NOVEL BENZOPYRAN DERIVATIVE AND USE THEREOF

Abstract

The present invention relates to a novel benzopyran derivative useful for preparing a drug for treating cancer, and more specifically, to a novel benzopyran derivative which is a micromolecule having a macrophage inhibitory effect and is useful for preparing a drug for cancer treatment. The drug particularly inhibits the differentiation of immune macrophages to stimulate the immune system, and thus is useful for treating immune-related cancers.

Claims

1. A compound of the following Formula 1, or a pharmaceutically acceptable salt or isomer thereof: ##STR00157## wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 are each independently carbon or nitrogen; R.sub.1 is halogen, hydroxy, nitro, amino, cyano, alkyl, cycloalkyl, alkylamino, dialkylamino, alkylcarbonyl, haloalkyl, haloalkoxy, hydroxyalkyl, hydroxyalkoxy, alkylsulfonyl, alkylsulfonylamino, aminosulfonyloxy, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl-oxy, 3- to 10-membered heterocyclyl-alkoxy, or any one of the following formulas (i) to (vii), wherein the heterocycloalkyl or heteroaryl may be substituted with one or more substituents selected from the group consisting of hydroxy, carboxy, alkyl, alkylsulfonyl, alkylcarbonyl, oxo, hydroxyalkyl and halophenyl; ##STR00158## Ra and Rb are each independently hydroxy or alkoxy; Rc is hydrogen; Rd is a direct bond, carbonyl or sulfonyl; Re is hydrogen, alkyl, haloalkyl, alkoxy, amino or 3- to 10-membered heterocycloalkyl; Rf is O or S; Rg is hydrogen, alkyl, aminocarbonylalkyl or guanidinoalkyl; Rh is hydrogen, alkyl, dialkylaminoalkyl, or may be fused with Ri to form 3- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of alkyl, oxo, aminoalkyl, dialkylaminoalkylcarbonyl, alkoxycarbonyl, acetylcarbonyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkylcarbonyl, 3- to 10-membered heterocycloalkyl-alkyl, 5- to 10-membered heteroarylalkyl, acetylcarbonylheterocycloalkyl, alkoxyalkoxyalkoxyalkylcarbonyl and alkylcarbonyl substituted with amino; Ri is hydrogen, alkyl, aminoalkyl, carboxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonyl, alkylcarbonyl, 3- to 10-membered heterocycloalkyl, alkyl substituted with alkoxycarbonyl, guanidinoalkyl substituted with carboxy, acetylamino or alkoxycarbonylalkyl; Rj is a direct bond, alkylene, arylene-alkyleneoxy or alkylene substituted with alkylcarbonylamino; Rk is alkyl, alkoxycarbonylalkyl, alkoxy, trialkylamino, nitro, alkyl substituted with amino, aminocarbonylalkyl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; RL is amino or dialkylamino; Rm is hydrogen or alkyl; RN is hydrogen or carboxyalkylcarbonyl; R.sub.2 and R.sub.3 are each independently alkyl or haloalkyl; R.sub.4 is hydrogen, halogen, alkyl, alkylcarbonyl, haloalkyl, carboxy, hydroxyalkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with alkyl or alkoxycarbonyl; R.sub.5 is hydrogen, halogen or alkyl; n is an integer of 1 to 3; r and p are an integer of 0 to 3; and q is an integer of 1 to 4; provided that when R.sub.1 is hydroxy and n is 1, i) R.sub.2 and R.sub.3 are not alkyl at the same time, ii) at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 is nitrogen, or iii) R.sub.4 is hydroxyalkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with alkyl or alkoxycarbonyl; and when R.sub.1 is halogen or alkylamino, R.sub.4 and R.sub.5 are not hydrogen at the same time; and wherein the heterocycloalkyl and heteroaryl have one or more heteroatoms selected from the group consisting of N, O and S.

2. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 are each independently CH, CH, N or N; or C or C when it is substituted with R.sub.4 or R.sub.5; R.sub.1 is halogen, hydroxy, nitro, amino, cyano, C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.7 alkylamino, di(C.sub.1-C.sub.7 alkyl)amino, C.sub.1-C.sub.7 alkylcarbonyl, halo-C.sub.1-C.sub.7 alkyl, halo-C.sub.1-C.sub.7 alkoxy, hydroxy-C.sub.1-C.sub.7 alkyl, hydroxy-C.sub.1-C.sub.7 alkoxy, C.sub.1-C.sub.7 alkylsulfonyl, C.sub.1-C.sub.7 alkylsulfonylamino, aminosulfonyloxy, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkyl-oxy, 3- to 10-membered heterocyclyl-alkoxy, or any one of the following formulas (i) to (vii), wherein the heterocycloalkyl or heteroaryl may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylsulfonyl, C.sub.1-C.sub.7 alkylcarbonyl, oxo, hydroxy-C.sub.1-C.sub.7 alkyl and halophenyl; ##STR00159## Ra and Rb are each independently hydroxy or C.sub.1-C.sub.7 alkoxy; Rc is hydrogen; Rd is a direct bond, carbonyl or sulfonyl; Re is hydrogen, C.sub.1-C.sub.7 alkyl, halo-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, amino or 3- to 10-membered heterocycloalkyl; Rf is O or S; Rg is hydrogen, C.sub.1-C.sub.7 alkyl, aminocarbonyl-C.sub.1-C.sub.7 alkyl or guanidino-C.sub.1-C.sub.7 alkyl; Rh is hydrogen, C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkyl, or may be fused with Ri to form 3- to 12-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with 1 to 4 substituents selected from the group consisting of C.sub.1-C.sub.7 alkyl, oxo, amino-C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkylcarbonyl, C.sub.1-C.sub.7 alkoxycarbonyl, acetylcarbonyl, 3- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocycloalkylcarbonyl, 3- to 10-membered heterocycloalkyl-C.sub.1-C.sub.7 alkyl, 5- to 10-membered heteroaryl-C.sub.1-C.sub.7 alkyl, acetylcarbonyl-3- to 10-membered heterocycloalkyl, C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkoxy-C.sub.1-C.sub.7 alkylcarbonyl and C.sub.1-C.sub.7 alkylcarbonyl substituted with amino; Ri is hydrogen, C.sub.1-C.sub.7 alkyl, amino-C.sub.1-C.sub.7 alkyl, carboxy-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylamino-C.sub.1-C.sub.7 alkyl, di(C.sub.1-C.sub.7 alkyl)amino-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylsulfonyl, C.sub.1-C.sub.7 alkylcarbonyl, 3- to 10-membered heterocycloalkyl, C.sub.1-C.sub.7 alkyl substituted with C.sub.1-C.sub.7 alkoxycarbonyl, guanidino-C.sub.1-C.sub.7 alkyl substituted with carboxy, acetylamino or C.sub.1-C.sub.7 alkoxycarbonyl-C.sub.1-C.sub.7 alkyl; Rj is a direct bond, C.sub.1-C.sub.7 alkylene, C.sub.6-C.sub.10 arylene-C.sub.1-C.sub.7 alkyleneoxy or C.sub.1-C.sub.7 alkylene substituted with C.sub.1-C.sub.7 alkylcarbonylamino; Rk is C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxycarbonyl-C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkoxy, tri(C.sub.1-C.sub.7 alkyl)amino, nitro, C.sub.1-C.sub.7 alkyl substituted with amino, aminocarbonyl-C.sub.1-C.sub.7 alkyl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; RL is amino or di(C.sub.1-C.sub.7 alkyl)amino; Rm is hydrogen or C.sub.1-C.sub.7 alkyl; RN is hydrogen or carboxy-C.sub.1-C.sub.7 alkylcarbonyl; R.sub.2 and R.sub.3 are each independently C.sub.1-C.sub.7 alkyl or halo-C.sub.1-C.sub.7 alkyl; R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.7 alkyl, C.sub.1-C.sub.7 alkylcarbonyl, halo-C.sub.1-C.sub.7 alkyl, carboxy, hydroxy-C.sub.1-C.sub.7 alkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with C.sub.1-C.sub.7 alkyl or C.sub.1-C.sub.7 alkoxycarbonyl; R.sub.5 is hydrogen, halogen or C.sub.1-C.sub.7 alkyl; n is an integer of 1 to 3; r and p are an integer of 0 to 3; and q is an integer of 1 to 4; provided that when R.sub.1 is hydroxy and n is 1, i) R.sub.2 and R.sub.3 are not C.sub.1-C.sub.7 alkyl at the same time, ii) at least one of X.sub.1, X.sub.2, X.sub.3, X.sub.4 and X.sub.5 is N or N, or iii) R.sub.4 is hydroxy-C.sub.1-C.sub.7 alkyl, 3- to 10-membered heterocycloalkylcarbonyl, or 3- to 10-membered heterocycloalkylcarbonyl substituted with C.sub.1-C.sub.7 alkyl or C.sub.1-C.sub.7 alkoxycarbonyl; and when R.sub.1 is halogen or C.sub.1-C.sub.7 alkylamino, R.sub.4 and R.sub.5 are not hydrogen at the same time; and wherein the heterocycloalkyl and heteroaryl have 1 to 4 heteroatoms selected from the group consisting of N, O and S.

3. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein the compound of Formula 1 is a compound of the following Formula 2: ##STR00160## wherein X.sub.1, X.sub.2, X.sub.4, X.sub.5, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are the same as defined in claim 1.

4. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein the compound of Formula 1 is a compound of the following Formula 3: ##STR00161## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n are the same as defined in claim 1.

5. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.1 is halogen, hydroxy, nitro, amino, cyano, C.sub.1-C.sub.5 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.5 alkylamino, di(C.sub.1-C.sub.5 alkyl)amino, C.sub.1-C.sub.5 alkylcarbonyl, halo-C.sub.1-C.sub.5 alkyl, halo-C.sub.1-C.sub.5 alkoxy, hydroxy-C.sub.1-C.sub.5 alkyl, hydroxy-C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkylsulfonyl, C.sub.1-C.sub.5 alkylsulfonylamino, aminosulfonyloxy, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heteroaryl, 4- to 8-membered heterocycloalkyl-oxy, 4- to 8-membered heterocyclyl-alkoxy, or any one of the following formulas (i) to (vii); wherein the heterocycloalkyl may be substituted with 1 to 4 substituents selected from the group consisting of hydroxy, carboxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkylsulfonyl, C.sub.1-C.sub.5 alkylcarbonyl, oxo, hydroxy-C.sub.1-C.sub.5 alkyl and halophenyl; and the heteroaryl may be substituted with 1 to 3 substituents selected from the group consisting of hydroxy, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkylsulfonyl, C.sub.1-C.sub.5 alkylcarbonyl and hydroxy-C.sub.1-C.sub.5 alkyl; ##STR00162## Ra and Rb are each independently hydroxy or C.sub.1-C.sub.5 alkoxy; Rc is hydrogen or; Rd is a direct bond, carbonyl or sulfonyl; Re is hydrogen, C.sub.1-C.sub.5 alkyl, halo-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, amino or 3- to 10-membered heterocycloalkyl; Rf is O or S; Rg is hydrogen, C.sub.1-C.sub.5 alkyl, aminocarbonyl-C.sub.1-C.sub.5 alkyl or guanidino-C.sub.1-C.sub.5 alkyl; Rh is hydrogen, C.sub.1-C.sub.5 alkyl, di(C.sub.1-C.sub.5 alkyl)amino-C.sub.1-C.sub.5 alkyl, or may be fused with Ri to form 4- to 8-membered heterocycloalkyl, wherein the heterocycloalkyl may be substituted with one or more substituents selected from the group consisting of C.sub.1-C.sub.5 alkyl, oxo, amino-C.sub.1-C.sub.5 alkyl, di(C.sub.1-C.sub.5 alkyl)amino-C.sub.1-C.sub.5 alkylcarbonyl, C.sub.1-C.sub.5 alkoxycarbonyl, acetylcarbonyl, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heteroaryl, 4-8 membered heterocycloalkylcarbonyl, 4- to 8-membered heterocycloalkyl-C.sub.1-C.sub.5 alkyl, 5- to 8-membered heteroaryl-C.sub.1-C.sub.5 alkyl, acetylcarbonyl-4- to 8-membered heterocycloalkyl, C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkoxy-C.sub.1-C.sub.5 alkylcarbonyl and C.sub.1-C.sub.5 alkylcarbonyl substituted with amino; Ri is hydrogen, C.sub.1-C.sub.5 alkyl, amino-C.sub.1-C.sub.5 alkyl, carboxy-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkylamino-C.sub.1-C.sub.5 alkyl, di(C.sub.1-C.sub.5 alkyl)amino-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkylsulfonyl, C.sub.1-C.sub.5 alkylcarbonyl, 3- to 10-membered heterocycloalkyl, C.sub.1-C.sub.5 alkyl substituted with C.sub.1-C.sub.5 alkoxycarbonyl, guanidino-C.sub.1-C.sub.5 alkyl substituted with carboxy, acetylamino or C.sub.1-C.sub.5 alkoxycarbonyl-C.sub.1-C.sub.5 alkyl; Rj is a direct bond, C.sub.1-C.sub.5 alkylene, C.sub.6-C.sub.10 arylene-C.sub.1-C.sub.5 alkyleneoxy, C.sub.1-C.sub.5 alkylene substituted with C.sub.1-C.sub.5 alkylcarbonylamino; Rk is C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxycarbonyl-C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, tri(C.sub.1-C.sub.5 alkyl)amino, nitro, C.sub.1-C.sub.5 alkyl substituted with amino, aminocarbonyl-C.sub.1-C.sub.5 alkyl, 4- to 8-membered heterocycloalkyl or 5- to 8-membered heteroaryl; RL is amino or di(C.sub.1-C.sub.5 alkyl)amino; Rm is hydrogen or C.sub.1-C.sub.5 alkyl; and RN is hydrogen or carboxy-C.sub.1-C.sub.5 alkylcarbonyl.

6. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.2 and R.sub.3 are each independently C.sub.1-C.sub.5 alkyl or halo-C.sub.1-C.sub.5 alkyl.

7. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein R.sub.4 is hydrogen, halogen, C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkylcarbonyl, halo-C.sub.1-C.sub.5 alkyl, carboxy, hydroxy-C.sub.1-C.sub.5 alkyl, 4- to 8-membered heterocycloalkylcarbonyl, or 4- to 8-membered heterocycloalkylcarbonyl substituted with C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkoxycarbonyl; and R.sub.5 is hydrogen, halogen or C.sub.1-C.sub.5 alkyl.

8. The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1, wherein wherein the compound of Formula 1 is selected from the group consisting of: 1) 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 2) 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 3) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)acetamide; 4) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 5) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)methanesulfonamide; 6) tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate; 7) 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 8) 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 9) N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)sulfuric diamide; 10) 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 11) 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 12) 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 13) 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo [1,2-a]pyridazine-1,3(2H)-dione; 14) 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 15) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)urea; 16) 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 17) 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 18) 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride; 19) 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 20) 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 21) 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 22) 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 23) 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 24) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-carbonitrile; 25) 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 26) 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 27) 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 28) 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 29) 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 30) 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 31) 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 32) 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 33) 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 34) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 35) 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 36) 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 37) 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 38) 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 39) 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 40) 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 41) 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 42) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 43) 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 44) 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid; 45) 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 46) 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 47) 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 48) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 49) 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 50) 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 51) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 52) 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 53) 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 54) tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate; 55) 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 56) 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 57) 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 58) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate; 59) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate; 60) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetate; 61) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate; 62) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate; 63) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate; 64) (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid; 65) sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate; 66) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-methylpiperazine-1-carboxylate hydrochloride; 67) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride; 68) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate; 69) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 70) disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate; 71) 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate; 72) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride; 73) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-methoxyethyl) carbonate; 74) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pyrrolidine-1-carboxylate; 75) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2,5,8,11-tetraoxatridecan-13-yl) carbonate; 76) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethylcarbamate; 77) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutaminate 2,2,2-trifluoroacetic acid; 78) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid; 79) 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate; 80) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-leucinate; 81) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid; 82) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride; 83) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid; 84) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride; 85) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride; 86) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride; 87) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine; 88) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate; 89) N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine; 90) sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate; 91) 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid; 92) sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate; 93) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate; 94) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride; 95) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride; 96) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate; 97) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate; 98) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride; 99) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride; 100) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride; 101) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride; 102) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-ylheptanoate; 103) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylbutanoate; 104) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl succinate; 105) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate; 106) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate; 107) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl) carbonate; 108) 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid; 109) sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate; 110) 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 111) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride; 112) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride; 113) 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione formate; 114) (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid; 115) disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate; 116) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride; 117) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1-carboxylate hydrochloride; 118) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride; 119) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)-2,2-dimethylpiperazine-1-carboxylate hydrochloride; 120) 2-(4-acetylphenyl)-10-(3-(4-(3-chlorophenyl)piperazin-1-yl)propoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione dihydrochloride; 121) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 122) 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 123) 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide; 124) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (4-nitrobenzyl) carbonate; 125) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperidine-1-carboxylate; 126) O-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) dimethylcarbamothioate; 127) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2-oxoimidazolidine-1-carboxylate; 128) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (3-(dimethylamino)-2,2-dimethylpropyl)carbamate formate; 129) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-(dimethylamino)ethyl)(methyl)carbamate formate; 130) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(piperidin-3-yl)carbamate hydrochloride; 131) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(methylsulfonyl)carbamate; 132) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid; 133) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid; 134) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetyl-L-glutaminate; 135) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid; 136) methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-valinate; 137) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl sulfamate; 138) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl picolinate hydrochloride; 139) 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isonicotinate hydrochloride; 140) 10-hydroxy-2-(4-(1-hydroxyethyl)phenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 141) 2-(4-acetylphenyl)-10-(azetidin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione; 142) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 143) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 144) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate; 145) 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate; 146) 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate; and 147) 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate.

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or isomer thereof as defined in claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, which is for the prevention or treatment of a cancer disease.

11. The pharmaceutical composition according to claim 10, wherein the cancer disease is selected from the group consisting of colon cancer, skin cancer, melanoma, glioblastoma, bone cancer, liver cancer, stomach cancer, pancreas cancer, colon cancer, rectal cancer, blood cancer, bladder cancer, kidney cancer, biliary tract cancer, cervical cancer, uterine cancer, ovarian cancer, breast cancer, lung cancer, non-small cell lung cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer and parathyroid cancer.

Description

MODE FOR THE INVENTION

[0283] Hereinafter, the present invention is explained in more detail with the following examples and experimental examples. However, it must be understood that the protection scope of the present disclosure is not limited to the examples and experimental examples.

[0284] The abbreviations used in the following examples are defined as follows.

TABLE-US-00001 TABLE 1 Abbreviation Full Name CDCl.sub.3 Chloroform D.sub.2O Deuterium oxide DMSO-D.sub.6 Dimethyl sulfoxide MeOH Methanol MPLC Medium pressure liquid chromatography Xphos 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

[0285] Intermediate 1: Synthesis of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione

(a) Synthesis of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate

[0286] N-aminocarbamate (5.59 g, 62.05 mmol) was dissolved in tetrahydrofuran (400 mL), and 1-(4-isocyanatophenyl)ethan-1-one (10 g, 62.05 mmol) was added thereto and stirred at room temperature for 15 hours. When the reaction was completed, the obtained solid was filtered, washed with hexane (200 mL) and dried to obtain methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate (15.4 g, 98%).

(b) Synthesis of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione

[0287] Methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate (15 g, 59.7 mmol) and potassium carbonate (37.13 g, 268.67 mmol) were added to water (600 mL) and stirred under reflux for 15 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, undissolved impurities were removed by filtration, and concentrated hydrochloric acid was added dropwise to the filtrate (pH<2) to precipitate a solid. The obtained solid was filtered, triturated with an ethyl acetate/hexane mixed solvent, filtered and dried to obtain 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione (11 g, 84%).

Intermediate 2: Synthesis of 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione

(a) Synthesis of methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate

[0288] Except that 1-isocyanato-4-(trifluoromethyl)benzene was used instead of 1-(4-isocyanatophenyl)ethan-1-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate (96%).

(b) Synthesis of 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione

[0289] Except that methyl 2-((4-(trifluoromethyl)phenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate, the same synthesis method as in Intermediate 1 (b) above was carried out to obtain 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione (94%).

Intermediate 3: Synthesis of 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione

(a) Synthesis of methyl 2-((4-fluorophenyl)carbamoyl)hydrazine-1-carboxylate

[0290] Except that 1-fluoro-4-isocyanatobenzene was used instead of 1-(4-isocyanatophenyl)ethan-1-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain methyl 2-((4-fluorophenyl)carbamoyl)hydrazine-1-carboxylate (98%).

(b) Synthesis of 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione

[0291] Except that methyl 2-((4-fluorophenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate, the same synthesis method as in Intermediate 1 (b) above was carried out to obtain 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione (93%).

Intermediate 4: Synthesis of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione

(a) Synthesis of methyl 2-((4-(tert-butyl)phenyl)carbamoyl)hydrazine-1-carboxylate

[0292] Except that 1-(tert-butyl)-4-isocyanatobenzene was used instead of 1-(4-isocyanato)ethan-1-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain methyl 2-((4-(tert-butyl)phenyl)carbamoyl)hydrazine-1-carboxylate (98%).

(b) Synthesis of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione

[0293] Except that methyl 2-((4-(tert-butyl)phenyl)carbamoyl)hydrazine-1-carboxylate was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate, the same synthesis method as in Intermediate 1 (b) above was carried out to obtain 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione (95%).

Intermediate 5: Synthesis of 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione

(a) Synthesis of methyl 2-((4-bromophenyl)carbamoyl)hydrazine-1-carboxylate

[0294] Except that 1-bromo-4-isocyanatobenzene was used instead of 1-(4-isocyanato)ethan-1-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain 2-((4-bromophenyl)carbamoyl)hydrazine-1-carboxylate (55%).

(b) Synthesis of 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione

[0295] Except that the compound methyl 2-((4-bromophenyl)carbamoyl)hydrazine-1-carboxylate was used instead of the compound methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate, the same synthesis method as in Intermediate 1 (b) above was carried out to obtain 4-(4-bromophenyl)-1,2,4-triazolidine-3,5-dione (42%).

Intermediate 6: Synthesis of 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid

(a) Synthesis of 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid

[0296] Except that 4-isocyanatobenzoic acid was used instead of 1-(4-isocyanato)ethan-1-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid (77%).

(b) Synthesis of 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid

[0297] Except that 4-(2-(methoxycarbonyl)hydrazine-1-carboxamido)benzoic acid was used instead of methyl 2-((4-acetylphenyl)carbamoyl)hydrazine-1-carboxylate, the same synthesis method as in Intermediate 1 (b) above was carried out to obtain 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid (57%).

Intermediate 7: Synthesis of ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

(a) Synthesis of 7-hydroxy-2,2-dimethylchroman-4-one

[0298] 1-(2,4-Dihydroxyphenyl)ethanone (500 mg, 3.29 mmol) was dissolved in ethanol (32.9 ml), and pyrrolidine (0.549 ml, 6.57 mmol) and acetone (2.413 ml, 32.9 mmol) were added thereto. The reaction mixture was stirred under reflux for 3 days. When the reaction was completed, the solvent was removed through distillation under reduced pressure, and the residue was diluted in dichloromethane and washed with 1 N aqueous hydrochloric acid solution and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:5, v/v) to obtain 7-hydroxy-2,2-dimethylchroman-4-one. (516 mg, 82%).

(b) Synthesis of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one

[0299] 7-Hydroxy-2,2-dimethylchroman-4-one (515 mg, 2.68 mmol) obtained in Intermediate 7 (a) above was dissolved in dichloromethane (5 mL), and copper (II) bromide (1.26 g, 5.63 mmol) was added thereto and stirred under reflux for 4 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:7, v/v) to obtain 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one (655 mg, 90%).

[0300] 3-Bromo-7-hydroxy-2,2-dimethylchroman-4-one (650 mg, 2.4 mmol) obtained in Intermediate 7 (b) above and imidazole (245 mg, 3.6 mmol) were added to dichloromethane (10 mL) and cooled to 0 C., and triisopropylsilyl chloride (616 l, 2.88 mmol) was added dropwise thereto and stirred at room temperature for 12 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with an aqueous ammonium chloride solution and an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:30, v/v) to obtain 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (931 mg, 91%).

(d) Synthesis of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0301] 3-Bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (500 mg, 1.17 mmol) obtained in Intermediate 7 (c) above was dissolved in ethanol (6 mL), and sodium borohydride (44 mg, 1.17 mmol) was added thereto, and heated and stirred at 40 C. for 1 hour. When the reaction was completed, the reaction mixture was diluted in water, neutralized with an aqueous ammonium chloride solution, and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The residue was dissolved in toluene (6 mL), p-toluenesulfonic acid (20 mg, 0.117 mmol) was added thereto, and heated and stirred at 80 C. for 4 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:30, v/v) to obtain ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (320 mg, 66.5%).

(e) Synthesis of ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0302] ((3-Bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (175 mg, 0.43 mmol) obtained in Intermediate 7 (d) above, tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.022 mmol) and sodium carbonate (113 mg, 1.06 mmol) were suspended in a mixed solvent of ethanol/toluene/water (1:2:2.5 mL), and vinylboronic acid dibutyl ester (113 l, 0.51 mmol) was added thereto, and heated and stirred at 70 C. for 12 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and distilled under reduced pressure to quantitatively obtain ((2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, which was used in the next reaction without purification.

Intermediate 8: Synthesis of 1-(2,2-dimethyl-7-((triisopropylsilyl)oxy)-3-vinyl-2H-chromen-6-yl)ethan-1-one

(a) Synthesis of 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethan-1-one

[0303] ((3-Bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (447 mg, 1.09 mmol) obtained in Intermediate 7 (d) above was added to dichloromethane (10 mL) and cooled to 0 C. Aluminum chloride (290 mg, 2.17 mmol) and acetyl chloride (1.16 mL, 16.3 mmol) were added thereto and stirred at 0 C. for 15 minutes. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and distilled under reduced pressure. The obtained residue was dissolved in MeOH (10 mL), and 1N aqueous sodium hydroxide solution (2.17 mL, 2.17 mmol) was added thereto, stirred at room temperature for 15 minutes, diluted in ethyl acetate, and washed with 1 N aqueous hydrochloric acid solution, water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:5, v/v) to obtain 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-yl)ethan-1-one (162 mg, 50%).

(b) Synthesis of 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one

[0304] Except that 1-(3-bromo-7-hydroxy-2,2-dimethyl-2H-chromen-6-ylethane-1-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (c) above was carried out to obtain 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one (80 mg, 60%).

[0305] Except that 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 1-(2,2-dimethyl-7-((triisopropylsilyl)oxy)-3-vinyl-2H-chromen-6-yl)ethan-1-one. The obtained compound was used in the next reaction without purification.

Intermediate 9: Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide

(a) Synthesis of 7-bromo-2,2-dimethylchroman-4-one

[0306] Except that 1-(4-bromo-2-hydroxyphenyl)ethan-1-one was used instead of 1-(2,4-dihydroxyphenyl)ethenone, the same synthesis method as in Intermediate 7 (a) above was carried out to obtain 7-bromo-2,2-dimethylchroman-4-one (950 mg, 85%).

(b) Synthesis of tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate

[0307] 7-Bromo-2,2-dimethylchroman-4-one (500 mg, 1.96 mmol) obtained in Intermediate 9 (a) above was dissolved in 1,4-dioxane (10 mL), and O-tert-butyl-carbamate (344 mg, 2.94 mmol), palladium(II) acetate (44 mg, 0.196 mmol), Xphos (187, mg, 0.392 mmol) and cesium carbonate (958 mg, 2.94 mmol) were added thereto and stirred under reflux for 1 hour. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1: 5, v/v) to obtain tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate (560 mg, 98%).

[0308] Except that tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 7-amino-3-bromo-2,2-dimethylchroman-4-one (320 mg, 54%).

(d) Synthesis of N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)acetamide

[0309] 7-Amino-3-bromo-2,2-dimethylchroman-4-one (120 mg, 0.44 mmol) obtained in Intermediate 9 (c) above and 1-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (128 mg, 0.67 mmol) were added to pyridine (2 mL), and acetic acid (25 l, 0.44 mmol) was added thereto. After the reaction mixture was stirred at room temperature for 12 hours, acetic acid (25 l, 0.44 mmol) was further added and stirred for additional 4 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)acetamide (126 mg, 91%).

(e) Synthesis of N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)acetamide

[0310] Except that N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)acetamide was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)acetamide (78 mg, 72%).

(f) Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide

[0311] Except that N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)acetamide was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide. The obtained compound was used in the next reaction without purification.

Intermediate 10: Synthesis of 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene

(a) Synthesis of 2,2-dimethyl-7-(methylsulfonyl)chroman-4-one

[0312] 7-Bromo-2,2-dimethylchroman-4-one (500 mg, 1.96 mmol) obtained in Intermediate 9 (a) above was dissolved in dimethyl sulfoxide (10 mL), and methanesulfonic acid (400 mg, 3.92 mmol, Na salt), L-proline (45 mg, 0.39 mmol), copper(I) iodide (37 mg, 0.2 mmol) and potassium carbonate (542 mg, 3.92 mmol) were added thereto, and heated and stirred at 130 C. for 2 hours. When the reaction was completed, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by column chromatography (ethyl acetate:hexane=1:10, v/v) to obtain 2,2-dimethyl-7-(methylsulfonyl)chroman-4-one (160 mg, 32%).

(b) Synthesis of 3-bromo-2,2-dimethyl-7-(methylsulfonyl)chroman-4-one

[0313] Except that 2,2-dimethyl-7-(methylsulfonyl)chroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-2,2-dimethyl-7-(methylsulfonyl)chroman-4-one (84 mg, 67%).

[0314] Except that 3-bromo-2,2-dimethyl-7-(methylsulfonyl)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-2H-chromene (53 mg, 65%).

(d) Synthesis of 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene

[0315] Except that 3-bromo-2,2-dimethyl-7-(methylsulfonyl)-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene. The obtained compound was used in the next reaction without purification.

Intermediate 11: Synthesis of N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide

(a) Synthesis of N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)methanesulfonamide

[0316] 7-Amino-3-bromo-2,2-dimethylchroman-4-one (200 mg, 0.74 mmol) obtained in Intermediate 9 (c) above was dissolved in dichloromethane (10 mL) and cooled to 0 C. Pyridine (299 l, 3.7 mmol) and methanesulfonyl chloride (288 l, 3.7 mmol) were added dropwise to the reaction mixture, raised to room temperature and stirred for 12 hours. When the reaction is completed, the solvent is removed by distillation under reduced pressure, and the residue is separated by MPLC (ethyl acetate:hexane: 1:5, v/v) to obtain N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)methanesulfonamide (230 mg, 89%).

(b) Synthesis of N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanesulfonamide

[0317] Except that N-(3-bromo-2,2-dimethyl-4-oxochroman-7-yl)methanesulfonamide was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanesulfonamide (170 mg, 70%).

[0318] Except that N-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanesulfonamide was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide. The obtained compound was used in the next reaction without purification.

Intermediate 12: Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)carbamate

(a) Synthesis of tert-butyl (2,2-dimethyl-2H-chromen-7-yl)carbamate

[0319] Except that tert-butyl (2,2-dimethyl-4-oxochroman-7-yl)carbamate was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain tert-butyl (2,2-dimethyl-2H-chromen-7-yl)carbamate (240 mg, 67%).

(b) Synthesis of tert-butyl (3-bromo-2,2-dimethyl-2H-chromen-7-yl)carbamate

[0320] Except that tert-butyl (2,2-dimethyl-2H-chromen-7-yl) carbamate was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain tert-butyl (3-bromo-2,2-dimethyl-2H-chromen-7-yl)carbamate (100 mg, 78%).

[0321] Except that tert-butyl (3-bromo-2,2-dimethyl-2H-chromen-7-yl)carbamate was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)carbamate. The obtained compound was used in the next reaction without purification.

Intermediate 13: Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine

(a) Synthesis of 1-(2-hydroxy-4-morpholinophenyl)-3-methylbut-2-en-1-one

[0322] Except that morpholine was used instead of 0-tert-butyl-carbamate, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 1-(2-hydroxy-4-morpholinophenyl)-3-methylbut-2-en-1-one (200 mg, 56%).

(b) Synthesis of 2,2-dimethyl-7-morpholinochroman-4-one

[0323] 1-(2-Hydroxy-4-morpholinophenyl)-3-methylbut-2-en-1-one (150 mg, 0.57 mmol) obtained in Intermediate 13 (a) above and triethylamine (173 mg, 1.71 mmol) were dissolved in 1,2-dichloroethane, and sodium tert-butoxide (55 mg, 0.57 mmol) was added thereto, and heated and stirred at 70 C. for 12 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:3, v/v) to obtain 2,2-dimethyl-7-morpholinochroman-4-one (149 mg, 99%).

[0324] Except that 2,2-dimethyl-7-morpholinochroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-2,2-dimethyl-7-morpholinochroman-4-one (105 mg, 87%).

(d) Synthesis of 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)morpholine

[0325] Except that 3-bromo-2,2-dimethyl-7-morpholinochroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)morpholine (55 mg, 58%).

(e) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine

[0326] Except that 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)morpholine was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (c) above was carried out to quantitatively obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine. The obtained compound was used in the next reaction without purification.

Intermediate 14: Synthesis of 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene

(a) Synthesis of 2,2,7-trimethylchroman-4-one

[0327] Except that 1-(2-hydroxy-4-methylphenyl)ethan-1-one was used instead of 1-(2,4-dihydroxyphenyl)ethenone, the same synthesis method as in Intermediate 7 (a) above was carried out to obtain 2,2,7-trimethylchroman-4-one (340 mg, 95%).

(b) Synthesis of 3-bromo-2,2,7-trimethylchroman-4-one

[0328] Except that 2,2,7-trimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-2,2,7-trimethylchroman-4-one (220 mg, 75%).

[0329] Except that 3-bromo-2,2,7-trimethylchroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain 3-bromo-2,2,7-trimethyl-2H-chromene (100 mg, 58%).

(d) Synthesis of 3-bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene

[0330] 3-Bromo-2,2,7-trimethyl-2H-chromene (50 mg, 0.2 mmol) obtained in Intermediate 14 (c) above was dissolved in dichloromethane (2 mL), and N-bromosuccinimide (35 mg, 0.2 mmol) and benzoyl peroxide (4.8 mg, 0.02 mmol) were added thereto and stirred under reflux for 1 hour. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure and separated by MPLC (ethyl acetate:hexane=1:4, v/v) to quantitatively obtain 3-bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene.

(e) Synthesis of 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene

[0331] 3-Bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene (45 mg, 0.14 mmol) obtained in Intermediate 14 (d) above was dissolved in methanol (5 mL), and 1 N aqueous sodium hydroxide solution (0.68 mL, 0.68 mmol) was added thereto and stirred at room temperature for 2 hours. Then, sodium methoxide (7.3 mg, 0.14 mmol) was added thereto and stirred for additional 1 hour at room temperature. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:5, v/v) to obtain 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene (22 mg, 57%).

(f) Synthesis of 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene

[0332] Except that 3-bromo-7-(methoxymethyl)-2,2-dimethyl-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 7-(methoxymethyl)-2,2-dimethyl-3-vinyl-2H-chromene. The obtained compound was used in the next reaction without purification

Intermediate 15: Synthesis of 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene

(a) Synthesis of (3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanol

[0333] 3-Bromo-7-(bromomethyl)-2,2-dimethyl-2H-chromene (120 mg, 0.36 mmol) obtained in Intermediate 14 (d) above was suspended in 1,4-dioxane (4 mL), N-methyl morpholine-N-oxide (169 mg, 1.45 mmol) was added thereto, and heated and stirred at 50 C. for 30 minutes. When the reaction was completed, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and distilled under reduced pressure. The obtained residue was dissolved in ethanol (4 mL), and sodium borohydride (21 mg, 0.54 mmol) was added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain (3-bromo-2,2-dimethyl-2H-chromen-7-yl)methanol (69 mg, 71%).

(b) Synthesis of 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-2H-chromene

[0334] (3-Bromo-2,2-dimethyl-2H-chromen-7-yl)methanol (72 mg, 0.27 mmol) obtained in Intermediate 15 (a) above was dissolved in pyridine (1.5 mL), 4-methoxytrityl chloride (165 mg, 0.54 mmol) was added thereto, and heated and stirred at 70 C. for 1 hour. When the reaction was completed, the reaction mixture was added to water and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-2H-chromene (115 mg, 79%).

[0335] Except that 3-bromo-7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene. The obtained compound was used in the next reaction without purification.

Intermediate 16: Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

(a) Synthesis of 7-bromo-2,2-dimethyl-2H-chromene

[0336] Except that 7-bromo-2,2-dimethylchroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain 7-bromo-2,2-dimethyl-2H-chromene (300 mg, 67%).

(b) Synthesis of tert-butyl 4-(2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0337] Except that 7-bromo-2,2-dimethyl-2H-chromene and tert-butyl piperazine-1-carboxylate were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain tert-butyl 4-(2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate (210 mg, 74%).

[0338] Except that tert-butyl 4-(2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain tert-butyl 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate (82 mg, 78%).

(d) Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0339] Except that tert-butyl 4-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate. The obtained compound was used in the next reaction without purification.

Intermediate 17: Synthesis of tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate

(a) Synthesis of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate

[0340] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and tert-butyl ethyl carbamate were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate (900 mg, 85%).

(b) Synthesis of tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate

[0341] Methyltriphenylphosphonium bromide (2.14 g, 6.00 mmol) was dissolved in tetrahydrofuran and cooled to 0 C. Potassium tert-butoxide (673 mg, 6.00 mmol) was added to the reaction mixture and stirred for 1 hour at 0 C. under nitrogen atmosphere. Then, tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate (800 mg, 2.4 mmol) dissolved in tetrahydrofuran (5 mL) was added dropwise thereto at 0 C. The reaction mixture was raised to room temperature and stirred for 2 hours. When the reaction was completed, the reaction mixture was placed in ice water and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered and concentrated by distillation under reduced pressure. The obtained residue was used in the next reaction without purification.

Intermediate 18: Synthesis of ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

(a) Synthesis of 2,4-difluorobenzene-1,3-diol

[0342] 1,3-Difluoro-2,4-dimethoxybenzene (645 mg, 3.7 mmol) was dissolved in dichloromethane (5 mL), and boron tribromide (11.11 mL, 11.11 mmol, 1M/hexane) was added dropwise thereto and stirred at room temperature for 19 hours. When the reaction was completed, water was added and extracted with diethyl ether. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:3, v/v) to obtain 2,4-difluorobenzene-1,3-diol (463 mg, 86%).

(b) Synthesis of 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one

[0343] 2,4-Difluorobenzene-1,3-diol (463 mg, 3.17 mmol) obtained in Intermediate 18 (a) above, zinc chloride (432 mg, 3.17 mmol) and 3,3-dimethylacrylic acid (317 mg, 3.17 mmol) were added to phosphoryl chloride (2.6 mL), and heated and stirred at 50 C. for 4 hours. When the reaction was completed, the reaction mixture was cooled to room temperature, placed in ice water, and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:3, v/v) to obtain 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one (234 mg, 32.4%).

[0344] Except that 6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one (299 mg, 90%).

(d) Synthesis of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one

[0345] Except that 3-bromo-6,8-difluoro-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (c) above was carried out to obtain 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (245 mg, 61%).

(e) Synthesis of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0346] Except that 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (127 mg, 51%).

(f) Synthesis of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol

[0347] ((6,8-Difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (125 mg, 0.34 mmol) obtained in Intermediate 18 (e) above was dissolved in a mixed solvent of dimethyl sulfoxide/water (5:1, 3 mL), and N-bromosuccinimide (154 mg, 0.86 mmol) was added thereto and stirred at room temperature for 4 hours. When the reaction is completed, the reaction mixture is separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol (158 mg).

(g) Synthesis of ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0348] 3-Bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol (135 mg, 0.29 mmol) obtained in Intermediate 18 (f) above was dissolved in toluene (3 mL), and p-toluenesulfonic acid (8.6 mg, 0.05 mmol) was added thereto, and heated and stirred at 80 C. for 2 hours. When the reaction was completed, the reaction mixture was diluted with ethyl acetate and then washed with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:dichloromethane=3:1, v/v) to obtain ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (105 mg, 81%).

(h) Synthesis of ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0349] Except that ((3-bromo-6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

Intermediate 19: Synthesis of 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine

(a) Synthesis of 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine

[0350] 7-Bromo-2,2-dimethyl-2H-chromene (500 mg, 2.09 mmol) obtained in Intermediate 16 (a) above, allylpalladium chloride dimer (153 mg, 0.42 mmol), [3,6-dimethoxy-2,4,6-tris(1-methylethyl) [1,1-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine (51 mg, 0.105 mmol) and phenol (0.2 mL, 2.3 mmol) were dissolved in 1,4-dioxane (21 mL), and potassium tert-butoxide (2.2 mL, 2.2 mmol, 1M/tetrahydrofuran) and 2,2,2 trifluoroethylamine (0.33 mL, 4.18 mmol) were added thereto, and stirred under reflux under nitrogen atmosphere for 1 hour. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:hexane=2:3, v/v) to obtain 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine (423 mg, 79%).

(b) Synthesis of 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine

[0351] Except that 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 1 (a) above was carried out to obtain 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine (200 mg, 86%).

[0352] Except that 3-bromo-2,2-dimethyl-N-(2,2,2-trifluoroethyl)-2H-chromen-7-amine was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine. The obtained compound was used in the next reaction without purification.

Intermediate 20: Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one

(a) Synthesis of 2,2-dimethyl-4-oxochroman-7-carbonitrile

[0353] 7-Bromo-2,2-dimethylchroman-4-one (170 mg, 0.64 mmol) obtained in Intermediate 9 (a) above, zinc cyanide (149 mg, 1.27 mmol), tris(dibenzylidine acetone)dipalladium(0) (29 mg, 0.032 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl (26 mg, 0.064 mmol) were added to a mixed solvent of N,N-dimethylformamide/water (10:1, 7 mL) and reacted using a microwave (150 W, 120 C., 20 minutes) under nitrogen atmosphere. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate=3:1, v/v) to obtain 2,2-dimethyl-4-oxochroman-7-carbonitrile (105 mg, 72%).

(b) Synthesis of 2,2-dimethyl-2H-chromen-7-carbonitrile

[0354] Except that 2,2-dimethyl-4-oxochroman-7-carbonitrile was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain 2,2-dimethyl-2H-chromen-7-carbonitrile (54 mg, 66%).

[0355] 2,2-Dimethyl-2H-chromen-7-carbonitrile (200 mg, 1.08 mmol) obtained in Intermediate 20 (b) above was dissolved in tetrahydrofuran (1 mL) and then cooled to 0 C. Methylmagnesium bromide (1.8 mL, 5.4 mmol, 3M/diethyl ether) was added dropwise thereto under nitrogen atmosphere and stirred at room temperature for 30 minutes. When the reaction was completed, the reaction mixture was cooled to 0 C., aqueous ammonium chloride solution was added dropwise thereto, stirred for 1 hour, and extracted with ethyl acetate. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (100% dichloromethane) to obtain 1-(2,2-dimethyl-2H-chromen-7-yl)ethan-1-one (110 mg, 50%).

(d) Synthesis of 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)ethan-1-one

[0356] Except that 1-(2,2-dimethyl-2H-chromen-7-yl)ethan-1-one was used instead of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 18 (f) above was carried out to obtain 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)ethan-1-one (58 mg, 58%).

(e) Synthesis of 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one

[0357] Except that 1-(3-bromo-4-hydroxy-2,2-dimethylchroman-7-yl)ethan-1-one was used instead of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol, the same synthesis method as in Intermediate 18 (g) above was carried out to obtain 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one (35 mg, 85%).

(f) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one

[0358] Except that 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)ethan-1-one was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one. The obtained compound was used in the next reaction without purification.

Intermediate 21: Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate

(a) Synthesis of tert-butyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)(methyl)carbamate

[0359] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and tert-butyl methylcarbamate were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain tert-butyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)(methyl)carbamate (500 mg, 88%).

(b) Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate

[0360] Except that tert-butyl (3-formyl-2,2-dimethyl-2H-chromen-7-yl)(methyl)carbamate was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate. The obtained compound was used in the next reaction without purification.

Intermediate 22: Synthesis of N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

(a) Synthesis of 7-(diethylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0361] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and diethylamine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 7-(diethylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde (500 mg, 88%).

(b) Synthesis of N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

[0362] Except that 7-(diethylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine. The obtained compound was used in the next reaction without purification.

Intermediate 23: Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)azetidine

(a) Synthesis of 1-(2,2-dimethyl-2H-chromen-7-yl)azetidine

[0363] Except that 7-bromo-2,2-dimethyl-2H-chromene and azetidine hydrochloride were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 1-(2,2-dimethyl-2H-chromen-7-yl)azetidine (520 mg, 84%).

(b) Synthesis of 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine

[0364] Except that 1-(2,2-dimethyl-2H-chromen-7-yl)azetidine was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine (580 mg, 90%).

[0365] Except that 1-(3-bromo-2,2-dimethyl-2H-chromen-7-yl)azetidine was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)azetidine. The obtained compound was used in the next reaction without purification.

Intermediate 24: Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine

(a) Synthesis of 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromen-3-carbaldehyde

[0366] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and piperidine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromen-3-carbaldehyde (550 mg, 94%).

(b) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine

[0367] Except that 2,2-dimethyl-7-(pyrrolidin-1-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine. The obtained compound was used in the next reaction without purification.

Intermediate 25: Synthesis of ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

(a) Synthesis of 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one

[0368] Except that 4-(trifluoromethoxy)benzene-1,3-diol was used instead of 2,4-difluorobenzene-1,3-diol, the same synthesis method as in Intermediate 18 (g) above was carried out to obtain 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one (700 mg, 84%).

(b) Synthesis of 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one

[0369] Except that 7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one (720 mg, 92%).

[0370] Except that 3-bromo-7-hydroxy-2,2-dimethyl-6-(trifluoromethoxy)chroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (c) above was carried out to obtain 3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-7-((triisopropylsilyl)oxy)chroman-4-one (500 mg, 75%).

(d) Synthesis of ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane

[0371] Except that 3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane (210 mg, 54%).

(e) Synthesis of ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0372] Except that ((3-bromo-2,2-dimethyl-6-(trifluoromethoxy)-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

Intermediate 26: Synthesis of 2,2-dimethyl-3-vinyl-2H-chromen-7-carbonitrile

(a) Synthesis of 3-formyl-2,2-dimethyl-2H-chromen-7-carbonitrile

[0373] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of 7-bromo-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 20 (a) above was carried out to obtain 3-formyl-2,2-dimethyl-2H-chromen-7-carbonitrile (320 mg, 65%).

(b) Synthesis of 2,2-dimethyl-3-vinyl-2H-chromen-7-carbonitrile

[0374] Except that 3-formyl-2,2-dimethyl-2H-chromen-7-carbonitrile was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 2,2-dimethyl-3-vinyl-2H-chromen-7-carbonitrile. The obtained compound was used in the next reaction without purification.

Intermediate 27: Synthesis of 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene

(a) Synthesis of (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol

[0375] 2-Bromo-5-nitrophenol (500 mg, 2.3 mmol) was dissolved in N,N-dimethylacetamide (11 mL), and 2-methylbut-3-en-2-ol (395 mg, 4.6 mmol), triphenylphosphine (241 mg, 0.92 mmol), palladium(II) acetate (103 mg, 0.46 mmol) and triethylamine (696 mg, 6.88 mmol) were added thereto and stirred under reflux at 130 C. for 4 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-90:10) to obtain (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol (288 mg, 56%).

(b) Synthesis of 2,2-dimethyl-7-nitro-2H-chromene

[0376] (E)-2-(3-hydroxy-3-methylbut-1-en-1-yl)-5-nitrophenol (288 mg, 1.29 mmol) obtained in Intermediate 27 (a) above was dissolved in N,N-dimethylformamide (2.4 mL), and silica gel (1,550 mg, 25.8 mmol) was added thereto, and heated and stirred at 140 C. for 18 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was filtered and washed with ethyl acetate. The filtrate was separated into layers of ethyl acetate and water, and the water layer was extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=10:90, v/v) to obtain 2,2-dimethyl-7-nitro-2H-chromene (190 mg, 72%).

[0377] Except that 2,2-dimethyl-7-nitro-2H-chromene was used instead of ((6,8-difluoro-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 18 (f) above was carried out to obtain 3-bromo-2,2-dimethyl-7-nitrochroman-4-ol (120 mg, 69%).

(d) Synthesis of 3-bromo-2,2-dimethyl-7-nitro-2H-chromene

[0378] Except that 3-bromo-2,2-dimethyl-7-nitrochroman-4-ol was used instead of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol, the same synthesis method as in Intermediate 18 (g) above was carried out to obtain 3-bromo-2,2-dimethyl-7-nitro-2H-chromene (60 mg, 58%).

(e) Synthesis of 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene

[0379] Except that 3-bromo-2,2-dimethyl-7-nitro-2H-chromene was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene. The obtained compound was used in the next reaction without purification.

Intermediate 28: Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine

(a) Synthesis of 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromen-3-carbaldehyde

[0380] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and N-methyl piperazine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromen-3-carbaldehyde (520 mg, 84%).

(b) Synthesis of 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine

[0381] Except that 2,2-dimethyl-7-(4-methylpiperazin-1-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine. The obtained compound was used in the next reaction without purification.

Intermediate 29: Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

(a) Synthesis of tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0382] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and N-tert-butoxycarbonyl piperazine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate (500 mg, 90%).

(b) Synthesis of tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate

[0383] Except that tert-butyl 4-(3-formyl-2,2-dimethyl-2H-chromen-7-yl)piperazine-1-carboxylate was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate. The obtained compound was used in the next reaction without purification.

Intermediate 30: Synthesis of ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

(a) Synthesis of 6-bromo-7-hydroxy-2,2-dimethylchroman-4-one

[0384] Except that 4-bromobenzene-1,3-diol was used instead of 2,4-difluorobenzene-1,3-diol, the same synthesis method as in Intermediate 18 (g) above was carried out to obtain 6-bromo-7-hydroxy-2,2-dimethylchroman-4-one (800 mg, 80%).

(b) Synthesis of 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one

[0385] 6-Bromo-7-hydroxy-2,2-dimethylchroman-4-one (180 mg, 0.66 mmol) obtained in Intermediate 30 (a) above and potassium carbonate (184 mg, 1.33 mmol) were dissolved in N,N-dimethylformamide (7 mL), and p-methoxybenzyl chloride (90 l, 0.66 mmol) was added dropwise thereto and stirred at room temperature for 12 hours. To the reaction mixture p-methoxybenzyl chloride (90 l, 0.66 mmol) and potassium carbonate (184 mg, 1.33 mmol) were added and stirred for 2 hours. Then, the reaction temperature was raised to 40 C. and stirred for additional 4 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one (240 mg, 92%).

[0386] Except that 6-bromo-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 6-cyclopropyl-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one (200 mg, 85%).

(d) Synthesis of 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethylchroman-4-one

[0387] Except that 6-cyclopropyl-7-((4-methoxybenzyl)oxy)-2,2-dimethylchroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to obtain 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethylchroman-4-one (160 mg, 78%).

(e) Synthesis of 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one

[0388] Except that 3-bromo-6-cyclopropyl-7-hydroxy-2,2-dimethylchroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (c) above was carried out to obtain 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one (140 mg, 80%).

(f) Synthesis of ((3-bromo-6-cyclopropyl-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0389] Except that 3-bromo-6-cyclopropyl-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one was used instead of 3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-one, the same synthesis method as in Intermediate 7 (d) above was carried out to obtain ((3-bromo-6-cyclopropyl-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane (55 mg, 52%).

(g) Synthesis of ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0390] Except that ((3-bromo-6-cyclopropyl-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

Intermediate 31: Synthesis of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

(a) Synthesis of 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one

[0391] 1-(2,4-Dihydroxyphenyl)ethanone (2.51 g, 16.47 mmol) and pyridinium p-toluenesulfonic acid (170 mg, 0.68 mmol) were dissolved in dichloromethane (25 mL), and 3,4-dihydro-2H-pyran (3.46 g, 41.18 mmol) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate=10:1, v/v) to obtain 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (3.65 g, 94%).

(b) Synthesis of 4-fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one

[0392] After cooling anhydrous tetrahydrofuran (15 mL) to 0 C., lithium diasopropylamide (15 mL, 30 mmol, 2M/tetrahydrofuran) was added thereto under nitrogen atmosphere, and 1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (3.02 g, 12.78 mmol) dissolved in anhydrous tetrahydrofuran (7 mL) was added dropwise thereto over 30 minutes. The reaction mixture was cooled to 40 C., and difluoroacetone (1.57 g, 16.71 mmol) diluted in anhydrous tetrahydrofuran (7 mL) was added dropwise thereto over 1 hour and stirred at 40 C. for additional 40 minutes. When the reaction was completed, the temperature of the reaction mixture was adjusted to 0 C., and aqueous ammonium chloride solution was added dropwise thereto. The reaction mixture was diluted in ethyl acetate, washed with aqueous ammonium chloride solution and aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain 4-fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one. The obtained compound was used in the next reaction without purification.

[0393] 4-Fluoro-3-(fluoromethyl)-3-hydroxy-1-(2-hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)butan-1-one (4.22 g, 12.78 mmol) obtained in Intermediate 31 (b) above was added to pyridine (30 mL) and cooled to 0 C. While maintaining the reaction mixture at 0 C., trifluoroacetic anhydride (5.55 g, 26.42 mmol) was added dropwise thereto for 2 hours, and ethanol (20 mL) and 1,8-diazabicyclo[5,4,0]undec-7-ene (12.24 g, 80.4 mmol) were then added sequentially. The reaction mixture was raised to 50 C., and heated and stirred for 1 hour. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with an aqueous ammonium chloride solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate=10:1, v/v) to obtain 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one (1.08 g, 27%).

(d) Synthesis of 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one

[0394] 2,2-Bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one (1.08 g, 3.45 mmol) obtained in Intermediate 31 (c) above was dissolved in tetrahydrofuran (10 mL), and p-toluenesulfonic acid (134 mg, 0.7 mmol) and methanol (10 mL) were added thereto, and heated and stirred at 50 C. for 2 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure and separated by MPLC (hexane:ethyl acetate=2:1, v/v) to obtain 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one (626 mg, 80%).

(e) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-hydroxychroman-4-one

[0395] Except that 2,2-bis(fluoromethyl)-7-hydroxychroman-4-one was used instead of 7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (b) above was carried out to quantitatively obtain 3-bromo-2,2-bis(fluoromethyl)-7-hydroxychroman-4-one. The obtained compound was used in the next reaction without purification.

(f) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-one

[0396] Except that 3-bromo-2,2-bis(fluoromethyl)-7-hydroxychroman-4-one was used instead of 3-bromo-7-hydroxy-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 7 (c) above was carried out to obtain 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-one (1.17 g, 92%).

(g) Synthesis of 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-ol

[0397] 3-Bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-one (1.17 g, 2.52 mmol) obtained in Intermediate 31 (f) above was dissolved in ethanol (12 mL) and cooled to 0 C., and sodium borohydride (48 mg, 1.28 mmol) was then added thereto. After the reaction mixture was stirred at 0 C. for 15 minutes, sodium borohydride (46 mg, 1.22 mmol) was added in portions three times and stirred at 0 C. for additional 5 minutes. When the reaction was completed, the temperature of the reaction mixture was adjusted to 0 C., aqueous ammonium chloride solution was added dropwise thereto, and extraction was performed several times with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-ol. The obtained compound was used in the next reaction without purification.

(h) Synthesis of ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)oxy)triisopropylsilane

[0398] Except that 3-bromo-2,2-bis(fluoromethyl)-7-((triisopropylsilyl)oxy)chroman-4-ol was used instead of 3-bromo-6,8-difluoro-2,2-dimethyl-7-((triisopropylsilyl)oxy)chroman-4-ol, the same synthesis method as in Intermediate 18 (g) above was carried out to obtain ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)oxy)triisopropylsilane (506 mg, 1.13 45%).

(i) Synthesis of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane

[0399] Except that ((3-bromo-2,2-bis(fluoromethyl)-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Intermediate 7 (e) above was carried out to quantitatively obtain ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane. The obtained compound was used in the next reaction without purification.

Intermediate 32: Synthesis of N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

(a) Synthesis of 7-(diisopropylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0400] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and diisopropylamine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 7-(diisopropylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde (620 mg, 93%).

(b) Synthesis of N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine

[0401] Except that 7-(diisopropylamino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine. The obtained compound was used in the next reaction without purification.

Intermediate 33: Synthesis of N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine

(a) Synthesis of 7-(isopropyl(methyl)amino)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0402] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and N-methylisopropylamine were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain 7-(isopropyl(methyl)amino)-2,2-dimethyl-2H-chromen-3-carbaldehyde (430 mg, 85%).

(b) Synthesis of N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine

[0403] Except that 7-(isopropyl(methyl)amino)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine. The obtained compound was used in the next reaction without purification.

Intermediate 34: Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(ethyl)carbamate

(a) Synthesis of tert-butyl ethyl(3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate

[0404] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and tert-butyl ethylcarbamate were used instead of 7-bromo-2,2-dimethylchroman-4-one and O-tert-butyl-carbamate, respectively, the same synthesis method as in Intermediate 9 (b) above was carried out to obtain tert-butyl ethyl(3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate (520 mg, 88%).

(b) Synthesis of tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(ethyl)carbamate

[0405] Except that tert-butyl ethyl(3-formyl-2,2-dimethyl-2H-chromen-7-yl)carbamate was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(ethyl)carbamate. The obtained compound was used in the next reaction without purification.

Intermediate 35: Synthesis of 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole

(a) Synthesis of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0406] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and (1,3-dimethyl-1H-pyrazol-5-yl)boronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde (300 mg, 85%).

(b) Synthesis of 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole

[0407] Except that 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole. The obtained compound was used in the next reaction without purification.

Intermediate 36: Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole

(a) Synthesis of 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0408] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and (1,3-dimethyl-1H-pyrazol-5-yl)boronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde (300 mg, 85%).

(b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole

[0409] Except that 7-(2,5-dimethylthiazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole. The obtained compound was used in the next reaction without purification.

Intermediate 37: Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole

(a) Synthesis of 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde

[0410] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 1-ethyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabororane-2-yl)-1H-pyrazole were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde (442 mg, 80%).

(b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole

[0411] Except that 7-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-2,2-dimethyl-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole. The obtained compound was used in the next reaction without purification.

Intermediate 38: Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

(a) Synthesis of 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromen-3-carbaldehyde

[0412] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 3-pyridyl boronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromen-3-carbaldehyde (300 mg, 85%).

(b) Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0413] Except that 2,2-dimethyl-7-(pyridin-3-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine. The obtained compound was used in the next reaction without purification.

Intermediate 39: Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

(a) Synthesis of 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromen-3-carbaldehyde

[0414] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 4-pyridyl boronic acid were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromen-3-carbaldehyde (270 mg, 78%).

(b) Synthesis of 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine

[0415] Except that 2,2-dimethyl-7-(pyridin-4-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine. The obtained compound was used in the next reaction without purification.

Intermediate 40: Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole

(a) Synthesis of 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromen-3-carbaldehyde

[0416] Except that 7-bromo-2,2-dimethyl-2H-chromen-3-carbaldehyde and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)isoxazole were used instead of ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and vinylboronic acid dibutyl ester, respectively, the same synthesis method as in Intermediate 7 (e) above was carried out to obtain 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromen-3-carbaldehyde (335 mg, 83%).

(b) Synthesis of 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole

[0417] Except that 2,2-dimethyl-7-(3-methylisoxazol-4-yl)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole. The obtained compound was used in the next reaction without purification.

Intermediate 41: Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene

(a) Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-3-carbaldehyde

[0418] 1-(2-Hydroxy-4-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (0.64 g, 2.9 mmol) obtained in Intermediate 31 (a) above and potassium carbonate (0.6 g, 4.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane/water (3:1, 8 mL), and 3-methylbut-2-enal (0.49 g, 5.8 mmol) was added dropwise thereto, and heated and stirred at 80 C. for 72 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-3-carbaldehyde. The obtained compound was used in the next reaction without purification.

(b) Synthesis of 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene

[0419] Except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-3-carbaldehyde was used instead of tert-butyl ethyl(3-formyl-2,2-dimethylchromen-7-yl)carbamate, the same synthesis method as in Intermediate 17 (b) above was carried out to quantitatively obtain 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene. The obtained compound was used in the next reaction without purification.

Example 1: Synthesis of 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0420] 4-Phenyl-1,2,4-triazolidine-3,5-dione (0.3 g, 1.7 mmol) was suspended in tetrahydrofuran (3 mL), and iodobenzene diacetate (0.55 g, 1.7 mmol) was added thereto and stirred for 30 minutes under light blocking. ((2,2-Bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane (0.67 g, 1.7 mmol) dissolved in tetrahydrofuran (3 mL) was added to the reaction mixture and stirred for additional 30 minutes. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane ethyl acetate=5:1, v/v) to obtain 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.61 g, 67%).

(b) Synthesis of 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0421] After dissolving 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.41 g, 0.72 mmol) obtained in Example 1 (a) above in tetrahydrofuran (5 mL), it was added to a conical centrifuge tube containing hydrogen fluoride-pyridine (3.85 mmol, 5 mL, 7:3, v/v) and stirred for 20 hours. When the reaction was completed, 2-(trimethylsilyl)ethanol (5 mL) was added dropwise to the reaction mixture and concentrated by distillation under reduced pressure. The obtained residue was separated by MPLC (hexane:ethyl acetate=5:1, v/v) to obtain 7,7-bis(fluoromethyl)-10-hydroxy-2-phenyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (296 mg, 54%).

[0422] .sup.1H NMR (400 MHz, acetone) 8.56 (s, 1H), 7.69-7.62 (m, 2H), 7.54 (dd, J=8.5, 7.1 Hz, 2H), 7.48-7.39 (m, 1H), 6.95-6.89 (m, 1H), 6.59-6.51 (m, 2H), 6.21-6.14 (m, 1H), 5.61 (d, J=1.4 Hz, 1H), 4.93 (t, J=2.1 Hz, 1H), 4.90-4.75 (m, 2H), 4.75-4.64 (m, 1H), 4.56 (dd, J=10.3, 2.7 Hz, 1H), 4.34-4.18 (m, 2H), 2.91-2.84 (m, 1H)

Example 2: Synthesis of 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0423] 4-(4-Acetylphenyl)-1,2,4-triazolidine-3,5-dione (0.3 g, 1.37 mmol) was suspended in tetrahydrofuran (3 mL), and iodobenzene diacetate (0.45 g), 1.37 mmol) was added thereto and stirred for 30 minutes under light blocking. ((2,2-Bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane (0.54 g, 1.37 mmol) dissolved in tetrahydrofuran (3 mL) was added to the reaction mixture and stirred for additional 30 minutes. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (hexane:ethyl acetate=5:1, v/v) to obtain 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.42 g, 53%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0424] Except that 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-bis(fluoromethyl)-10-hydroxy-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (132 mg, 60%).

[0425] .sup.1H NMR (400 MHz, acetone) 9.62 (s, 1H), 8.14-8.12 (m, 1H), 7.80-7.78 (m, 1H), 6.81-6.79 (m, 1H), 6.45-6.11 (m, 1H), 5.63 (s, 1H), 4.88-4.53 (m, 4H), 4.24 (s, 1H), 2.63 (s, 3H), 2.07 (s, 1H)

Example 3: Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)acetamide

[0426] Except that N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)acetamide was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydroxy-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)acetamide (28 mg, 36%).

[0427] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.95 (s, 1H), 8.17-8.10 (m, J=8.6 Hz, 2H), 7.85-7.78 (m, J=8.6 Hz, 1H), 7.33 (s, 1H), 7.06-6.97 (m, 2H), 5.97 (br s, 1H), 5.66 (s, 1H), 4.20 (br s, 2H), 2.64 (s, 3H), 2.02 (s, 3H), 1.57 (s, 3H), 1.52 (s, 3H)

Example 4: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0428] Except that 2,2-dimethyl-7-(methylsulfonyl)-3-vinyl-2H-chromene was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylsulfonyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (58 mg, 39%).

[0429] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.12 (m, J=8.4 Hz, 2H), 7.84-7.80 (m, J=8.4 Hz, 2H), 7.54 (d, J=7.81 Hz, 1H), 7.39 (s, 1H), 7.38 (d, J=8.1 Hz, 1H), 6.07 (br s, 1H), 5.84 (s, 1H), 4.24 (br s, 2H), 3.21 (s, 3H), 2.67-2.63 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H)

Example 5: Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)methanesulfonamide

[0430] Except that N-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)methanesulfonamide was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)methanesulfonamide (78 mg, 46%).

[0431] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.88-9.71 (m, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.82 (br d, J=8.3 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.01 (br s, 1H), 5.69 (s, 1H), 4.21 (br s, 2H), 2.98 (s, 3H), 2.65 (s, 3H), 1.56 (d, J=15.8 Hz, 6 h)

Example 6: Synthesis of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate

[0432] Except that tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)carbamate was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate (67 mg, 36%).

[0433] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.36 (s, 1H), 8.16-8.11 (m, J=8.6 Hz, 2H), 7.82-7.78 (m, J=8.6 Hz, 2H), 7.10 (s, 1H), 7.01-6.94 (m, 2H), 5.97 (br s, 1H), 5.65 (s, 1H), 4.20 (br s, 2H), 2.64 (s, 3H), 1.56 (s, 3H), 1.52 (s, 3H), 1.46 (s, 9 h)

Example 7: Synthesis of 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0434] Tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate (40 mg, 0.077 mmol) obtained in Example 6 above was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (8.8 mg, 0.077 mmol) was added dropwise thereto and stirred at room temperature for 30 minutes. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (22 mg, 68%).

[0435] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.11 (m, J=8.6 Hz, 2H), 7.82-7.76 (m, J=8.6 Hz, 2H), 6.72 (d, J=8.3 Hz, 1H), 6.16 (dd, J=1.8, 8.3 Hz, 1H), 6.08-6.04 (m, 1H), 5.92 (br s, 1H), 5.56 (s, 1H), 5.09 (br s, 2H), 4.24-4.12 (m, 2H), 2.64 (s, 3H), 1.51 (d, J=7.8 Hz, 6 h)

Example 8: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0436] Except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)morpholine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (80 mg, 46%).

[0437] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.09-8.03 (m, J=8.4 Hz, 2H), 7.74-7.69 (m, J=8.4 Hz, 2H), 6.87 (d, J=8.6 Hz, 1H), 6.48 (dd, J=2.0, 8.6 Hz, 1H), 6.33 (d, J=2.0 Hz, 1H), 5.91 (br s, 1H), 5.59 (s, 1H), 4.12 (br s, 2H), 3.62 (br t, J=4.5 Hz, 4H), 3.02-2.93 (m, 4H), 2.57 (s, 3H), 1.47 (d, J=6.8 Hz, 6 h)

Example 9: Synthesis of N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)sulfuric diamide

[0438] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 0.043 mmol) obtained in Example 7 above was dissolved in N,N-dimethylacetamide (0.5 mL), and sulfamoyl chloride (9.9 mg, 0.086 mmol) was added dropwise thereto and stirred at room temperature for 18 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain N-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)sulfuric diamide (4 mg, 19%).

[0439] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.44 (br s, 1H), 8.09-8.03 (m, J=8.6 Hz, 2H), 7.76-7.70 (m, J=8.6 Hz, 2H), 7.03 (s, 2H), 6.90 (d, J=8.3 Hz, 1H), 6.67 (d, J=8.7 Hz, 1H), 6.64 (d, J=1.8 Hz, 1H), 5.92 (br s, 1H), 5.59 (s, 1H) 4.13 (br s, 2H), 2.57 (s, 3H), 1.50 (s, 3H), 1.46 (s, 3H)

Example 10: Synthesis of 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0440] Except that ((3-bromo-2,2-dimethyl-2H-chromen7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (120 mg, 42%).

(b) Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0441] Except that 2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (57 mg, 62%).

(c) Synthesis of 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0442] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 0.072 mmol) obtained in Example 10 (b) above was suspended in acetonitrile (2 mL), and N-bromosuccinimide (15 mg, 0.086 mmol) was added thereto and stirred at room temperature for 2 hours. 1-Bromopyrrolidine-2,5-dione (3.82 mg, 0.021 mmol) was added thereto and stirred for additional 2 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-9,11-dibromo-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (17 mg, 41%).

[0443] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.97 (s, 1H), 8.15-8.13 (m, 2H), 7.78-7.76 (m, 2H), 7.23 (s, 1H), 6.02-6.01 (m, 1H), 5.66 (s, 1H), 4.26-4.15 (m, 2H), 2.63 (s, 3H), 1.61 (s, 3H), 1.52 (s, 3H)

Example 11: Synthesis of 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0444] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (71 mg, 0.17 mmol) obtained in Example 10 (b) above was suspended in acetonitrile (2 mL), and N-chlorosuccinimide (27 mg, 0.203 mmol) was added thereto, and heated and stirred at 70 C. for 3 hours. 1-Chloropyrrolidine-2,5-dione (18 mg, 0.136 mmol) was added thereto, and heated and stirred at 70 C. for additional 4 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-9,11-dichloro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (9 mg, 11%).

[0445] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 10.20 (s, 1H), 8.15-8.12 (m, 2H), 7.79-7.76 (m, 2H), 7.09 (s, 1H), 6.04-6.02 (m, 1H), 5.64 (s, 1H), 4.26-4.18 (m, 2H), 2.63 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H)

Example 12: Synthesis of 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0446] Except that ((3-bromo-2,2-dimethyl-2H-chromen-7-yl)oxy)triisopropylsilane and 1,2,4-triazolidine-3,5-dione were used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, respectively, the same synthesis method as in Example 2 (a) above was carried out to obtain 7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 48%).

(b) Synthesis of 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0447] 7,7-Dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (35 mg, 0.076 mmol) obtained in Example 12 (a) above was dissolved in N,N-dimethylformamide (3 mL), and 2, 6-difluoropyridine (14 mg, 0.12 mmol) and cesium carbonate (50 mg, 0.15 mmol) were added thereto, and heated and stirred at 80 C. for 2 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-80:20) to obtain 2-(6-fluoropyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (7 mg, 23%).

[0448] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 11.71-11.57 (m, 1H), 8.09-7.78 (m, 1H), 7.01-6.97 (m, 1H), 6.90 (ddd, J=2.0, 8.1, 11.2 Hz, 2H), 6.77 (dd, J=2.4, 8.4 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.08-5.86 (m, 1H), 5.59 (s, 1H), 4.16-4.05 (m, 1H), 4.05-3.94 (m, 1H), 1.55 (d, J=19.6 Hz, 6 h)

Example 13: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo [1,2-a]pyridazine-1,3(2H)-dione

[0449] Except that 2,2-dimethyl-7-nitro-3-vinyl-2H-chromene was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-nitro-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo [1,2-a]pyridazine-1,3(2H)-dione (54 mg, 68%).

[0450] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.13 (m, 2H), 7.88-7.82 (m, 3H), 7.68-7.67 (m, 1H), 7.41-7.38 (m, 1H), 6.08-6.08 (m, 1H), 5.87 (m, 1H), 4.24 (s, 2H), 2.64 (s, 3H), 1.65 (s, 3H), 1.55 (s, 3H)

Example 14: Synthesis of 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-10-(((4-methoxyphenyl)diphenylmethoxy)methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0451] Except that 7-(((4-methoxyphenyl)diphenylmethoxy)methyl)-2,2-dimethyl-3-vinyl-2H-chromene was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(((4-methoxyphenyl)diphenylmethoxy)methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (142 mg, 62%).

(b) Synthesis of 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0452] 2-(4-Acetylphenyl)-10-(((4-methoxyphenyl)diphenylmethoxy)methyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 0.14 mmol) obtained in Example 14 (a) above was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (16 mg, 0.14 mmol) was added dropwise thereto and stirred at room temperature for 20 minutes. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-10-(hydroxymethyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (43 mg, 70%).

[0453] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.07 (br d, J=8.2 Hz, 2H), 7.73 (br d, J=7.8 Hz, 2H), 6.94 (br d, J=7.7 Hz, 1H), 6.84 (br d, J=7.6 Hz, 1H), 6.76 (br s, 1H), 5.90 (br s, 1H), 5.61 (br s, 1H), 5.13-5.09 (m, 1H), 4.39-4.32 (m, 2H), 4.13 (br s, 2H), 2.59-2.55 (m, 3H), 1.51 (br s, 3H), 1.43 (br s, 3H)

Example 15: Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)urea

[0454] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 0.043 mmol) obtained in Example 7 above was dissolved in a mixed solvent of acetic acid/water (2:1, 1 mL), and sodium cyanate (5.6 mg, 0.086 mmol) was added thereto and stirred at room temperature for 30 minutes. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)urea (11 mg, 55%).

[0455] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.07 (br d, J=8.2 Hz, 2H), 7.73 (br d, J=7.8 Hz, 2H), 6.94 (br d, J=7.7 Hz, 1H), 6.84 (br d, J=7.6 Hz, 1H), 6.76 (br s, 1H), 5.90 (br s, 1H), 5.61 (br s, 1H), 5.13-5.09 (m, 1H), 4.39-4.32 (m, 2H), 4.13 (br s, 2H), 2.59-2.55 (m, 3H), 1.51 (br s, 3H), 1.43 (br s, 3H)

Example 16: Synthesis of 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(ethyl)carbamate

[0456] Except that tert-butyl (2,2-dimethyl-3-vinylchromen-7-yl)(ethyl)carbamate was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(ethyl)carbamate (54 mg, 52%).

(b) Synthesis of 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0457] Except that tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(ethyl)carbamate was used instead of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate, the same synthesis method as in Example 7 above was carried out to obtain 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (26 mg, 72%).

[0458] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-8.07 (m, J=8.7 Hz, 2H), 7.88-7.80 (m, J=8.6 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.19 (dd, J=2.2 Hz, 8.4 Hz, 1H), 6.11 (d J=2.2 Hz, 1H), 5.87-5.80 (m, 1H), 5.73 (s, 1H), 4.31 (dd, J=4.8, 16.0 Hz, 1H), 4.09 (td, J=2.3, 16.4 Hz, 1H), 3.60 (br, s, 1H), 3.09 (q, J=7.1 Hz, 2H), 2.65 (s, 3H), 1.60 (d, J=9.5 Hz, 6H), 1.30-1.14 (m, 3H)

Example 17: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0459] Except that 2,2-dimethyl-N-(2,2,2-trifluoroethyl)-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-((2,2,2-trifluoroethyl)amino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (58 mg, 60%).

[0460] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-8.08 (m, J=8.7 Hz, 2H), 7.86-7.81 (m, J=8.1 Hz, 2H), 6.91 (d, J=8.4 Hz, 1H), 6.19 (br d, J=8.6 Hz, 1H), 6.21 (s, 1H), 5.86 (br s, 1H), 5.73 (br s, 1H), 4.36-4.27 (m, 1H), 4.11 (br d, J=17.4 Hz, 1H), 4.01-3.92 (m, 1H), 3.77-3.66 (m, 2H), 2.65 (s, 3H), 1.60 (br d, J=9.7 Hz, 6H)

Example 18: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride

(a) Synthesis of tert-butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl)piperazine-1-carboxylate

[0461] Except that tert-butyl 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)piperazine-1-carboxylate was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain tert-butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl)piperazine-1-carboxylate (100 mg, 50%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride

[0462] Tert-butyl 4-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl)piperazine-1-carboxylate (55 mg, 0.09 mmol) obtained in Example 18 (a) above was dissolved in dichloromethane (1 mL), and 4M hydrochloric acid solution (94 L, 0.374 mmol, 4M HCl/dioxane) was added dropwise thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, triturated with ethyl acetate, and the obtained solid was filtered to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (31 mg, 63%).

[0463] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.07 (br s, 2H), 8.15-8.13 (m, 2H), 7.78-7.77 (m, 2H), 6.98-6.96 (m, 1H), 6.61-6.60 (m, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 5.67 (s, 1H), 4.20 (s, 1H), 3.30 (s, 4H) 3.18 (s, 4H), 2.59 (s, 3H), 1.56 (br s, 3H), 1.53 (br s, 3H)

Example 19: Synthesis of 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0464] 2-(4-Acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (20 mg, 0.038 mmol) obtained in Example 18 (b) above was dissolved in dimethyl sulfoxide (0.5 mL), acetic anhydride (4.32 L, 0.046 mmol) and triethylamine (5.32 L, 0.038 mmol) were added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-10-(4-acetylpiperazin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 89%).

[0465] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.14-8.12 (m, 2H), 7.79-7.77 (m, 2H), 6.98-6.96 (m, 1H), 6.61-6.60 (m, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 5.67 (s, 1H), 4.20 (s, 1H), 3.04 (s, 4H) 3.03 (s, 4H), 2.66 (s, 1H), 2.01 (s, 3H), 1.54 (br s, 3H), 1.53 (br s, 3H)

Example 20: Synthesis of 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0466] Except that 1-(6-fluoropyridin-3-yl)ethan-1-one was used instead of 2,6-difluoropyridine, the same synthesis method as in Example 12 (b) above was carried out to obtain 2-(5-acetylpyridin-2-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (46 mg, 34%).

[0467] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 11.65 (br s, 1H), 8.75 (d, J=2.3 Hz, 1H), 8.30 dd, J=2.4, 8.7 Hz, 1H), 7.12 (d, J=8.6 Hz), 6.99 (d, J=8.3 Hz, 1H), 6.77 (dd, J=2.3, 8.4 Hz, 1H), 6.69 (d, J=2.3 Hz 1H), 6.05-5.91 (m, 1H), 4.14-4.06 (m, 1H), 2.55 (s, 1H), 2.56-2.54 (m, 1H), 2.56-2.54 (m, 1H), 2.61-2.53 (m, 1H), 2.61-2.53 (m, 1H), 1.57 (s, 3H)

Example 21: Synthesis of 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0468] Except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)ethan-1-one was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 10-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (37 mg, 46%).

[0469] .sup.1H NMR (400 MHz, CDCl.sub.3) =8.12 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.7 Hz, 2H), 7.57 (dd, J=1.5, 8.1 Hz, 1H), 7.49 (d, J=1.5 Hz, 1H), 7.14 (d, J=7.9 Hz, 1H), 5.88-5.84 (m, 1H), 5.72 (s, 1H), 4.31 (dd, J=3.7, 16.7 Hz, 1H), 4.17 (td, J=2.6, 16.6 Hz, 1H), 2.66 (s, 3H), 2.56 (s, 3H), 1.65 (s, 3H), 1.60-1.58 (m, 3H)

Example 22: Synthesis of 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 11-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0470] Except that 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 11-acetyl-2-(4-acetylphenyl)-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (45 mg, 50%).

(b) Synthesis of 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0471] Except that 1-(3-bromo-2,2-dimethyl-7-((triisopropylsilyl)oxy)-2H-chromen-6-yl)ethan-1-one was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 11-acetyl-2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 57%).

[0472] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 12.20 (s, 1H), 8.17-8.13 (m, J=8.6 Hz, 2H), 7.81-7.76 (m, J=8.6 Hz, 2H), 7.69 (s, 1H), 6.36 (s, 1H), 6.13 (br s, 1H), 5.80 (s, 1H), 4.25 (br s, 2H), 2.64 (s, 1H), 2.49-2.48 (m, 3H), 1.61 (d, J=5.6 Hz, 6H)

Example 23: Synthesis of 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0473] Except that 1-(5-fluoropyridin-2-yl)ethan-1-one was used instead of 2,6-difluoropyridine, the same synthesis method as in Example 12 (b) above was carried out to obtain 2-(6-acetylpyridin-3-yl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (32 mg, 38%).

[0474] .sup.1H NMR (400 MHz, DMSO-D.sub.6) =8.48-8.48 (m, 1H), 7.97-7.95 (m, 1H), 7.46-7.44 (m, 1H), 7.05-7.03 (m, 1H), 6.76-6.73 (m, 1H), 6.64 (s, 1H), 5.95-5.94 (m, 1H), 5.49-5.49 (m, 1H), 4.04-4.00 (m, 1H), 3.85-3.81 (m, 1H), 2.60 (s, 3H), 1.55-1.51 (m, 6H)

Example 24: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-carbonitrile

[0475] Except that 2,2-dimethyl-3-vinyl-2H-chromene-7-carbonitrile was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-carbonitrile (34 mg, 46%).

[0476] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.14-8.13 (m, 2H), 7.81-7.79 (m, 2H), 7.46-7.40 (m, 2H), 7.31-7.29 (m, 1H), 6.06-6.05 (m, 1H), 5.81 (s, 1H), 4.22 (s, 1H), 2.64 (s, 3H), 1.63 (s, 3H), 1.52 (s, 3H)

Example 25: Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0477] Except that ((2,2-dimethyl-6-(trifluoromethoxy)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 42%).

(b) Synthesis of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0478] Except that 2-(4-acetylphenyl)-7,7-dimethyl-11-(trifluoromethoxy)-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-11-(trifluoromethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 60%).

[0479] .sup.1H NMR (400 MHz, DMSO-D.sub.6) =10.30 (s, 1H), 8.17-8.11 (m, J=8.6 Hz, 2H), 7.76-7.70 (m, J=8.4 Hz, 2H), 7.02 (s, 1H), 6.47 (s, 1H), 6.07 (m, 1H), 5.69 (s, 1H), 4.21 (br s, 2H), 2.63 (s, 3H), 1.54 (d, J=3.1 Hz, 6H)

Example 26: Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0480] Except that ((6-cyclopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (54 mg, 50%).

(b) Synthesis of 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0481] Except that 2-(4-acetylphenyl)-11-cyclopropyl-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 2-(4-acetylphenyl)-11-cyclopropyl-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (18 mg, 48%).

[0482] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.37 (s, 1H), 8.12-8.06 (m, J=8.6 Hz, 2H), 7.70-7.65 (m, J=8.6 Hz, 2H), 6.38 (s, 1H), 6.22 (s, 1H), 5.88 (br s, 1H), 5.51 (s, 1H), 4.17-4.06 (m, 2H), 2.57 (s, 3H), 1.87-1.79 (m, 1H), 1.44 (d, J=2.2, 8.3 Hz, 2H), 0.28 (br t, J=5.9 Hz, 2H)

Example 27: Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0483] Except that ((6,8-difluoro-2,2-dimethyl-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (54 mg, 52%).

(b) Synthesis of 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0484] Except that 2-(4-acetylphenyl)-9,11-difluoro-7,7-dimethyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 7,7-bis(fluoromethyl)-2-phenyl-10-((triisopropylsilyl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 1 (b) above was carried out to obtain 2-(4-acetylphenyl)-9,11-difluoro-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (15 mg, 58%).

[0485] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 10.31 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 2H), 6.83-6.80 (m, 2H), 6.02 (s, 1H), 5.67 (s, 1H), 4.25-4.15 (m, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H)

Example 28: Synthesis of 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0486] Except that 2-(4-acetylamine)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 10 (c) above was carried out to obtain 2-(4-acetylphenyl)-10-amino-9,11-dibromo-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 32%).

[0487] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.11 (m, 2H), 7.80-7.75 (m, 2H), 7.15 (d, J=1.1 Hz, 1H), 6.01 (br s, 1H), 5.64 (s, 1H), 5.39 (s, 2H), 4.26-4.12 (m, 2H), 2.64 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H)

Example 29: Synthesis of 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0488] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (713 mg, 1.7 mmol) obtained in Example 7 above was dissolved in 1,2-dichloroethane (7 mL), and 2-methoxyprop-1-ene (253 mg, 3.41 mmol), sodium triacetoxyborohydride (533 mg, 3.41 mmol) and acetic acid (368 mg, 5.94 mmol) were added thereto and stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with aqueous sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (526 mg, 66%).

[0489] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.11 (m, 2H), 7.81-7.77 (m, J=8.7 Hz, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.16 (dd, J=2.2, 8.4 Hz, 1H), 6.01 (d, J=2.1 Hz, 1H), 5.94 (br d, J=1.8 Hz, 1H), 5.58 (s, 1H), 5.43 (d, J=8.1 Hz, 1H), 4.25-4.13 (m, 2H), 3.50-3.36 (m, 1H), 2.64 (s, 3H), 1.52 (d, J=3.3 Hz, 5H), 1.48-1.47 (m, 1H), 1.08 (d, J=6.4 Hz, 6H)

Example 30: Synthesis of 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0490] 2-(4-Acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 0.24 mmol) obtained in Example 7 above was dissolved in nitromethane (1 mL), and copper(II) trifluoromethanesulfonate (4.3 mg, 0.012 mmol) and tert-butyl trichloroacetimidate (107 L, 0.6 mmol) were added thereto and stirred at room temperature for 12 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 2-(4-acetylphenyl)-10-(tert-butylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (5 mg, 4.4%).

[0491] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.09-8.03 (m, 2H), 7.75-7.69 (m, 2H), 6.72-6.65 (m, 1H), 6.28-6.21 (m, 1H), 6.12-6.07 (m, 1H), 5.90-5.83 (m, 1H), 5.54-5.48 (m, 1H), 5.18-5.12 (m, 1H), 4.19-4.03 (m, 2H), 2.58-2.56 (m, 3H), 1.47-1.43 (m, 6H), 1.19-1.17 (m, 9H)

Example 31: Synthesis of 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0492] Except that 2-(4-acetylamine)-7,7-dimethyl-10-morpholino-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 11 above was carried out to obtain 2-(4-acetylphenyl)-10-amino-9,11-dichloro-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (53 mg, 38%).

[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) =8.16-8.09 (m, J=8.4 Hz, 2H), 7.86-7.82 (m, J=8.6 Hz, 2H), 6.94 (s, 1H), 5.85 (br s, 1H), 5.64 (br s, 1H), 4.50 (s, 2H), 4.29 (dd, J=4.4, 16.6 Hz, 1H), 4.16 (br d, J=16.5 Hz, 1H), 2.66 (s, 3H), 2.03-2.00 (m, 1H), 1.64 (d, J=6.5 Hz, 6H)

Example 32: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(methyl)carbamate

[0494] Except that tert-butyl (2,2-dimethyl-3-vinyl-2H-chromen-7-yl)(methyl)carbamate was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(methyl)carbamate (54 mg, 36%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0495] Except that tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)(methyl)carbamate was used instead of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate, the same synthesis method as in Example 7 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (23 mg, 58%).

[0496] .sup.1H NMR (400 MHz, CDCl.sub.3) =8.15-8.10 (m, J=8.4 Hz, 2H), 7.89-7.83 (m, J=8.4 Hz, 2H), 6.95 (d, J=8.3 Hz, 1H), 6.22 (dd, J=2.0, 8.4 Hz, 1H), 6.14 (s, 1H), 5.89-5.54 (m, 1H), 5.76 (br s, 1H), 4.33 (dd, J=4.9, 16.5 Hz, 1H), 4.12 (br d, J=16.4 Hz, 1H), 3.76 (br s, 1H), 2.80 (S, 3H), 2.67 (s, 3H), 2.03 (s, 1H), 1.65-1.60 (m, 6H)

Example 33: Synthesis of 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0497] Except that N,N-diethyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(diethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 51%).

[0498] .sup.1H NMR (400 MHz, DMSO-D.sub.6) =8.14-8.12 (m, 2H) 7.79-7.78 (m, 2H), 6.87-6.85 (m, 1H), 6.27-6.24 (m, 1H), 6.07 (s, 1H), 5.98 (s, 1H), 5.62 (s, 1H), 4.24-4.14 (m, 2H), 3.29-3.23 (m, 4H), 2.64 (s, 3H), 1.53 (s, 6H), 1.05-1.02 (m, 6H)

Example 34: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0499] Except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 42%).

[0500] .sup.1H NMR (400 MHz, DMSO-D.sub.6) =8.14-8.12 (m, 2H) 7.79-7.77 (m, 2H), 6.88-6.86 (m, 1H), 6.16 (m, 1H), 5.98 (s, 1H), 5.95-5.95 (m, 1H), 5.63 (s, 1H), 4.24-4.14 (m, 2H), 3.14 (s, 4H), 2.64 (s, 3H), 1.91 (s, 4H), 1.53 (s, 6H)

Example 35: Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of tert-butyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate

[0501] Except that 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, the same synthesis method as in Example 6 above was carried out to obtain tert-butyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate (82 mg, 43%).

(b) Synthesis of 10-amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0502] Except that tert-butyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate was used instead of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate, the same synthesis method as in Example 7 above was carried out to obtain 10-amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (56 mg, 78%).

(c) Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0503] 10-Amino-2-(4-fluorophenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (17 mg, 0.043 mmol) obtained in Example 35 (b) above was dissolved in dichloromethane (1 mL) and cooled to 0 C., and 3-oxetanone (4.15 L, 0.065 mmol), acetic acid (2.468 L, 0.043 mmol), sodium triacetoxyborohydride (73 mg, 0.35 mmol) and titanium(IV) propane-2-oleate (12.8 L, 0.043 mmol) were added thereto and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with aqueous sodium bicarbonate solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 2-(4-fluorophenyl)-7,7-dimethyl-10-(oxetan-3-ylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (8 mg, 41%).

[0504] .sup.1H NMR (400 MHz, CDCl.sub.3) =7.63 (br dd, J=4.6, 8.8 Hz, 2H), 7.23 (br t, J=8.5 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 6.17-6.11 (m, 1H), 5.98 (s, 1H), 5.90-5.84 (m, 1H), 5.73 (br s, 1H), 4.99 (br t, J=6.4 Hz, 2H), 4.58 (br d, J=5.6 Hz, 1H), 4.55-4.48 (m, 2H), 4.32 (dd, J=4.9, 16.4 Hz, 1H), 4.10 (br d, J=16.3 Hz, 1H), 1.60 (s, 6H)

Example 36: Synthesis of 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0505] Except that 2-(4-acetylphenyl)-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 11 above was carried out to obtain 2-(4-acetylphenyl)-9,11-dichloro-7,7-dimethyl-10-(methylamino)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (32 mg, 28%).

[0506] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15-8.08 (m, 2H), 7.87-7.80 (m, 2H), 6.97-6.92 (m, 1H), 5.83 (t, J=3.5 Hz, 1H), 5.61 (s, 1H), 4.34-4.24 (m, 1H), 4.17 (dt, J=16.5, 2.8 Hz, 1H), 4.00 (p, J=6.4 Hz, 1H), 2.65 (d, J=0.6 Hz, 3H), 1.65 (s, 3H), 1.60 (s, 3H), 1.16 (dd, J=6.4, 4.5 Hz, 6H)

Example 37: Synthesis of 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0507] Except that 2-(4-acetylphenyl)-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 11 above was carried out to obtain 2-(4-acetylphenyl)-9,11-dichloro-10-(isopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (22 mg, 30%).

[0508] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.16-8.08 (m, 2H), 7.87-7.79 (m, 2H), 6.95 (d, J=1.2 Hz, 1H), 5.88-5.81 (m, 1H), 5.61 (d, J=2.7 Hz, 1H), 4.28 (ddd, J=16.6, 4.5, 1.4 Hz, 1H), 4.17 (dt, J=16.5, 2.8 Hz, 1H), 3.01 (s, 3H), 2.65 (s, 3H), 1.63 (d, J=15.3 Hz, 7H)

Example 38: Synthesis of 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0509] Except that 5-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1,3-dimethyl-1H-pyrazole was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(1,3-dimethyl-1H-pyrazol-5-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (42 mg, 50%).

[0510] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.18-8.10 (m, 2H), 7.85-7.77 (m, 2H), 7.18 (dd, J=8.0, 1.0 Hz, 1H), 7.10 (dd, J=7.9, 1.7 Hz, 1H), 6.99 (d, J=1.7 Hz, 1H), 6.15 (s, 1H), 6.03 (td, J=3.7, 1.8 Hz, 1H), 5.77 (d, J=1.7 Hz, 1H), 4.23 (dd, J=4.0, 2.0 Hz, 2H), 3.74 (s, 3H), 2.64 (s, 3H), 2.14 (s, 3H), 1.62 (s, 3H), 1.55 (s, 3H)

Example 39: Synthesis of 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0511] Except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-2,5-dimethylthiazole was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(2,5-dimethylthiazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (28 mg, 48%).

[0512] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.18-8.10 (m, 2H), 7.85-7.78 (m, 2H), 7.26 (dd, J=8.0, 1.7 Hz, 1H), 7.18-7.11 (m, 2H), 6.00 (td, J=3.7, 1.8 Hz, 1H), 5.75 (d, J=2.3 Hz, 1H), 4.23 (q, J=2.0 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 2.48 (s, 3H), 1.62 (s, 3H), 1.53 (s, 3H)

Example 40: Synthesis of 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0513] Except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-1-ethyl-3,5-dimethyl-1H-pyrazole was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (38 mg, 51%).

[0514] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.18-8.10 (m, 2H), 7.85-7.77 (m, 2H), 7.09 (dd, J=7.9, 1.1 Hz, 1H), 6.87 (dd, J=7.9, 1.7 Hz, 1H), 6.74 (d, J=1.6 Hz, 1H), 6.00 (h, J=1.8 Hz, 1H), 5.73 (s, 1H), 4.23 (q, J=2.6 Hz, 2H), 4.00 (q, J=7.2 Hz, 2H), 2.64 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 1.61 (s, 3H), 1.53 (s, 3H), 1.29 (t, J=7.2 Hz, 3H)

Example 41: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0515] Except that 4-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-3-methylisoxazole was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(3-methylisoxazol-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (33 mg, 54%).

[0516] .sup.1H NMR (499 MHz, CDCl.sub.3) 8.41 (s, 1H), 8.12 (d, J=8.7 Hz, 2H), 7.88-7.84 (m, 2H), 7.15-7.11 (m, 1H), 6.98 (dd, J=8.0, 1.7 Hz, 1H), 6.92 (d, J=1.7 Hz, 1H), 5.91-5.86 (m, 1H), 5.77 (s, 1H), 4.33 (dd, J=16.5, 4.8 Hz, 1H), 4.16 (dt, J=16.5, 2.6 Hz, 1H), 2.65 (s, 3H), 2.40 (s, 3H), 1.64 (d, J=11.2 Hz, 6H)

Example 42: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0517] Except that 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-3-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (25 mg, 60%).

[0518] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.80 (dd, J=2.2, 0.8 Hz, 1H), 8.59 (dd, J=4.8, 1.6 Hz, 1H), 8.15-8.10 (m, 2H), 7.89-7.84 (m, 2H), 7.82 (dt, J=8.0, 2.1 Hz, 1H), 7.37-7.32 (m, 1H), 7.19 (d, J=1.3 Hz, 2H), 7.15-7.11 (m, 1H), 5.91-5.86 (m, 1H), 5.79 (s, 1H), 4.37-4.29 (m, 1H), 4.17 (dt, J=16.4, 2.6 Hz, 1H), 2.65 (s, 3H), 1.65 (d, J=10.6 Hz, 7H)

Example 43: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0519] Except that 3-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyridine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(pyridin-4-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (42 mg, 50%).

[0520] .sup.1H NMR (400 MHz,) 8.66-8.61 (m, 2H), 8.15-8.09 (m, 2H), 7.89-7.83 (m, 2H), 7.47-7.42 (m, 2H), 7.24 (dd, J=8.1, 1.7 Hz, 1H), 7.22-7.16 (m, 2H), 5.89 (dt, J=4.7, 2.3 Hz, 1H), 5.78 (q, J=1.6 Hz, 1H), 4.33 (ddd, J=16.5, 4.8, 1.4 Hz, 1H), 4.17 (dt, J=16.5, 2.7 Hz, 1H), 2.65 (s, 3H), 1.65 (d, J=12.1 Hz, 6H)

Example 44: Synthesis of 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid

[0521] Except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)pyrrolidine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid (34 mg, 45%).

[0522] .sup.1H NMR (500 MHz,) 8.24 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 6.99 (dd, J=8.6, 1.0 Hz, 1H), 6.17 (dd, J=8.6, 2.4 Hz, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.84 (dd, J=4.9, 2.2 Hz, 1H), 5.77 (s, 1H), 4.35-4.27 (m, 1H), 4.10 (dt, J=16.3, 2.5 Hz, 1H), 3.25-3.17 (m, 4H), 2.03-1.91 (m, 4H), 1.61 (d, J=12.6 Hz, 6H)

Example 45: Synthesis of 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0523] Except that N-isopropyl-N,2,2-trimethyl-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(isopropyl(methyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (20 mg, 38%).

[0524] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-8.06 (m, 2H), 7.87-7.82 (m, 2H), 6.98 (d, J=8.7 Hz, 1H), 6.37 (dd, J=8.8, 2.6 Hz, 1H), 6.26 (d, J=2.5 Hz, 1H), 5.87-5.81 (m, 1H), 5.75 (s, 1H), 4.34-4.27 (m, 1H), 4.09 (d, J=16.4 Hz, 1H), 4.02 (p, J=6.6 Hz, 1H), 2.68 (s, 3H), 2.64 (s, 3H), 1.60 (d, J=11.9 Hz, 6H), 1.12 (dd, J=6.6, 1.2 Hz, 6H)

Example 46: Synthesis of 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0525] Except that 2-(4-acetylphenyl)-10-(ethylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 29 above was carried out to obtain 2-(4-acetylphenyl)-10-(ethyl(isopropyl)amino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (15 mg, 39%).

[0526] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.82-7.74 (m, 2H), 6.87 (dd, J=8.7, 1.0 Hz, 1H), 6.32 (dd, J=8.8, 2.5 Hz, 1H), 6.13 (d, J=2.5 Hz, 1H), 5.96 (q, J=2.5 Hz, 1H), 5.62 (s, 1H), 4.25-4.13 (m, 2H), 3.95 (p, J=6.7 Hz, 1H), 3.16 (q, J=6.9 Hz, 2H), 2.64 (s, 3H), 1.53 (s, 6H), 1.09 (d, J=6.6 Hz, 6H), 1.05 (t, J=6.9 Hz, 3H)

Example 47: Synthesis of 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0527] Except that N,N-diisopropyl-2,2-dimethyl-3-vinyl-2H-chromen-7-amine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(diisopropylamino)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 40%).

[0528] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.83-7.75 (m, 2H), 6.85 (dd, J=8.7, 1.0 Hz, 1H), 6.43 (dd, J=8.7, 2.5 Hz, 1H), 6.21 (d, J=2.4 Hz, 1H), 5.96 (dt, J=4.7, 2.3 Hz, 1H), 5.62 (s, 1H), 4.27-4.12 (m, 2H), 3.74 (hept, J=6.6 Hz, 2H), 2.64 (s, 3H), 1.53 (d, J=3.5 Hz, 6H), 1.15 (dd, J=6.7, 1.4 Hz, 12H)

Example 48: Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0529] Except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)-4-methylpiperazine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (22 mg, 47%).

[0530] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.52 (s, 3H), 7.03 (d, J=8.7 Hz, 1H), 6.50 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.86-5.82 (m, 1H), 5.73 (s, 1H), 4.29 (dd, J=16.3, 5.0 Hz, 1H), 4.07 (d, J=16.2 Hz, 1H), 3.21-3.13 (m, 4H), 2.54 (s, 4H), 2.33 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H), 1.35 (s, 9H)

Example 49: Synthesis of 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0531] Except that 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione, the same synthesis method as in Example 48 above was carried out to obtain 7,7-dimethyl-10-(4-methylpyrerazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 60%).

[0532] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.86 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.6, 2.5 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 5.87-5.83 (m, 1H), 5.73 (s, 1H), 4.31 (dd, J=16.3, 5.0 Hz, 1H), 4.15-4.07 (m, 1H), 3.19 (t, J=4.8 Hz, 4H), 2.58 (s, 4H), 2.36 (s, 3H), 1.60 (d, J=6.8 Hz, 6H)

Example 50: Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0533] Except that 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione, the same synthesis method as in Example 48 above was carried out to obtain 2-(4-fluorophenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (30 mg, 60%).

[0534] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.63-7.58 (m, 2H), 7.20 (dd, J=9.0, 8.2 Hz, 2H), 7.01 (dd, J=8.8, 1.1 Hz, 1H), 6.50 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.88-5.82 (m, 1H), 5.72 (s, 1H), 4.29 (dd, J=16.6, 5.2 Hz, 1H), 4.13-4.05 (m, 1H), 3.26-3.16 (m, 4H), 2.66 (t, J=4.9 Hz, 4H), 2.40 (s, 3H), 1.59 (d, J=6.9 Hz, 6H)

Example 51: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0535] Except that 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione was used instead of 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione, the same synthesis method as in Example 48 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-methylpiperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (32 mg, 48%).

[0536] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.10 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.01 (dd, J=8.4, 0.9 Hz, 1H), 6.50 (dd, J=8.7, 2.5 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H), 5.88-5.82 (m, 1H), 5.73 (s, 1H), 4.30 (dd, J=16.5, 5.0 Hz, 1H), 4.15-4.07 (m, 1H), 3.24 (t, J=5.1 Hz, 4H), 2.70 (s, 4H), 2.64 (s, 3H), 2.43 (s, 3H), 1.60 (d, J=5.9 Hz, 6H)

Example 52: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0537] Except that 2-(4-acetylphenyl)-7,7-dimethyl-10-(piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride was used instead of 7-amino-3-bromo-2,2-dimethylchroman-4-one, the same synthesis method as in Intermediate 11 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(4-(methylsulfonyl)piperazin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (34 mg, 70%).

[0538] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.5 Hz, 1H), 6.51 (dd, J=8.6, 2.5 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.31 (dd, J=16.4, 4.9 Hz, 1H), 4.14-4.09 (m, 1H), 3.36-3.31 (m, 4H), 3.27-3.23 (m, 4H), 2.81 (s, 3H), 2.65 (s, 3H), 1.6 (d, J=4.0 Hz, 6H)

Example 53: Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid

[0539] Except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene and 4-(3,5-dioxo-1,2,4-triazolidin-4-yl)benzoic acid were used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, respectively, the same synthesis method as in Example 2 (a) above was carried out to obtain 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid (100 mg, 30%).

(b) Synthesis of 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0540] 4-(7,7-Dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid (230 mg, 0.46 mmol) obtained in Example 53 (a) above was dissolved in N,N-dimethylformamide (3 mL), and triethylamine (92 mg, 0.91 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (131 mg, 0.68 mmol) and 1-hydroxybenzotriazole (92 mg, 0.68 mmol) were added thereto and stirred at room temperature for 10 minutes. Morpholine (51.4 mg, 0.59 mmol) was added thereto and stirred for additional 3 hours at room temperature. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol=30:1, v/v) to obtain 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (140 mg, 54%).

(c) Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0541] Except that 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain 10-hydroxy-7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 70%).

[0542] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.47 (s, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.59 (d, J=8.5 Hz, 2H), 6.85 (dd, J=8.3, 1.1 Hz, 1H), 6.40-6.36 (m, 1H), 6.25 (d, J=2.3 Hz, 1H), 5.95 (dt, J=4.8, 2.3 Hz, 1H), 5.60 (s, 1H), 4.25-4.18 (m, 1H), 4.18-4.11 (m, 1H), 3.63 (s, 8H), 1.54 (s, 3H), 1.51 (s, 3H)

Example 54: Synthesis of tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate

(a) Synthesis of tert-butyl 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate

[0543] Except that 1-(tert-butoxycarbonyl)piperazine was used instead of morpholine, the same synthesis method as in Example 53 (b) above was carried out to obtain tert-butyl 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate (100 mg, 70%).

(b) Synthesis of tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate

[0544] Except that tert-butyl 4-(4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate (38 mg, 51%).

[0545] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76 (d, J=8.5 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.29 (s, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.41 (dd, J=8.4, 2.5 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 5.84 (d, J=3.0 Hz, 1H), 5.70 (s, 1H), 4.92 (s, 1H), 4.36-4.21 (m, 1H), 4.11 (d, J=16.4 Hz, 1H), 3.49 (s, 8H), 1.60 (s, 6H), 1.48 (s, 9H)

Example 55: Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0546] Except that tert-butyl 4-(4-(10-hydroxy-7,7-dimethyl-1,3-dioxo-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoyl)piperazine-1-carboxylate was used instead of tert-butyl (2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)carbamate, the same synthesis method as in Example 7 above was carried out to obtain 10-hydroxy-7,7-dimethyl-2-(4-(piperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (12 mg, 70%).

[0547] .sup.1H NMR (400 MHz, cd3od) 8.31 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.5 Hz, 2H), 6.92-6.84 (m, 1H), 6.39 (dd, J=8.5, 2.5 Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 5.96 (d, J=2.1 Hz, 1H), 5.67 (s, 1H), 4.31-4.22 (m, 1H), 4.20-4.12 (m, 1H), 3.83 (s, 4H), 3.25 (s, 4H), 1.58 (d, J=10.7 Hz, 6H)

Example 56: Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0548] Except that N-methyl piperazine was used instead of morpholine, the same synthesis method as in Example 53 (b) above was carried out to obtain 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (80 mg, 56%).

(b) Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0549] Except that 7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain 10-hydroxy-7,7-dimethyl-2-(4-(4-methylpiperazine-1-carbonyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (42 mg, 72%).

[0550] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.1 Hz, 1H), 6.43-6.36 (m, 2H), 5.87-5.81 (m, 1H), 5.70 (s, 1H), 4.30 (dd, J=16.3, 4.9 Hz, 1H), 4.15-4.06 (m, 1H), 3.89 (s, 2H), 3.59 (s, 2H), 2.62 (d, J=39.6 Hz, 4H), 2.43 (s, 3H), 1.59 (s, 6H)

Example 57: Synthesis of 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0551] Except that 4-(7,7-dimethyl-1,3-dioxo-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid was used instead of 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid, the same synthesis method as in Example 53 (b) above was carried out to obtain 7,7-dimethyl-2-(4-(morpholine-4-carbonyl)phenyl)-10-(pyrrolidin-1-yl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (40 mg, 62%).

[0552] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.76 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.6 Hz, 1H), 6.19-6.12 (m, 1H), 6.06 (d, J=2.3 Hz, 1H), 5.83 (d, J=5.1 Hz, 1H), 5.75 (s, 1H), 4.30 (dd, J=16.3, 5.0 Hz, 1H), 4.08 (d, J=16.4 Hz, 1H), 3.73 (s, 7H), 3.51 (s, 1H), 3.21 (d, J=6.6 Hz, 4H), 1.99-1.92 (m, 4H), 1.60 (d, J=10.3 Hz, 6H)

Example 58: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate

[0553] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10 (b) above was dissolved in dichloromethane (7 mL), and triethylamine (220 mg, 2.15 mmol) was added thereto and stirred at room temperature for 10 minutes. Trimethylacetyl chloride (136 mg, 1.12 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pivalate (331 mg, 91%).

[0554] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.02 (h, J=1.8 Hz, 1H), 5.75-5.70 (m, 1H), 4.22 (dd, J=3.7, 2.0 Hz, 2H), 2.64 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H), 1.27 (s, 9H).

Example 59: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate

[0555] Except that 3-methylbutanoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 3-methylbutanoate (100 mg, 90%).

[0556] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.02 (q, J=3.1 Hz, 1H), 5.73 (d, J=2.3 Hz, 1H), 4.22 (dd, J=3.7, 2.0 Hz, 2H), 2.64 (s, 3H), 2.43 (d, J=7.1 Hz, 2H), 2.14-2.02 (m, 1H), 1.60 (s, 3H), 1.53 (s, 3H), 0.98 (d, J=6.7 Hz, 6H).

Example 60: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetate

[0557] Except that acetyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetate (102 mg, 98%).

[0558] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.10 (m, 2H), 7.84-7.77 (m, 2H), 7.11 (dd, J=8.4, 1.1 Hz, 1H), 6.73 (dd, J=8.4, 2.3 Hz, 1H), 6.68 (d, J=2.3 Hz, 1H), 6.02 (d, J=1.9 Hz, 1H), 5.72 (d, J=2.4 Hz, 1H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H).

Example 61: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate

[0559] Except that ethyl chloroformate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl carbonate (120 mg, 94%).

[0560] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.09 (dd, J=8.4, 1.1 Hz, 1H), 6.80-6.72 (m, 2H), 5.87 (dt, J=4.7, 2.3 Hz, 1H), 5.72 (q, J=1.6 Hz, 1H), 4.33-4.25 (m, 3H), 4.13 (dt, J=16.5, 2.7 Hz, 1H), 2.64 (s, 3H), 1.61 (d, J=4.5 Hz, 6H), 1.37 (t, J=7.1 Hz, 3H)

Example 62: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate

[0561] Except that dimethylcarbamoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate (400 mg, 99%).

[0562] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.08 (dd, J=8.4, 1.1 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.01 (td, J=3.7, 1.8 Hz, 1H), 5.74-5.66 (m, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 3.01 (s, 3H), 2.88 (s, 3H), 2.64 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H).

Example 63: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate

[0563] Except that 4-morpholinecarbonyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl morpholine-4-carboxylate (210 mg, 96%).

[0564] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.09 (dd, J=8.4, 1.1 Hz, 1H), 6.75 (dd, J=8.4, 2.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 6.01 (q, J=3.1 Hz, 1H), 5.71 (s, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 3.62 (dd, J=5.7, 4.0 Hz, 4H), 3.47 (d, J=58.3 Hz, 4H), 2.64 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

Example 64: Synthesis of (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

(a) Synthesis of (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0565] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (1 g, 2.38 mmol) obtained in Example 10 (b) above, methyl (2S,3S,4S,5R,6R)-3,4,5-triacetoxy-6-bromo-tetrahydropyran-2-carboxylate (1.42 g, 3.58 mmol) and 4 molecular sieve (3 g) were suspended in dichloromethane (10 mL) and stirred for 1 hour under nitrogen atmosphere. Silver carbonate (1.31 g, 4.77 mmol) was added to the reaction mixture, stirred for 5 minutes and then cooled to 0 C. Trifluoromethanesulfonic acid (358 mg, 2.38 mmol) was added thereto and stirred for additional 15 hours at room temperature. When the reaction was completed, a few drops of triethylamine were added to the reaction mixture, and the insoluble solid was filtered through Celite and washed with dichloromethane. The filtrate was washed with water, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (178 mg, 10%).

(b) Synthesis of (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0566] (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (178 mg, 0.24 mmol) obtained in Example 64 (a) above was dissolved in a mixed solvent of methanol/triethylamine (1:1, 10 mL), and water (9 mL) was added dropwise thereto and stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (90 mg, 62%).

[0567] .sup.1H NMR (500 MHz, MeOD) 8.18-8.13 (m, 2H), 7.86-7.81 (m, 2H), 7.03 (dd, J=8.6, 1.1 Hz, 1H), 6.71 (ddd, J=8.6, 4.2, 2.4 Hz, 1H), 6.62 (dd, J=4.8, 2.4 Hz, 1H), 6.01-5.94 (m, 1H), 5.71 (t, J=2.0 Hz, 1H), 4.97-4.91 (m, 1H), 4.31-4.22 (m, 1H), 4.23-4.13 (m, 1H), 3.96 (d, J=9.8 Hz, 1H), 3.59 (ddt, J=9.5, 7.4, 1.8 Hz, 1H), 3.48-3.44 (m, 2H), 2.66 (s, 3H), 1.61 (s, 3H), 1.57 (d, J=4.3 Hz, 3H).

Example 65: Synthesis of sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate

[0568] (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (100 mg, 0.17 mmol) obtained in Example 64 (b) was suspended in water (1 mL), and sodium bicarbonate (14.11 mg, 0.17 mmol) was added thereto and stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was triturated with ethyl acetate to obtain sodium (2S,3S,4S,5R,6S)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylate (97 mg, 94%).

[0569] .sup.1H NMR (500 MHz, D.sub.2O) 7.98-7.90 (m, 2H), 7.59-7.50 (m, 2H), 6.94 (ddd, J=24.0, 8.7, 1.0 Hz, 1H), 6.73 (ddd, J=9.4, 8.5, 2.5 Hz, 1H), 6.66 (dd, J=4.1, 2.4 Hz, 1H), 5.94 (dd, J=3.9, 1.9 Hz, 1H), 5.64 (d, J=7.8 Hz, 1H), 5.08-4.97 (m, 1H), 4.20-4.09 (m, 2H), 3.91-3.83 (m, 1H), 3.64-3.55 (m, 3H), 2.62 (s, 3H), 1.57-1.50 (m, 6H).

Example 66: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-methylpiperazine-1-carboxylate hydrochloride

[0570] Except that 4-methylpiperazine-1-carbonyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-methylpiperazine-1-carboxylate hydrochloride (400 mg, 87%).

[0571] .sup.1H NMR (400 MHz, D.sub.2O) 8.13 (d, J=8.3 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.3 Hz, 1H), 6.84 (d, J=11.9 Hz, 2H), 6.03 (s, 1H), 5.79 (s, 1H), 4.28 (s, 3H), 3.63 (d, J=12.5 Hz, 2H), 3.53 (s, 1H), 3.37 (s, 1H), 3.24 (s, 2H), 3.00 (s, 3H), 2.71 (s, 3H), 1.62 (d, J=20.3 Hz, 6H)

Example 67: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride

(a) Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate

[0572] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (4 g, 9.54 mmol) obtained in Example 10 (b) above was dissolved in dichloromethane (40 mL), and triethylamine (2.9 g, 11.44 mmol) was added thereto and stirred for 10 minutes. Tert-butyl 4-chlorocarbonylpiperazine-1-carboxylate (2.85 g, 11.44 mmol) and 4-dimethylaminopyridine (350 mg, 2.86 mmol) were added thereto and stirred for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water and aqueous ammonium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate (6 g, 99%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride

[0573] 1-(2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)4-(tert-butyl)piperazine-1,4-dicarboxylate (6 g, 9.5 mmol) obtained in Example 67 (a) above was dissolved in 1,4-dioxane (30 mL), and 4M hydrochloric acid solution (10 mL, 4M/dioxane) was added dropwise thereto and stirred at room temperature for 15 hours. When the reaction was completed, the resulting solid was filtered and washed with ethyl acetate to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (5.2 g, 96%).

[0574] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.3 Hz, 1H), 6.79-6.72 (m, 2H), 6.02 (s, 1H), 5.71 (s, 1H), 4.22 (s, 2H), 3.75 (s, 2H), 3.63 (s, 2H), 3.18 (s, 4H), 2.64 (s, 3H), 1.60 (s, 3H), 1.52 (s, 3H).

Example 68: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate

[0575] Except that pyruvic acid and 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride were used instead of 4-(7,7-dimethyl-1,3-dioxo-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-2(3H)-yl)benzoic acid and morpholine, respectively, the same synthesis method as in Example 53 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-oxopropanoyl)piperazine-1-carboxylate (100 mg, 53%).

[0576] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.08 (dd, J=8.4, 1.2 Hz, 1H), 6.73-6.65 (m, 2H), 5.89-5.81 (m, 1H), 5.72 (s, 1H), 4.30 (dd, J=16.4, 4.8 Hz, 1H), 4.16-4.10 (m, 1H), 3.70 (s, 4H), 3.61 (d, J=17.3 Hz, 4H), 2.64 (s, 3H), 2.47 (s, 3H), 1.60 (d, J=5.7 Hz, 6H).

Example 69: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate

[0577] Except that diethyl chlorophosphate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (3 g, 95%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

[0578] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (1.5 g, 2.7 mmol) obtained in Example 69 (a) above was dissolved in dichloromethane (15 mL), and bromotrimethylsilane (1.65 g, 10.8 mmol) was added thereto and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and methanol (30 mL) was added to the resulting residue and stirred at room temperature for 1 hour. The reaction mixture was concentrated by distillation under reduced pressure and recrystallized with ethanol to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (1.3 g, 96%).

[0579] .sup.1H NMR (500 MHz, D.sub.2O) 8.22 (dt, J=8.4, 0.5 Hz, 2H), 7.80-7.74 (m, 2H), 7.09-7.05 (m, 1H), 6.93 (ddd, J=8.5, 2.3, 1.0 Hz, 1H), 6.86 (dd, J=2.3, 1.0 Hz, 1H), 6.02 (td, J=4.2, 3.8, 1.9 Hz, 1H), 5.81 (s, 1H), 4.36-4.28 (m, 2H), 2.76 (s, 3H), 1.67 (s, 3H), 1.62 (s, 3H).

Example 70: Synthesis of disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate

[0580] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (100 mg, 0.2 mmol) obtained in Example 69 (b) above was suspended in water (3 mL), and sodium bicarbonate (33.78 mg, 0.4 mmol) was added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was added dropwise to acetone (10 mL), and the precipitated solid was filtered and washed with acetone to obtain disodium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate (80 mg, 80%).

[0581] .sup.1H NMR (400 MHz, D.sub.2O) 8.30-8.22 (m, 2H), 7.89-7.78 (m, 2H), 7.13 (d, J=8.5 Hz, 1H), 7.05-6.96 (m, 1H), 6.93 (d, J=2.3 Hz, 1H), 6.08 (d, J=3.5 Hz, 1H), 5.87 (s, 1H), 4.36 (t, J=3.1 Hz, 2H), 2.82 (s, 3H), 1.71 (d, J=19.9 Hz, 6H).

Example 71: Synthesis of 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate

[0582] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (100 mg, 0.2 mmol) obtained in Example 69 (b) above was suspended in water (3 mL), and tromethamine (24 mg, 0.4 mmol) was added thereto and stirred at room temperature for 1 hour. When the reaction was completed, the reaction mixture was added dropwise to acetone (10 mL), and the precipitated solid is filtered and washed with acetone to obtain 1,3-dihydroxy-2-(hydroxymethyl)propane-2-aminium 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl phosphate (78 mg, 53%).

[0583] .sup.1H NMR (400 MHz, D.sub.2O) 8.22 (d, J=8.7 Hz, 2H), 7.86-7.73 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 7.00-6.95 (m, 1H), 6.92 (dd, J=2.4, 1.2 Hz, 1H), 6.07 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 4.35 (d, J=2.9 Hz, 2H), 3.83 (s, 12H), 2.80 (s, 3H), 2.32 (s, 2H), 1.70 (d, J=18.5 Hz, 6H).

Example 72: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride

[0584] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (2 g, 4.77 mmol) obtained in Example 10 (b) above was dissolved in dichloromethane (10 mL), and triethylamine (1.45 g, 14.31 mmol) and 2-(dimethylamino)acetyl chloride (0.87 g, 7.15 mmol) were added thereto and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was dissolved in acetone (20 mL), and 4M hydrochloric acid solution (10 mL, 4M/dioxane) was added dropwise thereto and stirred at room temperature for 30 minutes. The obtained solid precipitate was filtered, washed with acetone to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride (900 mg, 35%).

[0585] .sup.1H NMR (500 MHz, D.sub.2O) 8.00-7.89 (m, 2H), 7.60-7.52 (m, 2H), 7.07 (dd, J=8.6, 1.2 Hz, 1H), 6.84-6.77 (m, 2H), 5.96-5.91 (m, 1H), 5.65 (s, 1H), 4.42 (s, 2H), 4.16 (dt, J=3.9, 2.3 Hz, 2H), 3.03 (d, J=0.8 Hz, 6H), 2.61 (s, 3H), 1.53 (d, J=9.7 Hz, 6H).

Example 73: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-methoxyethyl) carbonate

[0586] Except that methoxyethyl carbonochloridate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-methoxyethyl) carbonate (120 mg, 95%).

[0587] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.07 (m, 2H), 7.85-7.74 (m, 2H), 7.14 (dd, J=8.4, 1.2 Hz, 1H), 6.84 (dd, J=8.4, 2.4 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.03 (td, J=3.8, 1.8 Hz, 1H), 5.76-5.68 (m, 1H), 4.34-4.26 (m, 2H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 3.62-3.55 (m, 2H), 3.28 (s, 3H), 2.64 (s, 3H), 1.60 (s, 3H), 1.54 (s, 3H).

Example 74: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pyrrolidine-1-carboxylate

[0588] Except that pyrrolidine-1-carbonyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl pyrrolidine-1-carboxylate (98 mg, 96%).

[0589] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.10 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.04 (dd, J=8.3, 1.1 Hz, 1H), 6.75-6.69 (m, 2H), 5.84 (dt, J=4.7, 2.3 Hz, 1H), 5.75-5.68 (m, 1H), 4.29 (ddd, J=16.5, 4.8, 1.4 Hz, 1H), 4.12 (dt, J=16.4, 2.6 Hz, 1H), 3.49 (dt, J=27.1, 6.4 Hz, 4H), 2.64 (s, 3H), 1.99-1.85 (m, 4H), 1.59 (d, J=6.6 Hz, 6H).

Example 75: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2,5,8,11-tetraoxatridecan-13-yl) carbonate

[0590] Except that 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl carbonochloridate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2,5,8,11-tetraoxatridecan-13-yl) carbonate (60 mg, 90%).

[0591] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.13-8.04 (m, 2H), 7.89-7.78 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.81-6.71 (m, 2H), 5.86 (dt, J=4.7, 2.2 Hz, 1H), 5.72 (s, 1H), 4.40-4.34 (m, 2H), 4.30 (dd, J=16.5, 4.8 Hz, 1H), 4.13 (dt, J=16.5, 2.6 Hz, 1H), 3.80-3.75 (m, 2H), 3.65 (dd, J=13.9, 5.4 Hz, 10H), 3.54 (dd, J=5.9, 3.4 Hz, 2H), 3.37 (s, 3H), 2.64 (s, 3H), 1.60 (d, J=3.9 Hz, 6H).

Example 76: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethylcarbamate

[0592] Except that diethylcarbamic chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethylcarbamate (120 mg, 94%).

[0593] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.05 (d, J=8.2 Hz, 1H), 6.74-6.68 (m, 2H), 5.84 (dt, J=4.7, 2.2 Hz, 1H), 5.73 (s, 1H), 4.29 (ddd, J=16.6, 4.8, 1.3 Hz, 1H), 4.12 (dt, J=16.4, 2.6 Hz, 1H), 3.38 (s, 4H), 2.64 (s, 3H), 1.60 (d, J=4.1 Hz, 6H), 1.26-1.15 (m, 6H).

Example 77: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutaminate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate

[0594] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (350 mg, 0.84 mmol) obtained in Example 10 (b) above, (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid (247 mg, 1.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg, 1.67 mmol) and 4-dimethylaminopyridine (20 mg, 0.17 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol=95:5, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate (250 mg, 46%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutaminate

[0595] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate (300 mg, 0.46 mmol) obtained in Example 77 (a) above was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added dropwise thereto and stirred at room temperature for 5 hours. When the reaction was completed, the reaction mixture was diluted in water and washed with ethyl acetate. The separated aqueous layer was freeze-dried to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-glutaminate (80 mg, 24%).

[0596] .sup.1H NMR (400 MHz, D.sub.2O) 8.10 (d, J=8.3 Hz, 2H), 7.68 (d, J=8.3 Hz, 2H), 7.18 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 6.04 (s, 1H), 5.78 (s, 1H), 4.50 (t, J=6.6 Hz, 1H), 4.28 (s, 2H), 2.71 (s, 3H), 2.66 (s, 2H), 2.42 (dd, J=17.8, 7.3 Hz, 2H), 1.93 (s, 1H), 1.63 (d, J=16.6 Hz, 6H), 1.32 (s, 3H).

Example 78: Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid

(a) Synthesis of tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate

[0597] Tert-butyl (2S)-2-amino-5-guanidino-pentanoate (790 mg, 2.48 mmol, 2HCl) and 4-dimethylaminopyridine (611 mg, 4.95 mmol) were dissolved in dichloromethane (10 mL), and a solution of bis-(4-nitrophenyl) carbonate (768 mg, 2.48 mmol) dissolved in 10 mL of dichloromethane was added dropwise to the reaction mixture. The reaction mixture was cooled to 10 C. and stirred for 5 hours, and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (1.25 g, 2.97 mmol) and 4-dimethylaminopyridine (305 mg, 2.48 mmol) dissolved in dichloromethane (10 mL) was added dropwise to the reaction mixture, stirred at 10 C. for 2 hours, raised to room temperature, and stirred for additional 72 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with 1 N aqueous hydrochloric acid solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol=9:1, v/v) to obtain tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate (800 mg, 47%).

(b) Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid

[0598] Tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate (600 mg, 0.89 mmol) obtained in Example 78 (a) above was dissolved in dichloromethane (3 mL), and the reaction mixture was cooled to 0 C. Trifluoroacetic acid (2.96 g, 26 mmol) was added dropwise thereto and stirred at 0 C. for 3 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue is triturated with diethyl ether to obtain (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-arginine 2,2,2-trifluoroacetic acid (611 mg, 91%).

[0599] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 3H), 7.84-7.76 (m, 2H), 7.53 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.71 (dt, J=8.5, 2.0 Hz, 1H), 6.62 (t, J=2.0 Hz, 1H), 6.02 (q, J=3.2 Hz, 1H), 5.71 (s, 1H), 4.25-4.19 (m, 2H), 3.99 (td, J=8.1, 4.4 Hz, 1H), 3.11 (q, J=6.5 Hz, 2H), 2.64 (s, 3H), 1.86-1.72 (m, 1H), 1.72-1.40 (m, 10H).

Example 79: Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate

[0600] Except that 1-(chlorocarbonyl)proline methyl ester was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 2-methyl (2S)-pyrrolidine-1,2-dicarboxylate (100 mg, 85%).

[0601] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.6 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.77-6.72 (m, 1H), 6.70-6.62 (m, 1H), 5.84 (s, 1H), 5.71 (s, 1H), 4.29 (d, J=16.5 Hz, 1H), 4.12 (d, J=16.2 Hz, 1H), 3.73 (s, 3H), 3.70-3.53 (m, 2H), 2.64 (s, 3H), 2.37-2.17 (m, 1H), 2.14-1.89 (m, 4H), 1.59 (d, J=4.4 Hz, 6H).

Example 80: Synthesis of methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-leucinate

[0602] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (189 mg, 0.45 mmol) obtained in Example 10 (b) above and triethylamine (69 mg, 0.68 mmol) were dissolved in tetrahydrofuran (2 mL), and a solution of methyl 2-isocyanato-4-methyl-pentanoate (100 mg, 0.58 mmol) dissolved in tetrahydrofuran (1 mL) and 4-dimethylaminopyridine (56 mg, 0.45 mmol) were added thereto and stirred at 100 C. for 20 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water and aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) to obtain methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-leucinate (141 mg, 53%).

[0603] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.24 (d, J=7.9 Hz, 1H), 8.17-8.09 (m, 2H), 7.83-7.76 (m, 2H), 7.09 (d, J=8.4 Hz, 1H), 6.74-6.67 (m, 1H), 6.62 (dd, J=2.4, 1.0 Hz, 1H), 6.04-5.99 (m, 1H), 5.71 (s, 1H), 4.21 (t, J=2.7 Hz, 2H), 4.09 (dq, J=5.0, 2.9 Hz, 1H), 3.65 (s, 3H), 2.64 (s, 3H), 1.66 (dd, J=14.8, 7.1 Hz, 1H), 1.63-1.45 (m, 8H), 0.89 (dd, J=12.4, 6.5 Hz, 6H).

Example 81: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate

[0604] Except that (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate (200 mg, 78%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid

[0605] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-leucinate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-leucinate 2,2,2-trifluoroacetic acid (39 mg, 35%).

[0606] .sup.1H NMR (400 MHz,) 8.64-8.33 (m, 3H), 8.17-8.09 (m, 2H), 7.85-7.74 (m, 2H), 7.19 (ddd, J=8.4, 3.4, 1.1 Hz, 1H), 6.81 (dd, J=8.4, 2.4 Hz, 1H), 6.77 (dd, J=2.4, 1.3 Hz, 1H), 6.04 (dt, J=5.9, 3.5 Hz, 1H), 5.75 (t, J=2.7 Hz, 1H), 4.27 (s, 1H), 4.25-4.18 (m, 2H), 2.64 (s, 3H), 1.83 (td, J=13.0, 12.0, 6.4 Hz, 2H), 1.74 (q, J=7.3, 6.7 Hz, 1H), 1.57 (d, J=28.9 Hz, 6H), 0.96 (dd, J=6.1, 3.3 Hz, 6H).

Example 82: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-prolyl)piperazine-1-carboxylate

[0607] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.35 mmol) obtained in Example 67 (b) above, N-(tert-butoxycarbonyl)-L-proline (91 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (135 mg, 0.7 mmol) and 4-dimethylaminopyridine (8.6 mg, 0.07 mmol) were dissolved in dichloromethane (4 mL), and the reaction mixture was stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-prolyl)piperazine-1-carboxylate (160 mg, 62%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride

[0608] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-prolyl)piperazine-1-carboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-prolyl)piperazine-1-carboxylate hydrochloride (50 mg, 78%).

[0609] .sup.1H NMR (400 MHz, D.sub.2O) 7.86 (d, J=8.2 Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.73-6.60 (m, 2H), 5.87 (s, 1H), 5.58 (s, 1H), 4.73 (s, 1H), 4.03 (q, J=16.4 Hz, 2H), 3.58 (d, J=20.7 Hz, 8H), 3.49-3.38 (m, 3H), 2.58 (s, 3H), 2.49 (s, 1H), 2.00 (ddd, J=50.6, 13.5, 6.9 Hz, 4H), 1.50 (d, J=6.6 Hz, 7H).

Example 83: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl tert-butyl ethane-1,2-diylbis(methylcarbamate)

[0610] Triphosgene (611 mg, 2.02 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0 C. Tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (400 mg, 2.02 mmol) was added dropwise thereto, and triethylamine (619 mg, 6.06 mmol) was subsequently added dropwise. The reaction mixture was stirred at 0 C. for 5 minutes, raised to room temperature and stirred for 1 hour. After adding water, the layer separation was carried out to extract the organic layer. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was dissolved in dichloromethane (10 mL), and triethylamine (1.86 g, 18.17 mmol) and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (847 mg, 2.02 mmol) dissolved in dichloromethane (10 mL) were added dropwise to the reaction mixture and stirred at room temperature for 30 minutes. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was separated by MPLC (ethyl acetate:hexane=1:9, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl tert-butyl ethane-1,2-diylbis(methylcarbamate) (1.01 g, 79%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid

[0611] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl tert-butyl ethane-1,2-diylbis(methylcarbamate) was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(2-(methylamino)ethyl)carbamate 2,2,2-trifluoroacetic acid (230 mg, 42%).

[0612] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.54 (d, J=34.8 Hz, 1H), 8.18-8.10 (m, 2H), 7.84-7.76 (m, 2H), 7.09 (dd, J=9.0, 1.1 Hz, 1H), 6.82-6.75 (m, 2H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.71 (q, J=1.9 Hz, 1H), 4.22 (dd, J=4.1, 2.0 Hz, 2H), 3.71-3.60 (m, 1H), 3.57-3.50 (m, 1H), 3.21-3.11 (m, 2H), 2.96 (d, J=42.0 Hz, 3H), 2.64 (s, 3H), 2.63-2.56 (m, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

Example 84: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((tert-butoxycarbonyl)amino)ethyl)(ethyl)carbamate

[0613] Except that tert-butyl N-[2-[chlorocarbonyl(ethyl)amino]ethyl]carbamate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to quantitatively obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((tert-butoxycarbonyl)amino)ethyl)(ethyl)carbamate. The obtained compound was used in the next reaction without purification.

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride

[0614] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((tert-butoxycarbonyl)amino)ethyl)(ethyl)carbamate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-aminoethyl)(ethyl)carbamate hydrochloride (80 mg, 54%).

[0615] .sup.1H NMR (500 MHz, D.sub.2O) 8.09 (dd, J=13.4, 8.3 Hz, 2H), 7.71-7.61 (m, 2H), 7.11 (dd, J=16.6, 8.5 Hz, 1H), 6.87-6.75 (m, 2H), 6.00 (s, 1H), 5.76 (s, 1H), 4.26 (s, 2H), 3.80 (s, 1H), 3.66 (s, 1H), 3.51 (d, J=7.3 Hz, 1H), 3.39 (d, J=7.2 Hz, 1H), 3.28 (dt, J=28.2, 6.1 Hz, 2H), 2.69 (d, J=2.7 Hz, 3H), 1.62 (d, J=2.3 Hz, 3H), 1.57 (s, 3H), 1.22 (dt, J=37.3, 7.1 Hz, 3H).

Example 85: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride

(a) Synthesis of tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)pyrrolidine-1-carboxylate

[0616] Except that N-methyl-N-pyrrolidin-3-yl-carbamoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)pyrrolidine-1-carboxylate (220 mg, 86%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride

[0617] Except that tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)pyrrolidine-1-carboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(pyrrolidin-3-yl)carbamate hydrochloride (80 mg, 54%).

[0618] .sup.1H NMR (500 MHz, D.sub.2O) 7.94 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.5 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.74 (s, 1H), 6.69 (s, 1H), 5.93 (s, 1H), 5.64 (s, 1H), 4.67-4.57 (m, 1H), 4.16-4.10 (m, 2H), 3.60-3.50 (m, 2H), 3.43 (s, 1H), 3.32 (d, J=21.5 Hz, 1H), 3.07 (s, 2H), 2.94 (s, 1H), 2.62 (s, 3H), 2.38 (dtd, J=12.8, 7.9, 4.5 Hz, 1H), 2.22 (s, 1H), 1.54 (d, J=4.1 Hz, 6H).

Example 86: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride

[0619] Triphosgene (772 mg, 2.6 mmol) was dissolved in dichloromethane (15 mL) and cooled to 0 C. Pyridine (3.1 g, 39 mmol) was added dropwise to the reaction mixture and stirred at 0 C. for 15 minutes. While maintaining the reaction mixture at 0 C., N-[3-(dimethylamino)propyl]-N,N-dimethyl-propane-1,3-diamine (974 mg, 5.2 mmol) was added dropwise, raised to room temperature and stirred for 6 hours. 4-Dimethylaminopyridine (974 mg, 5.2 mmol) was added to the reaction mixture, and a solution of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (545 mg, 1.3 mmol) dissolved in dichloromethane (10 mL) was added dropwise thereto and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, separated by column chromatography (dichloromethane:methanol=9:1, v/v), and concentrated under reduced pressure. The obtained residue was purified with ethyl acetate (0.5 mL), and the solid was precipitated by adding 4M hydrochloric acid solution (1 mL, 4M/diethyl ether). The precipitated solid was filtered to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl bis(3-(dimethylamino)propyl)carbamate dihydrochloride (88 mg, 9.6%).

[0620] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 10.33 (d, J=40.8 Hz, 2H), 8.25-8.03 (m, 2H), 7.93-7.72 (m, 2H), 7.10 (dd, J=8.4, 1.1 Hz, 1H), 6.88-6.74 (m, 2H), 6.04 (td, J=3.8, 1.8 Hz, 1H), 5.72 (d, J=2.5 Hz, 1H), 4.23 (t, J=2.8 Hz, 2H), 3.35 (d, J=6.8 Hz, 4H), 3.15-3.00 (m, 4H), 2.76 (d, J=4.0 Hz, 12H), 2.65 (s, 3H), 2.07-1.92 (m, 4H), 1.57 (d, J=24.2 Hz, 6H)

Example 87: Synthesis of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine

(a) Synthesis of tert-butyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate

[0621] Except that tert-butyl (2S)-2-(methylamino)propanoate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain tert-butyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate (120 mg, 40%).

(b) Synthesis of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine

[0622] Except that tert-butyl N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate was used instead of tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate, the same synthesis method as in Example 78 (b) above was carried out to obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine (600 mg, 52%).

[0623] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 9.48 (s, 1H), 8.16-8.09 (m, 2H), 7.82-7.72 (m, 2H), 6.87 (dd, J=8.4, 1.1 Hz, 1H), 6.37 (dd, J=8.4, 2.4 Hz, 1H), 6.25 (d, J=2.4 Hz, 1H), 5.98-5.92 (m, 1H), 5.63-5.58 (m, 1H), 4.39 (q, J=7.1 Hz, 1H), 4.25-4.12 (m, 2H), 2.84 (s, 3H), 2.63 (s, 3H), 1.54 (s, 3H), 1.51 (s, 3H), 1.38 (d, J=7.1 Hz, 3H)

Example 88: Synthesis of sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate

[0624] N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alanine (530 mg, 0.97 mmol) obtained in Example 87 (b) above was suspended in water (20 mL), and sodium bicarbonate (82 mg, 0.98 mmol) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was diluted in water and washed with ethyl acetate. The separated aqueous layer was freeze-dried to obtain sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methyl-L-alaninate (510 mg, 88%).

[0625] .sup.1H NMR (500 MHz, D.sub.2O) 8.06 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.09 (t, J=9.4 Hz, 1H), 6.88-6.71 (m, 2H), 5.97 (s, 1H), 5.72 (s, 1H), 4.28-4.15 (m, 2H), 3.45 (q, J=6.9 Hz, 1H), 2.99 (d, J=43.2 Hz, 3H), 2.67 (s, 3H), 2.58 (s, 2H), 1.61 (s, 3H), 1.57 (s, 3H), 1.40 (d, J=7.0 Hz, 3H).

Example 89: Synthesis of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine

(a) Synthesis of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate

[0626] Except that tert-butyl 2-(methylamino)acetate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate (620 mg, 42%).

(b) Synthesis of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine

[0627] Except that N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate was used instead of tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate, the same synthesis method as in Example 78 (b) above was carried out to obtain N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine (220 mg, 58%).

[0628] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 12.83 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.84-7.77 (m, 2H), 7.13-7.05 (m, 1H), 6.78-6.66 (m, 1H), 6.66-6.54 (m, 1H), 6.01 (dt, J=3.8, 2.4 Hz, 1H), 5.71 (s, 1H), 4.21 (t, J=2.5 Hz, 2H), 4.10 (s, 1H), 3.98 (s, 1H), 3.05-2.89 (amide tautomer, m, 3H), 2.64 (s, 3H), 1.59 (d, J=1.8 Hz, 3H), 1.53 (s, 3H)

Example 90: Synthesis of sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate

[0629] N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine (155 mg, 0.29 mmol) obtained in Example 89 (b) above was suspended in water (4 mL), and sodium bicarbonate (25 mg, 0.29 mmol) was added thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was diluted in water and washed with ethyl acetate. The separated aqueous layer was freeze-dried to obtain sodium N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycinate (139 mg, 83%).

[0630] .sup.1H NMR (500 MHz, D.sub.2O) 7.95-7.88 (m, 2H), 7.58-7.52 (m, 2H), 7.00 (ddd, J=23.8, 8.4, 1.1 Hz, 1H), 6.83-6.73 (m, 1H), 6.73-6.66 (m, 1H), 5.91-5.87 (m, 1H), 5.64-5.58 (m, 1H), 4.15-4.06 (m, 2H), 4.00 (s, 1H), 3.87 (d, J=2.7 Hz, 1H), 3.05 (d, J=59.3 Hz, 3H), 2.61 (s, 3H), 1.57-1.50 (m, 6H).

Example 91: Synthesis of 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid

(a) Synthesis of tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate

[0631] Except that tert-butyl 3-(methylamino)propanoate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate (230 mg, 38%).

(b) Synthesis of 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid

[0632] Except that tert-butyl 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate was used instead of tert-butyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-argininate, the same synthesis method as in Example 78 (b) above was carried out to obtain 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid (90 mg, 50%).

[0633] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 12.28 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.84-7.77 (m, 2H), 7.08 (d, J=8.4 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.67 (d, J=2.7 Hz, 1H), 6.01 (s, 1H), 5.71 (s, 1H), 4.24-4.19 (m, 2H), 3.59 (t, J=7.2 Hz, 1H), 3.47 (t, J=7.3 Hz, 1H), 3.02-2.87 (amide tautomer, m, 3H), 2.64 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H)

Example 92: Synthesis of sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate

[0634] Except that 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoic acid was used instead of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine, the same synthesis method as in Example 90 above was carried out to obtain sodium 3-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)(methyl)amino)propanoate (92 mg, 87%).

[0635] .sup.1H NMR (500 MHz, D.sub.2O) 7.98 (dd, J=8.5, 4.1 Hz, 2H), 7.59 (dd, J=8.4, 4.5 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H), 6.78-6.69 (m, 2H), 5.93 (s, 1H), 5.66 (s, 1H), 4.19-4.12 (m, 2H), 3.70 (t, J=7.2 Hz, 1H), 3.55 (t, J=7.3 Hz, 1H), 3.03 (d, J=59.9 Hz, 3H), 2.64 (s, 3H), 2.54 (t, J=7.1 Hz, 1H), 2.45 (t, J=7.3 Hz, 1H), 1.58-1.53 (m, 6H).

Example 93: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate

[0636] Except that tert-butyl N-(4-piperidylmethyl)carbamate was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate (250 mg, 50%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate

[0637] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-1-carboxylate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(aminomethyl)piperidine-1-carboxylate trifluoroacetate (50 mg, 31%).

[0638] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.10 (m, 2H), 7.86-7.76 (m, 4H), 7.08 (dt, J=8.4, 1.2 Hz, 1H), 6.73 (dd, J=8.5, 2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 6.02 (q, J=3.2 Hz, 1H), 5.73-5.68 (m, 1H), 4.22 (dd, J=4.0, 2.0 Hz, 2H), 4.13-3.95 (m, 2H), 2.94-2.81 (m, 1H), 2.80-2.71 (m, 2H), 2.64 (s, 3H), 1.88-1.76 (m, 2H), 1.74-1.67 (m, 1H), 1.59 (s, 3H), 1.52 (s, 3H), 1.47-1.37 (m, 1H), 1.25-1.19 (m, 1H).

Example 94: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate

[0639] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate were used instead of 2-(4-acetylphenyl)-10-amino-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and 2-methoxyprop-1-ene, respectively, the same synthesis method as in Example 29 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate (200 mg, 40%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride

[0640] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)piperazine-1-carboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl)piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride (200 mg, 89%).

[0641] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 11.70 (s, 1H), 9.07 (s, 1H), 8.85 (s, 1H), 8.18-8.09 (m, 2H), 7.87-7.72 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.83-6.66 (m, 2H), 6.02 (q, J=3.1 Hz, 1H), 5.71 (s, 1H), 4.27-4.10 (m, 3H), 3.69-3.42 (m, 7H), 3.22-3.11 (m, 2H), 2.95-2.85 (m, 2H), 2.64 (s, 3H), 2.34-2.23 (m, 2H), 2.04-1.85 (m, 2H), 1.60 (s, 3H), 1.53 (s, 3H).

Example 95: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride

[0642] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.35 mmol) obtained in Example 67 (b) was dissolved in tetrahydrofuran, and sodium hydride (25 mg, 1.06 mmol, 60%) was added thereto and stirred at room temperature for 30 minutes. 2-(Chloromethyl)pyridine (87 mg, 0.53 mmol, HCl) was added thereto and stirred at room temperature for 12 hours. When the reaction was completed, the reaction mixture was quenched by adding water (5 mL) and extracted with dichloromethane. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was separated by MPLC (ethyl acetate hexane=3:7, v/v) and concentrated by distillation under reduced pressure. The obtained residue was dissolved in ethyl acetate, and 4M hydrochloric acid solution (1 mL, 4M/dioxane) was added thereto and stirred for 1 hour. The obtained precipitate was filtered and washed with ethyl acetate to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(pyridin-2-ylmethyl)piperazine-1-carboxylate dihydrochloride (115 mg, 47%).

[0643] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.72-8.68 (m, 1H), 8.16-8.11 (m, 2H), 7.96 (td, J=7.7, 1.9 Hz, 1H), 7.82-7.77 (m, 2H), 7.62 (d, J=7.7 Hz, 1H), 7.51 (dd, J=7.7, 5.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.79-6.69 (m, 2H), 6.02 (q, J=2.5, 1.8 Hz, 1H), 5.71 (d, J=2.4 Hz, 1H), 4.52 (s, 2H), 4.21 (d, J=3.3 Hz, 2H), 3.80 (d, J=56.2 Hz, 8H), 2.64 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

Example 96: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate

[0644] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid were used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, respectively, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate (200 mg, 78%).

[0645] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.6 Hz, 2H), 7.88-7.80 (m, 2H), 7.09-7.04 (m, 1H), 6.76-6.64 (m, 2H), 5.85 (dt, J=4.7, 2.2 Hz, 1H), 5.72 (d, J=2.6 Hz, 1H), 4.33-4.27 (m, 1H), 4.23 (s, 2H), 4.13 (dt, J=16.7, 2.7 Hz, 1H), 3.72-3.52 (m, 17H), 2.64 (s, 3H), 1.60 (d, J=5.7 Hz, 6H).

Example 97: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-valyl)piperazine-1-carboxylate

[0646] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride (200 mg, 0.38 mmol) obtained in Example 67 (b), (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (91 mg, 0.41 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (189 mg, 0.49 mmol) were dissolved in acetonitrile (5 mL), and triethylamine (156 mg, 1.52 mmol) was added dropwise thereto and stirred at room temperature for 2 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, and the obtained residue was separated by MPLC (ethyl acetate:hexane=3:7, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-valyl)piperazine-1-carboxylate (200 mg, 73%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate

[0647] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-valyl)piperazine-1-carboxylate (200 mg, 0.27 mmol) obtained in Example 97 (a) above was dissolved in dichloromethane (1 mL), and 4M hydrochloric acid solution (0.6 mL, 4M/dioxane) was added dropwise thereto and stirred at room temperature for 3 hours. When the reaction was completed, the reaction mixture was concentrated by reduced pressure distillation, and the obtained residue was separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) and freeze-dried to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-valyl)piperazine-1-carboxylate formate (179 mg, 94%).

[0648] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.24 (amine, d, J=1.5 Hz, 2H), 8.17-8.09 (m, 2H), 7.84-7.76 (m, 2H), 7.10 (dd, J=8.3, 1.1 Hz, 1H), 6.76 (dd, J=8.4, 2.3 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.71 (d, J=2.5 Hz, 1H), 4.22 (dd, J=3.8, 2.0 Hz, 2H), 3.73 (d, J=5.2 Hz, 1H), 3.69-3.36 (m, 8H), 2.69 (s, 1H), 2.54 (s, 1H), 1.81 (dt, J=13.1, 6.7 Hz, 1H), 1.59 (s, 3H), 1.53 (s, 3H), 0.92 (d, J=6.8 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).

Example 98: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-leucyl)piperazine-1-carboxylate

[0649] Except that (2S)-2-(tert-butoxycarbonylamino)-4-methyl-pentanoic acid was used instead of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid, the same synthesis method as in Example 97 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-leucyl)piperazine-1-carboxylate (200 mg, 76%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride

[0650] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)-L-leucyl)piperazine-1-carboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(L-leucyl)piperazine-1-carboxylate hydrochloride (120 mg, 88%).

[0651] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.20 (s, 3H), 8.16-8.12 (m, 2H), 7.84-7.76 (m, 2H), 7.10 (dd, J=8.5, 1.1 Hz, 1H), 6.76 (dd, J=8.4, 2.4 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.02 (q, J=3.4 Hz, 1H), 5.72 (d, J=2.3 Hz, 1H), 4.39 (s, 1H), 4.25-4.20 (m, 2H), 3.81-3.71 (m, 2H), 3.65-3.58 (m, 2H), 3.43-3.24 (m, 4H), 2.64 (s, 3H), 1.77-1.71 (m, 1H), 1.60 (s, 3H), 1.53 (s, 3H), 1.50-1.42 (m, 2H), 0.94 (d, J=6.5 Hz, 3H), 0.90 (d, J=6.5 Hz, 3H).

Example 99: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride

[0652] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 72 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)piperazine-1-carboxylate hydrochloride (320 mg, 67%).

[0653] .sup.1H NMR (400 MHz, D.sub.2O) 8.19 (d, J=8.4 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.2 Hz, 2H), 6.10 (s, 1H), 5.86 (s, 1H), 4.43 (s, 2H), 4.34 (s, 2H), 3.88-3.63 (m, 8H), 3.08 (s, 6H), 2.79 (s, 3H), 1.70 (d, J=18.4 Hz, 6H).

Example 100: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride

(a) Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate

[0654] Except that tert-butyl 4-chlorocarbonyl-3,5-dimethyl-piperazine-1-carboxylate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate (700 mg, 88%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride

[0655] Except that 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,6-dimethylpiperazine-1,4-dicarboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride (180 mg, 88%).

[0656] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 9.31 (s, 1H), 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.7 Hz, 2H), 7.10 (dd, J=8.3, 1.1 Hz, 1H), 6.75 (dd, J=8.4, 2.3 Hz, 1H), 6.71 (d, J=2.3 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.75-5.69 (m, 1H), 4.53-4.45 (m, 1H), 4.40 (t, J=6.5 Hz, 2H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 3.46-3.42 (m, 2H), 3.04 (t, J=12.6 Hz, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.30 (d, J=6.6 Hz, 6H).

Example 101: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)prolyl)-2,6-dimethylpiperazine-1-carboxylate

[0657] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethylpiperazine-1-carboxylate hydrochloride and 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid were used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperazine-1-carboxylate hydrochloride and (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid, respectively, the same synthesis method as in Example 97 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)prolyl)-2,6-dimethylpiperazine-1-carboxylate (100 mg, 70%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride

[0658] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-((tert-butoxycarbonyl)prolyl)-2,6-dimethylpiperazine-1-carboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,6-dimethyl-4-prolylpiperazine-1-carboxylate hydrochloride (78 mg, 88%).

[0659] .sup.1H NMR NMR (500 MHz, D.sub.2O) 7.99 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.3 Hz, 2H), 7.06 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 6.71 (s, 1H), 5.96 (s, 1H), 5.69 (s, 1H), 4.22 (s, 1H), 4.17 (s, 2H), 3.76 (dd, J=24.6, 12.7 Hz, 1H), 3.53-3.37 (m, 4H), 3.09-3.01 (m, 1H), 2.65 (s, 3H), 2.54 (dd, J=13.8, 7.0 Hz, 1H), 2.24-1.92 (m, 5H), 1.56 (d, J=9.4 Hz, 6H), 1.34 (s, 3H), 1.28-1.24 (m, 3H).

Example 102: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-ylheptanoate

[0660] Except that heptanoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-ylheptanoate (100 mg, 92%).

[0661] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.15-8.07 (m, 2H), 7.88-7.80 (m, 2H), 7.08 (dd, J=8.3, 1.1 Hz, 1H), 6.73-6.60 (m, 2H), 5.86 (dt, J=4.7, 2.3 Hz, 1H), 5.73 (d, J=2.5 Hz, 1H), 4.30 (ddd, J=16.5, 4.8, 1.3 Hz, 1H), 4.13 (dt, J=16.6, 2.7 Hz, 1H), 2.64 (s, 3H), 2.52 (t, J=7.5 Hz, 2H), 1.72 (p, J=7.4 Hz, 2H), 1.60 (d, J=4.5 Hz, 6H), 1.42-1.29 (m, 6H), 0.93-0.86 (m, 3H).

Example 103: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylbutanoate

[0662] Except that 2,2-dimethylbutanoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylbutanoate (115 mg, 95%).

[0663] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-8.07 (m, 2H), 7.86-7.80 (m, 2H), 7.11-7.04 (m, 1H), 6.66-6.59 (m, 2H), 5.88-5.82 (m, 1H), 5.73 (s, 1H), 4.34-4.26 (m, 1H), 4.13 (dt, J=16.4, 2.6 Hz, 1H), 2.65 (d, J=0.6 Hz, 3H), 1.69 (q, J=7.5 Hz, 2H), 1.60 (d, J=3.6 Hz, 6H), 1.55 (s, 3H), 1.29-1.25 (m, 6H), 0.98-0.90 (m, 3H).

Example 104: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yi ethyl succinate

[0664] Except that ethyl 4-chloro-4-oxo-butanoate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl ethyl succinate (120 mg, 92%).

[0665] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.84-7.77 (m, 2H), 7.13 (dd, J=8.4, 1.1 Hz, 1H), 6.71 (dd, J=8.4, 2.3 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.75-5.69 (m, 1H), 4.22 (dd, J=3.8, 2.0 Hz, 2H), 4.08 (q, J=7.1 Hz, 2H), 2.80 (dd, J=7.6, 5.4 Hz, 2H), 2.67-2.62 (m, 5H), 1.60 (s, 3H), 1.53 (s, 3H), 1.18 (t, J=7.1 Hz, 3H).

Example 105: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate

[0666] Except that N,N-diisopropylcarbamoyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diisopropylcarbamate (80 mg, 95%).

[0667] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.10 (m, 2H), 7.82-7.77 (m, 2H), 7.12-7.03 (m, 1H), 6.70 (dd, J=8.4, 2.3 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.02 (q, J=3.2 Hz, 1H), 5.71 (s, 1H), 4.21 (t, J=2.8 Hz, 2H), 4.02-3.89 (m, 2H), 2.63 (s, 3H), 1.56 (d, J=21.8 Hz, 6H), 1.20 (d, J=19.9 Hz, 14H).

Example 106: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate

[0668] Except that isopropyl chloroformate 1M solution (1M/toluene) was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isopropyl carbonate (120 mg, 93%).

[0669] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.83-7.76 (m, 2H), 7.12 (dd, J=8.4, 1.1 Hz, 1H), 6.91-6.72 (m, 2H), 6.02 (td, J=3.7, 1.8 Hz, 1H), 5.73 (d, J=1.9 Hz, 1H), 4.84 (p, J=6.2 Hz, 1H), 4.21 (dd, J=3.8, 2.0 Hz, 2H), 2.63 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.29 (d, J=6.2 Hz, 6H).

Example 107: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl) carbonate

[0670] Except that 2-hydroxyethyl disulfide was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl) carbonate (830 mg, 58%).

[0671] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.14-7.99 (m, 2H), 7.94-7.70 (m, 2H), 7.09 (dd, J=8.5, 1.1 Hz, 1H), 6.88-6.66 (m, 2H), 5.87 (dt, J=4.9, 2.3 Hz, 1H), 5.73 (d, J=2.3 Hz, 1H), 4.48 (td, J=6.7, 1.1 Hz, 2H), 4.37 (t, J=6.5 Hz, 2H), 4.31 (ddd, J=16.1, 4.7, 1.2 Hz, 1H), 4.14 (dt, J=16.3, 2.7 Hz, 1H), 3.03-2.93 (m, 4H), 2.64 (d, J=2.7 Hz, 6H), 1.61 (d, J=6.3 Hz, 6H).

Example 108: Synthesis of 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid

[0672] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-((2-hydroxyethyl)disulfanyl)ethyl) carbonate (700 mg, 1.17 mmol) obtained in Example 107 above and 4-dimethylaminopyridine (71 mg, 0.58 mmol) were dissolved in dichloromethane (30 mL), and tetrahydrofuran-2,5-dione (467 mg, 4.67 mmol) was added thereto, and heated and stirred at 35 C. for 1 hour. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with aqueous ammonium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=3:1, v/v) to obtain 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H, 7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid (0.81 g, 99%).

[0673] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.05-5.99 (m, 1H), 5.73 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 4.21 (d, J=6.7 Hz, 4H), 3.08 (t, J=6.2 Hz, 2H), 2.98 (t, J=6.5 Hz, 2H), 2.63 (s, 3H), 2.38 (d, J=6.4 Hz, 2H), 2.13 (t, J=7.8 Hz, 2H), 1.60 (s, 3H), 1.54 (s, 3H).

Example 109: Synthesis of sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate

[0674] Except that 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoic acid was used instead of N-(((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-N-methylglycine, the same synthesis method as in Example 90 above was carried out to obtain sodium 4-(2-((2-((((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)oxy)ethyl)disulfanyl)ethoxy)-4-oxobutanoate (100 mg, 90%).

[0675] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13 (d, J=8.6 Hz, 2H), 7.80 (d, J=8.1 Hz, 2H), 7.14 (d, J=8.4 Hz, 1H), 6.85 (dd, J=8.3, 2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.05-5.99 (m, 1H), 5.73 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 4.21 (d, J=6.7 Hz, 4H), 3.08 (t, J=6.2 Hz, 2H), 2.98 (t, J=6.5 Hz, 2H), 2.63 (s, 3H), 2.38 (d, J=6.4 Hz, 2H), 2.13 (t, J=7.8 Hz, 2H), 1.60 (s, 3H), 1.54 (s, 3H)

Example 110: Synthesis of 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0676] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (500 mg, 1.19 mmol) obtained in Example 10 (b) above and potassium carbonate (752 mg, 3.58 mmol) were suspended in acetone, and 2-bromoethanol (298 mg, 2.38 mmol) was added to the reaction mixture, and heated and stirred at 60 C. for 24 hours. When the reaction was completed, acetone was removed by distillation under reduced pressure. The obtained residue was diluted in ethyl acetate and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (478 mg, 87%).

[0677] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.13 (d, J=8.0 Hz, 2H), 7.79 (d, J=7.7 Hz, 2H), 6.99 (d, J=8.9 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.44 (d, J=3.0 Hz, 1H), 5.99 (d, J=4.1 Hz, 1H), 5.66 (s, 1H), 4.20 (d, J=3.7 Hz, 2H), 3.92 (q, J=4.1 Hz, 2H), 3.67 (s, 2H), 2.64 (d, J=2.5 Hz, 3H), 1.55 (d, J=16.2 Hz, 6H)

Example 111: Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride

(a) Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucinate

[0678] Except that 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and N-(tert-butoxycarbonyl)-L-leucine monohydrate were used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, respectively, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucinate (98 mg, 62%).

(b) Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride

[0679] Except that 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl (tert-butoxycarbonyl)-L-leucinate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl L-leucinate hydrochloride (70 mg, 80%).

[0680] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.51 (s, 3H), 8.17-8.11 (m, 2H), 7.82-7.76 (m, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.55 (dd, J=8.6, 2.5 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.00 (d, J=2.5 Hz, 1H), 5.67 (s, 1H), 4.54 (dq, J=13.0, 4.5 Hz, 1H), 4.44-4.39 (m, 1H), 4.20 (q, J=4.1 Hz, 4H), 3.98 (s, 1H), 2.64 (s, 3H), 1.75 (dt, J=13.4, 6.8 Hz, 1H), 1.62 (td, J=7.2, 2.6 Hz, 2H), 1.57 (s, 3H), 1.53 (s, 3H), 0.87-0.84 (m, 6H).

Example 112: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride

[0681] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10 (b) above and potassium carbonate (395 mg, 2.86 mmol) were suspended in acetone, and 1-(2-chloroethyl)piperidine (158 mg, 0.86 mmol, HCl) was added thereto and stirred at 70 C. for 5 hours. When the reaction was completed, acetone was removed by distillation under reduced pressure, and the obtained residue was diluted in dichloromethane and washed with water. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, separated by MPLC (ethyl acetate:hexane=1:1, v/v), and concentrated by distillation under reduced pressure. The obtained residue was dissolved in ethyl acetate (3 mL), and 4M hydrochloric acid solution (2 mL, 4M/dioxane) was added dropwise thereto and stirred at room temperature for 30 minutes. The obtained solid precipitate was filtered and washed with ethyl acetate to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-(piperidin-1-yl)ethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione hydrochloride (120 mg, 30%).

[0682] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 10.14 (s, 1H), 8.11 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.59 (dd, J=8.6, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 5.66 (s, 1H), 4.33 (t, J=5.1 Hz, 2H), 4.19 (t, J=2.9 Hz, 2H), 3.49-3.38 (m, 6H), 3.02-2.85 (m, 2H), 2.62 (s, 3H), 1.82-1.62 (m, 5H), 1.54 (d, J=13.7 Hz, 6H).

Example 113: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione formate

[0683] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (560 mg, 1.34 mmol) obtained in Example 10 (b) above was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (64 mg, 2.67 mmol, 60%) was added thereto and stirred at room temperature for 30 minutes. 4-(2-Chloroethyl)morpholine hydrochloride (298 mg, 1.6 mmol) was added to the reaction mixture and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was quenched by adding water (5 mL) and extracted with dichloromethane. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure. The obtained residue was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) and freeze-dried to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(2-morpholinoethoxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione formate (60 mg, 70%).

[0684] .sup.1H NMR (500 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.09-7.05 (m, 1H), 6.72-6.67 (m, 2H), 5.86 (dt, J=4.6, 2.3 Hz, 1H), 5.72 (s, 1H), 4.34-4.24 (m, 1H), 4.14 (dt, J=16.5, 2.6 Hz, 1H), 3.64 (d, J=60.0 Hz, 9H), 2.65 (s, 3H), 2.47 (s, 3H), 1.61 (s, 3H), 1.59 (s, 3H).

Example 114: Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid

(a) Synthesis of diethyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate

[0685] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (300 mg, 0.72 mmol) obtained in Example 10 (b) above was dissolved in N,N-dimethylformamide (8 mL), and sodium hydride (17 mg, 0.72 mmol, 60%) was added thereto and stirred at room temperature for 1 hour. Diethoxyphosphorylmethyl 4-methylbenzenesulfonate (346 mg, 1.07 mmol) was added to the reaction mixture and stirred at room temperature under nitrogen atmosphere for 15 hours. When the reaction was completed, the reaction mixture was diluted in ethyl acetate and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, and concentrated by distillation under reduced pressure to quantitatively obtain diethyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate. The obtained compound was used in the next reaction without purification.

(b) Synthesis of (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid

[0686] Except that diethyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate, the same synthesis method as in Example 69 (b) above was carried out to obtain (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid (70 mg, 50%).

[0687] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.09 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.1 Hz, 2H), 7.23 (d, J=14.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 6.61 (s, 1H), 6.51 (d, J=8.4 Hz, 1H), 6.42 (s, 1H), 5.87 (d, J=14.2 Hz, 1H), 4.05 (d, J=10.1 Hz, 2H), 2.62 (s, 3H), 1.43 (s, 6H)

Example 115: Synthesis of disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate

[0688] Except that (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonic acid was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate, the same synthesis method as in Example 70 above was carried out to obtain disodium (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)methyl)phosphonate.

[0689] .sup.1H NMR (500 MHz, D.sub.2O) 8.17-8.10 (m, 2H), 7.60-7.54 (m, 2H), 7.30 (d, J=14.0 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.68 (dd, J=8.4, 2.5 Hz, 1H), 6.61 (s, 1H), 6.56 (d, J=2.5 Hz, 1H), 6.11 (dd, J=14.1, 1.0 Hz, 1H), 3.99 (d, J=9.8 Hz, 3H), 2.71 (s, 3H), 1.53 (s, 7H)

Example 116: Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride

[0690] Except that 2-(4-acetylphenyl)-10-(2-hydroxyethoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 72 above was carried out to obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)ethyl dimethylglycinate hydrochloride (98 mg, 62%).

[0691] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 10.35 (s, 1H), 8.14 (d, J=7.9 Hz, 2H), 7.79 (q, J=5.9, 4.5 Hz, 2H), 7.05-6.96 (m, 1H), 6.57 (d, J=8.9 Hz, 1H), 6.49 (s, 1H), 6.00 (s, 1H), 5.67 (s, 1H), 4.48 (s, 2H), 4.32-4.12 (m, 6H), 2.83 (t, J=3.4 Hz, 6H), 2.63 (d, J=4.4 Hz, 3H), 1.61-1.46 (m, 6H).

Example 117: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1-carboxylate hydrochloride

[0692] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(piperidin-4-yl)piperazine-1-carboxylate dihydrochloride (201 mg, 0.29 mmol) obtained in Example 94 (b) above, pyruvic acid (32 mg, 0.35 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (225 mg, 0.58 mmol) were dissolved in dichloromethane (4 mL), and this reaction mixture was added dropwise to triethylamine (131 mg, 0.58 mmol) and stirred at room temperature for 19 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, separated by MPLC (ethyl acetate:hexane=3:7, v/v), and concentrated by distillation under reduced pressure. The obtained residue was dissolved in dichloromethane (1 mL), and 1M hydrochloric acid solution (1 mL, 1 M/diethyl ether) was added dropwise thereto and stirred at room temperature for 30 minutes. The obtained solid precipitate was filtered and washed with diethyl ether to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(1-(2-oxopropanoyl)piperidin-4-yl)piperazine-1-carboxylate hydrochloride (51 mg, 0.07 mmol).

[0693] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 11.18 (s, 1H), 8.17-8.10 (m, 2H), 7.83-7.76 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.81-6.73 (m, 2H), 6.02 (td, J=3.8, 1.8 Hz, 1H), 5.71 (d, J=2.5 Hz, 1H), 4.39 (d, J=13.2 Hz, 1H), 4.31-4.18 (m, 3H), 4.12 (s, 1H), 3.77 (d, J=13.7 Hz, 1H), 3.54 (s, 2H), 3.48 (d, J=12.8 Hz, 3H), 3.12 (dd, J=24.6, 12.6 Hz, 3H), 2.82-2.70 (m, 1H), 2.64 (s, 3H), 2.38 (s, 3H), 2.18 (dd, J=22.4, 12.3 Hz, 2H), 1.64 (s, 2H), 1.60 (s, 3H), 1.52 (s, 3H).

Example 118: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride

(a) Synthesis of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,2-dimethylpiperazine-1,4-dicarboxylate

[0694] Except that tert-butyl 4-(chlorocarbonyl)-3,3-dimethylpiperidine-1-carboxylate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,2-dimethylpiperazine-1,4-dicarboxylate (200 mg, 78%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride

[0695] Except that 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) 2,2-dimethylpiperazine-1,4-dicarboxylate was used instead of 1-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 4-(tert-butyl) piperazine-1,4-dicarboxylate, the same synthesis method as in Example 67 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride (100 mg, 80%).

[0696] .sup.1H NMR (500 MHz, D.sub.2O) 8.08 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.76 (d, J=8.9 Hz, 2H), 5.97 (s, 1H), 5.73 (s, 1H), 3.73 (d, J=1.4 Hz, 3H), 3.59-3.53 (m, 4H), 3.46 (t, J=5.6 Hz, 4H), 3.43 (s, 2H), 3.37 (s, 3H), 3.28 (s, 2H), 1.55 (s, 6H).

Example 119: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)-2,2-dimethylpiperazine-1-carboxylate hydrochloride

[0697] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2,2-dimethylpiperazine-1-carboxylate hydrochloride was used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione, the same synthesis method as in Example 72 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 4-(dimethylglycyl)-2,2-dimethylpiperazine-1-carboxylate hydrochloride (50 mg, 74%).

[0698] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 9.70 (d, J=40.2 Hz, 1H), 8.15-8.10 (m, 2H), 7.81-7.77 (m, 2H), 7.09 (dd, J=8.4, 3.2 Hz, 1H), 6.72 (ddd, J=8.5, 6.5, 2.3 Hz, 1H), 6.66 (dd, J=11.1, 2.3 Hz, 1H), 6.03 (dt, J=5.3, 2.4 Hz, 1H), 5.72 (s, 1H), 4.28 (dd, J=10.4, 4.9 Hz, 2H), 4.22 (t, J=2.8 Hz, 2H), 3.87 (dt, J=21.6, 6.0 Hz, 2H), 3.56 (dt, J=19.4, 5.8 Hz, 3H), 2.83 (d, J=4.6 Hz, 6H), 2.64 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.41 (d, J=12.6 Hz, 6H).

Example 120: Synthesis of 2-(4-acetylphenyl)-10-(3-(4-(3-chlorophenyl)piperazin-1-yl)propoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione dihydrochloride

[0699] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (500 mg, 1.19 mmol) obtained in Example 10 (b) above was dissolved in N,N-dimethylformamide (10 mL), and potassium tert-butoxide (401 mg, 3.58 mmol) was added thereto and stirred at room temperature for 30 minutes. 1-(3-Chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride (554 mg, 1.79 mmol) was added to the reaction mixture and stirred at room temperature for additional 15 hours. When the reaction was completed, the reaction mixture was quenched by adding water (5 mL) and extracted with ethyl acetate. The separated organic layer was washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, separated by MPLC (ethyl acetate:hexane=3:7, v/v), and concentrated by distillation under reduced pressure. The obtained residue was dissolved in ethyl acetate (5 mL), and 4M hydrochloric acid solution (1 mL, 4M/dioxane) was added dropwise thereto and stirred at room temperature for 30 minutes. The obtained solid precipitate was filtered and washed with ethyl acetate to obtain 2-(4-acetylphenyl)-10-(3-(4-(3-chlorophenyl)piperazin-1-yl)propoxy)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione dihydrochloride (128 mg, 16%).

[0700] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 10.69 (s, 1H), 8.11-8.06 (m, 2H), 7.73-7.68 (m, 2H), 7.29-7.19 (m, 2H), 7.08-7.02 (m, 2H), 6.97 (dd, J=8.4, 2.4 Hz, 1H), 6.88 (dd, J=7.9, 1.9 Hz, 1H), 6.61 (s, 1H), 6.47 (dd, J=8.3, 2.5 Hz, 1H), 6.40 (d, J=2.4 Hz, 1H), 5.91 (d, J=14.2 Hz, 1H), 4.04 (q, J=7.0, 6.5 Hz, 2H), 3.90 (d, J=10.7 Hz, 3H), 3.27 (d, J=10.8 Hz, 3H), 3.21-3.06 (m, 5H), 2.62 (s, 3H), 2.19 (dd, J=10.1, 5.9 Hz, 2H), 1.43 (s, 6H).

Example 121: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0701] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (500 mg, 1.19 mmol) obtained in Example 10 (b) above was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (71 mg, 1.79 mmol, 60%) was added thereto and stirred at room temperature for 30 minutes. Acetobromo--D-glucose (734 mg, 1.79 mmol) was added thereto and stirred at room temperature for 4 hours. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (ethyl acetate:hexane=1:1, v/v) to obtain (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (450 mg, 50%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0702] Except that (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate was used instead of (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, the same synthesis method as in Example 64 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (200 mg, 52%).

[0703] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.12-8.03 (m, 2H), 7.76-7.68 (m, 2H), 7.23 (d, J=14.3 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.53 (dd, J=8.3, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 5.87 (dd, J=14.3, 1.0 Hz, 1H), 5.12 (s, 1H), 4.84 (s, 1H), 4.79 (d, J=7.6 Hz, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 3.68 (d, J=3.3 Hz, 1H), 3.61-3.43 (m, 6H), 2.62 (s, 3H), 1.43 (d, J=5.2 Hz, 6H).

Example 122: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

(a) Synthesis of (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate

[0704] Except that acetobromo--D-galactose was used instead of acetobromo--D-glucose, the same synthesis method as in Example 121 (a) above was carried out to obtain (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (500 mg, 54%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0705] Except that (2R,3S,4S,5R,6S)-2-(acetoxymethyl)-6-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate was used instead of (2S,3R,4S,5S,6S)-2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, the same synthesis method as in Example 64 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-10-(((2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (142 mg, 58%).

[0706] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.12-8.05 (m, 2H), 7.74-7.67 (m, 2H), 7.24 (d, J=14.3 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.54 (dd, J=8.3, 2.4 Hz, 1H), 6.43 (d, J=2.3 Hz, 1H), 5.87 (d, J=14.2 Hz, 1H), 5.76 (s, 1H), 5.28 (s, 1H), 5.04 (d, J=29.3 Hz, 2H), 4.83 (d, J=7.6 Hz, 1H), 4.58 (s, 1H), 3.68 (d, J=11.4 Hz, 1H), 3.24 (d, J=8.9 Hz, 3H), 3.16 (dt, J=26.4, 8.7 Hz, 3H), 2.62 (s, 3H), 1.43 (d, J=1.9 Hz, 6H).

Example 123: Synthesis of 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide

[0707] 2-(4-Acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylglycinate hydrochloride (200 mg, 0.37 mmol) obtained in Example 72 above was dissolved in dichloromethane (5 mL), and triethylamine (75 mg, 0.74 mmol) was added thereto and stirred at room temperature for 30 minutes. Water (5 mL) was added to the reaction mixture, and the organic layer was separated by layer separation. The separated organic layer was concentrated by distillation under reduced pressure. The obtained residue was dissolved in acetone (3 mL), and iodomethane (222 mg, 0.79 mmol) was added dropwise thereto and stirred at room temperature for 3 hours. The obtained solid precipitate was filtered and washed with acetone to obtain 2-((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)-N,N,N-trimethyl-2-oxoethan-1-aminium iodide (220 mg, 46%).

[0708] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.09 (m, 2H), 7.83-7.76 (m, 2H), 7.19 (dd, J=8.3, 1.1 Hz, 1H), 6.89-6.84 (m, 2H), 6.05 (td, J=3.7, 1.7 Hz, 1H), 5.77-5.71 (m, 1H), 4.71 (s, 2H), 4.23 (dd, J=4.2, 2.0 Hz, 2H), 3.29 (s, 9H), 2.64 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H).

Example 124: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (4-nitrobenzyl) carbonate

[0709] Except that (4-nitrophenyl)methyl carbonochloridate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (4-nitrobenzyl) carbonate (120 mg, 90%).

[0710] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 11.18 (s, 1H), 8.17-8.10 (m, 2H), 7.83-7.76 (m, 2H), 7.10 (d, J=8.2 Hz, 1H), 6.81-6.73 (m, 2H), 6.02 (td, J=3.8, 1.8 Hz, 1H), 5.71 (d, J=2.5 Hz, 1H), 4.39 (d, J=13.2 Hz, 1H), 4.31-4.18 (m, 3H), 4.12 (s, 1H), 3.77 (d, J=13.7 Hz, 1H), 3.54 (s, 2H), 3.48 (d, J=12.8 Hz, 3H), 3.12 (dd, J=24.6, 12.6 Hz, 3H), 2.82-2.70 (m, 1H), 2.64 (s, 3H), 2.38 (s, 3H), 2.18 (dd, J=22.4, 12.3 Hz, 2H), 1.64 (s, 2H), 1.60 (s, 3H), 1.52 (s, 3H).

Example 125: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperidine-1-carboxylate

[0711] Except that piperidine-1-carbonyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl piperidine-1-carboxylate (140 mg, 92%).

[0712] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.85-7.76 (m, 2H), 7.08 (dd, J=8.4, 1.1 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.01 (td, J=3.7, 1.9 Hz, 1H), 5.73-5.67 (m, 1H), 4.21 (dd, J=3.9, 2.0 Hz, 2H), 3.44 (d, J=51.2 Hz, 4H), 2.64 (s, 3H), 1.56 (d, J=25.9 Hz, 12H).

Example 126: Synthesis of O-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) dimethylcarbamothioate

[0713] Except that dimethylcarbamothioic chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain O-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) dimethylcarbamothioate (200 mg, 95%).

[0714] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.11 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H), 7.10 (dd, J=8.5, 1.1 Hz, 1H), 6.67 (dd, J=8.4, 2.3 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 5.88-5.82 (m, 1H), 5.74 (s, 1H), 4.36-4.27 (m, 1H), 4.13 (dt, J=16.5, 2.6 Hz, 1H), 3.44 (s, 3H), 3.31 (s, 3H), 2.64 (s, 3H), 1.61 (d, J=4.9 Hz, 6H).

Example 127: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2-oxoimidazolidine-1-carboxylate

[0715] Except that 2-oxoimidazolidine-1-carbonyl chloride was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl 2-oxoimidazolidine-1-carboxylate (132 mg, 92%).

[0716] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.6 Hz, 2H), 7.55 (s, 1H), 7.17-7.09 (m, 1H), 6.79 (dd, J=8.4, 2.4 Hz, 1H), 6.73 (d, J=2.3 Hz, 1H), 6.02 (s, 1H), 5.73 (d, J=6.1 Hz, 1H), 4.22 (s, 2H), 3.95-3.85 (m, 2H), 3.34 (s, 1H), 3.29 (s, 1H), 2.64 (s, 3H), 1.60 (s, 3H), 1.53 (s, 3H).

Example 128: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (3-(dimethylamino)-2,2-dimethylpropyl)carbamate formate

[0717] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (830 mg, 1.98 mmol) obtained in Example 10 (b) above was dissolved in dichloromethane (10 mL), and triphosgene (300 mg, 0.99 mmol) and N,N-diisopropylethylamine (307 mg, 2.37 mmol) were added thereto and stirred at room temperature for 10 minutes. N,N-tetramethylpropane-1,3-diamine (503 mg, 3.86 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 30 minutes. When the reaction was completed, the reaction mixture was diluted in dichloromethane and washed with saline. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, separated by reverse-phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0), and freeze-dried to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (3-(dimethylamino)-2,2-dimethylpropyl)carbamate formate (170 mg, 14%).

[0718] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.13 (dd, J=8.6, 2.1 Hz, 2H), 7.83-7.77 (m, 2H), 7.69 (t, J=6.2 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 6.69 (dd, J=8.4, 2.2 Hz, 1H), 6.61 (d, J=2.3 Hz, 1H), 6.01 (s, 1H), 5.71 (s, 1H), 4.21 (d, J=3.7 Hz, 2H), 2.94 (d, J=6.2 Hz, 2H), 2.63 (d, J=2.3 Hz, 4H), 2.22 (s, 6H), 2.11 (s, 2H), 1.59 (d, J=2.2 Hz, 3H), 1.53 (s, 3H), 0.83 (d, J=1.8 Hz, 6H).

Example 129: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-(dimethylamino)ethyl)(methyl)carbamate formate

[0719] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (664 mg, 1.58 mmol) obtained in Example 10 (b) above was dissolved in dichloromethane (5 mL), and triphosgene (383 mg, 1.27 mmol) and N,N-diisopropylethylamine (245 mg, 1.9 mmol) were added thereto and stirred at room temperature for 10 minutes. N,N,N-trimethylethane-1,2-diamine (250 mg, 2.37 mmol) was added dropwise to the reaction mixture and stirred at room temperature for 30 minutes. When the reaction was completed, the undissolved solid product was filtered and washed with dichloromethane. The filtered solid product was separated by reverse phase chromatography (acetonitrile containing 0.1% formic acid:water containing 0.1% formic acid=5:95-100:0) and freeze-dried to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (2-(dimethylamino)ethyl)(methyl)carbamate formate (330 mg, 35%).

[0720] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 11.00 (s, 1H), 10.53 (s, 1H), 9.41 (s, 1H), 8.11 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.10-7.02 (m, 1H), 6.83-6.74 (m, 2H), 6.00 (s, 1H), 5.69 (s, 1H), 4.20 (dd, J=3.8, 2.0 Hz, 2H), 3.19 (s, 3H), 3.15 (s, 1H), 3.01 (s, 2H), 2.94 (s, 2H), 2.91 (s, 1H), 2.80 (s, 4H), 2.77 (d, J=4.6 Hz, 6H), 2.62 (s, 3H), 2.57 (d, J=5.9 Hz, 2H), 1.57 (s, 3H), 1.51 (s, 3H).

Example 130: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(piperidin-3-yl)carbamate hydrochloride

[0721] Except that N-methyl-N-(3-piperidyl)carbamoyl chloride was used instead of 2-(dimethylamino)acetyl chloride, the same synthesis method as in Example 72 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(piperidin-3-yl)carbamate hydrochloride (120 mg, 74%).

[0722] .sup.1H NMR (500 MHz, D.sub.2O) 8.16 (d, J=8.3 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.15 (s, 1H), 6.84 (dd, J=28.7, 10.7 Hz, 3H), 6.02 (s, 1H), 5.80 (s, 1H), 4.30 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.40 (s, 2H), 3.20 (s, 2H), 3.04 (s, 1H), 2.92 (s, 1H), 2.71 (s, 2H), 2.07 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H).

Example 131: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(methylsulfonyl)carbamate

[0723] Except that N-methylmethanesulfonamide was used instead of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate, the same synthesis method as in Example 83 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl methyl(methylsulfonyl)carbamate (58 mg, 46%).

[0724] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.17-8.09 (m, 2H), 7.86-7.76 (m, 2H), 7.16 (dd, J=8.3, 1.1 Hz, 1H), 6.93-6.78 (m, 2H), 6.03 (td, J=3.8, 1.8 Hz, 1H), 5.74 (d, J=1.7 Hz, 1H), 4.22 (dd, J=4.0, 2.0 Hz, 2H), 3.45 (s, 3H), 3.27 (s, 3H), 2.64 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H).

Example 132: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-valinate

[0725] Except that (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-valinate (214 mg, 50%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid

[0726] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-valinate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-valinate 2,2,2-trifluoroacetic acid (70 mg, 48%).

[0727] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.16-8.10 (m, 2H), 7.82-7.78 (m, 2H), 7.13 (dt, J=8.4, 1.4 Hz, 1H), 6.72 (dt, J=8.4, 2.1 Hz, 1H), 6.64 (d, J=2.3 Hz, 1H), 6.06-5.99 (m, 1H), 5.73 (d, J=2.6 Hz, 1H), 4.22 (t, J=2.9 Hz, 2H), 3.34-3.32 (m, 1H), 2.64 (s, 3H), 2.04-1.94 (m, 1H), 1.84 (s, 2H), 1.57 (d, J=25.1 Hz, 7H), 0.95 (dd, J=17.6, 6.8 Hz, 6H).

Example 133: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 1-(tert-butyl) (2S)-pyrrolidine-1,2-dicarboxylate

[0728] Except that 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 1-(tert-butyl) (2S)-pyrrolidine-1,2-dicarboxylate (120 mg, 48%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid

[0729] Except that 2-(2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl) 1-(tert-butyl) (2S)-pyrrolidine-1,2-dicarboxylate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-prolinate 2,2,2-trifluoroacetic acid (48 mg, 55%).

[0730] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.16-8.09 (m, 2H), 7.83-7.77 (m, 2H), 7.18 (dt, J=9.0, 1.4 Hz, 1H), 6.89-6.80 (m, 2H), 6.04 (q, J=2.9, 2.3 Hz, 1H), 5.74 (s, 1H), 4.67 (t, J=8.1 Hz, 1H), 4.23 (dd, J=4.3, 2.0 Hz, 2H), 3.41-3.34 (m, 1H), 3.29 (td, J=16.0, 13.5, 8.7 Hz, 2H), 2.64 (s, 3H), 2.43-2.34 (m, 2H), 2.23 (dq, J=13.0, 7.6 Hz, 1H), 2.02-1.93 (m, 2H), 1.61 (s, 3H), 1.53 (s, 3H).

Example 134: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetyl-L-glutaminate

[0731] Except that (2S)-2-acetamido-5-amino-5-oxo-pentanoic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl acetyl-L-glutaminate (90 mg, 70%).

[0732] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.45 (d, J=6.7 Hz, 1H), 8.16-8.09 (m, 2H), 7.82-7.77 (m, 2H), 7.36-7.30 (m, 1H), 7.13 (ddd, J=8.4, 2.2, 1.1 Hz, 1H), 6.82 (s, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.03 (tt, J=3.9, 1.8 Hz, 1H), 5.73 (q, J=1.7 Hz, 1H), 4.33 (ddt, J=8.9, 6.1, 3.0 Hz, 1H), 4.22 (dd, J=3.9, 2.0 Hz, 2H), 2.64 (s, 3H), 2.22 (t, J=7.5 Hz, 2H), 2.04 (td, J=6.9, 5.9, 2.1 Hz, 1H), 1.97-1.89 (m, 1H), 1.88 (s, 3H), 1.60 (s, 3H), 1.54 (s, 3H).

Example 135: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid

(a) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-argininate

[0733] Except that (2S)-2-(tert-butoxycarbonylamino)-5-guanido-pentanoic acid was used instead of (2S)-5-amino-2-(tert-butoxycarbonylamino)-5-oxo-pentanoic acid, the same synthesis method as in Example 77 (a) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-argininate (320 mg, 59%).

(b) Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid

[0734] Except that 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-argininate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl (tert-butoxycarbonyl)-L-glutaminate, the same synthesis method as in Example 77 (b) above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl L-argininate 2,2,2-trifluoroacetic acid (60 mg, 38%).

[0735] .sup.1H NMR (400 MHz, D.sub.2O) 8.13 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 6.94-6.84 (m, 2H), 6.06 (s, 1H), 5.81 (s, 1H), 4.55-4.49 (m, 1H), 4.30 (s, 2H), 3.35 (t, J=6.8 Hz, 2H), 3.29 (d, J=6.9 Hz, 1H), 2.29-2.13 (m, 2H), 2.01-1.88 (m, 2H), 1.86-1.73 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H).

Example 136: Synthesis of methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-valinate

[0736] Except that methyl 2-isocyanato-methyl-butanoate was used instead of methyl 2-isocyanato-4-methyl-pentanoate, the same synthesis method as in Example 80 above was carried out to obtain methyl (((2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl)oxy)carbonyl)-L-valinate (67 mg, 58%).

[0737] .sup.1H NMR (500 MHz, DMSO-D.sub.6) 8.22 (d, J=8.1 Hz, 1H), 8.13 (dd, J=8.6, 2.4 Hz, 2H), 7.80 (dd, J=8.8, 2.5 Hz, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.71 (dt, J=8.5, 1.9 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.04-5.98 (m, 1H), 5.71 (s, 1H), 4.21 (t, J=3.6 Hz, 2H), 4.09-3.90 (m, 1H), 3.65 (d, J=4.2 Hz, 3H), 2.63 (d, J=2.0 Hz, 3H), 2.08 (dt, J=13.5, 6.8 Hz, 1H), 1.60-1.50 (m, 7H), 0.96-0.88 (m, 7H).

Example 137: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl sulfamate

[0738] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (200 mg, 0.48 mmol) obtained in Example 10 (b) above was dissolved in tetrahydrofuran (5 mL), and sodium hydride (23 mg, 0.95 mmol, 60%) was added thereto and stirred at room temperature for 30 minutes. Sulfamoyl chloride (83 mg, 0.72 mmol) was added thereto and stirred at 70 C. for 12 hours. When the reaction was completed, the reaction mixture was quenched by adding water (5 mL) and extracted with dichloromethane. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol=9:1, v/v) to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl sulfamate (102 mg, 41%).

[0739] .sup.1H NMR (500 MHz, CDCl.sub.3) 9.28 (s, 2H), 8.10 (d, J=8.7 Hz, 2H), 7.84-7.79 (m, 2H), 6.99 (dd, J=9.1, 1.0 Hz, 1H), 6.97-6.94 (m, 2H), 5.82 (dt, J=4.5, 2.1 Hz, 1H), 5.67 (d, J=2.5 Hz, 1H), 4.28 (ddd, J=16.4, 4.9, 1.3 Hz, 1H), 4.12 (dt, J=16.4, 2.7 Hz, 1H), 2.64 (s, 3H), 1.57 (d, J=8.9 Hz, 6H).

Example 138: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl picolinate hydrochloride

[0740] Except that picolinoyl chloride was used instead of 2-(dimethylamino)acetyl chloride, the same synthesis method as in Example 72 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl picolinate hydrochloride (500 mg, 89%).

[0741] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.80 (ddd, J=4.7, 1.7, 0.9 Hz, 1H), 8.22 (dt, J=7.9, 1.1 Hz, 1H), 8.17-8.10 (m, 2H), 8.08 (td, J=7.7, 1.8 Hz, 1H), 7.86-7.78 (m, 2H), 7.74 (ddd, J=7.7, 4.7, 1.2 Hz, 1H), 7.19 (dd, J=8.4, 1.1 Hz, 1H), 6.95-6.85 (m, 2H), 6.38 (s, 1H), 6.05 (td, J=3.7, 1.8 Hz, 1H), 5.79-5.74 (m, 1H), 4.24 (dd, J=4.0, 2.0 Hz, 2H), 2.64 (s, 3H), 1.62 (s, 3H), 1.56 (s, 3H).

Example 139: Synthesis of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isonicotinate hydrochloride

[0742] Except that isonicotinoyl chloride was used instead of 2-(dimethylamino)acetyl chloride, the same synthesis method as in Example 72 above was carried out to obtain 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl isonicotinate hydrochloride (420 mg, 87%).

[0743] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.00-8.87 (m, 2H), 8.18-8.04 (m, 4H), 7.81 (d, J=8.4 Hz, 2H), 7.51 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 7.00-6.86 (m, 2H), 6.05 (q, J=3.2 Hz, 1H), 5.76 (d, J=3.3 Hz, 1H), 4.24 (t, J=2.8 Hz, 2H), 1.62 (s, 3H), 1.55 (s, 3H).

Example 140: Synthesis of 10-hydroxy-2-(4-(1-hydroxyethyl)phenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0744] 2-(4-Acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 0.24 mmol) obtained in Example 10 (b) above was suspended in methanol, and sodium borohydride (11 mg, 0.29 mmol). mmol) was added thereto and stirred at room temperature for 15 hours. When the reaction was completed, the reaction mixture was concentrated by distillation under reduced pressure, diluted in dichloromethane, and washed with aqueous sodium chloride solution. The separated organic layer was dried over sodium sulfate, filtered, concentrated by distillation under reduced pressure, and separated by MPLC (dichloromethane:methanol=20:1, v/v) to obtain 10-hydroxy-2-(4-(1-hydroxyethyl)phenyl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (50 mg, 48%).

[0745] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 9.50 (s, 1H), 7.50 (d, J=2.6 Hz, 4H), 6.83 (d, J=8.5 Hz, 1H), 6.38 (dd, J=8.3, 2.6 Hz, 1H), 6.24 (d, J=2.5 Hz, 1H), 5.94 (d, J=4.3 Hz, 1H), 5.58 (s, 1H), 5.27 (d, J=4.0 Hz, 1H), 4.79 (s, 1H), 4.23-4.09 (m, 2H), 1.52 (d, J=11.7 Hz, 6H), 1.36 (d, J=6.4 Hz, 3H).

Example 141: Synthesis of 2-(4-acetylphenyl)-10-(azetidin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0746] Except that 1-(2,2-dimethyl-3-vinyl-2H-chromen-7-yl)azetidine was used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-acetylphenyl)-10-(azetidin-1-yl)-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (25 mg, 60%).

[0747] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 8.13-8.12 (m, 2H), 7.79-7.77 (m, 2H), 6.87-6.85 (m, 1H), 6.02-5.99 (m, 1H), 5.95-5.95 (m, 1H), 5.87 (s, 1H) 5.62 (s, 1H), 4.24-4.13 (m, 2H), 3.74-3.71 (m, 4H), 2.64 (s, 3H), 2.28-2.21 (m, 2H), 1.53-1.52 (m, 6H)

Example 142: Synthesis of 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

(a) Synthesis of 7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0748] Except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene and 4-(4-(trifluoromethyl)phenyl)-1,2,4-triazolidine-3,5-dione were used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, respectively, the same synthesis method as in Example 2 (a) above was carried out to obtain 7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.97 g, 15%).

(b) Synthesis of 10-hydroxy-7,7-dimethyl-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0749] Except that 7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain 10-hydroxy-7,7-dimethyl-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.41 g, 50%).

(c) Synthesis of 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate

[0750] Except that diethyl chlorophosphate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (230 mg, 90%).

(d) Synthesis of 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

[0751] Except that 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate, the same synthesis method as in Example 69 (b) above was carried out to obtain 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (43 mg, 50%).

[0752] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.95 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.06 (d, J=8.5 Hz, 1H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.04-5.97 (m, 1H), 5.70 (s, 1H), 4.27-4.15 (m, 2H), 1.58 (s, 3H), 1.54 (s, 3H).

Example 143: Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

(a) Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0753] Except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene and 4-(4-fluorophenyl)-1,2,4-triazolidine-3,5-dione were used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, respectively, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-fluorophenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.6 g, 10%).

(b) Synthesis of 2-(4-fluorophenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0754] Except that 2-(4-fluorophenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain 2-(4-fluorophenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.37 g, 74%).

(c) Synthesis of diethyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl) phosphate

[0755] Except that diethyl chlorophosphate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain diethyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl) phosphate (230 mg, 89%).

(d) Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

[0756] Except that diethyl (2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-10-yl) phosphate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate, the same synthesis method as in Example 69 (b) above was carried out to obtain 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (50 mg, 44%).

[0757] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.66 (dd, J=8.8, 5.0 Hz, 2H), 7.40 (t, J=8.8 Hz, 2H), 7.04 (d, J=8.5 Hz, 1H), 6.75 (dd, J=8.5, 2.3 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 6.06-5.93 (m, 1H), 5.68 (s, 1H), 4.26-4.12 (m, 2H), 1.58 (s, 3H), 1.54 (s, 3H).

Example 144: Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

(a) Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0758] Except that 2,2-dimethyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-vinyl-2H-chromene and 4-(4-(tert-butyl)phenyl)-1,2,4-triazolidine-3,5-dione were used instead of ((2,2-bis(fluoromethyl)-3-vinyl-2H-chromen-7-yl)oxy)triisopropylsilane and 4-(4-acetylphenyl)-1,2,4-triazolidine-3,5-dione, respectively, the same synthesis method as in Example 2 (a) above was carried out to obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (0.46 g, 7%).

(b) Synthesis of 2-(4-(tert-butyl)phenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione

[0759] Except that 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-10-((tetrahydro-2H-pyran-2-yl)oxy)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione was used instead of 2,2-bis(fluoromethyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one, the same synthesis method as in Intermediate 31 (d) above was carried out to obtain 2-(4-(tert-butyl)phenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione (100 mg, 28%).

(c) Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate

[0760] Except that diethyl chlorophosphate was used instead of trimethylacetyl chloride, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate (80 mg, 90%).

(d) Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate

[0761] Except that 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate was used instead of 2-(4-acetylphenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl diethyl phosphate, the same synthesis method as in Example 69 (b) above was carried out to obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dihydrogen phosphate (25 mg, 40%).

[0762] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.57 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.79-6.72 (m, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.00 (s, 1H), 5.68 (s, 1H), 4.24-4.11 (m, 2H), 1.58 (s, 3H), 1.54 (s, 3H), 1.33 (s, 9H).

Example 145: Synthesis of 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate

[0763] Except that 10-hydroxy-7,7-dimethyl-2-(4-(trifluoromethyl)phenyl)-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and dimethylcarbamoyl chloride were used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and trimethylacetyl chloride, respectively, the same synthesis method as in Example 58 above was carried out to obtain 7,7-dimethyl-1,3-dioxo-2-(4-(trifluoromethyl)phenyl)-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate (32 mg, 99%).

[0764] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.96 (d, J=8.6 Hz, 2H), 7.90 (d, J=8.4 Hz, 2H), 7.09 (dd, J=8.4, 1.3 Hz, 1H), 6.75-6.68 (m, 1H), 6.65 (d, J=2.1 Hz, 1H), 6.05-5.98 (m, 1H), 5.74-5.68 (m, 1H), 4.25-4.19 (m, 2H), 3.00 (s, 3H), 2.88 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H).

Example 146: Synthesis of 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate

[0765] Except that 2-(4-fluorophenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and dimethylcarbamoyl chloride were used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and trimethylacetyl chloride, respectively, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-fluorophenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate (40 mg, 96%).

[0766] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.70-7.60 (m, 2H), 7.46-7.35 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.72 (dd, J=8.4, 2.4 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.04-5.97 (m, 1H), 5.69 (s, 1H), 4.22-4.16 (m, 2H), 3.01 (s, 3H), 2.88 (s, 3H), 1.59 (s, 3H), 1.52 (s, 3H).

Example 147: Synthesis of 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate

[0767] Except that 2-(4-(tert-butyl)phenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and dimethylcarbamoyl chloride were used instead of 2-(4-acetylphenyl)-10-hydroxy-7,7-dimethyl-5,12b-dihydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazine-1,3(2H)-dione and trimethylacetyl chloride, respectively, the same synthesis method as in Example 58 above was carried out to obtain 2-(4-(tert-butyl)phenyl)-7,7-dimethyl-1,3-dioxo-2,3,5,12b-tetrahydro-1H,7H-chromeno[4,3-c][1,2,4]triazolo[1,2-a]pyridazin-10-yl dimethylcarbamate (44 mg, 99%).

[0768] .sup.1H NMR (400 MHz, DMSO-D.sub.6) 7.57 (d, J=8.7 Hz, 2H), 7.53-7.46 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.72 (dd, J=8.4, 2.3 Hz, 1H), 6.65 (d, J=2.3 Hz, 1H), 6.01 (s, 1H), 5.69 (s, 1H), 4.25-4.12 (m, 2H), 3.01 (s, 3H), 2.88 (s, 3H), 1.59 (s, 3H), 1.53 (s, 3H), 1.33 (s, 9H)

TABLE-US-00002 Compound No. Structure 1 [00007] embedded image 2 [00008] 3 [00009] 4 [00010] 5 [00011] 6 [00012] 7 [00013] 8 [00014] 9 [00015] 10 [00016] 11 [00017] 12 [00018] 13 [00019] 14 [00020] 15 [00021] 16 [00022] 17 [00023] 19 [00024] 20 [00025] 21 [00026] 22 [00027] 23 [00028] 18 [00029] 25 [00030] 26 [00031] 27 [00032] 28 [00033] 24 [00034] embedded image 31 [00035] 32 [00036] 33 [00037] 34 [00038] 29 [00039] 30 [00040] 37 [00041] 38 [00042] 39 [00043] 35 [00044] 36 [00045] 43 [00046] 44 [00047] 45 [00048] 40 [00049] 41 [00050] 42 [00051] 49 [00052] 50 [00053] 46 [00054] 47 [00055] 48 [00056] 55 [00057] 56 [00058] 51 [00059] 52 [00060] embedded image 53 [00061] 54 [00062] 61 [00063] 57 [00064] 58 [00065] 59 [00066] 60 [00067] 67 [00068] 62 [00069] 63 [00070] 64 [00071] 65 [00072] 66 [00073] 68 [00074] 69 [00075] 70 [00076] 71 [00077] [00078] [00079] 72 [00080] 73 [00081] 74 [00082] 75 [00083] 76 [00084] 77 [00085] 79 [00086] 80 [00087] embedded image 81 [00088] 82 [00089] 83 [00090] 78 [00091] 85 [00092] 86 [00093] 87 [00094] 88 [00095] 84 [00096] 91 [00097] 92 [00098] 93 [00099] 94 [00100] 89 [00101] 90 [00102] 97 [00103] 98 [00104] 99 [00105] 95 [00106] 96 [00107] 103 [00108] 104 [00109] 105 [00110] 111 [00111] 112 [00112] 113 [00113] embedded image 114 [00114] 121 [00115] 117 [00116] 118 [00117] 119 [00118] 120 [00119] 127 [00120] 100 [00121] 101 [00122] 102 [00123] 109 [00124] 110 [00125] 106 [00126] 107 [00127] 108 [00128] 115 [00129] 116 [00130] 122 [00131] 123 [00132] 124 [00133] 125 [00134] 126 [00135] 128 [00136] 129 [00137] embedded image 130 [00138] 131 [00139] 132 [00140] 133 [00141] 134 [00142] 135 [00143] 136 [00144] 137 [00145] 139 [00146] 140 [00147] 141 [00148] 142 [00149] 143 [00150] 138 [00151] 145 [00152] 146 [00153] 144 [00154] 147 [00155] [00156] text missing or illegible when filed

Experimental Example 1: Confirmation of Tumor Growth Inhibition Effect

[0769] The tumor growth inhibition effect of benzopyrene derivatives was evaluated in a C57BL/6 mouse tumor model (syngeneic mouse model) in which melanoma cells (B316F10) derived from C57BL/6 mice are implanted.

[0770] After the quarantine and acclimation period was over, a cell suspension prepared with 510.sup.5 cells/0.1 mL PBS was filled into a disposable syringe and administered in an amount of 0.1 mL PBS/head subcutaneously to the right back of healthy test animals (female C57BL/6, 7 weeks old) for implantation. After cell line implantation, general symptoms were observed once daily during the engraftment and growth period. Animals with no abnormalities in their health and whose tumor volume reached 50 to 100 mm.sup.3 when measured with a digital caliper were selected. Then, based on tumor volume and body weight, the groups were separated so that the average tumor volume per group was 70 to 100 mm.sup.3. Ten (10) animals were separated per group, and 20 mg/kg of benzopyran derivatives were administered orally once a day for 9 or 10 days. Tumor volume was measured once every 2 or 3 days.

[0771] The measured tumor volume of the test compound administered groups was compared with that of the control group and is represented in Table 2 as the tumor growth inhibition (TGI, %).

[0772] As a result, as can be seen from Table 2, it was confirmed that the compounds of Example 44, Example 46, Example 68, Example 69, Example 71, Example 72, Example 74, Example 81 and Example 91 show 25 to 66% tumor growth inhibition effect.

TABLE-US-00003 TABLE 2 Example TGI (%)* 60 56.5 62 32.3 68 33.7 70 26.2 72 29.6 73 31.0 75 25.5 82 66.3 92 25.5 *TGI(%) = (Contral group TV Test compound administered group TV)/Control group TV 100

Experimental Example 2: Confirmation of Inhibitory Effect Against the Activity of Human M2 Macrophages

[0773] To obtain human M2 macrophages, human monocytes (THP-1 monocyte, CD4 expression) were stabilized in a 96-well plate for 24 hours and then incubated in culture media containing 100 ng/mL phorbal 12-myristate-13-acetate (PMA; Sigma, P8139) for 24 hours to differentiate into M0 macrophages (macrophage-like phenotype). It was confirmed that differentiated M0 macrophages had reduced CD4 expression and expressed CD11b. M0 macrophages in the plate well were washed once with culture media and incubated in culture media containing 25 ng/mL hIL-4 (Peprotech, 200-04-50) and 25 ng/mL hIL-13 (Peprotech, 200-13-50) for 72 hours to differentiate into M2-like macrophages. Test compounds were diluted by concentration in M2 differentiation media and treated simultaneously during a differentiation period of 72 hours. The inhibitory effect of the test compounds on M2 macrophages was determined by measuring hCCL22 in the medium culture supernatant cultured for 72 hours using an ELISA assay (R&D system, DMD00). The results of the activity measurements are represented in Table 3 (EC.sub.50), Table 4 (hML22 inhibitory activity at 5 M) and Table 5 (hCCL22 inhibitory activity at 10 M).

[0774] As a result, in Tables 3 to 5 it was confirmed that the secretion of hCCL22 was suppressed in differentiated M2 macrophages by the Example compounds at 100 M or less.

TABLE-US-00004 TABLE 3 Example EC.sub.50 (M) 7 4.5 16 4.0 17 8.2 29 3.3 30 4.3 31 2.0 32 6.1 33 5.8 34 7.7 35 4.8 36 10.8 37 14.7 38 31.6 39 73.1 40 53.8 42 31.2 43 19.2 44 9.5 45 9.1 46 7.0 47 8.1 48 9.7 49 12.1 50 25.6 51 33.5 52 26.4 53 4.5 54 1.5 58 58.7 62 41.3 67 17.5 68 74.7 70 9.4 72 4.7 78 5.2 82 68.6 99 32.0 100 15.9 101 17.9 115 >80.0 118 5.3 119 9.5 141 7.2 142 6.3 143 9.4 144 5.4 145 77.3 146 >80 147 >80

TABLE-US-00005 TABLE 4 Example Activity (%) 25 42.00 27 29.86 28 71.22

TABLE-US-00006 TABLE 5 Example Activity (%) 1 80.36 2 64.37 3 16.93 4 51.86 5 42.26 7 83.43 8 60.70 9 74.81 10 98.43 11 78.07 12 16.76 16 79.87 19 18.75 29 95.23 30 97.33 31 97.23 32 84.37 33 96.47 34 73.70 35 96.67 141 94.23

NOVEL BENZOPYRAN DERIVATIVE AND USE THEREOF

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Classification Explorer

A61K31/675

HUMAN NECESSITIES

Classification Explorer

A61P35/00

HUMAN NECESSITIES

Abstract

Claims

Description