JNK INHIBITOR, AND PHARMACEUTICAL COMPOSITION AND USE THEREOF

Abstract

A compound of formula (I), and racemates, stereoisomers, tautomers, isotopic markers, solvates, polymorphs and oxynitrides of the compound, or a pharmaceutically acceptable salt thereof can be used as JNK inhibitors. A method for preparing the compound of formula (I) and a pharmaceutical composition comprising the compound of formula (I) are provided. The compound of formula (I) can be used for preparing drugs. The resulting drugs are used for treating diseases that can be treated by inhibiting JNK activity.

##STR00001##

Claims

1-10. (canceled)

11. A compound of formula (I) and a racemate, a stereoisomer, a tautomer, an isotopically labeled compound, a solvate, a polymorph and a nitrogen oxide thereof, or pharmaceutically acceptable salts thereof: ##STR00160## wherein, Y.sub.1 and Y.sub.2 are each independently CR.sub.4 or N; X and W are each independently selected from CR.sub.5R.sub.6, O and NR.sub.7; R.sub.1 is selected from H, hydroxy, halogen, cyano, nitro, NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(═S)NR.sub.11R.sub.12, S(O).sub.2NR.sub.11R.sub.12, C(═NR.sub.3)NR.sub.11R.sub.12, NHC(O)NR.sub.11R.sub.12, P(O).sub.2NR.sub.11R.sub.12, P(O)R.sub.13NR.sub.11R.sub.12, C(O)R.sub.14, NHC(O)R.sub.14, C(O)OR.sub.15, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.2 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl, C.sub.6-20 aryl-C.sub.1-40 alkyl, 5-20 membered heteroaryl and 5-20 membered heteroaryl-C.sub.1-40 alkyl; or R.sub.2, together with X, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: NHC(O)NR.sub.11R.sub.12, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.3 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(O)R.sub.14, C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; or R.sub.3, together with W, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NHC(O)NR.sub.11R.sub.12, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.4 is selected from H, hydroxy, halogen, cyano, nitro, amino, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl and C.sub.1-40 alkoxy; R.sub.5 and R.sub.6 are each independently selected from H, hydroxy, halogen, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl and C.sub.1-40 alkoxy, with the proviso that R.sub.5 and R.sub.6 are not both hydroxy, cyano or C.sub.1-40 alkoxy simultaneously; or, R.sub.5 and R.sub.6, together with the carbon atom attached thereto, form carbonyl; R.sub.7 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.11 and R.sub.12 are each independently selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C(O)R.sub.14, C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; or R.sub.11 and R.sub.12, together with the nitrogen atom attached thereto, form the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: 3-20 membered heterocyclyl and 5-20 membered heteroaryl; R.sub.13 is selected from H, hydroxy, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-40 alkyl and C.sub.1-40 alkoxy; R.sub.14 is selected from H, hydroxy, halogen, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-40alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.15 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-40 alkyl, C.sub.2-40 alkenyl, C.sub.2-40 alkynyl, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; each R.sub.a is independently selected from CN, halogen, OH, NH.sub.2, oxo, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-40 alkyl and C.sub.1-40 alkoxy; each R.sub.b is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, oxo, S(O).sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.3, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; each R.sub.c is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, C(O)NH.sub.2, C(O)NHOH, C(O)N(OH)CH.sub.3, oxo, C(O)CH.sub.2COOH, C(O)CH.sub.2CN, C(O)CH.sub.2C.sub.2, C(O)CH.sub.2F, C(O)CH.sub.2Br, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-40 alkyl, C.sub.1-40 alkoxy, C.sub.3-20 cycloalkyl, 3-20 membered heterocyclyl, C.sub.6-20 aryl and 5-20 membered heteroaryl; R.sub.d, R.sub.e and R.sub.f are each the same or different, and are each independently selected from CN, halogen, OH, NH.sub.2, oxo, S(O).sub.2CH.sub.3, C.sub.1-40 alkyl, C.sub.1-40 haloalkyl, C.sub.1-40 alkoxy and C.sub.1-40 haloalkoxy.

12. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein, Y.sub.1 and Y.sub.2 are independently CR.sub.4 or N; X and W are independently selected from CR.sub.5R.sub.6, O and NR.sub.2; R.sub.1 is selected from H, hydroxy, halogen, cyano, nitro, NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(S)NR.sub.11R.sub.12, S(O).sub.2NR.sub.11R.sub.12, C(═NR.sub.13)NR.sub.11R.sub.12, NHC(O)NR.sub.11R.sub.12, P(O).sub.2NR.sub.11R.sub.12, P(O)R.sub.13NR.sub.11R.sub.12, C(O)R.sub.14, NHC(O)R.sub.11, C(O)OR.sub.15, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.2 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl, C.sub.6-14 aryl-C.sub.1-10 alkyl, 5-14 membered heteroaryl and 5-14 membered heteroaryl-C.sub.1-10alkyl; or R.sub.2, together with X, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: NHC(O)NR.sub.11R.sub.12, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.3 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(O)R.sub.14, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; or R.sub.3, together with W, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NHC(O)NR.sub.11R.sub.12, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.4 is selected from H, hydroxy, halogen, cyano, nitro, amino, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl and C.sub.1-10 alkoxy; R.sub.5 and R.sub.6 are each independently selected from H, hydroxy, halogen, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl and C.sub.1-10 alkoxy, with the proviso that R.sub.5 and R.sub.6 are not both hydroxy, cyano or C.sub.1-10 alkoxy simultaneously; or, R.sub.5 and R.sub.6, together with the carbon atom attached thereto, form carbonyl, i.e., CR.sub.5R.sub.6 is C(═O); R.sub.7 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.11 and R.sub.12 are each independently selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C(O)R.sub.14, C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; or R.sub.11 and R.sub.12, together with the nitrogen atom attached thereto, form the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: 3-10 membered heterocyclyl and 5-14 membered heteroaryl; R.sub.13 is selected from H, hydroxy, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-10 alkyl and C.sub.1-10 alkoxy; R.sub.14 is selected from H, hydroxy, halogen, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.15 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-10 alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; each R.sub.a is independently selected from CN, halogen, OH, NH.sub.2, oxo, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-10 alkyl and C.sub.1-10alkoxy; each R.sub.b is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, oxo, S(O).sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.3, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; each R.sub.c is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, C(O)NH.sub.2, C(O)NHOH, C(O)N(OH)CH.sub.3, oxo, C(O)CH.sub.2COOH, C(O)CH.sub.2CN, C(O)CH.sub.2Cl, C(O)CH.sub.2F, C(O)CH.sub.2Br, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-10 alkyl, C.sub.1-10 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.d, R.sub.e and R.sub.f are each the same or different, and are each independently selected from CN, halogen, OH, NH.sub.2, oxo, S(O).sub.2CH.sub.3, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.1-10 alkoxy and C.sub.1-10 haloalkoxy.

13. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein, Y.sub.1 and Y.sub.2 are independently CR.sub.4 or N; X and W are independently selected from CR.sub.5R.sub.6, O and NR.sub.7; R.sub.1 is selected from H, hydroxy, halogen, cyano, nitro, NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(═S)NR.sub.11R.sub.12, S(O).sub.2N.sub.11R.sub.12, C(═NR.sub.13)NR.sub.11R.sub.12, NHC(O)NR.sub.11R.sub.12, P(O).sub.2NR.sub.11R.sub.12, P(O)R.sub.13NR.sub.11R.sub.12, C(O)R.sub.14, NHC(O)R.sub.14, C(O)OR.sub.15, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.2 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl, C.sub.6-14 aryl-C.sub.1-6 alkyl, 5-14 membered heteroaryl and 5-14 membered heteroaryl-C.sub.1-6 alkyl; or R.sub.2, together with X, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: NHC(O)NR.sub.11R.sub.12, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.3 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(O)R.sub.14, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; or R.sub.3, together with W, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NHC(O)NR.sub.11R.sup.12, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.4 is selected from H, hydroxy, halogen, cyano, nitro, amino, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6 alkoxy; R.sub.5 and R.sub.6 are each independently selected from H, hydroxy, halogen, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.d: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl and C.sub.1-6 alkoxy, with the proviso that R.sub.5 and R.sub.6 are not both hydroxy, cyano or C.sub.1-6 alkoxy simultaneously; or, R.sub.5 and R.sub.6, together with the carbon atom attached thereto, form carbonyl, i.e., CR.sub.5R.sub.6 is C(═O); R.sub.7 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.11 and R.sub.12 are each independently selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C(O)R.sub.14, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; or R.sub.11 and R.sub.12, together with the nitrogen atom attached thereto, form the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: 3-10 membered heterocyclyl and 5-14 membered heteroaryl; R.sub.13 is selected from H, hydroxy, cyano, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-6 alkyl and C.sub.1-6 alkoxy; R.sub.14 is selected from H, hydroxy, halogen, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.15 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; each R.sub.a is independently selected from CN, halogen, OH, NH.sub.2, oxo, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl and C.sub.1-6 alkoxy; each R.sub.b is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, oxo, S(O).sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.3, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; each R.sub.c is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, C(O)NH.sub.2, C(O)NHOH, C(O)N(OH)CH.sub.3, oxo, C(O)CH.sub.2COOH, C(O)CH.sub.2CN, C(O)CH.sub.2Cl, C(O)CH.sub.2F, C(O)CH.sub.2Br, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-10 cycloalkyl, 3-10 membered heterocyclyl, C.sub.6-14 aryl and 5-14 membered heteroaryl; R.sub.d, R.sub.e and R.sub.f are each the same or different, and are each independently selected from CN, halogen, OH, NH.sub.2, oxo, S(O).sub.2CH.sub.3, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkoxy.

14. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein, Y.sub.1 and Y.sub.2 are independently CR.sub.4 or N; X and W are independently O or NR.sub.7; R.sub.1 is selected from H, hydroxy, halogen, cyano, nitro, NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(═S)NR.sub.11R.sub.12, S(O).sub.2NR.sub.11R.sub.12, C(═NR.sub.13)NR.sub.11R.sub.12, NHC(O)NR.sub.11R.sub.12, P(O).sub.2NR.sub.11R.sub.12, P(O)R.sub.13NR.sub.11R.sub.12, C(O)R.sub.14, NHC(O)R.sub.14, C(O)OR.sub.15, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.a: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; R.sub.2 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, benzyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl-C.sub.1-6 alkyl; or R.sub.2, together with X, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.b: NHC(O)NR.sub.11R.sub.12, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; R.sub.3 is selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NR.sub.11R.sub.12, C(O)NR.sub.11R.sub.12, C(O)R.sub.14, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; or R.sub.3, together with W, forms the following groups unsubstituted or optionally substituted with one, two or more R.sub.c: NHC(O)NR.sub.11R.sub.12, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; R.sub.4 is selected from H, hydroxy and halogen; R.sub.7 is H; R.sub.11 and R.sub.12 are each independently selected from H and the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: C.sub.1-6 alkyl, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; or R.sub.11 and R.sub.12, together with the nitrogen atom attached thereto, form the following groups unsubstituted or optionally substituted with one, two or more R.sub.e: 3-7 membered heterocyclyl and 5-6 membered heteroaryl; R.sub.13 is selected from H, cyano, methyl and hydroxy; R.sub.14 is selected from H, hydroxy, halogen, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy and C.sub.3-6 cycloalkyl; R.sub.15 is selected from H and C.sub.1-6 alkyl unsubstituted or optionally substituted with one, two or more R.sub.f; each R.sub.a is independently selected from CN, halogen, OH, NH.sub.2, oxo, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl and C.sub.1-6 alkoxy; each R.sub.b is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, oxo, S(O).sub.2CH.sub.3, C(O)NHCH.sub.2CH.sub.3, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; each R.sub.c is independently selected from CN, halogen, OH, NH.sub.2, COOH, NO.sub.2, C(O)NH.sub.2, C(O)NHOH, C(O)N(OH)CH.sub.3, oxo, C(O)CH.sub.2COOH, C(O)CH.sub.2CN, C(O)CH.sub.2Cl, C(O)CH.sub.2F, C(O)CH.sub.2Br, and the following groups unsubstituted or optionally substituted with one, two or more R.sub.f: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 3-7 membered heterocyclyl and 5-6 membered heteroaryl; R.sub.e and R.sub.f are each the same or different, and are each independently selected from CN, halogen, OH, NH.sub.2, oxo, S(O).sub.2CH.sub.3, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy and C.sub.1-6 haloalkoxy.

15. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein the compound of formula (I) is a compound of formula (II): ##STR00161## wherein, Y.sub.2, X, R.sub.1 and R.sub.2 are defined as in claim 11; Y.sub.3 is CR.sub.8R.sub.9 or NR.sub.10; R.sub.8 and R.sub.9 are the same or different, and are each independently selected from H, hydroxy, halogen, cyano, and the following groups unsubstituted or optionally substituted with one, two or more hydroxy or halogen: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; or R.sub.8 and R.sub.9, together with the carbon atom attached thereto, form carbonyl, i.e., CR.sub.8R.sub.9 is C(═O); R.sub.10 is selected from H, C(O)NH.sub.2, C(O)CH.sub.2CN, C(O)CH.sub.2COOH, and the following groups unsubstituted or optionally substituted with one, two or more hydroxy or halogen: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl; R.sub.3a and R.sub.3b are the same or different, and are each independently selected from H, hydroxy, halogen, cyano, oxo, and the following groups unsubstituted or optionally substituted with one, two or more hydroxy or halogen: C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.2-6 alkenyl and C.sub.2-6 alkynyl.

16. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein the compound of formula (I) is selected from a compound of formula (II-1): ##STR00162## wherein, Y.sub.2, X, R.sub.1 and R.sub.2 are defined as in claim 11.

17. The compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, wherein the compound of formula (I) is selected from 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carbothioamide 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carbonitrile (E)-2-(tert-butylamino)-N′-hydroxy-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboximidamide 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboximidamide 2-((4H-1,2,4-triazol-4-yl)amino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide Methyl 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxylate (1R,2R,5R)-5-((2-(tert-butylamino)-5-(2-hydroxypropan-2-yl) pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol 2-(tert-butylamino)-4-(4-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-((1-(2-cyanoacetyl)piperidin-3-yl)amino)pyrimidine-5-carboxamide 3-(3-((2-(tert-butylamino)-5-carbamoylpyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanoic acid 2-(tert-butylamino)-4-(((5-oxopyrrolidin-2-yl)methyl)amino)pyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-((4-methoxyphenyl)amino)pyrimidine-5-carboxamide 3-((2-tert-butylamino)-5-carbamoylpyrimidin-4-yl)amino)benzoic acid (1R,2R,5R)-5-((2-(tert-butylamino)-5-fluoropyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-chloropyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-methylpyrimidin-4-yl)amino)-2-methylcyclohex-1-ol 2-((2-oxaspiro[3.3]heptan-6-yl)amino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-((6-oxopiperidin-3-yl)amino)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-((1-(2-hydroxyethyl)-6-oxopiperidin-3-yl)amino)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-(3-(hydroxymethyl)piperidin-1-yl)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-(3-(2-hydroxypropan-2-yl)azetidin-1-yl)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-((1-carbamoylpiperidin-3-yl)amino)pyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-morpholinopyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-(3-oxopiperazin-1-yl)pyrimidine-5-carboxamide 2-((1-(ethylcarbamoyl)piperidin-4-yl)amino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino) pyrimidine-5-carboxamide 2-(tert-butylamino)-4-(piperidin-3-ylamino)pyrimidine-5-carboxamide 2-(tert-butylamino)-4-((3-(hydroxymethyl)phenyl)amino)pyrimidine-5-carboxamide Aziridin-1-yl(2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidin-5-yl)methanone (1R,2R,5R)-5-((2-(tert-butylamino)-5-(difluoromethyl)pyrimidin-4-yl)amino)-2-methylcyclohex-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-methoxypyrimidin-4-yl)amino)-2-methylcyclohex-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-(fluoromethyl)pyrimidin-4-yl)amino)-2-methylcyclohex-1-ol 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-sulfamide 2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-ol (1R,2R,5)-5-((5-bromo-2-(tert-butylamino)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-(1H-imidazol-1-yl)pyrimidin-4-yl)amino)-2-methylcyclohex-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-(1H-1,2,4-triazol-1-yl)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-(1H-1,2,3-triazol-1-yl)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,4R)-4-((4-((1-(2-(methylsulfonyl)ethyl)-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol (1R,4R)-4-((4-((1(2-(methylsulfonyl)ethyl)-1H-pyrazol-5-yl)amino)pyrimidin-2-yl)amino)cyclohexan-1-ol 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-(((1R,4R)-4-hydroxycyclohexyl)oxy)pyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-(4-methoxyphenoxy)pyrimidine-5-carboxamide (1R,2R,5R)-5-((5-bromo-2-(tert-butoxy)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol 2-cyclopropoxy-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide 2-(tert-butoxy)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidine-5-carboxamide 6-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinonitrile 6-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((2-hydroxyethyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-(isopropylamino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((3-hydroxycyclopentyl)amino)nicotinamide 6-(cyclobutylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((2-hydroxycyclobutyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((3-hydroxycyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((4-hydroxycyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((3-hydroxycyclohexyl)amino)nicotinamide 6-(cyclohexylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((2-hydroxycyclopentyl)amino)nicotinamide 6-(cyclopentylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinamide 6-((2-fluoropropan-2-yl)amino)-4-(((1R,31R,4R)-3-hydroxy-4-methylcyclohexyl)amino)nicotinamide 6-(cyclopropylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylbicyclohexyl)amino)nicotinamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-6-((2-hydroxycyclopropyl)amino)nicotinamide 6-(((1R,2R)-bicyclo[1.1.0]butan-2-yl)amino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino) nicotinamide (1R,2R,5R)-5-((2-(tert-butylamino)-5-nitropyrimidin-4-yl)amino)-2-methylcyclohex-1-ol (1R,2R,5R)-5-((5-amino-2-(tert-butylamino)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-ethynylpyrimidin-4-yl)amino)-2-methylcyclohex-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-(prop-1-yn-1-yl)pyrimidin-4-yl)amino)-2-methylcyclohexan-1-ol (1R,2R,5R)-5-((2-(tert-butylamino)-5-vinylpyrimidin-4-yl)amino)-2-methylcyclohex-1-ol 1-(2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidin-5-yl)ethan-1-one (2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidin-5-yl)(cyclopropyl)methanone 1-(2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidin-5-yl)propan-1-one 1-(2-(tert-butylamino)-4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)pyrimidin-5-yl)-2-methylpropan-1-one 1-(4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-((1,1,1-trifluoro-2-methylpropan-2-yl)amino)pyrimidin-5-yl)ethan-1-one 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-((4-(methylsulfonyl)phenyl)amino)pyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino) pyrimidine-5-carboxamide 4-(((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl)amino)-2-((4-methoxybenzyl)amino)pyrimidine-5-carboxamide.

18. A method for preparing the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, being one of the following schemes 1-3: ##STR00163## in this scheme, R.sub.2′ is R.sub.2—X, R.sub.3′ is R.sub.3—W, Nu is a nucleophilic group, and R.sub.1, R.sub.2, R.sub.3, X, and W are defined as in claim 11; scheme 1 comprises the following steps 1a and 1b: (1a) subjecting SM-1A to a reaction with a nucleophilic reagent containing R.sub.3′ in the presence of a Lewis base to give IM-1A; and (1b) subjecting IM-1A to a reaction with a nucleophilic reagent containing R.sub.2′ in the presence of a Lewis base to give a corresponding product or intermediate: ##STR00164## in this scheme, R.sub.1′ is R.sub.1 or a group that can derive into R.sub.1, R.sub.2′ is R.sub.2—X, R.sub.3′ is R.sub.3—W, Nu is a nucleophilic group, and R.sub.1, R.sub.2, R.sub.3, X and W are defined as in claim 11; scheme 2 comprises the following steps 2a-2d: (2a) subjecting SM-1B to a reaction with sodium thiomethoxide to give IM-1B, and optionally, carrying out derivatization reaction on R.sub.1′ in the IM-1B before proceeding to subsequent steps; (2b) subjecting IM-1B to a reaction with a nucleophilic reagent containing R.sub.2′ in the presence of a Lewis base to give IM-2B; (2c) subjecting IM-2B to a reaction with m-chloroperoxybenzoic acid to give IM-3B; and (2d) subjecting IM-3B to a reaction with a nucleophilic reagent containing R.sub.3′ in the presence of a Lewis base to give a corresponding product or intermediate, and optionally, further carrying out a derivatization reaction; ##STR00165## in this scheme, R.sub.2 is defined as in claim 11; scheme 3 comprises the following steps 3a-3c (3a) subjecting SM-1C to a reaction with SM-2C in the presence of a Lewis base to give IM-1C; (3b) subjecting IM-1C to a reaction with R.sub.2NH.sub.2 in the presence of a Lewis base to give a corresponding product or intermediate; and (3c) subjecting IM-2C to a reaction with H.sub.2O.sub.2 in the presence of a Lewis base to give a corresponding product.

19. A pharmaceutical composition, comprising a therapeutically effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11 and one or more pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary material can be one or more selected from a disintegrant, a glidant, a lubricant, a diluent, a filler, an adhesive and a colorant.

20. A method for modulating JNK kinase function, which comprises administering to an individual in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11.

21. A method for modulating JNK kinase function, which comprises administering to an individual in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutical composition according to claim 19.

22. A method for inhibiting a kinase in a cell expressing said kinase, which comprises contacting said cell with an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11.

23. The method according to claim 22, wherein, the kinase is JNK1, JNK2, or a mutant or an isoform thereof or a combination thereof.

24. A method for treating or preventing a hepatic fibrosis disease, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, and hepatic fibrosis accompanied by long-term or repeated alcohol intake (alcoholic hepatitis), accompanied by an infection (e.g., viral infection, such as HCV), accompanied by liver transplantation or accompanied by drug-induced liver injury (e.g., acetaminophen toxicity), and the method comprises administering to a subject in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11.

25. A method for treating or preventing diabetes or metabolic syndrome resulting in hepatic or pulmonary fibrosis diseases, such as non-alcoholic steatohepatitis, steatosis (i.e., fatty liver), cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis and hepatitis, and the method comprises administering to a subject in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11.

26. A method for treating or preventing one or more disorders selected from idiopathic pulmonary fibrosis (IPF), systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection and lupus, and the method comprises administering to a subject in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph and the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11.

27. A method for treating or preventing a disease or disorder treatable or preventable by inhibiting JNK1 and/or JNK2, and the method comprises administering to a subject in need thereof an effective amount of the compound and the racemate, the stereoisomer, the tautomer, the isotopically labeled compound, the solvate, the polymorph or the nitrogen oxide thereof or the pharmaceutically acceptable salts thereof according to claim 11, and the diseases or disorders comprise: rheumatoid arthritis; rheumatoid spondylitis; osteoarthritis; asthma; bronchitis; allergic rhinitis; chronic obstructive pulmonary disease; cystic fibrosis; inflammatory bowel disease; irritable bowel syndrome; mucous colitis; ulcerative colitis; Crohn's disease; Huntington's disease; hepatitis; pancreatitis; nephritis; multiple sclerosis; lupus erythematosus; type II diabetes; obesity; atherosclerosis; post-angioplasty restenosis; left ventricular hypertrophy; myocardial infarction; stroke; ischemic injury of the heart, lung, intestine, kidney, liver, pancreas, spleen and brain; acute or chronic organ transplant rejection; preservation of organs for transplantation; organ failure or loss of limb (e.g., including but not limited to those resulting from ischemia-reperfusion injury, trauma, gross bodily injury, car accident, crush injury or transplantation failure); graft versus host disease; endotoxic shock; multiple organ failure; psoriasis; burns caused by exposure to fire, chemicals or radiation; eczema; dermatitis; skin grafting; ischemia; ischemic disorders associated with surgery or traumatic injury (e.g., vehicular accident, gunshot wound or limb crush); epilepsy; Alzheimer's disease; Parkinson's disease; immune response to bacterial or viral infection; cachexia; angiogenic and proliferative diseases; solid tumor; and cancers of various tissues, such as colon, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, bladder, ovary or uterus, in particular, the diseases or disorders comprise: hepatic and pulmonary fibrosis diseases, such as non-alcoholic steatohepatitis, steatosis, cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, hepatitis, hepatocellular carcinoma, hepatic fibrosis accompanied by long-term or repeated alcohol intake, accompanied by an infection, accompanied by liver transplantation or accompanied by drug-induced liver injury, and idiopathic pulmonary fibrosis; systemic sclerosis, scleroderma, chronic allograft nephropathy, antibody-mediated rejection, or lupus, such as lupus erythematosus or systemic lupus.

Description

DETAILED DESCRIPTION

[0320] The compounds of the general formulas disclosed herein and the preparation method and use thereof will be described in detail with reference to the following examples. The following examples are merely exemplary illustration and explanation of the present disclosure, and should not be construed as limiting the protection scope of the present disclosure. All techniques implemented based on the aforementioned content of the present disclosure are encompassed within the protection scope of the present disclosure.

[0321] Unless otherwise stated, the starting materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

PREPARATION EXAMPLES

Example 1: Preparation of Compounds (T001A) and (T001)

[0322] ##STR00130##

[0323] 1.1 Preparation of Compound (T001-2)

[0324] Sodium thiomethoxide (2.4 g, 34.8 mmol) was added to a solution of 5-bromo-2,4-dichloropyrimidine (4 g, 17.4 mmol) in acetonitrile (40 mL) at normal temperature. After the addition was completed, the reaction mixture was stirred at room temperature overnight. Water was added, and the reaction mixture was extracted with ethyl acetate. The organic phase was collected, dried, concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/50) to give 3.48 g of a white solid with a yield of 82.8%. .sup.1H NMR (400 MHz, CDCl.sub.3): δ=8.31 (s, 1H), 2.59 (s, 3H).

[0325] 1.2 Preparation of Compound (T001-3)

[0326] Compound T001-2 (3.48 g, 14.54 mmol), dioxane (10 mL) and tert-butylamine (6.38 g, 87.2 mmol) were added to a sealed tube. After the addition was completed, the tube was sealed and the reaction mixture was reacted at 100° C. for 72 h. After the reaction was completed, as detected by TLC plate (PE/EA=10/1, R.sub.f=0.6), the reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/20) to give 2.35 g of a white solid with a yield of 59%.

[0327] .sup.1H NMR (400 MHz, DMSO-d6). δ=8.08 (s, 1H), 7.04 (s, 1H), 1.44 (s, 3H), 1.38 (s, 9H).

[0328] 1.3 Preparation of Compound (T001-4)

[0329] Compound T001-3 (2 g, 7.2 mmol), DMF (5 mL), zinc cyanide (1.7 g, 14.5 mmol) and tetrakis(triphenylphosphine)palladium(O) (0.84 g, 0.72 mmol) were added to a microwave tube at normal temperature. After the addition was completed, nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 120° C. for 1.5 h under microwave in a temperature mode. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/20) to give 1.48 g of a white solid with a yield of 91%.

[0330] 1.4 Preparation of Compound (T001-5)

[0331] m-chloroperoxybenzoic acid (4 g, 19.9 mmol) was added in portions to a solution of compound T001-4 (1.48 g, 6.63 mmol) in dichloromethane (30 mL) under an ice bath. After the addition was completed, the reaction mixture was stirred at room temperature for 4 h and the reaction was completed as detected. Excessive m-chloroperoxybenzoic acid was washed away with saturated sodium bicarbonate solution, and the organic phase was washed with water, dried, concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=3/20) to give 0.44 g of a white solid with a yield of 26.2%.

[0332] 1.5 Preparation of Compound (T001A)

[0333] N,N-diisopropylethylamine (i.e., DIEA, 0.15 g, 1.18 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (CAS: 1403864-98-1, 0.13 g, 0.787 mmol) were added to a solution of compound T001-5 (0.2 g, 0.787 mmol) in ethanol (3 mL) at normal temperature. After the addition was completed, the reaction mixture was heated at 90° C. for 0.5 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=3/10) to give 80 mg of a white solid with a yield of 33.4%.

[0334] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=8.04 (s, 1H), 4.14-4.07 (m, 1H), 3.16-3.10 (m, 1H), 2.22-2.19 (m, 1H), 1.93-1.89 (m, 1H), 1.81-1.77 (m, 1H), 1.44 (s, 9H), 1.39-1.29 (m, 3H), 1.12-1.05 (m, 1H), 1.02 (d, J=6.8 Hz, 3H). Rt=3.629 min, [M+H].sup.+=304.2.

[0335] 1.6 Preparation of Compound (T001)

[0336] Compound T001A (80 mg, 0.264 mmol), DMF (1 mL), methanol (1 mL) and aqueous ammonium sulfide solution (20%, 0.8 mL, 0.246 mmol) were added to a microwave tube at normal temperature. After the addition was completed, nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 100° C. for 1 h under microwave in a temperature mode. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 19 mg of a white solid with a yield of 21.3%.

[0337] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=8.15 (s, 1H), 4.08-4.02 (m, 1H), 3.16-3.09 (m, 1H), 2.36-2.33 (m, 1H), 2.07-2.04 (m, 1H), 1.81-1.77 (m, 1H), 1.46 (s, 9H), 1.35-1.24 (m, 3H), 1.13-1.06 (m, 1H), 1.03 (d, J=6 Hz, 3H); Rt=3.569 min, [M+H].sup.+=338.1.

Example 2: Preparation of Compound (T002)

[0338] Hydroxylamine hydrochloride (114 mg, 1.65 mmol) and triethylamine (166 mg, 1.65 mmol) were added to a solution of compound T001A (100 mg, 0.33 mmol) in ethanol (2 mL) at normal temperature. The reaction mixture was warmed to 80° C. and heated for 2 h, and then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 100 mg of a white solid with a yield of 90%.

[0339] .sup.1H NMR (400 MHz, DMSO-d6): δ=9.48 (s, 1H), 8.43-8.34 (m, 1H), 8.09 (s, 1H), 6.17 (s, 1H), 5.72 (s, 1H), 4.57-4.56 (m, 1H), 3.90-3.87 (m, 1H), 2.98-2.96 (m, 1H), 2.17-2.14 (m, 1H), 1.95-1.92 (m, 1H), 1.69-1.65 (m, 1H), 1.36 (s, 9H), 1.23-0.98 (m, 4H), 0.94 (d, J=6 Hz, 3H); Rt=3.214 min, [M+H].sup.+=337.2.

Example 3: Preparation of Compound (T003)

[0340] ##STR00131##

[0341] Two drops of acetic acid, 2 drops of acetic anhydride and wet palladium on carbon (about 10 mg) were added to a solution of compound T002 (50 mg, 0.148 mmol) in methanol (3 mL) at normal temperature. After the addition was completed, purge with nitrogen and purge with hydrogen were carried out successively, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 17.1 mg of a yellow solid with a yield of 35.8%.

[0342] .sup.1H NMR (400 MHz, DMSO-d6): δ=10.62-10.60 (br, 1H), 6.17 (s, 1H), 6.57-6.28 (brs, 1H), 6.24-6.07 (brs, 1H), 6.04-5.96 (brs, 2H), 4.55-4.54 (m, 1H), 3.87-3.84 (m, 1H), 2.98-2.93 (m, 1H), 2.15-2.12 (m, 1H), 1.92-1.90 (m, 1H), 1.67-1.63 (m, 1H), 1.36 (s, 9H), 1.20-0.97 (m, 4H), 0.93 (d, J=6.4 Hz, 3H); Rt=2.846 min, [M+H].sup.+=321.2.

Example 4: Preparation of Compound (T004)

[0343] ##STR00132##

[0344] 4.1 Preparation of Compound (T004-2)

[0345] Phosphorus pentachloride (29.6 g, 142 mmol) was slowly added in portions to a solution of 2,4-dihydroxypyrimidine-5-carboxylic acid (CAS: 23945-44-0, 6.2 g, 40 mmol) in phosphorus oxychloride (30 mL) with stirring under an ice-water bath, and the reaction mixture was stirred for 30 min under an ice bath. The reaction mixture was then gradiently warmed to reflux (oil bath temperature: 120° C.). The reaction mixture was refluxed for 16 h, and then cooled to room temperature. The reaction mixture was carefully concentrated under reduced pressure to give phosphorus oxychloride as distillate, and the reaction was quenched with warm water. The residue was dissolved in dichloromethane and filtered. The mother solution was concentrated to give 6.7 g of oil (crude product) with a yield of 78.8%, which was directly used in the next step.

[0346] 4.2 Preparation of Compound (T004-3)

[0347] Aqueous ammonia (14 mL) was added dropwise to a solution of compound T004-2 (8.8 g, 41.5 mmol) in dichloromethane (30 mL) with stirring at −20° C., and a white solids appeared. The reaction mixture was stirred at −20° C. for 30 min, filtered, washed with water and dried to give 2.8 g of a white solid with a yield of 35%.

[0348] 4.3 Preparation of Compound (T004-4)

[0349] Diisopropylethylamine (516 mg, 4.0 mmol) was added dropwise to a solution of T004-3 (384 mg, 2.0 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (397 mg, 2.4 mmol) in isopropanol (10 mL) with stirring under an ice bath. After stirring overnight at room temperature, the reaction was completed. The reaction mixture was concentrated under reduced pressure, added with water, and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was then concentrated under reduced pressure, slurried with dichloromethane and filtered to give 500 mg of a white solid with a yield of 88%.

[0350] 4.4 Preparation of Compound (T004)

[0351] Compound T004-4 (50 mg, 0.175 mmol), 4-amino-1,2,4-triazole (29.4 mg, 0.35 mmol), Pd.sub.2(dba).sub.3 (10 mg, 0.075 mmol), Xantphos (13 mg, 0.026 mmol) and potassium tert-butoxide (39.2 mg, 0.35 mmol) were dispersed in anhydrous toluene (5 mL). After purged with nitrogen, the reaction mixture was heated to 110° C. and refluxed for 12 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 17 mg of a white solid with a yield of 29%.

[0352] .sup.1HNMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H), 9.03 (d, J=7.6 Hz, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 7.81 (brs, 1H), 7.23 (brs, 1H), 4.54 (d, J=5.6 Hz, 1H), 3.57 (brs, 1H), 2.89-2.85 (m, 1H), 2.02-1.97 (m, 1H), 1.78-1.75 (m, 1H), 1.60-1.56 (m, 1H), 1.19-0.99 (m, 3H), 0.88-0.79 (m, 4H). LCMS: Rt=2.207 min, [M+H].sup.+=333.1.

Example 5: Preparation of Compounds (T005) and (T005A)

[0353] ##STR00133##

[0354] 5.1 Preparation of Compound (T005-3)

[0355] m-chloroperoxybenzoic acid (7.5 g, 43.6 mmol) was added in portions to a solution of compound T001-3 (4 g, 14.5 mmol) in dichloromethane (80 mL) under an ice bath. After the addition was completed, the reaction mixture was stirred at normal temperature for 3 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was washed with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was collected, dried and concentrated under reduced pressure to give compound T005-2 (crude product).

[0356] DIEA (3.75 g, 29.0 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (2.4 g, 14.5 mmol) were added to a solution of compound T005-2 (crude product) in DMF (40 mL) at room temperature. After the addition was completed, the reaction mixture was stirred at 120° C. overnight. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated to dryness under reduced pressure and purified by normal phase column chromatography (EA/PE=1/5) to give 1.637 g of a yellow oil with a two-step yield of 31.5%.

[0357] 5.2 Preparation of Compound (T005A)

[0358] Compound T005-3 (300 mg, 0.84 mmol), triethylamine (254 mg, 2.52 mmol), bis(triphenylphosphine)palladium(II) dichloride (61 mg, 0.084 mmol) and methanol (20 mL) were added to an autoclave at normal temperature. After the addition was completed, the reaction mixture was purged with carbon monoxide, and then pressurized to 1.5 MPa and stirred overnight at 100° C. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated to dryness under reduced pressure and purified by normal phase column chromatography (EA/PE=1/5) to obtain 267 mg of yellow oil with a yield of 94.6%.

[0359] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=8.40 (s, 1H), 4.08-4.06 (m, 1H), 3.79 (s, 3H), 3.17-3.11 (m, 1H), 2.33-2.30 (m, 1H), 2.05-2.00 (m, 1H), 1.82-1.77 (m, 1H), 1.46 (s, 9H), 1.35-1.25 (m, 3H), 1.11-1.07 (m, 1H), 1.03 (d, J=6.4 Hz, 3H). Rt=3.861 min, [M+H].sup.+=338.2.

[0360] 5.3 Preparation of Compound (T005)

[0361] A solution of methyllithium in ether (1.6M) (1.8 mL, 2.97 mmol) was slowly added dropwise to a solution of compound T005A (100 mg, 0.297 mmol) in tetrahydrofuran (3 mL) under an ice bath. After the addition was completed, the reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed as detected by liquid chromatography, the reaction was quenched with aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was collected, dried, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 50 mg of a white solid with a yield of 33.3%.

[0362] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=7.54 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 5.73 (s, 1H), 5.34 (s, 1H), 4.56 (d, J=5.6 Hz, 1H), 3.88-3.83 (m, 1H), 2.99-2.93 (m, 1H), 2.17-2.11 (m, 1H), 1.94-1.91 (m, 1H), 1.68-1.64 (m, 1H), 1.40 (s, 6H), 1.34 (s, 9H), 1.24-0.98 (m, 4H), 0.94 (d, J=6.8 Hz, 3H). Rt=3.005 min, [M+H].sup.+=337.2.

Example 6: Preparation of Compound (T006)

[0363] ##STR00134##

[0364] 6.1 Preparation of Compound (T006-2)

[0365] Phosphorus pentachloride (29.6 g, 142 mmol) was slowly added in portions to a solution of 2,4-dihydroxypyrimidine-5-carboxylic acid (CAS: 38324-83-3, 6.2 g, 40 mmol) in phosphorus oxychloride (30 mL) with stirring under an ice-water bath, and the reaction mixture was stirred for 30 min in an ice bath. The reaction mixture was then gradiently warmed to reflux (oil bath temperature: 120° C.). The reaction mixture was refluxed for 16 h and then cooled to room temperature. The reaction mixture was carefully concentrated under reduced pressure to give phosphorus oxychloride as distillate, and the reaction was quenched with warm water. The residue was dissolved in dichloromethane and filtered. The mother solution was concentrated to give 6.7 g of oil (crude product) with a yield of 78.8%, which was directly used in the next step.

[0366] 6.2 Preparation of Compound (T006-3)

[0367] Aqueous ammonia (14 mL) was added dropwise to a solution of compound T006-2 (8.8 g, 41.5 mmol) in dichloromethane (30 mL) with stirring at −20° C. and a white solid appeared. The reaction mixture was stirred at −20° C. for 30 min, filtered, washed with water and dried to give 2.8 g of a white solid with a yield of 35%.

[0368] 6.3 Preparation of Compound (T006-4) Diisopropylethylamine (193 mg, 1.5 mmol) was added dropwise to a solution of compound T006-3 (192 mg, 1.0 mmol) and 4-hydroxypiperidine (CAS: 5382-16-1, 111 mg, 1.1 mmol) in isopropanol (5 mL) with stirring under an ice bath. After stirring for 2 h, the reaction was completed. The reaction mixture was concentrated under reduced pressure, added with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, slurried with dichloromethane and filtered to give 54 mg of a white solid with a yield of 21%.

[0369] 6.4 Preparation of Compound (T006)

[0370] Compound T006-4 (54 mg, 0.21 mmol), tert-butylamine (438 mg) and acetonitrile (5 mL) were added to a sealed glass tube. The tube was sealed, and the reaction mixture was heated to 90° C. After 12 h of reaction, the reaction mixture was cooled to room temperature, concentrated, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 27 mg of a white solid with a yield of 44%.

[0371] .sup.1HNMR (400 MHz, CD.sub.3OD) δ 8.09 (s, 1H), 3.87-3.93 (m, 3H), 3.19-3.25 (m, 2H), 1.91-1.96 (m, 2H), 1.55-1.59 (m, 2H), 1.46 (s, 9H). LCMS: Rt=2.22 min, [M+H].sup.+=294.1.

Example 7: Preparation of Compound (T007)

[0372] ##STR00135##

[0373] 7.1 Preparation of Compound (T007-2)

[0374] Compound 3-tert-butoxycarbonylaminopiperidine (CAS: 172603-05-3, 1 g, 4.98 mmol), cyanoacetic acid (636 mg, 7.4 mmol) and triethylamine (1.0 g, 9.96 mmol) were dissolved in dichloromethane (20 mL) at room temperature, and 2-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (2.26 g, 5.96 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was added with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography to give 898 mg of a yellow solid with a yield of 69%.

[0375] 7.2 Preparation of Compound (T007-3)

[0376] Compound T007-2 (848 mg, 3.17 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (2 mL) at room temperature, and the reaction mixture was stirred for 4 h and concentrated under reduced pressure to give 380 mg of a white solid with a yield of 71%.

[0377] 7.3 Preparation of Compound (T007-4)

[0378] Compound T007-3 (350 mg, 2.09 mmol) and compound T006-3 (482 mg, 2.5 mmol) were dissolved in isopropanol (10 mL), and DIEA (808 mg, 6.27 mmol) was added dropwise with stirring under an ice bath, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, added with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained after concentration was slurried with dichloromethane and filtered to give 300 mg of T007-4 (a white solid) with a yield of 44.6%. The filtrate was concentrated and subjected to high performance liquid chromatography (ammonium bicarbonate method) to give 70 mg of cyano hydrolyzed by-product T007-5.

[0379] 7.4 Preparation of Compound (T007)

[0380] Compound T007-4 (200 mg, 0.62 mmol), acetonitrile (2 mL) and tert-butylamine (1 mL) were added to a sealed tube. The tube was sealed, and the reaction mixture was heated to 90° C. and reacted overnight. The reaction mixture was then cooled to room temperature, concentrated, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 15 mg of a white solid with a yield of 6.7%.

[0381] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.27 (d, J=7.6 Hz, 1H), 8.02 (s, 1H), 7.49 (s, 1H), 7.13 s, 1H), 6.61 (br, 1H), 3.76-3.74 (m, 2H), 3.63 (s, 2H), 3.60-3.56 (m, 1H), 3.04-2.94 (m, 2H), 1.83-1.81 (m, 1H), 1.68-1.69 (m, 1H), 1.58-1.36 (m, 2H), 1.36 (s, 9H). LCMS: Rt=3.992 min, [M+H].sup.+=360.2.

Example 8: Preparation of Compound (T008)

[0382] Compound T007-5 (70 mg, 0.185 mmol) was dissolved in acetonitrile (1 mL), and tert-butylamine (1 mL) was added. The reaction mixture was heated to 90° C. in a sealed tube and reacted overnight. The reaction mixture was then cooled to room temperature, concentrated, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 8.7 mg of a white solid with a yield of 11.5%.

[0383] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.28-8.26 (m, 1H), 4.25-4.20 (m, 1H), 3.90-3.85 (m, 1H), 3.70-3.30 (m, 4H), 2.05-1.95 (m, 1H), 1.8-1.60 (m, 4H), 1.36 (s, 9H). LCMS: Rt=2.688 min, [M+H].sup.+=378.2.

Example 9: Preparation of Compound (T009)

[0384] ##STR00136##

[0385] 9.1 Preparation of Compound (T009-2)

[0386] DIEA (516 mg, 4.0 mmol) was added dropwise to a solution of compound T006-3 (384 mg, 2.0 mmol) and 5-aminomethyl-2-pyrrolidone (272 mg, 2.4 mmol) in isopropanol (10 mL) with stirring under an ice bath. After the addition was completed, the reaction mixture was stirred at room temperature for 4 h, and the reaction was completed. A white solid was precipitated out. The reaction mixture was filtered and washed with water to give 400 mg of a white product with a yield of 74%.

[0387] 9.2 Preparation of Compound (T009)

[0388] Compound T009-2 (210 mg, 0.73 mmol), tert-butylamine (730 mg, 7.4 mmol) and N,N-dimethylformamide (5 mL) were added to a sealed tube. After the tube was sealed, the reaction mixture was heated to 90° C. and reacted for 12 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 67 mg of a white solid with a yield of 30%.

[0389] .sup.1HNMR (400 MHz, CD.sub.3OD) δ 8.30 (s, 1H), 4.01-3.95 (m, 1H), 3.74-3.71 (m, 1H), 3.70-3.56 (m, 1H), 2.44-2.23 (m, 3H), 1.94-1.85 (m, 1H), 1.48 (s, 9H). LCMS: Rt=2.673 min, [M+H].sup.+=307.1.

Example 10: Preparation of Compound (T010)

[0390] ##STR00137##

[0391] p-toluenesulfonic acid monohydrate (134 mg, 0.705 mmol) was added to a mixed solution of compound T004-4 (80 mg, 0.282 mmol) and p-methoxyaniline (42 mg, 0.338 mmol) in isopropanol (10 mL) at room temperature. After purged with nitrogen, the reaction mixture was heated to reflux for 16 h. After the reaction mixture was cooled to room temperature, a white solid was precipitated out, and the reaction mixture was filtered, washed with isopropanol and dried under vacuum to give 65 mg of pure product with a yield of 62%.

[0392] .sup.1H NMR (400 MHz, CD.sub.3OD): δ8.27 (s, 1H), 7.38-7.36 (m, 2H), 7.02-7.00 (m, 2H), 4.02-3.98 (m, 1H), 3.83 (s, 3H), 3.13-3.07 (m, 1H), 2.30-2.27 (m, 1H), 2.00-1.97 (m, 1H), 1.81-1.77 (m, 1H), 1.38-1.29 (m, 4H), 1.02 (d, J=6.4 Hz, 3H). Rt=3.012 min, [M+H].sup.+=372.1.

Example 11: Preparation of Compound (T011)

[0393] ##STR00138##

[0394] 11.1 Preparation of Compound (T011-2)

[0395] Methyl 3-amino-benzoate (474 mg, 3.1 mmol, CAS: 4518-10-9) and DIEA (503 mg, 3.9 mmol) were added to a solution of 2,6-dichloro-nicotinamide (500 mg, 2.6 mmol, CAS: 62068-78-4) in isopropanol (5 mL), and the reaction mixture was heated to reflux for 16 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was filtered and concentrated under reduced pressure to give compound TO 11-2 (600 mg, crude product), which was used directly in the next step. LCMS: Rt=1.450 min, [M+H].sup.+=306.8.

[0396] 11.2 Preparation of Compound (T011-3)

[0397] Tert-butylamine (0.5 mL) was added to a solution of compound T011-2 (150 mg, 0.49 mmol) in DMF (0.5 mL), and the reaction mixture was reacted at 100° C. for 18 h in a sealed tube. After the reaction was completed as detected by chromatography, the reaction mixture was concentrated under reduced pressure to give 200 mg of compound TO 11-3 (crude product), which was used directly in the next step. LCMS: Rt=1.572 min, [M+H].sup.+=343.9.

[0398] 11.3 Preparation of Compound (T011)

[0399] Water (0.3 mL) and lithium hydroxide (100 mg, 2.5 mmol) were added to a solution of compound T011-3 (crude product, 0.49 mmol) in THF (1.5 mL), and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was adjusted to pH=4.0 with 1 mol/L hydrochloric acid, concentrated by rotary evaporation, dissolved in DMF (2 mL), filtered to remove insoluble matter, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 24 mg of a white solid with a three-step yield of 15%.

[0400] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=12.89 (br, 1H), 11.72 (brs, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 7.88-7.72 (m, 2H), 7.61 (d, J=7.8 Hz, 1H), 7.43 (t, J=8 Hz, 1H), 7.27 (br, 1H), 7.05 (brs, 1H), 1.38 (s, 9H). LCMS: Rt=2.623 min, [M+H].sup.+=330.1.

Example 12: Preparation of Compound (T012)

[0401] ##STR00139##

[0402] 12.1 Preparation of Compound (T012-2)

[0403] DIEA (997 mg, 7.7 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (467 mg, 2.8 mmol) were added to a solution of 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.5 mmol, CAS: 2927-71-1) in isopropanol (10 mL) at normal temperature. The reaction mixture was reacted for 3 h at room temperature, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/3) to give 510 mg of a yellow solid with a yield of 69.1%.

[0404] 12.2 Preparation of Compound (T012)

[0405] Compound T012-2 (510 mg, 1.78 mmol), dioxane (5 mL) and tert-butylamine (2 mL) were added to a sealed tube at normal temperature. After the addition was completed, the tube was sealed and the reaction mixture was heated to 90° C. and reacted for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and extracted with water and ethyl acetate, and the organic phase was dried and concentrated to give 420 mg of crude product as a yellow solid with a yield of 72.7%.

[0406] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=8.82 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 4.10-4.06 (m, 1H), 3.06-3.01 (m, 1H), 2.13-2.10 (m, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.45-1.36 (m, 10H), 1.29-1.23 (m, 2H), 1.03-0.93 (m, 4H). Rt=4.064 min, [M+H].sup.+=324.1.

Example 13: Preparation of Compound (T013)

[0407] ##STR00140##

[0408] 13.1 Preparation of Compound (T013-2)

[0409] Compound 2,4,5-trichloropyrimidine (CAS: 5750-76-5, 366 mg, 2 mmol) and sodium thiomethoxide (154 mg, 2.2 mmol) were dissolved in tetrahydrofuran (50 mL) at room temperature, and the reaction mixture was stirred overnight at room temperature. After the reaction was completed as detected by LC-MS, the reaction mixture was purified by column chromatography to give 335 mg of a white solid with a yield of 86.3%.

[0410] 13.2 Preparation of Compound (T013-3)

[0411] Compound T013-2 (340 mg, 1.75 mmol) was dissolved in dioxane (3 mL), and tert-butylamine (1.5 mL) was added. The reaction mixture was reacted at 100° C. overnight in a sealed tube. The reaction mixture was cooled, concentrated and purified by column chromatography to give 110 mg of a white solid with a yield of 27%.

[0412] 13.3 Preparation of Compound (T013-4)

[0413] Compound T013-3 (110 mg, 0.47 mmol) was dissolved in dichloromethane (20 mL), and m-CPBA (246 mg, 1.42 mmol) was added in portions under an ice bath. After the addition was completed, the reaction was warmed to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane (30 mL) and washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and subjected to column chromatography to give 60 mg of a white solid with a yield of 48.8%.

[0414] 13.4 Preparation of Compound (T013)

[0415] Compound T013-4 (60 mg, 0.228 mmol) was dissolved in dioxane (10 mL), and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (56.5 mg, 0.342 mmol) and diisopropylethylamine (88.3 mg, 0.684 mmol) were added. The reaction mixture was stirred at 100° C. for 20 h. The reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 20 mg of a white solid with a yield of 28%.

[0416] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.73 (s, 1H), 5.07 (br, 1H), 4.91 (s, 1H), 3.99-3.95 (m, 1H), 3.32-3.26 (m, 1H), 2.39-2.35 (m, 1H), 2.06-2.02 (m, 1H), 1.83-1.77 (m, 1H), 1.38 (s, 9H), 1.38-1.25 (m, 3H), 1.15-1.05 (m, 1H), 1.03 (d, J=6.6 Hz, 3H). LCMS: Rt=4.524 min, [M+H].sup.+=313.1.

Example 14: Preparation of Compound (T014)

[0417] ##STR00141##

[0418] 14.1 Preparation of Compound (T014-2)

[0419] Compound T001-3 (230 mg, 0.836 mmol), methylboronic acid (251 mg, 4.18 mmol), potassium carbonate (346 mg, 0.250 mmol) and Pd(dppf)Cl.sub.2 (50 mg, 0.068 mmol) were dispersed in a mixed solution of dioxane (5 mL) and water (2 mL). After purged with nitrogen, the reaction mixture was heated to reflux for 4 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give 130 mg of an oil in with a yield of 74%.

[0420] 14.2 Preparation of Compound (T014-3)

[0421] 3-chlorobenzoperoxoic acid (296 mg, 1.70 mmol) was added to a solution of compound T014-2 (180 mg, 0.853 mmol) in dichloromethane (2 mL) with stirring under an ice bath. After stirring at room temperature for 4 h, the reaction was completed. The reaction mixture was diluted with dichloromethane and filtered, and the organic phase was washed with sodium bicarbonate solution, concentrated under reduced pressure at low temperature and purified by column chromatography to give 150 mg of a white solid with a yield of 72%.

[0422] 14.3 Preparation of Compound (T014)

[0423] Compound T014-3 (50 mg, 0.205 mmol), isopropanol (2 mL), (1R,3R,4R)-5-amino-2-methylcyclohexanol hydrochloride (34 mg, 0.205 mmol) and DIEA (53 mg, 0.41 mmol) were added to an 8 mL microwave tube. The microwave tube was sealed, the reaction mixture was reacted at 140° C. for 2 h in a microwave reactor. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 8.1 mg of a white solid with a yield of 13.5%.

[0424] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 7.43 (s, 1H), 4.23-4.17 (m, 1H), 3.20-3.14 (m, 1H), 2.24-2.21 (m, 1H), 2.20 (s, 3H), 1.96-1.92 (m, 1H), 1.86-1.82 (m, 1H), 1.55-1.52 (m, 11H), 1.48-1.36 (m, 1H), 1.09-1.07 (m, 1H), 1.04 (d, J=6.4 Hz, 3H). LCMS: Rt=3.168 min, [M+H].sup.+=293.2.

[0425] Preparation of Other Compounds of the Same Type

[0426] Reference was made to the above process routes and procedures of Examples 1-14 to prepare the compounds in Table 2 below:

TABLE-US-00002 TABLE 2 Example Compound No. Ms + 1 15 T015 362.1 16 T016 307.1 17 T017 351.1 18 T018 308.1 19 T019 294.2 20 T020 308.2 21 T021 336.3 22 T022 336.1 23 T023 349.1 24 T024 420.1 25 T025 293.3 26 T026 316.1 27 T027 348.3 28 T028 329.1 29 T029 309.1 30 T030 311.1

Example 31: Preparation of Compound (T031)

[0427] ##STR00142## ##STR00143##

[0428] 31.1 Preparation of Compound (T031-2)

[0429] 5-bromouracil (CAS: 51-20-7, 3 g, 0.015 mol), benzylmercaptan (2.1 g, 0.017 mol), tetrabutylammonium hydrogen sulfate (CAS: 32503-27-8, 1.3 g, 0.25 mol) and potassium carbonate (4.5 g, 0.033 mol) were dissolved in DMF (20 mL), and the reaction mixture was reacted at 60° C. overnight (about 16 h). After the reaction was completed as detected by liquid chromatography, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and slurried with petroleum ether to give 2.1 g of a white solid with a yield of 57.2%.

[0430] LCMS: Rt=0.964 min, [M+H].sup.+=235.1.

[0431] 31.2 Preparation of Compound (T031-3)

[0432] Compound T031-2 was dissolved in phosphorus oxychloride, and the reaction mixture was reacted at 110° C. overnight. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated under reduced pressure, and aqueous sodium bicarbonate solution and ethyl acetate were added to the concentrated solution for liquid separation. The organic phase was concentrated and purified by silica gel column chromatography (PE) to give 420 mg of a yellow oil with a yield of 24.7%.

[0433] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.74 (s, 1H), 7.43 (d, J=8.4 Hz, 2H), 7.35 (t, J=7.2 Hz, 2H), 7.31-7.26 (m, 1H), 4.46 (s, 2H).

[0434] 31.3 Preparation of Compound (T031-4)

[0435] Hydrochloric acid solution (2 M, 0.3 mL) was dissolved in acetonitrile (10 mL), and N-chlorosuccinimide (NCS, CAS: 128-09-6; 635 mg, 4.74 mmol) was added under an ice-bath. The reaction mixture was stirred for 5 min, and then a solution of compound T031-3 (320 mg, 1.18 mmol) in acetonitrile was added dropwise to the reaction mixture. The resulting reaction mixture was reacted for 30 min under an ice bath, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the concentrated solution for liquid separation, and the organic phase was concentrated to give 300 mg of crude product, which was used directly in the next step.

[0436] 31.4 Preparation of Compound (T031-5)

[0437] Compound T031-4 (crude product) was dissolved in tetrahydrofuran solution, and aqueous ammonia (0.3 mL) was added dropwise under an ice bath. The reaction mixture was reacted at 0° C. for 5 min. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the concentrated solution for liquid separation. The organic phase was concentrated and purified by silica gel column chromatography (EA/PE=1/3) to give 190 mg of a yellow oil with a two-step yield of 71.1%.

[0438] LCMS: Rt=1.390 min, [M−H].sup.−=225.9.

[0439] 31.5 Preparation of Compound (T031-6)

[0440] DIEA (325 mg, 2.52 mmol) and compound (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (166 mg, 100 mmol) were added to a solution of compound T031-5 (190 mg, 0.84 mmol) in isopropanol (4 mL) at normal temperature, and the reaction mixture was reacted at room temperature for 3 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/1) to give 110 mg of a yellow oil with a yield of 40.8%.

[0441] LCMS: Rt=1.036 min, [M+H].sup.+=320.8.

[0442] 31.6 Preparation of Compound (T031)

[0443] Compound T031-6 (90 mg, 0.28 mmol), acetonitrile (2 mL) and tert-butylamine (0.5 mL) were added to a sealed tube at normal temperature. After the addition was completed, the tube was sealed and the reaction mixture was heated to 90° C. and reacted for 6 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (aqueous ammonia method) and lyophilized to give 2.2 mg of a white solid with a yield of 2.2%.

[0444] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 8.75 (s, 1H), 4.13-4.07 (m, 1H), 3.10-3.03 (m, 1H), 2.23-2.20 (m, 1H), 1.94-1.91 (m, 1H), 1.75-1.70 (m, 1H), 1.37 (s, 9H), 1.32-1.18 (m, 3H), 1.05-0.97 (m, 1H), 0.95 (d, J=6.4 Hz, 3H). LCMS: Rt=3.060 min, [M+H].sup.+=358.1.

Example 32: Preparation of Compound (T032)

[0445] Reference was made to the process route and procedures of Example 31, benzylthiol was replaced by benzyl alcohol, and substitution reaction was performed before debenzylation reaction, thus obtaining compound T032; [M+H].sup.+=295.3.

Example 33: Preparation of Compound (T033)

[0446] ##STR00144##

[0447] 33.1 Preparation of Compound (T033-2)

[0448] (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (119.8 mg, 0.724 mmol) and DIEA (169.8 mg, 1.316 mmol) were added to a solution of compound 5-bromo-2,4-dichloropyrimidine (150 mg, 0.658 mmol) in isopropanol (2 mL) at normal temperature. After the addition was completed, the reaction mixture was heated to 70° C. and reacted for 1 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure and purified by normal phase column chromatography (EA/PE=3/10) to give 377 mg of a colorless oil with a yield of 89.5%.

[0449] 33.2 Preparation of Compound (T033)

[0450] Compound T033-2 (377 mg, 1.178 mmol), dioxane (1.2 mL) and tert-butylamine (517 mg, 7.068 mmol) were added to a sealed tube at normal temperature. After the addition was completed, the tube was sealed, and the reaction mixture was heated to 100° C. and reacted for 72 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 61 mg of a white solid with a yield of 14.5%.

[0451] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=7.80 (s, 1H), 6.28-6.26 (m, 1H), 4.64-4.63 (m, 1H), 3.95-3.93 (m, 1H), 2.98-2.95 (m, 1H), 2.01-1.98 (m, 1H), 1.76-1.65 (m, 2H), 1.43-1.18 (m, 13H), 0.98-0.90 (m, 3H). Rt=2.918 min, [M+H].sup.+=359.1.

Example 34: Preparation of Compound (T034)

[0452] ##STR00145##

[0453] Compound T005-3 (210 mg, 0.58 mmol), imidazole (47.6 mg, 0.7 mmol), potassium carbonate (296 mg, 2.32 mmol), L-proline (66.7 mg, 0.58 mmol) and copper(I) iodide (55.1 mg, 0.29 mmol) were dissolved in dimethyl sulfoxide (3 mL). The reaction mixture was reacted overnight at 120° C. under nitrogen atmosphere, and the reaction was completed as detected by liquid chromatography. The reaction mixture was filtered, added with water and extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 8.8 mg of a white solid with a yield of 4%.

[0454] .sup.1H NMR (400 MHz, CD.sub.3OD): δ 7.67 (s, 1H), 7.62 (s, 1H), 7.15-713 (m, 2H), 4.11-4.04 (m, 1H), 3.15-3.09 (m, 1H), 2.19-2.14 (m, 1H), 1.90-1.86 (m, 1H), 1.77-1.73 (m, 1H), 1.46 (s, 9H), 1.33-1.25 (m, 3H), 1.07-1.00 (d, J=6.4 Hz, 3H). LCMS: Rt=3.244 min, [M+H].sup.+=345.2.

Example 35: Preparation of Compound (T035)

[0455] Reference was made to the process route and procedures of Example 34 above, and imidazole was replaced by 1,2,4-triazole, thus obtaining compound T035; [M+H].sup.+=346.3.

Example 36: Preparation of Compound (T036)

[0456] Reference was made to the process route and procedures of Example 34 above, and imidazole was replaced by 1,2,3-triazole, thus obtaining compound T036; [M+H].sup.+=346.3.

Example 37: Preparation of Compound (T037)

[0457] ##STR00146##

[0458] 37.1 Preparation of Compound (T037-2)

[0459] Thionyl chloride (5.76 g, 48.3 mmol) was slowly added dropwise to a solution of 2-hydroxyethyl methyl sulfone (CAS: 15205-66-0, 2 g, 16.1 mmol) and pyridine (1.27 g, 16.1 mmol) in toluene (20 mL) at room temperature. After the addition was completed, the reaction mixture was heated to 80° C. and reacted for 10 h. The reaction mixture was then cooled to room temperature, and the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL). Liquid separation was performed to give a toluene layer, and the aqueous layer was extracted with ethyl acetate. The organic phases were combined, dried and concentrated to give 1.5 g of 1-chloro-2-methanesulfonyl ethane (crude product, brownish yellow oil) with a yield of 66%.

[0460] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 3.93 (t, J=6.4 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 3.04 (s, 3H).

[0461] 37.2 Preparation of Compound (T037-3)

[0462] T037-2 (377 mg, 2.65 mmol), 3-nitropyrazole (250 mg, 2.21 mmol), potassium carbonate (460 mg, 3.31 mmol), potassium iodide (about 5 mg, catalytic amount) and DMF (3 mL) were added to a Biotage microwave tube. Nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 150° C. for 3 h under microwave in a temperature mode. The reaction mixture was then cooled to room temperature, diluted with water, extracted with ethyl acetate and concentrated. The residue was purified by silica gel column chromatography (PE/EA=25% to 40%) to give 160 mg of a yellow solid with a yield of 33%.

[0463] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.63 (d, J=2.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 4.72 (t, J=6.4 Hz, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.78 (s, 3H).

[0464] 37.3 Preparation of Compound (T037-4)

[0465] Compound T037-3 (160 mg, 0.727 mmol) and Pd/C (aqueous, about 30 mg) were dispersed in ethyl acetate (40 mL) and methanol (10 mL), and hydrogenation at normal pressure was carried out using a balloon. The reaction mixture was reacted at room temperature for 16 h. The reaction mixture was then filtered, dried and concentrated to give 160 mg of a crude product in the form of brown oil.

[0466] 37.4 Preparation of Compound (T037-5)

[0467] Compound T037-4 (160 mg, 0.73 mmol), 2,4-dichloropyrimidine (91 mg, 0.615 mmol), DIEA (0.33 mL, 1.845 mmol) and DMF (2 mL) were added to a Biotage microwave tube. Nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 140° C. for 2 h under microwave in a temperature mode. The reaction mixture was concentrated under reduced pressure and separated by a preparative silica gel plate (PE/EA=1:1) to give 140 mg of a yellow solid with a yield of 75%.

[0468] 37.5 Preparation of Compound (T037)

[0469] Compound T037-5 (120 mg, 0.397 mmol), trans-4-aminocyclohexanol (91 mg, 0.795 mmol), DIEA (0.14 mL, 0.795 mmol) and n-butanol (3 mL) were added to a Biotage microwave tube. Nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 165° C. for 2 h under microwave in a temperature mode. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (2.5 mL), filtered, purified by preparative high performance liquid chromatography (TFA method) and lyophilized to give 25.2 mg of a white solid with a yield of 17%.

[0470] .sup.1H NMR (400 MHz, CD.sub.3OD): δ7.70 (s, 2H), 6.76 (s, 1H), 6.28 (s, 1H), 4.58 (t, J=6.4 Hz, 2H), 3.93-3.87 (m, 1H), 3.69 (t, J=6.4 Hz, 2H), 3.63-3.58 (m, 1H), 2.80 (s, 3H), 2.08-2.00 (m, 4H), 1.46-1.37 (m, 4H). LCMS: Rt=3.311 min, [M+H].sup.+=381.1.

Example 38: Preparation of Compound (T038)

[0471] ##STR00147##

[0472] 38.1 Preparation of Compound (T038-2)

[0473] A solution of 1H-pyrazole-3-carboxylic acid (CAS: 1621-91-6, 2 g, 17.85 mmol) and concentrated sulfuric acid (2.9 mL, 53.56 mmol) in ethanol (80 mL) was heated at reflux for 14 h. The reaction mixture was then cooled to room temperature, subjected to distillation under reduced pressure to remove ethanol, added with ethyl acetate (50 mL) and extracted and washed with saturated aqueous sodium bicarbonate solution, and the organic phase was dried and concentrated to give 1.7 g of a white solid with a yield of 68%.

[0474] 38.2 Preparation of Compound (T038-3)

[0475] Potassium carbonate (2.06 g, 14.86 mmol) and potassium iodide (190 mg, 1.14 mmol) were added to a solution of compound T038-2 (1.6 g, 11.43 mmol) and compound T037-2 (1.95 g, 13.71 mmol) in DMF (50 mL) at room temperature. The reaction mixture was heated to 120° C. and reacted for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by silica gel column chromatography (PE/EA=55%) to obtain 2 positional isomers. Based on NOE two-dimensional nuclear magnetic spectrum, it was confirmed that the isomer with smaller polarity and lower conversion was the target product (190 mg, a white solid, a yield of 6.7%).

[0476] .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.52 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 5.04 (t, J=6.8 Hz, 2H), 4.40-4.34 (m, 2H), 3.58 (t, J=6.8 Hz, 2H), 2.86 (s, 3H), 1.40-1.35 (m, 3H).

[0477] 38.3 Preparation of Compound (T038-4)

[0478] Sodium hydroxide (37 mg, 0.92 mmol) was added to a solution of compound T038-3 (190 mg, 0.77 mmol) in ethanol (5 mL) and water (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated to remove ethanol, diluted with water (5 mL) and acidified to pH=1 with hydrochloric acid (1 M), and a white solid was precipitated out. The mixture was filtered to give the product (140 mg) with a yield of 84%.

[0479] 38.4 Preparation of Compound (T038-5)

[0480] DPPA (227 mg, 0.82 mmol) and triethylamine (112 mg, 1.1 mmol) were added to a solution of compound T038-4 (120 mg, 0.55 mmol) in tert-butanol (anhydrous, 10 mL) at room temperature. The reaction mixture was heated to 90° C. and reacted for 16 h. The reaction mixture was then concentrated under reduced pressure and purified by preparative silica gel plate (DCM/MeOH=20:1) to give 160 mg of crude product as a brown solid with a yield of 100%.

[0481] 38.5 Preparation of Compound (T038-6)

[0482] A solution of compound T038-5 (160 mg, 0.55 mmol) in a solution of hydrochloric acid in dioxane (4 M, 10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude hydrochloride salt (110 mg, a yellow gum) with a yield of 89%.

[0483] 38.6 Preparation of Compound (T038-7)

[0484] Compound T038-6 (110 mg, 0.489 mmol), 2,4-dichloropyrimidine (61 mg, 0.407 mmol), DIEA (0.37 mL, 2.035 mmol) and DMF (2 mL) were added to a Biotage microwave tube. Nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 145° C. for 3 h under microwave in a temperature mode. The reaction mixture was then cooled to room temperature, diluted with water, extracted with ethyl acetate and concentrated. The residue was purified by a preparative silica gel plate (PE/EA=40%) to give 30 mg of a yellow solid with a yield of 24%.

[0485] 38.7 Preparation of Compound (T038)

[0486] Compound T038-7 (30 mg, 0.1 mmol), trans-4-aminocyclohexanol (23 mg, 0.2 mmol), DIEA (40 mg, 0.3 mmol) and n-butanol (1 mL) were added to a Biotage microwave tube. Nitrogen was introduced, the tube was sealed, and the reaction mixture was reacted at 165° C. for 3 h under microwave in a temperature mode. The reaction mixture was concentrated under reduced pressure, dissolved in methanol (1 mL), filtered, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 3.5 mg of a yellow solid with a yield of 9.2%.

[0487] .sup.1H NMR (400 MHz, CD.sub.3OD): δ7.85-7.83 (m, 1H), 7.52-7.49 (m, 1H), 8.28-8.24 (m, 1H), 6.01.5.99 (m, 1H), 4.49 (t, J=6.4 Hz, 2H), 3.68-3.64 (m, 2H), 3.60-3.52 (m, 2H), 2.77 (s, 3H), 1.99-1.92 (m, 4H), 1.36-1.26 (m, 4H). LCMS: Rt=2.349 min, [M+H].sup.+=381.1.

Example 39: Preparation of Compound (T039)

[0488] ##STR00148##

[0489] Sodium hydride (60%, 94 mg, 2.46 mmol) was added in portions to a suspension of compound T004-4 (143 mg, 1.232 mmol) in THE (15 mL) under an ice bath. After the addition was completed, trans-1,4-cyclohexanediol (CAS: 6995-79-5, 70 mg, 0.246 mmol) was added after the reaction mixture was stirred under an ice bath for 30 min. The reaction mixture was slowly warmed to reflux for 14 h. The reaction mixture was then cooled to room temperature, and the reaction was quenched with methanol and aqueous ammonium chloride solution. The reaction mixture was concentrated under reduced pressure, purified twice by preparative high performance liquid chromatography (TFA method and ammonium bicarbonate method) and lyophilized to give 16 mg of a white solid with a yield of 18%.

[0490] .sup.1H NMR (400 MHz, CD.sub.3OD): δ8.43 (s, 1H), 4.84-4.91 (m, 1H), 4.00-3.98 (m, 1H), 3.69-3.66 (m, 1H), 3.19-3.14 (m, 1H), 2.34-2.31 (m, 1H), 2.18-2.15 (m, 2H), 2.03-2.00 (m, 3H), 1.82-1.77 (m, 1H), 1.60-1.55 (m, 2H), 1.47-1.41 (m, 2H), 1.35-1.24 (m, 4H), 1.18-1.09 (m, 1H), 1.04 (d, J=6.4 Hz, 3H). Rt=2.576 min, [M+H].sup.+=365.2.

Example 40: Preparation of Compound (T040)

[0491] ##STR00149##

[0492] Potassium carbonate (78 mg, 0.564 mmol) was added to a mixed solution of compound T004-4 (80 mg, 0.282 mmol) and p-hydroxyanisole (CAS: 150-76-5, 38 mg, 0.309 mmol) in DMF (5 mL) at room temperature. After purged with nitrogen, the reaction mixture was heated to 80° C. and reacted for 16 h. The reaction mixture was cooled to room temperature and extracted with water and ethyl acetate. The reaction mixture was then purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 60 mg of a white solid with a yield of 57%.

[0493] .sup.1H NMR (400 MHz, CD.sub.3OD): δ8.49 (s, 1H), 7.08-7.05 (m, 2H), 6.97-6.93 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 2.94-2.88 (m, 1H), 2.15-2.11 (m, 1H), 1.83-1.80 (m, 1H), 1.66-1.61 (m, 1H), 1.22-1.08 (m, 3H), 0.97 (d, J=6.0 Hz, 3H), 0.90-0.78 (m, 1H). Rt=2.576 min, [M+H].sup.+=365.2.

Example 41: Preparation of Compound (T041)

[0494] ##STR00150##

[0495] 41.1 Preparation of Compound (T041-2)

[0496] Potassium tert-butoxide (56 mg, 0.50 mmol) was added to a solution of compound T001-2 (60 mg, 0.251 mmol) in N,N-dimethylformamide (2 mL) with stirring under an ice bath. After stirring overnight at room temperature, the reaction was completed. The reaction mixture was added with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After reaction mixture was concentrated under reduced pressure and subjected to column chromatography to give 60 mg of a colorless liquid with a yield 86%.

[0497] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ8.40 (s, 1H), 2.55 (s, 3H), 1.54 (s, 9H).

[0498] 41.2 Preparation of Compound (T041-3)

[0499] 3-chlorobenzoperoxoic acid (1.9 g, 10.8 mmol) was added to a solution of compound T041-2 (1.5 g, 5.41 mmol) in dichloromethane (20 mL) with stirring under an ice bath. After stirring at room temperature for 7 h, the reaction was completed. The reaction mixture was diluted with dichloromethane and filtered, and the aqueous phase was washed with sodium bicarbonate solution, concentrated under reduced pressure at low temperature and purified by column chromatography to give 700 mg of a white solid with a yield of 42%. The compound was unstable and needed to be used immediately.

[0500] 41.3 Preparation of Compound (T041)

[0501] (1R,3R,4R)-5-amino-2-methylcyclohexanol hydrochloride (57 mg, 0.342 mmol) and DIEA (132 mg, 1.026 mmol) were added to a solution of compound T041-3 (100 mg, 0.342 mmol) in isopropanol (3 mL) at room temperature with stirring. After stirring at room temperature for 3 h, the reaction was completed. The reaction mixture was added with water and extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 40 mg of a white solid with a yield of 34%. The compound was also unstable due to susceptibility to acid, base, water vapor and the like.

[0502] .sup.1H NMR (400 MHz, CD.sub.3OD) δ7.97 (s, 1H), 4.09-4.03 (m, 1H), 3.20-3.15 (m, 1H), 2.25-2.21 (m, 1H), 1.96-1.92 (m, 1H), 1.85-1.81 (m, 1H), 1.55 (s, 9H), 1.50-1.32 (m, 3H), 1.17-1.08 (m, 1H), 1.04 (d, J=6.4 Hz, 3H). LCMS: Rt=4.113 min, [M+H].sup.+=358.1, 340.1.

Example 42: Preparation of Compound (T042)

[0503] ##STR00151##

[0504] 42.1 Preparation of Compound (T042-2)

[0505] Under nitrogen atmosphere, sodium hydride (96 mg, 60%, 2.4 mmol) was added to a solution of cyclopropanol (70 mg, 1.20 mmol) in N,N-dimethylformamide (3 mL) with stirring under an ice bath. After the reaction mixture was stirred for 1 h under an ice bath, compound T001-2 (288 mg, 1.2 mmol) was added to the reaction mixture, and the resulting reaction mixture was stirred overnight at room temperature. Ammonium chloride solution was added at room temperature to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic phase was dried, concentrated and subjected to column chromatography to give 150 mg of a colorless liquid with a yield of 40%.

[0506] LCMS: Rt=1.730 min, [M+H].sup.+=261.0.

[0507] 42.2 Preparation of Compound (T042-3)

[0508] 3-chlorobenzoperoxoic acid (59 mg, 0.343 mmol) was added to a solution of compound T042-2 (30 mg, 0.114 mmol) in dichloromethane (2 mL) with stirring under an ice bath. After stirring at room temperature for 3 h, the reaction was completed. The reaction mixture was diluted with dichloromethane and filtered, and the aqueous phase was washed with sodium bicarbonate solution, concentrated under reduced pressure at low temperature and purified by column chromatography to give 30 mg of a white solid with a yield of 88%.

[0509] 42.3 Preparation of Compound (T042-4)

[0510] (1R,3R,4R)-5-amino-2-methylcyclohexanol hydrochloride (57 mg, 0.342 mmol) and DIEA (132 mg, 1.026 mmol) were added to a solution of compound T042-3 (100 mg, 0.342 mmol) in isopropanol (3 mL) at room temperature with stirring. After stirring overnight at room temperature, the reaction was completed. The reaction mixture was concentrated under reduced pressure and then subjected to column chromatography to give 50 mg of a white solid with a yield of 43%. LCMS: Rt=1.523 min, [M+H].sup.+=341.1, 343.1.

[0511] 42.4 Preparation of Compound (T042-5)

[0512] Compound T042-4 (40 mg, 0.30 mmol) and cuprous cyanide (104 mg, 1.17 mmol) were dispersed in DMF (2 mL). The reaction mixture was heated to 150° C. and reacted for 5 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was then cooled to room temperature, added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to give 30 mg of a white solid with a yield of 88%.

[0513] 42.5 Preparation of Compound (T042)

[0514] Commercially available 30% hydrogen peroxide (0.5 mL) and aqueous sodium hydroxide solution (0.2 mL, 1 M) were added dropwise to an aqueous solution (2 mL) of compound T042-5 (40 mg, 0.30 mmol) at room temperature with stirring. After the addition was completed, the reaction mixture was stirred at room temperature for 2 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was then filtered, and the filtrate was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 10 mg of a white solid with a yield of 27%.

[0515] .sup.1H NMR (400 MHz, CD.sub.3OD) δ 8.46 (s, 1H), 4.32-4.28 (m, 1H), 4.12-4.06 (m, 1H), 3.20-3.14 (m, 1H), 2.41-2.37 (m, 1H), 2.10-2.07 (m, 1H), 1.82-1.78 (m, 1H), 1.35-1.19 (m, 3H), 1.16-1.12 (m, 1H), 1.04 (d, J=6.0 Hz, 3H), 0.84-0.79 (m, 4H). LCMS: Rt=2.722 min, [M+H].sup.+=307.1.

Example 43: Preparation of Compound (T043)

[0516] Reference was made to the process routes and procedures of Examples 41-42 above to obtain compound T043; [M+H].sup.+=323.1.

Example 44: Preparation of Compound (T044)

[0517] 44.1 Preparation of Compound (T044-2)

[0518] DIEA (300 mg, 2.32 mmol) was added to a suspension of 4,6-dichloronicotinonitrile (CAS: 166526-03-0; 200 mg, 1.16 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (180 mg, 1.39 mmol) in isopropanol (10 mL) at room temperature, and the reaction mixture was heated to 60° C. and reacted overnight. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure to remove isopropanol, added with ethyl acetate and extracted with water. The organic phase was washed with saturated brine, dried, concentrated and purified by silica gel column chromatography (PE/EA=1/1) to give a white solid with a yield of 55%.

[0519] 44.2 Preparation of Compound (T044)

##STR00152##

[0520] Compound T044-2 (200 mg, 0.75 mmol), Cs.sub.2CO.sub.3 (490 mg, 1.5 mmol), Pd.sub.2(dba).sub.3 (68 mg, 0.075 mmol), BINAP (46 mg, 0.075 mmol), dioxane (3 mL) and tert-butylamine (1 mL) were added to a sealed tube at room temperature. After purged with nitrogen for 2 min, the tube was sealed, and the reaction mixture was heated to 100° C. and reacted for 24 h. The reaction mixture was then cooled to room temperature, concentrated under reduced pressure to remove dioxane and added with ethyl acetate and water before extraction. The organic phase was dried, concentrated and purified by thin layer chromatography plate (DCM/MeOH=10/1) to give 130 mg of a yellow solid (crude product) with a yield of 57%.

[0521] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=8.00 (s, 1H), 6.87 (d, J=7.6 Hz, 1H), 5.89 (s, 1H), 4.86 (s, 1H), 4.52 (d, J=5.6 Hz, 1H), 3.71 (s, 1H), 2.99-2.93 (m, 1H), 2.09-2.07 (m, 1H), 1.83 (d, J=12.4 Hz, 1H), 1.64-1.60 (m, 1H), 1.36 (s, 9H), 1.17-0.95 (m, 4H), 0.93 (d, J=6.0 Hz, 3H). Rt=3.440 min, [M+H].sup.+=303.1.

Example 45: Preparation of Compound (T045)

[0522] ##STR00153##

[0523] Potassium carbonate (124 mg, 0.9 mmol) and 30% hydrogen peroxide (0.15 mL, about 1.2 mmol) were added to a solution of compound T044 (90 mg, 0.3 mmol) in DMSO (0.5 mL) at room temperature. The reaction mixture was reacted at room temperature for 5 min, and saturated sodium sulfite solution was added to quench the reaction. The reaction mixture was then filtered, and the filtrate was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 18.3 mg of a white solid with a yield of 19%.

[0524] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=8.65 (s, 1H), 8.17 (s, 1H), 7.50 (br, 1H), 6.78 (br, 1H), 6.35 (d, J=8.0 Hz, 1H), 5.72 (s, 1H), 4.51 (d, J=5.2 Hz, 1H), 3.66 (s, 1H), 3.00-2.94 (m, 1H), 2.10-2.07 (m, 1H), 1.85-1.82 (m, 1H), 1.64-1.60 (m, 1H), 1.32 (s, 9H), 1.16-0.99 (m, 4H), 0.93 (d, J=6.4 Hz, 3H).

[0525] Rt=2.918 min; [M+H].sup.+=321.2.

Example 46: Preparation of Compound (T046)

[0526] ##STR00154##

[0527] 46.1 Preparation of Compound (T046-2)

[0528] Compound 4,6-dichloronicotinonitrile (CAS: 166526-03-0, 100 mg, 0.578 mmol), (1R,3R,4R)-5-amino-2-methylcyclohexanol hydrochloride (95.4 mg, 0.578 mmol) and DIEA (149 mg, 1.156 mmol) were dispersed in isopropanol (5 mL). The reaction mixture was stirred at 60° C. for 2 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was added with water and ethyl acetate before extraction and liquid separation. The organic phase was dried and concentrated to give 130 mg of a yellow crude product with a yield of 85%.

[0529] 46.2 Preparation of Compound (T046-3)

[0530] Compound T046-2 (100 mg, 0.377 mmol), 2-aminoethanol (1 mL) and DIEA (97 mg, 0.75 mmol) were well mixed. The reaction mixture was heated to 120° C. and stirred for 2 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by preparative high performance liquid chromatography (ammonium bicarbonate method) to give 20 mg of a white solid with a yield of 18%.

[0531] 46.3 Preparation of Compound (T046)

[0532] Compound T046-3 (20 mg, 0.075 mmol) and potassium carbonate (20.7 mg, 0.15 mmol) were dispersed in DMSO (1 mL). Commercially available 30% hydrogen peroxide (0.5 mL) was added under an ice bath. The reaction mixture was warmed to room temperature and stirred for 1 h, and the reaction was completed as detected by liquid chromatography. The reaction mixture was then filtered and purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 6.0 mg of a white solid with a yield of 26%.

[0533] .sup.1H NMR (400 MHz, CD.sub.3OD): δ8.15 (s, 1H), 5.62 (s, 1H), 3.77-3.74 (m, 2H), 3.70-3.67 (m, 1H), 3.33-3.26 (m, 2H), 3.23-3.17 (m, 1H), 2.29-2.25 (m, 1H), 1.99-1.96 (m, 1H), 1.78-1.74 (m, 1H), 1.32-1.13 (m, 4H), 1.05 (d, J=6.0 Hz, 3H). LCMS: Rt=2.759 min; [M+H].sup.+=309.1.

[0534] Reference was made to the above process route and procedures of Example 46 to prepare the compounds in Table 3 below:

TABLE-US-00003 TABLE 3 Example Compound No. Ms + 1 47 T047 307.2 48 T048 349.1 49 T049 319.1 50 T050 335.1 51 T051 335.1 52 T052 363.1 53 T053 363.1 54 T054 347.2 55 T055 349.2 56 T056 333.1 57 T057 325.1 58 T058 305.1 59 T059 321.1 60 T060 317.2

Example 61: Preparation of Compound (T062)

[0535] ##STR00155##

[0536] 61.1 Preparation of Compound (T062-2)

[0537] DIEA (997 mg, 7.7 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (467 mg, 2.8 mmol) were added to a solution of 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.5 mmol, CAS: 49845-33-2) in isopropanol (10 mL) at normal temperature. The reaction mixture was reacted for 3 h at room temperature, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/3) to give 510 mg of a yellow solid with a yield of 69.1%.

[0538] 61.2 Preparation of Compound (T062)

[0539] Compound T062-2 (510 mg, 1.78 mmol), acetonitrile (5 mL) and tert-butylamine (2 mL) were added to a sealed tube at normal temperature. After the addition was completed, the tube was sealed and the reaction mixture was heated to 90° C. and reacted for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and extracted with water and ethyl acetate, and the organic phase was dried and concentrated to give 420 mg of crude product (a yellow solid) with a yield of 72.7%.

[0540] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ=8.82 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 8.52 (d, J=5.2 Hz, 1H), 4.10-4.06 (m, 1H), 3.06-3.01 (m, 1H), 2.13-2.10 (m, 1H), 1.88-1.85 (m, 1H), 1.74-1.70 (m, 1H), 1.45-1.36 (m, 10H), 1.29-1.23 (m, 2H), 1.03-0.93 (m, 4H). Rt=4.064 min, [M+H].sup.+=324.1.

Example 62: Preparation of Compound (T063)

[0541] ##STR00156##

[0542] Iron powder (361 mg, 6.46 mmol) and ammonium chloride (348 mg, 6.46 mmol) were added to a mixed solution of compound T062 (300 mg, 0.92 mmol) in ethanol (10 mL) and water (2 mL), and the reaction mixture was reacted at 80° C. for 3 h. The reaction mixture filtered, and the filtrate was concentrated under reduced pressure and extracted with water and ethyl acetate. The organic phase was dried and concentrated to give 250 mg of a yellow oil with a yield of 93%. The crude product (50 mg) was purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 5.8 mg of a yellow solid.

[0543] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=7.37 (s, 1H), 4.15-4.10 (m, 1H), 3.40-3.36 (m, 1H), 2.43-2.40 (m, 1H), 2.12-2.08 (m, 1H), 1.84-1.80 (m, 1H), 1.51 (s, 9H), 1.46-1.34 (m, 3H), 1.25-1.22 (m, 1H), 1.13 (d, J=8.8 Hz, 3H). Rt=2.362 min, [M+H].sup.+=294.2.

Example 63: Preparation of Compound (T064)

[0544] ##STR00157##

[0545] 63.1 Preparation of Compound (T064-2)

[0546] Triethylamine (551 mg, 5.4 mmol), bis(diphenylphosphine)palladium(II) dichloride (382 mg, 0.54 mmol), copper(I) iodide (104 mg, 0.54 mmol) and triisopropylsilyl acetylene (497 mg, 2.7 mmol) were added to a solution of compound T001-3 (500 mg, 1.8 mmol) in N,N-dimethylformamide at normal temperature. After the addition was completed, the reaction mixture was purged with nitrogen, then stirred at 130° C. overnight, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (EA/PE=1/5) to give 236 mg of a yellow oil with a yield of 34.3%.

[0547] 63.2 Preparation of Compound (T064-4)

[0548] m-chloroperoxybenzoic acid (189 mg, 0.936 mmol) was added in portions to a solution of compound T064-2 (236 mg, 0.624 mmol) in dichloromethane (3 mL) under an ice bath. After the addition was completed, the reaction mixture was stirred overnight at room temperature. After the reaction was completed as detected by liquid chromatography, the reaction mixture was washed with aqueous sodium bicarbonate solution and extracted with dichloromethane (20 mL×3). The organic phase was collected, dried and concentrated under reduced pressure to give compound T064-3 (crude product).

[0549] DIEA (96.7 mg, 0.75 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (82.5 mg, 0.5 mmol) were added to a solution of compound T064-3 (crude product) in DMF (3 mL) at normal temperature. After the addition was completed, the reaction mixture was stirred at 110° C. overnight. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated to dryness under reduced pressure and purified by column chromatography (EA/PE=1/3) to give 100 mg of a yellow oil with a two-step yield of 43.8%.

[0550] 63.3 Preparation of Compound (T064)

[0551] A solution of tetrabutylammonium fluoride in tetrahydrofuran (0.2 mL) was added to a solution of compound T064-4 (95 mg, 0.198 mmol) in THE (3 mL) under an ice bath. After the addition was completed, the reaction mixture was stirred overnight at room temperature, and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 15 mg of a white solid with a yield of 25%.

[0552] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=7.82 (s, 1H), 4.11-4.05 (m, 1H), 3.80 (s, 1H), 3.20-3.14 (m, 1H), 2.30-2.25 (m, 1H), 2.00-1.96 (m, 1H), 1.84-1.78 (m, 1H), 1.46 (s, 9H), 1.43-1.33 (m, 3H), 1.16-1.09 (m, 1H), 1.05 (d, J=6.4 Hz, 3H). LCMS: Rt=4.384 min, [M+H].sup.+=303.2.

Example 64: Preparation of Compound (T065)

[0553] Reference was made to the process route and procedures of Example 64 above, and triisopropylsilyl acetylene was replaced by propyne, thus obtaining compound T065; [M+H].sup.+=317.1.

Example 65: Preparation of Compound (T066)

[0554] ##STR00158##

[0555] Potassium carbonate (174 mg, 1.26 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (15.4 mg, 0.02 mmol) and potassium vinyltrifluoroborate (84.9 mg, 0.63 mmol) were added to a solution of compound T033 (150 mg, 0.42 mmol) in dioxane at normal temperature. After the addition was completed, the reaction mixture was purged with nitrogen, then stirred overnight at 105° C., and the reaction was completed as detected by liquid chromatography. The reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 42 mg of a white solid with a yield of 33%.

[0556] .sup.1H NMR (400 MHz, CDCl.sub.3): δ=7.81 (s, 1H), 6.42-6.35 (m, 1H), 5.40-5.35 (m, 1H), 5.14-5.11 (m, 1H), 4.90 (s, 1H), 4.78 (br, 1H), 4.09-4.01 (m, 1H), 3.34-3.28 (m, 1H), 2.41-2.35 (m, 1H), 2.07-2.04 (m, 1H), 1.82-1.77 (m, 1H), 1.43 (s, 9H), 1.42-1.34 (m, 1H), 1.27-1.08 (m, 3H), 1.06 (d, J=6.8 Hz, 3H). LCMS: Rt=3.301 min, [M+H].sup.+=305.2.

Example 66: Preparation of Compound (T067)

[0557] ##STR00159##

[0558] 66.1 Preparation of Compound (T067-2)

[0559] Tributyl(1-ethoxyvinyl)tin (1.5 g, 4.3 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.2 g, 1.8 mmol) were added to a solution of compound T001-3 (1 g, 3.6 mmol) in dioxane (15 mL) at normal temperature. After the addition was completed, the reaction mixture was purged with nitrogen, then reacted at 80° C. for 16 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (EA/PE=1/5) to give 0.8 g of a white solid with a yield of 91.7%. Rt=1.652 min, [M+H].sup.+=240.1.

[0560] 66.2 Preparation of Compound (T067-3)

[0561] m-chloroperoxybenzoic acid (0.5 g, 2 mmol) was added in portions to a solution of compound T067-2 (0.25 g, 1 mmol) in dichloromethane (5 mL) under an ice bath. After the addition was completed, the ice bath was removed, the reaction mixture was stirred at room temperature for 4 h, and the reaction was completed as detected by liquid chromatography. Excessive m-chloroperoxybenzoic acid was washed away with saturated sodium bicarbonate solution, and the organic phase was washed with water, dried and concentrated under reduced pressure to give 0.2 g of crude product. Rt=1.43 min, [M+H].sup.+=272.5.

[0562] 66.3 Preparation of Compound (T067)

[0563] DIEA (0.3 g, 2.2 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol (0.12 g, 0.7 mmol) were added to a solution of compound T067-3 (0.2 g, 0.7 mmol) in DMF (3 mL) at normal temperature. After the addition was completed, the reaction mixture was heated to 110° C. and reacted for 16 h. After the reaction was completed as detected by liquid chromatography, the reaction mixture was concentrated under reduced pressure, purified by preparative high performance liquid chromatography (ammonium bicarbonate method) and lyophilized to give 50 mg of a white solid with a yield of 21.2%.

[0564] .sup.1H NMR (400 MHz, CD.sub.3OD): δ=9.8.51 (s, 1H), 4.13-4.07 (m, 1H), 3.33-3.12 (m, 1H), 2.42 (s, 3H), 2.35-2.32 (m, 1H), 2.06-2.03 (m, 1H), 1.83-1.79 (m, 1H), 1.48 (s, 9H), 1.39-1.25 (m, 3H), 1.16-1.09 (m, 1H), 1.06 (d, J=6.4 Hz, 3H). Rt=3.894 min, [M+H].sup.+=321.2.

[0565] Reference was made to the above process route and procedures of Example 66 to prepare the compounds in Table 4 below:

TABLE-US-00004 TABLE 4 Example Compound No. Ms + 1 67 T068 347.1 68 T069 335.2 69 T070 349.2 70 T071 375.2

[0566] Reference was made to the above process route and procedures of Example 10 to prepare the compounds in Table 5 below:

TABLE-US-00005 TABLE 5 Example Compound No. Ms + 1 71 T072 420.1 72 T073 440.2 73 T074 386.2

[0567] <Biological Activity Assay>

[0568] Kinase Activity Screening

[0569] JNK1 activity screening. JNK1 activity was detected using a 96-well (Cisbio, 66PL96025) time-resolved fluorometric assay. The JNK1 assay was conducted in the following assay buffer: 10 mM MgCl.sub.2 (Sigma, M1028), 1 mM MnCl.sub.2 (Sigma, M1787), 1 mM DTT (Sigma, D0632) and 1× Enzymatic buffer/kinase (Cisbio, 62EZBFDC). By using the assay buffer, 3 μL of 0.1 ng/μL JNK1 kinase (Carna Biosciences, 04-163) was added to a 96-well microplate, and then 4 μL of a compound diluted appropriately (with a DMSO content of 2.5%) was added. The resulting mixture was incubated at room temperature for 0.5 h. To start the reaction, the assay buffer was used to mix 0.003 μM ATP (Aladdin, A7699) and 30 μM substrate ATF2-GST fusion (Cisbio, 64CUS000AFPEB), and 3 μL of the mixed solution was added to the microplate. The resulting mixture was incubated at room temperature for 2.5 h. HTRF detection buffer (Gibco, 62SDBRDD) was used then to prepare a mixture of 5 μg/mL MAb Anti GST-XL665 (Cisbio, 61GSTXLA) and 0.045 μg/mL PAb Anti-phospho ATF2-K (Cisbio, 61P12KAZ), and 10 μL of the mixture was added to the plate to terminate the reaction. After incubation for about 12 h, the plate was read on a Perkin-Elmer Envision reader.

[0570] Cell Evaluation Method

[0571] 1. RAW264.7 Phosphorylated c-Jun Whole Cell Assay

[0572] RAW264.7 (ATCC TIB-71) cells were purchased from BeNa Culture Collection and maintained in a high-glucose DMEM medium (Gibco) containing 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). All cells were cultured at 37° C. in 95% air and 5% CO.sub.2. All cells were seeded into 120 μL of cell culture medium in a 96-well plate at a density of 2×10.sup.5 cells per well. The stock solution of compound (15 mM) was serially diluted in DMSO (Sigma) and further diluted in growth medium, and it was then added at 15 μL per well as a 10× concentrated solution, well mixed with the cells and incubated with the cells for 30 min. Concentration of the compound vehicle (DMSO) in each well was 0.2%. After incubation for 30 min, the cells were activated with ng/mL lipopolysaccharide (Sigma). Lipopolysaccharide was added to the growth medium as a 10× concentrated solution at 15 μL per well. The cell plate was incubated for 1 h, and then all the medium was removed. The level of C-Jun protein with phosphorylation of serine at site 63 was measured using the whole cell lysate kit-phosphorylated C-Jun assay (PathScan® Phospho-c-Jun (Ser63) Sandwich ELISA Kit) (CST, 7145C) according to the manufacturer's instructions.

[0573] 2. Jurkat T-Cell IL-2 Production Assay

[0574] Jurkat T cells (clone E6-1) were purchased from China Center for Type Culture Collection and maintained in RPMI1640 (Gibco) containing 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco). All cells were cultured at 37° C. in 95% air and 5% CO.sub.2. All cells were seeded into 120 μL of cell culture medium in a 96-well plate at a density of 1×10.sup.5 cells per well. The stock solution of compound (15 mM) was serially diluted in DMSO (Sigma) and further diluted in growth medium, and it was then added at 15 μL per well as a 10× concentrated solution, well mixed with the cells and incubated with the cells for 30 min. Concentration of the compound vehicle (DMSO) in each well was 0.2%. After incubation for 30 min, the cells were activated with PMA (phorbol myristate acetate; final concentration: 50 ng/mL) (Sigma) and PHA (phytohemagglutinin; final concentration: 1 μg/mL) (Sigma). PMA and PHA were added to the growth medium as prepared 10× concentrated solutions at 15 μL per well. The cell plate was incubated for 6 h. The cells were allowed to deposit using a microplate centrifuge (Hunan Xiangyi), and the cell supernatant was collected and stored at −20° C. The amount of IL-2 in the supernatant was measured using a human IL-2 assay kit (Human IL-2 Valukine™ ELISA Kit) (R&D Systems, VAL 110) according to the manufacturer's instructions.

[0575] The compounds in Table 6 below were all tested using enzymatic assay and cytological assay in the biochemical test for JNK1, and it was found that the compounds disclosed herein have good activity. In the enzymatic assay, IC.sub.50 below 100 nM of a compound was reported as activity level A, IC.sub.50 between 100 nM and 500 nM as activity level B, IC.sub.50 between 500 nM and 1 μM as activity level C, and IC.sub.50 greater than 1 μM as activity level D. In the cytological assay, IC.sub.50 below 100 nM of a compound was reported as activity level A, IC.sub.50 between 100 nM and 500 nM as activity level B, IC.sub.50 between 500 nM and 1 μM as activity level C, and IC.sub.50 greater than 1 μM as activity level D.

TABLE-US-00006 TABLE 6 Raw264.7 Example Compound No. JNK1 IC.sub.50 C-Jun 1 T001 A B 1 T001A B B 2 T002 A B 3 T003 C D 4 T004 D D 5 T005A D D 5 T005 D D 6 T006 D D 7 T007 D D 8 T008 D D 9 T009 D D 10 T010 A A 11 T011 C D 12 T012 D D 13 T013 C D 14 T014 D D 15 T015 A C 16 T016 A C 17 T017 A C 18 T018 B C 19 T019 B C 20 T020 B C 21 T021 B D 22 T022 C D 23 T023 C D 24 T024 A B 25 T025 A D 26 T026 A B 27 T027 C D 28 T028 D D 29 T029 D D 30 T030 D D 31 T031 D D 32 T032 D D 33 T033 A C 34 T034 D D 35 T035 B C 36 T036 B C 37 T037 D D 38 T038 D D 39 T039 B D 40 T040 B C 41 T041 C D 42 T042 C D 43 T043 C D 44 T044 D D 45 T045 D D 46 T046 C D 47 T047 C D 48 T048 C D 49 T049 C D 50 T050 C D 51 T051 C D 52 T052 C D 53 T053 D D 54 T054 D D 55 T055 D D 56 T056 C D 57 T057 D D 58 T058 D D 59 T059 D D 60 T060 D D 61 T062 D D 62 T063 D D 63 T064 C D 64 T065 D D 65 T066 D D 66 T067 B B 67 T068 B B 68 T069 B B 69 T070 C D 70 T071 C D 71 T072 A A 72 T073 A B 73 T074 A A