1. Patent Search
  2. Details

JAK INHIBITOR COMPOUND AND USE THEREOF

20230192711 · 2023-06-22

    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 (G), 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 (G), ##STR00136## 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, in which L is C═O, O═S═O, CH.sub.2 or a bond; 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.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.13 is H, —N(R.sub.17)(R.sub.18), C.sub.1-6 alkoxy, —SR.sub.12, —OR.sub.12, —CN, halogen, —NO.sub.2, —SF.sub.5, —S—C.sub.1-4 alkyl, 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.5-11bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R.sub.13 is substituted with 0, 1, 2, 3 or 4 R.sub.1(s), in which R.sub.17, and R.sub.18 are each independently selected from H, 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, C.sub.3-7 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.5-11bicycloalkyl, and 5-11 membered bicyclic heteroalkyl and are optionally substituted with one or more substitutes each independently selected from —OH, —CN, —SH, halogen, —NO.sub.2, —SF.sub.5, —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, wherein the —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, and 7-11 membered bicyclic heteroaryl are optionally substituted with 1, 2 or 3 substitutes each independently selected from 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; or R.sub.17, R.sub.18 and the N atom connected thereto together form a 3-14 membered ring; and 0, 1, 2, 3 or 4 R.sub.2(s) are present in formula (G), and 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, 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.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, 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.1)(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.1 is 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.5-11bicycloalkyl, 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.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, 3 or 4 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.11 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 (G), wherein all Hs are each independently and optionally substituted with 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 N or 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 1, wherein X.sub.1, X.sub.2 and X.sub.3 are CH.

    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 1, wherein L is C═O, O═S═O or CH.sub.2.

    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 1, wherein R.sub.13 is H, —N(R.sub.17)(R.sub.18), C.sub.1-6 alkoxy, —OH, —SH, —CN, halogen, —NO.sub.2, —SF.sub.5, —S—C.sub.1-4 alkyl, 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.5-11bicycloalkyl, or 5-11 membered bicyclic heteroalkyl, and R.sub.13 is substituted with 0, 1, 2, 3 or 4 R.sub.1(s), in which R.sub.17 and R.sub.18 are each independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, C.sub.5-7 aryl, and 5-7 membered heteroaryl, and are optionally substituted with one or more of —OH, —CN, —SH, halogen, —NO.sub.2, -and SF.sub.5.

    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 R.sub.13 is H, —N(R.sub.17)(R.sub.18), C.sub.1-6 alkoxy, —OH, —SH, —CN, halogen, —NO.sub.2, —SF.sub.5, —S—C.sub.1-4 alkyl, C.sub.1-6 alkyl, 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 R.sub.13 is substituted with 0, 1, 2, 3 or 4 R.sub.1(s).

    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, —N(R.sub.17)(R.sub.18), C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, or 5-7 membered heteroaryl, and R.sub.13 is substituted with 0, 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 and R.sub.18 are each independently selected from H, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and C.sub.3-7 heterocycloalkyl, and are optionally substituted with one or more of —OH, —CN, —SH, halogen, —NO.sub.2, and SF.sub.5.

    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 L is C═O, and R.sub.13 is —N(R.sub.17)(R.sub.18), C.sub.1-6 alkoxy, —OH, —SH, —CN, halogen, —NO.sub.2, —SF.sub.5, or —S—C.sub.1-4 alkyl, and R.sub.13 is substituted with 0, 1, 2, 3 or 4 R.sub.1(s) in which R.sub.17 and R.sub.18 are each independently selected from H, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 heterocycloalkyl, C.sub.5-7 aryl, and 5-7 membered heteroaryl, and are optionally substituted with one or more of —OH, —CN, —SH, halogen, —NO.sub.2, -and SF.sub.5, or R.sub.17, R.sub.18 and the N atom connected thereto together form a 3-14 membered ring.

    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 1, 2 or 3 R.sub.2(s) are present and 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.

    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 1, 2 or 3 R.sub.2(s) are present, and R.sub.2 is selected from halogen, C.sub.1-6 alkyl, and C.sub.3-6 cycloalkyl, in which the C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl 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.

    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 or 2 R.sub.2(s) are present, and R.sub.2 is selected from halogen, and C.sub.1-6 alkyl.

    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 a compound of Formula (I), ##STR00137## in which L is a bond; and X is CH or N; the ring A is 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; 0, 1, 2, 3 or 4 R.sub.1(s) are present in formula (I), and R.sub.1 is selected from H, halogen, 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, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, and 7-11 membered bicyclic heteroaryl, in which the 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, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, 5-7 membered heteroaryl, C.sub.7-11 bicyclic aryl, 7-11 membered bicyclic heteroaryl are optionally substituted with 1, 2, 3 or 4 R.sub.4(s), 0, 1, 2, 3 or 4 R.sub.2(s) are present in formula (I), and R.sub.2 is selected from H, halogen, —OH, —NO.sub.2, —CN, —SF.sub.5, C.sub.1-6alkyl, 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, —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 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, —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; R.sub.3 is selected from halogen, cyano, C.sub.1-3 alkyl, hydroxyl, C.sub.1-6 alkoxy, —N(R.sub.5)(R.sub.6), —CON(R.sub.7)(R.sub.8) or 3-7 membered heterocycloalkyl, in which the 3-7 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R.sub.4(s); R.sub.4 is selected from halogen, C.sub.1-3 alkyl, hydroxyl, C.sub.1-6 alkoxy, —NH.sub.2, —NHCH.sub.3 or —N(CH.sub.3).sub.2; R.sub.5, R.sub.6, R.sub.7, R.sub.8 are each independently hydrogen or C.sub.1-4 alkyl; R.sub.9 is selected from H, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl or C.sub.3-7 cycloalkyl; R.sub.10 is H or selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, 4-10 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 each substituent included in the above group is optionally substituted with 1, 2, 3 or 4 substituent(s) each independently selected from the group consisting of —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, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy; R.sub.11 is selected from H, C.sub.1-4 alkyl and C.sub.3-7 cycloalkyl; and R.sub.12 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, 4- to 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 each substituent included in the above group is optionally substituted with 1, 2 or 3 substituent(s) each independently selected from the group consisting of halogen, —CF.sub.3, —CN, —OH, —NH.sub.2, —NH(CH.sub.3), —N(CH.sub.3).sub.2, oxo, —S—C.sub.1-4 alkyl, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy and C.sub.1-4 haloalkoxy.

    16. 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 15, wherein X is CH.

    17. 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 15, wherein the ring A is C.sub.3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C.sub.5-7 aryl, or 5-7 membered heteroaryl.

    18. 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 15, wherein the ring A is 5-6 membered heteroaryl, or phenyl.

    19. 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: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinylpyrazin-2-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(1-methylpiperidin-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone; (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperzin-1-yl)pyrazin-2-yl)ketone; 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol; 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol; 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone; 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; Cyclobutyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol; 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol; 4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol; 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one; 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone; Azetidine-1-yl((2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperzin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperzin-1-yl)ketone; Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone; Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; Cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone; (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidine-1-yl)ketone; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidine-3-nitrile; 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate; Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate; (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone; 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile; 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide; (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone; (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol; (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol; -5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol; 5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol; and 3-ethyl-4-{3-[5-(4-methylpiperazin-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

    20. 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.

    21. A method for the treatment and/or prevention of a JAK-related disease or disorder, the method comprising administering to a patient in need thereof 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.

    22. The method according to claim 21, 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

    DESCRIPTION OF THE DRAWINGS

    [0390] FIG. 1 shows the NMR spectrum of compound MDI-2.

    [0391] FIG. 2 shows the NMR spectrum of compound MDI-201.

    [0392] FIG. 3 shows the NMR spectrum of compound MDI-202.

    [0393] FIG. 4 shows the NMR spectrum of compound MDI-206.

    [0394] FIGS. 5A to 5D show IC50 curve of JAK1 experiments for MDI-201, MDI-202, and MDI-206, in which Filgotinib was used as a positive control.

    [0395] FIGS. 6A to 6D show IC50 curve of JAK2 experiments for MDI-201, MDI-202, and MDI-206, in which Filgotinib was used as a positive control.

    [0396] FIGS. 7A to 7D show IC50 curve of JAK3 experiments for MDI-201, MDI-202, and MDI-206, in which Filgotinib was used as a positive control.

    [0397] FIGS. 8A to 8D show IC50 curve of TYK2 experiments for MDI-201, MDI-202, and MDI-206, in which Filgotinib was used as a positive control.

    EXAMPLES

    [0398] The compounds of formula (G), the compounds of formula (G′) or 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 (G), the compounds of formula (G′) or 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 (G), formula (G′) or formula (I).

    [0399] 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:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone (MDI-2)

    [0400] ##STR00015##

    [0401] Synthetic Route of Target Compound 8 (i.e. MDI-2):

    ##STR00016##

    [0402] Synthetic Route of Intermediate 10

    ##STR00017##

    [0403] Synthetic Route of Intermediate 16

    ##STR00018##

    [0404] Synthetic Route of Intermediate 20

    ##STR00019##

    Synthesis Method

    Synthesis of Intermediate 1:6-bromo-1H-indazole-3-formaldehyde

    [0405] Sodium nitrite (14.00 g, 200 mmol) was dissolved in 75 ml DMF and 100 ml water, and then cooled to 0° C. Under nitrogen protection, 3N HCl (23 ml, 68.9 mmol) was slowly added dropwise and after addition, the reaction was carried out for 10 minutes. At 0° C., to the reaction solution, 6-bromoindole (5.00 g, 25.5 mmol) in DMF (35 ml) was slowly added dropwise. After the dropwise addition was complete, the reaction was continued at room temperature overnight. The resulting mixture was extracted with ethyl acetate 3 times, and then the organic phases were combined, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate 1, with a yield of 83.6%.

    [0406] .sup.1H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=4.0 Hz, 1H).

    Synthesis of Intermediate 2: 6-bromo-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-indazole-3-formaldehyde

    [0407] Intermediate 1 (1.56 g, 6.93 mmol) was dissolved in dry tetrahydrofuran, and then cooled to 0° C. Sodium hydride (0.33 g, 8.32 mmol) was added slowly, the reaction was carried out at room temperature for 1 hour, and then cooled to 0° C. After that, 2-(trimethylsilyl)ethoxymethyl chloride (1.73 g, 10.40 mmol) was added dropwise and the reaction was carried out at room temperature overnight. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined and washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 2, with a yield of 49.2%.

    [0408] .sup.1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 8.22 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.88 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 7.52 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 5.81 (s, 2H), 3.63-3.58 (m, 2H), 0.97-0.93 (m, 2H), 0.04 (s, 9H).

    Synthesis of Intermediate 16: Tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate

    1. Synthesis of Intermediate 11: Tert-butyl 2,5-dihydro-1H-pyrrole-1-carboxylate

    [0409] 3-pyrroline (10.0 g, 0.15 mol) was dissolved in 400 ml dichloromethane and triethylamine (40.6 ml, 0.29 mol), and then cooled to 0° C. (Boc).sub.2O (37.9 g, 0.17 mol) was slowly added. The reaction was carried out at room temperature overnight. Water was added and the mixture was extracted twice with dichloromethane. The organic phases was combined, washed with water three times, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 11 with a yield of 91.0%.

    2. Synthesis of Intermediate 12: Tert-butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate

    [0410] Intermediate 11 (24.5 g, 0.15 mol) was dissolved in 450 ml of dichloromethane, and then cooled to 0° C. M-chloroperoxybenzoic acid (37.5 g, 0.22 mol) was slowly added in batches. The reaction was carried out at room temperature overnight. After that, saturated sodium thiosulfate (40 ml) was added, and then stirred for 30 minutes. The aqueous phase was extracted twice with dichloromethane, washed with saturated potassium carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 12 with a yield of 84.9%.

    [0411] .sup.1H NMR (400 MHz, CDCl3) δ 3.85 (d, J=12.0 Hz, 1H), 3.77 (d, J=12.0 Hz, 1H), 3.69-3.67 (m, 2H), 3.36-3.30 (m, 2H), 1.45 (s, 9H).

    3. Synthesis of Intermediate 13: Tert-butyl 3-azido-4-hydroxyl pyrrolidinyl-1-carboxylate

    [0412] Intermediate 12 (20.8 g, 0.12 mol) was dissolved in 150 ml 1,4-dioxane and 50 ml water, and then sodium azide (24.0 g, 0.37 mol) was added. The mixture was heated to 106° C. and reacted for 18 hours, then cooled to room temperature, followed by adding 100 ml of saturated brine. The resulting mixture was extracted with dichloromethane (250 ml*4), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford Intermediate 13, with a yield of 100%.

    [0413] .sup.1H NMR (400 MHz, CDCl3) δ 4.27-4.24 (m, 1H), 3.94 (s, 1H), 3.73-3.59 (m, 2H), 3.41-3.36 (m, 2H), 1.47 (s, 9H).

    4. Synthesis of Intermediate 14: Tert-butyl 3-azido-4-((methanesulfonyl) oxy)pyrrolidinyl-1-carboxylate

    [0414] Intermediate 13 (28.0 g, 0.12 mol) was dissolved in 350 ml of dichloromethane and triethylamine (37.3 g, 0.37 mol), and cooled to 0° C., followed by slowly adding methanesulfonyl chloride (16.9 g, 0.15 mol) dropwise. After the addition, the reaction was carried out at room temperature for 2 hours, the reaction was quenched with water, and the resulting mixture was extracted twice with dichloromethane. The organic phases was combined, washed with saturated sodium bicarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford Intermediate 14, with a yield of 98.0%.

    5. Synthesis of Intermediate 15: Tert-butyl 3,4-diazidopyrrolidinyl-1-carboxylate

    [0415] Intermediate 14 (36.9 g, 0.12 mol) was dissolved in 250 ml DMF, to which sodium azide (23.5 g, 0.36 mol) was added. The mixture was heated to 90° C., reacted for 2 days, and cooled to room temperature, following by adding 750 ml of water. The resulting mixture was extracted with butyl tert-butyl ether (400 ml*4), and the organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and purified by silica gel column to afford Intermediate 15 with a yield of 62.2%.

    6. Synthesis of Intermediate 16: Tert-butyl 3,4-diaminopyrrolidinyl-1-carboxylate

    [0416] Intermediate 15 (18.9 g, 0.08 mol) was dissolved in 200 ml methanol, and 10% Pd/C was added where it was replaced with hydrogen 3 times. The mixture was heated to 40° C., and reacted for 2 days. The resulting mixture was filtered and concentrated to afford Intermediate 16, with a yield of 78%.

    [0417] .sup.1H NMR (400 MHz, CDCl3) δ 3.51-3.49 (m, 2H), 3.40-3.36 (m, 2H), 3.21-3.11 (m, 2H), 1.47 (s, 9H).

    Synthesis of Intermediate 3: Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)3,4,6,6a-tetrahydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

    [0418] Intermediate 2 (1.56 g, 6.93 mmol) and tert-butyl 3,4-diaminopyrroline-1-carboxylate (1.56 g, 6.93 mmol) were dissolved in 5 ml of hexafluoroisopropanol and heated to 40° C. for 2 days. The resulting mixture was concentrated and purified by a silica gel column to afford Intermediate 3 with a yield of 54.7%.

    Synthesis of Intermediate 4: Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

    [0419] Oxalyl chloride (0.53 g, 4.20 mmol) was dissolved in dry 15 ml dichloromethane, and cooled to −78° C. under the protection of nitrogen. DMSO (0.61 g, 7.84 mmol) was slowly added dropwise. After the addition was complete, it was allowed to react for 30 minutes. Intermediate 3 (1.00 g, 1.87 mmol) in dichloromethane was slowly added dropwise. After the dropwise addition, it was allowed to react for 30 minutes. Dry triethylamine (1.89 g, 18.66 mmol) was added slowly dropwise, and it was allowed to react for 10 minutes. The temperature was increased slowly and the reaction was carried out at room temperature for 2 hours. The reaction was quenched with saturated ammonium chloride solution and the resulting mixture was extracted twice with dichloromethane, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 4 with a yield of 36.3%.

    [0420] .sup.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=4.0 Hz, 1H), 7.78 (d, J=4.0 Hz, 1H), 7.44 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.69 (s, 2H), 4.64-4.52 (m, 4H), 3.67-3.56 (m, 2H), 1.56 (s, 9H), 0.95-0.89 (m, 2H), 0.03 (s, 9H).

    Synthesis of Intermediate 5: Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

    [0421] Intermediate 4 (110 mg, 0.21 mmol) was dissolved in dry tetrahydrofuran, and cooled to 0° C. Sodium hydride (12.3 mg, 0.31 mmol) was added and it allowed to react at room temperature for 30 minutes. The mixture was cooled to 0° C. 2-(tri methylsilyl)ethoxymethyl chloride (41.2 mg, 0.25 mmol) was added slowly dropwise, and it allowed to react at room temperature for 4 hours. The reaction was quenched with water and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to intermediate 5 with a yield of 73.1%.

    [0422] .sup.1H NMR (400 MHz, CDCl3) δ 8.41-8.36 (m, 1H), 7.79 (s, 1H), 7.44 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (s, 2H), 4.65-4.52 (m, 4H), 3.63-3.57 (m, 4H), 1.56 (s, 9H), 0.96-0.91 (m, 4H), 0.03 (s, 18H)).

    Synthesis of Intermediate 10: 5-(piperidin-1-yl)pyrazine-2 carboxylic acid

    1. Synthesis of Intermediate 9: Methyl 5-(piperidin-1-yl)pyrazine-2-carboxylate

    [0423] Methyl 5-chloro-pyrazine-2-carboxylate (1.72 g, 10 mmol) was dissolved in 10 ml DMF, and N,N-diisopropylethylamine (4.3 ml, 25.0 mmol) and piperidine hydrochloride (1.45 g, 12.0 mmol) were added. The mixture was stirred overnight at room temperature. Under vigorous stirring, water was added. A solid was precipitated, filtered, and the filter cake was washed with water, and dried to afford Intermediate 9 with a yield of 80.0%.

    2. Synthesis of Intermediate 10: 5-(piperidin-1-yl)pyrazin-2-carboxylic acid

    [0424] Intermediate 9 (430 mg, 1.95 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of water, to which lithium hydroxide (163 mg, 3.88 mmol) was added. The reaction was carried out at room temperature for 4 hours. The mixture was concentrated by distilling off tetrahydrofuran under reduced pressure, and the pH was adjusted to 4 with 1N HCl. A solid precipitated, filtered, and the filter cake was washed with water, and dried to afford Intermediate 10 with a yield of 91.5%.

    [0425] .sup.1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.02 (s, 1H), 3.76-3.73 (m, 4H), 1.78-1.65 (m, 6H).

    Synthesis of Intermediate 6: (2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

    [0426] Intermediate 10 (34.3 mg, 0.17 mmol) and N,N-diisopropylethylamine (58.2 mg, 0.45 mmol) were dissolved in DMF, HATU (85.7 mg, 0.22 mmol) was added, and the reaction was carried out at room temperature for 10 minutes. Intermediate 5 (100 mg, 0.15 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and was then slowly added to the previous reaction solution. It was allowed to react overnight at room temperature.

    [0427] The reaction was quenched with water, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate 6 with a yield of 57.3%.

    [0428] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.87 (d, J=8.0 Hz, 1H), 8.41-8.37 (m, 1H), 8.09-8.04 (m, 1H), 7.80 (s, 1H), 7.44-7.41 (m, 1H), 5.96 (s, 2H), 5.75 (d, J=8.0 Hz, 2H), 5.28 (s, 1H), 5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s, 1H), 3.74-3.68 (m, 4H), 3.67-3.64 (m, 2H), 3.63-3.59 (m, 2H), 1.71-1.68 (m, 6H), 0.95-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate 20: (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

    1. Synthesis of Intermediate 17: 5-ethyl-2-fluorophenol

    [0429] 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.

    [0430] 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%.

    [0431] .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).

    2. Synthesis of Intermediate 18: 4-bromo-5-ethyl-2-fluorophenol

    [0432] Intermediate 17 (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%.

    [0433] .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).

    3. Synthesis of Intermediate 19: (2-((4-bromo-5-ethyl-2-fluorophenoxy)methoxy)ethyl)trimethylsilane

    [0434] Intermediate 18 (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%.

    [0435] .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).

    4. Synthesis of Intermediate 20: (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane

    [0436] Compound 19 (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%.

    [0437] .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 7: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

    [0438] Intermediate 6 (65.0 mg, 0.09 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (40.9 mg, 0.10 mmol), Pd(dppf)Cl.sub.2 (6.3 mg, 0.01 mmol) and potassium phosphate (25.3 mg, 0.26 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the mixture was extracted 2 times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 7 with a yield of 52.8%.

    [0439] .sup.1H NMR (400 MHz, CDCl3) δ 8.87 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.54 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s, 2H), 5.79 (d, J=4.0 Hz, 2H), 5.35 (s, 2H), 5.33 (s, 1H), 5.29 (s, 1H), 5.20 (s, 1H), 5.01 (s, 1H), 3.91 (t, J=8.0 Hz, J=20.0 Hz, 2H), 3.76-3.74 (m, 4H), 3.64-3.62 (m, 4H), 2.58 (t, J=8.0 Hz, J=16.0 Hz, 2H), 1.74-1.72 (m, 6H), 1.10-1.06 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.04 (s, 9H), 0.03 (s, 9H).

    Synthesis of Compound 8 (i.e. MDI-2): (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-(piperidin-1-yl)pyrazin-2-yl)ketone

    [0440] Intermediate 7 (43.0 mg, 0.05 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The resulting solid was dissolved in 1 ml methanol, pH was adjusted to 8-9 with sodium bicarbonate solution, and then the resulting mixture was extracted 4 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 4.5 mg of the final product with a yield of 18.0%.

    [0441] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.67 (s, 1H), 8.28 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.21 (s, 1H), 7.40 (s, 1H), 7.18 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.96-6.89 (m, 2H), 5.14 (s, 2H), 4.82 (s, 2H), 3.76-3.73 (m, 4H), 2.58 (dd, J=12.0 Hz, J=8.0 Hz, 2H), 1.76-1.66 (m, 6H), 1.10 (t, J=8.0 Hz, 3H).

    Example 2: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone (MDI-201)

    [0442] ##STR00020##

    [0443] Synthetic Route of MDI-201:

    ##STR00021##

    Synthesis Method

    Synthesis of Intermediate MDI-201-1: Methyl 5-morpholine pyrazin-2-carboxylate

    [0444] Methyl 5-chloro-pyrazine-2-carboxylate (1.5 g, 8.7 mmol) was dissolved in 10 ml DMF, and N,N-diisopropylethylamine (3.0 ml, 17.4 mmol) and morpholine (0.91 g, 10.4 mmol) were added. The mixture was stirred overnight at room temperature. Under vigorous stirring, water was added and a solid precipitated out, and filtered. The resulting filter cake was washed with water, and dried to afford the intermediate MDI-201-1 with a yield of 72.2%.

    Synthesis of Intermediate MDI-201-2: 5-morpholinepyrazin-2-carboxylic acid

    [0445] The intermediate MDI-201-1 (1.4 g, 6.27 mmol) was dissolved in 20 ml of tetrahydrofuran and 20 ml of water, lithium hydroxide (0.32 g, 7.53 mmol) was added, and the reaction was carried out at room temperature for 4 hours. The reaction mixture was concentrated by distilling off tetrahydrofuran under reduced pressure and adjusted with 1N HCl to pH=4. A solid precipitated out, and filtered. The resulting filter cake was washed with water, and dried to afford the intermediate MDI-201-2 with a yield of 99.1%.

    [0446] .sup.1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.04 (s, 1H), 3.88-3.86 (m, 4H), 3.80-3.77 (m, 4H).

    Synthesis of Intermediate MDI-201-3: (2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

    [0447] The intermediate MDI-201-2 (27.4 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) was dissolved in DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF, and then slowly added to the previous reaction solution. It was allowed to react at room temperature overnight, and water was added to quench the reaction. The mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford intermediate MDI-201-3 with a yield of 47.8%.

    [0448] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.91 (d, J=8.0 Hz, 1H), 8.44-8.36 (m, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.46-7.41 (m, 1H), 5.96 (s, 2H), 5.74 (d, J=4.0 Hz, 2H), 5.27 (s, 1H), 5.19 (s, 1H), 5.00 (s, 1H), 4.92 (s, 1H), 3.90-3.88 (m, 4H), 3.75-3.72 (m, 4H), 3.64-3.58 (m, 4H), 0.96-0.89 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-201-4: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

    [0449] The intermediate MDI-201-3 (43.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-201-4 with a yield of 40.9%.

    [0450] .sup.1H NMR (400 MHz, CDCl3) δ 8.91 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 8.52 (dd, J=8.0 Hz, J=16.0 Hz, 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49 (s, 1H), 7.27 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s, 2H), 5.79 (d, J=4.0 Hz, 2H), 5.35 (s, 2H), 5.29 (s, 1H), 5.20 (s, 1H), 5.02 (s, 1H), 4.94 (s, 1H)), 3.91-3.86 (m, 6H), 3.76-3.72 (m, 4H), 3.65-3.61 (m, 4H), 2.58 (t, J=8.0 Hz, 2H), 1.10-1.03 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.04 (s, 9H), 0.03 (s, 9H).

    Synthesis of MDI-201:(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(5-morpholinepyrazin-2-yl)ketone

    [0451] The intermediate MDI-201-4 (22.0 mg, 0.02 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The resulting solid was dissolved with 1 ml methanol, to which 2 ml concentrated aqueous ammonia was added. The resulting mixture was concentrated to a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting residue was and purified by a preparation plate to afford 8 mg of the final product, with a yield of 61.9%.

    [0452] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.89 (s, 1H), 8.66 (d, J=4.0 Hz, 1H), 8.38-8.33 (m, 2H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 5.05 (s, 2H), 4.72 (s, 2H), 3.76-3.74 (m, 4H), 3.71-3.68 (m, 4H), 2.52 (dd, J=12.0 Hz, J=4.0 Hz, 2H), 1.05 (t, J=8.0 Hz, 3H).

    Example 3: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone (MDI-202)

    [0453] ##STR00022##

    [0454] Synthetic Route of MDI-202:

    ##STR00023##

    Synthesis Method

    Synthesis of Intermediate MDI-202-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

    [0455] The intermediate 1-methyl-1H-pyrazole-4-carboxylic acid (16.5 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF and then slowly added to the previous reaction solution. It was allowed to react at room temperature overnight, and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-202-1 with a yield of 41.3%.

    [0456] .sup.1H NMR (400 MHz, CDCl3) δ 8.43 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 2H), 7.81 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 5.96 (s, 2H), 5.75 (s, 2H), 5.02-4.85 (m, 4H), 4.01 (s, 3H), 3.64-3.59 (m, 4H), 0.97-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-202-2: (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

    [0457] The intermediate MDI-202-1 (33 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (23.3 mg, 0.06 mmol), Pd(dppf)Cl.sub.2 (3.6 mg, 0.005 mmol) and potassium phosphate (31.3 mg, 0.15 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times and the mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-202-2 with a yield of 85.0%.

    [0458] .sup.1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 2H), 7.49 (s, 1H), 7.20 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.00 (s, 2H), 5.79 (s, 2H), 5.35 (s, 2H), 5.04-4.87 (m, 4H), 4.01 (s, 3H), 3.91 (t, J=8.0 Hz, J=20.0 Hz, 2H), 3.67-3.61 (m, 4H), 2.58 (d, J=8.0 Hz, 2H), 1.11-1.07 (m, 3H), 0.95-0.91 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-202: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(1-methyl-1H-pyrazol-4-yl)ketone

    [0459] The intermediate MDI-202-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved with 1 ml methanol, to which 2 ml of concentrated aqueous ammonia was added. The mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a preparation plate to afford 5.0 mg of the final product with a yield of 25.4%.

    [0460] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.33 (s, 1H), 12.87 (s, 1H), 9.89 (s, 1H), 8.35 (d, J=8.0 Hz, 2H), 7.94 (s, 1H), 7.42 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.95 (d, J=12.0 Hz, 1H), 4.89 (s, 2H), 4.67 (s, 2H), 3.92 (s, 3H), 2.51-2.48 (m, 2H), 1.05 (t, J=8.0 Hz, 3H).

    Example 4: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(1-methylpiperidin-4-yl)ketone (MDI-203)

    [0461] MDI-203 may also be named as 5-ethyl-2-fluoro-4-{3-[5-(1-methylpiperidin-4-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

    ##STR00024##

    [0462] Synthetic Route of MDI-203:

    ##STR00025##

    Synthesis Method

    Synthesis of Intermediate MDI-203-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

    [0463] 1-methylpiperidine-4-carboxylic acid (18.6 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) was dissolved in DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness (to remove trifluoroacetic acid), which was repeated 3 times. Then the resulting residue was dissolved in DMF, which was slowly added to the previous reaction solution. It was allowed to react at room temperature overnight. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-203-1 with a yield of 40.2%.

    [0464] .sup.1H NMR (400 MHz, CDCl3) δ8.29-8.22 (m, 1H), 7.76 (s, 1H), 7.41-7.26 (m, 1H), 5.85 (s, 2H), 5.69 (s, 2H), 4.88-4.59 (m, 4H), 3.63-3.54 (m, 6H), 3.21-2.81 (m, 5H), 2.28-2.01 (m, 4H), 0.93-0.83 (m, 5H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-203-2: (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)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

    [0465] The intermediate MDI-203-1 (41.29 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-203-2 with a yield of 40.9%.

    [0466] .sup.1H NMR (400 MHz, CDCl3) δ8.50-8.44 (m, 1H), 7.49 (s, 1H), 7.22 (dd, J=12.0 Hz, 2H), 7.04 (d, J=12.0 Hz, 1H), 5.98 (d, J=12.0 Hz, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.84-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 3.38-3.30 (m, 2H), 2.61-2.54 (m, 5H), 2.13-2.05 (m, 4H), 1.10-1.01 (m, 5H), 0.97-0.89 (m, 3H), 0.03 (s, 9H), 0.02 (s, 18H).

    Synthesis of Compound MDI-203: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(1-methylpiperidin-4-yl)ketone

    [0467] Intermediate MDI-203-2 (26.4 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, to which 2 ml concentrated ammonia water was added. It was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness (to remove ammonia water), which was repeated 3 times. After separation, 5.0 mg of the final product was obtained with a yield of 34.2%.

    [0468] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.87 (s, 1H), 9.24 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.96 (d, J=12.0 Hz, 1H), 4.80 (s, 2H), 4.48 (s, 2H), 3.04-3.01 (m, 2H), 2.79 (s, 3H), 2.55-2.51 (m, 2H), 2.05-1.99 (m, 3H), 1.85-1.78 (m, 2H), 1.01-0.98 (m, 3H). The signals of the two H were masked by the water peak (δ=3.37).

    Example 5: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone (MDI-204)

    [0469] MDI-204 may also be named as 5-ethyl-2-fluoro-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

    ##STR00026##

    [0470] Synthetic Route of MDI-204:

    ##STR00027##

    Synthesis Method

    Synthesis of Intermediate MDI-204-1: (2-(6-bromol-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0471] 5-(4-methylpiperazin-1-yl)pyrazine-2-carboxylic acid (28.9 mg, 0.13 mmol) and N,N-diisopropylethylamine (46.0 mg, 0.36 mmol) were dissolved in DMF, to which HATU (67.8 mg, 0.18 mmol) was added. It was allowed to react at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness (to remove trifluoroacetic acid), which was repeated 3 times. Then the resulting residue was dissolved in DMF, which was slowly added to the previous reaction solution. It was allowed to react at room temperature overnight. Water was added to quench the reaction, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-204-1 with a yield of 43%.

    [0472] .sup.1H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.41-8.33 (m, 1H), 8.07-8.05 (m, 1H), 7.76 (d, J=4.0 Hz, 1H), 7.42-7.38 (m, 1H), 5.92 (s, 2H), 5.70 (d, J=4.0 Hz, 2H), 5.23-4.88 (m, 4H), 3.77-3.65 (m, 4H), 3.61-3.55 (m, 4H), 2.55 (t, J=4.0 Hz, 4H), 2.37 (s, 3H), 0.94-0.83 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-204-2: (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)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0473] The intermediate MDI-204-1 (46.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl.sub.2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-204-2 with a yield of 47.2%.

    [0474] .sup.1H NMR (400 MHz, CDCl3) δ8.86-8.84 (m, 1H), 8.51-8.43 (m, 1H), 8.08-8.06 (m, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.26-7.23 (m, 1H), 7.21-7.14 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 5.97 (s, 2H), 5.75 (d, J=4.0 Hz, 2H), 5.32 (s, 2H), 5.25-5.16 (m, 2H), 4.99-4.90 (m, 2H), 3.87-3.83 (m, 2H), 3.77-3.74 (m, 4H), 3.63-3.56 (m, 4H), 2.56-2.51 (m, 6H), 2.37 (s, 3H), 1.07-1.01 (m, 3H), 0.99-0.88 (m, 6H), 0.03 (s, 9H), −0.07 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-204: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0475] Intermediate MDI-204-2 (28.7 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The resulting solid was dissolved in 1 ml methanol, to which 2 ml concentrated ammonia water was added. It was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness (to remove ammonia water), which was repeated 3 times. After separation, 4.0 mg of the final product was obtained with a yield of 23.51%.

    [0476] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.79 (d, J=16.0 Hz, 1H), 9.85 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.34-8.30 (m, 1H), 7.40 (s, 1H), 7.14-7.10 (m, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H), 5.08-4.65 (m, 4H), 2.55-2.49 (m, 6H), 2.24 (s, 3H), 2.03-1.97 (m, 4H), 1.04-1.02 (m, 3H).

    Example 6: (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone (MDI-205)

    [0477] MDI-205 may also be named as 3-ethyl-4-{3-[5-(4-methylpiperazine-1-carbonyl)-1H,4H,5H,6H-pyrrolo[3,4-d]imidazol-2-yl]-1H-indazol-6-yl}phenol.

    ##STR00028##

    [0478] Synthetic Route of MDI-205:

    ##STR00029##

    Synthesis Method

    Synthesis of Intermediate MDI-205-1: 4-benzyloxy-2-ethyl-iodobenzene

    [0479] 3-ethyl-4-iodophenol (200 mg, 0.81 mmol), benzyl bromide (165.5 mg, 0.97 mmol) and potassium carbonate (222.9 mg, 1.61 mmol) were dissolved in DMF. It was allowed to react at room temperature for two hours. Water was added and the resulting mixture was extracted twice with EA. The organic phases were combined, washed with water, saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 250 mg of colorless oily product with a yield of 91.7%.

    [0480] .sup.1H NMR (400 MHz, CDCl3) δ7.70 (d, J=8.0 Hz, 1H), 7.46-7.36 (m, 5H), 6.92 (d, J=4.0 Hz, 1H), 6.57 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 5.06 (s, 2H), 2.72 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.22 (t, J=8.0 Hz, 3H).

    Synthesis of Intermediate MDI-205-2: (2-(4-(phenoxy)-2-ethyl phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane

    [0481] MDI-205-1 (250.0 mg, 0.74 mmol), pinacol borate (225.1 mg, 0.89 mmol), Pd(dppf)Cl.sub.2 (54.0 mg, 0.07 mmol) and KOAc (217.6 mg, 2.22 mmol) were dissolved in 1,4-dioxane (10 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C. and reacted 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 with a yield of 70%.

    [0482] .sup.1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.0 Hz, 1H), 7.47-7.34 (m, 5H), 6.86-6.80 (m, 2H), 5.11 (s, 2H), 2.93 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.35 (s, 12H), 1.21 (t, J=8.0 Hz, 3H).

    Synthesis of Compound MDI-205-3: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0483] The intermediate 5-(4-methylpiperazin-1-yl)pyrazine-2 carboxylic acid (64.2 mg, 0.29 mmol) and N,N-diisopropylethylamine (93.2 mg, 0.72 mmol) were dissolved in DMF, to which HATU (109.7 mg, 0.29 mmol) was added. It was allowed to react at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilylethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (160.0 mg, 0.24 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and concentrated to dryness (to remove trifluoroacetic acid), which was repeated 3 times. Then the resulting residue was dissolved in DMF, which was slowly added to the previous reaction solution. It was allowed to react at room temperature overnight. Water was added to quench the reaction, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-205-3 with a yield of 49.2%.

    [0484] .sup.1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.42 (dd, J=8.0 Hz, J=20.0 Hz 1H), 8.10 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.80 (s, 1H), 7.41-7.46 (m, 1H), 5.96 (s, 2H), 5.74 (d, J=4.0 Hz, 2H), 5.27 (s, 1H), 5.19 (s, 1H), 4.99 (s, 1H), 4.91 (s, 1H), 3.80-3.78 (m, 4H), 3.63-3.59 (m, 4H), 2.59-2.56 (m, 4H), 2.40 (s, 3H), 0.97-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-205-4: (2-(6-(4-(phenoxy)-2-ethyl-phenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0485] Intermediate MDI-205-3 (91.0 mg, 0.12 mmol), intermediate MDI-205-2 (48.1 mg, 0.14 mmol), Pd(PPh3)4 (13.6 mg, 00.1 mmol) and potassium phosphate (75.4 mg, 0.36 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, and the resulting mixture was extracted 2 times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-205-4 with a yield of 44.1%.

    [0486] .sup.1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=4.0 Hz 1H), 8.46 (dd, J=4.0 Hz, J=8.0 Hz 1H), 8.11 (dd, J=8.0 Hz, J=4.0 Hz 1H), 7.52-7.31 (m, 6H), 7.27-7.22 (m, 2H), 7.00 (d, J=4.0 Hz, 1H), 6.91 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.00 (s, 2H), 5.77 (d, J=4.0 Hz, 2H), 5.20 (s, 1H), 5.19 (s, 1H), 5.15 (s, 2H), 5.01 (s, 1H), 4.93 (s, 1H), 3.81-3.77 (m, 4H), 3.65-3.61 (m, 4H), 2.62-2.57 (m, 6H), 2.40 (s, 3H), 1.10 (t, J=8.0 Hz, 3H), 0.95-0.91 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-205-5: (2-(6-(2-ethyl-4-hydroxyphenyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0487] Intermediate MDI-205-4 (47.0 mg, 0.05 mmol) was dissolved in 10 ml methanol, to which 5 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. It was allowed to react at room temperature overnight. The palladium on carbon was filtered off and the filtrate was concentrated to afford intermediate MDI-205-5 with a yield of 78.0%, which was directly used in the next step.

    Synthesis of Compound MDI-205: (2-(6-(2-ethyl-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(5-(4-methylpiperazin-1-yl)pyrazin-2-yl)ketone

    [0488] The intermediate MDI-205-5 (33.0 mg, 0.04 mmol) was dissolved in 4 ML methanol, to which 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness (to remove hydrochloric acid), which was repeated 3 times. The resulting product was dissolved 1 ml methanol and 2 ml aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness (to remove aqueous ammonia), which was repeated 2 times. The obtained product was purified by a preparation plate to afford 6.2 mg of the product with a yield of 27.7%.

    [0489] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.72 (d, J=4.0 Hz, 1H), 8.28 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 7.40 (s, 1H), 7.18 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.80 (d, J=4.0 Hz, 1H), 6.72-6.69 (m, 1H), 5.17 (s, 2H), 4.85 (s, 2H), 3.83-3.81 (m, 4H), 2.67-2.64 (m, 4H), 2.60 (dd, J=4.0 Hz, J=8.0 Hz, 2H), 2.43 (s, 3H), 1.10 (t, J=8.0 Hz, 3H).

    Example 7: 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydro pyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-206)

    [0490] ##STR00030##

    [0491] Synthetic Route of MDI-206:

    ##STR00031##

    Synthesis Method

    Synthesis of Intermediate MDI-206-1: (6-bromo-3-(5-(benzenesulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1, 4, 5, 6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0492] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue (to remove trifluoroacetic acid). The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ML DCM and Et.sub.3N (0.08 ml, 0.59 mmol), cooled to 0° C., and benzenesulfonyl chloride (28.6 mg, 0.16 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted twice with DCM, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-206-1 with a yield of 41.4%.

    [0493] .sup.1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 2H), 7.77 (s, 1H), 7.62-7.55 (m, 3H), 7.42 (d, J=8.0 Hz, 1H), 5.85 (s, 2H), 5.70 (s, 2H), 4.66-4.58 (m, 4H), 3.59-3.51 (m, 4H), 0.94-0.87 (m, 4H), 0.03 (s, 18H).

    Synthesis of Intermediate MDI-206-2: (6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methyl)hydroxyphenyl)-3-(5-benzenesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0494] The intermediate MDI-206-1 (53.0 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (35.8 mg, 0.09 mmol), Pd(dppf)Cl.sub.2 (5.5 mg, 0.008 mmol) and potassium phosphate (47.9 mg, 0.23 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford intermediate MDI-206-2 with a yield of 74.3%.

    [0495] .sup.1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=8.0 Hz, 1H), 7.96-7.94 (m, 2H), 7.62-7.57 (m, 3H), 7.46 (s, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.89 (s, 2H), 5.75 (s, 2H), 5.34 (s, 2H), 4.67-4.60 (m, 4H), 3.90-3.86 (m, 2H), 3.62-3.51 (m, 4H), 2.58 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.09-1.05 (m, 3H), 0.93-0.88 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-206: 5-ethyl-2-fluoro-4-(3-(5-(benzenesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0496] Intermediate MDI-206-2 (50.0 mg, 0.06 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The resulting solid was dissolved in 1 ml methanol, and pH was adjusted with sodium bicarbonate solution to 8-9. The resulting mixture was extracted 4 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 13 mg of the final product with a yield of 46.2%.

    [0497] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.22 (d, J=8.0 Hz, 1H), 7.98-7.96 (m, 2H), 7.69-7.65 (m, 3H), 7.41 (s, 1H), 7.16 (d, J=8.0 Hz, 1H), 6.96-6.89 (m, 2H), 4.61-4.52 (m, 4H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 8: 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-207)

    [0498] ##STR00032##

    [0499] Synthetic Route of MDI-207:

    ##STR00033##

    Synthesis Method

    Synthesis of Intermediate MDI-207-1: (6-bromo-3-(5-(pyrazin-2ylmethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

    [0500] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (47.0 mg, 0.07 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate solution was used to adjust pH=9. The resulting mixture was extracted with DCM. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting solid was dissolved in 1,2-dichloroethane, to which 2-pyrazinecarboxaldehyde (30.6 mg, 0.28 mmol) was added. The mixture was stirred at room temperature for 1 hour, to which sodium triacetylborohydride (60.0 mg, 0.28 mmol) was added. It was allowed to react at room temperature for 4 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the product MDI-207-1 with a yield of 49.5%.

    [0501] .sup.1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.54 (d, J=4.0 Hz, 1H), 8.39 (d, J=8.0 Hz, 1H), 7.77 (d, J=4.0 Hz, 1H), 7.41 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.88 (s, 2H), 5.72 (s, 2H), 4.28 (s, 2H), 4.12 (dd, J=4.0 Hz, J=12.0 Hz, 4H), 3.62-3.55 (m, 4H), 0.96-0.87 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-207-2: (6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-3-(5-(pyrazin-2ylmethyl)1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0502] The intermediate MDI-207-1 (20.0 mg, 0.03 mmol), the intermediate (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (14.5 mg, 0.04 mmol), Pd(dppf)Cl.sub.2 (2.3 mg, 0.003 mmol) and potassium phosphate (19.4 mg, 0.09 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice, the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-207-2 with a yield of 93.0%.

    [0503] .sup.1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=4.0 Hz, 1H), 8.60 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 8.54 (d, J=4.0 Hz, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.47 (d, J=4.0 Hz, 1H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.92 (s, 2H), 5.77 (s, 2H), 5.34 (s, 2H), 4.30 (s, 2H), 4.13 (dd, J=4.0 Hz, J=12.0 Hz, 4H), 3.88-3.86 (m, 2H), 3.63-3.58 (m, 4H), 2.57 (d, J=8.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H), 0.92-0.90 (m, 6H), 0.06 (s, 9H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-207: 5-ethyl-2-fluoro-4-(3-(5-(pyrazin-2ylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0504] The intermediate MDI-207-2 (24.0 mg, 0.03 mmol) was dissolved in 4 ML methanol, to which 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting product was dissolved 1 ml methanol and 2 ml aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 2 times. The obtained product was purified by a preparation plate to afford 8 mg of the product with a yield of 61.8%.

    [0505] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.80 (d, J=4.0 Hz, 1H), 8.65 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 8.56 (d, J=4.0 Hz, 1H), 8.26 (dd, J=4.0 Hz, J=4.0 Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.17 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 6.91-6.89 (m, 2H), 4.30 (s, 2H), 4.07 (s, 4H), 2.56 (dd, J=8.0 Hz, J=16.0 Hz, 2H), 1.07 (t, J=8.0 Hz, 3H).

    Example 9: 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-208)

    [0506] ##STR00034##

    [0507] Synthetic Route of MDI-208:

    ##STR00035##

    Synthesis Method

    Synthesis of Intermediate MDI-208-1:(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate Tert-butyl

    [0508] Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (500.0 mg, 0.75 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboran (401.9 mg, 1.13 mmol), Pd(PPh.sub.3).sub.4 (86.9 mg, 0.08 mmol) and potassium phosphate (478.9 mg, 2.26 mmol) were dissolved in 1,4-dioxane (30 ml) and water (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was exacted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford intermediate MDI-208-1 with a yield of 85.1%.

    [0509] .sup.1H NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.37 (m, 6H), 7.26 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.99 (d, J=12.0 Hz, 1H), 5.97 (d, J=8.0 Hz, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.67-4.54 (m, 4H), 3.65-3.59 (m, 4H), 2.55 (d, J=8.0 Hz, 2H), 1.57 (s, 9H), 1.05 (t, J=8.0 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), 0.01 (s, 9H).

    Synthesis of Intermediate MDI-208-2: (6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0510] Tert-butyl 2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate solution was used to adjust pH=9. The resulting mixture was extracted with DCM, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was dissolved in 2 ml DMF, and Et.sub.3N (0.1 ml) and bromomethylcyclopropane (27.0 mg, 0.20 mmol) were added. The mixture was heated to 60° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with EA, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford MDI-208-2 with a yield of 33.5%.

    [0511] .sup.1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.0 Hz, 1H), 7.53-7.37 (m, 6H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.06 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 5.94 (d, J=4.0 Hz, 2H), 5.76 (s, 2H), 5.23 (s, 2H), 4.13 (d, J=36.0 Hz, 4H), 3.67-3.58 (m, 4H), 2.80 (d, J=8.0 Hz, 2H), 2.55 (dd, J=12.0 Hz, J=8.0 Hz, 2H), 2.32-2.22 (m, 1H), 1.06 (t, J=8.0 Hz, 3H), 0.92-0.90 (m, 4H), 0.63 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz, 2H), 0.03 (s, 9H), 0.02 (s, 9H).

    Synthesis of Compound MDI-208: 4-(3-(5-(cyclopropylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0512] Intermediate MDI-208-2 (28.0 mg, 0.04 mmol) was dissolved in 10 ml methanol, to which 5 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. The mixture was heated to 40° C. and reacted overnight, filtered to remove palladium on carbon, and concentrated. The resulting solid was dissolved in 4 ml methanol, to which 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours and concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness, which was repeated 3 times. The resulting product was dissolved 1 ml methanol and 2 ml aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness (to remove aqueous ammonia), which was repeated 2 times. The obtained product was purified by a preparation plate to afford 2 mg of the product with a yield of 13.1%.

    [0513] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (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), 6.97-6.89 (m, 2H), 4.02 (s, 4H), 2.80 (d, J=8.0 Hz, 2H), 2.59-2.53 (m, 2H), 1.10 (m, 4H), 0.66-0.61 (m, 2H), 0.30-0.27 (m, 2H).

    Example 10: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone (MDI-209)

    [0514] ##STR00036##

    [0515] Synthetic Route of MDI-209:

    ##STR00037##

    Synthesis Method

    Synthesis of Intermediate MDI-209-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl) pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(cyclopropyl)ketone

    [0516] The intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was lowered to 0° C., and cyclopropylformyl chloride (18.8 mg, 0.18 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction was warmed up to room temperature and was allowed to react for 1-2 h. Water was added to quench the reaction and liquids were separated. The organic phase was dried over sodium sulfate and concentrated by column chromatography to afford compound MDI-209-1 with a yield of 45%.

    [0517] .sup.1H NMR (400 MHz, CDCl3) δ 8.36 (dd, J=17.8 Hz, J=8.6 Hz, 1H), 7.80-7.79 (m, 1H), 7.41 (d, J=8.6 Hz, 1H), 5.97-5.92 (m, 2H), 5.71 (d, J=2.4 Hz, 2H), 4.96-4.66 (m, 4H), 3.62-3.54 (m, 4H), 1.78-1.67 (m, 1H), 1.10-1.07 (m, 2H), 0.94-0.84 (m, 6H), −0.05 (s, 9H), −0.08 (s, 9H).

    Synthesis of Intermediate MDI-209-2: cyclopropyl(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)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0518] The intermediate MDI-209-1 (50.5 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl) trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl.sub.2 (5.9 mg, 0.008 mmol) and potassium phosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purify by silica gel column to afford intermediate MDI-209-2 with a yield of 76.1%.

    [0519] .sup.1H NMR (400 MHz, CDCl3) δ 8.50-8.43 (m, 1H), 7.46-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H), 5.99-5.94 (m, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.98-4.67 (m, 4H), 3.88-3.84 (m, 2H), 3.64-3.55 (m, 4H), 2.57-2.51 (m, 2H), 1.79-1.68 (m, 1H), 1.07-1.02 (m, 6H), 0.95-0.87 (m, 5H), 0.03 (s, 9H), −0.06-0.08 (m, 18H).

    Synthesis of Compound MDI-209: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0520] The intermediate MDI-209-2 (50 mg, 0.06 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, to which 2 ml concentrated aqueous ammonia was added. The mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a preparation plate to afford 10.0 mg of the final product with a yield of 38.1%.

    [0521] .sup.1H NMR (400 MHz, MeOD-d4) 68.28 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.98 (d, J=12.0 Hz, 1H), 6.92 (d, J=12.0 Hz, 1H), 4.95 (s, 2H), 4.65 (s, 2H), 2.59-2.53 (m, 2H), 1.98-1.89 (m, 1H), 1.08 (t, J=8.0 Hz, 3H), 1.02-1.00 (m, 2H), 0.98-0.92 (m, 2H).

    Example 11: 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-210)

    [0522] ##STR00038##

    [0523] Synthetic Route of MDI-210:

    ##STR00039##

    Synthesis Method

    Synthesis of Intermediate MDI-210-1: (6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-3-(5-(cyclobutylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0524] Tert-butyl 2-(6-(4-(phenoxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80.0 mg, 0.10 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added and saturated sodium bicarbonate solution was used to adjust pH=9. The resulting mixture was extracted with DCM, washed with water and saturated brine, dried over sodium sulfate and concentrated. The obtained solid was dissolved in 3 ml DMF, followed by addition of DIPEA (126.8 mg, 0.98 mmol) and bromomethylcyclobutane (29.3 mg, 0.20 mmol). The mixture was heated to 60° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with EA, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford MDI-210-1 with a yield of 35.1%.

    [0525] .sup.1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.53-7.51 (m, 2H), 7.46-7.37 (m, 4H), 7.23 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.06 (d, J=12.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.76 (s, 2H), 5.22 (s, 2H), 4.02 (s, 2H), 3.94 (s, 2H), 3.65-3.56 (m, 4H), 2.93 (d, J=8.0 Hz, 2H), 2.68-2.64 (m, 1H), 2.57 (dd, J=16.0 Hz, J=8.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.97-1.67 (m, 4H), 1.06 (t, J=8.0 Hz, 3H), 0.94-0.89 (m, 4H), 0.02 (s, 18H).

    Synthesis of Compound MDI-210: 4-(3-(5-(cyclobutylmethyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0526] Intermediate MDI-210-1 (35.0 mg, 0.05 mmol) was dissolved in 10 ml methanol, to which 5 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. The mixture was heated to 40° C. and reacted overnight, filtered to remove palladium on carbon, and concentrated. The resulting solid was dissolved in 4 ml methanol, to which 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting product was dissolved 1 ml methanol and 2 ml concentrated aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 2 times. The obtained product was purified by a preparation plate to afford 4 mg of the product with a yield of 20.7%.

    [0527] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (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), 6.97-6.89 (m, 2H), 3.98 (s, 4H), 3.00 (d, J=8.0 Hz, 2H), 2.72-2.68 (m, 1H), 2.59-2.53 (m, 2H), 2.21-2.18 (m, 2H), 1.89-1.85 (m, 4H), 1.07 (t, J=8.0 Hz, 3H).

    Example 12: cyclobutyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone (MDI-211)

    [0528] ##STR00040##

    [0529] Synthetic Route of MDI-211:

    ##STR00041##

    Synthesis Method

    Synthesis of Intermediate MDI-211-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy) methyl) pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)(cyclobutyl)ketone

    [0530] The intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DCM, to which triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was reduced to 0° C. and cyclobutyl carbonyl chloride (21.3 mg, 0.18 mmol) was slowly added dropwise. After the dropwise addition was completed, the reaction was warmed up to room temperature and was allowed to react for 1-2 h. Water was added to quench the reaction and liquids were separated. The organic phase was dried over sodium sulfate and concentrated by column chromatography to afford compound MDI-211-1 with a yield of 43%.

    [0531] .sup.1H NMR (400 MHz, CDCl3) δ 8.39-8.31 (m, 1H), 7.77-7.76 (m, 1H), 7.42-7.38 (m, 1H), 5.92-5.89 (m, 2H), 5.71-5.70 (m, 2H), 4.73-4.57 (m, 4H), 3.60-3.54 (m, 4H), 3.37-3.27 (m, 1H), 2.46-2.39 (m, 2H), 2.34-2.20 (m, 3H), 2.10-1.93 (m, 3H), 0.93-0.88 (m, 4H), −0.05 (s, 9H), −0.09 (s, 9H).

    Synthesis of Intermediate MDI-211-2: cyclobutyl (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)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0532] The intermediate MDI-211-1 (51.6 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl.sub.2 (5.9 mg, 0.008 mmol) and potassium phosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-211-2 with a yield of 75.2%.

    [0533] .sup.1H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (d, J=12.0 Hz, 1H), 5.96-5.93 (m, 2H), 5.75 (s, 2H), 5.32 (s, 2H), 4.75-4.58 (m, 4H), 3.88-3.83 (m, 2H)), 3.63-3.55 (m, 4H), 3.38-3.28 (m, 1H), 2.57-2.51 (m, 2H), 2.48-2.20 (m, 4H), 2.06-2.00 (m, 1H), 1.96-1.92 (m, 1H), 1.08-1.05 (m, 3H), 0.93-0.85 (m, 6H), 0.03 (s, 9H), −0.06-0.08 (m, 18H).

    Synthesis of Compound MDI-211: cyclobutyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0534] The intermediate MDI-211-2 (45 mg, 0.054 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, 2 ml of concentrated aqueous ammonia was added, and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was separated by a preparation plate to afford 8.2 mg of the final product with a yield of 34.2%.

    [0535] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17 (dd, J=8.4, 1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.68-4.63 (m, 4H), 3.54-3.46 (m, 1H), 2.57-2.53 (m, 2H), 2.43-2.26 (m, 4H), 2.16-2.04 (m, 1H), 1.98-1.89 (m, 1H), 1.08 (t, J=8.0 Hz, 3H).

    Example 13: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone (MDI-213)

    [0536] ##STR00042##

    [0537] Synthetic Route of MDI-213:

    ##STR00043##

    Synthesis Method

    Synthesis of Intermediate MDI-213-1: (3-(benzyloxy)cyclobutyl)(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0538] The intermediate 3-benzyloxy-cyclobutanecarboxylic acid (44.6 mg, 0.22 mmol) and N,N-diisopropylethylamine (69.9 mg, 0.54 mmol) were dissolved in DMF, to which HATU (82.3 mg, 0.22 mmol) was added. The mixture was reacted at room temperature for 10 minutes. Intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (120.0 mg, 0.18 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF, and then slowly added to the previous reaction solution. It was allowed to react at room temperature overnight, and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-213-1 with a yield of 35.3%.

    [0539] .sup.1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80-7.78 (m, 1H), 7.43-7.31 (m, 6H), 5.94 (d, J=12.0 Hz, 2H), 5.73 (d, J=4.0 Hz, 2H), 4.76-4.61 (m, 4H), 4.49 (s, 2H), 4.10-4.04 (m, 1H), 3.63-3.57 (m, 4H)), 2.80-2.78 (m, 1H), 2.58-2.53 (m, 2H), 2.46-2.41 (m, 2H), 0.96-0.90 (m, 4H), 0.02 (s, 9H), −0.03 (s, 9H).

    Synthesis of Intermediate MDI-213-2: (3-(benzyloxy)cyclobutyl)(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)pyrrolo[3,4-d]imidazol-5(1H, 4H,6H)-yl)ketone

    [0540] Intermediate MDI-213-1 (48.0 mg, 0.06 mmol), intermediate MDI-10-2 (30.4 mg, 0.08 mmol), Pd(dppf)Cl2 (4.7 mg, 0.01 mmol) and potassium phosphate (40.6 mg, 0.19 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, and the resulting mixture was extracted 2 times with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-213-2 with a yield of 71.5%.

    [0541] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.49-7.48 (m, 1H), 7.38-7.32 (m, 5H), 7.28-7.24 (m, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.99 (d, J=12.0 Hz, 2H), 5.78 (d, J=4.0 Hz, 2H), 5.34 (s, 2H), 4.78-4.62 (m, 4H), 4.50 (s, 2H), 4.12-4.05 (m, 1H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.80-2.78 (m, 1H), 2.59-2.54 (m, 4H), 2.46-2.44 (m, 2H), 1.10-1.05 (m, 3H), 0.95-0.90 (m, 6H), 0.06 (s, 9H), −0.04 (s, 18H).

    Synthesis of Intermediate MDI-213-3: (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)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxylcyclobutyl)ketone

    [0542] Intermediate MDI-213-2 (43.0 mg, 0.05 mmol) was dissolved in 10 ml methanol, and 5 mg of 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated three times. The mixture was reacted overnight at room temperature, filtered off palladium carbon, and concentrated to afford intermediate MDI-213-3, which was directly used in the next step.

    Synthesis of Compound MDI-213: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)(3-hydroxyl cyclobutyl)ketone

    [0543] The intermediate MDI-213-3 (36.1 mg, 0.05 mmol) was dissolved in 4 ML methanol and 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting product was dissolved 1 ml methanol and 2 ml aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 2 times. The obtained product was purified by a preparation plate to afford 4 mg of the product with a yield of 16.4%.

    [0544] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.28 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42 (m, 1H), 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.97-6.89 (m, 2H), 4.72-4.62 (m, 4H), 4.23-4.20 (m, 1H), 2.95-2.91 (m, 1H), 2.63-2.53 (m, 4H), 2.26-2.18 (m, 2H), 1.10 (t, J=8.0 Hz, 3H).

    Example 14: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone (MDI-214)

    [0545] ##STR00044##

    [0546] Synthetic Route of MDI-214:

    ##STR00045##

    Synthesis Method

    Synthesis of Intermediate MDI-214-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H, 4H,6H)-yl)(pyridazin-4-yl)ketone

    [0547] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (45 mg, 0.06 mmol) was dissolve in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DMF, followed by addition of pyridazine-4-carboxylic acid (9 mg, 0.07 mmol), HATU (32 mg, 0.08 mmol) and DIPEA (0.05 ml, 0.30 mmol). It was allowed to react at room temperature for 16 hours and water was added to quench the reaction. The mixture was extracted twice with EA, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 23 mg of intermediate MDI-214-1 with a yield of 51.2%.

    [0548] .sup.1H NMR (400 MHz, CDCl3) δ 9.45-9.50 (m, 2H), 8.34 (dd, J=38.3 Hz, J=8.6 Hz, 1H), 7.79 (t, J=1.9 Hz, 1H), 7.69-7.66 (m, 1H), 7.45-7.41 (m, 1H), 5.92 (d, J=31.9 Hz, 2H), 5.72 (d, J=5.3 Hz, 2H), 4.95-4.93 (m, 2H), 4.68-4.66 (m, 2H), 3.65-3.54 (m, 4H), 1.08-0.77 (m, 4H), 0.05-0.13 (m, 18H).

    Synthesis of Intermediate MDI-214-2: (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)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

    [0549] The intermediate MDI-214-1 (23 mg, 0.03 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (20 mg, 0.05 mmol), Pd(dppf)Cl.sub.2 (3 mg, 0.003 mmol) and potassium phosphate (22 mg, 0.10 mmol) were dissolved in 1,4-dioxane (5 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 16 h, and cooled to room temperature. Water was added and the resulting mixture was extracted 2 times with ethyl acetate and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 25 mg of intermediate MDI-214-2 with a yield of 84.7%.

    [0550] .sup.1H NMR (400 MHz, CDCl3) δ 9.46-9.42 (m, 2H), 8.62-8.31 (m, 1H), 7.71-7.67 (m, 1H), 7.51-7.47 (m, 1H), 7.25 (dd, J=8.4, 1.3 Hz, 1H), 7.18 (dd, J=8.4, 4.0 Hz, 1H), 7.03 (dd, J=11.6, 6.0 Hz, 1H), 5.96 (d, J=31.6 Hz, 2H), 5.78 (d, J=5.2 Hz, 2H), 5.34 (d, J=2.7 Hz, 2H), 5.02-4.95 (m, 2H), 4.71-4.67 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.62 (m, 4H), 2.57-2.54 (m, 2H), 1.14-0.81 (m, 9H), 0.06 (d, J=2.1 Hz, 9H), −0.04 (dd, J=12.1 Hz, J=8.6 Hz, 18H).

    Synthesis of Compound MDI-214: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-4-yl)ketone

    [0551] Intermediate MDI-214-2 (25 mg, 0.03 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolve in methanol, 1 ml of aqueous ammonia was added, and then the mixture was concentrated, and purified by a preparation plate to afford 4 mg of the final product with a yield of 29.4%.

    [0552] .sup.1H NMR (400 MHz, MeOD-d4) δ 9.48 (dd, J=2.3, J=1.3 Hz, 1H), 9.42 (dd, J=5.2, J=1.3 Hz, 1H), 8.26 (s, 1H), 8.02 (dd, J=5.3, J=2.2 Hz, 1H), 7.43 (d, J=1.1 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.93 (dd, J=19.7, J=10.4 Hz, 2H), 4.90 (s, 2H), 4.73 (s, 2H), 2.55 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 15: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone (MDI-215)

    [0553] ##STR00046##

    [0554] Synthetic Route of MDI-215:

    ##STR00047##

    Synthesis Method

    Synthesis of Intermediate MDI-215-1: (2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

    [0555] Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl) ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 10 ml of DMF, followed by addition of pyridazine-3-carboxylic acid (45 mg, 0.36 mml), HATU (164 mg, 0.43 mmol) and DIPEA (0.18 ml, 1.08 mmol). It was allowed to react at room temperature for 16 hours and water was added to quench the reaction. The resulting mixture was extracted twice with EA, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to afford 98 mg of intermediate MDI-215-1 with a yield of 49.2%.

    [0556] .sup.1H NMR (400 MHz, CDCl3) δ 9.35-9.30 (m, 1H), 8.40 (dd, J=19.4 Hz, J=8.6 Hz, 1H), 8.25 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.79 (dd, J=3.1, J=1.5 Hz, 1H), 7.72-7.68 (m, 1H), 7.46-7.43 (m, 1H), 5.95 (d, J=21.7 Hz, 2H), 5.73 (d, J=3.2 Hz, 2H), 5.40-5.24 (m, 2H), 5.06-4.98 (m, 2H), 3.66-3.56 (m, 4H), 0.98-0.87 (m, 4H), 0.00-0.05 (m, 9H), −0.09 (s, 9H).

    Synthesis of Intermediate MDI-215-2: (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)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

    [0557] The intermediate MDI-215-1 (98 mg, 0.15 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (100 mg, 0.25 mmol), Pd(dppf)Cl.sub.2 (15 mg, 0.015 mmol) and potassium phosphate (110 mg, 0.50 mmol) were dissolved in 1,4-dioxane (25 ml) and water (5 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 16 h, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford 97 mg of intermediate MDI-215-2 with a yield of 77.1%.

    [0558] .sup.1H NMR (400 MHz, CDCl3) δ 9.33-9.32 (d, J=4.0 Hz, 1H), 8.52-8.48 (m, 1H), 8.26-8.21 (m, 1H), 7.71-7.69 (m, 1H), 7.48 (dd, J=2.8 Hz, J=1.2 Hz, 1H), 7.26 (dd, J=8.4 Hz, J=1.3 Hz, 1H), 7.18 (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 (dd, J=11.6 Hz, J=4.2 Hz, 1H), 5.99 (d, J=22.2 Hz, 2H), 5.78 (d, J=3.0 Hz, 2H), 5.40 (d, J=2.4 Hz, 1H), 5.34 (s, 2H), 5.25 (t, J=2.1 Hz, 1H), 5.08-4.99 (m, 2H), 3.90-3.88 (m, 2H), 3.67-3.58 (m, 4H), 2.56 (q, J=7.5 Hz, 2H), 1.10-0.77 (m, 9H), 0.06 (d, J=1.2 Hz, 9H), −0.01-0.10 (m, 18H).

    Synthesis of Compound MDI-215: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-pyrrolo[3,4-d]imidazol-5-(1H,4H,6H)-yl)(pyridazin-3-yl)ketone

    [0559] Intermediate MDI-215-2 (97 mg, 0.11 mmol) was dissolved in methanol (10 ml), to which concentrated hydrochloric acid (5 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolve in methanol, 1 ml of aqueous ammonia was added, and the mixture was concentrated, and purified by a preparation plate to afford 10 mg of the final product with a yield of 18.9%.

    [0560] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 12.83 (d, J=33.0 Hz, 1H), 9.85 (s, 1H), 9.39 (dd, J=5.0 Hz, J=1.7 Hz, 1H), 8.37-8.31 (m, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.5 Hz, J=5.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.1 Hz, 1H), 7.03 (d, J=11.9 Hz, 1H), 6.92 (d, J=9.1 Hz, 1H), 4.84-4.45 (m, 4H), 2.49 (q, J=7.5 Hz, 2H), 1.02 (t, J=7.5 Hz, 3H).

    Example 16: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-216)

    [0561] ##STR00048##

    [0562] Synthetic Route of MDI-216:

    ##STR00049##

    Synthesis Method

    Synthesis of Intermediate MDI-216-1: 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy) methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

    [0563] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (500 mg, 0.75 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (401 mg, 1.13 mmol), Pd(dppf)Cl2 (75 mg, 0.075 mmol) and potassium phosphate (495 mg, 2.25 mmol) were dissolved in 1,4-dioxane (30 ml) and water (6 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 16 hours and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column. The purified product was dissolved in 25 ml of dichloromethane, and 5 ml of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified with silica gel column to afford 210 mg of intermediate MDI-216-1 with a yield of 39.2%.

    [0564] .sup.1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8.3 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 7.49-7.37 (m, 5H), 7.25 (d, J=8.4 Hz, 1H), 7.23-6.96 (m, 2H), 5.93 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.21 (d, J=35.1 Hz, 4H), 3.66-3.52 (m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Intermediate MDI-216-2: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-(benzyloxy)pyrrolidin-1-yl)ketone

    [0565] Triphosgene (25.8 mg, 0.09 mmol) was dissolved in 5 ml of tetrahydrofuran, and intermediate MDI-216-1 (80 mg, 0.09 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 10 minutes and (S)-3-(benzyloxy) pyrrolidine (31.9 mg, 0.18 mmol) in tetrahydrofuran was added. The mixture was stirred at room temperature for 5 minutes, and water was added. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over aqueous sodium sulfate, concentrated, and purified by silica gel column to afford 71 mg of intermediate MDI-216-2 with a yield of 86.1%.

    [0566] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.42 (m, 3H), 7.39-7.29 (m, 6H), 7.24 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 7.07-6.97 (m, 2H), 5.95 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.92-4.88 (m, 2H), 4.76-4.69 (m, 2H), 4.60 (s, 2H), 4.23 (s, 1H), 3.76-3.70 (m, 2H), 3.66-3.58 (m, 6H), 2.54 (q, J=7.5 Hz, 2H), 2.15-2.13 (m, 1H), 2.06-2.02 (m, 1H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.91 (m, 4H), −0.01-0.11 (m, 18H).

    Synthesis of Compound MDI-216: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

    [0567] Intermediate MDI-216-2 (83 mg, 0.11 mmol) was dissolved in methanol (10 ml), to which 10 mg Pd/C and concentrated hydrochloric acid (5 ml) were added. The mixture was heated to 50° C., reacted for 6 hours, filtered and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolve in methanol, 1 ml of aqueous ammonia was added, and then the mixture was concentrated, and purified by a preparation plate to afford 8 mg of the final product with a yield of 15.2%.

    [0568] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.81-4.61 (m, 4H), 4.46-4.44 (m, 1H), 3.79-3.69 (m, 2H), 3.50-3.43 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1.99 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 17: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-217)

    [0569] ##STR00050##

    [0570] Synthetic Route of MDI-217:

    ##STR00051##

    Synthesis Method

    Synthesis of Intermediate MDI-217-1: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

    [0571] Tert-butyl 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg, 0.08 mmol) was dissolved in 5 ml dichloromethane, and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes. Water was added, pH was adjusted with saturated sodium bicarbonate to pH=9, and the resulting mixture was extracted with DCM, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained solid was dissolved in 1,2-dichloroethane, and 4-hydroxycyclohexanone (17.4 mg, 0.15 mmol) was added, which was stirred at room temperature for 1 hour. And then sodium triacetyl borohydride (32.3 mg, 0.15 mmol) was added, and it was allowed to react at room temperature for 3 hours. Water was added to quench the reaction, and the resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the product MDI-217-1 with a yield of 38.2%.

    [0572] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.44 (s, 1H), 7.22 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.02-6.95 (m, 2H), 5.93 (d, J=4.0 Hz, 2H), 5.77 (d, J=4.0 Hz, 2H), 4.27-4.07 (m, 4H), 3.76-3.74 (m, 1H), 3.65-3.56 (m, 4H), 2.76-2.74 (m, 1H), 2.55-2.49 (m, 2H), 2.11-2.03 (m, 3H), 1.88-1.86 (m, 2H), 1.74-1.66 (m, 3H), 1.08 (t, J=4.0 Hz, 3H), 0.94-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

    Synthesis of Compound MDI-217: 5-ethyl-2-fluoro-4-(3-(5-(4-hydroxylcyclohexyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0573] Intermediate MDI-217-1 (21.0 mg, 0.03 mmol) was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. To the resulting residue, 1 ml of methanol was added, 2 ml of concentrated aqueous ammonia was added for neutralization, and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 2 times. The resulting residue was purified by a preparation plate to afford 5.3 mg of the product with a yield of 39.5%.

    [0574] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 7.43-7.42 (m, 1H), 7.19 (dd, J=4.0 Hz, J=8.0 Hz, 1H), 6.96-6.88 (m, 2H), 3.98 (s, 4H), 3.93 (m, 1H), 2.74-2.72 (m, 1H), 2.58 (q, J=8.0 Hz, 2H), 2.04-2.05 (m, 1H), 1.90-1.80 (m, 5H), 1.64-1.62 (m, 2H), 1.10 (t, J=8.0 Hz, J=16.0 Hz, 3H).

    Example 18: 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-218)

    [0575] ##STR00052##

    [0576] Synthetic Route of MDI-218:

    ##STR00053##

    Synthesis Method

    Synthesis of Intermediate MDI-218-1: 6-bromo-3-(5-(cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

    [0577] Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, quenched with sodium bicarbonate, and extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in 5 ml DCM and Et3N (0.08 ml, 0.59 mmol), and cooled to 0° C. Cyclopropylsulfonyl chloride (22.4 mg, 0.16 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-218-1 with a yield of 36.0%.

    [0578] .sup.1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=8.0 Hz, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.73 (s, 2H), 4.75-4.74 (m, 2H), 4.66-4.65 (m, 2H), 3.63-3.58 (m, 4H), 2.50-2.44 (m, 1H), 1.33-1.31 (m, 2H), 1.06-1.02 (m, 2H), 0.96-0.91 (m, 4H), 0.00-0.05 (m, 18H).

    Synthesis of Intermediate MDI-218-2: 3-(5-cyclopropanesulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole

    [0579] The intermediate MDI-218-1 (36.0 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (25.5 mg, 0.06 mmol), Pd(dppf)Cl2 (3.9 mg, 0.005 mmol) and potassium phosphate (34.2 mg, 0.16 mmol) were dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heat to 100° C., reacted overnight, and cooled to room temperature. Water was added, and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate MDI-218-2, the yield was 70.0%.

    [0580] .sup.1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.95 (s, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.76 (s, 2H), 4.68 (s, 2H), 3.88 (t, J=8.0 Hz, 2H), 3.68-3.57 (m, 4H), 2.56 (q, J=7.6 Hz, 2H), 2.24 (t, J=7.7 Hz, 1H), 1.12-0.86 (m, 13H), −0.01-0.06 (m, 27H).

    Synthesis of Compound MDI-218: 4-(3-(5-(cyclopropanesulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0581] Intermediate MDI-218-2 (36.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, and pH was adjusted with sodium bicarbonate to 8-9, and the resulting mixture was extracted 4 times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 16 mg of the final product with a yield of 81.4%.

    [0582] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.65 (s, 4H), 2.76-2.69 (m, 1H), 2.60-2.51 (m, 2H), 1.20-1.18 (m, 2H), 1.10-1.06 (m, 5H).

    Example 19: 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-219)

    [0583] ##STR00054##

    [0584] Synthetic Route of MDI-219:

    ##STR00055##

    [0585] Synthesis Method

    Synthesis of Intermediate MDI-219-1: 6-bromo-3-(5-(cyclobutylsulfonyl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0586] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in 5 ml DCM and Et3N (0.08 ml, 0.59 mmol), and cooled to 0° C.

    [0587] Cyclobutylsulfonyl chloride (24.6 mg, 0.16 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-219-1 with a yield of 32.1%.

    [0588] .sup.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.43 (d, J=8 Hz, 1H), 5.92 (d, J=4.0 Hz, 2H), 5.73 (s, 2H), 4.70 (s, 2H), 4.60 (s, 2H), 4.03-3.95 (m, 1H), 3.65-3.56 (m, 4H), 2.75-2.64 (m, 2H), 2.37-2.30 (m, 2H), 2.11-2.04 (m, 2H), 0.95-0.90 (m, 4H), 0.00-0.05 (m, 18H).

    Synthesis of Intermediate MDI-219-2: 3-(5-(cyclobutylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

    [0589] The intermediate MDI-219-1 (33.0 mg, 0.05 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (22.6 mg, 0.06 mmol), Pd(dppf)Cl.sub.2 (3.5 mg, 0.005 mmol), and potassium phosphate (30.2 mg, 0.14 mmol) were dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-219-2 with a yield of 73.5%.

    [0590] .sup.1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J=8.3 Hz, J=1.3 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 1H), 5.93 (s, 2H), 5.77 (s, 2H), 5.34 (s, 2H), 4.74-4.70 (m, 2H), 4.64-4.60 (m, 2H), 4.00-3.98 (m, 1H), 3.91-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.75-2.66 (m, 2H), 2.58-2.54 (m, 2H), 2.11-2.02 (m, 4H), 1.10-1.04 (m, 3H), 1.01-0.96 (m, 6H), −0.02-0.05 (m, 27H).

    Synthesis of Compound MDI-219: 4-(3-(5-(cyclobutylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0591] Intermediate MDI-219-2 (31.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, and pH was adjusted with sodium bicarbonate to pH=8-9. The resulting mixture was extracted with dichloromethane 4 times, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 12 mg of the final product with a yield of 65.7%.

    [0592] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.60 (s, 4H), 4.26-4.18 (m, 1H), 2.68-2.52 (m, 4H), 2.40-2.31 (m, 2H), 2.13-2.02 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 20: 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-220)

    [0593] ##STR00056##

    [0594] Synthetic Route of MDI-220:

    ##STR00057##

    Synthesis Method

    Synthesis of Intermediate MDI-220-1: 6-bromo-3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrol[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol

    [0595] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (100 mg, 0.15 mmol) was dissolved in 5 ml dichloromethane, and 1 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in 5 ml DCM and Et3N (0.08 ml, 0.59 mmol), and cooled to 0° C.

    [0596] Cyclopentylsulfonyl chloride (26.8 mg, 0.16 mmol) was slowly added and it was allowed to react at room temperature for 2 hours. And then water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-220-1 with a yield of 38.1%.

    [0597] .sup.1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.43 (dd, J=8.0 Hz, J=1.6 Hz, 1H), 5.90 (s, 2H)), 5.73 (s, 2H), 4.78-4.72 (m, 2H), 4.68-4.62 (m, 2H), 4.33 (t, J=8.0 Hz, 1H), 3.63-3.57 (m, 4H), 2.14-2.03 (m, 4H), 1.75-1.56 (m, 4H), 0.96-0.90 (m, 4H), −0.02-0.05 (m, 18H).

    Synthesis of Intermediate MDI-220-2: 3-(5-(cyclopentylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-1H-indazole

    [0598] The intermediate MDI-220-1 (40 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.3 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.5 mg, 0.17 mmol) were dissolved in 1,4-dioxane (6 ml) and water (1 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted with ethyl acetate twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-220-2 with a yield of 62.9%.

    [0599] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 7.26 (dd, J=8.0 Hz, J=1.2 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.04 (d, J=12.0 Hz, 1H), 5.94 (s, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.80-4.75 (m, 2H), 4.70-4.65 (m, 2H), 4.33 (t, J=8.0 Hz, 1H), 3.82-3.80 (m, 2H), 3.73-3.58 (m, 4H), 2.58-2.53 (m, 2H), 2.18-2.05 (m, 4H), 1.79-1.58 (m, 4H), 1.11-1.04 (m, 3H), 0.93-0.90 (m, 6H), −0.02-0.06 (m, 27H).

    Synthesis of Compound MDI-220: 4-(3-(5-(cyclopentylsulfonyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0600] Intermediate MDI-220-2 (32.0 mg, 0.04 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, and pH was adjusted with sodium bicarbonate to 8-9. The resulting mixture was extracted 4 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 10 mg of the final product with a yield of 55.8%.

    [0601] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 7.43 (s, 1H), 7.17 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.65 (s, 4H), 3.91-3.83 (m, 1H), 2.58-2.52 (m, 2H), 2.13-2.03 (m, 4H), 1.89-1.78 (m, 2H), 1.75-1.64 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 21: 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-221)

    [0602] ##STR00058##

    [0603] Synthetic Route of MDI-221:

    ##STR00059## ##STR00060##

    Synthesis Method

    Synthesis of Intermediate 21: Tert-butyl 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0604] The intermediate tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(tri methyl silyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (39.8 mg, 0.06 mmol), intermediate (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (27.1 mg, 0.07 mmol), Pd(dppf)Cl2 (4.2 mg, 0.006 mmol) and potassium phosphate (36.2 mg, 0.17 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford Intermediate 21 with a yield of 78%.

    [0605] .sup.1H NMR (400 MHz, CDCl3) δ8.46 (dd, J=12.0 Hz, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.24-7.21 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 7.01 (d, J=12.0 Hz, 1H), 5.93 (d, J=12.0 Hz, 2H), 5.75 (s, 2H), 5.31 (s, 2H), 4.65-4.50 (m, 4H)), 3.88-3.84 (m, 2H), 3.63-3.55 (m, 4H), 2.57-2.51 (m, 2H), 1.54 (s, 9H), 1.07-1.03 (m, 3H), 0.90-0.85 (m, 4H), 0.03 (s, 9H), —0.07 (s, 18H).

    Synthesis of Intermediate 22: 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0606] The intermediate Tert-butyl 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (40 mg, 0.046 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by silica gel column to afford Intermediate 22 with a yield of 43%.

    [0607] .sup.1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.3 Hz, J=1.4 Hz, 1H), 6.95 (dd, J=20.0 Hz, J=8.0 Hz, 1H), 5.91 (s, 2H), 5.47 (s, 2H), 4.26-4.16 (m, 4H), 3.64-3.55 (m, 4H), 2.53-2.47 (m, 2H), 1.04 (t, J=8.0 Hz, 3H), 0.92-0.86 (m, 4H), −0.07 (s, 9H), −0.08 (s, 9H).

    Synthesis of Intermediate MDI-221-1: 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

    [0608] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl) ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (40 mg, 0.064 mmol) and 1-methyl-1H-pyrazol-4-formaldehyde (8.5 mg, 0.077 mmol) were dissolved in 5 ml 1,2-dichloroethane. It was allowed to react at room temperature for 10 minutes. The reaction was cooled to 0° C. and sodium triacetoxyborohydride (26.9 mg, 0.128 mmol) was added. After the addition was completed, the mixture was warmed to room temperature and reacted for 1-2 h. After the completion of the reaction, water was added to quench the reaction, the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate MDI-221-1, yield 43.4%.

    [0609] .sup.1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=8.0 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J=4.0 Hz, 2H), 7.19-7.16 (m, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H), 5.87 (s, 2H), 5.73 (s, 2H), 4.01-3.98 (m, 4H), 3.95 (s, 2H), 3.91 (s, 3H), 3.62-3.52 (m, 4H), 2.51-2.45 (m, 2H), 1.01 (t, J=6.0 Hz, 3H), 0.91-0.85 (m, 4H), −0.08 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-221: 5-ethyl-2-fluoro-4-(3-(5-((1-methyl-1H-pyrazol-4-yl)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl) phenol

    [0610] Intermediate MDI-221-1 (28 mg, 0.039 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, and 2 ml concentrated aqueous ammonia was added and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a preparation plate to afford 5.0 mg of the final product with a yield of 28%.

    [0611] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.16 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.03-3.96 (m, 6H), 3.92 (s, 3H), 2.58-2.53 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 22: 4-(3-(5-cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol (MDI-224)

    [0612] ##STR00061##

    [0613] Synthetic Route of MDI-224:

    ##STR00062##

    Synthesis Method

    Synthesis of Intermediate MDI-224-1: 4-(3-(5-(cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0614] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-((2-trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (31.2 mg, 0.05 mmol) and cyclopentanone (5.1 mg, 0.06 mmol) were dissolved in 5 ml 1,2-dichloroethane. It was allowed to react at room temperature for 10 minutes. The reaction was cooled to 0° C., and sodium triacetoxyborohydride (21 mg, 0.1 mmol) was added. After the addition was completed, the mixture was warmed to room temperature and reacted for 1-2 h. After the completion of the reaction, water was added to quench the reaction, the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate MDI-221-1 with a yield of 56.8%.

    [0615] .sup.1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.0 Hz, 1H), 7.41 (s, 1H), 7.16 (dd, J=8.3 Hz, J=1.4 Hz, 1H), 6.93 (dd, J=24.0 Hz, J=12.0 Hz, 2H), 5.89 (s, 2H), 5.73 (s, 2H), 4.08 (s, 2H), 3.99 (s, 2H), 3.62-3.55 (m, 4H), 3.22-3.19 (m, 1H), 2.50-2.45 (m, 2H), 1.98-1.89 (m, 2H), 1.84-1.75 (m, 2H), 1.70-1.56 (m, 4H), 1.01 (t, J=8.0 Hz, 3H), 0.91-0.86 (m, 4H), −0.08 (s, 9H), −0.09 (s, 9H).

    Synthesis of Compound MDI-224: 4-(3-(5-(cyclopentyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)-5-ethyl-2-fluorophenol

    [0616] Intermediate MDI-224-1 (25 mg, 0.036 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (5 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in methanol and 2 ml of concentrated aqueous ammonia was added, and the mixture was concentrated to give a residue.

    [0617] The residue was dissolved in methanol, and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a preparation plate to afford 7.0 mg of the final product with a yield of 45.1%.

    [0618] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.05-3.94 (m, 4H), 3.27-3.25 (m, 1H), 2.59-2.54 (m, 2H), 2.08-2.01 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.56 (m, 4H), 1.08 (t, J=8.0 Hz, 3H).

    Example 23: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (MDI-225)

    [0619] ##STR00063##

    [0620] Synthetic Route of MDI-225:

    ##STR00064##

    Synthesis Method

    Synthesis of Intermediate MDI-225-1: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)phenol

    [0621] 5-ethyl-2-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol (60 mg, 0.096 mmol) was dissolved in 5 ml 1,2-dichloroethane, and tetrahydropyrone (14 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and sodium triacetyl borohydride (41 mg, 0.19 mmol) was added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted twice with DCM, and the organic phases were combined, washed with water and saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-225-1 with a yield of 51.4%.

    [0622] .sup.1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.20 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 6.96 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 5.93 (s, 2H), 5.76 (s, 2H), 4.08 (s, 4H), 4.00 (s, 2H), 3.66-3.56 (m, 4H), 3.55-3.47 (m, 2H), 2.95-2.86 (m, 1H), 2.54-2.46 (m, 2H), 1.99-1.90 (m, 2H), 1.80-1.71 (m, 2H), 1.04 (t, J=8.0 Hz, 3H), 0.95-0.87 (m, 4H), −0.03-0.08 (m, 18H).

    Synthesis of Compound MDI-225: 5-ethyl-2-fluoro-4-(3-(5-(tetrahydro-2H-pyran-4-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol-6-yl)phenol

    [0623] Intermediate MDI-225-1 (35.0 mg, 0.05 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, and pH was adjusted with sodium bicarbonate to 8-9. The resulting mixture was extracted 4 times with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by a preparation plate to afford 12 mg of the final product with a yield of 64.1%.

    [0624] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.26 (dd, J=12.0 Hz, J=4.0 Hz, 1H), 7.42 (s, 1H), 7.16 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 6.93 (dd, J=20.0 Hz, J=12.0 Hz, 2H), 4.07-3.99 (m, 6H), 3.52-3.49 (m, 2H), 2.95-2.90 (m, 1H), 2.58-2.53 (m, 2H), 2.00-1.97 (m, 2H), 1.69-1.59 (m, 2H), 1.08 (t, J=8.0 Hz, 3H).

    Example 24: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-226)

    [0625] ##STR00065##

    [0626] Synthetic Route of MDI-226:

    ##STR00066##

    Synthesis Method

    Synthesis of Intermediate MDI-226-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

    [0627] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in 10 ml DCM, and Et3N (0.16 ml, 1.18 mmol) was added. The mixture was cooled to 0° C., and acetyl chloride (25.0 mg, 0.32 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-226-1 with a yield of 54.8%.

    [0628] .sup.1H NMR (400 MHz, chloroform-d) δ 8.36-8.29 (m, 1H), 7.78-7.77 (m, 1H), 7.42-7.39 (m, 1H), 5.93-5.88 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.73 (m, 2H), 4.67-4.63 (m, 2H), 3.61-3.54 (m, 4H), 2.20 (s, 3H), 0.94-0.88 (m, 4H)), −0.03-0.09 (m, 18H).

    Synthesis of Intermediate MDI-226-2: 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

    [0629] The intermediate MDI-226-1 (100 mg, 0.16 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (78.3 mg, 0.20 mmol), Pd(dppf)Cl2 (12.0 mg, 0.016 mmol) and potassium phosphate (104.8 mg, 0.49 mmol) were dissolved in 1,4-dioxane (12 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate MDI-226-2 with a yield of 76.2%.

    [0630] .sup.1H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.49 (s, 1H), 7.27-7.25 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H) 6.00-5.95 (m, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.80-4.77 (m, 2H), 4.71-4.69 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.22 (d, J=8 Hz, 3H), 1.10-1.06 (m, 3H), 1.03-0.91 (m, 6H), −0.02-0.06 (m, 27H).

    Synthesis of Compound MDI-226: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

    [0631] Intermediate MDI-226-2 (100 mg, 0.13 mmol) was dissolved in methanol (5 ml), to which concentrated hydrochloric acid (2.5 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml of methanol, and pH was adjusted to 8-9 with aqueous ammonia. The resulting mixture was concentrated, and purified by silica gel column to afford 5 mg of the final product with a yield of 9.8%.

    [0632] .sup.1H NMR (400 MHz, methanol-d4) δ 8.28 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8 Hz, 1H), 6.94 (dd, J=22, 10 Hz, 2H), 4.79 (s, 2H), 4.65 (s, 2H), 2.59-2.53 (m, 2H), 2.23 (s, 3H), 1.08 (t, J=7.5 Hz, 3H).

    Example 25: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one (MDI-227)

    [0633] ##STR00067##

    [0634] Synthetic Route of MDI-77

    ##STR00068##

    Synthesis Method

    Synthesis of Intermediate MDI-227-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

    [0635] Tert-butyl 2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxylate (200 mg, 0.30 mmol) was dissolved in 10 ml dichloromethane, and 2 ml trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, concentrated, and quenched with sodium bicarbonate. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained compound was dissolved in 10 ml DCM and Et3N (0.16 ml, 1.18 mmol), and cooled to 0° C.

    [0636] Propionyl chloride (29 mg, 0.32 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-227-1 with a yield of 53.5%.

    [0637] .sup.1H NMR (400 MHz, chloroform-d) δ 8.39-8.32 (m, 1H), 7.77-7.76 (m, 1H), 7.42-7.38 (m, 1H), 5.93-5.89 (m, 2H), 5.71 (d, J=4 Hz, 2H), 4.76-4.70 (m, 2H), 4.65-4.63 (m, 2H), 3.61-3.55 (m, 4H), 2.46-2.40 (m, 2H), 1.25-1.23 (m, 3H), 0.93-0.89 (m, 4H), −0.05-0.08 (m, 18H).

    Synthesis of Intermediate MDI-227-2: 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)propan-1-one

    [0638] The intermediate MDI-227-1 (100 mg, 0.16 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (76.5 mg, 0.19 mmol), Pd(dppf)Cl2 (11.8 mg, 0.016 mmol) and potassium phosphate (102.4 mg, 0.48 mmol) were dissolved in 1,4-dioxane (12 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford the intermediate MDI-227-2 with a yield of 76.7%.

    [0639] .sup.1H NMR (400 MHz, chloroform-d) δ 8.52-8.45 (m, 1H), 7.48 (d, J=4 Hz, 1H), 7.28-7.25 (m, 1H), 7.18 (d, J=8 Hz, 1H), 7.04 (d, J=12 Hz, 1H), 5.98 (d, J=12 Hz, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.78 (s, 2H), 4.69-4.68 (m, 2H), 3.90-3.86 (m, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.49-2.40 (m, 2H), 1.31-1.26 (m, 5H)), 1.10-1.05 (m, 3H), 0.96-0.91 (m, 4H), −0.02-0.05 (m, 27H).

    Synthesis of Compound MDI-227: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl) propan-1-one

    [0640] Intermediate MDI-227-2 (100 mg, 0.12 mmol) was dissolved in methanol (5 ml), to which concentrated hydrochloric acid (2.5 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml of methanol and pH was adjusted to 8-9 with aqueous ammonia. The resulting mixture was concentrated, and purified by silica gel column to afford 18 mg of final product with a yield of 34.8%.

    [0641] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 12.80 (s, 1H), 9.85 (s, 1H), 8.33 (d, J=8 Hz, 1H), 7.40 (s, 1H), 7.12 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.92 (d, J=12 Hz, 1H), 4.73-4.58 (m, 2H), 4.50-4.42 (m, 2H), 2.50-2.47 (m, 2H), 2.43-2.37 (m, 2H), 1.08-1.01 (m, 6H).

    Example 26: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one (MDI-228)

    [0642] ##STR00069##

    [0643] Synthetic Route of MDI-228:

    ##STR00070##

    Synthesis Method

    Synthesis of Intermediate MDI-228-1: (1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one)

    [0644] The intermediate tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (80 mg, 0.12 mmol) was dissolved in 5 ml of dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of DCM, and then triethylamine (24.3 mg, 0.24 mmol) was added. The temperature was lowered to 0° C., and isobutyryl chloride (19.2 mg, 0.18 mmol) was slowly added dropwise. After the dropwise addition was completed, the mixture was warmed to room temperature and reacted for 1-2 h. Water was added to the reaction to quench the reaction. The liquids were separated, and the organic phase was dried over sodium sulfate and concentrated by column chromatography to afford compound MDI-228-1 with a yield of 58.7%.

    [0645] .sup.1H NMR (400 MHz, CDCl3) .sup.1H NMR (400 MHz, CDCl3) δ 8.39-8.32 (m, 1H), 7.77-7.76 (m, 1H), 7.42-7.38 (m, 1H), 5.92-5.89 (m, 2H), 5.71-5.69 (m, 2H), 4.83-4.64 (m, 4H), 3.63-3.55 (m, 4H), 2.81-2.70 (m, 1H), 1.22 (d, J=8 Hz, 6H), 0.98-0.86 (m, 4H), —0.05-0.08 (m, 18H).

    Synthesis of Intermediate MDI-228-2: 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one

    [0646] The intermediate MDI-228-1 (50.65 mg, 0.08 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (34.8 mg, 0.1 mmol), Pd(dppf)Cl2 (5.9 mg, 0.008 mmol) and potassium phosphate (50.9 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to afford intermediate MDI-228-2 with a yield of 77.5%.

    [0647] .sup.1H NMR (400 MHz, CDCl3) δ 8.49-8.42 (m, 1H), 7.46-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.16 (d, J=8 Hz, 1H), 7.02 (d, J=12 Hz, 1H), 5.97-5.92 (m, 2H), 5.76 (s, 2H), 5.32 (s, 2H), 4.83-4.67 (m, 4H), 3.88-3.84 (m, 2H), 3.64-3.56 (m, 4H), 2.82-2.73 (m, 1H), 2.57-2.51 (m, 2H), 1.22 (d, J=8 Hz, 6H), 1.08-0.99 (m, 5H), 0.93-0.88 (m, 4H), 0.03 (s, 9H), −0.06-0.07 (m, 18H).

    Synthesis of Compound MDI-228: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-methylpropan-1-one

    [0648] Intermediate MDI-228-2 (50 mg, 0.061 mmol) was dissolved in methanol (4 ml), to which concentrated hydrochloric acid (2 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml methanol, 2 ml concentrated aqueous ammonia was added, and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was purified by a preparation plate to afford 15 mg of the final product with a yield of 57.0%.

    [0649] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.26 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.17 (d, J=8 Hz, 1H), 6.93 (dd, J=20, 12 Hz, 2H), 4.83-4.59 (m, 4H), 2.94-2.90 (m, 1H), 2.58-2.52 (m, 2H), 1.22 (d, J=8.0 Hz, 6H), 1.08 (t, J=8.0 Hz, 3H).

    Example 27: 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one (MDI-229)

    [0650] ##STR00071##

    [0651] Synthetic Route of MDI-229:

    ##STR00072##

    [0652] Synthesis Method

    Synthesis of Intermediate MDI-229-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-2-cyclopropylethan-1-one

    [0653] 2-cyclopropylacetic acid (14.5 mg, 0.14 mmol) and N,N-diisopropylethylamine (46.6 mg, 0.36 mmol) were dissolved in DMF, and HATU (54.9 mg, 0.14 mmol) was added. It was allowed to react at room temperature for 10 minute. Intermediate tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate (80.0 mg, 0.12 mmol) was dissolved in 5 ml dichloromethane, to which 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in DMF, and then was slowly added to the previous reaction solution. It was allowed to react at room temperature overnight, and water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-229-1 with a yield of 57.8%.

    [0654] .sup.1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=8.0 Hz, J=20.0 Hz, 1H), 7.80 (s, 1H), 7.44-7.41 (m, 1H), 5.92 (s, 2H), 5.74 (s, 2H), 4.78-4.66 (m, 4H), 3.63-3.58 (m, 4H), 2.39-2.35 (m, 2H), 2.04 (s, 1H), 0.96-0.91 (m, 4H), 0.66 (d, J=8.0 Hz, 2H), 0.27 (d, J=4.0 Hz, 2H), 0.02 (s, 18H).

    Synthesis of Intermediate MDI-229-2: 2-cyclopropyl-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)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

    [0655] The intermediate MDI-229-1 (45.0 mg, 0.07 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (33.1 mg, 0.08 mmol), Pd(dppf)Cl2 (5.1 mg, 0.007 mmol) and potassium phosphate (44.3 mg, 0.21 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-229-1 with a yield of 55.0%.

    [0656] .sup.1H NMR (400 MHz, CDCl3) δ 8.50 (dd, J=8.0 Hz, J=16.0 Hz, 1H), 7.49 (s, 1H), 7.27 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05 (d, J=12.0 Hz, 1H), 5.96 (s, 2H), 5.78 (s, 2H), 5.34 (s, 2H), 4.79-4.66 (m, 4H), 3.88 (t, J=8.0 Hz, 2H), 3.66-3.58 (m, 4H), 2.59-2.54 (m, 2H), 2.39-2.36 (m, 2H), 2.06-2.04 (m, 1H), 1.05 (t, J=8.0 Hz, 3H), 0.96-0.91 (m, 6H), 0.66-0.63 (m, 2H), 0.28-0.26 (m, 2H), 0.06-0.05 (m, 27H).

    Synthesis of Compound MDI-229: 2-cyclopropyl-1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ethan-1-one

    [0657] The intermediate MDI-229-4 was dissolved in 4 ML methanol and 2 ml concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved 1 ml methanol and 2 ml aqueous ammonia was added for neutralization, and the resulting mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 2 times, thereby obtaining 3.8 mg of the product with a yield of 12.2%.

    [0658] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.29 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.19-7.17 (m, 1H), 6.98-6.90 (m, 2H), 4.73-4.61 (m, 4H), 2.59-2.53 (m, 2H), 2.46 (d, J=8.0 Hz, 2H), 1.17 (m, 1H), 1.08 (t, J=8.0 Hz, 3H), 0.64-0.59 (m, 2H), 0.30-0.26 (m, 2H).

    Example 28: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one (MDI-230)

    [0659] ##STR00073##

    [0660] Synthetic Route of MDI-230:

    ##STR00074##

    Synthesis Method

    Synthesis of Intermediate MDI-230-1: 1-(2-(6-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

    [0661] Tert-butyl 2-(6-bromol-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (100 mg, 0.15 mmol) was dissolve in 5 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added. The mixture was stirred at room temperature for 30 minutes, and concentrated to give a residue. The residue was dissolved in dichloromethane and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml of dichloromethane and triethylamine (0.08 ml, 0.59 mmol) and cooled to 0° C. 3-methylbutyryl chloride (36.6 mg, 0.30 mmol) was slowly added. It was allowed to react at room temperature for 2 hours, and water was added to quench the reaction. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 64 mg of intermediate MDI-230-1, with a yield of 65.8%.

    [0662] .sup.1H NMR (400 MHz, CDCl3) δ 8.42-8.35 (m, 1H), 7.80-7.79 (m, 1H), 7.45-7.41 (m, 1H), 5.96-5.91 (m, 2H), 5.74-5.73 (m, 2H), 4.78-4.69 (m, 4H), 3.67-3.58 (m, 4H), 2.31-2.22 (m, 3H), 1.08-1.05 (m, 6H), 0.97-0.90 (m, 4H), −0.02-0.05 (m, 18H).

    Synthesis of Intermediate MDI-230-2: 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

    [0663] The intermediate MDI-230-1 (98 mg, 0.15 mmol), (2-((5-ethyl-2-fluoro-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (64 mg, 0.10 mmol), Pd(dppf)Cl2 (10 mg, 0.01 mmol) and potassium phosphate (70 mg, 0.30 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heat to 100° C., reacted for 16 h, and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 50 mg of intermediate MDI-230-2 with a yield of 59.7%.

    [0664] .sup.1H NMR (400 MHz, CDCl3) δ8.52-8.45 (m, 1H), 7.49 (s, 1H), 7.25 (d, J=2.8 Hz, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.04 (d, J=11.8 Hz, 1H), 5.98 (d, J=15.6 Hz, 2H), 5.78 (s, 2H), 5.36 (s, 2H), 4.78-4.72 (m, 4H), 3.91-3.86 (m, 2H), 3.66-3.59 (m, 4H), 2.60 [0665] 2.56 (m, 2H), 2.32-2.30 (m, 3H), 1.11-1.01 (m, 6H), 0.99-0.89 (m, 7H), 0.03 (s, 9H), −0.03-0.05 (m, 18H).

    Synthesis of Compound MDI-230: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)-3-methylbutan-1-one

    [0666] The intermediate MDI-230-2 (50 mg, 0.06 mmol) was dissolved in methanol (6 ml), to which concentrated hydrochloric acid (3 ml) was added. It was heated to 50° C. and allowed to react for 6 hours. The reaction mixture was concentrated to give a residue. The residue was dissolved in methanol and concentrated to dryness (to remove hydrochloric acid), which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml ammonia water was added. Then the mixture was concentrated and filtered, the filtrate was concentrated and purified by a preparation plate to afford 15 mg of the final product with a yield of 55.9%.

    [0667] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.29-8.26 (m, 1H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 6.97-6.89 (m, 2H), 4.75-4.70 (m, 4H), 2.56 (q, J=7.5 Hz, 2H), 2.36 (m, 2H), 2.29-2.20 (m, 1H), 1.10-1.05 (m, 9H).

    Example 29: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone (MDI-231)

    [0668] ##STR00075##

    [0669] Synthetic Route of MDI-231:

    ##STR00076##

    Synthesis Method

    Synthesis of intermediate MDI-231-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl) (pyrrolidin-1-yl)ketone

    [0670] Triphosgene (64.4 mg, 0.21 mmol) was dissolved in 15 ml of dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl) ethoxy)methyl)-3-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (150 mg, 0.21 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., followed by addition of triethylamine (63.6 mg, 0.63 mmol). The mixture was stirred at room temperature for 5 minutes and pyrrolidine (29.8 mg, 0.42 mmol) in dichloromethane was added. The resulting mixture was stirred at room temperature for 10 minutes, and water was added. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 140 mg of intermediate MDI-231-1 with a yield of 82.4%.

    [0671] .sup.1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=8 Hz, 1H), 7.53-7.38 (m, 6H), 7.22 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.81 (s, 2H), 4.67 (s, 2H), 3.66-3.59 (m, 4H), 3.53-3.51 (m, 4H), 2.56-2.52 (m, 2H), 1.93-1.88 (m, 4H), 1.03 (t, J=8 Hz, 3H), 0.93-0.87 (m, 4H), −0.05-0.09 (m, 18H).

    Synthesis of Compound MDI-231: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(pyrrolidin-1-yl)ketone

    [0672] Intermediate MDI-231-1 (140 mg, 0.173 mmol) was dissolved in methanol (6 ml), to which 15 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 21 mg of the final product with a yield of 26.3%.

    [0673] .sup.1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 12.69 (s, 1H), 9.83 (s, 1H), 8.31 (d, J=8 Hz, 1H), 7.39 (s, 1H), 7.11 (d, J=8 Hz, 1H), 7.02 (d, J=12 Hz, 1H), 6.91 (d, J=12 Hz, 1H), 4.57-4.56 (m, 2H), 4.49-4.48 (m, 2H), 3.32-3.31 (m, 4H), 2.48-2.44 (m, 2H), 1.85-1.79 (m, 4H), 1.02 (t, J=7 Hz, 3H).

    Example 30: Azetidin-1-yl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone (MDI-232)

    [0674] ##STR00077##

    [0675] Synthetic Route of MDI-232:

    ##STR00078##

    Synthesis Method

    Synthesis of Intermediate MDI-232-1: Azetidin-1-yl(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone

    [0676] Triphosgene (49.1 mg, 0.165 mmol) was dissolved in 15 ml of tetrahydrofuran, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (118 mg, 0.165 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C. and then triethylamine (50.0 mg, 0.495 mmol) was added. The mixture was stirred at room temperature for 5 minutes, and azetidine (18.8 mg, 0.330 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 105 mg of intermediate MDI-232-1, with a yield of 79.8%.

    [0677] .sup.1H NMR (400 MHz, CDCl3) δ 8.52 (d, J=8.3 Hz, 1H), 7.58-7.55 (m, 2H), 7.52-7.40 (m, 4H), 7.30-7.28 (m, 1H), 7.11-7.01 (m, 2H), 5.82 (s, 2H), 5.43 (s, 2H), 5.27 (s, 2H), 4.78-4.61 (m, 4H), 4.22-4.19 (m, 4H), 3.70-3.56 (m, 4H), 2.62 (q, J=7.5 Hz, 2H), 2.41-2.36 (m, 2H), 1.03 (t, J=7.5 Hz, 3H), 0.99-0.94 (m, 4H), 0.07 (d, J=2.7 Hz, 18H).

    Synthesis of Compound MDI-232: Azetidin-1-yl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)ketone

    [0678] Intermediate MDI-232-1 (105 mg, 0.132 mmol) was dissolved in methanol (6 ml), to which 11 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 25 mg of the final product with a yield of 42.6%.

    [0679] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.29 (dd, J=8.4 Hz, J=4.0 Hz, 1H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.62-4.53 (m, 4H), 3.69-3.66 (m, 2H), 3.43-3.40 (m, 2H), 2.54 (q, J=7.5 Hz, 2H), 2.09-2.02 (m, 2H), 1.06 (t, J=7.5 Hz, 3H).

    Example 31: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone (MDI-233)

    [0680] ##STR00079##

    [0681] Synthetic Route of MDI-233:

    ##STR00080##

    Synthesis Method

    Synthesis of Intermediate MDI-233-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone

    [0682] Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml of tetrahydrofuran, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C., followed by addition of triethylamine (55.2 mg, 0.550 mmol). The mixture was stirred at room temperature for 5 minutes, and piperidine hydrochloride (44.4 mg, 0.364 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 105 mg of intermediate MDI-233-1, with a yield of 66.6%.

    [0683] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H), 7.44-7.35 (m, 4H), 7.23-7.20 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H), 5.74 (s, 2H), 5.20 (s, 2H), 4.69 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H), 3.31 (s, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.64 (s, 6H), 1.03 (t, J=7.5 Hz, 3H), 0.93-0.86 (m, 4H), −0.07 (d, J=2.7 Hz, 18H).

    Synthesis of Compound MDI-233: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(piperidin-1-yl)ketone

    [0684] Intermediate MDI-233-1 (100 mg, 0.121 mmol) was dissolved in methanol (6 ml), to which 10 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 33 mg of the final product with a yield of 57.3%.

    [0685] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.65 (m, 4H), 3.35-3.33 (m, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.67-1.65 (m, 6H), 1.06 (t, J=7.5 Hz, 3H).

    Example 32: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone (MDI-234)

    [0686] ##STR00081##

    [0687] Synthetic Route of MDI-234:

    ##STR00082##

    Synthesis Method

    Synthesis of Intermediate MDI-234-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone

    [0688] Triphosgene (54.1 mg, 0.182 mmol) was dissolved in 5 ml of tetrahydrofuran, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.182 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C., followed by addition of triethylamine (55.1 mg, 0.546 mmol). The mixture was stirred at room temperature for 5 minutes, and morpholine (31.7 mg, 0.364 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 120 mg of intermediate MDI-234-1, with a yield of 79.7%.

    [0689] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.26-7.23 (m, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.68 (d, J=54.8 Hz, 4H), 3.80-3.78 (m, 3H), 3.67-3.59 (m, 4H), 3.43-3.40 (m, 3H), 3.27-3.21 (m, 6H), 2.54 (q, J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.96-0.89 (m, 4H), −0.04 (d, J=2.7 Hz, 18H).

    Synthesis of Compound MDI-234: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(morpholino)ketone

    [0690] Intermediate MDI-234-1 (120 mg, 0.145 mmol) was dissolved in methanol (6 ml), to which 12 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 42 mg of the final product with a yield of 60.9%.

    [0691] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.19-7.16 (m, 1H), 6.97-6.90 (m, 2H), 4.71-4.66 (m, 4H), 3.78-3.75 (m, 4H), 3.41-3.39 (m, 4H), 2.54 (q, J=7.5 Hz, 2H), 1.06 (t, J=7.5 Hz, 3H).

    Example 33: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone (MDI-235)

    [0692] ##STR00083##

    [0693] Synthetic Route of MDI-235:

    ##STR00084##

    Synthesis Method

    Synthesis of Intermediate MDI-235-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone

    [0694] Triphosgene (8.3 mg, 0.028 mmol) was dissolved in 5 ml of tetrahydrofuran, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (20 mg, 0.028 mmol) in tetrahydrofuran (5 ml) was added dropwise at 0° C., followed by addition of triethylamine (8.5 mg, 0.084 mmol). The mixture was stirred at room temperature for 5 minutes, and 1-methylpiperazine (5.60 mg, 0.056 mmol) in tetrahydrofuran was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 20 mg of intermediate MDI-235-1, with a yield of 85.1%.

    [0695] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (d, J=8.3 Hz, 1H), 7.50-7.48 (m, 2H), 7.44-7.33 (m, 4H), 7.23-7.21 (m, 1H), 7.04-6.94 (m, 2H), 5.93 (s, 2H), 5.75 (s, 2H), 5.20 (s, 2H), 4.70 (d, J=54.8 Hz, 4H), 3.64-3.56 (m, 4H), 3.43-3.41 (m, 4H), 2.56-2.49 (m, 6H), 2.34 (s, 3H), 1.03 (t, J=7.5 Hz, 3H), 0.93-0.86 (m, 4H), −0.07 (d, J=2.7 Hz, 18H).

    Synthesis of Compound MDI-235: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-methylpiperazin-1-yl)ketone

    [0696] Intermediate MDI-235-1 (20 mg, 0.024 mmol) was dissolved in methanol (6 ml), to which 5 mg Pd/C was added and concentrated hydrochloric acid (3 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 3 mg of the final product with a yield of 14.8%.

    [0697] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.25 (d, J=8.4 Hz, 1H), 7.40 (s, 1H), 7.16-7.14 (m, 1H), 6.95-6.87 (m, 2H), 4.83-4.66 (m, 4H), 3.44-3.41 (m, 4H), 2.56-2.51 (m, 6H), 2.35 (s, 3H), 1.06 (t, J=7.5 Hz, 3H).

    Example 34: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone (MDI-236)

    [0698] ##STR00085##

    [0699] Synthetic Route of MDI-236:

    ##STR00086##

    Synthesis Method

    Synthesis of Intermediate MDI-236-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethyl piperazin-1-yl)ketone

    [0700] Triphosgene (54.07 mg, 0.182 mmol) was dissolved in 15 ml of dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (20 mg, 0.028 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., followed by addition of triethylamine (55.2 mg, 0.55 mmol). The mixture was stirred at room temperature for 5 minutes, and 1-ethylpiperazine (41.5 mg, 0.364 mmol) in dichloromethane was added. The resulting mixture was stirred at room temperature for 10 minutes. Water was added and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 100 mg of intermediate MDI-236-1, with a yield of 64.3%.

    [0701] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.44 (d, J=8 Hz, 1H), 8.28 (s, 1H), 7.50-7.33 (m, 5H), 7.22 (d, J=8 Hz, 1H), 7.03 (d, J=12 Hz, 1H), 6.95 (d, J=8 Hz, 1H), 5.93 (s, 2H), 5.74 (s, 2H), 5.20 (s, 2H), 4.77 (s, 2H), 4.63 (s, 2H), 3.63-3.61 (m, 4H), 3.43-3.42 (m, 4H), 2.53-2.46 (m, 8H), 1.03 (t, J=6 Hz, 3H), 0.93-0.86 (m, 7H), −0.06-0.08 (m, 18H).

    Synthesis of Compound MDI-236: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-ethylpiperazin-1-yl)ketone

    [0702] Intermediate MDI-236-1 (100 mg, 0.117 mmol) was dissolved in methanol (10 ml), to which 10 mg Pd/C was added and concentrated hydrochloric acid (5 ml) was added dropwise. The mixture was heated to 50° C., reacted for 6 hours, filtered, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml of ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 21 mg of the final product with a yield of 35.6%.

    [0703] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8 Hz, 1H), 7.43 (s, 1H), 7.17 (d, J=8 Hz, 1H), 6.96 (d, J=12 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 4.75-4.60 (m, 4H), 3.48-3.44 (m, 4H), 2.61-2.48 (m, 8H), 1.17 (t, J=8 Hz, 3H), 1.08 (t, J=8 Hz, 3H).

    Example 35: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-237)

    [0704] ##STR00087##

    [0705] Synthetic Route of MDI-237:

    ##STR00088## ##STR00089##

    Synthesis Method

    Synthesis of Intermediate MDI-237-1: 6-bromo-1H-pyrazolo[4,3-b]pyridine-3-formaldehyde

    [0706] Sodium nitrite (2.81 g, 40.72 mmol) was dissolved in 12 ml DMF and 16 ml water, and cooled to 0° C. Under nitrogen protection, 2N HCl (17.7 ml, 35.4 mmol) was slowly added dropwise, and after the addition was complete, the reaction continued for 10 minutes.

    [0707] At 0° C., 6-bromo-4-azaindole (1.0 g, 5.08 mmol) in DMF (8 ml) was slowly added to the reaction solution dropwise. After the addition was completed, it was allowed to react at room temperature overnight. After the reaction was completed, 50 ml of water was added to the reaction. The resulting mixture was stirred at room temperature for 0.5 hours, and filtered with suction to afford 580 mg of intermediate MDI-237-1 with a yield of 50.5%.

    [0708] .sup.1H NMR (400 MHz, DMSO) δ 14.52 (s, 1H), 10.27 (s, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H).

    Synthesis of Intermediate MDI-237-2: 6-bromo-1-((2-(trimethylsilyl) ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

    [0709] The intermediate MDI-237-1 (250 mg, 1.11 mmol) was dissolved in 5 ml DMF, and then was cooled to 0° C. NaH (60%) (53.1 mg, 1.33 mmol) was added in batches at 0° C.

    [0710] After the addition was completed, it was allowed to react for 30 minutes, and then SEMCl (276.6 mg, 1.66 mmol) was added dropwise to the reaction. After the dropwise addition was completed, the temperature was raised to room temperature for reaction. After the reaction was completed, it was quenched with water, and the resulting mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by column chromatography to afford 157.4 mg of intermediate MDI-237-2 with a yield of 39.9%.

    [0711] .sup.1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.39 (d, J=2.0 Hz, 1H), 6.14 (s, 2H), 3.69-3.65 (m, 2H), 0.98-0.92 (m, 2H), −0.03 (s, 9H).

    Synthesis of Intermediate MDI-237-3: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-formaldehyde

    [0712] The intermediate MDI-237-2 (176 mg, 0.49 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (196 mg, 0.49 mmol), Pd(dppf)Cl2 (36.1 mg, 0.05 mmol) and potassium carbonate (205 mg, 1.48 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted overnight, and cooled to room temperature. Water was added, the resulting mixture was extracted with ethyl acetate twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 169.5 mg of intermediate MDI-237-3 with a yield of 62.7%.

    [0713] .sup.1H NMR (400 MHz, CDCl3) δ 10.58 (s, 1H), 8.76 (d, J=2.0 Hz, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.02 (d, J=11.3 Hz, 1H), 6.19 (s, 2H), 5.33 (s, 2H), 3.88-3.83 (m, 2H), 3.72-3.69 (m, 2H), 2.59-2.53 (m, 2H), 1.10 (t, J=8.0 Hz, 3H), 1.02-0.94 (m, 4H), 0.03 (s, 9H), −0.03 (s, 9H).

    Synthesis of Intermediate MDI-237-4: tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0714] The intermediate MDI-237-3 (170 mg, 0.31 mmol) and tert-butyl 3,4-diaminopyrroline-1-carboxylate (69.0 mg, 0.34 mmol) were dissolved in 10 ml tert-butanol, to which I.sub.2 (98.8 mg, 0.39 mmol) and K.sub.2CO.sub.3 (129 mg, 0.93 mmol) were added. The mixture was heated to 70° C. and reacted for 3 hours. After the reaction was completed, aqueous sodium thiosulfate was added to quench the reaction. The resulting mixture was extract twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried with anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 150 mg of intermediate MDI-237-4 with a yield of 66.2%.

    [0715] .sup.1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=1.9 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.01 (d, J=11.3 Hz, 1H), 6.60-6.20 (m, 2H), 5.33 (s, 2H), 5.00-4.87 (m, 1H), 4.58-4.46 (m, 1H), 3.88-3.83 (m, 2H), 3.79-3.64 (m, 6H), 2.58-2.52 (m, 2H), 1.57 (s, 9H), 1.09 (t, J=8.0 Hz, 3H), 1.02-0.96 (m, 4H), 0.03 (s, 9H), −0.03 (s, 9H).

    Synthesis of Intermediate MDI-237-5: Tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0716] Intermediate MDI-237-4 (100 mg, 0.14 mmol) and 2-iodoyl benzoic acid (77.0 mg, 0.28 mmol) were dissolved in 10 ml DMSO, heated to 45° C. and reacted for 5 hours. After the reaction was completed, the reaction was quenched by aqueous sodium thiosulfate. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 75.0 mg of intermediate MDI-237-5, with a yield 75.2%.

    [0717] .sup.1H NMR (400 MHz, CDCl3) δ 11.78 (d, J=8.8 Hz, 1H), 8.52-8.50 (m, 1H), 7.99-7.98 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.03 (d, J=11.3 Hz, 1H), 6.44 (s, 2H), 5.33 (s, 2H), 4.66-4.51 (m, 4H), 3.88-3.79 (m, 4H), 2.60-2.54 (m, 2H), 1.54 (s, 9H), 1.11 (t, J=8.0 Hz, 3H), 1.03-0.98 (m, 4H), 0.03 (s, 9H), −0.05 (s, 9H).

    Synthesis of Intermediate MDI-237-6: tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0718] The intermediate MDI-237-5 (20.0 mg, 0.03 mmol) was dissolved in 10 ml of THF, the temperature was reduced to 0° C., and then NaH (60%) (1.2 mg, 0.03 mmol) was added. The reaction mixture was stirred for 0.5 hours. SEMCl (5.1 mg, 0.03 mmol) was added to the mixture, which was warmed to room temperature and stirred for 1 hour. After the reaction was completed, water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to afford 15.0 mg of intermediate MDI-237-6 with a yield of 63.5%.

    [0719] .sup.1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=2.0 Hz, 1H), 8.00 (t, J=2.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 7.03 (d, J=11.4 Hz, 1H), 6.13 (d, J=4.5 Hz, 2H), 5.57 (d, J=3.7 Hz, 2H), 5.33 (s, 2H), 4.66-4.50 (m, 4H), 3.88-3.84 (m, 2H), 3.75-3.64 (m, 2H), 3.43-3.38 (m, 2H), 2.60-2.54 (m, 2H), 1.54 (s, 9H), 1.11 (t, J=8.0 Hz, 3H), 1.02-0.98 (m, 2H), 0.93-0.88 (m, 2H), 0.82-0.77 (m, 2H), 0.03 (s, 9H), −0.03 (s, 9H), −0.06 (s, 9H).

    Synthesis of Intermediate MDI-237-7: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-2-((2-(trimethylsilanyl)ethoxy)methyl)-2H-pyrazolo[4,3-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

    [0720] Intermediate MDI-237-6 (30.0 mg, 0.04 mmol) was dissolved in 10 ml DCM, to which zinc bromide (31.6 mg, 0.14 mmol) was added. The mixture was stirred for 5 hours, and water was added to the reaction to quench the reaction. The resulting mixture was extracted twice with DCM, and the organic phases were combined, washed with aqueous ammonia, then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was dissolved in 10 ml DCM, to which DIPEA (5.4 mg, 0.04 mmol) was added and then the mixture was cooled down 0° C. Then, cyclopropylformyl chloride (4.4 mg, 0.04 mmol) was added dropwise. After the addition was complete, the temperature was raised to room temperature for reaction. After the reaction was completed, water was added to quench the reaction, and the resulting mixture was extracted twice with DCM, and the organic phases were combined, wash with water and saturated brine, dried over anhydrous sodium sulfate, and concentrate to afford 23.0 mg of crude MDI-237-7, which was directly used in the next reaction. The crude yield was 79.6%.

    Synthesis of Compound MDI-237: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d] imidazol-5(1H)-yl)ketone

    [0721] The intermediate MDI-237-7 (23.0 mg, 0.03 mmol) was dissolved in 4 ml MeOH, to which 2 ml concentrated hydrochloric acid was added. After the addition, the temperature was raised to 50° C. for reaction. After 6 hours of reaction, the temperature was lowered to room temperature, and the reaction solvent was evaporated by concentration under reduced pressure. After that, 4 ml methanol and 0.5 ml aqueous ammonia were added. After concentration, the residue was subject to thin layer chromatography to afford 3.2 mg of white solid MDI-237 with a yield of 26.5%.

    [0722] .sup.1H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 12.60-12.48 (m, 1H), 10.02 (s, 1H), 8.53 (d, J=1.6 Hz, 1H), 7.95 (s, 1H), 7.16 (d, J=11.8 Hz, 1H), 6.98 (d, J=9.1 Hz, 1H), 4.91-4.41 (m, 4H), 2.51-2.47 (m, 2H), 1.96-1.84 (m, 1H)), 1.03 (t, J=8.0 Hz, 3H), 0.87-0.80 (m, 4H). LC-MS m/z (ESI) [M+H]+ calculated value for C.sub.23H.sub.22FN.sub.6O.sub.2: 433.2; measured value: 433.2.

    Example 36: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-239)

    [0723] ##STR00090##

    [0724] Synthetic Route of MDI-239:

    ##STR00091##

    Synthesis Method

    Synthesis of Intermediate MDI-239-1: 6-bromo-4-methyl-1H-indazol-3-formaldehyde

    [0725] Sodium nitrite (1.05 g, 15.2 mmol) was dissolved in 5 ml DMF and 5 ml water, and cooled to 0° C. Under nitrogen protection, 3N HCl (4.5 ml, 13.3 mmol) was slowly added dropwise, and the reaction was completed dropwise for 10 minutes. At 0° C., 6-bromo-4-methyl-1H-indole (400 mg, 1.90 mmol) in DMF (20 ml) was slowly added to the reaction solution dropwise. After the dropwise addition was completed, it was allowed to react at room temperature overnight. The mixture was extracted with ethyl acetate 3 times, and the organic phases were combined, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 388 mg of intermediate MDI-239-1 with a yield of 84.3%.

    [0726] .sup.1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1H), 10.24 (s, 1H), 7.58 (d, J=1.3 Hz, 1H), 7.27 (d, J=1.2 Hz, 1H), 2.90 (s, 3H).

    Synthesis of Intermediate MDI-239-2: 6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-formaldehyde

    [0727] Intermediate MDI-239-1 (388 mg, 1.62 mmol) was dissolved in 25 ml of dry tetrahydrofuran, and cooled to 0° C. Sodium hydride (60%) (117 mg, 4.86 mmol) was slowly added, and the mixture was stirred for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (540 mg, 3.24 mmol) was added slowly dropwise, and the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction, and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 371 mg of intermediate MDI-239-2 with a yield of 61.9%.

    [0728] .sup.1H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 5.78 (s, 2H), 3.61-3.57 (m, 2H), 2.89 (s, 3H), 0.96-0.89 (m, 2H), −0.02 (s, 9H).

    Synthesis of Intermediate MDI-239-3: tert-butyl 2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0729] The intermediate MDI-239-2 (371 mg, 1.00 mmol) and tert-butyl 3,4-diaminopyrroline-1-carboxylate (242 mg, 1.20 mmol) were dissolved in 10 ml tert-butanol, followed by addition of iodine (317 mg, 1.25 mmol) and potassium carbonate (414 mg, 3.00 mmol), and the reaction was carried out at 70° C. for 3 hours. The reaction was quenched by adding a saturated aqueous solution of sodium thiosulfate and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 330 mg of intermediate MDI-239-3 with a yield of 60.0%.

    [0730] .sup.1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.20 (s, 1H), 5.68 (s, 2H), 4.77-4.66 (m, 2H), 3.77-3.60 (m, 4H), 3.57-3.53 (m, 2H), 2.89 (s, 3H), 1.46 (s, 9H), 0.94-0.89 (m, 2H), −0.02 (s, 9H).

    Synthesis of Intermediate MDI-239-4: tert-butyl 2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0731] MDI-239-3 (330 mg, 0.60 mmol) was dissolved in 15 ml DMSO, and IBX (252 mg, 0.90 mmol) was added. It was allowed to react at 50° C. for 16 hours. The reaction was quenched by adding water, and resulting mixture was extracted twice with ethyl acetate.

    [0732] The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford 240 mg of intermediate MDI-239-4 with a yield of 73.0%.

    [0733] .sup.1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.19 (s, 1H), 5.67 (s, 2H), 4.62-4.50 (m, 4H), 3.67-3.54 (m, 2H), 2.98 (d, J=7.2 Hz, 3H), 1.55 (s, 9H), 0.98-0.89 (m, 2H), —0.03 (s, 9H).

    Synthesis of Intermediate MDI-239-5: tert-butyl 2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0734] Intermediate MDI-239-4 (145 mg, 0.26 mmol) was dissolved in 15 ml of dry tetrahydrofuran, and cooled to 0° C. Sodium hydride (60%) (19.0 mg, 0.79 mmol) was slowly added, and the mixture was stirred for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (86.7 mg, 0.52 mmol) was added slowly dropwise. After the addition, the reaction was carried out at room temperature for 1 hour. The reaction was quenched by adding water, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 148 mg of intermediate MDI-239-5 with a yield of 84.0%.

    [0735] .sup.1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.17 (s, 1H), 5.73 (s, 2H), 5.44 (d, J=4.7 Hz, 2H), 4.65-4.51 (m, 4H), 3.61-3.57 (m, 2H), 3.38-3.34 (m, 2H), 2.54 (d, J=5.8 Hz, 3H), 1.56 (s, 9H), 0.97-0.88 (m, 4H), −0.02 (s, 9H), −0.11 (s, 9H).

    Synthesis of Intermediate MDI-239-6: (2-(6-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4, 6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

    [0736] Intermediate MDI-239-5 (148 mg, 0.22 mmol) was dissolved in 15 ml of dichloromethane, and zinc bromide (197 mg, 0.87 mmol) was added. The mixture was stirred at 25° C. for 4 hours, and 10 ml of aqueous ammonia was added to the reaction solution. After liquid separation, the organic phase was washed with saturated sodium bicarbonate, and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 10 ml of dichloromethane and triethylamine (66.8 mg, 0.66 mmol), and cooled to 0° C. Cyclopropionyl chloride (46.0 mg, 0.44 mmol) was slowly added, and it was allowed to react at room temperature for 1 hour. The reaction was quenched by adding water. The resulting mixture was extracted with dichloromethane twice, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford intermediate MDI-239-694 mg, with a yield of 65.8%.

    [0737] .sup.1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.20 (s, 1H), 5.75 (s, 2H), 5.48 (d, J=15.8 Hz, 2H), 5.00-4.69 (m, 4H), 3.63-3.59 (m, 2H), 3.46-3.34 (m, 2H), 2.57 (d, J=7.7 Hz, 3H), 2.09-2.05 (m, 1H), 1.09-1.00 (m, 4H), 0.98-0.89 (m, 4H), 0.00-0.05 (m, 18H).

    Synthesis of Intermediate MDI-239-7: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-4-methyl-1-((2-(trimethylsilanyl) ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

    [0738] The intermediate MDI-239-6 (40.0 mg, 0.06 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (36.8 mg, 0.09 mmol), tetrakistriphenylphosphine palladium (6.9 mg, 0.01 mmol) and potassium phosphate (39.4 mg, 0.19 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 16 hours, and cooled to room temperature. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by a silica gel column to afford 27.3 mg of intermediate MDI-239-7 with a yield of 52.6%.

    [0739] .sup.1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.06-6.92 (m, 2H), 5.79 (d, J=7.0 Hz, 2H), 5.53 (d, J=14.4 Hz, 2H), 5.33 (d, J=5.3 Hz, 2H), 5.00-4.69 (m, 4H), 3.90-3.86 (m, 2H), 3.64-3.58 (m, 2H), 3.42-3.37 (m, 2H), 2.64-2.56 (m, 5H), 2.06-2.03 (m, 1H), 1.13-1.07 (m, 4H), 1.05-1.01 (m, 3H), 0.95-0.89 (m, 6H), 0.02 (s, 9H), −0.03-0.12 (m, 18H).

    Synthesis of Compound MDI-239: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

    [0740] Intermediate MDI-239-7 (27.3 mg, 0.03 mmol) was dissolved in methanol (6 ml), to which concentrated hydrochloric acid (3 ml) was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol, and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, and 1 ml aqueous ammonia was added. The mixture was concentrated, and filtered. The resulting filtrate was concentrated, and purified by a preparation plate to afford 5.1 mg of the final product with a yield of 34.7%.

    [0741] .sup.1H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.96 (s, 2H), 4.66 (s, 2H), 2.63 (s, 3H), 2.55 (q, J=7.5 Hz, 2H), 1.98-1.92 (m, 1H), 1.07 (t, J=7.5 Hz, 3H), 1.04-0.92 (m, 4H).

    Example 37: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-240)

    [0742] ##STR00092##

    [0743] Synthetic Route of MDI-240

    ##STR00093##

    Synthesis Method

    Synthesis of Intermediate MDI-240-1: tert-butyl 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0744] Tert-butyl 2-(6-bromo-4-methyl-1-(((2-(trimethylsilanyl)ethoxy)methyl)-1H-indazol-3-yl)-1-(((2-(trimethylsilanyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (60.0 mg, 0.09 mmol), 2-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (47.2 mg, 0.13 mmol), tetrakistriphenylphosphine palladium (10.4 mg, 0.01 mmol) and potassium phosphate (55.9 mg, 0.26 mmol) were dissolved in 1,4-dioxane (10 ml) and water (2 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 16 hours, and cooled to room temperature. Water was added, the resulting mixture was extracted 2 times with ethyl acetate, and the organic phases were combined, washes with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by a silica gel column to afford 63.2 mg of the intermediate MDI-240-1 with a yield of 86.7%.

    [0745] .sup.1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=7.4 Hz, 2H), 7.46-7.34 (m, 4H), 7.03-6.96 (m, 3H), 5.77 (s, 2H), 5.50 (d, J=4.1 Hz, 2H), 5.22 (s, 2H), 4.67-4.53 (m, 4H), 3.64-3.60 (m, 2H), 3.40-3.35 (m, 2H), 2.59-2.51 (m, 5H), 1.56 (s, 9H), 1.06 (t, J=7.5 Hz, 3H), 0.98-0.89 (m, 4H), −0.04 (s, 9H), −0.12 (s, 9H).

    Synthesis of intermediate MDI-240-2: (S)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxyl pyrrolidin-1-yl)ketone

    [0746] Intermediate MDI-240-1 (63.2 mg, 0.08 mmol) was dissolved in 10 ml of dichloromethane, and zinc bromide (68.7 mg, 0.31 mmol) was added. The mixture was stirred at 25° C. for 4 hours, and 6 ml of aqueous ammonia was added to the reaction solution. After liquid separation, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The concentrate was dissolved in 8 ml dichloromethane, at 0° C. triphosgene (22.5 mg, 0.08 mmol) was added, and triethylamine (76.7 mg, 0.76 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 10 minutes, and (S)-pyrrolidine butan-3-ol (13.2 mg, 0.15 mmol) in dichloromethane was added. The mixture was stirred at room temperature for 20 minutes. Water was added, the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column to afford 44.0 mg of intermediate MDI-240-2 with a yield of 68.9%.

    [0747] .sup.1H NMR (400 MHz, CDCl3) δ 7.51 (d, J=7.0 Hz, 2H), 7.45-7.34 (m, 4H), 7.03-6.95 (m, 3H), 5.77 (s, 2H), 5.49 (s, 2H), 5.22 (s, 2H), 4.76-4.53 (m, 4H), 4.46-4.44 (m, 1H), 3.64-3.54 (m, 4H), 3.44-3.33 (m, 4H), 2.57-2.51 (m, 5H), 2.06-1.90 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 1.00-0.88 (m, 4H), −0.04 (s, 9H), −0.13 (s, 9H).

    Synthesis of Compound MDI-240: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-4-methyl-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

    [0748] MDI-240-2 (44.0 mg, 0.05 mmol) was dissolved in 6 ml methanol, to which 5 mg 10% palladium on carbon was added. The atmosphere was replaced with hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the resulting mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol, and 3 ml concentrated hydrochloric acid was added. It was allowed to react for 7 hours at 50° C., and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified by a preparation plate to afford 5.7 mg of the final product with a yield of 22.3%.

    [0749] .sup.1H NMR (400 MHz, MeOD) δ 7.27 (s, 1H), 6.95-6.88 (m, 3H), 4.85-4.82 (m, 2H), 4.62-4.59 (m, 2H), 4.46-4.45 (m, 1H), 3.79-3.69 (m, 2H), 3.64-3.57 (m, 1H), 3.46-3.42 (m, 1H), 2.61 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1.98 (m, 2H), 1.07 (t, J=7.5 Hz, 3H).

    Example 38: cyclopropyl(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-242)

    [0750] ##STR00094##

    [0751] Synthetic Route of MDI-242:

    ##STR00095##

    Synthesis Method

    Synthesis of Intermediate MDI-242-1: 6-bromo-1H-pyrazolo[4,3-c]pyridine-3-formaldehyde

    [0752] Sodium nitrite (1.68 g, 24.4 mmol) was dissolved in 15 ml DMF and 15 ml water, and 3N HCl (7.1 ml, 21.3 mmol) was added at 0° C. The mixture was stirred for 10 minutes, and 6-bromo-1H-pyrrolo[3,2-c]pyridine (600 mg, 3.04 mmol) in DMF (15 ml) was added dropwise at 0° C. It was allowed to react at room temperature for 30 minutes, and to react at 50° C. for 3 hours. The resulting mixture was extracted 3 times with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 350 mg of intermediate MDI-242-1 with a yield of 50.9%.

    [0753] .sup.1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 9.25 (s, 1H), 7.88 (s, 1H).

    Synthesis of Intermediate MDI-242-2: tert-butyl 2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0754] Intermediate MDI-242-1 (350 mg, 1.55 mmol) was dissolved in 15 ml tert-butanol, followed by addition of tert-butyl 3,4-diaminopyrrolidine-1-carboxylate (3734 mg, 1.86 mmol), potassium carbonate (775 mg, 5.57 mmol) and iodine (590 mg, 2.32 mmol). The mixture was stirred at 60° C. for 3 hours, and aqueous saturated sodium thiosulfate was added. The resulting mixture was extracted 3 times with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 240 mg of intermediate MDI-242-2 with a yield of 38.1%.

    [0755] .sup.1H NMR (400 MHz, CDCl3) δ 9.29 (d, J=0.9 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 5.00-4.95 (m, 1H), 4.52-4.49 (m, 1H), 3.77-3.70 (m, 3H), 3.57-3.53 (m, 1H), 1.42 (s, 9H).

    Synthesis of Intermediate MDI-242-3: Tert-butyl 2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0756] Intermediate MDI-242-2 (240 mg, 0.59 mmol) was dissolved in 15 ml DMSO, and IBX (330 mg, 1.18 mmol) was added. The mixture was stirred overnight at 45° C., and extracted 3 times with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 100 mg of intermediate MDI-242-3, with a yield of 41.9%.

    [0757] .sup.1H NMR (400 MHz, CDCl3) δ 9.46 (d, J=6.1 Hz, 1H), 7.78 (s, 1H), 4.65-4.53 (m, 4H), 1.54 (s, 9H).

    Synthesis of Intermediate MDI-242-4: Tert-butyl 2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0758] Intermediate MDI-242-3 (100 mg, 0.25 mmol) was dissolved in 15 ml THE and cooled to 0° C. NaH (60%) (21.7 mg, 0.54 mmol) was added and the mixture was stirred at 0° C. for 20 minutes. After that, SEM-Cl (103 mg, 0.62 mmol) was added. It was allowed to react for 2 hours. The resulting mixture was extracted 3 times with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel column to afford 100 mg of intermediate MDI-242-4 with a yield of 75.7%.

    [0759] .sup.1H NMR (400 MHz, CDCl3) δ 9.53-9.51 (m, 1H), 7.77 (d, J=1.2 Hz, 1H), 5.85 (d, J=7.2 Hz, 2H), 4.65-4.52 (m, 4H), 3.66-3.61 (m, 2H), 1.54 (s, 9H), 0.90-0.86 (m, 2H), −0.02 (s, 9H).

    Synthesis of Intermediate MDI-242-5: (2-(6-bromo-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(cyclopropyl)ketone

    [0760] Intermediate MDI-242-4 (100 mg, 0.19 mmol) was dissolved in 5 ml of dichloromethane, and zinc bromide (168 mg, 0.75 mmol) was added. The mixture was stirred at room temperature for 4 hours and aqueous ammonia was added. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained compound was dissolved in 5 ml of dichloromethane, and triethylamine (56.6 mg, 0.56 mmol) was added. The mixture was cooled to 0° C., and cyclopropylformyl chloride (29.3 mg, 0.28 mmol) was added. It was allowed to react at room temperature for 2 hours. Water was added to quench the reaction, and the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 60.0 mg of intermediate MDI-242-5 with a yield of 63.8%.

    [0761] .sup.1H NMR (400 MHz, CDCl3) δ 9.53 (d, J=7.4 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 5.86 (s, 2H), 4.97-4.67 (m, 4H), 3.68-3.61 (m, 2H), 1.77-1.72 (m, 1H), 1.13-1.09 (m, 2H), 0.99-0.89 (m, 4H), −0.05 (s, 9H).

    Synthesis of Intermediate MDI-242-6: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone

    [0762] Intermediate MDI-242-5 (60 mg, 0.12 mmol) was dissolved in 5 ml dioxane and 1 ml water, followed by addition of (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (56.7 mg, 0.14 mmol), Pd(PPh.sub.3).sub.4 (13.8 mg, 0.01 mmol) and potassium carbonate (49.4 mg, 0.36 mmol). The atmosphere was replaced with nitrogen. The mixture was stirred at 100° C. for 2 hours. Water was added to quench the reaction, and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 40 mg of intermediate MDI-242-6 with a yield of 48.4%.

    [0763] .sup.1H NMR (400 MHz, CDCl3) δ 9.79 (d, J=8.7 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.26-7.18 (m, 2H), 5.95-5.90 (m, 2H), 5.33 (s, 2H), 5.00-4.70 (m, 4H), 3.86-3.82 (m, 2H), 3.69-3.62 (m, 2H), 2.74-2.68 (m, 2H), 1.79-1.70 (m, 1H), 1.14-1.08 (m, 5H), 1.02-0.96 (m, 4H), 0.92-0.88 (m, 2H), 0.03 (s, 9H), −0.02-0.04 (m, 9H).

    Synthesis of Compound MDI-242: cyclopropyl (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[4,3-c]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)ketone (MDI-242)

    [0764] Intermediate MDI-242-6 (40 mg, 0.06 mmol) was dissolved in 4 ml of methanol, and 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated. The solid was dissolved in 1 ml of methanol, and pH was adjusted with aqueous ammonia to 8-9. The resulting mixture was concentrated and purified by a preparation plate to afford 8.0 mg of the final product with a yield of 32.0%.

    [0765] .sup.1H NMR (400 MHz, MeOD) δ 9.61 (d, J=1.0 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 5.07-4.88 (m, 2H), 4.68-4.62 (m, 2H), 2.69-2.64 (m, 2H), 1.98-1.89 (m, 1H), 1.09-1.05 (m, 3H)), 1.01-0.98 (m, 2H), 0.96-0.94 (m, 2H).

    Example 39: (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-243)

    [0766] ##STR00096##

    [0767] Synthetic Route of MDI-243:

    ##STR00097##

    Synthesis Method

    Synthesis of Intermediate MDI-243-1: (R)-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

    [0768] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane, and at 0° C., the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml), was added dropwise. After the addition, anhydrous triethylamine (55.2 mg, 0.55 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. (R)-Pyrrolidin-3-ol (31.8 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 118 mg of intermediate MDI-243-1, with a yield of 78.4%.

    [0769] .sup.1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.75-7.73 (m, 2H), 7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.95-4.56 (m, 4H), 4.50-4.45 (m, 1H), 3.79-3.72 (m, 2H), 3.66-3.58 (m, 5H), 3.46-3.42 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.06-2.01 (m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Compound MDI-243: (R)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

    [0770] MDI-243-1 (118 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 12 ml methanol and 6 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml methanol, and 0.8 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 28 mg of the final product with a yield of 41.2%.

    [0771] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.82-4.60 (m, 4H), 4.47-4.45 (m, 1H), 3.79-3.70 (m, 2H), 3.60-3.57 (m, 1H), 3.46-3.43 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.09-1.98 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 40: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidin-1-yl)ketone (MDI-244)

    [0772] ##STR00098##

    [0773] Synthetic Route of MDI-244:

    ##STR00099##

    Synthesis Method

    Synthesis of Intermediate MDI-244-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylazetidin-1-yl)ketone

    [0774] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane, and at 0° C., the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml), was added dropwise. After the addition, anhydrous triethylamine (185 mg, 1.8 mmol) was added dropwise. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Azetidine-3-ol (26.7 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 110 mg of intermediate MDI-244-1, with a yield of 74.3%.

    [0775] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H), 7.48-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.96 (m, 2H), 5.96 (s, 2H), 5.76 (s, 2H), 5.23 (s, 2H), 4.73-4.58 (m, 4H), 4.39-4.31 (m, 2H), 4.22-4.18 (m, 1H), 4.03-4.00 (m, 1H), 3.88-3.85 (m, 1H), 3.65-3.57 (m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Compound MDI-244: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(3-hydroxylazetidin-1-yl)ketone

    [0776] MDI-241-1 (110 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 12 ml methanol and 6 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml methanol, and 0.8 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 34 mg of the final product with a yield of 54.4%.

    [0777] .sup.1H NMR (400 MHz, MeOD-d4) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.62-4.56 (m, 4H), 4.00-3.94 (m, 1H), 3.70-3.66 (m, 1H), 3.62-3.55 (m, 1H), 3.51-3.46 (m, 1H), 3.41-3.37 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 41: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone (MDI-245)

    [0778] ##STR00100##

    [0779] Synthetic Route of MDI-245:

    ##STR00101##

    Synthesis Method

    Synthesis of Intermediate MDI-245-1: (2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone

    [0780] Triphosgene (54.1 mg, 0.18 mmol) was dissolved in 10 ml of dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (130 mg, 0.18 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., followed by addition of anhydrous triethylamine (185 mg, 1.8 mmol). The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Piperidin-4-ol (36.9 mg, 0.36 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 116 mg of intermediate MDI-245-1, with a yield of 75.7%.

    [0781] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H), 5.75 (s, 2H), 5.37 (s, 2H), 4.79-4.66 (m, 4H), 3.95-3.92 (m, 1H), 3.75-3.72 (m, 2H), 3.66-3.52 (m, 4H), 3.12-3.07 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 2.02-1.91 (m, 2H), 1.68-1.63 (m, 2H), 1.06 (t, J=7.5 Hz, 3H), 0.99-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Compound MDI-245: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-yl)(4-hydroxylpiperidin-1-yl)ketone

    [0782] MDI-243-1 (116 mg, 0.14 mmol) was dissolved in 20 ml methanol, and 20 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 12 ml methanol and 6 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 8 ml methanol, and 0.8 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 30 mg of the final product with a yield of 44.4%.

    [0783] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.72-4.65 (m, 4H), 3.88-3.82 (m, 1H), 3.76-3.73 (m, 2H), 3.13-3.06 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.97-1.95 (m, 2H), 1.63-1.55 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 42: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide (MDI-246)

    [0784] ##STR00102##

    [0785] MDI-246 custom-character Synthetic Route:

    ##STR00103##

    Synthesis Method

    Synthesis of Intermediate MDI-246-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

    [0786] Triphosgene (20.8 mg, 0.07 mmol) was dissolved in 5 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (50 mg, 0.07 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (70.9 mg, 0.70 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Methylamine hydrochloride (9.5 mg, 0.14 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 42 mg of intermediate MDI-246-1, with a yield of 77.8%.

    [0787] .sup.1H NMR (400 MHz, CDCl3) δ 8.47 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.37 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H), 2.64 (s, 3H), 2.56 (q, J=7.6 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.04-0.05 (m, 9H).

    Synthesis of Compound MDI-246: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

    [0788] MDI-246-1 (42 mg, 0.055 mmol) was dissolved in 10 ml methanol, and 8 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 10.3 mg of the final product with a yield of 45.1%.

    [0789] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.56 (s, 4H), 2.84 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 43: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide (MDI-247)

    [0790] ##STR00104##

    [0791] Synthetic Route of MDI-247:

    ##STR00105##

    Synthesis Method

    Synthesis of Intermediate MDI-247-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

    [0792] Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (55 mg, 0.08 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (78.0 mg, 0.8 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Ethylamine hydrochloride (12.6 mg, 0.16 mmol) was added. The resulting mixture was stirred at room temperature for 20 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 47 mg of intermediate MDI-247-1, with a yield of 77.7%.

    [0793] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.72-4.54 (m, 4H), 3.65-3.58 (m, 4H), 3.45-3.38 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.18-1.14 (m, 3H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Compound MDI-247: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-ethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

    [0794] MDI-247-1 (47 mg, 0.06 mmol) was dissolved in 10 ml methanol, and 8 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 11 mg of the final product with a yield of 42.4%.

    [0795] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.57 (s, 4H), 3.38-3.28 (m, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.21 (t, J=7.2 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).

    Example 44: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide (MDI-248)

    [0796] ##STR00106##

    [0797] Synthetic Route of MDI-248:

    ##STR00107##

    Synthesis Method

    Synthesis of Intermediate MDI-248-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5-(1H)-carboxamide

    [0798] Triphosgene (22.9 mg, 0.08 mmol) was dissolved in 6 ml of dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (55 mg, 0.08 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (78 mg, 0.8 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Ethanolamine (9.4 mg, 0.16 mmol) in dichloromethane (5 ml) was added. The resulting mixture was stirred at room temperature for 1 hour. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 44 mg of intermediate MDI-248-1, with a yield of 71.3%.

    [0799] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H), 7.48-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.73-4.57 (m, 4H), 3.65-3.53 (m, 6H), 3.33-3.29 (m, 2H), 2.54 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

    Synthesis of Compound MDI-248: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(2-hydroxylethyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0800] MDI-248-1 (44 mg, 0.06 mmol) was dissolved in 10 ml methanol, and 8 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 14 mg of the final product with a yield of 56.6%.

    [0801] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.59 (s, 4H), 3.68 (t, J=5.8 Hz, 2H), 3.40 (t, J=5.8 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H)

    Example 45: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)Azetidin-3-nitrile (MDI-249)

    [0802] ##STR00108##

    [0803] Synthetic Route of MDI-249:

    ##STR00109##

    Synthesis Method

    Synthesis of Intermediate MDI-249-1: 1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)azetidine-3-nitrile

    [0804] Triphosgene (15.8 mg, 0.05 mmol) was dissolved in 5 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (38 mg, 0.05 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (53.9 mg, 0.50 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Azetidine-3-nitrile hydrochloride (8.8 mg, 0.10 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 26 mg of intermediate MDI-249-1, with a yield of 59.4%.

    [0805] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.45 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.48-7.36 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.72-4.56 (m, 4H), 4.42-4.34 (m, 2H), 4.26-4.17 (m, 2H), 3.65-3.58 (m, 4H), 3.46-3.39 (m, 1H), 2.53 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.04-0.05 (m, 9H).

    Synthesis of Compound MDI-249: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)azetidin-3-nitrile

    [0806] MDI-249-1 (26 mg, 0.03 mmol) was dissolved in 10 ml methanol, and 6 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 5.3 mg of the final product with a yield of 33.5%.

    [0807] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 3.86-3.81 (m, 2H), 3.65-3.53 (m, 2H), 3.19-3.13 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 46: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-3-nitrile (MDI-250)

    [0808] ##STR00110##

    [0809] Synthetic Route of MDI-250:

    ##STR00111##

    Synthesis Method

    Synthesis of Intermediate MDI-250-1: 1-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-5-carbonyl)pyrrolidine-3-nitrile

    [0810] Triphosgene (14.9 mg, 0.05 mmol) was dissolved in 6 ml of dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (36 mg, 0.05 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (51.1 mg, 0.50 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Pyrrolidine-3-nitrile hydrochloride (9.7 mg, 0.10 mmol) was added. The resulting mixture was stirred at room temperature for 20 minutes. Water was added to quench the reaction and the resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 26 mg of intermediate MDI-250-1, with a yield of 61.6%.

    [0811] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.3 Hz, 1H), 7.53-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.80-4.67 (m, 4H), 3.79-3.46 (m, 8H), 3.12-3.05 (m, 1H), 2.54 (q, J=7.6 Hz, 2H), 2.38-2.16 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.96-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (d, J=3.4 Hz, 9H).

    Synthesis of Compound MDI-250: 1-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl) pyrrolidin-3-nitrile

    [0812] MDI-250-1 (26 mg, 0.03 mmol) was dissolved in 10 ml methanol, and 6 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 4 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 6 mg of the final product with a yield of 39.8%.

    [0813] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.98-6.90 (m, 2H), 4.70 (s, 4H), 3.89-3.85 (m, 1H), 3.78-3.76 (m, 1H), 3.70-3.59 (m, 2H), 3.23-3.18 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.42-2.19 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 47: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide (MDI-251)

    [0814] ##STR00112##

    [0815] Synthetic Route of MDI-251:

    ##STR00113##

    Synthesis Method

    Synthesis of intermediate MDI-251-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide

    [0816] Triphosgene (19.1 mg, 0.06 mmol) was dissolved in 6 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (46 mg, 0.06 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (65.3 mg, 0.6 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. Tetrahydrofuran-3-amine hydrochloride (16.4 mg, 0.13 mmol) was added. It was allowed to react at 38° C. for 5 hours. Water was added to quench the reaction and the resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 32 mg of intermediate MDI-251-1, with a yield of 60.3%.

    [0817] .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.46 (d, J=8.3 Hz, 1H), 7.73-7.51 (m, 2H), 7.47-7.35 (m, 4H), 7.27-7.24 (m, 1H), 7.07-6.97 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.70-4.53 (m, 4H), 4.51-4.41 (m, 1H), 4.06-3.58 (m, 8H), 2.54 (q, J=7.6 Hz, 2H), 2.40-1.99 (m, 2H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

    Synthesis of Compound MDI-251: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N-(tetrahydrofuran-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0818] MDI-251-1 (32 mg, 0.04 mmol) was dissolved in 10 ml methanol, and 6 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 3 mg of the final product with a yield of 16.3%.

    [0819] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.63 (s, 4H), 4.45-4.40 (m, 1H), 4.03-3.94 (m, 2H), 3.87-3.81 (m, 1H), 3.71-3.68 (m, 1H), 2.56 (q, J=7.5 Hz, 2H), 2.32-1.87 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 48: Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (MDI-252)

    [0820] ##STR00114##

    [0821] Synthetic Route of MDI-252:

    ##STR00115##

    Synthesis Method

    Synthesis of Intermediate MDI-252-1: Methyl 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-((trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0822] Triphosgene (16.6 mg, 0.06 mmol) was dissolved in 5 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (40 mg, 0.06 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (56.8 mg, 0.56 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. The reaction mixture was concentrated and was dissolved in 10 ml of methanol. DMAP (6.9 mg, 0.06 mmol) was added. It was allowed to react at 70° C. for 4 hours. The reaction mixture was concentrated to which water was added. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 30 mg of intermediate MDI-252-1, with a yield of 69.4%.

    [0823] .sup.1H NMR (400 MHz, CDCl3) δ 8.44-8.39 (m, 1H), 7.53-7.51 (m, 2H), 7.48-7.36 (m, 4H), 7.23 (d, J=8.4 Hz, 1H), 7.05-6.96 (m, 2H), 5.95 (s, 2H), 5.78 (s, 2H), 5.23 (s, 2H), 4.75-4.59 (m, 4H), 3.85 (s, 3H), 3.66-3.57 (m, 4H), 2.53 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H), 0.95-0.88 (m, 4H), 0.02 (s, 9H), −0.04-0.05 (m, 9H).

    Synthesis of Compound MDI-252: Methyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0824] MDI-252-1 (30 mg, 0.04 mmol) was dissolved in 10 ml methanol, and 6 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml methanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml methanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 8 mg of the final product with a yield of 48.9%.

    [0825] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.61 (s, 4H), 3.83 (s, 3H), 2.56 (q, J=7.5 Hz, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 49: Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (MDI-253)

    [0826] ##STR00116##

    [0827] Synthetic Route of MDI-253:

    ##STR00117##

    Synthesis Method

    Synthesis of Intermediate MDI-253-1: Ethyl 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

    [0828] Triphosgene (20.1 mg, 0.07 mmol) was dissolved in 5 ml of dry dichloromethane, to which the intermediate 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole (48 mg, 0.07 mmol) in dichloromethane (5 ml) was added dropwise at 0° C., then anhydrous triethylamine (68.1 mg, 0.67 mmol) was added slowly. The mixture was stirred at room temperature for 10 minutes. TLC monitored that the raw materials disappeared. The reaction mixture was concentrated and was dissolved in 10 ml ethanol. DMAP (8.2 mg, 0.07 mmol) was added. It was allowed to react at 80° C. for 4 hours. The reaction mixture was concentrated to which water was added. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 33 mg of intermediate MDI-253-1, with a yield of 62.5%.

    [0829] .sup.1H NMR (400 MHz, CDCl3) δ 8.50-8.45 (m, 1H), 7.53-7.51 (m, 2H), 7.47-7.37 (m, 4H), 7.25 (d, J=8.4 Hz, 1H), 7.07-6.96 (m, 2H), 5.96 (s, 2H), 5.77 (s, 2H), 5.23 (s, 2H), 4.72-4.59 (m, 4H), 4.29-4.25 (m, 2H), 3.65-3.58 (m, 4H), 2.54 (q, J=7.6 Hz, 2H), 1.38-1.34 (m, 3H), 1.05 (t, J=7.5 Hz, 3H), 0.95-0.89 (m, 4H), 0.02 (s, 9H), −0.05 (s, 9H).

    Synthesis of Compound MDI-253: Ethyl 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxylate

    [0830] MDI-253-1 (33 mg, 0.04 mmol) was dissolved in 10 ml ethanol, and 6 mg palladium on carbon was added. The atmosphere was replaced hydrogen. It was allowed to react at 40° C. for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated. The concentrate was dissolved in 6 ml ethanol and 3 ml concentrated hydrochloric acid was added. It was allowed to react at 50° C. for 7 hours and the mixture was concentrated to give a residue. The residue was dissolved in ethanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in 5 ml ethanol, and 0.5 ml aqueous ammonia was added. The resulting mixture was concentrated, and purified to afford 10 mg of the final product with a yield of 54.8%.

    [0831] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.97-6.90 (m, 2H), 4.60 (s, 4H), 4.26 (q, J=7.1 Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H), 1.08 (t, J=7.5 Hz, 3H).

    Example 50: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone (MDI-255)

    [0832] ##STR00118##

    [0833] Synthetic Route of MDI-255:

    ##STR00119## ##STR00120##

    Synthesis Method

    Synthesis of Intermediate MDI-551-1: 6-bromo-1H-pyrazolo[3,4-b]pyridine-3-formaldehyde

    [0834] Sodium nitrite (2.80 g, 40.6 mmol) was dissolved in 15 ml DMF and 20 ml water, and cooled to 0° C. 3N HCl (11.9 ml, 35.6 mmol) was slowly added dropwise, and after the addition, the reaction was carried out for 10 minutes. At 0° C., 6-bromo-1H-pyrrolo[2,3-b]pyridine (1.00 g, 5.08 mmol) in DMF (15 ml) was slowly added to the reaction solution dropwise. After the addition, the mixture was heated to 50° C. It was allowed to react for 5 hours. The resulting mixture was extracted with ethyl acetate 3 times, and the organic phases were combined, washed 3 times with water, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 540 mg of intermediate MDI-255-1 with a yield of 47.0%.

    [0835] .sup.1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H).

    Synthesis of Intermediate MDI-255-2: Tert-butyl 2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-3a,4,6,6a-tetrahydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0836] Intermediate MDI-255-1 (540 mg, 2.39 mmol) and tert-butyl 3,4-diaminopyrroline-1-carboxylate (529 mg, 2.63 mmol) were dissolved in 30 ml tert-butanol and stirred at room temperature for 30 minutes, followed by addition of I.sub.2 (759 mg, 2.99 mmol) and K.sub.2CO.sub.3 (989.1 mg, 7.17 mmol). The mixture was heated to 70° C. for 3 hours, and cooled to room temperature. Saturated sodium thiosulfate was added and the mixture was stirred for 20 minutes until the color of iodine disappeared. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 396 mg of intermediate MDI-255-2 with a yield of 40.7%.

    [0837] .sup.1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 4.99-4.94 (m, 1H), 4.54-4.50 (m, 1H), 3.76-3.68 (m, 3H), 3.60-3.58 (m, 1H), 1.45 (s, 9H).

    Synthesis of Intermediate MDI-255-3: Tert-butyl 2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0838] MDI-255-2 (396 mg, 0.97 mmol) was dissolved in 6 ml DMSO, and IBX (543 mg, 1.94 mmol) was added. It was allowed to react at 50° C. for 6 hours. The reaction was quenched by adding water. The resulting mixture was extracted twice with ethyl acetate and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford 227 mg of intermediate MDI-255-3 with a yield of 57.6%.

    [0839] .sup.1H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 8.64 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.67-4.53 (m, 4H), 1.56 (s, 9H).

    Synthesis of Intermediate MDI-255-4: Tert-butyl 2-(6-bromo-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0840] Intermediate MDI-255-3 (227 mg, 0.56 mmol) was dissolved in 15 ml of dry tetrahydrofuran, and cooled to 0° C., to which sodium hydride (60%) (67.2 mg, 1.68 mmol) was slowly added. The mixture was stirred for 10 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (280.3 mg, 1.68 mmol) was added slowly dropwise, and after the addition, the reaction was carried out at room temperature for 1 hour. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 126 mg of intermediate MDI-255-4 with a yield of 42.0%.

    [0841] .sup.1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.63 (dd, J=8.0 Hz, J=4.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 2H), 4.67-4.52 (m, 4H), 3.69-3.64 (m, 2H), 1.56 (s, 9H), 1.01-0.97 (m, 2H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-255-5: Tert-butyl 2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate

    [0842] Intermediate MDI-255-4 (126 mg, 0.24 mmol), (2-((5-ethyl-2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methoxy)ethyl)trimethylsilane (143 mg, 0.36 mmol), Pd(PPh3)4 (27.2 mg, 0.02 mmol) and potassium carbonate (99.4 mg, 0.72 mmol) were dissolved in 1,4-dioxane (20 ml) and water (4 ml). The atmosphere was replaced with nitrogen, which was repeated 3 times. The mixture was heated to 100° C., reacted for 3 hours, cooled to room temperature. Water was added, and the resulting mixture was extracted twice with ethyl acetate. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified on a silica gel column to afford 83 mg of intermediate MDI-255-5 with a yield of 47.7%.

    [0843] .sup.1H NMR (400 MHz, CDCl3) δ 8.88 (dd, J=8.0 Hz, J=12.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.25-7.21 (m, 2H), 5.95 (d, J=8.0 Hz, 2H), 5.36 (s, 2H), 4.69-4.54 (m, 4H), 3.89-3.84 (m, 2H), 3.72-3.65 (m, 2H), 2.82-2.76 (m, 2H)), 1.59 (s, 9H), 1.18-1.12 (m, 3H), 1.04-0.99 (m, 4H), 0.05 (s, 9H), 0.02 (s, 9H).

    Synthesis of Intermediate MDI-255-6: 6-(2-ethyl-5-fluoro-4-((2-(trimethylsilanyl)ethoxy)methoxy)phenyl)-3-(1-((2-(trimethylsilanyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridine

    [0844] Intermediate MDI-255-5 (83 mg, 0.11 mmol) was dissolved in 15 ml of dichloromethane, and zinc bromide (103 mg, 0.46 mmol) was added. The mixture was stirred at 25° C. for 4 hours, and 10 ml of aqueous ammonia was added to the reaction solution. After liquid separation, the organic phase was washed with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to afford 65 mg of intermediate MDI-255-6, with a yield of 95.6%. The crude product was directly used in the next step.

    Synthesis of Intermediate MDI-255-7: (S)-(2-(6-(2-ethyl-5-fluoro-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxyl pyrrolidin-1-yl)ketone

    [0845] Intermediate MDI-241-6 (20 mg, 0.03 mmol) was dissolved in 5 ml of dry dichloromethane, and cooled to 0° C., to which triphosgene (9.5 mg, 0.03 mmol) was added, and triethylamine (32.3 mg, 0.32 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature for 10 minutes, to which (S)-3-hydroxypyrrolidine hydrochloride (7.7 mg, 0.06 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water was added and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford 19 mg of intermediate MDI-255-7. The crude product was directly used in the next step.

    Synthesis of Compound MDI-255: (S)-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(3-hydroxylpyrrolidin-1-yl)ketone

    [0846] Intermediate MDI-255-1 (19 mg, 0.03 mmol) was dissolved in 4 ml of methanol, to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol to which 1 ml of aqueous ammonia was added to neutralize. The resulting mixture was concentrated and purified by a preparation plate to afford 4.9 mg of the final product 4.9 mg with a total yield of the two steps of 32.0%.

    [0847] .sup.1H NMR (400 MHz, DMSO) δ 13.61 (s, 1H), 10.22 (s, 1H), 8.78 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.34 (d, J=12.0 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 4.93 (d, J=4.0 Hz, 1H), 4.75-4.42 (m, 4H), 4.30-4.27 (m, 1H), 3.58-3.53 (m, 2H), 3.41-3.40 (m, 1H), 3.26-3.23 (m, 1H), 2.73-2.71 (m, 2H), 2.01-1.79 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

    Example 51: 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile (MDI-256)

    [0848] ##STR00121##

    [0849] Synthetic Route of MDI-256:

    ##STR00122##

    Synthesis Method

    Synthesis of Intermediate MDI-256-1: 3-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile

    [0850] 6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy) methyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indole (50 mg, 0.07 mmol) was dissolved in 5 ml of dichloromethane, to which Et3N (21.2 mg, 0.21 mmol) was added. The mixture was cooled to 0° C. and to which 2-cyanoacetyl chloride (8.7 mg, 0.08 mmol) was slowly added. It was allowed to react at room temperature for 1 hour, and water was added to quench the reaction. The resulting mixture was extracted twice with dichloromethane, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column to afford 31 mg of intermediate MDI-256-1 with a yield of 56.7%.

    Synthesis of Compound MDI-256: 3-(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)-3-oxypropionitrile

    [0851] Intermediate MDI-256-1 (31 mg, 0.04 mmol) was dissolved in methanol (6 ml), and 6 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated, to which 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of aqueous ammonia was added to neutralize. The resulting mixture was concentrated and purified by a preparation plate to afford 3 mg of the final product with a yield of 17.4%.

    [0852] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.97 (dd, J=8.0 Hz, J=20.0 Hz, 2H), 4.77-4.70 (m, 4H), 3.62 (s, 2H), 2.59-2.53 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

    Example 52: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide (MDI-257)

    [0853] ##STR00123##

    [0854] Synthetic Route of MDI-257:

    ##STR00124##

    Synthesis Method

    Synthesis of Intermediate MDI-257-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N,N-dimethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0855] The synthesis process was similar to that of the intermediate MDI-246-1 with the exception that dimethylamine hydrochloride was used instead of methylamine hydrochloride.

    Synthesis of Compound MDI-257: 2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-N,N-dimethyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0856] Intermediate MDI-257-1 (41 mg, 0.05 mmol) was dissolved in methanol (6 ml), and 8 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated, to which 4 ml of methanol and 1 ml of concentrated hydrochloric acid were added. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol, and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of ammonia was added to neutralize. The resulting mixture was concentrated and purified by a preparation plate to afford 8 mg of the final product with a yield of 35.2%.

    [0857] .sup.1H NMR (400 MHz, DMSO) δ 13.28 (s, 1H), 9.85 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.03 (d, J=12.0 Hz, 1H), 6.93 (d, J=12.0 Hz, 1H), 4.54-4.53 (m, 4H), 2.85 (s, 6H), 2.50-2.46 (m, 2H), 1.04 (t, J=8.0 Hz, 3H).

    Example 53: N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazole-5(1H)-carboxamide (MDI-258)

    [0858] ##STR00125##

    [0859] Synthetic Route of MDI-258:

    ##STR00126##

    Synthesis Method

    Synthesis of Intermediate MDI-258-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-(2-cyanoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0860] The synthesis process was similar to that of the intermediate MDI-246-1 with the exception that 3-aminopropionitrile was used instead of methylamine hydrochloride.

    Synthesis of Compound MDI-258: N-(2-cyanoethyl)-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0861] Intermediate MDI-258-1 (36 mg, 0.04 mmol) was dissolved in methanol (4 ml), and 3.6 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated. The concentrated product was dissolved in 4 ml of methanol to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 60° C., reacted for 6 hours, and concentrated. The solid was dissolved in methanol, which was adjusted with aqueous ammonia to pH=8-9. The resulting mixture was concentrated and purified by a preparation plate to afford 7.0 mg of the final product with a yield of 34.2%.

    [0862] .sup.1H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.16 (d, J=8.4 Hz, 1H), 6.91 (dd, J=20.8, 10.3 Hz, 2H), 4.61-4.54 (m, 4H), 3.55-3.50 (m, 2H), 2.66-2.51 (m, 4H), 1.06 (t, J=7.5 Hz, 3H).

    Example 54: N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide (MDI-259)

    [0863] ##STR00127##

    [0864] Synthetic Route of MDI-259:

    ##STR00128##

    Synthesis Method

    Synthesis of Intermediate MDI-259-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-cyclopropyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0865] The synthesis process was similar to that of the intermediate MDI-246-1 with the exception that cyclopropylamine was used instead of methylamine hydrochloride.

    Synthesis of Compound MDI-259: N-cyclopropyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0866] Intermediate MDI-259-1 (36 mg, 0.04 mmol) was dissolved in methanol (4 ml), and 3.6 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated. The concentrated product was dissolved in 4 ml of methanol to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 60° C., reacted for 6 hours, and concentrated. The solid was dissolved in methanol, which was adjusted with aqueous ammonia to pH=8-9. The resulting mixture was concentrated and purified by a preparation plate to afford 8.0 mg of the final product with a yield of 39.6%.

    [0867] .sup.1H NMR (400 MHz, MeOD) δ 8.25 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.16 (dd, J=8.4, 1.4 Hz, 1H), 6.91 (dd, J=20.6, 10.4 Hz, 2H), 4.66-4.48 (m, 4H), 2.68-2.62 (m, 1H), 2.59-2.53 (m, 2H), 1.08 (t, J=7.5 Hz, 3H), 0.76-0.71 (m, 2H), 0.60-0.56 (m, 2H).

    Example 55: N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide (MDI-260)

    [0868] ##STR00129##

    [0869] Synthetic Route of MDI-260:

    ##STR00130##

    Synthesis Method

    Synthesis of Intermediate MDI-260-1: 2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-N-cyclobutyl-1-(((2-(trimethylsilyl)ethoxy)methyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0870] The synthesis process was similar to that of the intermediate MDI-246-1 with the exception that cyclobutylamine was used instead of methylamine hydrochloride.

    Synthesis of Compound MDI-260: N-cyclobutyl-2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxamide

    [0871] Intermediate MDI-260-1 (37 mg, 0.04 mmol) was dissolved in methanol (4 ml), and 3.7 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated. The concentrated product was dissolved in 4 ml of methanol to which 2 ml of concentrated hydrochloric acid was added. The mixture was heated to 60° C., reacted for 6 hours, and concentrated. The solid was dissolved in methanol, which was adjusted with aqueous ammonia to pH=8-9. The resulting mixture was concentrated and purified by a preparation plate to afford 4.0 mg of the final product with a yield of 19.0%.

    [0872] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.4 Hz, 1H), 7.43 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.01-6.85 (m, 2H), 4.57 (s, 4H), 4.35-4.31 (m, 1H), 2.59-2.53 (m, 2H), 2.36-2.30 (m, 2H), 2.11-2.04 (m, 2H), 1.76-1.69 (m, 2H), 1.08 (t, J=7.5 Hz, 3H).

    Example 56: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone (MDI-261)

    [0873] ##STR00131##

    [0874] Synthetic Route of MDI-261:

    ##STR00132##

    Synthesis Method

    Synthesis of Intermediate MDI-261-1: Tert-butyl 6-(2-(6-(4-(benzyloxy)-2-ethyl-5-fluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

    [0875] The synthesis process was similar to that of the intermediate MDI-246-1 with the exception that tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate oxalate was used instead of methylamine hydrochloride.

    Synthesis of Compound MDI-261: (2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)ketone

    [0876] Intermediate MDI-261-1 (52 mg, 0.06 mmol) was dissolved in methanol (6 ml), and 10.1 mg 10% Pd/C was added. The atmosphere was replaced with hydrogen, which was repeated 3 times. The mixture was heated to 40° C., reacted for 1 hour, filtered, and concentrated, followed by addition of 4 ml of methanol and 1 ml of concentrated hydrochloric acid. The mixture was heated to 50° C., reacted for 6 hours, and concentrated to give a residue. The residue was dissolved in methanol, and was concentrated to dryness, which was repeated 3 times. The resulting residue was dissolved in methanol, to which 1 ml of ammonia was added to neutralize. The resulting mixture was concentrated and purified by a preparation plate to afford 6 mg of the final product with a yield of 22.2%.

    [0877] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.95 (dd, J=12.0 Hz, J=12.0 Hz, 2H), 4.90 (s, 2H), 4.66 (s, 2H), 4.22 (d, J=12.0 Hz, 2H), 4.02-3.94 (m, 4H), 3.60 (d, J=4.0 Hz, 2H), 2.59-2.54 (m, 2H), 1.09 (t, J=8.0 Hz, 3H).

    Example 57: (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol (MDI-262)

    [0878] ##STR00133##

    [0879] Synthetic Route of MDI-262:

    ##STR00134##

    Synthesis Method

    Synthesis of Intermediate MDI-262-1: Tert-butyl (S)-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)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-5-carbonyl)pyrrolidin-1-carboxylate

    [0880] Tert-butyl 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)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-carboxylate (65.0 mg, 0.08 mmol) was dissolved in 10 ml DCM, to which zinc bromide (68.6 mg, 0.31 mmol) was added. The mixture was stirred for 5 hours, and water was added to quench the reaction. The resulting mixture was extracted with DCM twice, and the organic phases were combined, washed with aqueous ammonia, then washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was dissolved in 10 ml DMF, to which Boc-L-proline (19.7 mg, 0.09 mmol), HATU (34.71 mg, 0.09 mmol), and DIPEA (11.8 mg, 0.09 mmol) were added. After the addition, it was allowed to react at room temperature. Water was added to quench the reaction. The resulting mixture was extracted twice with ethyl acetate, and the organic phases were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated to afford 43.0 mg of intermediate MDI-262-1 with a yield of 59.4%.

    [0881] .sup.1H NMR (400 MHz, CDCl3) δ 8.50-8.41 (m, 1H), 7.47-7.45 (m, 1H), 7.25-7.22 (m, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.01 (d, J=10.3 Hz, 1H), 6.05-5.87 (m, 2H), 5.76-5.75 (m, 2H), 5.31 (s, 2H), 5.02-4.23 (m, 5H), 3.89-3.83 (m, 2H), 3.70-3.42 (m, 6H), 2.57-2.51 (m, 2H), 2.37-1.88 (m, 3H), 1.73-1.70 (m, 1H), 1.47 (s, 9H), 1.07-0.98 (m, 5H), 0.94-0.88 (m, 4H), 0.03 (s, 9H), −0.06-0.08 (m, 18H).

    Synthesis of Compound MDI-262: (S)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazole

    [0882] The intermediate MDI-262-1 (33.0 mg, 0.04 mmol) was dissolved in 4 ml MeOH, to which 2 ml concentrated hydrochloric acid was added. After the addition, the temperature was raised to 50° C. for reaction. After 6 hours of reaction, the temperature was reduced to room temperature, and the reaction solvent was evaporated by concentration under reduced pressure, followed by addition of 4 ml methanol and 0.5 ml aqueous ammonia. After concentration, the residue was subject to thin layer chromatography to afford 1.8 mg of white solid MDI-262 with a yield of 11.3%.

    [0883] .sup.1H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.96 (d, J=11.7 Hz, 1H), 6.91 (d, J=8.9 Hz, 1H), 4.80-4.64 (m, 4H), 4.09-4.05 (m, 1H), 3.26-3.22 (m, 2H), 2.59-2.53 (m, 2H), 2.06-1.86 (m, 4H), 1.08 (t, J=8.0 Hz, 3H). LC-MS m/z (ESI) [M+H].sup.+ calculated value for C.sub.25H.sub.26FN.sub.6O.sub.2: 461.2; measured value: 461.2.

    Example 58: (R)-6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-3-(5-prolyl-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazol-2-yl)-1H-indazol (MDI-263)

    [0884] ##STR00135##

    [0885] The synthesis process was similar to that of MDI-262, with the exception that Boc-D-proline was used instead of Boc-L-proline.

    [0886] .sup.1H NMR (400 MHz, MeOD) δ 8.27 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.96 (d, J=12.2 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 4.82-4.60 (m, 4H), 4.21-4.15 (m, 1H), 3.33-3.23 (m, 1H), 3.08-2.99 (m, 1H), 2.59-2.53 (m, 2H), 2.08-1.86 (m, 4H), 1.08 (t, J=8.0 Hz, 3H).

    Example 59: Evaluation I of Pharmacological Activity

    [0887] 1. Experimental Principle

    [0888] 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 IRS1, IGF1Rtide, and Poly (4:1 Glu, Tyr), consuming ATP to produce ADP, wherein the ADP-Glo reagent and luminescence method can be used to detect the amount of the product to reflect the activity of the kinase.

    [0889] 2. Experimental Scheme

    [0890] 2.1 Experimental Materials and Instruments

    TABLE-US-00001 Item Name Source/Supplier Catalogue No. 1 HEPES Life Technologies 15630-080 2 BRIJ 35 detergent (10%) Merck 203728 3 MgCl2 Sigma M1028 4 EGTA Sigma E3889 5 ADP-Glo Kinase Assay Promega V9101 6 JAK1 Invitrogen PV4774 7 JAK2 Invitrogen PV4210 8 JAK3 Invitrogen PV3855 9 TYK2 Invitrogen PV4790 10 ATP Promega V915B 11 IRS1 Signalchem I40-58-1000 12 IGF1Rtide Signalchem I15-58 13 Poly (4:1 Glu, Tyr) Sigma P0275 14 Topseal A PerkinElmer E5341 15 OptiPlate-384 PerkinElmer 6007290 16 384-Well Polypropylene Labcyte PP-0200 microplate 17 Envision Perkin Elmer 2104 18 Echo Labcyte 550 19 Centrifuge Eppendorf 5810R

    [0891] 2.2 Experimental Methods

    [0892] 2.2.1 Kinase Reaction Reagent Formulation

    [0893] 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

    [0894] 2 mM DTT, ready to use

    [0895] 2.2.1.2 2× Kinase Formulation

    TABLE-US-00003 JAK1 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK1 7072.4 nM  0.8 μL 8 nM 4 nM (884X) 1X Kinase 706.5 μL Reaction Buffer

    TABLE-US-00004 JAK2 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK2 4955 nM 0.2 μL 1 nM 0.5 nM (4955X) 1X Kinase 990.8 μL Reaction Buffer

    TABLE-US-00005 JAK3 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK3 5341.2 nM 0.2 μL 1 nM 0.5 nM (5341.2X) 1X Kinase 1068 μL Reaction Buffer

    TABLE-US-00006 TYK2 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration TYK2 6104.7 nM 1 μL 8 nM 4 nM (763X) 1X Kinase 762 μL Reaction Buffer

    [0896] 2.2.1.3 2×Substrate Mixture Formulation

    TABLE-US-00007 JAK1 substrate mixture solution Stock 2X Final Final Name concentration Volume Concentration Concentration ATP 10 mM (250X) 2.8 μL 40 μM 20 μM IRS1  l mg/mL(10X) 70 μL 0.1 mg/mL 0.05 mg/mL 1X Kinase 627.2 μL Reaction Buffer

    TABLE-US-00008 JAK2 substrate mixture solution 2X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (500X) 1.4 μL 20 μM 10 μM IGF1Rtide 1 mg/mL 14 μL 0.02 mg/mL 0.01 mg/ (50X) mL 1X Kinase 684.6 μL Reaction Buffer

    TABLE-US-00009 JAK3 substrate mixture solution 2X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (500X) 1.4 μL 20 μM 10 μM Poly (4:1 5 mg/mL 8.4 μL 0.06 mg/mL 0.03 mg/ Glu, Tyr) (83.3X) mL Peptide 1X Kinase 690.2 μL Reaction Buffer

    TABLE-US-00010 TYK2 substrate mixture solution 2X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (500X) 1.4 μL 20 μM 10 μM IRS1 1 mg/mL 42 μL 0.06 mg/mL 0.03 mg/ (16.67X) mL 1X Kinase 656.6 μL Reaction Buffer

    [0897] 2.2.1.4 Compounds to be tested

    TABLE-US-00011 Molecular Concentration/ Name Mass/mg weight mM Filgotinib 5.0 420.5 10 MDI-2 3.3 552.24 10 MDI-201 2.0 554.59 10 MDI-202 1.9 471.50 10 MDI-206 2.0 503.55 10 MDI-203 1.8 488.57 10 MDI-204 2.1 567.63 10 MDI-205 1.9 549.64 10 MDI-207 1.5 455.50 10 MDI-209 1.9 431.47 10 MDI-211 1.6 445.50 10 MDI-213 1.5 461.50 10 MDI-217 1.6 461.54 10

    [0898] 2.2.2 Kinase Reaction Experiment Procedure

    [0899] 2.2.2.1 JAK1 & JAK2 Kinase Reaction Experimental Procedure

    [0900] a) Dilute Filgotinib (10 mM stock solution) by 10 times, and dilute a compound solution to be tested by 10 times with 100% DMSO, and then perform a series of dilutions at a ratio of 1:3 in a 384-well dilution plate (Labcyte, PP-0200). Concentrations of Filgotinib: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, 0.02, and 0 μM; and concentrations of the compound to be tested: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.

    [0901] b) Use Echo to transfer 0.1 μL of the compound solution to be tested (prepared in step a) to a 384-well reaction plate (PE, 6007290), and centrifuge it at 1000 rpm/min for 1 min.

    [0902] c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 15 min.

    [0903] d) Transfer 5 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 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentration of DMSO is 1%.

    [0904] e) Transfer 10 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.

    [0905] f) Transfer 20 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.

    [0906] g) Use Envision multi-function plate reader to read the RLU (Relative luminescence unit) signal. The signal intensity is used to characterize the degree of kinase activity.

    [0907] 2.2.2.2 JAK3 Kinase Reaction Experimental Procedure

    a) Dilute Filgotinib (10 mM stock solution) and a compound solution to be tested by 10 times with 100% DMSO, and then perform a series of dilutions at a ratio of 1:3 in a 384-well dilution plate (Labcyte, PP-0200). Filgotinib concentrations are: 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51, 0.17, and 0 μM; and concentrations of the compound to be tested are: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.
    b) Use Echo to transfer 0.1 μL of the compound solution to be tested (prepared in step a) to a 384-well reaction plate (PE, 6007290), and centrifuge it at 1000 rpm/min for 1 min.
    c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 15 min.
    d) Transfer 5 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 100, 33.33, 11.11, 3.70, 1.23, 0.412, 0.137, 0.046, 0.015, 0.005, 0.002, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentration of DMSO is 1%.
    e) Transfer 10 μLADP-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.
    f) Transfer 20 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.
    g) Use Envision multi-function plate reader to read the RLU (Relative luminescence unit) signal. The signal intensity is used to characterize the degree of kinase activity.

    [0908] 2.2.2.3 TYK2 Kinase Reaction Experimental Procedure

    [0909] a) Dilute Filgotinib (10 mM stock solution) by 3.3 times, and a compound solution to be tested by 10 times with 100% DMSO, and then perform a series of dilutions at a ratio of 1:3 in a 384-well dilution plate (Labcyte, PP-0200). The concentrations of Filgotinib are: 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM; and the concentrations of the compound to be tested are: 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, and 0 μM.

    [0910] b) Use Echo to transfer 0.1 μL of the compound solution to be tested (prepared in step a) to a 384-well reaction plate (PE, 6007290), and centrifuge it at 1000 rpm/min for 1 min.

    [0911] c) Transfer 5 μL of kinase (prepared according to 2.2.1.2) to the 384-well reaction plate (prepared in step b), centrifuge it at 1000 rpm/min for 1 min, and incubate it at 25° C. for 15 min.

    [0912] d) Transfer 5 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 30, 10, 3.3333, 1.1111, 0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentrations of the compound to be tested are: 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, 0.0005, and 0 μM. The final concentration of DMSO is 1%.

    [0913] e) Transfer 10 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.

    [0914] f) Transfer 20 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.

    [0915] g) Use Envision multi-function plate reader to read the RLU (Relative luminescence unit) signal. The signal intensity is used to characterize the degree of kinase activity.

    [0916] 2.2.3 Experimental Data Processing Method


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

    [0917] Negative control: DMSO

    [0918] Positive control: 10 μM/100 μM/30 μM Filgotinib

    [0919] 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))

    [0920] X: log value of the compound concentration

    [0921] Y: Compound inhibition rate (% inh)

    [0922] Z′ factor calculation equation:


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

    in which:
    Min is the RLU value of the positive control 10 μM/100 μM/30 μM Filgotinib, and Max is the RLU value of the negative control; and
    SD is the standard error, and AVE is the average value of RLU.

    [0923] 3. Experimental Results

    [0924] 3.1 Quality Control Results of Binding Experiment

    [0925] 3.1.1 Quality Control Result of JAK1 Binding Experiment

    [0926] Z′=0.77CV % (min)=0% CV % (max)=6.2%

    [0927] 3.1.2 Quality Control Result of JAK2 Binding Experiment

    [0928] Z′=0.78CV % (min)=2.9% CV % (max)=5.7%

    [0929] 3.1.3 Quality Control Result of JAK3 Binding Experiment

    [0930] Z′=0.71CV % (min)=7.0% CV % (max)=11.3%

    [0931] 3.1.4 Quality Control Result of TYK2 Binding Experiment

    [0932] Z′=0.77CV % (min)=3.9% CV % (max)=6.8%

    [0933] 3.2 Summary of Test Results as Obtained

    TABLE-US-00012 Item Tested compound Hillslope IC50 (nM) JAK1 Filgotinib 1.067 25.550 Experiment MDI-2 1.356 0.8056 MDI-201 3.487 0.138 MDI-202 5.052 0.125 MDI-206 1.091 0.943 JAK2 Filgotinib 1.142 67.920 Experiment MDI-2 1.271 0.7723 MDI-201 1.633 0.217 MDI-202 2.385 0.279 MDI-206 1.457 0.556 JAK3 Filgotinib 1.318 1343 Experiment MDI-2 1.569 0.7649 MDI-201 1.989 0.187 MDI-202 2.038 0.160 MDI-206 1.216 0.628 TYK2 Filgotinib 1.037 128.0 Experiment MDI-2 1.630 MDI-201 1.411 0.281 MDI-202 1.416 0.318 MDI-206 0.744 7.229

    [0934] For brevity, only IC50 values are shown for the below tested compounds.

    TABLE-US-00013 Item Tested compound IC50 (nM) JAK1 Filgotinib 25.550 Experiment MDI-203 0.160 MDI-204 0.152 MDI-205 0.121 MDI-207 0.120 MDI-209 0.128 MDI-211 0.162 MDI-213 0.146 MDI-217 0.122 JAK2 Filgotinib 67.920 Experiment MDI-203 0.208 MDI-204 0.176 MDI-205 0.158 MDI-207 0.160 MDI-209 0.165 MDI-211 0.198 MDI-213 0.166 MDI-217 0.217 JAK3 Filgotinib 1343 Experiment MDI-203 0.212 MDI-204 0.238 MDI-205 0.178 MDI-207 0.132 MDI-209 0.158 MDI-211 0.160 MDI-213 0.116 MDI-217 0.137 TYK2 Filgotinib 128.0 Experiment MDI-203 0.328 MDI-204 0.200 MDI-205 0.194 MDI-207 0.474 MDI-209 0.281 MDI-211 0.266 MDI-213 0.146 MDI-217 0.391

    [0935] The above experimental results demonstrate that: MDI-2, MDI-201, MDI-202, MDI-206, MDI-203, MDI-204, MDI-207, MDI-209, MDI-211, MDI-213, and MDI-217 can inhibit JAK1, JAK2, JAK3, and TYK2 at an extremely low concentration, and the inhibitory activities of the compounds in these examples are much higher than that of Filgotinib.

    Example 60: Evaluation II of Pharmacological Activity

    [0936] 1. Experimental Principle

    [0937] The experimental principle of the pharmacological activity evaluation in this example is the same as that described in Example 59, but the experimental materials or instruments as used, and/or some specific test condition parameters (such as the kinase formulation, substrate formulation, kinase reaction experiment procedures, and the like) were varied and adjusted.

    [0938] 2. Experimental Scheme

    [0939] 2.1 Experimental Materials and Instruments

    TABLE-US-00014 Source/ Catalogue No. Name Supplier No. 1 HEPES Life 15630-080 Technologies 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 IGF1Rtide Signalchem I15-58 13 Poly (4:1 Glu, Tyr) Sigma P0275 15 384-Well polystyrene Greiner 784075 shallow flat white 16 384-Well Polypropylene Labcyte PP-0200 microplate 17 Biotek Microplate Reader Biotek Synergy 4 18 Microplate Low Speed XiangZhi TD5B Centrifuge

    [0940] 2.2 Experimental Methods

    [0941] 2.2.1 Kinase Reaction Reagent Formulation

    [0942] 2.2.1.1 1× Kinase Reaction Buffer (400 mL)

    [0943] It was the same as the formulation of the 1× kinase reaction buffer in Example 59.

    [0944] 2.2.1.2 2×Kinase Formulation

    TABLE-US-00015 JAK1 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK1 3225 nM  5.21 μL 40 nM 20 nM (884X) 1X Kinase 414.79 μL Reaction Buffer

    TABLE-US-00016 JAK2 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK2 4256 nM 0.2 μL 2 nM 1 nM (4955X) 1X Kinase 419.8 μL Reaction Buffer

    TABLE-US-00017 JAK3 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration JAK3 3195 nM 0.5 μL 4 nM 2 nM (5341.2X) 1X Kinase 419.5 μL Reaction Buffer

    TABLE-US-00018 TYK2 kinase solution Stock 2X Final Final Name concentration Volume Concentration Concentration TYK2 3174 nM 2.65 μL 20 nM 10 nM (763X) 1X Kinase 417.35 μL Reaction Buffer

    [0945] 2.2.1.3 4× Substrate Mixture Formulation

    TABLE-US-00019 JAK1 substrate mixture solution Stock 4X Final Final Concen- Concen- Name concentration Volume tration tration ATP 10 mM (125X) 2.4 μL 80 μM 20 μM IRS1 1 mg/mL (5X) 60 μL 0.2 mg/mL 0.05 mg/ mL 1X Kinase 237.6 μL Reaction Buffer

    TABLE-US-00020 JAK2 substrate mixture solution 4X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (500X) 6 μL 20 μM 5 μM IGF1Rtide 1 mg/mL 12 μL 0.04 mg/mL 0.01 mg/ (25X) mL 1X Kinase 287.4 μL Reaction Buffer

    TABLE-US-00021 JAK3 substrate mixture solution 4X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (250X) 1.2 μL 40 μM 10 μM Poly (4:1 5 mg/mL 6 μL 0.12 mg/mL 0.03 mg/ Glu, Tyr) (41.6X) mL Peptide 1X Kinase 292.8 μL Reaction Buffer

    TABLE-US-00022 TYK2 substrate mixture solution 4X Final Final Stock Concen- Concen- Name concentration Volume tration tration ATP 10 mM (250X) 1.2 μL 40 μM 10 μM IRS1 1 mg/mL 60 μL 0.08 mg/mL 0.02 mg/ (5X) mL 1X Kinase 238.8 μL Reaction Buffer

    [0946] 2.2.1.4 Compounds to be Tested

    TABLE-US-00023 Molecular Concentration/ Name Mass/mg weight mM Filgotinib 5.0 420.5 10 MDI-208 1.6 417.49 10 MDI-210 1.4 431.52 10 MDI-214 1.5 469.48 10 MDI-215 1.5 469.48 10 MDI-218 1.5 467.52 10 MDI-219 1.7 481.55 10 MDI-220 1.5 495.57 10 MDI-221 1.5 457.51 10 MDI-224 1.5 431.52 10 MDI-225 1.6 447.51 10 MDI-216 1.5 476.51 10 MDI-226 1.7 405.43 10 MDI-227 1.6 419.46 10 MDI-228 1.5 433.49 10 MDI-229 1.5 445.50 10 MDI-230 1.4 447.51 10 MDI-233 1.6 474.54 10 MDI-235 1.8 489.56 10 MDI-231 1.5 460.51 10 MDI-232 1.8 446.49 10 MDI-234 1.5 476.51 10 MDI-236 1.8 503.58 10 MDI-237 2.3 432.5 10 MDI-239 1.5 445.5 10 MDI-240 1.6 490.5 10 MDI-242 1.4 432.5 10 MDI-243 1.7 476.5 10 MDI-244 1.8 462.5 10 MDI-245 1.6 490.5 10 MDI-246 1.5 420.5 10 MDI-247 1.8 434.5 10 MDI-248 1.5 450.5 10 MDI-249 1.9 471.5 10 MDI-250 1.6 485.5 10 MDI-251 2.1 476.5 10 MDI-252 1.8 421.4 10 MDI-253 1.6 435.5 10 MDI-255 1.4 477.5 10 MDI-256 1.4 430.4 10 MDI-257 1.6 434.5 10 MDI-258 1.5 459.5 10 MDI-259 1.7 446.5 10 MDI-260 1.7 460.5 10 MDI-261 1.6 487.5 10 MDI-262 1.7 460.5 10 MDI-263 1.3 460.5 10

    [0947] 2.2.2 Kinase Reaction Experiment Procedure

    [0948] 2.2.2.1 JAK1 & JAK2 Kinase Reaction Experimental 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 0.50.
    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.

    [0949] 2.2.2.2 JAK3 & TYK2 Kinase Reaction Experimental 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, and 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, 16.67, 5.555, 1.851, 0.617, 0.205, 0.0686, 0.0228, 0.00762, and 0.0025 μM. The final concentrations of the compound to be tested are 10, 3.33, 1.11, 0.37, 0.12, 0.04, 0.014, 0.0046, 0.0015, and 0.0005 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.

    [0950] 2.2.3 Experimental Data Processing Method

    The same as the experimental data processing method used in Example 59.

    [0951] 3. Experimental Results

    TABLE-US-00024 Tested Item Compound IC50 (nM) JAK1 Filgotinib 88 Experiment MDI-208 0.153 MDI-210 0.347 MDI-214 0.303 MDI-215 0.197 MDI-218 0.825 MDI-219 1.38 MDI-220 2.02 MDI-221 0.128 MDI-224 0.248 MDI-225 0.226 MDI-216 0.134 MDI-226 0.308 MDI-227 0.224 MDI-228 0.398 MDI-229 0.753 MDI-230 0.819 MDI-233 1.31 MDI-235 0.0395 MDI-231 0.530 MDI-232 0.745 MDI-234 0.206 MDI-236 0.0403 JAK2 Filgotinib 71 Experiment MDI-208 0.440 MDI-210 1.11 MDI-214 0.273 MDI-215 0.277 MDI-218 0.614 MDI-219 1.38 MDI-220 1.38 MDI-221 0.363 MDI-224 0.754 MDI-225 0.390 MDI-216 0.233 MDI-226 0.371 MDI-227 0.246 MDI-228 0.355 MDI-229 0.356 MDI-230 0.555 MDI-233 1.33 MDI-235 0.166 MDI-231 1.17 MDI-232 1.04 MDI-234 0.737 MDI-236 0.329 JAK3 Filgotinib 1463 Experiment MDI-208 1.11 MDI-210 0.979 MDI-214 0.352 MDI-215 0.308 MDI-218 0.948 MDI-219 2.29 MDI-220 3.15 MDI-221 0.379 MDI-224 2.01 MDI-225 0.487 MDI-216 0.247 MDI-226 0.676 MDI-227 0.441 MDI-228 0.565 MDI-229 0.481 MDI-230 0.821 MDI-233 2.60 MDI-235 0.183 MDI-231 0.893 MDI-232 0.868 MDI-234 0.375 MDI-236 0.141 TYK2 Filgotinib 532 Experiment MDI-208 9.31 MDI-210 31.5 MDI-214 2.8 MDI-215 1.58 MDI-218 1.75 MDI-219 1.88 MDI-220 5.56 MDI-221 7.60 MDI-224 16.1 MDI-225 3.50 MDI-216 1.62 MDI-226 4.18 MDI-227 3.89 MDI-228 4.76 MDI-229 4.71 MDI-230 6.57 MDI-233 3.50 MDI-235 0.142 MDI-231 1.31 MDI-232 2.26 MDI-234 0.438 MDI-236 0.0954 JAK1 Filgotinib 46.2 Experiment MDI-237 0.758 MDI-239 1.15 MDI-240 0.450 MDI-242 67.2 MDI-243 0.118 MDI-244 0.248 MDI-245 0.178 MDI-246 0.241 MDI-247 0.557 MDI-248 0.093 MDI-249 0.307 MDI-250 0.395 MDI-251 0.144 MDI-252 1.8 MDI-253 2.9 MDI-255 57.2 MDI-256 0.700 MDI-257 0.185 MDI-258 0.939 MDI-259 0.659 MDI-260 2.28 MDI-261 0.154 MDI-262 0.319 MDI-263 0.120 JAK2 Filgotinib 47.6 Experiment MDI-237 0.588 MDI-239 1.20 MDI-240 0.842 MDI-242 28.6 MDI-243 0.499 MDI-244 0.915 MDI-245 0.648 MDI-246 0.973 MDI-247 1.88 MDI-248 0.560 MDI-249 0.697 MDI-250 0.974 MDI-251 0.818 MDI-252 2.6 MDI-253 1.6 MDI-255 37.4 MDI-256 3.06 MDI-257 0.600 MDI-258 3.31 MDI-259 1.30 MDI-260 2.99 MDI-261 0.703 MDI-262 1.54 MDI-263 0.717 JAK3 Filgotinib 1051 Experiment MDI-237 1.39 MDI-239 4.94 MDI-240 2.02 MDI-242 152 MDI-243 0.269 MDI-244 0.550 MDI-245 0.306 MDI-246 0.709 MDI-247 1.30 MDI-248 0.303 MDI-249 0.398 MDI-250 0.497 MDI-251 0.406 MDI-252 2.2 MDI-253 1.5 MDI-256 2.71 MDI-257 0.381 MDI-258 2.36 MDI-259 1.29 MDI-260 2.47 MDI-261 0.473 MDI-262 1.22 MDI-263 0.458 TYK2 Filgotinib 233 Experiment MDI-237 9.68 MDI-239 19.2 MDI-240 5.34 MDI-242 583 MDI-243 0.167 MDI-244 1.31 MDI-245 0.365 MDI-246 1.52 MDI-247 2.35 MDI-248 0.578 MDI-249 1.93 MDI-250 0.993 MDI-251 1.33 MDI-252 22 MDI-253 31 MDI-256 6.14 MDI-257 0.684 MDI-258 6.27 MDI-259 2.94 MDI-260 8.98 MDI-261 1.16 MDI-262 2.59 MDI-263 0.717

    [0952] The above experimental results show that among the compounds of the present disclosure tested in Example 60, except that few example compound has a comparable activity as Filgotinib, most of the tested compounds 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.

    [0953] 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.