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JAK INHIBITOR COMPOUND AND USE THEREOF

20220388992 · 2022-12-08

    Inventors

    Cpc classification

    International classification

    Abstract

    The present disclosure relates to a class of JAK inhibitor compounds and uses thereof. Specifically, the present disclosure discloses a compound represented by formula (I), isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof. The present disclosure also relates to the application of the compounds in medicine.

    ##STR00001##

    Claims

    1. A compound of Formula (I) as a JAK inhibitor ##STR00089## or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein L is C═O, O═S═O, CH.sub.2 or a linkage; and X.sub.1 is N or CR.sub.14; and X.sub.2 is N or CR.sub.15; and X.sub.3 is N or CR.sub.16; and R.sub.13 is H, C.sub.1-6 alkyl or C.sub.3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl, C.sub.5-11 bicycloalkyl, 5-11 membered bicyclic heteroalkyl, and R.sub.13 is substituted with 0, 1, 2, 3, or 4 R.sub.1(s); and R.sub.17 is selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, (C.sub.3-7 cycloalkyl)-C.sub.1-4 Aalkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (5-10-membered heteroaryl)-C.sub.1-4 alkyl-, —C(═O)—N(R.sub.9)(R.sub.10), —C(═O)—R.sub.12, —C(═O)—OR.sub.12, and —S(═O).sub.2—N(R.sub.9)(R.sub.10), in which each option in the group is optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy; or R.sub.13 and R.sub.17 form a 4-10 membered heterocycloalkyl with L and N atoms to which they are attached together, and the 4-10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; and R.sub.18 and R.sub.19 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, (C.sub.3-7 cycloalkyl)-C.sub.1-4 alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl-, (5-10-membered heteroaryl)-C.sub.1-4 alkyl-, in which each option in the group is optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy; or R.sub.18 and R.sub.19 form C.sub.3-10 cycloalkyl or a 4-10 membered heterocycloalkyl with carbon atom to which they are attached together, and the C.sub.3-10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy; and 0, 1, 2, 3 or 4 R.sub.2(s) are present in formula (G), and each R.sub.2 is independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, —N(R.sub.9)(R.sub.10), —N(R.sub.11)(C(═O)R.sub.12), —C(═O)—N(R.sub.9)(R.sub.10), —C(═O)—R.sub.12, —C(═O)—OR.sub.12, —OC(═O)R.sub.12, —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12, in which the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, 4-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2 or 3 substituent(s) each independently selected from the group consisting of halogen, —CN, —OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, —N(R.sub.9)(R.sub.10), —N(R.sub.11)(C(═O)R.sub.12), —C(═O)—OR.sub.12, —C(═O)H, —C(═O)R.sub.12, —C(═O)—N(R.sub.9)(R.sub.10), —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12; and each R.sub.1 is independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-8 alkoxy, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, 11-15 membered tricyclyl, C.sub.5-11 bicycloalkyl, 5-11 membered bicyclic heteroalkyl, —N(R.sub.9)(R.sub.10), —N(R.sub.11)(C(═O)R.sub.12), —C(═O)—N(R.sub.9)(R.sub.10), —C(═O)—R.sub.12, —C(═O)—OR.sub.12, —OC(═O)R.sub.12, —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12, in which the —S—C.sub.1-4 alkyl, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, and C.sub.1-8 alkoxy are optionally substituted with 1, 2, 3, or 4 R.sub.3(s), and in which the C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, and 7-11 membered bicyclic heteroaryl are optionally substituted with 1, 2, 3, or 4 R.sub.4(s); and R.sub.14, R.sub.15, R.sub.16 are each independently selected from H, —OH, —SH, —CN, halogen, —NO.sub.2, —SF.sub.5, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, —N(R.sub.9)(R.sub.10), —N(R.sub.11)(C(═O)R.sub.12), —C(═O)—N(R.sub.9)(R.sub.10), —C(═O)—R.sub.12, —C(═O)—OR.sub.12, —OC(═O)R.sub.12, —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12, in which the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, and 3-7 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 substitutes selected from halogen, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl)(C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; and R.sub.3 and R.sub.4 are each independently selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, —N(R.sub.5)(R.sub.6), —N(R.sub.11)(C(═O)R.sub.12), —CON(R.sub.7)(R.sub.8), —C(═O)—R.sub.12, —C(═O)—OR.sub.12, —OC(═O)R.sub.12, —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12, in which the C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, 3-10 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, and 7-11 membered bicyclic heteroaryl are each optionally substituted with 1, 2, or 3 substituent(s) each independently selected from the group consisting of halogen, —CN, —OH, C.sub.1-4 alkyl, C.sub.1-6 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, C.sub.3-6 cycloalkyl, —N(R.sub.9)(R.sub.10), —N(R.sub.11)(C(═O)R.sub.12), —C(═O)—OR.sub.12, —C(═O)H, —C(═O)R.sub.12, —C(═O)—N(R.sub.9)(R.sub.10), —N(R.sub.11)(S(═O).sub.2R.sub.12), —S(═O).sub.2—N(R.sub.9)(R.sub.10), —SR.sub.12 and —OR.sub.12; and R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, and R.sub.12 are each independently H or selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, (C.sub.3-7 cycloalkyl)-C.sub.1-4 alkyl-, (4-10 membered heterocycloalkyl)-C.sub.1-4 alkyl-, (C.sub.6-10 aryl)-C.sub.1-4 alkyl- and (5-10 membered heteroaryl)-C.sub.1-4 alkyl-, wherein the substituents included in the above group are each optionally substituted with 1, 2, 3 or 4 substituent(s) each independently selected from the group consisting of halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy.

    2. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, which is an isotopically labeled compound of the compound of formula (I), wherein all Hs are each independently and optionally replaced by D.

    3. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein X.sub.1 is CR.sub.14, X.sub.2 is CR.sub.15, and X.sub.3 is CR.sub.16.

    4. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 2, wherein X.sub.1 is CR.sub.14, X.sub.2 is CR.sub.15, and X.sub.3 is CR.sub.16.

    5. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 3, wherein X.sub.1, X.sub.2 and X.sub.3 are CH.

    6. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 4, wherein X.sub.1, X.sub.2 and X.sub.3 are CH.

    7. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein L is C═O, O═S═O or CH.sub.2.

    8. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.13 is H, C.sub.1-6 alkyl, or C.sub.3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl, or 11-15 membered tricyclyl, and optionally substituted with 1, 2, 3 or 4 R.sub.1(s).

    9. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.17 is H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C.sub.6-10 aryl, or 5-10 membered heteroaryl, and optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy.

    10. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.13 and R.sub.17 form a 4-6 membered heterocycloalkyl with L and N atoms to which they are attached together, and the 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy.

    11. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.18 and R.sub.19 are each independently selected from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-4 haloalkyl, C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, 4-14 membered heterocycloalkyl, C.sub.6-10 aryl, and 5-10 membered heteroaryl, in which each option in the group is optionally substituted with 1, 2, 3 or 4 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 hydroxyalkyl, —S—C.sub.1-4 alkyl, —C(═O)H, —C(═O)—C.sub.1-4 alkyl, —C(═O)—O—C.sub.1-4 alkyl, —C(═O)—NH.sub.2, —C(═O)—N(C.sub.1-4 alkyl).sub.2, —N(C.sub.1-4 alkyl) (C(═O) C.sub.1-4 alkyl), C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4haloalkoxy.

    12. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.18 and R.sub.19 form C.sub.3-6 cycloalkyl or a 4-6 membered heterocycloalkyl with carbon atom to which they are attached together, and the C.sub.3-6 cycloalkyl and 4-6 membered heterocycloalkyl are optionally substituted with 1, 2, or 3 substitutes each independently selected from halogen, —CF.sub.3, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, oxo, and C.sub.1-4 alkyl.

    13. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein 1, 2 or 3 R.sub.2(s) are present and each independently R.sub.2 is selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, —SH, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, and 4-10 membered heterocycloalkyl, in which the —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituent(s) each independently selected from the group consisting of halogen, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, —CN, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy.

    14. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein R.sub.13 is substituted with 0 or 1 R.sub.1, and R.sub.1 is selected from halogen, —OH, C.sub.1-6 alkyl, 5-7 membered heterocycloalkyl, and C.sub.3-7 cycloalkyl, in which the C.sub.1-6 alkyl is optionally substituted with 1, 2, or 3 R.sub.3(s) and in which the 5-7 membered heterocycloalkyl, and C.sub.3-7 cycloalkyl is optionally substituted with 1, 2, 3 or 4 C.sub.1-3 alkyl.

    15. The compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, wherein the compound is selected from a group consisting of: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-5-(piperidin-1-yl)pyrazine-2-carboxamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propionamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanecarboxamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)isobutyramide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)methanesulfonamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-5-morpholinopyrazine-2-carboxamide; (S)-1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)pyrrolidin-3-ol; 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)piperidin-4-ol; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-N-methylcyclopropanecarboxamide (Ex-10) 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)piperidine-4-nitrile; 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)pyrrolidine-3-carbonitrile; 5-ethyl-2-fluoro-4-(3-(4-(morpholinomethyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol; 5-ethyl-2-fluoro-4-(3-(4-((pyridin-3-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol; 5-ethyl-2-fluoro-4-(3-(4-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol; 3-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-(2-hydroxyethyl)-1-methylurea; 4-(3-(4-(((cyclopropylmethyl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluoro phenol; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanesulfonamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)ethanesulfonamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-hydroxypiperidine-1-carboxamide; (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxy-N-methylpyrrolidine-1-carboxamide; (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide; (S)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide; 5-ethyl-2-fluoro-4-(3-(4-(((2-hydroxyethyl)(methyl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propane-2-sulfonamide; methyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)carbamate; 2-cyanoethyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl) carbamate; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclobutanecarboxamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methylpyrrolidine-3-carboxamide; 4-(3-(4-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 4-(3-(4-((cyclobutylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 5-ethyl-2-fluoro-4-(3-(4-(((tetrahydrofuran-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl) phenol; 5-ethyl-2-fluoro-4-(3-(4-((pyridin-2-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide; 5-ethyl-2-fluoro-4-(3-(4-(((1-methylpyrrolidin-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazole-6-yl)phenol; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)morpholine-4-carboxamide; N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-methylpiperazine-1-carboxamide; and 5-ethyl-4-(3-(4-((4-ethylpiperazin-1-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-2-fluorophenol.

    16. A pharmaceutical composition, comprising the compound, or an isotopically labeled compound thereof, or an optical isomer thereof, a geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.

    17. A method for treating a JAK-related disease or disorder, comprising administrating to a patient in need, preferably a human patient, a therapeutically effective amount of the compound, or isotopically labeled compound thereof, or optical isomer thereof, geometric isomer thereof, a tautomer thereof or a mixture of various isomers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof according to claim 1.

    18. The method according to claim 17, wherein the JAK-related disease or disorder is selected from the group consisting of arthritis, autoimmune diseases or disorders, cancer or tumor, diabetes, eye diseases, disorders or conditions, intestinal inflammation, allergies or conditions, neurodegenerative diseases, skin diseases, conditions or disorders, allergies, asthma and other obstructive airway diseases, and transplant rejection.

    Description

    EXAMPLES

    [0144] The compounds of formula (I) of the present disclosure can be synthesized by various methods familiar to those skilled in the art of organic synthesis. The following specific examples give some exemplary synthesis methods of the compounds of formula (I), and these methods are well-known in the field of synthetic chemistry. Obviously, referring to the exemplary embodiments of the present application, those skilled in the art can appropriately adjust reactants, reaction conditions, and protective groups to easily design other synthetic routes for compounds of formula (I).

    [0145] The following further describes the present disclosure in conjunction with examples. Nevertheless, these examples do not limit the scope of the present disclosure.

    Example 1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-5-(piperidin-1-yl)pyrazine-2-carboxamide (MDI-3)

    [0146] ##STR00009##

    Synthetic Route of Target Compound 16 (i.e., MDI-3)

    [0147] ##STR00010## ##STR00011## ##STR00012## ##STR00013##

    Synthetic Route of Intermediate 17

    [0148] ##STR00014##

    Synthetic Route of Intermediate 19

    [0149] ##STR00015##

    Synthetic Route of Intermediate 21

    [0150] ##STR00016##

    Synthesis Method

    Synthesis of Intermediate 1: 5-ethyl-2-fluorophenol

    [0151] 5-bromo-2-fluorophenol (200.0 mg, 1.05 mmol) and bis(tri-tert-butylphosphorus) palladium (10.7 mg, 0.02 mmol) was dissolved in 10 ml THF. The atmosphere was replaced with nitrogen, which was repeated 3 times. The temperature was lowered to 10-20° C. 1 mol/L diethyl zinc solution (2.3 ml, 2.30 mmol) was added dropwise. After the addition was completed, the temperature was heated up to 50° C. It was allowed to react overnight, and the temperature was cooled to 0° C. The reaction was quenched with water, and filtered with celite. The celite pad was washed with ethyl acetate. The resulting filtrate was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After drying, it was concentrated and separated by column chromatography to afford an oily liquid with a yield of 65.1%.

    [0152] .sup.1H NMR (400 MHz, CDCl.sub.3) δ6.97 (d, J=8.0 Hz, 1H), 6.85 (d, J=12.0 Hz, 1H), 6.69-6.65 (m, 1H), 2.61-2.55 (m, 2H), 1.21 (t, J=8.0 Hz, 3H).

    Synthesis of Intermediate 2: 4-bromo-5-ethyl-2-fluorophenol

    [0153] Intermediate 1 (200.1 mg, 1.43 mmol) was dissolved in 6 ml of acetonitrile, to which CuBr.sub.2 (957.5 mg, 4.29 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil, yield: 78.1%.

    [0154] .sup.1H NMR (400 MHz, CDCl3) δ7.25 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz, 1H), 2.69-2.63 (m, 2H), 1.19 (t, J=12.0 Hz, 3H).

    Synthesis of Intermediate 3: 2-((4-bromo-5-ethyl-2-fluorophenoxy) methoxy)ethyl)trimethylsilane

    [0155] Intermediate 2 (220.0 mg, 1.00 mmol) was dissolved in 6 ml DCM, DIPEA (130.5 mg, 1.10 mmol) was added, and the temperature was reduced to 0° C. SEMCl (168.2 mg, 1.10 mmol) was added dropwise at 0° C. After the addition, the temperature was raised to room temperature, and it was allowed to react for 8 hours. The reaction was quenched with water, and extracted with DCM. The organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated to afford a colorless oil, the crude yield: 99.1%.

    [0156] .sup.1H NMR (400 MHz, CDCl3) δ7.26 (d, J=12.0 Hz, 1H), 6.89 (d, J=12.0 Hz, 1H), 5.24 (s, 2H) 3.82-3.78 (m, 2H) 2.67-2.62 (m, 2H), 1.19 (t, J=12.0 Hz, 3H), 0.98-0.94 (m, 2H), 0.01 (s, 9H).

    Synthesis of Intermediate 4: (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

    [0157] Intermediate 3 (280.0 mg, 0.80 mmol), pinacol borate (206.1 mg, 0.80 mmol), Pd(dppf)Cl.sub.2 (59.2 mg, 0.08 mmol) and KOAc (237.5 mg, 2.40 mmol) were dissolved in 1, 4-dioxane (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C. and it was allowed to react overnight. After the reaction was completed, it was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil, yield: 56.2%.

    [0158] .sup.1H NMR (400 MHz, CDCl3) δ7.48 (d, J=12.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.28 (s, 2H), 3.82-3.78 (m, 2H) 2.89-2.83 (m, 2H), 1.35 (s, 12H), 1.17 (t, J=8.0 Hz, 3H), 0.98-0.94 (m, 2H), 0.01 (s, 9H).

    Synthesis of Intermediate 17: 6-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0159] The compound 6-iodoindazole (200 mg, 0.82 mmol) and 5 ml of THF were added and the resulting mixture was cooled to 0° C. At 0° C., NaH (32.8 mg (60%), 0.82 mmol) was added to the resulting mixture in batches. After the addition was complete, it was allowed to react at 0° C. for 1 h. Then SEMCl (143.5 mg, 0.86 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a product, yield: 82.2%.

    [0160] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.16 (s, 1H), 8.07 (s, 1H), 8.21 (d, J=1.4 Hz, 1H), 7.47-7.43 (m, 1H), 5.69 (s, 2H), 3.63-3.58 (m, 2H), 0.96-0.91 (m, 2H), −0.04 (s, 9H).

    Synthesis of Intermediate 5: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0161] Under N.sub.2 protection, intermediate 4 (85 mg, 0.21 mmol), intermediate 17 (80 mg, 0.21 mmol), Pd(dppf)Cl (15.6 mg, 0.021 mmol), K.sub.3PO.sub.4 (136.3 mg, 0.64 mmol), and 1,4-dioxane (2 ml) were added. After the addition was complete, the mixture was heated to 100° C. and it was allowed to react overnight. After the reaction was completed, it was quenched with water, extracted with EA, and the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 66.9 mg, yield: 60.6%.

    [0162] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.14 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.05-7.01 (m, 2H), 5.74 (s, 2H), 5.31 (s, 2H), 3.88-3.84 (m, 2H), 3.70-3.65 (m, 2H), 2.61-2.52 (m, 2H), 1.09 (t, J=8.0 Hz, 3H), 1.03-0.96 (m, 4H), 0.01 (s, 9H), −0.03 (s, 9H).

    Synthesis of Intermediate 6: 5-ethyl-2-fluoro-4-(1H-indazol-6-yl)phenol

    [0163] Intermediate 5 (30 mg, 0.12 mmol), 2 ml of methanol, and 1 ml of concentrated hydrochloric acid were added. After the addition was complete, the reaction mixture was heated to 60° C. and it was allowed to react. After the reaction was completed, saturated NaHCO.sub.3 solution was added to adjust pH=7, and the resulting mixture was extracted with EA, and the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a white solid 12 mg, yield: 80.6%.

    [0164] .sup.1H NMR (400 MHz, MeOD) δ8.08 (d, J=1.1 Hz, 1H), 7.79 (dd, J=0.8 Hz, J=8.3 Hz, 1H), 7.42-7.40 (m, 1H), 7.08 (dd, J=1.4 Hz, J=8.3 Hz, 1H), 6.95-6.88 (m, 2H), 2.58-2.51 (m, 2H), 1.06 (t, J=8.0 Hz 3H).

    Synthesis of Intermediate 7: 5-ethyl-2-fluoro-4-(3-iodo-1H-indazol-6-yl)phenol

    [0165] Intermediate 6 (134 mg, 0.52 mmol), 2 ml DMF, and KOH (117 mg, 2.08 mmol) were added. After the addition was complete, it was allowed to cool to 0° C. At 0° C., I.sub.2 (132 mg, 0.52 mmol) in DMF (2 ml) was added dropwise. After the dropwise addition was completed, the reaction mixture was raised to room temperature and it was allowed to react. After the reaction was completed, 1M HCl was added to adjust pH=7, and the resulting mixture was extracted with EA, and the organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a white solid 150 mg, yield: 75.5%.

    [0166] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.52 (dd, J=0.8 Hz, J=8.3 Hz, 1H), 7.35 (t, J=1.1 Hz, 1H), 7.15 (dd, J=1.3 Hz, J=8.4 Hz, 1H), 6.98-6.94 (m, 2H), 2.50 (q, J=7.6 Hz, 2H), 1.06 (t, J=7.6 Hz, 3H).

    Synthesis of Intermediate 8: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0167] The intermediate 7 (180 mg, 0.47 mmol) and 4 ml of DMF were added and the resulting mixture was cooled to 0° C. At 0° C., NaH (37.6 mg (60%), 0.94 mmol) was added to the resulting mixture in batches. After the addition was complete, it was stirred for 1 hour. Then at 0° C., SEMCl (143.5 mg, 0.86 mmol) was added dropwise. After the addition was complete, the reaction mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 220 mg, yield: 72.9%.

    [0168] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.52-7.41 (m, 2H), 7.23-7.12 (m, 2H), 7.02-6.97 (m, 1H), 5.73 (s, 2H), 5.30 (s, 2H), 3.88-3.81 (m, 2H), 3.67-3.55 (m, 2H), 2.56-2.48 (m, 2H), 1.06 (t, J=8.0 Hz, 3H), 1.03-0.96 (m, 4H), 0.03 (s, 9H), −0.07 (s, 9H).

    Synthesis of Intermediate 9: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(trimethylstannyl)-1H-indazole

    [0169] Under the protection of N.sub.2, intermediate 8 (20 mg, 0.031 mmol), Sn.sub.2Me.sub.6 (20.3 mg, 0.062 mmol), Pd(PPh.sub.3).sub.4 (3.6 mg, 0.0031 mmol), and 5 ml of anhydrous toluene were added. After the addition was completed, the reaction mixture was raised to 80° C. and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 14.8 mg, yield: 70.2%.

    [0170] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.72 (d, J=8.0 Hz, 1H), 7.45 (s, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.08 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.77 (s, 2H), 5.31 (s, 2H), 3.88-3.84 (m, 2H), 3.60-3.56 (m, 2H), 2.55 (q, J=8.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H), 1.02-0.98 (m, 2H), 0.90-0.85 (m, 2H), 0.48 (s, 9H), 0.03 (s, 9H), −0.07 (s, 9H).

    Synthesis of Intermediate 19: Methyl 2-iodo-1-((2-(trimethylsilyl)ethoxy methyl)-1H-imidazole-4-carboxylate

    1. Synthesis of Intermediate 18: Methyl 1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazole-4-carboxylate

    [0171] Compound methyl 1H-imidazole-4-carboxylate (Ig, 7.9 mmol), K.sub.2CO3 (2.74 g, 19.8 mmol), and 20 ml DMF were added and then SEMCl (1.71 g, 10.2 mmol) was added dropwise. After the dropwise addition was complete, the reaction mixture was heated to 80° C. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a product 750 mg, yield: 37.1%.

    [0172] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.68 (s, 1H), 7.58 (s, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 3.48-3.43 (m, 2H), 0.88-0.83 (m, 2H), −0.05 (s, 9H).

    2. Synthesis of Intermediate 19: methyl 2-iodo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazole-4-carboxylate

    [0173] Intermediate 18 (4 g, 15.6 mmol), NIS (7 g, 31.1 mmol), AIBN (0.26 g, 1.58 mmol), 20 ml CHCl.sub.3 were added and the reaction mixture was warmed to 65° C. After the reaction was complete, it was allowed to cool to room temperature. The reaction was quenched with 5% aqueous solution of sodium thiosulfate, extracted with DCM, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a product 3 g, yield: 50.2%.

    [0174] .sup.1H NMR (400 MHz, CDCl.sub.3) δ7.80 (s, 1H), 5.26 (s, 2H), 3.89 (s, 3H), 3.58-3.52 (m, 2H), 0.95-0.85 (m, 2H), −0.01 (s, 9H).

    Synthesis of Intermediate 10: Methyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-methyl)-1-((2-(trimethylsilyl)ethoxy) Methyl)-1H-imidazole-4-carboxylic acid

    [0175] Under the protection of N.sub.2, Intermediate 9 (40 mg, 0.059 mmol), Intermediate 19 (22.4 mg, 0.059 mmol), CuI (2.23 mg, 0.012 mmol), Pd(PPh.sub.3).sub.4 (6.8 mg, 0.0059 mmol), and 4 ml THF were added. After the addition was completed, the reaction mixture was heated to 65° C. and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 14 mg, yield: 30.8%.

    [0176] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.57 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 7.25 (dd, J=1.2 Hz, J=8.4 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H), 5.96 (s, 2H), 5.76 (s, 2H), 5.31 (s, 2H), 3.96 (s, 3H), 3.88-3.84 (m, 2H), 3.61-3.57 (m, 4H), 2.53 (q, J=8.0 Hz, 2H), 1.05 (t, J=8.0 Hz, 3H), 1.03-0.98 (m, 2H), 0.92-0.87 (m, 4H), 0.03 (s, 9H), −0.07 (s, 9H), −0.08 (s, 9H).

    Synthesis of Intermediate 11: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) methanol

    [0177] Under the protection of N.sub.2, intermediate 10 (22 mg, 0.028 mmol) and 4 ml of THF were added, and the resulting mixture was lowered to −78° C. At −78° C., DIBAL-H (0.038 ml, 1.5 Mol/L, 0.057 mmol) was added. After the addition was completed, the reaction mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was cooled to 0° C. and quenched with water, passed through diatomaceous earth, and rinsed with EA. The filtrate was extracted with EA, and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 17 mg, yield: 81.8%.

    [0178] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.48 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.18-7.15 (m, 2H), 7.02 (d, J=12.0 Hz, 1H), 5.92 (s, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.75 (s, 2H), 3.88-3.84 (m, 2H), 3.62-3.55 (m, 4H), 2.54 (q, J=8.0 Hz, 2H), 1.06 (t, J=8.0 Hz, 3H), 1.04-0.98 (m, 2H), 0.92-0.86 (m, 4H), 0.04 (s, 9H), −0.07 (s, 9H), −0.08 (s, 9H).

    Synthesis of Intermediate 12: 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde

    [0179] Intermediate 11 (12 mg, 0.016 mmol), 4 ml of CHCl.sub.3, and MnO.sub.2 (57.4 mg, 0.66 mmol) were added, and the resulting mixture was heated to 60° C. and it was allowed to react. After the reaction was completed, the reaction mixture was then lowered to room temperature, passed through celite, and washed with DCM. The filtrate was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 10 mg, yield: 84.4%.

    [0180] .sup.1H NMR (400 MHz, CDCl.sub.3) δ10.04 (s, 1H), 8.59 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.48 (s, 1H), 7.29 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H), 6.03 (s, 2H), 5.77 (s, 2H), 5.32 (s, 2H), 3.88-3.84 (m, 2H), 3.64-3.59 (m, 4H), 2.55 (q, J=8.0 Hz, 2H), 1.06 (t, J=8.0 Hz, 3H), 1.04-0.99 (m, 2H), 0.93-0.88 (m, 4H), 0.04 (s, 9H), −0.06 (s, 9H), −0.07 (s, 9H).

    Synthesis of Intermediate 13: 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde oxime

    [0181] Intermediate 12 (10 mg, 0.016 mmol), TEA (1.68 mg, 0.017 mmol), 2 ml of DCM were added and the resulting mixture was cooled to 0° C., to which hydroxylamine hydrochloride (1.15 mg, 0.017 mmol) were added in batches. After the addition was complete, the reaction mixture was raised to room temperature and it was allowed to react. After the reaction was completed, the reaction mixture was quenched with water, and extracted with DCM. The layers were separated and the organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated to obtain 7 mg of colorless oil, which was directly used in the next reaction, yield: 68.4%.

    Synthesis of Intermediate 14: 4-(3-(4-(aminomethyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0182] Intermediate 13 (10 mg, 0.013 mmol), Pd/C (2 mg), 2 ml of MeOH, and catalytic amount of HCl were added, and the atmosphere was replaced with H.sub.2 three times. The reaction was carried out at room temperature (H2 pressure 1 atm). After the reaction was completed, the system was passed through diatomaceous earth. It was concentrated and separated by column chromatography to afford a colorless oil 5 mg, yield: 63.0%.

    [0183] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.39 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.13-7.10 (m, 2H), 6.96-6.91 (m, 2H,), 5.89 (s, 2H), 5.74 (s, 2H), 4.01 (s, 2H), 3.61-3.55 (m, 4H), 2.46 (q, J=8.0 Hz, 2H), 1.00 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), −0.08 (s, 9H), −0.09 (s, 9H).

    Synthesis of Intermediate 21: 5-(piperidin-1-yl)pyrazine-2-carboxylic acid

    1. Synthesis of Intermediate 20: methyl 5-(piperidin-1-yl)pyrazine-2-carboxylate

    [0184] Methyl 5-chloro-pyrazine-2-carboxylate (1.72 g, 10 mmol) was dissolved in 10 ml of DMF, and then N,N-diisopropylethylamine (4.3 ml, 25.0 mmol) and piperidine hydrochloride were added (1.45 g, 12.0 mmol). The resulting mixture was stirred overnight at room temperature, to which water was added under vigorous stirring. A solid was precipitated and filtered. The filter cake was washed with water, and dried to obtain Intermediate 20 with a yield of 80.0%.

    2. Synthesis of Intermediate 21: 5-(piperidin-1-yl)pyrazine-2-carboxylic acid

    [0185] Intermediate 20 (430 mg, 1.95 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of water, and then lithium hydroxide (163 mg, 3.88 mmol) was added. The reaction was carried out at room temperature for 4 hours. The tetrahydrofuran was distilled off under reduced pressure, and the resulting mixture was adjusted with iN HCl to pH 4. A solid was precipitated and filtered. The filter cake was washed with water and dried to obtain Intermediate 21 with a yield of 91.5%.

    [0186] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.84 (s, 1H), 8.02 (s, 1H), 3.76-3.73 (m, 4H), 1.78-1.65 (m, 6H).

    Synthesis of Intermediate 15: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-imidazol-4-yl)methyl)-5-(piperidin-1-yl)pyrazine-2-carboxamide

    [0187] Intermediate 21 (10.4 mg, 0.050 mmol), HATU (22.9 mg, 0.060 mmol), DIPEA (12.9 mg, 0.10 mmol), and 2 ml DMF were added, and it was allowed to react at room temperature for 1 h. The reaction mixture was lowered to 0° C., to which compound 14 (30 mg, 0.049 mmol) in DMF (0.5 ml) was added dropwise. After the dropwise addition was complete, the resulting mixture was warmed to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 127 mg, yield: 67.2%.

    [0188] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.86 (d, J=1.3 Hz, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.95 (d, J=1.4 Hz, 1H), 7.44 (s, 1H), 7.22-7.20 (m, 2H), 7.00-6.94 (m, 2H), 5.89 (s, 2H), 5.75 (s, 2H), 4.71 (d, J=5.7 Hz, 2H), 3.69-3.66 (m, 4H), 3.61-3.55 (m, 4H), 2.51 (q, J=8.0 Hz, 2H), 1.71-1.65 (m, 6H), 1.04 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), −0.08 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound 16 (MDI-3): N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazole-4-yl)methyl)-5-(piperidin-1-yl) pyrazine-2-carboxamide

    [0189] Compound 15 (30 mg, 0.037 mmol), 4 ml of MeOH, and 2 ml of concentrated hydrochloric acid were added. After the addition was completed, the resulting mixture was heated to 60° C. and it was allowed to react. After the reaction was completed, the reaction mixture was adjusted with saturated NaHCO.sub.3 to pH=7, and extracted with EA. The layers were separated, and resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated by thin chromatography to afford 14 mg of white solid, yield: 69.2%.

    [0190] .sup.1H NMR (400 MHz, MeOD) δ8.70 (d, J=1.4 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H), 7.43 (s, 1H), 7.19-7.17 (m, 2H), 6.98-6.90 (m, 2H), 4.67 (s, 2H), 3.78-3.75 (m, 4H), 2.56 (q, J=8.0 Hz, 2H), 1.79-1.67 (m, 6H), 1.08 (t, J=8.0 Hz, 3H).

    Example 2: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propionamide (MDI-301)

    [0191] ##STR00017##

    Synthetic Route of MDI-301

    [0192] ##STR00018##

    Synthesis Method

    Synthesis of Intermediate MDI-301-1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)propionamide

    [0193] Intermediate 14 (30 mg, 0.049 mmol), DIPEA (7.6 mg, 0.059 mmol), and 5 ml DCM were added. The resulting mixture was lowered to 0° C., and propionyl chloride (4.5 mg, 0.049 mmol) was added dropwise. After the dropwise addition was completed, the resulting mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 18 mg, yield: 55.0%.

    [0194] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.41 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 6.96 (t, J=10.0 Hz, 2H), 5.88 (s, 2H), 5.75 (s, 2H), 4.50 (d, J=8.0 Hz, 2H), 3.62-3.54 (m, 4H), 2.54-2.48 (m, 2H), 2.30-2.20 (m, 2H), 1.20 (t, J=8.0 Hz, 3H), 1.05 (t, J=8.0 Hz, 3H), 0.92-0.86 (m, 4H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-301: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propionamide

    [0195] Intermediate MDI-301-1 (18 mg, 0.027 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 3 mg of white solid, yield: 27.3%.

    [0196] .sup.1H NMR (400 MHz, MeOD) δ8.27 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.91 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.44 (s, 2H), 2.53 (q, J=8.0 Hz, 2H), 2.87 (q, J=8.0 Hz, 2H), 1.16 (t, J=8.0 Hz, 3H), 1.06 (t, J=8.0 Hz, 3H).

    Example 3: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanecarboxamide (MDI-302)

    [0197] ##STR00019##

    Synthetic Route of MDI-302

    [0198] ##STR00020##

    Synthesis Method

    Synthesis of Intermediate MDI-302-1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-4-yl)methyl)cyclopropanecarboxamide

    [0199] Intermediate 14 (30 mg, 0.049 mmol), DIPEA (7.6 mg, 0.059 mmol), and 5 ml DCM were added. The resulting mixture was lowered to 0° C., and cyclopropionyl chloride (5.1 mg, 0.049 mmol) was added dropwise. After the dropwise addition was completed, the resulting mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 22 mg, yield: 66.1%.

    [0200] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.42 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 6.9 (t, J=12.0 Hz, 2H), 5.88 (s, 2H), 5.75 (s, 2H), 4.52 (d, J=8.0 Hz, 2H), 3.62-3.54 (m, 4H), 2.53-2.47 (m, 2H), 1.75-1.68 (m, 1H), 1.06 (t, J=8.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.91-0.87 (m, 4H), 0.76-0.72 (m, 2H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-302: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanecarboxamide

    [0201] Intermediate MDI-302-1 (20 mg, 0.029 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 8.5 mg of white solid, yield: 69.9%.

    [0202] .sup.1H NMR (400 MHz, MeOD) δ8.28 (d, J=8.0 Hz 1H), 7.40 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.91 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.45 (s, 2H), 2.54 (q, J=8.0 Hz, 2H), 1.67-1.61 (m, 1H), 1.06 (t, J=8.0 Hz, 3H), 0.92-0.85 (m, 2H), 0.79-0.75 (m, 2H).

    Example 4: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)isobutyramide (MDI-303)

    [0203] ##STR00021##

    Synthetic Route of MDI-303

    [0204] ##STR00022##

    Synthesis Method

    Synthesis of Intermediate MDI-303-1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)isobutyramide

    [0205] Intermediate 14 (20 mg, 0.033 mmol), DIPEA (5.1 mg, 0.039 mmol), and 5 ml DCM were added. The resulting mixture was lowered to 0° C., and isobutyryl chloride (3.48 mg, 0.033 mmol) was added dropwise. After the dropwise addition was completed, the resulting mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 14 mg, yield: 62.3%.

    [0206] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.38 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 6.96-6.92 (m, 2H), 5.87 (s, 2H), 5.75 (s, 2H), 4.50 (d, J=8.0 Hz, 2H), 3.62-3.54 (m, 4H), 2.52-2.46 (m, 2H), 2.44-2.39 (m, 1H), 1.19 (d, J=4.0 Hz, 6H), 1.03 (t, J=8.0 Hz, 3H), 0.92-0.86 (m, 4.0H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-303: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)isobutyramide (MDI-303)

    [0207] Intermediate MDI-303-1 (14 mg, 0.021 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 4.9 mg of white solid, yield: 56.6%.

    [0208] .sup.1H NMR (400 MHz, MeOD) δ8.29 (d, J=8.0 Hz, 1H), 7.43 (s, 1H,), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.93 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.46 (s, 2H), 2.68-2.50 (m, 3H), 1.17 (d, J=4.0 Hz, 6H), 1.08 (t, J=8.0 Hz, 3H).

    Example 5: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)methanesulfonamide (MDI-304)

    [0209] ##STR00023##

    Synthetic Route of MDI-304

    [0210] ##STR00024##

    Synthesis Method

    Synthesis of Intermediate MDI-304-1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-4-yl)methyl)methanesulfonamide

    [0211] Intermediate 14 (30 mg, 0.049 mmol), DIPEA (7.6 mg, 0.059 mmol), and 5 ml DCM were added. The resulting mixture was lowered to 0° C., and methanesulfonyl chloride (5.61 mg, 0.049 mmol) was added dropwise. After the dropwise addition was completed, the resulting mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 12 mg, yield: 35.5%.

    [0212] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.40 (d, J=8.0 Hz, 1H), 7.46 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.00-6.95 (m, 2H), 5.91 (s, 2H), 5.75 (s, 2H), 4.41 (d, J=4.0 Hz, 2H), 2.97 (s, 3H), 2.55-2.49 (m, 2H), 1.06 (t, J=8.0 Hz, 3H), 0.92-0.86 (m, 4H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-304: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)methanesulfonamide (MDI-304)

    [0213] Intermediate MDI-304-1 (12 mg, 0.017 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 3.0 mg of white solid, yield: 40.2%.

    [0214] .sup.1H NMR (400 MHz, MeOD) δ8.21 (d, J=8.0 Hz, 1H), 7.43 (s, 1H,), 7.21-7.17 (m, 2H), 6.93 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.37 (s, 2H), 2.97 (s, 3H), 2.56 (q, J=8.0 Hz, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 6: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-5-morpholinopyrazine-2-carboxamide (MDI-305)

    [0215] ##STR00025##

    Synthetic Route of MDI-305

    [0216] ##STR00026##

    Synthesis Method

    Synthesis of Intermediate MDI-305-1: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-5-morpholinopyrazine-2-carboxamide

    [0217] Compound 5-(4-morpholinyl)-2-pyrazinecarboxylic acid (6.84 mg, 0.033 mmol), HATU (13.05 mg, 0.034 mmol), DIPEA (5.06 mg, 0.039 mmol), and 5 ml of DMF were added and it was allowed to react at room temperature for 1 h. The resulting mixture was lowered to 0° C., and compound 14 (20 mg, 0.033 mmol) in DMF (2.0 ml) was added dropwise. After the dropwise addition was completed, the resulting mixture was heated to room temperature and it was allowed to react. After the reaction was completed, it was quenched with water, extracted with EA, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to afford a colorless oil 14 mg, yield: 52.9%.

    [0218] .sup.1H NMR (400 MHz, CDCl.sub.3) δ8.91 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 7.44 (s, 1H), 7.22-7.20 (m, 2H), 7.00-6.95 (m, 2H), 5.90 (s, 2H), 5.75 (s, 2H), 4.71 (d, J=8.0 Hz, 2H), 3.83-3.81 (m, 4H), 3.68-3.66 (m, 4H), 3.62-3.55 (m, 4H), 2.51 (q, J=8.0 Hz, 2H), 1.05 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-305: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl) Methyl)-5-morpholinopyrazine-2-carboxamide

    [0219] Intermediate MDI-305-1 (14 mg, 0.017 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 3.9 mg of white solid, yield: 41.2%.

    [0220] .sup.1H NMR (400 MHz, MeOD) δ8.73 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 7.40 (s, 1H), 7.17-7.14 (m, 2H), 6.95-6.87 (m, 2H), 4.65 (s, 2H), 3.80-3.77 (m, 4H), 3.73-3.70 (m, 4H), 2.53 (q, J=8.0 Hz, 2H), 1.06 (t, J=8.0 Hz, 3H).

    Example 7: (S)-1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)pyrrolidin-3-ol (MDI-306)

    [0221] ##STR00027##

    Synthetic Route of MDI-306

    [0222] ##STR00028##

    Synthesis Method

    Synthesis of Intermediate MDI-306-1: (S)-1-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl) pyrrolidin-3-ol

    [0223] (S)-1-N-tert-butoxycarbonyl-3-hydroxypyrrolidine (9.1 mg, 0.049 mmol), 2 ml of DCM, and 2 ml of trifluoroacetic acid were added. After the addition was complete, the resulting mixture was stirred at room temperature for 30 min. After the reaction was complete, the reaction mixture was concentrated, and 5 ml of 1,2-dichloroethane and intermediate 12 (30 mg, 0.041 mmol) were added. After the addition was complete, the resulting mixture was stirred at room temperature for 30 min. Then sodium triacetylborohydride (17.08 mg, 0.081 mmol) was added and it was allowed to react at room temperature. After the reaction was completed, it was quenched with water, extracted with DCM, and the resulting organic phase was washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. It was concentrated and separated by thin chromatography to afford product 20 mg, yield: 60.8%.

    [0224] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.24-7.21 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.0 (d, J=12.0 Hz, 1H), 5.91 (s, 2H), 5.75 (s, 2H), 5.32 (s, 2H), 4.44-4.39 (m, 1H), 3.92-3.84 (m, 4H), 3.64-3.55 (m, 4H), 3.29-3.19 (m, 1H), 3.12-3.07 (m, 1H), 2.96-2.88 (m, 1H), 2.78-2.66 (m, 1H), 2.57-2.51 (m, 2H), 2.24-2.20 (m, 1H), 1.91-1.87 (m, 1H), 1.05 (t, J=8.0 Hz, 3H), 1.03-0.98 (m, 2H), 0.92-0.86 (m, 4H), 0.03 (s, 9H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-306: (S)-1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazole-4-yl)methyl)pyrrolidin-3-ol

    [0225] Intermediate MDI-306-1 (20 mg, 0.025 mmol), 4 ml MeOH, and 2 ml concentrated hydrochloric acid were added. After the addition was completed, the reaction mixture was raised to 50° C. and it was allowed to react for 6 hours. The reaction mixture was lowered to room temperature, and the reaction solvent was distilled off under reduced pressure. And then 4 ml of methanol, and 0.5 ml of aqueous ammonia were added. After concentration, the residue was separated by thin chromatography to obtain 6.2 mg of white solid, yield: 59.7%.

    [0226] .sup.1H NMR (400 MHz, MeOD) δ8.31 (d, J=8.0 Hz, 1H), 7.43 (s, 1H,), 7.18-7.16 (m, 2H), 6.97-6.89 (m, 2H), 4.44-4.39 (m, 1H), 3.90-3.82 (m, 2H), 3.01-2.95 (m, 2H), 2.77-2.74 (m, 2H), 2.58-2.53 (m, 2H), 2.25-2.16 (m, 1H), 1.84-1.78 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

    Example 9:1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)piperidin-4-ol (Ex-9)

    [0227] ##STR00029##

    Synthetic Route of Ex-9

    [0228] ##STR00030##

    Synthesis Method

    Synthesis of Compound Ex-9: 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)piperidin-4-ol

    [0229] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (30 mg, 0.04 mmol) was dissolved in DCM, to which piperidin-4-ol (4.9 mg, 0.05 mmol) was added. The resulting mixture was reacted at room temperature for 0.5 hours. To the reaction mixture was added sodium triacetylborohydride (17.2 mg, 0.08 mmol). It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified on silica gel plate. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting mixture was dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated, and purified by preparative plate to obtain 6 mg of the final product with a yield of 32.8%.

    [0230] .sup.1H NMR (400 MHz, MeOD) δ 8.33 (d, J=12.0 Hz, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.90-6.97 (m, 2H), 4.01-4.08 (m, 2H), 3.81-3.86 (m, 1H), 3.23-3.30 (m, 2H), 2.78-2.92 (m, 2H), 2.53-2.59 (m, 2H), 1.98-2.04 (m, 2H), 1.72-1.80 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 10: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-N-methylcyclopropanecarboxamide (Ex-10)

    [0231] ##STR00031##

    Synthetic Route of Ex-10

    [0232] ##STR00032##

    Synthesis Method

    Synthesis of Compound Ex-10: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxy phenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-N-methylcyclopropane carboxamide

    [0233] 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)-N-methylmethylamine (20 mg, 0.03 mmol) was dissolved in DCM, to which triethylamine (5.3 mg, 0.05 mmol) was added. The resulting mixture was cooled to zero, and cyclopropanecarbonyl chloride (3.3 mg, 0.03 mmol) was added dropwise. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified on silica gel plate. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting mixture was dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated, and purified by preparative plate to obtain 4 mg of the final product with a yield of 34.9%.

    [0234] .sup.1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 12.62 (s, 1H), 9.86 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.0 Hz, 2H), 7.04 (d, J=12.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 4.51-4.67 (m, 2H), 3.17-3.23 (s, 3H), 2.46-2.48 (m, 2H), 1.99-2.01 (m, 1H), 1.02 (t, J=8.0 Hz, 3H), 0.76-0.87 (m, 4H). LC-MS m/z (ESI) [M+H]+ calculated for C.sub.24H.sub.25FN.sub.5O.sub.2: 434.2; Measured: 434.2.

    Example 11: 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)piperidine-4-nitrile (Ex-11)

    [0235] ##STR00033##

    Synthetic Route of Ex-11

    [0236] ##STR00034##

    Synthesis Method

    Synthesis of Intermediate 11-1: 1-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)piperidine-4-carbonitrile

    [0237] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (25.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane, to which 4-cyanopiperidine (5.6 mg, 0.05 mmol) was added, the resulting mixture was allowed to react at room temperature for 30 minutes and to the mixture was added sodium triacetylborohydride (10.7 mg, 0.05 mmol). It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with dichloromethane. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 24.2 mg of Intermediate 11-1 with a yield of 86.0%.

    Synthesis of Compound Ex-11: 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl) methyl)piperidine-4-carbonitrile

    [0238] The intermediate 11-1 (24.2 mg, 0.03 mmol) was dissolved in 2 ml of methanol, to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting mixture was dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated, and purified by preparative plate to obtain 3.4 mg of the final product with a yield of 26.4%.

    [0239] .sup.1H NMR (400 MHz, MeOD) δ 8.30 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.19-7.16 (m, 2H), 6.95 (dd, J=8.0 Hz, J=20.0 Hz, 2H), 3.75 (s, 2H), 2.89-2.86 (m, 3H), 2.59-2.53 (m, 4H), 2.06-2.03 (m, 2H), 1.97-1.86 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 12: 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)pyrrolidine-3-carbonitrile (Ex-12)

    [0240] ##STR00035##

    Synthetic Route of Ex-12

    [0241] ##STR00036##

    Synthesis Method

    Synthesis of Intermediate 12-1: 1-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethyl silyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)pyrrolidine-3-carbonitrile

    [0242] The intermediate 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy) methoxy) phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-(((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) was dissolved in 5 ml of dichloromethane, to which pyrrolidine-3-carbonitrile (5.1 mg, 0.05 mmol) was added. The resulting mixture was stirred at room temperature for 0.5 hours, and then sodium triacetyl borohydride (17.0 mg, 0.08 mmol) was added. It was allowed to further react at room temperature for 2 h. The reaction mixture was quenched with a small amount of water and the solvent was evacuated with a vacuum pump and then the resulting residue was purified on a silica gel plate to obtain 21 mg of intermediate 12-1 with a yield of 56.9%.

    Synthesis of Compound Ex-12: 1-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl) methyl)pyrrolidine-3-carbonitrile

    [0243] The intermediate 12-1 (20.0 mg, 0.02 mmol) was dissolved in 2 ml of methanol, to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated, and purified by preparative plate to obtain 3 mg of the final product with a yield of 28.6%.

    [0244] .sup.1H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 12.58 (s, 1H), 9.87 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.13 (d, J=7.5 Hz, 2H), 7.04 (d, J=11.9 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 3.61 (s, 2H), 3.17-3.18 (m, 1H), 2.98-3.11 (m, 1H), 2.75-2.82 (m, 1H), 2.62-2.72 (m, 1H), 2.55-2.61 (m, 1H), 2.43-2.49 (m, 2H), 1.96-2.04 (m, 2H), 1.02 (t, J=7.5 Hz, 3H).

    Example 13: 5-ethyl-2-fluoro-4-(3-(4-(morpholinomethyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-13)

    [0245] ##STR00037##

    Synthetic Route of Ex-13

    [0246] ##STR00038##

    Synthesis Method

    Synthesis of Compound Ex-13: 5-ethyl-2-fluoro-4-(3-(4-(morpholinomethyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0247] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) was dissolved in DCM, to which morpholine (4.4 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 0.5 hours. To the reaction mixture was added sodium triacetylborohydride (17.2 mg, 0.08 mmol). It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by preparative plate to obtain 8 mg of the final product with a yield of 46.9%.

    [0248] .sup.1H NMR (400 MHz, DMSO) δ 13.23 (s, 1H), 12.55 (d, J=20.0 Hz, 1H), 9.85 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.10-7.14 (m, 1H), 6.95-7.05 (m, 2H), 6.92 (t, J=8.0 Hz, 1H), 3.59 (t, J=4 Hz, 4H), 3.49-3.55 (m, 2H), 2.49-2.50 (m, 2H), 2.42-2.48 (m, 4H), 1.02 (t, J=8 Hz, 3H).

    Example 14: 5-ethyl-2-fluoro-4-(3-(4-((pyridin-3-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-14)

    [0249] ##STR00039##

    Synthetic Route of Ex-14

    [0250] ##STR00040##

    Synthesis Method

    Synthesis of Intermediate 14-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)pyridin-3-amine

    [0251] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) was dissolved in 5 ml of toluene, to which 3-aminopyridine (5.6 mg, 0.06 mmol) and 1 drop of glacial acetic acid were added. The resulting mixture was heated to 90° C. and it was allowed to react for 24 hours. The reaction mixture was cooled to room temperature, and sodium triacetylborohydride (12.7 mg, 0.06 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with ethyl acetate. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 23 mg of intermediate 14-1 with a yield of 69.3%.

    Synthesis of Compound Ex-14: 5-ethyl-2-fluoro-4-(3-(4-((pyridin-3-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazole-6-yl)phenol

    [0252] The intermediate 14-1 (23.0 mg, 0.03 mmol) was dissolved in 2 ml methanol, to which 1 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 2 ml methanol, to which 0.5 ml of aqueous ammonia was added. It was concentrated and purified by a preparative silica gel plate, to obtain 7.1 mg of final product with a yield of 59.0%.

    [0253] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (dd, J=4.0 Hz, J=12.0 Hz, 1H), 8.05 (d, J=4.0 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.20-7.14 (m, 4H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.44 (s, 2H), 2.59-2.53 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 15: 5-ethyl-2-fluoro-4-(3-(4-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-15)

    [0254] ##STR00041##

    Synthetic Route of Ex-15

    [0255] ##STR00042##

    Synthesis Method

    Synthesis of Intermediate 15-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-1-methyl-1H-pyrazol-4-amine

    [0256] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) was dissolved in 5 ml of toluene, to which 1-methyl-1H-pyrazol-4-amine (5.9 mg, 0.06 mmol) and 1 drop of glacial acetic acid were added. The resulting mixture was heated to 90° C. and it was allowed to react for 24 hours. The reaction mixture was cooled to room temperature, and sodium triacetylborohydride (12.7 mg, 0.06 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with ethyl acetate. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 22.9 mg of intermediate 15-1 with a yield of 68.8%.

    Synthesis of Compound Ex-15: 5-ethyl-2-fluoro-4-(3-(4-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)-1H-imidazole-2-yl)-1H-indazol-6-yl)phenol

    [0257] The intermediate 15-1 (22.9 mg, 0.03 mmol) was dissolved in 2 ml methanol, to which 1 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 2 ml methanol, to which 0.5 ml of aqueous ammonia was added. It was concentrated and purified by a preparative silica gel plate, to obtain 5.4 mg of final product with a yield of 45.0%.

    [0258] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (dd, J=4.0 Hz, J=12.0 Hz, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.25 (d, J=4.0 Hz, 1H), 7.21 (d, J=4.0 Hz, 1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.13 (s, 1H), 6.94 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.21 (s, 2H), 3.80 (s, 3H), 2.59-2.53 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 16: 3-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-(2-hydroxyethyl)-1-methylurea (Ex-16)

    [0259] ##STR00043##

    Synthetic Route of Ex-16

    [0260] ##STR00044##

    Synthesis of Compound Ex-16: 3-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-(2-hydroxyethyl)-1-methylurea

    [0261] Triphosgene (11.1 mg, 0.04 mmol) was dissolved in DCM, and cooled to zero. To the resulting solution was added (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (25.0 mg, 0.03 mmol) in DCM. It was allowed to react for 5 minutes. Then triethylamine (10.2 mg, 0.10 mmol was dropwise added slowly. It was allowed to react at 0° C. for 0.5 hours. Then 2-(methylamino)ethane-1-ol (3.8 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by preparative silica gel plate to obtain 7 mg of the final product with a yield of 45.9%.

    [0262] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.89-6.97 (m, 2H), 4.44 (s, 2H), 3.71 (t, J=6.0 Hz, 2H), 3.45 (t, J=6.0 Hz, 2H), 3.01 (s, 3H), 2.53-2.59 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 17: 4-(3-(4-(((cyclopropylmethyl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluoro phenol (Ex-17)

    [0263] ##STR00045##

    Synthetic Route of Ex-17

    [0264] ##STR00046##

    Synthesis Method

    Synthesis of Compound Ex-17: 4-(3-(4-(((cyclopropylmethyl) amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0265] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) and cyclopropylmethylamine (4.2 mg, 0.06 mmol) were dissolved in DCM. It was allowed to react at room temperature for 0.5 h. To the reaction solution was added sodium triacetylborohydride (16.4 mg, 0.06 mmol). It was allowed to react at room temperature for 1.5 hours, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified on silica gel plate. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours and concentrated. The resulting residue was dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by preparative silica gel plate to obtain 6.4 mg of the final product with a yield of 39.0%.

    [0266] .sup.1H NMR (400 MHz, MeOD) δ 8.35 (d, J=8 Hz, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 7.22-7.17 (m, 1H), 6.99-6.88 (m, 2H), 4.19 (s, 2H), 2.91 (d, J=8 Hz, 2H), 2.62-2.51 (m, 2H), 1.18-1.11 (m, 1H), 1.08 (t, J=8 Hz, 3H), 0.74-0.67 (m, 2H), 0.42-0.35 (m, 2H).

    Example 18: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanesulfonamide (Ex-18)

    [0267] ##STR00047##

    Synthetic Route of Ex-18

    [0268] ##STR00048##

    Synthesis Method

    Synthesis of Intermediate 18-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethyl silyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)cyclopropanesulfonamide

    [0269] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)methanamine (30.0 mg, 0.04 mmol), TEA (13.1 mg, 0.12 mmol), and 5 ml of DCM were added. It was allowed to cool to 0° C., to which cyclopropanesulfonyl chloride (7.4 mg, 0.05 mmol) was added dropwise. After the dropwise addition was complete, the reaction mixture was heated to room temperature and it was allowed to react for 1 hour. After the reaction was completed, the reaction mixture was quenched with water and extracted with DCM. The layers were separated and the resulting organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 24 mg of colorless oil with a yield of 70.0%.

    Synthesis of Compound Ex-18: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclopropanesulfonamide

    [0270] The intermediate 18-1 (24 mg, 0.03 mmol), 2 ml methanol, and 2 ml concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 6 hours and concentrated. To the resulting residue were added 4 ml methanol, and 0.5 ml of aqueous ammonia. It was concentrated and purified on a silica gel plate to obtain 8 mg of white solid with a yield of 61.3%. LC-MS m/z (ESI) [M+H]+ calculated for C.sub.22H.sub.23FN.sub.5O.sub.3S: 456.1; found: 456.1.

    Example 19: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)ethanesulfonamide (Ex-19)

    [0271] ##STR00049##

    Synthetic Route of Ex-19

    [0272] ##STR00050##

    Synthesis Method

    Synthesis of Intermediate 19-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)ethane sulfonamide

    [0273] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-yl)methanamine (30.0 mg, 0.04 mmol), TEA (12.3 mg, 0.12 mmol), and 5 ml of DCM were added. It was allowed to cool to 0° C., to which ethylsulfonyl chloride (7.8 mg, 0.06 mmol) was added dropwise. After the dropwise addition was complete, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, water was added for quenching, DCM was added for extraction, and the layers were separated. The organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentrated column chromatography gave 22 mg of colorless oil, yield: 65.16%.

    Synthesis of Compound Ex-19: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)ethanesulfonamide

    [0274] The intermediate 19-1 (22 mg, 0.03 mmol), 4 ml methanol, and 2 ml concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 6 hours and concentrated. To the resulting residue were added 4 ml methanol, and 0.5 ml of aqueous ammonia. It was concentrated and purified on a silica gel plate to obtain 3 mg of white solid with a yield of 25.7%. LC-MS m/z (ESI) [M+H]+ calculated for C.sub.21H.sub.23FN.sub.5O.sub.3S: 444.1; found: 444.1.

    Example 20: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-hydroxypiperidine-1-carboxamide (Ex-20)

    [0275] ##STR00051##

    Synthetic Route of Ex-20

    [0276] ##STR00052##

    Synthesis Method

    Synthesis of Intermediate 20-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-4-hydroxy piperidine-1-carboxamide

    [0277] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) methylamine (25.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane and then was cooled to 0° C. Triphosgene (10.0 mg, 0.03 mmol) was added and it was allowed to react for 5 minutes. And then triethylamine (34.1 mg, 0.34 mmol) was added slowly and it was allowed to react for 30 minutes. After that, 4-hydroxypiperidine (4.1 mg, 0.04 mmol) was added and it was allowed to react at room temperature for 1 hour. Water was added to the reaction mixture and the resulting reaction mixture was extracted twice with dichloromethane. The resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified to obtain 19.1 mg of intermediate 20-1 with a yield of 65.2%.

    Synthesis of Compound Ex-20: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-hydroxypiperidine-1-carboxamide

    [0278] The intermediate 20-1 (19.1 mg, 0.02 mmol) was dissolved in 2 ml methanol, to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml methanol, to which 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified by a preparative silica gel plate to obtain 3.6 mg of final product with a yield of 34.2%.

    [0279] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.09 (s, 1H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.44 (s, 2H), 3.90-3.78 (m, 3H), 3.13-3.06 (m, 2H), 2.59-2.53 (m, 2H), 1.90-1.85 (m, 2H), 1.48-1.45 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 21: (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxy-N-methylpyrrolidine-1-carboxamide (Ex-21)

    [0280] ##STR00053##

    Synthetic Route of Ex-21

    [0281] ##STR00054##

    Synthesis Method

    Synthesis of Intermediate 21-1: 1-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-N-methylmethylamine

    [0282] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (50 mg, 0.07 mmol) and methylamine hydrochloride (5.3 mg, 0.08 mmol) were dissolved in DCM, to which triethylamine (9.8 mg, 0.10 mmol) was added. It was allowed to react at room temperature for 0.5 hours. To the reaction mixture was added sodium triacetylborohydride (28.6 mg, 0.13 mmol) and it was allowed to react at room temperature for 1.5 hours. Water was added to the reaction solution, and the resulting mixture was extracted twice with DCM, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified on silica gel plate to obtain 37 mg of intermediate 21-1 with a yield of 72.5%.

    [0283] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.48 (d, J=8.0 Hz, 1H), 7.44 (d, J=12.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.0 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.91 (s, 2H), 5.75 (s, 2H), 5.32 (s, 2H), 4.14 (s, 2H), 3.86 (t, J=10.0 Hz, 2H), 3.56-3.62 (m, 4H), 2.71 (s, 3H), 2.51-2.57 (m, 2H), 1.05 (t, J=8.0 Hz, 3H), 0.86-0.91 (m, 6H), 0.02-0.04 (m, 9H), −0.10-−0.07 (m, 18H).

    Synthesis of Compound Ex-21: (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxy phenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxy-N-methylpyrrolidine-1-carboxamide

    [0284] Triphosgene (14.5 mg, 0.05 mmol) was dissolved in DCM, and cooled to zero. To the resulting solution was added intermediate 21-1 (37 mg, 0.05 mmol) in DCM. It was allowed to react for 5 minutes. Then triethylamine (14.8 mg, 0.15 mmol) was dropwise added slowly. It was allowed to react at 0° C. for 0.5 hours. Then (R)-pyrrolidin-3-ol (6.4 mg, 0.07 mmol) in DCM was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then it was concentrated and purified by preparative silica gel plate to obtain 11 mg of the final product with a yield of 47.0%.

    [0285] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17-7.19 (m, 2H), 6.90-6.97 (m, 2H), 4.47 (s, 2H), 4.40-4.42 (m, 1H), 3.62-3.75 (m, 2H), 3.49-3.54 (m, 1H), 3.37-3.38 (m, 1H), 2.94 (s, 3H), 2.53-2.58 (m, 2H), 1.90-2.01 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 22: (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide (Ex-22)

    [0286] ##STR00055##

    Synthetic Route of Ex-22

    [0287] ##STR00056##

    Synthesis Method

    Synthesis of Intermediate 22-1: (R)—N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-3-hydroxy pyrrolidine-1-carboxamide

    [0288] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) methylamine (25.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and was cooled to 0° C., to which triphosgene (10.0 mg, 0.03 mmol) was added. It was allowed to react for 5 minutes. And then triethylamine (34.1 mg, 0.34 mmol) was added slowly and it was allowed to react for 30 minutes. After that (R)-pyrrolidin-3-ol (3.5 mg, 0.04 mmol) was added and it was allowed to react at room temperature for 1 hour. Water was added to the reaction solution, the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified to obtain 21.0 mg of intermediate 22-1 with a yield of 72.9%.

    Synthesis of Compound Ex-22: (R)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazole-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide

    [0289] The intermediate 22-1 (21.0 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then it was concentrated and purified by preparative silica gel plate to obtain 6.7 mg of the final product with a yield of 58.6%.

    [0290] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.45-4.43 (m, 3H), 3.54-3.49 (m, 3H), 3.40-3.37 (m, 1H), 2.59-2.53 (m, 2H), 2.08-2.02 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 23: (S)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide (Ex-23)

    [0291] ##STR00057##

    Synthetic Route of Ex-23

    [0292] ##STR00058##

    Synthesis Method

    Synthesis of Intermediate 23-1: (S)—N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-3-hydroxy pyrrolidine-1-carboxamide

    [0293] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methylamine (25.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and was cooled to 0° C., to which triphosgene (10.0 mg, 0.03 mmol) was added. It was allowed to react for 5 minutes. And then triethylamine (34.1 mg, 0.34 mmol) was added slowly and it was allowed to react for 30 minutes. After that (S)-pyrrolidin-3-ol (3.5 mg, 0.04 mmol) was added and it was allowed to react at room temperature for 1 hour. Water was added to the reaction solution, the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified to obtain 17.8 mg of intermediate 22-1 with a yield of 61.6%.

    Synthesis of Compound Ex-23: (S)—N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-3-hydroxypyrrolidine-1-carboxamide

    [0294] The intermediate 23-1 (17.8 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then it was concentrated and purified by preparative silica gel plate to obtain 4.2 mg of the final product with a yield of 43.5%.

    [0295] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (d, J=4.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.45-4.43 (m, 3H), 3.53-3.49 (m, 3H), 3.40-3.37 (m, 1H), 2.59-2.53 (m, 2H), 2.07-2.03 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 24: 5-ethyl-2-fluoro-4-(3-(4-(((2-hydroxyethyl)(methyl)amino) methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-24)

    [0296] ##STR00059##

    Synthetic Route of Ex-24

    [0297] ##STR00060##

    Synthesis Method

    Synthesis of Compound Ex-24: 5-ethyl-2-fluoro-4-(3-(4-(((2-hydroxyethyl)(methyl)amino)methyl)-1H-imidazol-2-yl)-1H-Indazol-6-yl)phenol

    [0298] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (20 mg, 0.03 mmol) and 2-(methylamino)ethane-1-ol (3 mg, 0.04 mmol) were dissolved in DCM. It was allowed to react at room temperature for 0.5 hours. To the reaction solution was added sodium triacetylborohydride (8.2 mg, 0.04 mmol). It was allowed to react at room temperature for 1.5 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified on silica gel plate. The purified concentrate was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then it was concentrated and purified by a silica gel plate to obtain 4.8 mg of the final product with a yield of 43.4%.

    [0299] .sup.1H NMR (400 MHz, MeOD) δ 8.34 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.22-7.17 (m, 1H), 7.00-6.89 (m, 2H), 4.47 (s, 2H), 3.98 (t, J=4.0 Hz, 2H), 3.43-3.37 (m, 2H), 3.00 (s, 3H), 2.60-2.51 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 25: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propane-2-sulfonamide (Ex-25)

    [0300] ##STR00061##

    Synthetic Route of Ex-25

    [0301] ##STR00062##

    Synthesis Method

    Synthesis of Intermediate 25-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)propane-2-sulfonamide

    [0302] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (17.0 mg, 0.02 mmol), TEA (7.0 mg, 0.07 mmol), and 5 ml of DCM were added. The resulting mixture was cooled to 0° C., to which propane 2-sulfonyl chloride (7.4 mg, 0.05 mmol) was added dropwise. After the dropwise addition was complete, it was allowed to react at room temperature for 1 hour. After the reaction was completed, the reaction mixture was quenched with water, and extracted with DCM. The layers were separated. The resulting organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 11 mg of colorless oil with a yield of 56.6%.

    Synthesis of Compound Ex-25: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)propane-2-sulfonamide

    [0303] The intermediate 25-1 (11 mg, 0.01 mmol), 4 ml methanol, and 2 ml concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and to the resulting concentrate were added 4 ml methanol, and 0.5 ml of aqueous ammonia. It was concentrated and purified on a preparative silica gel plate to obtain 3 mg of white solid with a yield of 50.5%. LC-MS m/z (ESI) [M+H]+ calculated for C.sub.22H.sub.25FN.sub.5O.sub.3S: 458.1; found: 458.1.

    Example 26: methyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)carbamate (Ex-26)

    [0304] ##STR00063##

    Synthetic Route of Ex-26

    [0305] ##STR00064##

    Synthesis Method

    Synthesis of Intermediate 26-1: methyl ((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate

    [0306] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) methylamine (30.0 mg, 0.04 mmol) was dissolved in 5 ml of anhydrous dichloromethane, and was cooled to 0° C., to which triphosgene (11.9 mg, 0.04 mmol) was added. It was allowed to react for 5 minutes. And then triethylamine (40.4 mg, 0.40 mmol) was added slowly and it was allowed to react for 30 minutes. The reaction mixture was concentrated and was dissolved in 2 ml of methanol. After that DMAP (4.9 mg, 0.04 mmol) was added. The resulting mixture was added to 70° C. and it was allowed to react for 4 hour. Water was added to the reaction solution, the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated and purified to obtain 17.9 mg of intermediate 26-1 with a yield of 55.3%.

    Synthesis of Compound Ex-26: methyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl) carbamate

    [0307] The intermediate 26-1 (17.9 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then it was concentrated and purified by preparative silica gel plate to obtain 3.9 mg of the final product with a yield of 42.5%.

    [0308] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.39 (s, 2H), 3.70 (s, 3H), 2.58-2.53 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 27: 2-cyanoethyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl) carbamate (Ex-27)

    [0309] ##STR00065##

    Synthetic Route of Ex-27

    [0310] ##STR00066##

    Synthesis Method

    Synthesis of Intermediate 27-1: 3-cyanoethyl ((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)carbamate

    [0311] 3-Hydroxypropionitrile (10.1 mg, 0.14 mmol), 5 ml of DMF, 0.2 ml of triethylamine, and CDI (10.0 mg, 0.06 mmol) were added. It was allowed to react for 10 minutes. To the reaction mixture, (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl) ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (30.0 mg, 0.04 mmol), and DMAP (0.6 mg, 0.005 ml) were added. It was allowed to react at room temperature for 17 h. After the reaction is completed, the reaction mixture was quenched with water and extracted with EA. The resulting organic phase was washed with aqueous ammonium chloride solution, washed with saturated sodium chloride solution, and dried over with anhydrous sodium sulfate. It was concentrated and purified by column chromatography to obtain 19 mg of colorless oil with a yield of 57%.

    Synthesis of Compound Ex-27: 2-cyanoethyl ((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazole-4-yl)methyl)carbamate

    [0312] The intermediate 27-1 (19 mg, 0.02 mmol), 4 ml of 1,4-dioxane, and 2 ml of concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 4 hours. The reaction mixture was concentrated and to the resulting concentrate were added 4 ml of 1,4-dioxane, and 0.5 ml of aqueous ammonia. It was concentrated and purified on a preparative silica gel plate to obtain 2 mg of white solid with a yield of 20.0%. LC-MS m/z (ESI) [M+H]+ calculated for C.sub.23H.sub.22FN.sub.6O.sub.3: 449.2; found: 449.2.

    Example 28: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)cyclobutanecarboxamide (Ex-28)

    [0313] ##STR00067##

    Synthetic Route of Ex-28

    [0314] ##STR00068##

    Synthesis Method

    Synthesis of Compound Ex-28: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl) methyl)cyclobutanecarboxamide

    [0315] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methylamine (30.0 mg, 0.04 mmol) was dissolved in 5 ml of anhydrous dichloromethane, to which triethylamine (4.9 mg, 0.05 mmol) and cyclobutylcarbonyl chloride (7.2 mg, 0.06 mmol) were added. It was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with water, and extracted twice with dichloromethane. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated to obtain coarse product. The obtained product was dissolved in 4 ml of methanol to which 2 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added. And then the resulting mixture was concentrated and purified by preparative plate to obtain 7.0 mg of the final product with a yield of 39.9%.

    [0316] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.17 (dd, J=1.4 Hz, J=8.4 Hz, 1H), 7.10 (s, 1H), 6.93 (dd, J=11.8 Hz, J=21.8 Hz, 2H), 4.45 (s, 2H), 3.22-3.14 (m, 1H), 2.55 (q, J=7.6 Hz, 2H), 2.37-2.27 (m, 2H), 2.23-2.13 (m, 2H), 2.07-1.96 (m, 2H), 1.08 (t, J=7.6 Hz, 3H).

    Example 29: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methylpyrrolidine-3-carboxamide (Ex-29)

    [0317] ##STR00069##

    Synthetic Route of Ex-29

    [0318] ##STR00070##

    Synthesis Method

    Synthesis of Intermediate 29-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-1-methyl pyrrolidine-3-carboxamide

    [0319] (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (50.0 mg, 0.07 mmol), 1-methylpyrrolidine-3-carboxylic acid (28.0 mg, 0.16 mmol), HATU (46.8 mg, 0.12 mmol), 10 ml DMF, and 0.4 ml DIEA were added. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was quenched with water and extracted with EA. The layers were separated, and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to obtain 28 mg of colorless oil with a yield of 40.0%.

    Synthesis of Compound Ex-29: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxy phenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methylpyrrolidine-3-carboxamide

    [0320] Intermediate 29-1 (28.0 mg, 0.03 mmol), 6 ml of MeOH, and 3 ml of concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated, to which 4 ml of methanol and 0.5 ml of aqueous ammonia were added. The resulting mixture was concentrated and purified by a preparative silica gel plate to obtain 2 mg of white solid with a yield of 13.1%. LC-MS m/z (ESI) [M+H]+ calcd for C.sub.25H.sub.28FN.sub.6O.sub.2: 463.2; Found: 463.2.

    Example 30: 4-(3-(4-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (Ex-30)

    [0321] ##STR00071##

    Synthetic Route of Ex-30

    [0322] ##STR00072##

    Synthesis Method

    Synthesis of Intermediate 30-1: 2-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-2-azabicyclo[2.2.2]octane

    [0323] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (55.0 mg, 0.08 mmol), 2-azabicyclo[2.2.2]octane (45.1 mg, 0.40 mmol), and 10 ml of 1,2-dichloroethane were added. The resulting mixture was stirred at room temperature for 2 h. Then sodium triacetylborohydride (53.6 mg, 0.24 mmol) was added. It was allowed to react at room temperature. After the reaction was completed, the reaction mixture was quenched with water and extracted with EA. The layers were separated. The resulting organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated and separated by column chromatography to obtain 36 mg of colorless oil with a yield of 49.3%.

    Synthesis of Compound Ex-30: 4-(3-(4-((2-azabicyclo[2.2.2]octan-2-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0324] Intermediate 30-1 (36 mg, 0.04 mmol), 6 ml of MeOH, and 3 ml of concentrated hydrochloric acid were added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated, to which 4 ml of methanol and 0.5 ml of aqueous ammonia were added. The resulting mixture was concentrated and purified by a preparative silica gel plate to obtain 12 mg of white solid with a yield of 62.6%. LC-MS m/z (ESI) [M+H]+ calcd for C.sub.26H.sub.29FN.sub.5O.sub.2: 446.2; Found: 446.2.

    Example 31: 4-(3-(4-((cyclobutylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (Ex-31)

    [0325] ##STR00073##

    Synthetic Route of Ex-31

    [0326] ##STR00074##

    Synthesis Method

    Synthesis of Compound Ex-31: 4-(3-(4-((cyclobutylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0327] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (20.0 mg, 0.03 mmol) and cyclobutylamine (3.1 mg, 0.04 mmol) were dissolved in DCM. It was allowed to react at room temperature for 0.5 h. To the reaction solution was added sodium triacetylborohydride (8.2 mg, 0.04 mmol). It was allowed to react at room temperature for 1.5 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified. The obtained product was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by silica gel plate to obtain 5.2 mg of the final product with a yield of 49.0%.

    [0328] .sup.1H NMR (400 MHz, MeOD) δ 8.39 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.22-7.17 (m, 1H), 7.00-6.89 (m, 2H), 4.19 (s, 2H), 3.97-3.87 (m, 1H), 2.62-2.51 (m, 2H), 2.46-2.36 (m, 2H), 2.3-2.22 (m, 2H), 2.02-1.93 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 32: 5-ethyl-2-fluoro-4-(3-(4-(((tetrahydrofuran-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl) phenol (Ex-32)

    [0329] ##STR00075##

    Synthetic Route of Ex-32

    [0330] ##STR00076##

    Synthesis Method

    Synthesis of Intermediate 32-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl) tetrahydrofuran-3-amine

    [0331] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-formaldehyde (20.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane, to which tetrahydrofuran-3-amine (3.5 mg, 0.04 mmol) was added. It was allowed to react at room temperature for 30 minutes. And then sodium triacetylborohydride (8.6 mg, 0.04 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 15.0 mg of intermediate 32-1 with a yield of 68.4%.

    Synthesis of Compound Ex-32: 5-ethyl-2-fluoro-4-(3-(4-(((tetrahydrofuran-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indzazol-6-yl) phenol

    [0332] The intermediate 32-1 (15.0 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by silica gel plate to obtain 4.3 mg of the final product with a yield of 55.1%.

    [0333] .sup.1H NMR (400 MHz, MeOD) δ 8.32 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.20-7.17 (m, 2H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.01-3.96 (m, 1H), 3.92 (d, J=4.0 Hz, 2H), 3.90-3.87 (m, 1H), 3.82-3.77 (m, 1H), 3.72-3.69 (m, 1H), 3.59-3.56 (m, 1H), 2.59-2.53 (m, 2H), 2.24-2.17 (m, 1H), 1.92-1.87 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

    Example 33: 5-ethyl-2-fluoro-4-(3-(4-((pyridin-2-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-33)

    [0334] ##STR00077##

    Synthetic Route of Ex-33

    [0335] ##STR00078##

    Synthesis Method

    Synthesis of Intermediate 33-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)pyridin-2-amine

    [0336] The intermediate 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy) methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-(((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-formaldehyde (30.0 mg, 0.04 mmol) and pyridin-2-amine (7.6 mg, 0.08 mmol) were dissolved in 3 ml of toluene. The resulting mixture was stirred at 100° C. for 20 hours. To the reaction mixture, sodium triacetylborohydride (17.0 mg, 0.08 mmol) was added. It was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with water and extracted twice with DCM. The resulting organic phases was combined, and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 20.0 mg of intermediate 33-1 with a yield of 60.3%.

    Synthesis of Compound Ex-33: 5-ethyl-2-fluoro-4-(3-(4-((pyridin-2-ylamino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0337] The intermediate 33-1 (18.0 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was vacuum concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and separated by silica gel plate to obtain 7 mg of the final product with a yield of 74.3%.

    [0338] .sup.1H NMR (400 MHz, MeOD) δ 8.30 (d, J=8.4 Hz, 1H), 8.07-7.91 (m, 1H), 7.50 (ddd, J=8.7 Hz, J=7.1 Hz, J=1.9 Hz, 1H), 7.42 (s, 1H), 7.24-7.10 (m, 2H), 7.01-6.85 (m, 2H), 6.74-6.55 (m, 2H), 4.57 (s, 2H), 2.55 (q, J=7.5 Hz, 2H), 1.07 (t, J=7.5 Hz, 3H).

    Example 34: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide (Ex-34)

    [0339] ##STR00079##

    Synthetic Route of Ex-34

    [0340] ##STR00080##

    Synthesis Method

    Synthesis of Compound Ex-34: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-1-methyl-1H-pyrazole-4-carboxamide

    [0341] 1-methylpyrazole-4-carboxylic acid (7.4 mg, 0.06 mmol) was dissolved in 10 ml of DMF, to which HATU (22.4 mg, 0.06 mmol) and DIEA (12.7 mg, 0.10 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes. (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl) methylamine (30.0 mg, 0.04 mmol) was added. It was allowed to react at room temperature for 2 hours. The reaction mixture was quenched with water and extracted twice with ethyl acetate. The resulting organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The resulting produce was dissolved in 4 ml of methanol, to which 2 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 2 ml of methanol, to which 0.5 ml of aqueous ammonia was added. It was concentrated and purified by a preparative silica gel plate to obtain 8.0 mg of the final product with a yield of 43.1%.

    [0342] .sup.1H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.3 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.17 (dd, J=1.4 Hz, J=8.3 Hz, 1H), 7.16 (s, 1H), 6.93 (dd, J=11.7 Hz, J=21.7 Hz, 2H), 4.61 (s, 2H), 3.94 (s, 3H), 2.55 (q, J=7.6 Hz, 2H), 1.08 (t, J=7.6 Hz, 3H).

    Example 35: 5-ethyl-2-fluoro-4-(3-(4-(((1-methylpyrrolidin-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol (Ex-35)

    [0343] ##STR00081##

    Synthetic Route of Ex-35

    [0344] ##STR00082##

    Synthesis Method

    Synthesis of Intermediate 35-1: N-((2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)-1-methyl pyrrolidin-3-amine

    [0345] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy) methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-(((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-formaldehyde (25.0 mg, 0.03 mmol) was dissolved in 3 ml of anhydrous dichloromethane, to which 1-methylpyrrolidin-3-amine (5.1 mg, 0.05 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture, sodium triacetylborohydride (10.7 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with water and extracted twice with DCM. The resulting organic phases was combined, washed with saturated saline and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 17.2 mg of intermediate 35-1 with a yield of 61.8%.

    Synthesis of Compound Ex-35: 5-ethyl-2-fluoro-4-(3-(4-(((1-methylpyrrolidin-3-yl)amino)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0346] The intermediate 35-1 (17.2 mg, 0.02 mmol) was dissolved in 2 ml of methanol to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by a preparative silica gel plate to obtain 3.4 mg of the final product with a yield of 37.6%.

    [0347] .sup.1H NMR (400 MHz, MeOD) δ 8.36 (d, J=8.0 Hz, 1H), 7.46 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 7.22-7.20 (m, 1H), 6.95 (dd, J=12.0 Hz, J=20.0 Hz, 2H), 4.22 (s, 2H), 4.10-4.04 (m, 1H), 3.67-3.54 (m, 3H), 3.37-3.33 (m, 1H), 2.96 (s, 3H), 2.61-2.52 (m, 3H), 2.32-2.21 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

    Example 36: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)morpholine-4-carboxamide (Ex-36)

    [0348] ##STR00083##

    Synthetic Route of Ex-36

    [0349] ##STR00084##

    Synthesis Method

    Synthesis of Compound Ex-36: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)morpholine-4-carboxamide

    [0350] Triphosgene (11 mg, 0.04 mmol) was dissolved in DCM and cooled to 0° C. To the solution, (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (25.0 mg, 0.03 mmol) in DCM was dropwise added. It was allowed to react for 5 minutes. To the reaction mixture, triethylamine (10.2 mg, 0.10 mmol) was dropwise add slowly. It was allowed to react at 0° C. for 0.5 hours. To the reaction mixture, morpholine (4.4 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified on silica gel plate. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by a preparative plate to obtain 5 mg of the final product with a yield of 32.0%.

    [0351] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.10 (s, 1H), 6.90-6.97 (m, 2H), 4.45 (s, 2H), 3.68 (t, J=4.0 Hz, 4H), 3.43 (t, J=4.0 Hz, 4H), 2.53-2.58 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 37: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-methylpiperazine-1-carboxamide (Ex-37)

    [0352] ##STR00085##

    Synthetic Route of Ex-37

    [0353] ##STR00086##

    Synthesis Method

    Synthesis of Compound Ex-37: N-((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1H-imidazol-4-yl)methyl)-4-methylpiperazine-1-carboxamide

    [0354] Triphosgene (11 mg, 0.04 mmol) was dissolved in DCM and cooled to 0° C. To the solution, (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methanamine (25.0 mg, 0.03 mmol) in DCM was dropwise added. It was allowed to react for 5 minutes. To the reaction mixture, triethylamine (10.2 mg, 0.10 mmol) was dropwise add slowly. It was allowed to react at 0° C. for 0.5 hours. To the reaction mixture, 1-methylpiperazine (5.1 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 1 hour, to which water was added, and then the reaction solution was extracted twice with DCM. The resulting organic phases was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. It was concentrated and purified. The obtained product was dissolved in 2 ml of methanol and 1 ml of concentrated hydrochloric acid. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated and dissolved in 3 ml of methanol, to which 0.5 ml of aqueous ammonia was added, and then it was concentrated and purified by a preparative plate to obtain 6 mg of the final product with a yield of 37.3%.

    [0355] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 6.90-6.97 (m, 2H), 4.46 (s, 2H), 3.67-3.74 (m, 4H), 3.10-3.15 (m, 4H), 2.80 (s, 3H), 2.53-2.58 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 38: 5-ethyl-4-(3-(4-((4-ethylpiperazin-1-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-2-fluorophenol (Ex-38)

    [0356] ##STR00087##

    Synthetic Route of Ex-38

    [0357] ##STR00088##

    Synthesis Method

    Synthesis of Intermediate 38-1: (6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0358] 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy) methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-(((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazole-4-formaldehyde (25.0 mg, 0.03 mmol) was dissolved in 5 ml of anhydrous dichloromethane, to which 1-ethylpiperazine (5.8 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 30 minutes. To the reaction mixture, sodium triacetylborohydride (10.7 mg, 0.05 mmol) was added. It was allowed to react at room temperature for 1 hour. The reaction mixture was quenched with water and extracted twice with DCM. The resulting organic phases was combined, washed with saturated saline and dried over anhydrous sodium sulfate. It was concentrated and purified to obtain 23.0 mg of intermediate 32-1 with a yield of 81.3%.

    Synthesis of Compound Ex-38: 5-ethyl-4-(3-(4-((4-ethylpiperazin-1-yl)methyl)-1H-imidazol-2-yl)-1H-indazol-6-yl)-2-fluorophenol

    [0359] Intermediate 38-1 (23.0 mg, 0.02 mmol) was dissolved in 2 mol of methanol, to which 1 ml of concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 6 hours. The reaction mixture was concentrated, and dissolved in 2 ml of methanol to which 0.5 ml of aqueous ammonia was added. The resulting mixture was concentrated and purified by a preparative silica gel plate to obtain 6.7 mg of final product with a yield of 54.5%. LC-MS m/z (ESI) [M+H]+ calcd for C.sub.25H.sub.30FN.sub.6O: 449.2; Found: 449.2.

    [0360] Assay: Evaluation of Pharmacological Activity

    [0361] 1. Experimental Principle

    [0362] A drug screening system based on kinases JAK1, JAK2, JAK3, and TYK2 was used to detect the inhibitory ability of small molecule compounds on kinase activity. A kinase undergoes an enzymatic reaction with its substrates IRS 1, IGF1Rtide, and Poly (4:1 Glu, Tyr), consuming ATP to produce ADP, wherein the ADP-Glo reagent and luminescence method were used to detect the amount of the product to reflect the activity of the kinase. 2.1 Experimental Materials and Instruments

    TABLE-US-00001 No. Name Source/Supplier Catalogue No. 1 HEPES Life Technologies 15630-080 2 BRIJ 35 detergent (10%) Sigma 1018940100 3 MgCl2 Sigma M1028 4 EGTA Sigma E3889 5 ADP-Glo Kinase Assay Promega V9101 6 JAK1 Carna 08-144 7 JAK2 Carna 08-045 8 JAK3 Carna 08-046 9 TYK2 Carna 08-147 10 ATP Promega V915B 11 IRS1 Signalchem I40-58-1000 12 IGFIRtide Signalchem I15-58 13 Poly (4:1 Glu, Tyr) Sigma P0275 15 384-Well polystyrene shallow flat Greiner 784075 white 16 384-Well Polypropylene microplate Labeyte PP-0200 17 Biotek Microplate Reader Biotek Synergy 4 18 Microplate Low Speed Centrifuge XiangZhi TD5B

    [0363] 2.2 Experimental Methods

    [0364] 2.2.1 Kinase Reaction Reagent Formulation

    [0365] 2.2.1.1 1× Kinase Reaction Buffer (400 ML)

    TABLE-US-00002 Stock Final Name Concentration Volume Concentration HEPES 1M (20X) 20 mL 50 mM MgCl.sub.2 1M (100X) 4 mL 10 mM BRIJ-35 10% (1000X) 400 μL 0.01% EGTA Powder 152 mg  1 mM ddH2O 375.6 mL 2 mM DTT, ready to use

    [0366] 2.2.1.2 2× Kinase Formulation

    TABLE-US-00003 Stock 2X Final Final Name concentration Volume Concentration Concentration JAK1 kinase solution JAK1 3225 nM  5.21 μL 40 nM 20 nM (884X) 1X Kinase 414.79 μL Reaction Buffer JAK2 kinase solution JAK2 4256 nM   0.2 μL  2 nM  1 nM (4955X) 1X Kinase  419.8 μL Reaction Buffer

    TABLE-US-00004 Stock 2X Final Final Name concentration Volume Concentration Concentration JAK3 kinase solution JAK3 3195 nM   0.5 μL  4 nM  2 nM (5341.2X) 1X Kinase  419.5 μL Reaction Buffer TYK2 kinase solution TYK2 3174 nM  2.65 μL 20 nM 10 nM (763X) 1X Kinase 417.35 μL Reaction Buffer

    [0367] 2.2.1.3 4× Substrate Mixture Formulation

    TABLE-US-00005 Stock 4X Final Final Name concentration Volume Concentration Concentration JAK1 substrate mixture solution ATP 10 mM (125X)  2.4 μL 80 μM 30 μM IRS1 1 mg/mL (5X)   60 μL 0.2 mg/mL 0.05 mg/mL 1X Kinase Reaction Buffer 237.6 μL JAK2 substrate mixture solution ATP 10 mM (500X)    6 μL 20 μM 5 μM IGF1Rtide 1 mg/mL (25X)   12 μL 0.04 mg/mL 0.01 mg/mL 1X Kinase Reaction Buffer 287.4 μL JAK3 substrate mixture solution ATP 10 mM (250X)  1.2 μL 40 μM 10 μM Poly (4:1 Glu, 5 mg/mL (41.6X)    6 μL 0.12 mg/mL 0.03 mg/mL Tyr) Peptide 1X Kinase Reaction Buffer 292.8 μL TYK2 substrate mixture solution ATP 10 mM (250X)  1.2 μL 40 μM 10 μM IRS1 1 mg/mL (5X)   60 μL 0.08 mg/mL 0.02 mg/mL 1X Kinase Reaction Buffer 238.8 μL

    [0368] 2.2.2 Kinase Reaction Experiment Procedure

    a) Dilute a compound solution to be tested by 5 times with 100% DMSO. Then, using 100% DMSO as diluent, perform a series of dilutions at a ratio of 1:3 for Filgotinib (10 mM stock solution) and the compound solution to be tested in a 96-well dilution plate. Take out 1 μL of the compound solution and add it to 49 μL of kinase reaction buffer, and shake the resulting mixture on a microplate shaker for 20 minutes.
    b) Transfer 2 μL of kinase (prepared according to 2.2.1.2) to a 384-well reaction plate, add 1 μL of the compound solution to be tested (prepared in step a) to the 384-well reaction plate (Greiner, 784075), centrifuge it at 1000 rpm/min for 1 min and incubate it at 25° C. for 10 min.
    c) Transfer 1 μL of the substrate mixture (prepared according to 2.2.1.3) to the 384-well reaction plate, centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 60 min. In the reaction system, the final concentrations of Filgotinib are 50, 12.5, 3.125, 0.7812, 0.1953, 0.0488, 0.0122, 0.003, 0.00076, 0.00019, and 0.000047 μM. The final concentrations of the compound to be tested are: 10, 2.5, 0.625, 0.15625, 0.039, 0.0097, 0.0024, 0.0006, 0.0015, 0.000038, and 0.0000095 μM. The final concentration of DMSO is 0.5%.
    d) Transfer 4 μL of ADP-Glo to the 384-well reaction plate, centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.
    e) Transfer 8 μL of Detection solution to the 384-well reaction plate, centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 40 min.
    f) Use Biotek multi-function plate reader to read the RLU (Relative luminescence unit) signal. The signal intensity is used to characterize the degree of kinase activity.

    [0369] 2.2.3 Experimental Data Processing Method


    Compound inhibition rate (% inh)=(negative control−compound)/(negative control−positive control)*100%

    [0370] Negative control: DMSO

    [0371] Positive control: 10 μM/50 μM Filgotinib

    [0372] IC50 (half inhibitory concentration) of the compound can be obtained using the following nonlinear fitting formula:


    Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope))

    [0373] X: log value of the compound concentration

    [0374] Y: Compound inhibition rate (% inh)

    [0375] Z′ factor calculation equation:


    Z′=1−3(SDmin+SDmax)/(AVEmax−AVEmin)

    in which:
    Min is the RLU value of the positive control 10 μM/50 μM Filgotinib, and Max is the RLU value of the negative control DMSO; and
    SD is the standard error, and AVE is the average value of RLU.

    [0376] 3. Experimental Results

    [0377] 3.1 Quality Control Results of Compound Test

    [0378] 3.1.1 Quality Control Result of JAK1 Binding Experiment


    Z′=0.79CV % (min)=4% CV % (max)=5%

    [0379] 3.1.2 Quality Control Result of JAK2 Binding Experiment


    Z′=0.74CV % (min)=9% CV % (max)=8%

    [0380] 3.1.3 Quality Control Result of JAK3 Binding Experiment


    Z′=0.76CV % (min)=15% CV % (max)=6%

    [0381] 3.1.4 Quality Control Result of TYK2 Binding Experiment


    Z′=0.84CV % (Min)=8% CV % (Max)=4%

    [0382] 3. Experimental Results

    TABLE-US-00006 Compound IC50(nM) ID JAK1 JAK2 JAK3 TYK2 Filgotinib 42.3 44.8 1473 293 MDI-3 1.96 1.35 1.41 32.2 MDI-301 0.317 0.466 1.13 6.82 MDI-302 0.359 0.420 0.812 12.9 MDI-303 0.430 0.641 1.34 6.26 MDI-304 0.172 1.32 0.912 8.26 MDI-305 3.18 1.49 2.20 63.8 MDI-306 0.104 0.428 0.600 9.07 Ex-9 1.3 1.5 1.3 19.8 Ex-10 1.2 5.2 4.5 27 Ex-11 0.31 0.85 2.5 18.4 Ex-12 0.1 0.74 0.67 6.1 Ex-13 0.48 0.84 1.7 11.3 Ex-14 0.47 1.2 1.6 9.6 Ex-15 0.29 0.78 0.76 4.9 Ex-16 0.16 0.5 0.43 0.97 Ex-17 0.36 1.2 2.9 6.5 Ex-18 0.15 1.4 1.1 3.7 Ex-19 0.33 3.3 2.3 6.4 Ex-20 0.1 0.53 0.43 1.0 Ex-21 0.21 0.72 0.64 6.9 Ex-22 0.14 0.68 0.48 1.1 Ex-23 0.15 0.68 0.49 0.96 Ex-24 0.37 1.3 3.3 23 Ex-25 0.4 2.8 2.5 7.0 Ex-26 0.43 0.43 0.57 1.7 Ex-27 0.92 6.3 4.4 9.2 Ex-28 0.14 0.86 1.0 1.6 Ex-29 1.1 13.3 9.3 16.8 Ex-30 0.52 1.8 4.5 30 Ex-31 0.1 1.6 3.7 17.3 Ex-32 0.27 0.89 1.9 11.6 Ex-33 0.58 1.4 1.7 13.3 Ex-34 0.15 1.0 0.5 1.1 Ex-35 0.32 0.63 0.85 5.2 Ex-36 0.11 0.55 0.48 0.83 Ex-37 0.1 0.66 0.55 1.9 Ex-38 0.1 1.2 2.1 11

    [0383] The above experimental results show that all compounds of the present disclosure tested in assay can inhibit JAK1, JAK2, JAK3, and TYK3 at very low concentrations and the inhibitory activities of these compounds are much higher than that of Filgotinib.

    [0384] Although specific embodiments of the present disclosure have been illustrated and described, it does not mean that these embodiments illustrate and describe all possible implementation forms of the present disclosure. More precisely, the language used in this specification are only descriptive words and not restrictive. It will be obvious to those skilled in the art that various kinds of changes and modifications can be made without departing from the general scope of the present disclosure. Therefore, the appended claims are intended to include all these changes and modifications within the scope of the present disclosure.