-7,9-dihydro-8H-purin-8-one (37a)

[0397] Compound 1i (1.0 g, 3.12 mmol) was dissolved in dimethyl sulfoxide (20 mL), and cesium carbonate (1.6 g, 6.24 mmol) was added at room temperature, followed by addition of deuterated iodomethane (0.4 g, 3.36 mmol) at 0° C. The reaction mixture was allowed to react at room temperature for 2 h. After the reaction was completed, 5 mL of water was added, followed by three extractions with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated, and a solid precipitated. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=15:1) to give compound 37a (white solid, 0.36 g, 34.66% yield).

[0398] LC-MS m/z (ESI)=457.20 [M+1].

Step 2

9-(3-Hydroxyadamantan-1-yl)-7-(methyl-d3)-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 37)

[0399] Compound 37a (135.1 mg, 0.4 mmol), compound 1e (40 mg, 0.3 mmol), cesium carbonate (391 mg, 1.2 mmol), tris(dibenzylideneacetone)dipalladium (40 mg, 0.04 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (622 mg, 0.08 mmol) were dissolved in dioxane, followed by nitrogen purging. The reaction mixture was stirred at 100° C. for 4 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=30/1) to give compound 37 (white solid, 12.6 mg, 2.5% yield).

[0400] .sup.1H NMR (400 MHz DMSO) δ 9.09 (s, 1H), 8.56 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 4.56 (s, 1H), 2.35-2.42 (m, 9H), 2.17 (s, 2H), 1.58-1.23 (m, 6H).

[0401] LC-MS m/z (ESI)=450.28 [M+1].

Example 38

9-(-4,4-Dimethoxyadamantan-1-yl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one (Compound 38)

[0402] ##STR00081##

[0403] Compound 18 (100 mg, 0.22 mmol) was dissolved in 3 mL of methanol and 5 mL of acetonitrile, and 0.5 mL of 2 M hydrochloric acid was added. The reaction mixture was let stand at room temperature for 30 min, with the reaction monitored by TLC until its completion. The reaction mixture was concentrated, and the residue was purified by Pre-HPLC to give compound 30 (white solid, 22.0 mg, 20.4% yield).

[0404] .sup.1H NMR (400 MHz DMSO) δ 9.11 (s, 1H), 8.61 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 3.25 (s, 3H), 3.08 (s, 3H), 3.07 (s, 3H), 2.93-2.96 (m, 2H), 2.66-2.69 (m, 4H), 2.39 (s, 3H), 1.94-1.99 (m, 2H), 1.81-1.84 (m, 2H), 1.34-1.49 (m, 2H).

[0405] LC-MS m/z (ESI)=491.24 [M+1].

Biological Assays

[0406] 1. Inhibition of DNA-PK Kinase

[0407] The inhibitory activity of the compounds against DNA-PK kinase was determined using a DNA-PK kinase assay kit (purchased from Promega, Cat. No. V4107, Batch No. 0000366495). The results were quantified using chemiluminescence, specifically as follows:

[0408] i. ADP-fluorescence standard curves at different concentrations were constructed according to the instructions of the kit;

[0409] ii. reaction systems (5 μL) were prepared in a 384-well white plate; 1 μL of a compound (concentration gradients 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM and 0.013 nM were set for each compound), 20 units of DNA-PK kinase, 0.2 μg/μL substrate, 10 μg/μL DNA, 50 μM ATP and 1% DMSO were successively added to each well;

[0410] iii. the mixtures were well mixed, centrifuged (1000 rpm, 30 s), and incubated at 37° C. for 60 min;

[0411] iv. the reactions were terminated by adding 5 μL of ADP-Glo™ Reagent; the mixtures were well mixed, centrifuged (1000 rpm, 30 s), and incubated at room temperature for 40 min;

[0412] v. 10 μL of Kinase Detection Reagent was added; the mixtures were well mixed by shaking, centrifuged (1000 rpm, 30 s), and incubated at room temperature for 30 min;

[0413] vi. fluorescence values were measured using a microplate reader (Thermo fisher, Varioskan LUX). IC.sub.50 was calculated using GraphPad Prism 8. The results are shown in Table 1.

TABLE-US-00001 TABLE 1 Inhibitory activity against DNA-PK kinase Compound No. IC.sub.50 (nM) Compound 1 1.30 Compound 2 0.01 Compound 3 14.95 Compound 4 0.45 Compound 5 3.87 Compound 6 0.08 Compound 7 0.01 Compound 8 0.01 Compound 9 1.10 Compound 10 2.26 Compound 11 0.10 Compound 12 0.01 Compound 13-1 0.68 Compound 13-2 51.90 Compound 14 0.01 Compound 15 1.10 Compound 16-1 0.52 Compound 16-2 2.49 Compound 17-1 0.01 Compound 17-2 2.20 Compound 18 0.06 Compound 18-2 0.13 Compound 19 0.03 Compound 20-1 0.03 Compound 20-2 1.10 Compound 21-1 0.01 Compound 21-2 0.10 Compound 22 0.01 Compound 23-1 2.84 Compound 23-2 0.85 Compound 24-1 0.66 Compound 24-2 8.39 Compound 25 0.01 Compound 26 0.01 Compound 27-1 10.5 Compound 27-2 0.48 Compound 28-1 0.75 Compound 28-2 0.10 Compound 29 0.50 Compound 30 0.08 Compound 31 0.10 Compound 32 2.30 Compound 33 6.40 Compound 34 7.50 Compound 35 0.48 Compound 36 0.32 Compound 37 1.30 Comparative 100.20 example Note: Compound 3 of J. Med. Chem (2020), 63 (7), 3461-3471 was used as the comparative example; it was prepared according to its preparation method.

[0414] The results show that the compounds of the present invention have more significant inhibitory effects on DNA-PK kinase than the comparative example.

[0415] 2. Inhibition of Graft Tumors

[0416] 2.1. Experimental materials: A549 cells (purchased from ATCC); doxorubicin liposome (Dox) (lipo doxorubicin, under trade name “Libod ()”, purchased from Shanghai Fudan-Zhangjiang Bio-Pharmaceutical Co., Ltd.); compounds 1, 6, 19, 22 and 34; female nude mice (18-20 g in weight) at the age of 6 weeks (Beijing Vital River Laboratory Animal Technology Co., Ltd.), 10 mice per group.

[0417] 2.2. Determination of inhibitory effect of doxorubicin in combination with compounds to be screened on A549 graft tumors:

[0418] 2.2.1. A549 cells growing at log phase were collected and washed twice with pre-cooled PBS for later use;

[0419] 2.2.2. Balb/c nude mice were acclimated to the laboratory environment for 3 days, and subcutaneously inoculated with A549 cells in the right flank in an amount of 5×10.sup.6 cells per mouse; a pharmacodynamic study was conducted when tumors had grown to a size of about 200 mm.sup.3;

[0420] 2.2.3. mice with tumors were randomly divided into groups as follows: doxorubicin (Dox) group, test compound+Dox group and control group (vehicle); the mice was intragastrically administrated (i.g.) at a volume of 5 mL/kg twice a day (BID) for 21 days (the solvent was 5% DMSO+30% 2-hydroxypropyl-β-cyclodextrin); one hour after the intragastric administration in the morning, lipo doxorubicin (2.5 mg/kg) was injected via the tail vein once a week (QW) at a volume of 5 mL/kg; the specific administration regimens are as follows:

TABLE-US-00002 Group Treatment Dosage 1 Vehicle — 2  Compound 1 +  Compound 1 (20 mg/kg, BID, i.g.) doxorubicin Dox (2.5 mg/kg, QW, i.v.) 3  Compound 6 +  Compound 6 (20 mg/kg, BID, i.g.) doxorubicin Dox (2.5 mg/kg, QW, i.v.) 4 Compound 19 + Compound 19 (20 mg/kg, BID, i.g.) doxorubicin Dox (2.5 mg/kg, QW, i.v.) 5 Compound 22 + Compound 22 (20 mg/kg, BID, i.g.) doxorubicin Dox (2.5 mg/kg, QW, i.v.) 6 Compound 34 + Compound 34 (20 mg/kg, BID, i.g.) doxorubicin Dox (2.5 mg/kg, QW, i.v.) 7 Lipo Doxorubicin 2.5 mg/kg, QW, i.v.

[0421] 2.2.4. the mice were weighed twice a week, and meanwhile the tumor volume was determined: tumor volume (V) was calculated as: V=½×L.sub.long×L.sub.short.sup.2; the tumor inhibition rate was calculated as: tumor inhibition rate (%)=(D21 tumor volume (vehicle)−D21 tumor volume (administration group))/D21 tumor volume (vehicle)×100;

[0422] 2.2.5. after 21 days of administration, tumors were isolated and weighed, and the rate of change in body weight was calculated as: rate of change in body weight (%)=(D21 body weight−D0 body weight)/D0 body weight×100.

TABLE-US-00003 TABLE 2 Experimental results for inhibition of graft tumors Group 1 Group 2 Group 3 Vehicle- Compound Vehicle- Compound 6 + Dox- Compound Test item 1 Dox-1 1 + Dox-1 2 Dox-2 Dox-2 Vehicle-3 3 19 + Dox-3 D0 mean tumor 171.60 171.80 171.60 185.88 182.25 185.63 186.21 186.23 185.99 volume (mm.sup.3) D0 mean body weight (g) 18.96 19.74 19.70 18.50 18.90 20.10 19.03 19.27 19.03 D21 mean tumor 596.17 474.28 371.06 1057.75 634.38 510.00 698.21 605.36 318.55 volume (mm.sup.3) D21 mean 20.24 18.96 17.83 21.30 18.70 20.50 20.91 19.81 18.03 body weight (g) D21 tumor inhibition rate (%) — 20.45 37.76 — 40.02 51.78 — 13.30 54.38 D21 weight 6.75 −3.95 −9.49 15.14 −1.05 1.99 9.88 2.80 −5.25 Rate of change (%) Group 4 Group 5 Vehicle- Dox- Compound Vehicle- Compound Test item 3 3 22 + Dox-3 3 Dox-3 34 + Dox-3 D0 mean tumor 186.21 186.23 184.94 186.21 186.23 185.95 volume (mm.sup.3) D0 mean body weight (g) 19.03 19.27 19.17 19.03 19.27 19.91 D21 mean tumor 698.21 605.36 502.56 698.21 605.36 451.01 volume (mm.sup.3) D21 mean 20.91 19.81 18.7 20.91 19.81 19.11 body weight (g) D21 tumor inhibition rate (%) — 13.30 28.02 — 13.30 35.40 D21 weight 9.88 2.80 −2.45 9.88 2.80 −4.01 Rate of change (%)

[0423] Conclusion: The experimental results show that all of the compounds of the present invention, when used in combination with doxorubicin, can improve the inhibitory effect of doxorubicin on tumors and will not cause significant weight loss.

[0424] While specific embodiments of the present invention have been described in detail in the specification, it will be understood by those skilled in the art that the embodiments described above are illustrative and are not to be construed as limiting the present invention, and that various changes and modifications can be made to the present invention without departing from the principles of the present invention, and the technical schemes resulting from these changes and modifications also fall within the protection scope of the appended claims.