LONG-ACTING HIV PROTEASE INHIBITOR

Abstract

The present invention provides useful compounds for HIV protease inhibitor. A compound represented by the following formula or its pharmaceutically acceptable salt:

##STR00001##

wherein ring A is

##STR00002## R.sup.4 is —Y—Z, hydrogen atom, halogen, hydroxy and the like, R.sup.5 is hydrogen atom, halogen, hydroxy and the like, R.sup.6 is each independently halogen, hydroxy, carboxy and the like, ring A may be substituted with said R.sup.6 at any substitutable position(s), a is an integer of 0 to 7, ring B is substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl, ring C is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.1 is —Y—Z, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl and the like, R.sup.2 and R.sup.3 are each independently —Y—Z or hydrogen atom, provided that at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is a group represented by formula: —Y—Z, Y is a bond, or a spacer of any combination selected from the group consisting of —O—, —S—, —NR.sup.7—, —C(═O)—, —SO—, —SO.sub.2—, —NR.sup.7—C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—NR.sup.7—, —O—C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—O—, —SO.sub.2—NR.sup.7—, —NR.sup.7—SO.sub.2—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted aromatic carbocyclediyl, substituted or unsubstituted non-aromatic carbocyclediyl, substituted or unsubstituted aromatic heterocyclediyl and substituted or unsubstituted non-aromatic heterocyclediyl, R.sup.7 are each independently hydrogen atom, hydroxy, carboxy and the like, and Z is substituted aromatic carbocyclyl, substituted non-aromatic carbocyclyl, substituted aromatic heterocyclyl or substituted non-aromatic heterocyclyl.

Claims

1. A compound represented by formula (I): ##STR02796## wherein ring A is a group represented by formula: ##STR02797## R.sup.4 is a group represented by formula: —Y—Z, hydrogen atom, halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aminocarbonyloxyalkyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.5 is hydrogen atom, halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl, R.sup.6 are each independently halogen, hydroxy, carboxy, formyl, formyloxy, sulfo, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfanyl, substituted or unsubstituted non-aromatic carbocyclylsulfanyl, substituted or unsubstituted aromatic heterocyclylsulfanyl, substituted or unsubstituted non-aromatic heterocyclylsulfanyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, ring A may be substituted with said R.sup.6 at any substitutable position(s), a is an integer of 0 to 7, ring B is substituted or unsubstituted aromatic carbocyclyl, or substituted or unsubstituted aromatic heterocyclyl, ring C is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.1 is a group represented by formula: —Y—Z, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, or substituted or unsubstituted non-aromatic heterocyclylalkyl, R.sup.2 and R.sup.3 are each independently a group represented by formula: —Y—Z, or hydrogen atom, provided that at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is a group represented by formula: —Y—Z, Y is each independently a bond, or a spacer of any combination selected from the group consisting of —O—, —S—, —NR.sup.7—, —C(═O)—, —SO—, —SO.sub.2—, —NR.sup.7—C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—NR.sup.7—, —O—C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—O—, —SO.sub.2—NR.sup.7—, —NR.sup.7—SO.sub.2—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted aromatic carbocyclediyl, substituted or unsubstituted non-aromatic carbocyclediyl, substituted or unsubstituted aromatic heterocyclediyl, and substituted or unsubstituted non-aromatic heterocyclediyl, provided that the groups selected from the group consisting of —O—, —S— and —NR.sup.7— are not connected adjacently in Y, and provided that the groups selected from the group consisting of —C(═O)—, —SO—, —SO.sub.2—, —NR.sup.7—C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—NR.sup.7—, —O—C(═O)—N.sup.7—, —NR.sup.7—C(═O)—O—, —SO.sub.2—NR.sup.7— and —NR.sup.7—SO.sub.2— are not connected adjacently in Y, R.sup.7 are each independently hydrogen atom, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, Z is each independently substituted aromatic carbocyclyl, substituted non-aromatic carbocyclyl, substituted aromatic heterocyclyl, or substituted non-aromatic heterocyclyl, provided that when R.sup.4 is hydrogen atom, at least one of substituents on Z is —COOH, provided that the following compounds are excluded: ##STR02798## or its pharmaceutically acceptable salt.

2. The compound or its pharmaceutically acceptable salt according to claim 1, wherein R.sup.2 is a group represented by formula: —Y—Z.

3. The compound or its pharmaceutically acceptable salt according to claim 1, wherein R.sup.4 is substituted or unsubstituted alkyl.

4. The compound or its pharmaceutically acceptable salt according to claim 1, wherein ring B is substituted or unsubstituted phenyl.

5. The compound or its pharmaceutically acceptable salt according to claim 1, wherein ring C is substituted or unsubstituted aromatic carbocyclyl or substituted or unsubstituted bicyclic aromatic heterocyclyl.

6. The compound or its pharmaceutically acceptable salt according to claim 2, wherein Y is a bond, a group represented by formula: ##STR02799## wherein a bond L.sub.Z is connecting to Z, R.sup.8 are each independently —O—, —S—, —NR.sup.7—, substituted or unsubstituted alkylene which may be intervened with one or more groups selected from the group consisting of —O—, —NR.sup.7—, —C(═O)—NR.sup.7— and —NR.sup.7—C(═O)—, substituted or unsubstituted alkenylene which may be intervened with one or more groups selected from the group consisting of —O—, —NR.sup.7—, —C(═O)—NR.sup.7— and —NR.sup.7—C(═O)—, or substituted or unsubstituted alkynylene which may be intervened with one or more groups selected from the group consisting of —O—, —NR.sup.7—, —C(═O)—NR.sup.7— and —NR.sup.7—C(═O)—, provided that the groups selected from the group consisting of —O—, —NR.sup.7—, —C(═O)—NR.sup.7— and —NR.sup.7—C(═O)— are not connected adjacently in R.sup.8, ring D and ring E are each independently substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.9 is —C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—, —NR.sup.7—C(═O)—NR.sup.7—, —NR.sup.7SO.sub.2—, —SO.sub.2NR.sup.7—, R.sup.7 is defined above.

7. The compound or its pharmaceutically acceptable salt according to claim 6, wherein Y is a group represented by formula: ##STR02800## ##STR02801## ##STR02802## ##STR02803## ##STR02804## wherein a bond L.sub.Z is connecting to Z, ring D and ring E are each independently substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.10 and R.sup.11 are each independently hydrogen atom, halogen, hydroxy, carboxy, sulfanyl, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, R.sup.10 and R.sup.11 connected to the same carbon atom may be taken together with the said carbon atom to form substituted or unsubstituted imino, substituted or unsubstituted non-aromatic carbocycle, or non-aromatic heterocycle, the two R.sup.10 and/or R.sup.11 connected to the adjacent carbon atoms may be taken together to form a bond, R.sup.7 is defined above, b are each independently an integer of 0 to 4.

8. The compound or its pharmaceutically acceptable salt according to claim 6, wherein Y is a group represented by formula: ##STR02805## ##STR02806## wherein a bond L.sub.Z is connecting to Z, R.sup.12 are each independently halogen, hydroxy, carboxy, sulfo, cyano, nitro, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, the two R.sup.12 connected to the adjacent carbon atoms constituting the ring may be taken together to form substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, substituted or unsubstituted aromatic hetererocycle, or substituted or unsubstituted non-aromatic heterocycle, R.sup.13 are each independently halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, R.sup.13 connected to the separated-non-adjacent and different carbon atoms may be taken together to form alkylene, R.sup.7 is defined above, R.sup.10 and R.sup.11 connected to the same carbon atom may be taken together with the said carbon atom to form substituted or unsubstituted imino, substituted or unsubstituted non-aromatic carbocycle, or non-aromatic heterocycle, the two R.sup.10 and/or R.sup.11 connected to the adjacent carbon atoms may be taken together to form a bond, b are each independently an integer of 0 to 4, c is an integer of 0 to 4, d is an integer of 0 to 3, e is an integer of 0 to 10, f is an integer of 0 to 5, g is 0 or 1, h is an integer of 0 to 7.

9. The compound or its pharmaceutically acceptable salt according to claim 1, wherein Z is bicyclic or tricyclic substituted non-aromatic carbocyclyl or bicyclic or tricyclic substituted non-aromatic heterocyclyl.

10. The compound or its pharmaceutically acceptable salt according to claim 9, wherein one of the substituents on bicyclic or tricyclic substituted non-aromatic carbocyclyl or bicyclic or tricyclic substituted non-aromatic heterocyclyl is —COOH or its biologically equivalent group.

11. The compound or its pharmaceutically acceptable salt according to claim 10, wherein Z is a group represented by formula: ##STR02807## wherein W.sup.1, W.sup.2, W.sup.3, W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are each independently C, CR.sup.26, O, S, N or NR.sup.27 W.sup.4 is C, or N, R.sup.26 are each independently —COOH or its biologically equivalent group, hydrogen atom, halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, provided that at least one of W.sup.1, W.sup.2 and W.sup.3 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, provided that at least one of W.sup.5, W.sup.6, W.sup.7 and W.sup.8 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, R.sup.27 are each independently hydrogen atom, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, ring I and ring J are each independently substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle.

12. The compound or its pharmaceutically acceptable salt according to claim 11, wherein Z is a group represented by formula: ##STR02808## wherein W.sup.10 is —S—, —O— or —NR.sup.27—, R.sup.27 is defined above, R.sup.28 is —COOH or its biologically equivalent group, R.sup.30 and R.sup.31 are each independently —COOH or its biologically equivalent group, a hydrogen atom, halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, provided that at least one of R.sup.30 and R.sup.31 is —COOH or its biologically equivalent group, R.sup.29 are each independently halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, two R.sup.29 connected to the adjacent carbon atoms may be taken together to form substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle, two R.sup.29 connected to the non-adjacent and different carbon atoms may be taken together to form substituted or unsubstituted alkylene, two R.sup.29 connected to the same carbon atom may be taken together to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, or two R.sup.29 connected to the same carbon atom may be taken together to form oxo, r is an integer of 0 to 8, s is an integer of 0 to 10, t is an integer of 0 to 12, u is an integer of 0 to 6.

13. A compound represented by formula (IV):
X—Y—Z wherein X is a compound residue of active ingredient, Y is a bond, or a spacer of any combination selected from the group consisting of —O—, —S—, —NR.sup.7—, —C(═O)—, —SO—, —SO.sub.2—, —NR.sup.7—C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—NR.sup.7—, —O—C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—O—, —SO.sub.2—NR.sup.7—, —NR.sup.7—SO.sub.2—, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted aromatic carbocyclyldiyl, substituted or unsubstituted non-aromatic carbocyclyldiyl, substituted or unsubstituted aromatic heterocyclyldiyl, and substituted or unsubstituted non-aromatic heterocyclyldiyl, provided that the groups selected from the group consisting of —O—, —S— and —NR.sup.7— are not connected adjacently in Y, and provided that the groups selected from the group consisting of —C(═O)—, —SO—, —SO.sub.2—, —NR.sup.7—C(═O)—, —C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—NR.sup.7—, —O—C(═O)—NR.sup.7—, —NR.sup.7—C(═O)—O—, —SO.sub.2—NR.sup.7— and —NR.sup.7—SO.sub.2— are not connected adjacently in Y, R.sup.7 are each independently hydrogen atom, hydroxy, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, Z is a group represented by formula: ##STR02809## wherein W.sup.1, W.sup.2, W.sup.3, W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are each independently C, CR.sup.26, O, S, N or NR.sup.27, W.sup.4 is C or N, R.sup.26 are each independently —COOH or its biologically equivalent group, hydrogen atom, halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, provided that at least one of W.sup.1, W.sup.2 and W.sup.3 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, provided that at least one of W.sup.5, W.sup.6, W.sup.7 and W.sup.8 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, R.sup.27 are each independently hydrogen atom, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, ring I and ring J are each independently substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle, the ring containing W.sup.1, W.sup.2, W.sup.3 and W.sup.4 as atoms constituting said ring is an aromatic ring, the ring containing W.sup.5, W.sup.6, W.sup.7 and W.sup.8 as atoms constituting said ring is an aromatic ring, or its pharmaceutically acceptable salt.

14. The compound or its pharmaceutically acceptable salt according to claim 13, wherein X is a residue of compound having HIV protease inhibitory activity.

15. The compound or its pharmaceutically acceptable salt according to claim 14, wherein X is a residue of Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Ritonavir, Nelfinavir, Saquinavir, Tipranavir or its derivative.

16. The compound or its pharmaceutically acceptable salt according to claim 15, wherein X is a residue of Darunavir derivative or Atazanavir derivative.

17. The compound or its pharmaceutically acceptable salt according to claim 13, wherein Z is a group represented by formula: ##STR02810## wherein W.sup.10 is —S—, —O— or —NR.sup.27—, ring S is 5-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atom, ring T is 6-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atoms ring U is 7-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atom R.sup.28 is —COOH, R.sup.29 is each independently halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, two R.sup.29 connected to the adjacent carbon atoms may be taken together to form substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle, two R.sup.29 connected to the non-adjacent and different carbon atoms may be taken together to form substituted or unsubstituted alkylene, two R.sup.29 connected to the same carbon atom may be taken together to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, or two R.sup.29 connected to the same carbon atom may be taken together to form oxo, v are each independently an integer of 0 to 4, w are each independently an integer of 0 to 6, x are each independently an integer of 0 to 8.

18. The compound or its pharmaceutically acceptable salt according to claim 13, wherein Z is a group represented by formula: ##STR02811##

19. A compound represented by any one of the following formulae or its pharmaceutically acceptable salt: ##STR02812## ##STR02813## ##STR02814## ##STR02815## ##STR02816## ##STR02817## ##STR02818## ##STR02819## ##STR02820## ##STR02821##

20. A method of lengthening half-life of active ingredient in pharmacokinetics and/or decreasing clearance by introducing a group represented by the following formula into active ingredient, ##STR02822## wherein W.sup.1, W.sup.2, W.sup.3, W.sup.5, W.sup.6, W.sup.7 and W.sup.8 are each independently C, CR.sup.26, O, S, N or NR.sup.27, W.sup.4 is C or N, R.sup.26 are each independently —COOH or its biologically equivalent group, hydrogen atom, halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, provided that at least one of W.sup.1, W.sup.2 and W.sup.3 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, provided that at least one of W.sup.5, W.sup.6, W.sup.7 and W.sup.8 is CR.sup.26, and at least one of said R.sup.26 is —COOH or its biologically equivalent group, R.sup.27 are each independently hydrogen atom, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclylalkyl, substituted or unsubstituted non-aromatic carbocyclylalkyl, substituted or unsubstituted aromatic heterocyclylalkyl, substituted or unsubstituted non-aromatic heterocyclylalkyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, or substituted or unsubstituted non-aromatic heterocyclylsulfonyl, ring I and ring J are each independently substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle, the ring containing W.sup.1, W.sup.2, W.sup.3 and W.sup.4 as atoms constituting said ring is an aromatic ring, and the ring containing W.sup.5, W.sup.6, W.sup.7 and W.sup.8 as atoms constituting said ring is an aromatic ring.

21. The method according to claim 20, wherein the group represented by the following formula: ##STR02823## wherein each symbol is defined above, is any one of the group represented by the following formulae: ##STR02824## wherein W.sup.10 is —S—, —O— or —NR.sup.27—, ring S is 5-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atom, ring T is 6-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atom, ring U is 7-membered non-aromatic heterocycle having one hetero atom selected from O, S or NR.sup.27, and said hetero atom is not a condensed positional atom, R.sup.28 is —COOH, R.sup.29 is each independently halogen, hydroxy, carboxy, cyano, ureido, amidino, guanidino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted amino, substituted or unsubstituted imino, substituted or unsubstituted alkylcarbonyloxy, substituted or unsubstituted alkenylcarbonyloxy, substituted or unsubstituted alkynylcarbonyloxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, or substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, two R.sup.29 connected to the adjacent carbon atoms may be taken together to form substituted or unsubstituted aromatic carbocycle, substituted or unsubstituted non-aromatic carbocycle, or substituted or unsubstituted non-aromatic heterocycle, two R.sup.29 connected to the non-adjacent and different carbon atoms may be taken together to form substituted or unsubstituted alkylene, two R.sup.29 connected to the same carbon atom may be taken together to form substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, or two R.sup.29 connected to the same carbon atom may be taken together to form oxo, v are each independently an integer of 0 to 4, w are each independently an integer of 0 to 6, x are each independently an integer of 0 to 8.

22. The method according to claim 20, wherein the group represented by the following formula: ##STR02825## wherein each symbol is defined above, is any one of the group represented by the following formula: ##STR02826##

23. A pharmaceutical composition comprising the compound according to claim 1, or its pharmaceutically acceptable salt.

24. The pharmaceutical composition according to claim 23, which has an HIV protease inhibitory activity.

25. The pharmaceutical composition according to claim 23, for medical treatment or prevention of HIV infection disease.

26. The pharmaceutical composition according to claim 23, which is be long acting injection.

27. The pharmaceutical composition according to claim 23, wherein dosage interval is once in a month or more.

28. A method for treating or preventing HIV infection disease by administering the compound of claim 1, or its pharmaceutically acceptable salt.

29. The compound of claim 1, or its pharmaceutically acceptable salt for treating or preventing HIV infection disease.

30. A compound represented by the following formula: ##STR02827## wherein R.sup.36 is hydrogen atom, a protecting group for hydroxy group or a group represented by the following formula: —C(═O)—R.sup.38 wherein R.sup.38 is a leaving group, R.sup.37 is hydrogen atom or a protecting group for hydroxy group, or its pharmaceutically acceptable salt.

31. A compound represented by the following formula: ##STR02828## wherein R.sup.39 is hydrogen atom, halogen, boronic acid, boronate ester, or a group represented by formula: —OR.sup.41 or —NH(R.sup.42), R.sup.41 is methanesulfonyl group, trifluoromethylsulfonyl group, p-toluenesulfonyl group or nonafluorobutanesulfonyl group, R.sup.42 is hydrogen atom or a protecting group for amino group, R.sup.40 is hydrogen atom or a protecting group for carboxy group, provided that the following compound is excluded: ##STR02829## or its pharmaceutically acceptable salt.

32. A compound represented by the following formula: ##STR02830## wherein R.sup.43 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, or a group represented by formula: —C(═O)—R.sup.45 or —SO.sub.2—R.sup.46, R.sup.45 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.46 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, R.sup.44 is hydrogen atom or a protecting group for carboxy group, provided that the following compounds are excluded: ##STR02831## or its pharmaceutically acceptable salt.

33. A compound represented by the following formula: ##STR02832## wherein ring W is 5- to 8-membered non-aromatic carbocyclyl, R.sup.29 is defined as the same in claim 17, when Ring W is 5-membered ring, y is an integer of 0 to 6, when Ring W is 6-membered ring, y is an integer of 0 to 8, when Ring W is 7-membered ring, y is an integer of 0 to 10, when Ring W is 8-membered ring, y is an integer of 0 to 12, R.sup.47 is halogen, boronic acid, boronate ester, or a group represented by formula: —OR.sup.49, R.sup.49 is methanesulfonyl group, trifluoromethylsulfonyl group, p-toluenesulfonyl group or nonafluorobutanesulfonyl group, R.sup.48 is hydrogen atom or a protecting group for carboxy group, provided that the following compounds are excluded: ##STR02833## or its pharmaceutically acceptable salt.

34. A compound represented by the following formula: ##STR02834## wherein R.sup.50 are each independently hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl, or two R.sup.50 may be taken together with the adjacent carbon atom to form substituted or unsubstituted non-aromatic carbocycle, provided that two R.sup.50 is not hydrogen atom at the same time, R.sup.51 is a protecting group for carboxy group, provided that the following compounds are excluded: ##STR02835## or its pharmaceutically acceptable salt.

Description

EXAMPLES

[0759] The present invention will be described in more detail with reference to, but not limited to, the following Examples, Reference Examples and Test Examples.

[0760] In this description, meaning of each abbreviation is as follows:

Ac: acetyl
AIBN: azobisisobutyronitrile
BINAP: 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
BOP: (Benzotriazol-1-yloxy)-tris(dimetylamino)phosphonium hexafluorophosphate
CDI: carbonyldiimidazole
DAST: N,N-diethylamino sulfurtrifluoride
DIBAL-H: diisobutylaluminium hydride

DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetoamide

[0761] DMEAD: di-2-methoxyethyl azodicarboxylate

DMF: N,N-dimethylformamide

[0762] DMSO: dimethyl sulfoxide
HATU: O-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium Hexafluorophosphate
HOBt: 1-hydroxybenzotriazole
HPLC: high performance liquid chromatography

MsCl: Methanesulfonyl Chloride

[0763] NaBH.sub.4: sodium borohydride
NaN.sub.3: sodium azide

NBS: N-Bromosuccinimide

NCS: N-Chlorosuccinimide

NIS: N-Iodosuccinimide

[0764] Pd/C: palladium on carbon
PdCl.sub.2 (dppf): [1, 1′-Bis(diphenylphosphino)ferrocene]palladium(II) Dichloride
PdCl.sub.2 (dppf) CH.sub.2Cl.sub.2: [1, 1′-Bis(diphenylphosphino)ferrocene]palladium(II) Dichloride Dichloromethane Adduct
PdCl.sub.2 (PPh.sub.3).sub.2: Bis(triphenylphosphine)palladium(II) dichloride
Pd(OH).sub.2: Palladium(II) hydroxide

Pd(OAc).SUB.2.: Palladium(II) Acetate

[0765] RT: retention time

TBAF: Tetrabutylammonium Fluoride

[0766] TBDPSCI: tert-Butyldiphenylchlorosilane
TFA: trifluoroacetic acid
THF: tetrahydrofuran

WSCD: Water Soluble Carbodiimide

[0767] NMR analysis of each example was performed by 300 MHz using DMSO-d.sub.6 or CDCl.sub.3.

[0768] LC/MS and HPLC are measured under the conditions as below:

(1) Condition A

Column: ACQUITY UPLC(R) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)

[0769] Flow rate: 0.8 mL/min
UV detection wavelength: 254 nm
Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1% formic acid in acetonitrile solvent.
Gradient: linear gradient of 5% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

(2) Condition B

Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

[0770] Flow rate: 1.6 mL/min
UV detection wavelength: 254 nm
Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1% formic acid in acetonitrile solvent.
Gradient: linear gradient of 5% to 100% solvent [B] for 3 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

(3) Condition C

Column: Gemini-NX (5 μm, i.d. 4.6×50 mm) (Phenomenex)

[0771] Flow rate: 3.0 mL/min
UV detection wavelength: 254 nm
Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1% formic acid in acetonitrile solvent.
Gradient: linear gradient of 5% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

(4) Condition D

Column: ACQUITY UPLC(R) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)

[0772] Flow rate: 0.55 mL/min
UV detection wavelength: 254 nm
Mobile phases: [A] is 0.1% formic acid solution, and [B] is 0.1% formic acid in acetonitrile solvent.
Gradient: linear gradient of 5% to 100% solvent [B] for 3 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

(5) Condition E

Column: ACQUITY UPLC(R) BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)

[0773] Flow rate: 0.8 mL/min
UV detection wavelength: 254 nm
Mobile phases: [A] is 10 mM ammonium carbonate solution, and [B] is acetonitrile. Gradient: linear gradient of 5% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

Reference Example 1

[0774] ##STR00136##

Step 1-2

[0775] After Compound i-2 was synthesized from Compound i-1 by the method written in Organic Process Research & Development 2007, 11, 972-980, Compound i-3 was synthesized by the method written in J. Org. Chem. 2004, 69, 7822-7829.

Compound i-2;

[0776] .sup.1H-NMR (CDCl.sub.3) δ: 1.53 (s, 3H), 1.82 (s, br), 1.90-1.98 (1, m), 2.27-2.33 (m, 1H), 2.55 (m, 1H), 3.69 (m, 1H), 3.91-4.04 (m, 2H), 4.12 (m, 2H), 4.46 (m, 1H).

Compound i-3;

[0777] .sup.1H-NMR (CDCl.sub.3) δ: 1.52 (s, 3H), 2.03-2.14 (m, 2H), 2.79-2.84 (m, 1H), 2.86 (s, 4H), 3.95-4.03 (m, 3H), 4.13-4.17 (m, 1H), 5.25-5.30 (m, 1H).

Reference Example 2

[0778] ##STR00137##

Step 1

[0779] After triethylamine (7.87 mL, 56.8 mmol) and benzoyl chloride (4.40 mL, 37.9 mmol) were added into dichloromethane (30 mL) solution of Compound i-2 (2.73 g, 18.9 mmol) under nitrogen atmosphere, the mixture was stirred overnight at room temperature. After saturated sodium bicarbonate aqueous solution was added into reaction mixture, the mixture was extracted with ethyl acetate. After organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound i-4 (3.7 g, 70%).

[0780] .sup.1H-NMR (CDCl.sub.3) δ: 1.56 (3H, s), 1.93-2.18 (2H, m), 2.89 (1H, t, J=8.6 Hz), 3.95-4.08 (3H, m), 4.23 (1H, t, J=8.6 Hz), 5.35-5.66 (OH, m), 5.51 (1H, q, J=7.4 Hz), 7.47 (2H, t, J=7.4 Hz), 7.60 (1H, t, J=7.4 Hz), 8.04 (2H, d, J=7.4 Hz).

Step 2

[Seeds Culture]

[0781] The aqueous solution (including 11.2 g/L M9 Minimal salts 5×, 10 g/L Casamino acids, 4 g/L D-glucose, 0.02 g/L Thymine, 0.02 g/L CaCl.sub.2.2H.sub.2O, 0.5 g/L MgSO.sub.4.7H.sub.2O and 0.1 g/L Carbenicillin) was prepared. After sterilization by filtration (bore size: 0.2 μm), sterilized solution (0.1 g/ml FeSO.sub.4.7H.sub.2O) 280 μl/L was added to be as seed cultural medium. The expressed vector (pET-CYP107Dhomolog-camA-camB) inserted CYP107D homolog gene (sequence number: 1) was transformed into E. coli BL21 (DE3) deletion of tolC (WO1200/8105513). The transformed E. coli was cultured at 25° C. for 24 hours in the reciprocal shaker at 300 rpm to be seeds.

[Main Culture]

[0782] The overnight auto induction system (SolutionI 20 ml/L, SolutionII 50 ml/L, SolutionIII 1 ml/L; Merck) was added into the aqueous solution (including 11.2 g/L M9 Minimal salts 5×, 10 g/L Casamino acids, 10 ml/L Glycerol, 0.02 g/L Thymine, 0.08 g/L 5-aminolevulinic acid and 0.1 g/L Carbenicillin). After sterilization by filtration (bore size: 0.2 μm), sterilized solution (0.1 g/ml FeSO.sub.4.7H.sub.2O) 280 μl/L was added to be as main cultural medium. After each 2.5 mL of the seeds was inoculated to each the main cultural medium 250 ml in four 2 L wide-mouth Erlenmeyer flask, the transformed E. coli was cultured at 25° C. for 24 hours in the rotary shaker at 200 rpm.

[Bacterial Cellular Reaction]

[0783] Sterilized 3.1 ml of 80% glycerol and 250 μL of DMSO solution of 20 mg/ml Compound i-4 as substrate was added into 250 ml each of four cultural solutions. The reaction is carried out at 30° C. for 24 hours in the rotary shaker at 200 rpm. Through the reaction, sampling was carried out. After same volume of ethanol was added into picked up cultured solution, the solution was centrifuged and supernatant was provided to reverse-phase UPLC. The conversion rate was calculated. Compound i-5 was produced 50.3% at 24 hours.

[Extract and Purification]

[0784] 1 L of cultural solution was separated to supernatant and bacterial body by centrifugation. After 1 L of ethyl acetate was added to supernatant, organic layer and water layer was separated. After 500 ml ethanol was added to precipitate and the mixture was suspended, the suspension was centrifuged. After the solvent of the supernatant was removed, ethyl acetate was added and the organic layer and water layer was separated. After the both ethyl acetate layer was combined, the solution was evaporated to 1 ml DMSO solution. Fractionation was carried out with acetonitrile (including 0.1% formic acid) under the condition of gradient of 20%-55% by Symmetry prep column (C18, 7 μm, 19×150 mm: Waters). The fraction including product was collected and lyophilized to give Compound i-5 (87.6 mg) (yield 43.8%, purity 99.7%).

[0785] .sup.1H-NMR (CDCl.sub.3) δ: 1.26 (1H, t, J=7.5 Hz), 1.51 (3H, s), 1.91-1.98 (1H, m), 2.36-2.42 (1H, m), 3.95-4.04 (4H, m), 4.28 (1H, t, J=7.5 Hz), 5.25 (1H, t, J=8.3 Hz), 7.49 (2H, t, J=7.5 Hz), 7.64 (1H, t, J=7.5 Hz), 8.06 (2H, d, J=7.5 Hz).

Step 3

[0786] After 2 mol/L sodium hydroxide aqueous solution (3.54 mL, 7.07 mmol) was added into methanol (20 mL) solution of Compound i-5 (623 mg, 2.35 mmol) under ice-cold, the mixture was stirred at room temperature for 2 hours. After 2 mol/L hydrochloric acid was added into the reaction mixture, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound i-6 (377 mg, 99%).

[0787] .sup.1H-NMR (MeOD) δ: 1.54 (3H, s), 2.03-2.15 (1H, m), 2.83-2.88 (1H, m), 3.69-3.77 (1H, m), 4.02-4.21 (3H, m), 4.38-4.48 (1H, m).

Reference Example 3

[0788] ##STR00138##

Step 1

[0789] Lithium aluminium hydride (980 mg, 25.8 mmol) was added into THF (80 ml) at 0° C. under nitrogen atmosphere. After THF (40 ml) solution of Compound i-7 (4.68 g, 12.91 mmol) was added by dropwise into the reaction mixture, the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with THF under ice-cold. After sodium sulfate decahydrate was added, the mixture was stirred at room temperature for 5 hours. After the precipitate was filtrated, the solvent was removed in vacuo to give residue. After DMF (10 ml), water (1.5 ml), palladium (II) chloride (74 mg, 0.417 mmol) and copper chloride (I) (620 mg, 6.26 mmol) were added, the mixture was stirred under oxygen atmosphere at room temperature for an hour. After the obtained above residue was added, the mixture was further stirred at room temperature for 16 hours. After 2 mol/L hydrochloric acid was added, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the organic layer was dried with magnesium sulfate anhydrous. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound i-8 (890 mg, 66%). LC/MS (ESI): 326 (M+1)

Step 2

[0790] After 4-methylbenzenesulfonic acid (2.79 mg, 0.016 mmol) and methanol (0.2 ml) were added into dichloromethane (1 mL) solution of Compound i-8 (50 mg, 0.162 mmol), the mixture was stirred at room temperature for 4 hours. After the reaction mixture was removed in vacuo, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound i-9 (33 mg, 81%). LC/MS (ESI): 251 (M+1)

Reference Example 4

[0791] ##STR00139##

Step 1

[0792] After Compound i-11 (2.87 g, 9.36 mmol), tetrabutylammonium iodide (230 mg, 0.624 mmol) and hexamethylphosphoric triamide (2.24 g, 12.48 mmol) were added into THF (17 mL) solution of Compound i-10 (1.70 g, 6.24 mmol), the mixture was stirred at 0° C. After sodium hydride (299 mg, 7.49 mmol) was added into the reaction mixture, the mixture was stirred overnight at room temperature. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound i-12 (1.40 g, 55%).

[0793] LC/MS (ESI): 429 (M+23)

Step 2

[0794] After THF (1 ml) solution of lithium aluminium hydride (24.3 mg, 0.640 mmol) was added by dropwise into THE solution of Compound i-12 (130 mg, 0.320 mmol) at 0° C. under nitrogen atmosphere, the mixture was stirred at room temperature2 hours. After the reaction mixture was diluted with THF under ice-cold, sodium sulfate decahydrate was added, and the mixture was stirred at room temperature for 5 hours. After the precipitate was filtrated, the solvent was removed to give residue. After dichloromethane (10 ml) and methanol (2.5 ml) were added into the obtained residue, the mixture was stirred at −78° C. for 30 minutes under ozone atmosphere. After the reaction mixture was exchanged with nitrogen, dimethyl sulfide (98 mg, 1.58 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. After the solvent mixture was removed in vacuo, dichloromethane (10 ml), methanol (2.5 ml) and 4-methylbenzenesulfonic acid (5.99 mg, 0.032 mmol) were added, and the mixture was stirred overnight at room temperature. After the solvent mixture was removed in vacuo, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound i-13 (44 mg, 60%).

[0795] LC/MS (ESI): 303 (M+23)

Reference Example 5

[0796] ##STR00140##

Step 1

[0797] After 2,2-dimethoxypropane (2.49 g, 23.9 mmol) and tosilate hydrate (0.09 g, 0.47 mmol) were added into dichloromethane (25 mL) solution of Compound ii-1 (2.5 g, 4.78 mmol), the mixture was refluxed for 5 hours. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water and saturated sodium bicarbonate aqueous solution, the mixture was dried with magnesium sulfate anhydrous. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound ii-2 (2.2 g, 81%).

[0798] LC/MS (ESI): 563 (M+1)

Step 2

[0799] After pyridine (170 mg, 2.147 mmol) and trifluoromethanesulfonic acid anhydrous (454 mg, 1.610 mmol) were added into dichloromethane (3 mL) solution of Compound ii-2 (604 mg, 1.073 mmol) under ice-cold, the mixture was stirred at 0° C. for 1.5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with 2 mol/L hydrochloric acid aqueous solution, water and brine, the mixture was dried with magnesium sulfate anhydrous. The solvent was removed in vacuo to give Compound ii-3 (727 mg, 98%) as crude.

[0800] LC/MS (ESI): 695 (M+1)

Step 3

[0801] After benzophenone imine (40.4 mg, 0.223 mmol), Pd (OAc).sub.2 (3.4 mg, 0.015 mmol), BINAP (18.5 mg, 0.03 mmol) and cesium carbonate (97 mg, 0.297 mmol) were added into THF (2 mL) solution of Compound ii-3 (103.3 mg, 0.149 mmol) under nitrogen atmospher, the mixture was refluxed for 24 hours. After cooling the reaction mixture, the obtained solids by adding ethyl acetate were filtrated. The filtrate was removed in vacuo. The obtained residue was used to next reaction without purification.

Step 4

[0802] After ammonium formate (94 mg, 1.49 mmol) and 10% Pd/C (50 mg) were added into methanol (4 mL) solution of Compound ii-4 (108 mg, 0.149 mmol), the mixture was refluxed for 5 hours. After cooling the reaction mixture, the obtained solids by adding dichloromethane were filtrated. The filtrated was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound ii-5 (39.7 mg, 48%).

[0803] LC/MS (ESI): 562 (M+1)

Reference Example 6

[0804] ##STR00141##

[0805] After DIBAL-H (1 mol/L hexane solution, 16.2 mL, 16.2 mmol) was added into THF (30 mL) solution of Compound ii-6 (928 mg, 1.62 mmol) by dropwise at −20° C. under nitrogen atmosphere, the mixture was stirred for 4.5 hours. Water and saturated potassium sodium tartrate aqueous solution were added to the reaction mixture. After the mixture was stirred at room temperature for 2 hours, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate to chloroform-methanol) to give Compound ii-7 (180 mg, 19%). LC/MS (ESI): 576 (M+1)

Reference Example 7

[0806] ##STR00142##

Step 1-2

[0807] After Compound iii-2 was synthesized from Compound iii-1 by the method written in Bioorganic & Medicinal Chemistry Letters, 2010, 20 (19), 5753-5756, Compound iii-3 was synthesized by the method written in Tetrahedron Letters, 2012, 53 (52), 7135-7139.

Compound iii-2; LC/MS (ESI): 282 (M+1)
Compound iii-3; LC/MS (ESI): 345 (M+1)

Step 3

[0808] Hexane solution of butyllithium (2.7 mol/L, 11.9 mL, 32.02 mmol) was added into THF (70 mL) solution of Compound iii-3 (8.5 g, 24.6 mmol) by dropwise for 20 minutes at −70° C. under nitrogen atmosphere. After triisopropyl borate (17.1 mL, 73.8 mmol) was added into the reaction mixture, the mixture was stirred at room temperature for 2.5 hours. 2 mol/L hydrochloric acid was added into the reaction mixture. After the mixture was stirred for an hour at room temperature, the reaction mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-4 (6.13 g, 80%). LC/MS (ESI): 311 (M+1)

Reference Example 8

[0809] ##STR00143##

Step 1

[0810] After 1-bromo-4-iodobenzene (293 mg, 1.035 mmol), PdCl.sub.2 (dppf) (25.2 mg, 0.034 mmol) and 2 mol/L sodium carbonate aqueous solution (1.035 mL, 2.07 mmol) were added into THF (4 mL) solution of Compound iii-4 (214.0 mg, 0.690 mmol) under nitrogen atmosphere, the mixture was reacted at 130° C. for 30 minutes by microwave device. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate and chloroform. After the organic layer was washed with brine, the solution was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-5 (182.9 mg, 62%). LC/MS (ESI): 421 (M+1)

Step 2

[0811] Bis (pinacolato)diboron (331 mg, 1.302 mmol), PdCl.sub.2 (dppf) CH.sub.2Cl.sub.2 (35.4 mg, 0.043 mmol) and potassium acetate (128 mg, 1.302 mmol) were added into DMF (2 mL) solution of Compound iii-5 (182.9 mg, 0.434 mmol), the mixture was refluxed at 110° C. for 4 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-6 (156.2 mg, 76%).

[0812] LC/MS (ESI): 469 (M+1)

Reference Example 9

[0813] ##STR00144##

Step 1

[0814] After NBS (5.58 g, 31.3 mmol) was added into dichloromethane (50 mL) solution of Compound iii-8 (5.26 g, 29.8 mmol) under cooling at 0° C., the mixture was stirred at room temperature for 20 minutes. After water was added into the reaction mixture, the reaction mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an isomeric mixture of Compound iii-8 (6.26 g).

[0815] LC/MS (ESI): 255 (M+1)

Step 2

[0816] After potassium carbonate (6.17 g, 44.7 mmol) and benzyl bromide (5.31 mL, 44.7 mmol) were added into DMF (57 mL) solution of Compound iii-8 (5.7 g, 22.34 mmol), the mixture was stirred at room temperature for 1.5 hours. 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After organic layer was washed with water, the mixture was dried with sodium sulfate, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an isomeric mixture of Compound (7.88 g).

[0817] Hexane solution (13.03 mL, 33.9 mmol) of 2.6 mol/L n-butyllithium was added into THF (78 mL) solution of the obtained Compound under cooling at −78° C., and the mixture was stirred for 10 minutes. After methyl chloroformate (3.49 mL, 45.2 mmol) was added into the reaction mixture, the mixture was stirred at −78° C. for 1.5 hours. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an isomeric mixture of Compound iii-9 (4.4 g).

[0818] LC/MS (ESI): 325 (M+1)

Step 3

[0819] 10% Pd/C (440 mg) was added into methanol (44 mL) solution of Compound iii-9 (4.4 g, 13.56 mmol) under hydrogen atmosphere for 2 hours. After the reaction mixture was filtrated by Celite®, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-10 (1.8 g, 57%).

[0820] LC/MS (ESI): 235 (M+1)

Step 4

[0821] After pyridine (0.259 mL, 3.2 mmol), trifluoromethanesulfonic acidanhydrous (0.43 mL, 2.56 mmol) was added into dichloromethane (5 mL) solution of Compound iii-10 (500 mg, 2.134 mmol) in an ice-bath under nitrogen atmosphere, the mixture was stirred at 0° C. for an hour. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium the mixture was dried with sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-11 (800 mg, 100%).

[0822] .sup.1H-NMR (CDCl.sub.3) δ: 0.98 (s, 6H), 1.57 (t, J=6.7, 2H), 2.54 (s, 2H), 2.83 (t, J=6.7, 2H), 3.95 (s, 3H), 7.07 (d, J=8.8, 1H), 7.23 (d, J=8.8, 1H) Step 5 potassium acetate (241 mg, 2.457 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (312 mg, 1.228 mmol) and PdCl.sub.2 (dppf) (59.9 mg, 0.082 mmol) were added into dioxane (3 mL) solution of Compound iii-11 (300 mg, 0.819 mmol) under nitrogen atmosphere, and the mixture was stirred under heat reflux for 3 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-12 (170 mg, 60%). LC/MS (ESI): 367 (M+1)

Reference Example 10

[0823] ##STR00145##

Step 1

[0824] After 2-(4-fluorophenyl)acetic acid (3.39 g, 22.03 mmol) was added into acetic anhydride (15.61 mL, 165 mmol) solution of Compound iii-13 (5 g, 22.03 mmol), the mixture was stirred at 100° C. for 30 minutes. After triethylamine (9.16 mL, 66.1 mmol) was added into the mixture, the mixture was stirred at 100° C. for 30 minutes. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-14 (3.5 g, 50%).

[0825] LC/MS (ESI): 319 (M+1)

Step 2

[0826] After potassium acetate (461 mg, 4.7 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (597 mg, 2.35 mmol), PdCl.sub.2 (dppf) (115 mg, 0.157 mmol) were added into dioxane (5 mL) solution of Compound iii-14 (500 mg, 1.567 mmol), the mixture was stirred under heat reflux for 1.5 hours. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-15 (330 mg, 58%). LC/MS (ESI): 364 (M-1)

Reference Example 11

[0827] ##STR00146##

[0828] After cyclohexanone (0.145 mL, 1.40 mmol), L-proline (30.7 mg, 0.267 mmol) and 2,6-dimethyl-1,4-dihydropyridine-3,5-diethyl dicarboxylate (338 mg, 1.33 mmol) were added into DMSO (6 mL) solution of Compound iii-16 (300 mg, 1.33 mmol) under nitrogen atmosphere, the mixture was stirred at room temperature for 24 hours. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with 0.1 mol/L hydrochloric acid, water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-17 (294 mg, 72%). LC/MS (ESI): 305 (M-1)

Reference Example 12

[0829] ##STR00147##

Step 1

[0830] Compound iii-18 (6.8 g, 48.5 mmol) and 3-bromo-2-oxopropanoic acid (9.72 g, 58.2 mmol) were added into water (20 mL) solution of sodium hydroxide (5.82 g, 146 mmol) in an ice-bath under nitrogen atmosphere, and stirred at 80° C. for 4.5 hours. Concentrated hydrochloric acid (16.17 mL, 194 mmol) was added, and the mixture was stirred at 70° C. for 1.5 hours. After water added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an isomeric mixture of Compound iii-19 (4.9 g).

[0831] LC/MS (ESI): 209 (M+1)

Step 2

[0832] After potassium carbonate (7.57 g, 54.8 mmol) and iodomethane (3.42 mL, 54.8 mmol) were added into DMF (17 mL) solution of Compound iii-19 (5.7 g, 27.4 mmol), the mixture was stirred at room temperature for 40 minutes. After water was added into the reaction mixture, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give an isomeric mixture of Compound iii-20 (2.97 g).

[0833] LC/MS (ESI): 223 (M+1)

Step 3

[0834] NaBH.sub.4 (494 mg, 13.05 mmol) was added into methanol (30 mL) solution of Compound iii-20 (2.9 g, 13.05 mmol), and the mixture was stirred at room temperature for 20 minutes. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-21 (790 mg, 3 Step, 6%).

[0835] LC/MS (ESI): 207 (M-17)

Step 4

[0836] TFA (0.748 mL, 9.71 mmol) was added into dichloromethane (8 mL) solution of Compound iii-21 (726 mg, 3.24 mmol) and triethylsilane (5.17 mL, 32.4 mmol) under ice-cold under nitrogen atmosphere, and the mixture was stirred at 0° C. for 30 minutes. Further the mixture was stirred at room temperature for 5 hours. After saturated sodium hydrogen carbonate aqueous solution was added into the reaction mixture under ice-cold, the mixture was extracted with chloroform. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-22 (528 mg, 78%).

[0837] .sup.1H-NMR (CDCl.sub.3) δ: 1.0 (s, 6H), 1.56-1.59 (m, 2H), 2.44 (s, 2H), 2.57 (t, J=6.3, 2H), 3.80 (s, 3H), 7.85 (s, 1H)

Step 5

[0838] 2 mol/L sodium hydroxide aqueous solution (3.80 mL, 7.61 mmol) was added into methanol (12 mL)-THF (2 mL) solution of Compound iii-22 (528 mg, 2.54 mmol), and the mixture was stirred at 45° C. for 8 hours. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer the mixture was dried with sodium sulfate, the solvent was removed in vacuo to give Compound iii-23 (470 mg, 95%).

[0839] LC/MS (ESI): 195 (M+H)

Step 6

[0840] Hexane solution (4.51 mL, 11.73 mmol) of 2.6 mol/L n-butyllithium was added into THE (20 mL) solution of Compound iii-23 (447 mg, 2.30 mmol) by dropwise under cooling at −78° C., and the mixture was stirred at 0° C. for 1.5 hours. Iodine (1.81 g, 7.13 mmol) was added, and the mixture was stirred at 0° C. for 15 minutes. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-24 (420 mg, 57%). LC/MS (ESI): 321 (M+H)

Step 7

[0841] After potassium carbonate (352 mg, 2.55 mmol) and iodomethane (0.239 mL, 3.82 mmol) were added into DMF (6 mL) solution of Compound iii-24 (447 mg, 2.30 mmol) under nitrogen atmosphere at 0° C., the mixture was stirred at room temperature for 30 minutes. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-25 (417 mg, 95%). LC/MS (ESI): 335 (M+H)

Reference Example 13

[0842] ##STR00148##

Step 1

[0843] NIS (377 mg, 1.67 mmol) was added into DMF (2 mL) solution of Compound iii-26 (200 mg, 1.11 mmol) under cooling in an ice-bath, and the mixture was stirred at 0° C. for 20 minutes. After saturated sodium bicarbonate aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-27 (300 mg, 88%). LC/MS (ESI): 306 (M+1)

Step 2

[0844] Potassium carbonate (136 mg, 0.983 mmol) and iodomethane (0.061 mL, 0.983 mmol) were added into DMF (1 mL) solution of Compound iii-27 (100 mg, 0.328 mmol), and the mixture was stirred at room temperature for 40 minutes. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-28 (27 mg, 26%).

[0845] .sup.1H-NMR (CDCl.sub.3) δ: 1.66-1.83 (m, 4H), 2.55 (t, J=6.0 Hz, 2H), 2.72 (t, J=6.0 Hz 2H), 3.51 (s, 3H), 3.81 (s, 3H)

Reference Example 14

[0846] ##STR00149##

Step 1

[0847] TFA (1 mL) was added into dichloromethane (5 mL) solution of Compound iii-29 (700 mg, 2.02 mmol), and the mixture was reacted at room temperature for 18 hours. After the solvent was removed in vacuo, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-30 (500 mg, 82%).

[0848] LC/MS (ESI): 303 (M+1)

Step 2

[0849] DAST (0.33 mL, 2.47 mmol) was added into dichloromethane (5 mL) solution of Compound iii-30 (250 mg, 0.83 mmol) at −78° C. After the mixture was stirred reacted at −78° C. for an hour, the mixture was reacted at room temperature for an hour. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-31 (61 mg, 23%).

[0850] LC/MS (ESI): 325 (M+1)

Reference Example 15

[0851] ##STR00150##

Step 1

[0852] Triethylamine (6.03 mL, 43.5 mmol) and HATU (9.92 g, 26.1 mmol) were added into Compound iii-32 (4.96 g, 21.7 mmol), and the mixture was stirred at room temperature for 3 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-33 (5.76 g, 60%). LC/MS (ESI): 440 (M+1)

Step 2

[0853] 1 mol/L sodium hexamethyldisilazane THF solution (41.9 mL, 41.9 mmol) was added into THF (115 mL) solution of Compound iii-33 (5.76 g, 13.1 mmol), and the mixture was stirred at room temperature for 30 minutes. After methanol (30 mL) was added into the reaction mixture, the solvent was removed in vacuo. After 1 mol/L hydrochloric acid (45 mL) was added into the obtained residue, the mixture made to be acid. After the obtained white solids were filtrated, the solids were washed with diethyl ether to give Compound iii-34 (4.53 g, 85%).

[0854] LC/MS (ESI): 408 (M+1)

Reference Example 16

[0855] ##STR00151##

[0856] 1,4-bis(bromomethyl)benzene (2.57 g, 9.73 mmol) and DIPEA (0.850 mL, 4.86 mmol) were added into DMA (15 mL) solution of Compound iii-35 (1.00 g, 3.24 mmol), and the mixture was stirred and heated at 140° C. for 30 minutes by microwave device. After water added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, and the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-chloroform) to give Compound iii-36 (1.12 g, 70%).

[0857] LC/MS (ESI): 491 (M+1)

Reference Example 17

[0858] ##STR00152##

Step 1

[0859] Compound iii-37 (240 mg, 1.08 mmol), 2-iodobenzylalchol (303 mg, 1.30 mmol), copper (I) iodide (41.1 mg, 0.216 mmol), N,N-dimethylglycinehydrochloric acid salt (60.3 mg, 0.432 mmol) and potassium carbonate (448 mg, 3.24 mmol) were dissolved into DMSO (4 mL) under nitrogen atmosphere, and the mixture was stirred at 150° C. for 45 minutes under microwave irradiation. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-38 (202 mg, purity 70%) and Compound iii-39 (80 mg, 26%). Compound iii-38; LC/MS (ESI): 329 (M+1) Compound iii-39; LC/MS (ESI): 283 (M+1)

Step 2

[0860] Concentrated sulfuric acid (0.153 mL, 2.87 mmol) was added into methanol (10 mL) solution of Compound iii-39 (270 mg, 0.956 mmol) under nitrogen atmosphere, and the mixture was stirred under heat reflux for 27 hours. After saturated sodium hydrogen carbonate was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. After the obtained residue was dissolved into dichloromethane (4 mL) and added into MsCl (0.112 mL, 1.43 mmol), triethylamine (0.212 mL, 1.53 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-40 (165 mg, 44%). LC/MS (ESI): 393 (M+1)

Reference Example 18

[0861] ##STR00153##

Step 1

[0862] Ethanol solution (11 mL) of Compound iii-41 (1.15 g, 7.55 mmol) was added into ethanol (44 mL) solution of 20% sodium ethoxide (ethanol solution, 9.52 mL, 22.7 mmol) by dropwise at 0° C. under nitrogen atmosphere. After diethyl oxalate (1.24 mL, 9.06 mmol) was added, the mixture was stirred at room temperature for 6 hours. After the mixture was condensed under depressing, the mixture was poring to 0.1 mol/L hydrochloric acid/ice and extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-42 (727 mg, 38%).

[0863] .sup.1H-NMR (CDCl.sub.3) δ: 15.17 (s, 1H), 4.34 (q, J=7.2 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 2.32 (s, 2H), 1.67-1.62 (m, 6H), 1.50-1.36 (m, 7H).

Step 2

[0864] After hydrazine monohydrate (0.154 mL, 3.16 mmol) was added into ethanol (15 mL) solution of Compound iii-42 (725 mg, 2.87 mmol) by dropwise at 0° C. under nitrogen atmosphere, the mixture was stirred for an hour. After the reaction mixture was condensed under depressing, water was added, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-43 (685 mg, 96%).

[0865] LC/MS (ESI): 249 (M+1)

Reference Example 19

[0866] ##STR00154##

Step 1

[0867] Pyridine (0.23 mL, 2.84 mmol) and trifluoromethanesulfonic acidanhydrous (0.38 mL, 2.27 mmol) were added into dichloromethane (30 mL) solution of Compound iii-44 (500 mg, 1.89 mmol) under cooling in an ice-bath under nitrogen atmosphere, and the mixture was stirred at room temperature for an hour. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-45 (725 mg, 97%).

[0868] .sup.1H-NMR (CDCl.sub.3) δ: 3.98 (s, 3H), 6.93-7.03 (m, 2H), 7.37-7.46 (m, 2H), 7.75 (dt, J=8.7 Hz, 2.0 Hz, 1H), 8.19-8.20 (m, 1H)

Step 2

[0869] Triethylamine (0.315 mL, 2.27 mmol), copper (I) iodide (14.4 mg, 0.076 mmol) and trimethylsilylacetylene (0.323 mL, 2.27 mmol) were added into THF (3 mL) solution of Compound iii-45 (300 mg, 0.757 mmol) under nitrogen atmosphere, and the mixture was stirred at 60° C. for 3.5 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-46 as crude.

Step 3

[0870] Potassium carbonate (740 mg, 5.36 mmol) was added into methanol (3 mL) solution of crude Compound iii-46, and the mixture was stirred at room temperature for 30 minutes. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-47 (230 mg, 2Step, 79%).

[0871] .sup.1H-NMR (CDCl.sub.3) δ: 3.45 (s, 1H), 3.95 (s, 3H), 6.91-7.01 (m, 2H), 7.40-7.46 (m, 1H), 7.61-7.7 (m, 2H), 8.07-8.10 (m, 1H)

Reference Example 20

[0872] ##STR00155##

Step 1

[0873] 2 mol/L potassium carbonate aqueous solution (22.7 mL, 45.4 mmol), 2,4-difluorobenzeneboronic acid (7.17 g, 45.4 mmol) and Pd (PPh.sub.3).sub.4 were added into DMF (50 mL) solution of Compound iii-48 (5.2 g, 22.7 mmol) under nitrogen atmosphere, and the mixture was stirred at 100° C. for 2 hours. After 2 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-49 (5.6 g, 94%).

[0874] LC/MS (ESI): 263 (M+1)

Step 2

[0875] NBS (0.71 g, 4.0 mmol) was added into carbon tetrachloride (10 mL) solution of Compound iii-49 (1 g, 3.81 mmol) under nitrogen atmosphere, and the mixture was stirred under heat reflux for 2 hours. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-50 (1.03 g, 79%).

[0876] .sup.1H-NMR (CDCl.sub.3) δ: 3.97 (s, 3H), 5.00 (s, 2H), 6.91-7.01 (m, 2H), 7.40-7.66 (m, 3H), 8.11 (s, 1H)

Reference Example 21

[0877] ##STR00156##

Step 1

[0878] Compound iii-51 (300 mg, 1.22 mmol), (2,4-difluorophenyl)boronic acid (290 mg, 1.84 mmol), PdCl.sub.2 (dppf) (90 mg, 0.12 mmol) and potassium phosphate (780 mg, 3.67 mmol) were dissolved into toluene (12 mL) under nitrogen atmosphere under microwave irradiation, and the mixture was stirred at 140° C. for 30 minutes. After the reaction mixture was filtrated by Celite®, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-52 (304 mg, 89%).

[0879] .sup.1H-NMR (CDCl.sub.3) δ: 8.09-8.05 (m, 2H), 7.72 (d, J=1.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.00-6.91 (m, 2H), 4.82 (d, J=5.8 Hz, 2H), 3.94 (s, 3H), 1.83 (t, J=5.9 Hz, 1H).

Step 2

[0880] MsCl (0.102 mL, 1.31 mmol) was added into triethylamine (0.226 mL, 1.63 mmol)-dichloromethane (6 mL) solution of Compound iii-52 (303 mg, 1.09 mmol) under ice-cold, and the mixture was stirred for 3 hours under nitrogen atmosphere. After 0.1 mol/L hydrochloric acid was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-53 (350 mg, 90%).

[0881] LC/MS (ESI): 379 (M+23)

Reference Example 22

[0882] ##STR00157##

Step 1

[0883] Compound iii-54 (800 mg, 3.11 mmol), PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2(254 mg, 0.331 mmol) and 2 mol/L sodium carbonate aqueous solution (6.22 mL, 12.5 mmol) were added into THF (16 mL) solution of o-tolylboronic acid (465 mg, 3.42 mmol), and the mixture was stirred for 30 minutes with heating to 130° C. by microwave device. After brine was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-55 (674 mg, 81%). Measurement condition A, HPLC: RT=2.92 min Step 2 NBS (415 mg, 2.53 mmol) and AIBN (4.0 mg, 0.025 mmol) were added into carbon tetrachloride (6.6 mL) solution of Compound iii-55 (465 mg, 3.42 mmol), and the mixture was stirred for an hour under heat reflux. After saturated sodium hydrogen carbonate aqueous solution was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-56 (822 mg, 96%).

[0884] Measurement condition A, HPLC: RT=2.91 min

Reference Example 23

[0885] ##STR00158##

Step 1

[0886] Phenol (518 mg, 5.51 mmol) and cesium carbonate (2.76 g, 8.47 mmol) were added into DMF (10.0 mL) solution of Compound iii-57 (1.00 g, 4.24 mmol), and the mixture was stirred at 45° C. for an hour. After the water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform) to give Compound iii-58 (775 mg, 73%). LC/MS (ESI): 250 (M+1) Step 2 NBS (589 mg, 3.31 mmol) and benzoyl peroxide (15.3 mg, 0.062 mmol) were added into carbon tetrachloride (8.85 mL) solution of Compound iii-58 (785 mg, 3.15 mmol), and the mixture was stirred for 30 minutes with heating to 100° C. by microwave device. After saturated sodium hydrogen carbonate aqueous solution and water were added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-59 (930 mg, 90%). LC/MS (ESI): 328 (M+1)

Reference Example 24

[0887] ##STR00159##

[0888] Step 1 Triethylamine (4.67 mL, 33.7 mmol) and 4-dimethylaminopyridine (137 mg, 1.12 mmol) were added into THF (90 mL) solution of Compound iii-60 (6.00 g, 22.4 mmol), and acetyl chloride (1.92 mL, 26.9 mmol) was added under ice-cold. The mixture was stirred at room temperature for 1.5 hours. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-61 (3.2 g, 46%).

[0889] LC/MS (ESI): 311 (M+1)

[0890] Step 2

[0891] 2,3-dichloro-5,6-dicyano-p-benzoquinone (5.64 g, 24.8 mmol) was added into 1,4-dioxane (64 mL) solution of Compound iii-61 (3.2 g, 10.3 mmol), and the mixture was stirred at 70° C. for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated. After filtrated solvent was removed in vacuo, saturated sodium bicarbonate aqueous solution was added into the obtained residue and stirred. 2 mol/L hydrochloric acid was added, and the mixture made to be acid. The solution was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. After ethyl acetate and hexane were added into the obtained residue, the obtained solids were filtrated to give Compound iii-62 (2.48 g, 79%).

[0892] LC/MS (ESI): 306 (M+1) Step 3

[0893] Pyrrolidine (6.72 mL, 81.0 mmol) was added into toluene (124 mL) solution of Compound iii-62 (2.48 g, 8.12 mmol), and the mixture was stirred at 100° C. for 20 hours. After the solvent was removed in vacuo, the obtained residue was purified by silica gel column chromatography (hexane-chloroform) to give Compound iii-63 (1.09 g, 51%).

[0894] LC/MS (ESI): 264 (M+1) Step 4-6

[0895] Compound iii-66 was obtained by the same manner of synthesis above Reference example.

[0896] LC/MS (ESI): 421 (M+1)

Reference Example 25

[0897] ##STR00160##

Step 1

[0898] 2-(4,4-dimethylcyclohex-1-ene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1738 mg, 7.36 mmol), PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2 (400 mg, 0.490 mmol) and 2 mol/L sodium carbonate aqueous solution (9.80 mL, 19.6 mmol) were added into THF (16 mL) solution of Compound iii-67 (800 mg, 2.45 mmol). The mixture was stirred for an hour under heating to 120 to 130° C. by microwave device. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-68 (872 mg, 100%).

[0899] LC/MS (ESI): 356 (M+1)

Step 2

[0900] 10% Pd/C (including 50% water) (31.7 mg) was added into ethyl acetate (21 mL) solution of Compound iii-68 (1.06 g, 2.98 mmol). The mixture was stirred at room temperature for 5 hours under hydrogen one atmosphere. After the reaction mixture was filtrated by Celite®, the filtrated solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-69 (623 mg, 58%).

[0901] LC/MS (ESI): 358 (M+1)

Step 3

[0902] NBS (296 mg, 1.66 mmol) and benzoyl peroxide (4.02 mg, 0.017 mmol) were added into carbon tetrachloride (30 mL) solution of Compound iii-69 (594 mg, 1.66 mmol), and the mixture was stirred for 4 hours with heat reflux. After saturated sodium hydrogen carbonate aqueous solution and water were added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate).

[0903] Further NBS (130 mg, 0.729 mmol) and benzoyl peroxide (1.76 mg, 0.007 mmol) were added into carbon tetrachloride (16 mL) solution of the obtained Compound (318 mg, 0.729 mmol), and the mixture was stirred for 5 hours with heat reflux. After saturated sodium hydrogen carbonate aqueous solution and water were added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-70 (221 mg, 2 Step, 49%). LC/MS (ESI): 514 (M+1)

Reference Example 26

[0904] ##STR00161##

[0905] 1,4-dioxane (20 mL), Compound iii-71 (1.00 g, 4.24 mmol), cesium carbonate (8.28 g, 25.4 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (592 mg, 1.27 mmol) and Pd (OAc).sub.2 (190 mg, 0.848 mmol) were added into dicyclohexylamine (1844 mg, 10.16 mmol), and the mixture was stirred for an hour with heating to 120 to 130° C. by microwave device. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-72 (290 mg, 20%).

[0906] LC/MS (ESI): 337 (M+1)

Reference Example 27

[0907] ##STR00162##

[0908] Sulfur (2.03 g, 63.4 mmol) was added into ethanol (40 mL) solution of Compound iii-1 (8.0 g, 63.4 mmol), malononitrile (6.28 g, 95 mmol) and diethylamine (3.31 mL, 31.7 mmol). After the mixture was stirred overnight at room temperature, the mixture was stirred at 50° C. for 5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-73 (4.55 g, 35%). LC/MS (ESI): 207 (M+1)

Reference Example 28

[0909] ##STR00163##

Step 1

[0910] 1,4-dioxane (15 mL), Compound iii-3 (773 mg, 2.24 mmol), tetrakistriphenylphosphine palladium complex (1.29 g, 1.12 mmol) and potassium phosphate (1.43 g, 6.72 mmol) were added into Compound iii-74 (876 mg, 2.24 mmol). The mixture was stirred for an hour with heating to 125° C. by using microwave device. After brine was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-75 (448 mg, 38%).

Measurement condition A, HPLC: RT=3.45 min

Step 2

[0911] 4 mol/L hydrochloric acid dioxane solution (4.6 mL, 18.4 mmol) was added into Compound iii-75 (488 mg, 0.921 mmol), and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo to give Compound iii-76 (376 mg, 99.5%).

[0912] Measurement condition A, HPLC: RT=1.84 min

Reference Example 29

[0913] ##STR00164##

Step 1

[0914] Compound iii-77 (1.31 g, 5.79 mmol), PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2 (424 mg, 0.58 mmol) and 2 mol/L sodium carbonate aqueous solution (11.6 mL, 23.2 mmol) were added into THF (15 mL) solution of Compound iii-3 (2.00 g, 5.79 mmol), and the mixture was stirred for 5 hours under heat reflux under nitrogen current. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, saturated sodium bicarbonate aqueous solution, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-78 (1.82 g, 86%).

[0915] LC/MS (ESI): 382 (M+18)

Step 2

[0916] 2 mol/L sodium hydroxide aqueous solution (5 mL, 9.99 mmol) was added into methanol (10 mL) solution of Compound iii-78 (1.82 g, 4.99 mmol), and the mixture was stirred at room temperature for 3 hours under hydrogen flow. After 2 mol/L hydrochloric acid aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-79 (1.53 g, 91%). LC/MS (ESI): 354 (M+18)

Reference Example 30

[0917] ##STR00165##

Step 1

[0918] NaBH.sub.4 (51 mg, 1.36 mmol) was added into methanol (10 mL) solution of Compound 36 (400 mg, 1.36 mmol), and the mixture was stirred at 0° C. for 10 minutes further at room temperature for an hour. After saturated ammonium chloride aqueous was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-80 (375 mg, 93%).

[0919] LC/MS (ESI): 297 (M+1)

Step 2

[0920] Triethylamine (0.33 mL, 2.36 mmol) and MsCl (203 mg, 1.77 mmol) were added into dichloromethane (10 mL) solution of Compound iii-80 (350 mg, 1.18 mmol), and the mixture was stirred at 0° C. for an hour. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo to give Compound iii-81.

[0921] LC/MS (ESI): 375 (M+1)

Step 3

[0922] Compound iii-81 was dissolved into DMF (10 mL), and NaN.sub.3 (230 mg, 3.54 mmol) was added. The mixture was stirred at room temperature for 5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and solvent was removed in vacuo.

[0923] The obtained residue was dissolved into ethyl acetate (10 mL), and Pd (OH).sub.2 (38 mg, 10% wt) was added. The mixture was stirred at room temperature for 3 hours under hydrogen flow. After the reaction mixture was filtrated, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-82 (317 mg, 91%).

[0924] LC/MS (ESI): 296 (M+1)

Reference Example 31

[0925] ##STR00166##

Step 1

[0926] 2-methyl-2-butene (15 mL) and sodium chlorite (4.61 g, 50.9 mmol)-sodium dihydrogen phosphate (4.69 g, 39.1 mmol) aqueous solution (20 mL) were added into 1,4-dioxane (75 mL) suspension of Compound 36 (5.00 g, 17.0 mmol), and the mixture was stirred at room temperature for 18 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine and dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate) to give Compound iii-83 (4.37 g, 83%).

[0927] .sup.1H-NMR (CDCl.sub.3) δ: 1.00 (s, 6H), 1.59 (t, J=6.4 Hz, 2H), 1.64 (s, 9H), 2.55 (s, 2H), 2.81 (t, J=6.4 Hz, 2H), 14.28 (s, 1H).

Step 2

[0928] HOBt (479 mg, 3.54 mmol) and WSCDhydrochloric acid salt (741 mg, 3.87 mmol) were added into dichloromethane (10 mL) suspension of Compound iii-83 (1.00 g, 3.22 mmol) under ice-cold, and the mixture was stirred at room temperature for an hour. After the reaction mixture was diluted with ethyl acetate, 1 mol/L sodium hydroxide aqueous solution was added, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-84 (864 mg, 63%).

[0929] LC/MS (ESI): 428 (M+1)

Step 3

[0930] (2-aminophenyl)methanol (79.8 mg, 0.648 mmol) was added into DMA (2 mL) solution of Compound iii-84 (222 mg, 0.518 mmol), and the mixture was stirred at 80° C. for 5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, and dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-85 (215 mg, 69%).

[0931] LC/MS (ESI): 416 (M+1)

Step 4

[0932] 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoquisole-3-(1H)-one (159 mg, 0.375 mmol) was added into dichloromethane (10 mL) suspension of Compound iii-85 (120 mg, 17.0 mml), and the mixture was stirred for 2 hours under ice-cold. After 5% thiosodium sulfate aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, and dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-86 (106 mg, 89%).

[0933] LC/MS (ESI): 414 (M+1)

Reference Example 32

[0934] ##STR00167##

Step 1

[0935] Compound iii-88 was obtained by same manner of synthesis of Compound iii-78.

[0936] .sup.1H-NMR (CDCl.sub.3) δ: 1.02 (s, 6H), 1.22 (s, 9H), 1.60 (t, J=6.3 Hz, 2H), 2.00-2.07 (m, 4H), 2.63 (s, 2H), 2.74 (t, J=6.3 Hz, 2H), 3.30-3.37 (m, 4H), 3.66 (s, 3H), 6.64 (d, J=8.3 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J=8.3 Hz, 1H).

Step 2

[0937] 1.02 m mol/L DIBAL-Hhexane solution (2.64 mL, 2.70 mmol) was added into THF (10 mL) solution of Compound iii-88 (422 mg, 0.099 mmol) under ice-cold, and the mixture was stirred at 0° C. for 1.5 hours. After L-(+)-potassium sodium tartrate aqueous solution was added into the reaction mixture, the mixture was stirred at room temperature for 2 hours. the mixture was extracted with ethyl acetate. After the organic layer was washed with brine and dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-89 (303 mg, 76%).

[0938] .sup.1H-NMR (CDCl.sub.3) δ: 1.03 (s, 6H), 1.30 (s, 9H), 1.60 (t, J=5.8 Hz, 2H), 1.97-2.05 (m, 4H), 2.57 (s, 2H), 2.73 (t, J=5.8 Hz, 2H), 3.29-3.36 (m, 4H), 4.48 (s, 2H), 6.47 (dd, J=8.3, 1.5 Hz, 1H), 6.69 (d, J=1.5 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H).

Step 3

[0939] 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoquisole-3-(1H)-one (187 mg, 0.442 mmol) was added into dichloromethane (1 mL) solution of Compound iii-89 (150 mg, 0.340 mml) under ice-cold, and the mixture was stirred at 0° C. for an hour. After saturated sodium hydrogen carbonate aqueous solution was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with brine, and dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-90 (85.4 mg, 57%).

[0940] .sup.1H-NMR (CDCl.sub.3) δ: 1.04 (s, 6H), 1.22 (s, 9H), 1.62 (t, J=6.4 Hz, 2H), 2.00-2.07 (m, 4H), 2.63 (s, 2H), 2.76 (t, J=6.4 Hz, 2H), 3.32-3.39 (m, 4H), 6.75 (dd, J=8.3, 2.8 Hz, 1H), 7.10 (d, J=2.8 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 9.93 (s, 1H).

Reference Example 33

[0941] ##STR00168##

Step 1

[0942] 60% sodium hydride (77.0 mg, 1.93 mmol) was added into THF (5 mL) suspension of (2-bromobenzyl)triphenylphosphonium bromide (990 mg, 1.93 mmol), and the mixture was stirred at room temperature for 2 hours. After Compound iii-91 (350 mg, 1.76 mmol) was added into the reaction mixture, the mixture was stirred for 17 hours under heating reflux. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, and dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound iii-92 (337 mg, 55%).

[0943] .sup.1H-NMR (CDCl.sub.3) δ: 1.47 (s, 9H), 2.28 (dd, J=5.5, 5.5 Hz, 2H), 2.37 (dd, J=5.5, 5.5 Hz, 2H), 3.40 (dd, J=5.5, 5.5 Hz, 2H), 3.53 (dd, J=5.5, 5.5 Hz, 2H), 6.31 (s, 1H), 7.10 (dd, J=7.9, 7.0 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.23-7.28 (m, 1H), 7.57 (d, J=7.9 Hz, 1H).

Step 2

[0944] Compound iii-93 was obtained by the same manner of synthesis of Compound iii-78.

[0945] .sup.1H-NMR (CDCl.sub.3) δ: 1.02 (s, 6H), 1.19 (s, 9H), 1.45 (s, 9H), 1.60 (t, J=6.4 Hz, 2H), 2.14-2.28 (m, 4H), 2.61 (s, 2H), 2.74 (t, J=6.4 Hz, 2H), 3.18-3.27 (m, 2H), 3.32-3.42 (m, 2H), 6.18 (s, 1H), 7.16-7.31 (m, 4H).

Step 3

[0946] 10% Palladium on carbon (40.0 mg, 0.018 mmol) was added into methanol (1 mL)-THF (1 mL) solution of Compound iii-93 (135 mg, 0.251 mmol), and the mixture was stirred at room temperature for 2.5 hours under hydrogen atmosphere. After insoluble matter was removed by filtration, the solvent was removed in vacuo to give Compound iii-94 (143 mg).

[0947] LC/MS (ESI): 540 (M+1)

Example 1

[0948] ##STR00169##

Step 1

[0949] 2-Iodobenzylbromide (208 mg, 0.70 mmol) and cesium carbonate (228 mg, 0.70 mmol) were added into acetonitrile (5 mL) solution of Compound ii-2 (263 mg, 0.46 mmol), and the mixture was stirred for 2 hours under reflux. After cooling, ethyl acetate was added into the reaction mixture, the obtained solids were removed by filtration, and the filtrate was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 1 (348 mg, 95%).

[0950] LC/MS (ESI): 779 (M+1)

Step 2

[0951] Compound iii-4 (51 mg, 0.16 mmol), PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2 (13 mg, 0.017 mmol) and 2 mol/L sodium carbonate aqueous solution (0.33 mL, 0.67 mmol) were added into THF (4 mL) solution of Compound 1 (130 mg, 0.16 mmol) under nitrogen atmosphere, and the mixture was reacted at 130° C. for 30 minutes by using microwave device. After water was added into reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and saturated sodium bicarbonate aqueous solution, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 2 (117 mg, 76%).

[0952] LC/MS (ESI): 934 (M+18)

Step 3

[0953] TFA (0.5 mL) was added into dichloromethane (2 mL) solution of Compound 2 (117 mg, 0.13 mmol), and the mixture was reacted at room temperature for 4 hours. After the solvent of the reaction mixture was removed, dichloromethane (2 mL), triethylamine (0.177 mL, 1.27 mmol) and Compound i-3 (43 mg, 0.15 mmol) were added into the obtained residue. After the mixture was stirred overnight at room temperature, the solvent of the reaction mixture was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-1 (93 mg, 81%).

[0954] Measurement condition: A, LC/MS (ESI): 908 (M+18)

Example 2

[0955] ##STR00170## ##STR00171##

Step 1

[0956] Potassium acetate (454 mg, 4.62 mmol), bis (pinacolato)diboron (978 mg, 3.85 mmol) and PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2 (113 mg, 0.154 mmol) were added into DMF (12 mL) solution of Compound 1 (1.2 g, 1.(4 mmol) under nitrogen atmosphere, and the mixture was stirred with heating at 80° C. for 3 hours. After cooling the reaction mixture, the mixture was diluted with ethyl acetate and water, after that, the mixture was filtrated by Celite®. After filtrate was extracted with ethyl acetate and the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 3 (1.18 g, 9875%).

[0957] LC/MS (ESI): 779 (M+1)

Step 2

[0958] Compound 4 (39.4 mg, 0.130 mmol), PdCl.sub.2 (dppf)CH.sub.2Cl.sub.2 (9.65 mg, 0.012 mmol) and 2 mol/L sodium carbonate aqueous solution (0.236 mL, 0.473 mmol) were added into THF (1 mL) solution of Compound 3 (92 mg, 0.118 mmol), and the mixture was reacted at 130° C. for 30 minutes by using a microwave device. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 5 (77 mg, 75%).

LC/MS (ESI): 875 (M+1)

Step 3

[0959] Compound 6 was obtained by the same synthesis method of Compound iii-23. LC/MS (ESI): 847 (M+1)

Step 4

[0960] Compound I-2 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 877 (M+1)

Example 3

[0961] ##STR00172##

Step 1

[0962] DMF (5.0 mL), Compound 1 (250 mg, 0.321 mmol), cesium carbonate (314 mg, 0.963 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (30.0 mg, 0.064 mmol) and Pd (OAc).sub.2 (7.21 mg, 0.032 mmol) were added into ethyl 2-phenylthiazole-4-carboxylate (150 mg, 0.642 mmol), and the mixture was stirred at 140° C. for 30 minutes by using a microwave device. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform) to give Compound 7 (132 mg, 474).

[0963] LC/MS (ESI): 885 (M+1)

Step 2

[0964] Compound I-3 was obtained by the same synthesis method of Compound I-2. Measurement condition: A, LC/MS (ESI): 872 (M+1)

Example 4

[0965] ##STR00173##

Step 1

[0966] NaBH.sub.4 (6.58 mg, 0.174 mmol) was added into THF (0.5 ml)-methanol (1 ml) solution of Compound 8 (100 mg, 0.174 mmol) at 0° C., the mixture was stirred at 0° C. for an hour. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and solvent was removed in vacuo to give Compound 9 as crude.

[0967] LC/MS (ESI): 577 (M+1)

Step 2

[0968] Triethylamine (25.8 mg, 0.255 mmol) was added into dichloromethane (1 ml) solution of Compound 9 (105 mg, 0.182 mmol), and the mixture was stirred at 0° C. After MsCl (25.0 mg, 0.218 mmol) was added into the reaction mixture, the mixture was stirred at 0° C. for 1.5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo.

[0969] 2-Bromophenol (14 mg, 0.081 mmol) and cesium carbonate (31.6 mg, 0.097 mmol) were added into DMF (1 ml) solution of the obtained crude (53 mg, 0.081 mmol), and the mixture was stirred at 50° C. for 2 hour. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 10 (37 mg, 63%).

[0970] LC/MS (ESI): 731 (M+1)

Step 3

[0971] Compound I-4 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 891 (M+1)

Example 5

[0972] ##STR00174##

Step 1

[0973] Carbon tetrachloride (1 mL), NBS (44 mg, 0.247 mmol) and AIBN (3.98 mg, 0.024 mmol) were added into Compound 11 (50 mg, 0.242 mmol), and the mixture was stirred at 70° C. for 4 hours. After the reaction mixture was filtrated, the solvent was removed in vacuo to give Compound 12 as crude.

[0974] LC/MS (ESI): 285 (M+18)

Step 2

[0975] Compound 13 was obtained by the same synthesis method of Compound 1. LC/MS (ESI): 767 (M+1)

Step 3

[0976] Compound I-5 was obtained by the same synthesis method of Compound I-2. Measurement condition: A, LC/MS (ESI): 783 (M+1)

Example 6

[0977] ##STR00175##

Step 1

[0978] 1-Bromo-2-iodobenzene (1786 mg, 6.31 mmol), sodium hydroxide (459 mg, 11.5 mmol) and copper (I) iodide (32.8 mg, 0.172 mmol) were added into isopropanol (6 mL) solution of Compound 14 (500 mg, 5.74 mmol), and the mixture was for 12 hours at 80° C. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water and saturated sodium bicarbonate aqueous solution and water, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 15 (390 mg, 28%).

[0979] LC/MS (ESI): 242 (M+1)

Step 2

[0980] Diisopropyl azodicarboxylate (0.078 mL, 0.40 mmol) was added into THF (2 mL) solution of Compound ii-2 (150 mg, 0.267 mmol), Compound 15 (77 mg, 0.32 mmol) and triphenylphosphine (105 mg, 0.40 mmol) under cooling at 0° C., and the mixture was incubated for 12 hours at room temperature. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, saturated sodium bicarbonate aqueous solution and water, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 16 (133 mg, 64%). LC/MS (ESI): 786 (M+1)

Step 3

[0981] Compound I-6 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 946 (M+1)

Example 7

[0982] ##STR00176##

Step 1

[0983] Methyl 2-bromo-2-methylpropanoate (257 mg, 1.422 mmol) and cesium carbonate (347 mg, 1.067 mmol) were added into DMF (4 mL) solution of Compound ii-2 (400 mg, 0.711 mmol), and the mixture was stirred overnight at room temperature. After the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 17 (446 mg, 95%).

[0984] LC/MS (ESI): 685 (M+23)

Step 2

[0985] 2 mol/L sodium hydroxide aqueous solution (1.68 ml, 3.36 mmol) was added into THF (4.5 mL)-methanol (2.5 ml) solution of Compound 17 (445 mg, 0.671 mmol), and the mixture was stirred at 60° C. for 2.5 hours. After 10% citric acid aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo.

[0986] DMF (2 ml), Compound iii-2 (47.4 mg, 0.168 mmol), DIPEA (26.8 mg, 0.207 mmol), HATU (73.8 mg, 0.194 mmol) and dimethylaminopyridine equivalent of catalyst were added into the obtained residue (84 mg, 0.129 mmol), and the mixture was stirred overnight at 90° C. After the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 18 (27 mg, 23%).

[0987] LC/MS (ESI): 912 (M+1)

Step 3

[0988] Compound I-7 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 903 (M+18)

Example 8

[0989] ##STR00177##

Step 1

[0990] Compound 19 was obtained by the same synthesis method of Compound 1. LC/MS (ESI): 590 (M+1)

Step 2

[0991] Morpholine (143 mg, 1.64 mmol) and Pd (Ph.sub.3P).sub.4 (95 mg, 0.08 mmol) were added into THF (5 mL) solution of Compound 19 (564 mg, 0.82 mmol), and the mixture was stirred at room temperature for 2 hours. After water was added into reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 20 (440 mg, 89%).

[0992] LC/MS (ESI): 606 (M+1)

Step 3

[0993] Compound 20 (78 mg, 0.17 mmol) and acetic acid (0.01 mL, 0.17 mmol) were added into toluene (10 mL) solution of Compound 21 (100 mg, 0.17 mmol), and the mixture was refluxed for 6 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 226 (110 mg, 63%).

[0994] LC/MS (ESI): 1026 (M+1)

Step 4

[0995] Compound I-8 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 966 (M+1)

Example 9

[0996] ##STR00178## ##STR00179##

Step 1

[0997] Water (0.4 mL), Compound iii-4 (290 mg, 0.934 mmol), sodium carbonate (198 mg, 1.868 mmol) and Pd (PPh.sub.3).sub.4 (108 mg, 0.093 mmol) were added into dioxane (4 mL) solution of Compound 23 (230 mg, 0.934 mmol) under nitrogen atmosphere, and the mixture was stirred at 90° C. for 1.5 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine. After the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 24 (151 mg, 45%).

[0998] LC/MS (ESI): 385 (M+23)

Step 2

[0999] Triethylamine (31.4 mg, 0.310 mmol), trimethylaminehydrochloric acid salt (1.98 mg, 0.021 mmol) and p-toluenesulphonylchrolide (47.3 mg, 0.248 mmol) were added into dichloromethane (1.5 mL) solution of Compound 24 (75 mg, 0.207 mmol), and the mixture was stirred at 0° C. for an hour. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine. After the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. After DMF (1 mL), Compound ii-2 (116 mg, 0.207 mmol) and cesium carbonate (88 mg, 0.269 mmol) were added into the obtained residue, the mixture was stirred at 50° C. for 1.5 hours. After the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and brine. After the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 25 (91 mg, 49%).

[1000] LC/MS (ESI): 929 (M+23)

Step 3

[1001] Palladium hydroxide (30 mg) was added into methanol (0.8 mL)-THF (0.8 ml) solution of Compound 25 (89 mg, 0.098 mmol), and the mixture was stirred at room temperature for an hour under hydrogen atmosphere. After the reaction mixture was filtrated by Celite®, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 26 (72 mg, 81%).

[1002] LC/MS (ESI): 931 (M+23)

Step 4

[1003] Compound 27 was obtained by the same synthesis method of Compound I-1. LC/MS (ESI): 900 (M+18)

Step 5 Optical Resolution by SFC

(Analysis)

<Analysis SFC (JASCO Corporation)>

Column: CHIRALPAK IF/SFC (5 μm, i.d.250×4.6 mm) (DAICEL)

[1004] Flow speed: 2.0 mL/minutes
UV detective wave length: 220 nm
Analytical condition: solution sending for 15 minutes with MeOH/CO.sub.2=40/60.
Elution time: front peak is 9.1 minutes (Compound I-9-1), rear peak is 11.3 minutes

(Compound I-9-2)

(Fractionation)

[1005] <SFC30 system (Waters)>

Column: CHIRALPAK IF/SFC (5 μm, i.d.250×20 mm) (DAICEL)

[1006] Flow speed: 30 mL/minutes
UV detective wave length: 241 nm
Analytical condition: solution sending for 15 minutes with MeOH/CO.sub.2=55/45.
Elution time: front peak is 8.2 minutes (Compound I-9-1), rear peak is 10.0 minutes

(Compound I-9-2)

Example 10

[1007] ##STR00180##

Compound 28; LC/MS (ESI): 915 (M+18)

[1008] Optical resolution by SFC
(analysis)

<Analysis SFC (JASCO Corporation)>

Column: CHIRALPAK IC-3/SFC (3 μm, i.d.250×4.6 mm) (DAICEL)

[1009] Flow speed: 2.0 mL/minutes
UV detective wave length: 250 nm
Analytical condition: solution sendinf for 15 minutes with MeOH/CO.sub.2=30/70.
Elution time: front peak is 12.2 minutes (Compound I-10-1), rear peak is 13.1 minutes (Compound I-10-2)

(Fractionation)

<Semi-fractionation SFC (JASCO Corporation)>

[1010] Column: CHIRALPAK IC/SFC (5 μm, i.d.250×20 mm) (DAICEL) with tandem of the two column
Flow speed: 40 mL/minutes
UV detective wave length: 250 nm
Analytical condition: solution sending for 21 minutes with MeOH/CO.sub.2=30/70.
Elution time: front peak is 16.7 minutes (Compound I-10-1), rear peak is 18.1 minutes (Compound I-10-2)

Example 11

[1011] ##STR00181##

Step 1

[1012] Triethylamine (91 mg, 0.904 mmol), PdCl.sub.2 (PPh.sub.3).sub.2 (10.6 mg, 0.015 mmol), copper (I) iodide (5.74 mg, 0.030 mmol) and ethynyltrimethylsilane (89 mg, 0.904 mmol) were added into DMF (1 mL) solution of Compound iii-3 (104 mg, 0.301 mmol) under nitrogen atmosphere, and the mixture was stirred under heating at 100° C. for an hour. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 29 (108 mg, 99%).

[1013] LC/MS (ESI): 363 (M+1)

Step 2

[1014] Potassium carbonate (120 mg, 0.869 mmol) was added into methanol (3 mL) solution of Compound 29 (300 mg, 0.827 mmol), and the mixture was stirred at 0° C. for 30 minutes. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo, Compound 30 as crude.

[1015] LC/MS (ESI): 291 (M+1)

Step 3

[1016] Compound 31 was obtained by the same synthesis method of Compound 29. LC/MS (ESI): 835 (M+1)

Step 4

[1017] Compound I-11 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 809 (M+1)

Example 12

[1018] ##STR00182##

Step 1

[1019] Palladium hydroxide (30 mg) was added into methanol (1 mL)-THF (0.2 ml) solution of Compound 32 (87 mg, 0.104 mmol), and the mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. After the reaction mixture was filtrated by Celite®, the solvent was removed in vacuo to give Compound 33 as crude.

[1020] LC/MS (ESI): 856 (M+18)

Step 2

[1021] Compound I-12 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 813 (M+1)

Example 13

[1022] ##STR00183##

Step 1

[1023] 2-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-amine hydrochloride (97 mg, 0.308 mmol), DMF (1 ml), triethylamine (78 mg, 0.770 mmol), WSCD HCl (38.4 mg, 0.200 mmol) and HOBt (29.1 mg, 0.216 mmol) were added into Compound 34 (91 mg, 0.154 mmol), and the mixture was stirred at 70° C. for 5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 35 (51 mg, 39%).

[1024] LC/MS (ESI): 850 (M+1)

Step 2

[1025] Compound I-13 was obtained by the same synthesis method of Compound 5 and Compound I-1.

Measurement condition: A, LC/MS (ESI): 948 (M+1)

Example 14

[1026] ##STR00184##

Step 1

[1027] Hexane solution (1.5M, 0.7 mL, 1.13 mmol) of n-butyllithium was added by dropwise to THF (6 mL) solution of Compound iii-3 (293 mg, 0.85 mmol) for 10 minutes under cooling at −70° C. under nitrogen atmosphere, and the mixture was stirred at −70° C. for an hour. DMF (0.13 mL, 1.70 mmol) was added, and the mixture was stirred for an hour. After saturated ammonium chloride was added into reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 36 (250 mg, 100%).

[1028] LC/MS (ESI): 295 (M+1)

Step 2

[1029] Acetic acid (0.1 mL), Compound 36 (25.0 mg, 0.085 mmol) and picolineborane (11.3 mg, 0.106 mmol) were added into methanol (2 mL) solution of Compound ii-5 (39.7 mg, 0.071 mmol), and the mixture was stirred at room temperature for an hour. After saturated sodium bicarbonate aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 37 (59.4 mg, 100%).

[1030] LC/MS (ESI): 840 (M+1)

Step 3

[1031] Compound I-14 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 814 (M+1)

Example 15

[1032] ##STR00185## ##STR00186##

Step 1 and 2

[1033] Compound 39 and 40 was obtained by the same synthesis method of Compound 29 and 33.

Compound 39; LC/MS (ESI): 816 (M+18)

Compound 40; LC/MS (ESI): 669 (M+1)

Step 3

[1034] Triethylamine (0.03 mL, 0.24 mmol) and 2-(methylthio)benzo[d]thiazole-6-sulfonyl chloride (56.0 mg, 0.20 mmol) were added into dichloromethane (1 mL) solution of Compound 40 (115 mg, 0.17 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 41 (106 mg, 67%). LC/MS (ESI): 912 (M+1)

Step 4

[1035] After m-chloroperoxybenzoic acid (45 mg, 0.169 mmol) was added into dichloromethane (2 mL) solution of Compound 41 (103 mg, 0.113 mmol) under ice-cold, the mixture was stirred at room temperature for an hour. After saturated thiosodium sulfate aqueous solution was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo to give Compound 42 as crude.

Step 5

[1036] 2 mol/L Ammonia ethanol solution (0.496 ml, 0.991 mmol) was added into dioxane (2 mL) solution of Compound 42 (92 mg, 0.099 mmol), and the mixture was stirred at 80° C. under heating for 19 hours. After the reaction mixture was removed in vacuo, the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 43 (76 mg, 87%).

[1037] LC/MS (ESI): 881 (M+1)

Step 6

[1038] Compound I-15 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 855 (M+1)

Example 16

[1039] ##STR00187## ##STR00188## ##STR00189##

Step 1 and 2

[1040] Compound 45 and 46 was obtained by the same synthesis method of Compound 2 and 28.

Compound 56; LC/MS (ESI): 747 (M+1)

Step 3

[1041] Triethylamine (0.074 mL, 0.535 mmol) and 3-bromo-4-nitrobenzene-1-sulfonyl chloride (121 mg, 0.402 mmol) were added into dichloromethane (3.0 mL) solution of Compound 46 (200 mg, 0.268 mmol), and the mixture was stirred at room temperature for an hour. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 47 (271 mg, 100%).

Step 4

[1042] Ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)acrylate (125 mg, 0.554 mmol), PdCl.sub.2 (dppf) CH.sub.2Cl.sub.2 (22.6 mg, 0.028 mmol) and 2 mol/L sodium carbonate aqueous solution (0.554 mL, 1.11 mmol) were added into THF (5.6 mL) solution of Compound 47 (271 mg, 0.268 mmol), and the mixture was stirred at 130° C. by using a microwave device for 30 minutes. After brine was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 48 (244 mg, 88%).

Step 5

[1043] 2 mol/L Sodium hydroxide aqueous solution (1.07 mL, 2.14 mmol) was added into methanol (4.4 mL)-water (2.2 mL)-THF (4.4 mL) solution of Compound 48 (220 mg, 0.214 mmol), and the mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution were added into the reaction mixture, and the mixture was extracted with chloroform. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo to give Compound 49 (213 mg, 99.5%).

Step 6

[1044] Triethylamine (0.118 mL, 0.850 mmol), ammonium chloride (34.1 mg, 0.638 mmol) and HATU (97 mg, 0.26 mmol) were added into DMF (2.1 mL) solution of Compound 49 (213 mg, 0.213 mmol), and the mixture was stirred at room temperature for 16 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 50 (173 mg, 81%).

LC/MS (ESI): 1002 (M+1)

Step 7

[1045] Compound 51 was obtained by the same synthesis method of Compound I-1. LC/MS (ESI): 975 (M+1)

Step 8

[1046] Ammonium chloride (52.1 mg, 0.974 mmol) and iron powder (27.2 mg, 0.487 mmol) were added into ethanol (0.95 mL)-water (0.32 mL) solution of Compound 51 (95 mg, 0.097 mmol), and the mixture was stirred at 80° C. for 2 hours. After water was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was dried with anhydrous sodium sulfate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-16 (32 mg, 35%). Measurement condition: A, LC/MS (ESI): 946 (M+1)

Example 17

[1047] ##STR00190##

[1048] 10% Pd/C (including 50% water) (3.38 mg) was added into THF (3.0 mL) solution of Compound I-16 (30 mg, 0.032 mmol), and the mixture was stirred under hydrogen atmosphere at room temperature for 1.5 hours. After the reaction mixture was filtrated by Celite®, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-17 (19.8 mg, 66%).

Measurement condition: A, LC/MS (ESI): 948 (M+1)

Example 18

[1049] ##STR00191## ##STR00192##

Step 1

[1050] Cesium carbonate (110 mg, 0.34 mmol) and Compound iii-50 (116 mg, 0.34 mmol) were added into DMF (1 mL) solution of Compound 52 (100 mg, 0.17 mmol), and the mixture was stirred at room temperature for 5 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 53 (134 mg, 93%).

[1051] LC/MS (ESI): 872 (M+23)

Step 2-3

[1052] Compound I-18 was obtained by the same synthesis method of Compound I-2. Measurement condition: B, LC/MS (ESI): 864 (M-1)

Example 19

[1053] ##STR00193##

Step 1 and 2

[1054] After Compound 56 was synthesized from Compound 55 by the method written in WO2005/064008, Compound I-19 was obtained by the same synthesis method of Compound I-1.

Measurement condition: A, LC/MS (ESI): 897 (M+1)

Example 20

[1055] ##STR00194##

[1056] Triethylamine (0.17 mL, 1.21 mmol), ammonium chloride (4.38 mg, 0.082 mmol) and HATU (18.7 mg, 0.049 mmol) were added into DMF (0.5 mL) solution of Compound I-1 (36.5 mg, 0.041 mmol), and the mixture was stirred at room temperature for an hour. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound I-20 (28 mg, 77%).

Measurement condition: A, LC/MS (ESI): 890 (M+1)

Example 21

[1057] ##STR00195## ##STR00196##

Step 1

[1058] 50% Hydroxylamine aqueous solution (125 mg, 1.90 mmol) was added into ethanol (3 mL) solution of Compound 57 (150 mg, 0.190 mmol), and the mixture was stirres at room temperature for 38 hours. After the reaction mixture was condensed, water was added, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo to give Compound 58 as crude. LC/MS (ESI): 823 (M+1)

Step 2

[1059] CDI (44 mg, 0.272 mmol) was added into THF (6 mL) solution of Compound 58 (149 mg, 0.181 mmol) under nitrogen atmosphere. After the mixture was stirred at room temperature for 30 minutes, the mixture was stirred at 85° C. for 8 hours. After citric acid aqueous solution and water were added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 59 (94 mg, 61%).

LC/MS (ESI): 847 (M-1)

Step 3

[1060] Compound I-21 was obtained by the same synthesis method of Compound I-1. Measurement condition: B, LC/MS (ESI): 877 (M-1)

Example 22

[1061] ##STR00197##

Step 1

[1062] NaN.sub.3 (54.3 mg, 0.836 mmol) and ammonium chloride (44.7 mg, 0.836 mmol) were added into DMA (2.4 mL) solution of Compound 57 (66 mg, 0.084 mmol) under nitrogen atmosphere, and the mixture was stirred at 140° C. for 8 hours. After water was added into the reaction mixture, the mixture made to be acid with 10% citric acid aqueous solution, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 60 (46 mg, 66%). LC/MS (ESI): 831 (M-1)

Step 2

[1063] TFA (0.5 mL) was added into dichloromethane (2.5 mL) solution of Compound 60 (57 mg, 0.068 mmol) and anisole (0.149 mL, 1.37 mmol), and the mixture was stirred at room temperature for 2 hours. After the solvent was removed in vacuo, dichloromethane (2.5 mL) and triethylamine (0.142 mL, 1.03 mmol) were added into the obtained residue. Compound i-3 (20 mg, 0.068 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After sodium hydrogen carbonate aqueous solution was added into the reaction mixture, the mixture is made to be acid with 10% citric acid aqueous solution, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was reverse phase HPLC to give Compound I-22 (23 mg, 39%) and Compound I-23 (7 mg, 11%).

Compound I-22; Measurement condition: B, LC/MS (ESI): 861 (M−1)
Compound I-23; Measurement condition: B, LC/MS (ESI): 941 (M+23)

Example 23

[1064] ##STR00198## ##STR00199##

Step 1

[1065] DIPEA (0.130 mL, 0.742 mmol) was added into DMF (2 mL) solution of Compound 61 (100 mg, 0.124 mmol), cyanamide (20.8 mg, 0.494 mmol) and BOP (65.6 mg, 0.148 mmol) under nitrogen atmosphere, and the mixture was stirred overnight at room temperature. After water was added into the reaction mixture, the mixture was made to be acid with 10% citric acid aqueous solution. The mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 62 (96 mg, 93%).

LC/MS (ESI): 831 (M−1)

Step 2

[1066] Compound I-24 and Compound I-25 was obtained by the same synthesis method of Compound I-22 and Compound I-23.

Compound I-24; Measurement condition: B, LC/MS (ESI): 879 (M−1)
Compound I-25; Measurement condition: B, LC/MS (ESI): 935 (M−1)

Example 24

[1067] ##STR00200##

Step 1

[1068] p-Toluenesulfonic acid monohydrate (2 mg, 10.5 μmol) was added into toluene (6 mL) solution of Compound 63 (50 mg, 0.091 mmol) and Compound 36 (29.5 mg, 0.100 mmol) under nitrogen atmosphere, and the mixture was stirred under he at reflux for 7 hours. After the solvent of the reaction mixture was removed in vacuo, THF (1 mL) was added into the obtained residue. NaBH.sub.4 (8.62 mg, 0.228 mmol) and methanol (0.5 mL) were added into at 0° C., and the mixture was stirred for 30 minutes. After saturated sodium hydrogen carbonate aqueous solution was added into the reaction mixture, the mixture was stirred at room temperature for 30 minutes, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 64 (60 mg, 80%).

LC/MS (ESI): 825 (M-1)

Step 2

[1069] Compound I-26 was obtained by the same synthesis method of Compound I-1. Measurement condition: B, LC/MS (ESI): 841 (M+1)

Example 25

[1070] ##STR00201##

Step 1

[1071] m-Chloroperoxybenzoic acid (39.8 mg, 0.231 mmol) was added into dichloromethane (2 mL) solution of Compound 65 (100 mg, 0.154 mmol) under ice-cold, and the mixture was stirred at 0° C. for an hour. After saturated thiosodium sulfate aqueous solution was added into the reaction mixture, the mixture was extracted with dichloromethane. After the organic layer was washed with brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo, Compound 66 (100 mg, 98%).

LC/MS (ESI): 666 (M+1)

Step 2

[1072] Triethylamine (0.214 mL, 1.54 mmol) and Compound iii-76 (190 mg, 0.231 mmol) were added into DMA (2 mL) solution of Compound 66 (100 m g, 0.150 mmol), and the mixture was stirred at 95° C. by using a microwave device for 20 minutes. After water and 2 mol/L hydrochloric acid were added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was HPLC (acetonitrile-water containing 0.1% formic acid) to give Compound I-27 (44 mg, 30%).

Measurement condition: A, LC/MS (ESI): 976 (M+1)

Example 26

[1073] ##STR00202##

[1074] Potassium carbonate (6 mg, 0.04 mmol) was added into methanol (5 mL) solution of the synthesized Compound I-28 (38 mg, 0.04 mmol), and the mixture was reacted at room temperature for an hour. Saturated ammonium chloride aqueous solution was added into the reaction mixture. The mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-29 (35 mg, 97%).

Compound I-28; Measurement condition: A, LC/MS (ESI): 933 (M+1)
Compound I-29; Measurement condition: A, LC/MS (ESI): 891 (M+1)

Example 27

[1075] ##STR00203##

Step 1

[1076] TFA (0.5 mL) was added into dichloromethane (1 mL) solution of Compound 1 (82 mg, 0.10 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for an hour. After the solvent was removed, the obtained residue was dissolved into DMA (1 mL). Compound 67 (51 mg, 0.16 mmol), DIPEA (0.18 mL, 0.18 mmol) and HATU (60 mg, 0.16 mmol) were added into, and the mixture was stirred at room temperature for 3 days. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 68 (40 mg, 41%).

[1077] LC/MS (ESI): 908 (M+1)

Step 2

[1078] Compound 69 was obtained by the same synthesis method of Compound 2.

[1079] LC/MS (ESI): 1046 (M+1)

Step 3

[1080] TFA (0.5 mL) was added into dichloromethane (1 mL) solution of Compound 69 (24 mg, 0.02 mmol) under nitrogen atmosphere, and the mixture was stirred at room temperature for an hour. The solvent was removed. After the obtained residue was adjusted to pH about 5 with saturated sodium bicarbonate aqueous solution, the mixture was extracted with chloroform. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-30 (22 mg, 96%). Measurement condition: A, LC/MS (ESI): 990 (M+1)

Example 28

[1081] ##STR00204## ##STR00205##

Step 1

[1082] Imidazole (7.75 g, 114 mmol) and 1 mol/L TBDPSCl—CH.sub.2Cl.sub.2 solution (114 mL, 114 mmol) were added into THF (300 mL) solution of Compound 70 (11.5 g, 114 mmol) under nitrogen flow, and the mixture was stirred at room temperature for 18 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo, Compound 71 (15.9 g, 16%).

[1083] .sup.1H-NMR (CDCl.sub.3) δ: 1.07 (s, 9H), 2.61 (t, 2H, J=2.1 Hz), 4.18 (s, 2H), 4.33 (t, 2H, J=2.1 Hz), 4.89 (s, 1H), 7.05-7.90 (m, 10H).

Step 2

[1084] Compound 72 was obtained by the same synthesis method of Compound (I-1). LC/MS (ESI): 831 (M+1)

Step 3

[1085] Pyridine (0.29 mL, 3.61 mmol) and acetic anhydride (0.34 mL, 3.61 mmol) were added into dichloromethane (30 mL) solution of Compound 72 (3.0 g, 3.61 mmol), and the mixture was stirred at room temperature for 24 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 73 (2.99 g, 95%).

[1086] LC/MS (ESI): 873 (M+1)

Step 4

[1087] Acetic acid (0.15 mL, 3.42 mmol) and 1 mol/L TBAF-THF solution (17.1 mL, 17.1 mmol) were added into THF (30 mL) solution of Compound 73 (2.99 g, 3.42 mmol), and the mixture was stirred at room temperature for 24 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 74 (1.30 g, 60%).

[1088] LC/MS (ESI): 635 (M+1)

Step 5

[1089] Pyridine (0.20 mL, 2.46 mmol) and anhydrous trifluoroemethanesulfonic acid (0.69 g, 2.46 mmol) were added into dichloromethane (20 mL) solution of Compound 74 (1.30 g, 2.05 mmol), and the mixture was stirred at 0° C. for 2 hours. After 2 mol/L hydrochloric acid aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo.

[1090] The obtained residue was dissolved into DMF (10 mL), and NaN.sub.3 (0.40 g, 6.14 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water was added into the reaction mixture, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo.

[1091] The obtained residue was dissolved into ethyl acetate (10 mL), and Pd (OH).sub.2 (135 mg, 10% wt) was added. The mixture was stirred under hydrogen flow at room temperature for 3 hours. The reaction mixture was filtrated, and filtrate was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 75 (1.10 g, 3 Step 85%).

[1092] LC/MS (ESI): 634 (M+1)

Step 6

[1093] Triethylamine (15.9 mg, 0.16 mmol), Compound iii-79 (50 mg, 0.08 mmol), WSCD HCl (18.2 mg, 0.10 mmol) and HOBt (12.8 mg, 0.10 mmol) were added into dichloromethane (5 mL) solution of Compound 75 (27 mg, 0.08 mmol), and the mixture was stirred at room temperature for 3 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 76 (42 mg, 59%).

[1094] LC/MS (ESI): 953 (M+1)

Step 7

[1095] Potassium carbonate (11.1 mg, 0.08 mmol) was added into methanol (5 mL) solution of Compound 76 (42 mg, 0.04 mmol), and the mixture was stirred at room temperature for 3 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 77 (35 mg, 96%).

[1096] LC/MS (ESI): 911 (M+1)

Step 8

[1097] TFA (0.2 mL) was added into dichloromethane (2 mL) solution of Compound 77 (35 mg, 0.04 mmol), and the mixture was reacted at room temperature for 24 hours. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound I-31 (32 mg, 94%). Measurement condition: A, LC/MS (ESI): 855 (M+1)

Example 29

[1098] ##STR00206##

Step 1

[1099] Dichloromethane (1 mL), pyridine (11.81 mg, 0.149 mmol) and 4-nitrophenyl carbonochloridate (30 mg, 0.149 mmol) were added into Compound 78 (50 mg, 0.075 mmol) synthesized by the same method of Compound 74, and the mixture was stirred at 0° C. for 3 hours. The solvent of reaction mixture was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 79 (50 mg, 80%).

[1100] LC/MS (ESI): 835 (M+1)

Step 2

[1101] DIPEA (10.44 mg, 0.081 mmol) and THF (1 ml) solution of Compound 80 (49.4 mg, 0.059 mmol) were added into acetonitrile (1 mL) solution of Compound 79 (20 mg, 0.054 mmol), and the mixture was stirred at room temperature for 8 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 81 (33 mg, 57%).

[1102] LC/MS (ESI): 1067 (M+1)

Step 3

[1103] Compound I-32 was obtained by the same synthesis method of Compound I-31.

Measurement condition: A, LC/MS (ESI): 969 (M+1)

Example 30

[1104] ##STR00207##

Step 1

[1105] DIPEA (103 mg, 0.80 mmol) and Compound iii-81 (67 mg, 0.18 mmol) were added into DMA (5 mL) solution of Compound 75 (100 mg, 0.16 mmol), and the mixture was stirred at 80° C. for 18 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 82 (95 mg, 65%).

LC/MS (ESI): 912 (M+1)

Step 2

[1106] Compound I-33 was obtained by the same synthesis method of Compound I-31. Measurement condition: A, LC/MS (ESI): 815 (M+1)

Example 31

[1107] ##STR00208##

Step 1

[1108] Triethylamine (0.32 mL, 2.27 mmol) and isobuthylchlorocarbonate (248 mg, 1.82 mmol) were added into THF (15 mL) solution of Compound iii-79 (510 mg, 1.52 mmol), and the mixture was stirred at 0° C. for 5 hours. After methanol (5 mL) was added into reaction mixture, NaBH.sub.4 (115 mg, 3.03 mmol) was added. The mixture was stirred at 0° C. for 10 minutes after that at room temperature for 5 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 83 (280 mg, 57%).

[1109] LC/MS (ESI): 323 (M+1)

Step 2

[1110] Pd (OH).sub.2 (87 mg, 0.12 mmol) was added into ethyl acetate (5 mL) solution of Compound 83 (400 mg, 1.24 mmol), and the mixture was stirred under hydrogen flow at room temperature for 2 hours. After the reaction mixture was filtrated, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 84 (403 mg, 100%). LC/MS (ESI): 325 (M+1)

Step 3

[1111] Compound 85 was obtained by the same synthesis method of Compound 79. LC/MS (ESI): 490 (M+1)

Step 4

[1112] Compound I-34 was obtained by the same synthesis method of Compound I-32. Measurement condition: A, LC/MS (ESI): 886 (M+1)

Example 32

[1113] ##STR00209##

Step 1

[1114] Pyridine (0.058 mL, 0.716 mmol) and anhydrous trifluoromethanesulfonic acid (0.048 mL, 0.286 mmol) were added into dichloromethane (1.6 mL) solution of Compound 78 (80 mg, 0.12 mmol) under ice-cold, and the mixture was stirred at 0° C. for 3 hours. The solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 86 (29 mg, 30%).

[1115] LC/MS (ESI): 802 (M+1)

Step 2

[1116] Sodium hydride (5.78 mg, 0.144 mmol) was added into DMF (0.87 mL) solution of Compound 87 (15.6 mg, 0.043 mmol), and the mixture was stirred at room temperature for 1.5 hours. Compound 86 (29 mg, 0.036 mmol) was added into the reaction mixture, and the mixture was stirred at room temperature for 14 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 88 (15.8 mg, 43%). LC/MS (ESI): 1010 (M+1)

Step 3

[1117] Compound I-35 was obtained by the same synthesis method of Compound I-31. Measurement condition: A, LC/MS (ESI): 912 (M+1)

Example 33

[1118] ##STR00210##

Step 1

[1119] Pyridine (734 mg, 9.27 mmol) and benzo[d]-thiazole-6-sulfonyl chloride (2.17 g, 9.27 mmol) were added into dichloromethane (40 mL) solution of Compound 89 (2.0 g, 7.13 mmol), and the mixture was stirred at room temperature for 18 hours. After the reaction mixture was condensed, the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 90 (931 mg, 27%). LC/MS (ESI): 478 (M+1)

Step 2

[1120] 1-bromo-3-(3-bromopropyl)benzene (69.8 mg, 0.251 mmol) and potassium carbonate (43.4 mg, 0.314 mmol) were added into acetonitrile (1 mL) solution of Compound 90 (100 mg, 0.209 mmol), and the mixture was stirred for 3 hours under heat reflux. After the reaction mixture was extracted with ethyl acetate, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 91 (106 mg, 75%). LC/MS (ESI): 674 (M+1)

Step 3

[1121] Compound I-36 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 874 (M+1)

Example 34

[1122] ##STR00211##

Step 1

[1123] 1-Chloro-N,N,2-trimethyl-1-propenylamine (0.046 mL, 0.344 mmol) was added into THF (1.6 mL) solution of Compound 92 (80.0 mg, 0.115 mmol) under ice-cold, and the mixture was stirred under ice-cold for an hour. Compound iii-2 (97.0 mg, 0.344 mmol) and pyridine (0.056 mL, 0.689 mmol) were added into the reaction mixture, and the mixture was stirred at room temperature for 4 hours. After saturated ammonium chloride aqueous solution was added into reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 93 (75.0 mg, 68%). LC/MS (ESI): 961 (M+1)

Step 2

[1124] Compound I-268 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 934 (M+1)

Example 35

[1125] ##STR00212##

Step 1

[1126] Suspension of Compound iii-2 (10.0 g, 35.5 mmol) and dichloromethane solution (100 mL) of phthalic anhydride (5.26 g, 35.5 mmol) was stirred at room temperature for 2 hours. N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)uronium Hexafluorophosphate (16.2 g, 42.6 mmol) and triethylamine (7.39 mL, 53.3 mmol) were added into the reaction mixture, and the mixture was stirred at room temperature for 16 hours. After 1 mol/L hydrochloric acid aqueous solution was added into the reaction mixture, the mixture was extracted with dichloromethane. Insoluble matter was filtrated and removed. After the organic layer was washed with water, the solvent was removed in vacuo. The obtained solids were washed with isopropanol to give Compound 94 (13.2 g, 91%).

[1127] .sup.1H-NMR (CDCl.sub.3) δ: 1.03 (s, 6H), 1.25 (s, 9H), 1.61 (t, J=6.3 Hz, 2H), 2.65 (s, 2H), 2.77 (t, J=6.3 Hz, 2H), 7.77-7.83 (m, 2H), 7.94-7.99 (m, 2H).

Step 2

[1128] Sodium borohydride (1.82 g, 48.2 mmol) was added into methanol (66 mL)-THF (132 mL) solution of Compound 94 (13.2 g, 32.1 mmol) at −40° C., and the mixture was stirred with heating to −25° C. for 80 minutes. After 1 mol/L hydrochloric acid ethyl acetate solution was added by dropwise into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was washed with diisopropyl ether to give Compound 95 (13.5 g).

[1129] .sup.1H-NMR (CDCl.sub.3) δ: 1.01 (s, 3H), 1.04 (s, 3H), 1.37 (s, 9H), 1.60 (t, J=5.8 Hz, 2H), 2.51 (d, J=16.9 Hz, 1H), 2.62 (d, J=16.9 Hz, 1H), 2.74 (t, J=5.8 Hz, 2H), 4.10 (d, J=10.4 Hz, 1H), 6.06 (d, J=10.4 Hz, 1H), 7.56 (ddd, J=7.3, 7.3, 1.8 Hz, 1H), 7.63-7.70 (m, 2H), 7.88 (d, J=7.3 Hz, 1H).

Step 3

[1130] Methanol (45 mL)-dichloromethane (15 mL)-acetic acid (3 mL) solution of Compound ii-5 (3.00 g, 5.34 mmol) and Compound 95 (2.21 g, 5.34 mmol) was stirred under nitrogen atmosphere at room temperature for 5 minutes. 2-Picolineborane (857 mg, 8.01 mmol) was added into the reaction mixture, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane, and the mixture was washed sodium hydrogen carbonate aqueous solution and water. After the mixture was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 96 (3.62 g, 71%).

[1131] LC/MS (ESI): 959 (M+1)

Step 4

[1132] Compound I-396 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 934 (M+1)

Example 36

[1133] ##STR00213##

Step 1

[1134] Chloroacetyl chloride (0.040 mL, 0.497 mmol) was added into chloroform (1.4 mL) solution of Compound iii-2 (70.0 mg, 0.249 mmol), and the mixture was stirred under heat reflux for 2 hours. The reaction mixture was condensed in vacuo to give Compound 97 (29.0 mg, 33%).

[1135] .sup.1H-NMR (CDCl.sub.3) δ: 0.98 (s, 6H), 1.56 (t, J=6.4 Hz, 2H), 1.60 (s, 9H), 2.53 (s, 2H), 2.67 (t, J=6.4 Hz, 2H), 4.23 (s, 2H), 12.13 (s, 1H).

Step 2

[1136] DMA (0.58 mL) solution of Compound ii-5 (45.5 mg, 0.081 mmol) and Compound 97 (29.0 mg, 0.081 mmol) was stirred at 120° C. for 2.5 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 98 (38.0 mg, 53%).

[1137] LC/MS (ESI): 883 (M+1)

Step 3

[1138] Compound I-593 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 857 (M+1)

Example 37

[1139] ##STR00214##

Step 1

[1140] Acetic acid (2.25 mL) and 10% palladium hydroxide (400 mg, 0.285 mmol) were added into methanol (4.5 mL)-THF (4.5 mL) solution of Compound 99 (900 mg, 2.15 mmol), and the mixture was stirred under hydrogen atmosphere (5 atm) at 60° C. for 6 hours. After the insoluble matter was filtrated and removed, the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 100 (408 mg, 45%).

[1141] .sup.1H-NMR (CDCl.sub.3) δ: 0.96 (s, 3H), 0.97 (s, 3H), 1.07 (t, J=7.1 Hz, 3H), 1.23-1.54 (m, 4H), 1.58 (s, 9H), 1.68-1.81 (m, 3H), 1.84-1.89 (m, 1H), 1.98-2.04 (m, 1H), 2.21 (ddd, J=24.0, 11.8, 3.4 Hz, 1H), 2.51 (s, 2H), 2.66 (t, J=6.5 Hz, 2H), 3.08 (ddd, J=4.2, 4.2, 4.2 Hz, 1H), 3.87 (ddd, J=11.5, 4.2, 4.2 Hz, 1H), 3.96 (q, J=7.1 Hz, 2H).

Step 2

[1142] Compound 101 was obtained by the same synthesis method of Compound iii-90. .sup.1H-NMR (CDCl.sub.3) δ: 0.98 (s, 6H), 1.39-1.65 (m, 15H), 1.76-1.89 (m, 2H), 1.94-2.01 (m, 1H), 2.15-2.22 (m, 1H), 2.53 (s, 2H), 2.68 (t, J=6.3 Hz, 2H), 2.95-3.01 (m, 1H), 3.99 (ddd, J=11.8, 4.1, 4.1 Hz, 1H), 9.75 (s, 1H).

Step 3

[1143] Compound 102 was obtained by the same synthesis method of Compound 37. LC/MS (ESI): 922 (M+1)

Step 4

[1144] Compound I-246 and Compound I-247 was obtained by the same synthesis method of Compound I-9-1 and Compound I-9-2.

Compound I-246; Measurement condition: A, LC/MS (ESI): 896 (M+1)
Compound I-247; Measurement condition: A, LC/MS (ESI): 896 (M+1)

Example 38

[1145] ##STR00215## ##STR00216##

Step 1

[1146] THF solution (41.4 mL, 41.4 mmol) of 1 mol/L lithium bis(trimethylsilyl)amide was added into THF (50 mL) solution of Compound 103 (5.23 g, 41.4 mmol) under nitrogen atmosphere at −78° C., and the mixture was stirred at −78° C. for 30 minutes. THF (20 mL) solution of di-t-butyl oxalate (8.38 g, 41.4 mmol) was added into the reaction mixture, and the mixture was stirred at room temperature with heating for 2.5 hours. The reaction mixture was poured to mixture of ethyl acetate and saturated ammonium chloride aqueous solution, and the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 104 (7.45 g, 71%).

[1147] .sup.1H-NMR (CDCl.sub.3) δ: 0.98 (s, 6H), 1.51 (t, J=6.8 Hz, 2H), 1.57 (s, 9H), 2.18 (s, 2H), 2.44 (t, J=6.8 Hz, 2H), 14.97 (s, 1H).

Step 2

[1148] Ethanol solution (30 mL) of [2-(benzyloxy)phenyl]hydrazine (3.51 g, 16.4 mmol) was added by dropwise into ethanol (70.2 mL) solution of Compound 104 (4.17 g, 16.4 mmol) under ice-cold. After the mixture was stirred at 0° C. for 1.5 hours, the mixture was stirred at 80° C. for 3 hours. The reaction mixture was condensed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 105 (3.6 g, 51%).

[1149] .sup.1H-NMR (CDCl.sub.3) δ: 1.06 (s, 6H), 1.25 (s, 9H), 1.64 (t, J=6.6 Hz, 2H), 2.61 (s, 2H), 2.76 (t, J=6.6 Hz, 2H), 4.99 (s, 2H), 6.99 (dd, J=7.6, 1.2 Hz, 1H), 7.06 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.17-7.21 (m, 2H), 7.21-7.31 (m, 3H), 7.33 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.44 (dd, J=7.6, 1.6 Hz, 1H).

Step 3

[1150] 10% Palladium hydroxide (350 mg, 0.250 mmol) was added into ethanol (144 mL) solution of Compound 105 (3.60 g, 8.32 mmol), and the mixture was stirred under hydrogen atmosphere at room temperature for 2.1 hours. After the insoluble matter was filtrated and removed, the reaction mixture was condensed in vacuo. After water was added into the obtained residue, the mixture was extracted with dichloromethane. After the organic layer was dried with magnesium sulfate anhydrous, the solvent was removed in vacuo, Compound 106 (2.89 g).

[1151] .sup.1H-NMR (CDCl.sub.3) δ: 1.05 (s, 6H), 1.41 (s, 9H), 1.64 (t, J=6.6 Hz, 2H), 2.57 (s, 2H), 2.74 (t, J=6.6 Hz, 2H), 6.91 (ddd, J=8.2, 8.2, 1.4 Hz, 1H), 7.08 (dd, J=8.2, 1.4 Hz, 1H), 7.12 (dd, J=8.2, 1.4 Hz, 1H), 7.23 (ddd, J=8.2, 8.2, 1.4 Hz, 1H), 7.93 (s, 1H).

Step 4

[1152] Compound 107 was obtained by the same synthesis method of Compound 16. LC/MS (ESI): 512 (M+1)

Step 5

[1153] Compound 107 (120 mg, 0.235 mmol) was dissolved with acetonitrile (1.2 mL), and p-toluenesulfonic acid hydrate (223 mg, 1.17 mmol) was added. The mixture was stirred at room temperature for 2.5 hours. After saturated sodium hydrogen carbonate aqueous solution was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give Compound 108 (97.0 mg, 74%). LC/MS (ESI): 412 (M+1)

Step 6

[1154] Compound 108 (71.0 mg, 0.173 mmol), cesium carbonate (112 mg, 0.345 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (8.05 mg, 0.017 mmol) and 2nd generation RuPhos pre-catalyst (13.4 mg, 0.017 mmol) were added into toluene (1.5 mL) solution of Compound ii-3 (120 mg, 0.173 mmol), and the mixture was stirred at 110° C. for 17 hours. After the insoluble matter was filtrated and removed, water was added into the reaction mixture, and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 109 (150 mg, 91%).

[1155] LC/MS (ESI): 956 (M+1)

Step 7

[1156] Compound I-596 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 931 (M+1)

Example 39

[1157] ##STR00217##

Step 1

[1158] Compound 110 was obtained by the same synthesis method of Compound 79. LC/MS (ESI): 447 (M+1)

Step 2

[1159] Triethylamine (0.050 mL, 0.364 mmol) was added into THF (1.5 mL) solution of Compound ii-5 (68.2 mg, 0.121 mmol) and Compound 110 (88.4 mg, 81.0 mg, 0.182 mmol), and the mixture was stirred at 50° C. for 4 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with magnesium sulfate anhydrous, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 111 (76.9 mg, 73%).

[1160] LC/MS (ESI): 869 (M+1)

Step 3 Compound I-192 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 843 (M+1)

Example 40

[1161] ##STR00218## ##STR00219##

Step 1

[1162] Pyridine (0.034 mL, 0.427 mmol) and 2-nitrobenzenesulfonyl chloride (87.0 mg, 0.392 mmol) were added into dichloromethane (2 mL) solution of Compound ii-5 (200 mg, 0.356 mmol) under ice-cold, and the mixture was stirred at room temperature for 2 hours. After saturated ammonium chloride aqueous solution was added into the reaction mixture, the mixture was extracted with chloroform. After the organic layer was washed with brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 112 (216 mg, 81%).

LC/MS (ESI): 747 (M+1)

Step 2

[1163] Compound 113 was obtained by the same synthesis method of Compound 16. LC/MS (ESI): 956,958 (M+1)

Step 3

[1164] Acetonitrile (1 mL) suspension of Compound 113 (148 mg, 0.130 mmol), dodecane-1-thiol (0.154 mL, 0.648 mmol) and cesium carbonate (254 mg, 0.778 mmol) was stirred at 50° C. for 20 hours. After water was added into the reaction mixture, the mixture was extracted with ethyl acetate. After the organic layer was washed with brine, the mixture was dried with anhydrous sodium sulfate, and the solvent was removed in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give Compound 114 (108 mg, 2 Step, 70%). LC/MS (ESI): 958 (M+1)

Step 4

[1165] Compound I-228 was obtained by the same synthesis method of Compound I-1. Measurement condition: A, LC/MS (ESI): 931 (M+1)

[1166] The following compounds were synthesized by the same synthesis method of above Reference example or Example by using compounds of Reference example or known compounds. The LC/MS measurement results of each compounds were represented as following.

[1167] In the tables, “No.” is compound number, “Structure” is chemical structure formula, “method” is above LC/MS (liquid chromatography-mass spectrometry) measurement condition, and “RT” is retention time (minutes).

TABLE-US-00001 TABLE 1 [00220] No. R1 R2 R3 R4 R5 salt I-37 [00221] H [00222] [00223] H I-38 [00224] H [00225] [00226] H I-39 [00227] H [00228] [00229] H I-40 [00230] H [00231] [00232] H I-41 [00233] H [00234] [00235] H I-42 [00236] H [00237] [00238] H I-43 [00239] H [00240] [00241] H I-44 [00242] H [00243] [00244] H

TABLE-US-00002 TABLE 2 No. R1 R2 R3 R4 R5 salt I-45 [00245] H [00246] [00247] H I-46 [00248] H [00249] [00250] H I-47 [00251] H [00252] [00253] H I-48 [00254] H [00255] [00256] H I-49 [00257] H [00258] [00259] H I-50 [00260] H [00261] [00262] H I-51 [00263] H [00264] [00265] H I-52 [00266] H [00267] [00268] H

TABLE-US-00003 TABLE 3 No. R1 R2 R3 R4 R5 salt I-53 [00269] H [00270] [00271] H I-54 [00272] H [00273] [00274] H I-55 [00275] [00276] [00277] [00278] H I-56 [00279] [00280] [00281] [00282] H I-57 [00283] H [00284] [00285] H I-58 [00286] H [00287] [00288] H I-59 [00289] H [00290] [00291] H I-60 [00292] H [00293] [00294] H I-61 [00295] H [00296] [00297] H

TABLE-US-00004 TABLE 4 No. R1 R2 R3 R4 R5 salt I-62 [00298] H [00299] [00300] H I-63 [00301] H [00302] [00303] H I-64 [00304] H [00305] [00306] H I-65 [00307] H [00308] [00309] H I-66 [00310] H [00311] [00312] H I-67 [00313] H [00314] [00315] H I-68 [00316] H [00317] [00318] H I-69 [00319] H [00320] [00321] H I-70 [00322] H [00323] [00324] H

TABLE-US-00005 TABLE 5 No. R1 R2 R3 R4 R5 salt I-71 [00325] H [00326] [00327] H I-72 [00328] H [00329] [00330] H I-73 [00331] H [00332] [00333] H I-74 [00334] H [00335] [00336] H I-75 [00337] H [00338] [00339] H I-76 [00340] H [00341] [00342] H I-77 [00343] H [00344] [00345] H I-78 [00346] H [00347] [00348] H

TABLE-US-00006 TABLE 6 No. R1 R2 R3 R4 R5 salt I-79 [00349] H [00350] [00351] H I-80 [00352] H [00353] [00354] H I-81 [00355] H [00356] [00357] H I-82 [00358] H [00359] [00360] H I-83 [00361] H [00362] [00363] H I-84 [00364] H [00365] [00366] H I-85 [00367] H [00368] [00369] H I-86 [00370] H [00371] [00372] H

TABLE-US-00007 TABLE 7 No. R1 R2 R3 R4 R5 salt I-87 [00373] H [00374] [00375] H I-88 [00376] H [00377] [00378] H I-89 [00379] H [00380] [00381] H I-90 [00382] H [00383] [00384] H I-91 [00385] H [00386] [00387] H I-92 [00388] H [00389] [00390] H I-93 [00391] H [00392] [00393] H I-94 [00394] H [00395] [00396] H

TABLE-US-00008 TABLE 8 No. R1 R2 R3 R4 R5 salt I-95  [00397] H [00398] [00399] H I-96  [00400] H [00401] [00402] H I-97  [00403] H [00404] [00405] H I-98  [00406] H [00407] [00408] H I-99  [00409] H [00410] [00411] OH I-100 [00412] H [00413] [00414] H I-101 [00415] H [00416] [00417] H I-102 [00418] H [00419] [00420] H

TABLE-US-00009 TABLE 9 No. R1 R2 R3 R4 R5 salt I-103 [00421] H [00422] [00423] H I-104 [00424] H [00425] [00426] H I-105 [00427] H [00428] [00429] H I-106 [00430] H [00431] [00432] H I-107 [00433] H [00434] [00435] H I-108 [00436] H [00437] [00438] H I-109 [00439] H [00440] [00441] H I-110 [00442] H [00443] [00444] H I-111 [00445] H [00446] [00447] H

TABLE-US-00010 TABLE 10 No. R1 R2 R3 R4 R5 salt I-112 [00448] H [00449] [00450] H I-113 [00451] H [00452] [00453] H I-114 [00454] H [00455] [00456] H I-115 [00457] H [00458] [00459] H I-116 [00460] H [00461] [00462] H I-117 [00463] H [00464] [00465] H I-118 [00466] H [00467] [00468] H I-119 [00469] H [00470] [00471] H

TABLE-US-00011 TABLE 11 No. R1 R2 R3 R4 R5 salt I-120 [00472] H [00473] [00474] H I-121 [00475] H [00476] [00477] H I-122 [00478] H [00479] [00480] H I-123 [00481] H [00482] [00483] H I-124 [00484] H [00485] [00486] H I-125 [00487] H [00488] [00489] H I-126 [00490] H [00491] [00492] H I-127 [00493] H [00494] [00495] H

TABLE-US-00012 TABLE 12 No. R1 R2 R3 R4 R5 salt I-128 [00496] H [00497] [00498] H I-129 [00499] H [00500] [00501] H I-130 [00502] H [00503] [00504] H I-131 [00505] H [00506] [00507] H I-132 [00508] H [00509] [00510] H I-133 [00511] H [00512] [00513] H I-134 [00514] H [00515] [00516] H I-135 [00517] H [00518] [00519] H

TABLE-US-00013 TABLE 13 No. R1 R2 R3 R4 R5 salt I-136 [00520] H [00521] [00522] H I-137 [00523] H [00524] [00525] H I-138 [00526] H [00527] [00528] H I-139 [00529] H [00530] [00531] H I-140 [00532] H [00533] [00534] H I-141 [00535] H [00536] [00537] H I-142 [00538] H [00539] [00540] H I-143 [00541] H [00542] [00543] H

TABLE-US-00014 TABLE 14 No. R1 R2 R3 R4 R5 salt I-144 [00544] H [00545] [00546] H I-145 [00547] H [00548] [00549] H I-146 [00550] H [00551] [00552] H I-147 [00553] H [00554] [00555] H I-148 [00556] H [00557] [00558] H I-149 [00559] H [00560] [00561] H I-150 [00562] H [00563] [00564] H I-151 [00565] H [00566] [00567] H I-152 [00568] H [00569] [00570] H

TABLE-US-00015 TABLE 15 No. R1 R2 R3 R4 R5 salt I-153 [00571] H [00572] [00573] H I-154 [00574] H [00575] [00576] H I-155 [00577] H [00578] [00579] H I-156 [00580] H [00581] [00582] H I-157 [00583] H [00584] [00585] H I-158 [00586] H [00587] [00588] H I-159 [00589] H [00590] [00591] H I-160 [00592] H [00593] [00594] H I-161 [00595] H [00596] [00597] H I-162 [00598] H [00599] [00600] H

TABLE-US-00016 TABLE 16 No. R1 R2 R3 R4 R5 salt I-163 [00601] H [00602] [00603] H I-164 [00604] H H [00605] H I-165 [00606] H H [00607] H I-166 [00608] H H [00609] H I-167 [00610] H H [00611] H I-168 [00612] H [00613] [00614] H I-169 [00615] H [00616] [00617] H I-170 [00618] H [00619] [00620] H I-171 [00621] H [00622] [00623] H

TABLE-US-00017 TABLE 17 No. R1 R2 R3 R4 R5 salt I-172 [00624] H [00625] [00626] H I-173 [00627] H [00628] [00629] H I-174 [00630] H [00631] [00632] H I-175 [00633] H [00634] [00635] H I-176 [00636] H [00637] 6[00638] H I-177 [00639] H [00640] [00641] H I-178 [00642] H [00643] [00644] H I-179 [00645] H [00646] [00647] H I-180 [00648] H [00649] [00650] H

TABLE-US-00018 TABLE 18 No. R1 R2 R3 R4 R5 salt I-181 [00651] H [00652] [00653] H I-182 [00654] H [00655] [00656] H I-183 [00657] H [00658] [00659] H I-184 [00660] H [00661] [00662] H I-185 [00663] H [00664] [00665] H I-186 [00666] H [00667] [00668] H I-187 [00669] H [00670] [00671] H I-188 [00672] H [00673] [00674] H I-189 [00675] H [00676] [00677] H

TABLE-US-00019 TABLE 19 No. R1 R2 R3 R4 R5 salt I-190 [00678] H [00679] [00680] H I-191 [00681] H [00682] [00683] H I-193 [00684] H [00685] [00686] H I-194 [00687] H [00688] [00689] H I-195 [00690] H [00691] [00692] H I-196 [00693] H [00694] [00695] H I-197 [00696] H [00697] [00698] H I-198 [00699] H [00700] [00701] H I-199 [00702] H [00703] [00704] H

TABLE-US-00020 TABLE 20 No. R1 R2 R3 R4 R5 salt I-200 [00705] H [00706] [00707] H I-201 [00708] H [00709] [00710] H I-202 [00711] H [00712] [00713] H I-203 [00714] H [00715] [00716] H I-204 [00717] H [00718] [00719] H I-205 [00720] H [00721] [00722] H I-206 [00723] H [00724] [00725] H I-207 [00726] H [00727] [00728] H I-208 [00729] H [00730] [00731] H

TABLE-US-00021 TABLE 21 No. R1 R2 R3 R4 R5 salt I-209 [00732] H [00733] [00734] H I-210 [00735] H [00736] [00737] H I-211 [00738] H [00739] [00740] H I-212 [00741] H [00742] [00743] H I-213 [00744] H [00745] [00746] H I-214 [00747] H [00748] [00749] H I-215 [00750] H [00751] [00752] H I-216 [00753] H [00754] [00755] H

TABLE-US-00022 TABLE 22 No. R1 R2 R3 R4 R5 salt I-217 [00756] H [00757] [00758] H I-218 [00759] H [00760] [00761] H I-219 [00762] H [00763] [00764] H I-220 [00765] H [00766] [00767] H I-221 [00768] H [00769] [00770] H I-222 [00771] H [00772] [00773] H I-223 [00774] H [00775] [00776] H I-224 [00777] H [00778] [00779] H I-225 [00780] H [00781] [00782] H

TABLE-US-00023 TABLE 23 No. R1 R2 R3 R4 R5 salt I-226 [00783] H [00784] [00785] H I-227 [00786] H [00787] [00788] H I-229 [00789] H [00790] [00791] H I-230 [00792] H [00793] [00794] H I-231 [00795] H [00796] [00797] H I-232 [00798] H [00799] [00800] H I-233 [00801] H [00802] [00803] H I-234 [00804] H [00805] [00806] H

TABLE-US-00024 TABLE 24 No. R1 R2 R3 R4 R5 salt I-235 [00807] H [00808] [00809] H I-236 [00810] H [00811] [00812] H I-237 [00813] H [00814] [00815] H I-238 [00816] H [00817] [00818] H I-239 [00819] H [00820] [00821] H I-240 [00822] H [00823] [00824] H I-241 [00825] H [00826] [00827] H

TABLE-US-00025 TABLE 25 No. R1 R2 R3 R4 R5 salt I-242 [00828] H [00829] [00830] H I-243 [00831] H [00832] [00833] H I-244 [00834] H [00835] [00836] H I-245 [00837] H [00838] [00839] H I-248 [00840] H [00841] [00842] H I-249 [00843] H [00844] [00845] H I-250 [00846] H [00847] [00848] H I-251 [00849] H [00850] [00851] H

TABLE-US-00026 TABLE 26 No. R1 R2 R3 R4 R5 salt I-252 [00852] H [00853] [00854] H I-253 [00855] H [00856] [00857] H I-254 [00858] H [00859] [00860] H I-255 [00861] H [00862] [00863] H I-256 [00864] H [00865] [00866] H I-257 [00867] H [00868] [00869] H I-258 [00870] H [00871] [00872] H I-259 [00873] H [00874] [00875] H

TABLE-US-00027 TABLE 27 No. R1 R2 R3 R4 R5 salt I-260 [00876] H [00877] [00878] H I-261 [00879] H [00880] [00881] H I-262 [00882] H [00883] [00884] H I-263 [00885] H [00886] [00887] H I-264 [00888] H [00889] [00890] H I-265 [00891] H [00892] [00893] H I-266 [00894] H [00895] [00896] H I-267 [00897] H [00898] [00899] H

TABLE-US-00028 TABLE 28 No. R1 R2 R3 R4 R5 salt I-269 [00900] H [00901] [00902] H I-270 [00903] H [00904] [00905] H I-271 [00906] H [00907] [00908] H I-272 [00909] H [00910] [00911] H I-273 [00912] H [00913] [00914] H I-274 [00915] H [00916] [00917] H I-275 [00918] H [00919] [00920] H I-276 [00921] H [00922] [00923] H

TABLE-US-00029 TABLE 29 No. R1 R2 R3 R4 R5 salt I-277 [00924] H [00925] [00926] H I-278 [00927] H [00928] [00929] H I-279 [00930] H [00931] [00932] H I-280 [00933] H [00934] [00935] H I-281 [00936] H [00937] [00938] H I-282 [00939] H [00940] [00941] H I-283 [00942] H [00943] [00944] H I-284 [00945] H [00946] [00947] H I-285 [00948] H [00949] [00950] H

TABLE-US-00030 TABLE 30 No. R1 R2 R3 R4 R5 salt I-286 [00951] H [00952] [00953] H I-287 [00954] H [00955] [00956] H I-288 [00957] H [00958] [00959] H I-289 [00960] H [00961] [00962] H I-290 [00963] H [00964] [00965] H I-291 [00966] H [00967] [00968] H I-292 [00969] H [00970] [00971] H I-293 [00972] H [00973] [00974] H I-294 [00975] H [00976] [00977] H

TABLE-US-00031 TABLE 31 No. R1 R2 R3 R4 R5 salt I-295 [00978] H [00979] [00980] H I-296 [00981] H [00982] [00983] H I-297 [00984] H [00985] [00986] H I-298 [00987] H [00988] [00989] H I-299 [00990] H [00991] [00992] H I-300 [00993] H [00994] [00995] H I-301 [00996] H [00997] [00998] H I-302 [00999] H [01000] [01001] H I-303 [01002] H [01003] [01004] H

TABLE-US-00032 TABLE 32 No. R1 R2 R3 R4 R5 salt I-304 [01005] H [01006] [01007] H I-305 [01008] H [01009] [01010] H I-306 [01011] H [01012] [01013] H I-307 [01014] H [01015] [01016] H I-308 [01017] H [01018] [01019] H I-309 [01020] H [01021] [01022] H I-310 [01023] H [01024] [01025] H I-311 [01026] H [01027] [01028] H I-312 [01029] H [01030] [01031] H I-313 [01032] H [01033] [01034] H I-314 [01035] H [01036] [01037] H I-315 [01038] H [01039] [01040] H

TABLE-US-00033 TABLE 33 No. R1 R2 R3 R4 R5 salt I-316 [01041] H [01042] [01043] H I-317 [01044] H [01045] [01046] H I-318 [01047] H [01048] [01049] H I-319 [01050] H [01051] [01052] H I-320 [01053] H [01054] [01055] H I-321 [01056] H [01057] [01058] H I-322 [01059] H [01060] [01061] H I-323 [01062] H [01063] [01064] H I-324 [01065] H [01066] [01067] H I-325 [01068] H [01069] [01070] H

TABLE-US-00034 TABLE 34 No. R1 R2 R3 R4 R5 salt I-326 [01071] H [01072] [01073] H I-327 [01074] H [01075] [01076] H I-328 [01077] H [01078] [01079] H I-329 [01080] H [01081] [01082] H I-330 [01083] H [01084] [01085] H I-331 [01086] H [01087] [01088] H I-332 [01089] H [01090] [01091] H

TABLE-US-00035 TABLE 35 No. R1 R2 R3 R4 R5 salt I-333 [01092] H [01093] [01094] H I-334 [01095] H [01096] [01097] H I-335 [01098] H [01099] [01100] H I-336 [01101] H [01102] [01103] H I-337 [01104] H [01105] [01106] H I-338 [01107] H [01108] [01109] H I-339 [01110] H [01111] [01112] H I-340 [01113] H [01114] [01115] H

TABLE-US-00036 TABLE 36 No. R1 R2 R3 R4 R5 salt I-341 [01116] H [01117] [01118] H I-342 [01119] H [01120] [01121] H I-343 [01122] H [01123] [01124] H I-344 [01125] H [01126] [01127] H I-345 [01128] H [01129] [01130] H I-346 [01131] H [01132] [01133] H I-347 [01134] H [01135] [01136] H I-348 [01137] H [01138] [01139] H

TABLE-US-00037 TABLE 37 No. R1 R2 R3 R4 R5 salt I-349 [01140] H [01141] [01142] H I-350 [01143] H [01144] [01145] H I-351 [01146] H [01147] [01148] H I-352 [01149] H [01150] [01151] H I-353 [01152] H [01153] [01154] H I-354 [01155] H [01156] [01157] H I-355 [01158] H [01159] [01160] H I-356 [01161] H [01162] [01163] H

TABLE-US-00038 TABLE 38 No. R1 R2 R3 R4 R5 salt I-357 [01164] H [01165] [01166] H I-358 [01167] H [01168] [01169] H I-359 [01170] H [01171] [01172] H I-360 [01173] H [01174] [01175] H I-361 [01176] H [01177] [01178] H I-362 [01179] H [01180] [01181] H I-363 [01182] H [01183] [01184] H I-364 [01185] H [01186] [01187] H I-365 [01188] H [01189] [01190] H

TABLE-US-00039 TABLE 39 No. R1 R2 R3 R4 R5 salt I-366 [01191] H [01192] [01193] H I-367 [01194] H [01195] [01196] H I-368 [01197] H [01198] [01199] H I-369 [01200] H [01201] [01202] H I-370 [01203] H [01204] [01205] H I-371 [01206] H [01207] [01208] H I-372 [01209] H [01210] [01211] H I-373 [01212] H [01213] [01214] H I-374 [01215] H [01216] [01217] H

TABLE-US-00040 TABLE 40 No. R1 R2 R3 R4 R5 salt I-375 [01218] H [01219] [01220] H I-376 [01221] H [01222] [01223] H I-377 [01224] H [01225] [01226] H I-378 [01227] H [01228] [01229] H I-379 [01230] H [01231] [01232] H I-380 [01233] H [01234] [01235] H I-381 [01236] H [01237] [01238] H I-382 [01239] H [01240] [01241] H

TABLE-US-00041 TABLE 41 No. R1 R2 R3 R4 R5 salt I-383 [01242] H [01243] [01244] H I-384 [01245] H [01246] [01247] H I-385 [01248] H [01249] [01250] H I-386 [01251] H [01252] [01253] H I-387 [01254] H [01255] [01256] H I-388 [01257] H [01258] [01259] H I-389 [01260] H [01261] [01262] H I-390 [01263] H [01264] [01265] H I-391 [01266] H [01267] [01268] H

TABLE-US-00042 TABLE 42 No. R1 R2 R3 R4 R5 salt I-392 [01269] H [01270] [01271] H I-393 [01272] H [01273] [01274] H I-394 [01275] H [01276] [01277] H I-395 [01278] H [01279] [01280] H I-397 [01281] [01282] [01283] Na I-398 [01284] H [01285] [01286] H I-399 [01287] H [01288] [01289] H I-400 [01290] H [01291] [01292] H

TABLE-US-00043 TABLE 43 No. R1 R2 R3 R4 R5 salt I-401 [01293] H [01294] [01295] H I-402 [01296] H [01297] [01298] H I-403 [01299] H [01300] [01301] H I-404 [01302] H [01303] [01304] H I-405 [01305] H [01306] [01307] H I-406 [01308] H [01309] [01310] H I-407 [01311] H [01312] [01313] H I-408 [01314] H [01315] [01316] H

TABLE-US-00044 TABLE 44 No. R1 R2 R3 R4 R5 salt I-409 [01317] H [01318] [01319] H I-410 [01320] H [01321] [01322] H I-411 [01323] H [01324] [01325] H I-412 [01326] H [01327] [01328] H I-413 [01329] H [01330] [01331] H I-414 [01332] H [01333] [01334] H I-415 [01335] H [01336] [01337] H

TABLE-US-00045 TABLE 45 No. R1 R2 R3 R4 R5 salt I-416 [01338] H [01339] [01340] H I-417 [01341] H [01342] [01343] H I-418 [01344] H [01345] [01346] H I-419 [01347] H [01348] [01349] H I-420 [01350] H [01351] [01352] H I-421 [01353] H [01354] [01355] H I-422 [01356] H [01357] [01358] H

TABLE-US-00046 TABLE 46 No. R1 R2 R3 R4 R5 salt I-423 [01359] H [01360] [01361] H I-424 [01362] H [01363] [01364] H I-425 [01365] H [01366] [01367] H I-426 [01368] H [01369] [01370] H I-427 [01371] H [01372] [01373] H I-428 [01374] H [01375] [01376] H I-429 [01377] H [01378] [01379] H

TABLE-US-00047 TABLE 47 No. R1 R2 R3 R4 R5 salt I-430 [01380] H [01381] [01382] H I-431 [01383] H [01384] [01385] H I-432 [01386] H [01387] [01388] H I-433 [01389] H [01390] [01391] H I-434 [01392] H [01393] [01394] H I-435 [01395] H [01396] [01397] H I-436 [01398] H [01399] [01400] H

TABLE-US-00048 TABLE 48 No. R1 R2 R3 R4 R5 salt I-437 [01401] H [01402] [01403] H I-438 [01404] H [01405] [01406] H I-439 [01407] H [01408] [01409] H I-440 [01410] H [01411] [01412] H I-441 [01413] H [01414] [01415] H I-442 [01416] H [01417] [01418] H I-443 [01419] H [01420] [01421] H I-444 [01422] H [01423] [01424] H I-445 [01425] H [01426] [01427] H

TABLE-US-00049 TABLE 49 No. R1 R2 R3 R4 R5 salt I-446 [01428] H [01429] [01430] H I-447 [01431] H [01432] [01433] H I-448 [01434] H [01435] [01436] H I-449 [01437] H [01438] [01439] H I-450 [01440] H [01441] [01442] H I-451 [01443] H [01444] [01445] H I-452 [01446] H [01447] [01448] H I-453 [01449] H [01450] [01451] H

TABLE-US-00050 TABLE 50 No. R1 R2 R3 R4 R5 salt I-454 [01452] H [01453] [01454] H I-455 [01455] H [01456] [01457] H I-456 [01458] H [01459] [01460] H I-457 [01461] H [01462] [01463] H I-458 [01464] H [01465] [01466] H I-459 [01467] H [01468] [01469] H I-460 [01470] H [01471] [01472] H

TABLE-US-00051 TABLE 51 No. R1 R2 R3 R4 R5 salt I-461 [01473] H [01474] [01475] H I-462 [01476] H [01477] [01478] H I-463 [01479] H [01480] [01481] H I-464 [01482] H [01483] [01484] H I-465 [01485] H [01486] [01487] H I-466 [01488] H [01489] [01490] H I-467 [01491] H [01492] [01493] H I-468 [01494] H [01495] [01496] H

TABLE-US-00052 TABLE 52 No. R1 R2 R3 R4 R5 salt I-469 [01497] H [01498] [01499] H I-470 [01500] H [01501] [01502] H I-471 [01503] H [01504] [01505] H I-472 [01506] H [01507] [01508] H I-473 [01509] H [01510] [01511] H I-474 [01512] H [01513] [01514] H I-475 [01515] H [01516] [01517] H I-476 [01518] H [01519] [01520] H

TABLE-US-00053 TABLE 53 No. R1 R2 R3 R4 R5 salt I-477 [01521] H [01522] [01523] H I-478 [01524] H [01525] [01526] H I-479 [01527] H [01528] [01529] H I-480 [01530] H [01531] [01532] H I-481 [01533] H [01534] [01535] H I-482 [01536] H [01537] [01538] H I-483 [01539] H [01540] [01541] H I-484 [01542] H [01543] [01544] H

TABLE-US-00054 TABLE 54 No. R1 R2 R3 R4 R5 salt I-485 [01545] H [01546] [01547] H I-486 [01548] H [01549] [01550] H I-487 [01551] H [01552] [01553] H I-488 [01554] H [01555] [01556] H I-489 [01557] H [01558] [01559] H I-490 [01560] H [01561] [01562] H I-491 [01563] H [01564] [01565] H I-492 [01566] H [01567] [01568] H

TABLE-US-00055 TABLE 55 No. R1 R2 R3 R4 R5 salt I-493 [01569] H [01570] [01571] H I-494 [01572] H [01573] [01574] H I-495 [01575] H [01576] [01577] H I-496 [01578] H [01579] [01580] H I-497 [01581] H [01582] [01583] H I-498 [01584] H [01585] [01586] H I-499 [01587] H [01588] [01589] H I-500 [01590] H [01591] [01592] H I-501 [01593] H [01594] [01595] H

TABLE-US-00056 TABLE 56 No. R1 R2 R3 R4 R5 salt I-502 [01596] H [01597] [01598] H I-503 [01599] H [01600] [01601] H I-504 [01602] H [01603] [01604] H I-505 [01605] H [01606] [01607] H I-506 [01608] H [01609] [01610] H I-507 [01611] H [01612] [01613] H I-508 [01614] H [01615] [01616] H I-509 [01617] H [01618] [01619] H

TABLE-US-00057 TABLE 57 No. R1 R2 R3 R4 R5 salt I-510 [01620] H [01621] [01622] H I-511 [01623] H [01624] [01625] H I-512 [01626] H [01627] [01628] H I-513 [01629] H [01630] [01631] H I-514 [01632] H [01633] [01634] H I-515 [01635] H [01636] [01637] H I-516 [01638] H [01639] [01640] H I-517 [01641] H [01642] [01643] H

TABLE-US-00058 TABLE 58 No. R1 R2 R3 R4 R5 salt I-518 [01644] H [01645] [01646] H I-519 [01647] H [01648] [01649] H I-520 [01650] H [01651] [01652] H I-521 [01653] H [01654] [01655] H I-522 [01656] H [01657] [01658] H I-523 [01659] H [01660] [01661] H I-524 [01662] H [01663] [01664] H I-525 [01665] H [01666] [01667] H

TABLE-US-00059 TABLE 59 No. R1 R2 R3 R4 R5 salt I-526 [01668] H [01669] [01670] H I-527 [01671] H [01672] [01673] H I-528 [01674] H [01675] [01676] H I-529 [01677] H [01678] [01679] H I-530 [01680] H [01681] [01682] H I-531 [01683] H [01684] [01685] H I-532 [01686] H [01687] [01688] H I-533 [01689] H [01690] [01691] H I-534 [01692] H [01693] [01694] H

TABLE-US-00060 TABLE 60 No. R1 R2 R3 R4 R5 salt I-535 [01695] H [01696] [01697] H I-536 [01698] H [01699] [01700] H I-537 [01701] H [01702] [01703] H I-538 [01704] H [01705] [01706] H I-539 [01707] H [01708] [01709] H I-540 [01710] H [01711] [01712] H I-541 [01713] H [01714] [01715] H I-542 [01716] H [01717] [01718] H

TABLE-US-00061 TABLE 61 No. R1 R2 R3 R4 R5 salt I-543 [01719] H [01720] [01721] H I-544 [01722] H [01723] [01724] H I-545 [01725] H [01726] [01727] H I-546 [01728] H [01729] [01730] H I-547 [01731] H [01732] [01733] H I-548 [01734] H [01735] [01736] H I-549 [01737] H [01738] [01739] H I-550 [01740] H [01741] [01742] H

TABLE-US-00062 TABLE 62 No. R1 R2 R3 R4 R5 salt I-551 [01743] H [01744] [01745] H I-552 [01746] H [01747] [01748] H I-553 [01749] H [01750] [01751] H I-554 [01752] H [01753] [01754] H I-555 [01755] H [01756] [01757] H I-556 [01758] H [01759] [01760] H I-557 [01761] H [01762] [01763] H I-558 [01764] H [01765] [01766] H I-559 [01767] H [01768] [01769] H

TABLE-US-00063 TABLE 63 No. R1 R2 R3 R4 R5 salt I-560 [01770] H [01771] [01772] H I-561 [01773] H [01774] [01775] H I-562 [01776] H [01777] [01778] H I-563 [01779] H [01780] [01781] H I-564 [01782] H [01783] [01784] H I-565 [01785] H [01786] [01787] H I-566 [01788] H [01789] [01790] H I-567 [01791] H [01792] [01793] H

TABLE-US-00064 TABLE 64 No. R1 R2 R3 R4 R5 salt I-568 [01794] H [01795] [01796] H I-569 [01797] H [01798] [01799] H I-570 [01800] H [01801] [01802] H I-571 [01803] H [01804] [01805] H I-572 [01806] H [01807] [01808] H I-573 [01809] H [01810] [01811] H I-574 [01812] H [01813] [01814] H I-575 [01815] H [01816] [01817] H I-576 [01818] H [01819] [01820] H

TABLE-US-00065 TABLE 65 No. R1 R2 R3 R4 R5 salt I-577 [01821] H [01822] [01823] H I-578 [01824] H [01825] [01826] H I-579 [01827] H [01828] [01829] H I-580 [01830] H [01831] [01832] H I-581 [01833] H [01834] [01835] H I-582 [01836] H [01837] [01838] H I-583 [01839] H [01840] [01841] H I-584 [01842] H [01843] [01844] H

TABLE-US-00066 TABLE 66 No. R1 R2 R3 R4 R5 salt I-585 [01845] H [01846] [01847] H I-586 [01848] H [01849] [01850] H I-587 [01851] H [01852] [01853] H I-588 [01854] H [01855] [01856] H I-589 [01857] H [01858] [01859] H I-590 [01860] H [01861] [01862] H I-591 [01863] H [01864] [01865] H I-592 [01866] H [01867] [01868] H I-594 [01869] H [01870] [01871] H

TABLE-US-00067 TABLE 67 No. R1 R2 R3 R4 R5 salt I-595 [01872] H [01873] [01874] H I-597 [01875] H [01876] [01877] H I-598 [01878] H [01879] [01880] H I-599 [01881] H [01882] [01883] H I-600 [01884] H [01885] [01886] H I-601 [01887] H [01888] [01889] H I-602 [01890] H [01891] [01892] H I-603 [01893] H [01894] [01895] H

TABLE-US-00068 TABLE 68 No. R1 R2 R3 R4 R5 salt I-604 [01896] H [01897] [01898] H I-605 [01899] H [01900] [01901] H I-606 [01902] H [01903] [01904] H I-607 [01905] H [01906] [01907] H I-608 [01908] H [01909] [01910] H I-609 [01911] H [01912] [01913] H I-610 [01914] H [01915] [01916] H I-611 [01917] H [01918] [01919] H

TABLE-US-00069 TABLE 69 No. R1 R2 R3 R4 R5 salt I-612 [01920] H [01921] [01922] H I-613 [01923] H [01924] [01925] H I-614 [01926] H [01927] [01928] H I-615 [01929] H [01930] [01931] H I-616 [01932] H [01933] [01934] H I-617 [01935] H [01936] [01937] H I-618 [01938] H [01939] [01940] H I-619 [01941] H [01942] [01943] H

TABLE-US-00070 TABLE 70 No. R1 R2 R3 R4 R5 salt I-620 [01944] H [01945] [01946] H I-621 [01947] H [01948] [01949] H I-622 [01950] H [01951] [01952] H I-623 [01953] H [01954] [01955] H I-624 [01956] H [01957] [01958] H I-625 [01959] H [01960] [01961] H I-626 [01962] H [01963] [01964] H I-627 [01965] H [01966] [01967] H

TABLE-US-00071 TABLE 71 No. R1 R2 R3 R4 R5 salt I-628 [01968] H [01969] [01970] H I-629 [01971] H [01972] [01973] H I-630 [01974] H [01975] [01976] H I-631 [01977] H [01978] [01979] H I-632 [01980] H [01981] [01982] H I-633 [01983] H [01984] [01985] H I-634 [01986] H [01987] [01988] H I-635 [01989] H [01990] [01991] H

TABLE-US-00072 TABLE 72 No. R1 R2 R3 R4 R5 salt I-636 [01992] H [01993] [01994] H I-637 [01995] H [01996] [01997] H I-638 [01998] H [01999] [02000] H I-639 [02001] H [02002] [02003] H I-640 [02004] H [02005] [02006] H I-641 [02007] H [02008] [02009] H I-642 [02010] H [02011] [02012] H I-643 [02013] H [02014] [02015] H

TABLE-US-00073 TABLE 73 No. R1 R2 R3 R4 R5 salt I-644 [02016] H [02017] [02018] H I-645 [02019] H [02020] [02021] H I-646 [02022] H [02023] [02024] H I-647 [02025] H [02026] [02027] H I-648 [02028] H [02029] [02030] H I-649 [02031] H [02032] [02033] H I-650 [02034] H [02035] [02036] H I-651 [02037] H [02038] [02039] H

TABLE-US-00074 TABLE 74 No. R1 R2 R3 R4 R5 salt I-652 [02040] H [02041] [02042] H I-653 [02043] H [02044] [02045] H I-654 [02046] H [02047] [02048] H I-655 [02049] H [02050] [02051] H I-656 [02052] H [02053] [02054] H I-657 [02055] H [02056] [02057] H I-658 [02058] H [02059] [02060] H I-659 [02061] H [02062] [02063] H

TABLE-US-00075 TABLE 75 No. R1 R2 R3 R4 R5 salt I-660 [02064] H [02065] [02066] H I-661 [02067] H [02068] [02069] H I-662 [02070] H [02071] [02072] H I-663 [02073] H [02074] [02075] H I-664 [02076] H [02077] [02078] H I-665 [02079] H [02080] [02081] H I-666 [02082] H [02083] [02084] H I-667 [02085] H [02086] [02087] H

TABLE-US-00076 TABLE 76 No. R1 R2 R3 R4 R5 salt I-668 [02088] H [02089] [02090] H I-669 [02091] H [02092] [02093] H I-670 [02094] H [02095] [02096] H I-671 [02097] H [02098] [02099] H I-672 [02100] H [02101] [02102] H I-673 [02103] H [02104] [02105] H I-674 [02106] H [02107] [02108] H I-675 [02109] H [02110] [02111] H

TABLE-US-00077 TABLE 77 No. R1 R2 R3 R4 R5 salt I-676 [02112] H [02113] [02114] H I-677 [02115] H [02116] [02117] H I-678 [02118] H [02119] [02120] H I-679 [02121] H [02122] [02123] H I-680 [02124] H [02125] [02126] H I-681 [02127] H [02128] [02129] H I-682 [02130] H [02131] [02132] H

TABLE-US-00078 TABLE 78 No. R1 R2 R3 R4 R5 salt I-683 [02133] H [02134] [02135] H I-684 [02136] H [02137] [02138] H I-685 [02139] H [02140] [02141] H I-686 [02142] H [02143] [02144] H I-687 [02145] H [02146] [02147] H I-688 [02148] H [02149] [02150] H I-689 [02151] H [02152] [02153] H I-690 [02154] H [02155] [02156] H

TABLE-US-00079 TABLE 79 No. R1 R2 R3 R4 R5 salt I-691 [02157] H [02158] [02159] H I-692 [02160] H [02161] [02162] H I-693 [02163] H [02164] [02165] H I-694 [02166] H [02167] [02168] H I-695 [02169] H [02170] [02171] H I-696 [02172] H [02173] [02174] H I-697 [02175] H [02176] [02177] H I-698 [02178] H [02179] [02180] H

TABLE-US-00080 TABLE 80 No. R1 R2 R3 R4 R5 salt I-699 [02181] H [02182] [02183] H I-700 [02184] H [02185] [02186] H I-701 [02187] H [02188] [02189] H I-702 [02190] H [02191] [02192] H I-703 [02193] H [02194] [02195] H I-704 [02196] H [02197] [02198] H I-705 [02199] H [02200] [02201] H

TABLE-US-00081 TABLE 81 No. R1 R2 R3 R4 R5 salt I-706 [02202] H [02203] [02204] H I-707 [02205] H [02206] [02207] H I-708 [02208] H [02209] [02210] H I-709 [02211] H [02212] [02213] H I-710 [02214] H [02215] [02216] H I-711 [02217] H [02218] [02219] H I-712 [02220] H [02221] [02222] H I-713 [02223] H [02224] [02225] H I-714 [02226] H [02227] [02228] H

TABLE-US-00082 TABLE 82 No. R1 R2 R3 R4 R5 salt I-715 [02229] H [02230] [02231] H I-716 [02232] H [02233] [02234] H I-717 [02235] H [02236] [02237] H I-718 [02238] H [02239] [02240] H I-719 [02241] H [02242] [02243] H I-720 [02244] H [02245] [02246] H I-721 [02247] H [02248] [02249] H I-722 [02250] H [02251] [02252] H

TABLE-US-00083 TABLE 83 No. R1 R2 R3 R4 R5 salt I-723 [02253] H [02254] [02255] H I-724 [02256] H [02257] [02258] H I-725 [02259] H [02260] [02261] H I-726 [02262] H [02263] [02264] H I-727 [02265] H [02266] [02267] H I-728 [02268] H [02269] [02270] H I-729 [02271] H [02272] [02273] H I-730 [02274] H [02275] [02276] H

TABLE-US-00084 TABLE 84 No. R1 R2 R3 R4 R5 salt I-731 [02277] H [02278] [02279] H I-732 [02280] H [02281] [02282] H I-733 [02283] H [02284] [02285] H I-734 [02286] H [02287] [02288] H I-735 [02289] H [02290] [02291] H I-736 [02292] H [02293] [02294] H I-737 [02295] H [02296] [02297] H

TABLE-US-00085 TABLE 85 No. R1 R2 R3 R4 R5 salt I-738 [02298] H [02299] [02300] H I-739 [02301] H [02302] [02303] H I-740 [02304] H [02305] [02306] H I-741 [02307] H [02308] [02309] H I-742 [02310] H [02311] [02312] H I-743 [02313] H [02314] [02315] H I-744 [02316] H [02317] [02318] H

TABLE-US-00086 TABLE 86 No. R1 R2 R3 R4 R5 salt I-745 [02319] H [02320] [02321] H I-746 [02322] H [02323] [02324] H I-747 [02325] H [02326] [02327] H I-748 [02328] H [02329] [02330] H I-749 [02331] H [02332] [02333] H I-750 [02334] H [02335] [02336] H I-751 [02337] H [02338] [02339] H I-752 [02340] H [02341] [02342] H

TABLE-US-00087 TABLE 87 No. R1 R2 R3 R4 R5 salt I-753 [02343] H [02344] [02345] H I-754 [02346] H [02347] [02348] H I-755 [02349] H [02350] [02351] H I-756 [02352] H [02353] [02354] H I-757 [02355] H [02356] [02357] H I-758 [02358] H [02359] [02360] H I-759 [02361] H [02362] [02363] H I-760 [02364] H [02365] [02366] H

TABLE-US-00088 TABLE 88 No. R1 R2 R3 R4 R5 salt I-761 [02367] H [02368] [02369] H I-762 [02370] H [02371] [02372] H I-763 [02373] H [02374] [02375] H I-764 [02376] H [02377] [02378] H I-765 [02379] H [02380] [02381] H I-766 [02382] H [02383] [02384] H I-767 [02385] H [02386] [02387] H I-768 [02388] H [02389] [02390] H

TABLE-US-00089 TABLE 89 No. R1 R2 R3 R4 R5 salt I-769 [02391] H [02392] [02393] H I-770 [02394] H [02395] [02396] H I-771 [02397] H [02398] [02399] H I-772 [02400] H [02401] [02402] H I-773 [02403] H [02404] [02405] H I-774 [02406] H [02407] [02408] H I-775 [02409] H [02410] [02411] H I-776 [02412] H [02413] [02414] H

TABLE-US-00090 TABLE 90 No R1 R2 R3 R4 R5 salt I-777 [02415] H [02416] [02417] H I-778 [02418] H [02419] [02420] H I-779 [02421] H [02422] [02423] H

TABLE-US-00091 TABLE 91 No. R1 R2 R3 R4 R5 I-780 [02424] H H [02425] [02426] I-781 [02427] H H [02428] [02429] I-782 [02430] H H [02431] [02432] I-783 [02433] H H [02434] [02435]

TABLE-US-00092 TABLE 92 No. R1 R2 R3 R4 R5 I-784 [02436] H [02437] [02438] [02439] I-785 [02440] H H [02441] [02442] I-786 [02443] H H [02444] [02445] I-787 [02446] H H [02447] [02448] I-788 [02449] H H [02450] [02451] I-789 [02452] H [02453] [02454] [02455] I-790 [02456] H [02457] [02458] [02459]

TABLE-US-00093 TABLE 93 No. R1 R2 R3 R4 R5 I-791 [02460] H [02461] [02462] H I-792 [02463] H [02464] [02465] H I-793 [02466] H [02467] [02468] H I-794 [02469] H [02470] [02471] H I-795 [02472] H [02473] [02474] H I-796 [02475] H H [02476] H I-797 [02477] H H [02478] H I-798 [02479] H H [02480] H

TABLE-US-00094 TABLE 94 No. R1 R2 R3 R4 R5 I-799 [02481] H H [02482] H I-800 [02483] H H [02484] H I-801 [02485] H H [02486] H I-802 [02487] H H [02488] H I-803 [02489] H H [02490] H I-804 [02491] H H [02492] H I-805 [02493] H H [02494] H

TABLE-US-00095 TABLE 95 [02495] No. R1 R2 R3 R4 I-806 [02496] H [02497] [02498] I-807 [02499] H [02500] [02501] I-808 [02502] [02503] [02504] [02505] I-809 [02506] [02507] [02508] [02509] I-810 [02510] H [02511] [02512] I-811 [02513] H [02514] [02515] I-812 [02516] H [02517] [02518] I-813 [02519] H [02520] [02521] I-814 [02522] H [02523] [02524]

TABLE-US-00096 TABLE 96 No. R1 R2 R3 R4 I-815 [02525] H [02526] [02527] I-816 [02528] H H [02529] I-817 [02530] H [02531] [02532] I-818 [02533] H [02534] [02535] I-819 [02536] H [02537] [02538] I-820 [02539] H [02540] [02541] I-821 [02542] H [02543] [02544] I-822 [02545] H [02546] [02547] I-823 [02548] H [02549] [02550]

TABLE-US-00097 TABLE 97 No. R1 R2 R3 R4 I-824 [02551] H [02552] [02553] I-825 [02554] H [02555] [02556] I-826 [02557] H [02558] [02559] I-827 [02560] H [02561] [02562] I-828 [02563] H [02564] [02565] I-829 [02566] H [02567] [02568] I-830 [02569] H [02570] [02571] I-831 [02572] H [02573] [02574] I-832 [02575] H [02576] [02577]

TABLE-US-00098 TABLE 98 No. R1 R2 R3 R4 I-833 [02578] H [02579] [02580] I-834 [02581] H [02582] [02583] I-835 [02584] H [02585] [02586] I-836 [02587] H [02588] [02589] I-837 [02590] H [02591] [02592] I-838 [02593] H [02594] [02595] I-839 [02596] H [02597] [02598] I-840 [02599] H [02600] [02601]

TABLE-US-00099 TABLE 99 No. R1 R2 R3 R4 I-841 [02602] H [02603] [02604] I-842 [02605] H [02606] [02607] I-843 [02608] H [02609] [02610] I-844 [02611] H [02612] [02613] I-845 [02614] H [02615] [02616] I-846 [02617] H [02618] [02619] I-847 [02620] H [02621] [02622] I-848 [02623] H [02624] [02625] I-849 [02626] H [02627] [02628]

TABLE-US-00100 TABLE 100 No. R1 R2 R3 R4 I-850 [02629] H [02630] [02631] I-851 [02632] H [02633] [02634] I-852 [02635] H [02636] [02637] I-853 [02638] [02639] [02640] [02641] I-854 [02642] H [02643] [02644] I-855 [02645] H [02646] [02647] I-856 [02648] H [02649] [02650] I-857 [02651] H [02652] [02653]

TABLE-US-00101 TABLE 101 No. R1 R2 R3 R4 I-858 [02654] H [02655] [02656] I-859 [02657] H [02658] [02659] I-860 [02660] H [02661] [02662] I-861 [02663] H [02664] [02665] I-862 [02666] H [02667] [02668] I-863 [02669] H [02670] [02671] I-864 [02672] H [02673] [02674] I-865 [02675] H [02676] [02677]

TABLE-US-00102 TABLE 102 No. R1 R2 R3 R4 I-866 [02678] H [02679] [02680] I-867 [02681] H [02682] [02683] I-868 [02684] H [02685] [02686] I-869 [02687] H [02688] [02689] I-870 [02690] H [02691] [02692] I-871 [02693] H [02694] [02695] I-872 [02696] H [02697] [02698] I-873 [02699] H [02700] [02701]

TABLE-US-00103 TABLE 103 No. R1 R2 R3 R4 I-874 [02702] H [02703] [02704] I-875 [02705] H [02706] [02707] I-876 [02708] H [02709] [02710] I-877 [02711] H [02712] [02713] I-878 [02714] H [02715] [02716] I-879 [02717] H [02718] [02719] I-880 [02720] H [02721] [02722] I-881 [02723] H [02724] [02725]

TABLE-US-00104 TABLE 104 No. R1 R2 R3 R4 I-882 [02726] H [02727] [02728] I-883 [02729] H [02730] [02731] I-884 [02732] H [02733] [02734] I-885 [02735] H [02736] [02737] I-886 [02738] H [02739] [02740] I-887 [02741] H [02742] [02743] I-888 [02744] H [02745] [02746]

TABLE-US-00105 TABLE 105 No. R1 R2 R3 [02747] I-889 [02748] [02749] [02750] I-890 [02751] [02752] [02753] I-891 [02754] [02755] [02756] I-892 [02757] [02758] [02759] I-893 [02760] [02761] [02762] [02763] I-894 [02764] [02765] [02766] I-895 [02767] [02768] [02769] I-896 [02770] [02771] [02772]

TABLE-US-00106 TABLE 106 [02773] No. R1 R2 R3 I-897 [02774] [02775] [02776] I-898 [02777] [02778] [02779] I-899 [02780] [02781] [02782]

TABLE-US-00107 TABLE 107 [02783] [02784] No. R1 I-900 [02785] I-901 [02786] I-902 [02787] I-903 [02788] I-904 [02789]

TABLE-US-00108 TABLE 108 No. Structure I-905 [02790] I-906 [02791] I-907 [02792] I-908 [02793] I-909 [02794] I-910 [02795]

TABLE-US-00109 TABLE 109 No. method RT MS I-37 A 3.14 909 M + 18 I-38 A 2.65 900 M + 1 I-39 A 3.13 923 M + 18 I-40 B 2.73 883 M − 1 I-41 A 2.71 785 M + 1 I-42 A 3.59 986 M + 1 I-43 A 2.73 799 M + 1 I-44 A 2.86 968 M + 1 I-45 A 2.86 890 M + 1 I-46 A 2.75 828 M + 1 I-47 A 3.01 904 M + 1 I-48 A 3.05 904 M + 1 I-49 B 2.71 873 M − 1 I-50 B 2.48 858 M − 1 I-51 B 2.57 931 M − 1 I-52 B 2.63 875 M − 1 I-53 B 2.63 901 M + 1 I-54 A 2.68 897 M − 1 I-55 A 3.14 1014 M + 18 I-56 A 2.76 929 M + 23 I-57 B 2.55 928 M − 1 I-58 B 2.77 994 M + 1 I-59 B 2.34 850 M − 1 I-60 B 2.32 865 M − 1 I-61 B 2.41 865 M − 1 I-62 B 2.28 865 M + 1 I-63 B 2.46 837 M − 1 I-64 A 2.34 831 M + 1 I-65 A 2.51 831 M + 1 I-66 A 2.16 830 M + 1 I-67 A 2.06 855 M + 23 I-68 A 2.69 848 M + 23 I-69 A 2.82 884 M − 1 I-70 B 2.70 919 M − 1 I-71 B 2.86 969 M − 1 I-72 B 2.90 907 M − 1 I-73 A 3.16 983 M + 1 I-74 A 3.37 990 M + 1 I-75 A 2.83 1013 M + 1 I-76 A 3.00 1004 M + 1 I-77 A 3.00 889 M + 18 I-78 A 2.95 909 M + 18 I-79 A 2.89 916 M + 1 I-80 A 2.96 933 M + 18 I-81 A 2.93 894 M + 18 I-82 A 3.18 976 M + 18 I-83 A 3.01 938 M + 18 I-84 A 3.20 959 M + 18 I-85 A 2.86 864 M + 1 I-86 A 2.97 926 M + 18 I-87 A 2.87 898 M + 1 I-88 A 2.64 893 M + 1 I-89 A 2.75 898 M + 1 I-90 A 2.63 892 M + 1 I-91 A 3.19 905 M + 1 I-92 A 3.17 927 M + 23 I-93 A 3.00 926 M + 1 I-94 A 3.60 1023 M + 23 I-95 A 3.07 960 M + 1 I-96 A 3.13 953 M + 18 I-97 A 2.41 810 M + 1 I-98 A 3.11 934 M + 18 I-99 A 2.85 908 M + 1 I-100 A 3.02 960 M + 1 I-101 A 3.14 946 M + 1 I-102 A 3.14 960 M + 1 I-103 A 3.19 960 M + 1 I-104 A 3.11 932 M + 1 I-105 A 3.15 841 M + 1 I-106 A 2.91 828 M + 1 I-107 A 2.79 840 M + 1 I-108 A 2.15 703 M + 1 I-109 A 2.12 704 M + 1 I-110 A 2.81 968 M + 1 I-111 A 3.07 974 M + 1 I-112 A 2.97 931 M − 1 I-113 A 3.29 919 M + 1 I-114 A 2.68 866 M + 18 I-115 A 2.96 894 M + 18 I-116 B 2.93 908 M + 18 I-117 B 2.37 894 M + 18 I-118 B 2.51 938 M + 18 I-119 A 3.08 945 M − 1 I-120 A 2.72 922 M + 18 I-121 A 2.51 938 M + 18 I-122 A 3.12 915 M + 18 I-123 A 2.42 925 M + 18 I-124 A 2.71 916 M + 18 I-125 A 1.75 847 M + 1 I-126 A 2.49 827 M + 18 I-127 A 2.68 877 M + 18 I-128 A 2.41 891 M + 1 I-129 A 2.62 905 M + 1 I-130 B 2.57 845 M − 1 I-131 A 2.80 933 M − 1 I-132 A 2.96 905 M + 1 I-133 A 3.02 877 M + 1 I-134 A 3.17 889 M − 1 I-135 A 3.19 944 M − 1 I-136 A 3.01 905 M − 1 I-137 A 3.15 922 M + 18 I-138 A 3.06 918 M + 1 I-139 B 2.62 901 M + 1 I-140 A 2.66 941 M + 1 I-141 A 2.63 941 M + 1 I-142 A 2.58 915 M + 1 I-143 A 2.55 881 M + 1 I-144 A 2.70 924 M + 1 I-145 A 2.97 929 M + 1 I-146 B 2.73 927 M + 1 I-147 A 2.70 926 M + 1 I-148 A 1.64 932 M + 1 I-149 B 2.31 837 M − 1 I-150 B 2.24 864 M − 1 I-151 B 2.33 866 M + 1 I-152 B 2.37 837 M − 1 I-153 B 2.41 837 M − 1 I-154 B 2.31 864 M − 1 I-155 B 2.33 847 M + 23 I-156 A 2.20 868 M + 1 I-157 A 2.12 868 M + 1 I-158 A 2.27 805 M + 1 I-159 A 2.30 830 M + 1 I-160 A 2.34 858 M + 1 I-161 A 2.45 858 M + 1 I-162 A 2.10 804 M + 1 I-163 A 2.30 832 M + 1 I-164 A 2.79 874 M + 1 I-165 A 2.77 876 M + 1 I-166 A 2.89 890 M + 1 I-167 B 2.36 845 M − 1 I-168 A 2.64 836 M − 1 I-169 A 2.52 788 M − 1 I-170 A 2.44 788 M − 1 I-171 A 2.67 784 M + 1 I-172 A 2.64 868 M + 1 I-173 B 2.57 793 M − 1 I-174 B 2.67 933 M − 1 I-175 B 2.62 947 M − 1 I-176 B 2.72 915 M − 1 I-177 B 2.77 918 M + 1 I-178 A 3.28 968 M + 1 I-179 A 2.67 859 M + 1 I-180 A 2.74 1011 M + 1 I-181 A 3.19 958 M + 18 I-182 A 2.89 910 M + 1 I-183 A 3.01 861 M + 1 I-184 A 2.20 884 M + 1 I-185 A 2.92 957 M + 1 I-186 A 2.96 919 M − 1 I-187 A 2.58 893 M + 1 I-188 A 2.64 921 M + 18 I-189 A 2.81 930 M + 1 I-190 A 3.06 928 M − 1 I-191 A 2.99 916 M + 1 I-193 A 2.91 861 M + 1 I-194 A 2.22 898 M + 1 I-195 A 2.88 969 M + 1 I-196 A 3.17 958 M + 18 I-197 A 2.26 886 M + 1 I-198 A 2.20 898 M + 1 I-199 A 2.73 921 M + 1 I-200 A 3.02 971 M + 1 I-201 A 3.08 985 M + 1 I-202 A 3.19 865 M + 1 I-203 A 3.01 883 M + 1 I-204 A 3.17 960 M + 1 I-205 A 2.13 941 M + 1 I-206 A 3.07 934 M + 1 I-207 A 2.37 960 M + 1 I-208 A 2.64 828 M + 1 I-209 A 3.05 945 M + 1 I-210 A 2.94 1034 M + 1 I-211 A 3.32 981 M + 1 I-212 A 2.95 966 M + 1 I-213 A 2.83 966 M + 1 I-214 A 2.81 934 M + 1

TABLE-US-00110 TABLE 110 No. method RT MS I-215 A 2.99 916 M + 1 I-216 A 2.86 915 M + 1 I-217 A 2.66 860 M + 1 I-218 A 2.54 860 M + 1 I-219 A 1.99 932 M + 1 I-220 A 2.75 857 M + 1 I-221 A 2.76 915 M + 1 I-222 A 3.11 902 M + 1 I-223 A 2.63 923 M + 1 I-224 A 2.59 897 M + 1 I-225 A 2.94 923 M + 1 I-226 A 3.08 916 M + 1 I-227 A 2.46 868 M + 1 I-229 A 2.81 949 M + 1 I-230 A 3.30 889 M + 18 I-231 A 2.97 894 M + 1 I-232 A 2.98 970 M + 1 I-233 A 3.06 996 M + 1 I-234 A 3.08 946 M + 1 I-235 A 3.06 946 M + 1 I-236 A 3.27 908 M + 1 I-237 A 3.02 945 M + 1 I-238 A 2.98 945 M + 1 I-239 A 2.77 959 M + 1 I-240 A 2.86 932 M + 1 I-241 A 2.90 916 M + 1 I-242 A 2.90 916 M + 1 I-243 A 3.15 895 M + 1 I-244 A 2.94 1040 M + 18 I-245 A 2.46 899 M + 1 I-248 A 2.87 938 M + 1 I-249 A 2.96 904 M + 1 I-250 A 2.38 918 M + 1 I-251 A 2.21 887 M + 1 I-252 A 3.11 940 M + 1 I-253 A 2.92 890 M + 1 I-254 A 2.90 890 M + 1 I-255 A 3.11 958 M + 1 I-256 A 2.91 915 M + 1 I-257 A 2.17 959 M + 1 I-258 A 3.23 945 M + 1 I-259 A 3.26 1013 M + 1 I-260 A 2.81 918 M + 1 I-261 A 2.98 918 M + 1 I-262 A 2.87 904 M + 1 I-263 A 2.77 918 M + 1 I-264 A 3.03 904 M + 1 I-265 A 3.04 904 M + 1 I-266 A 2.43 919 M + 1 I-267 A 2.42 919 M + 1 I-269 A 2.81 933 M + 1 I-270 A 2.76 919 M + 1 I-271 A 2.98 908 M + 1 I-272 A 3.00 904 M + 1 I-273 A 2.38 891 M + 1 I-274 A 2.93 920 M + 1 I-275 A 2.98 908 M + 1 I-276 A 2.82 880 M + 1 I-277 A 2.91 908 M + 1 I-278 A 2.84 921 M + 1 I-279 A 2.99 926 M + 1 I-280 A 2.95 908 M + 1 I-281 A 2.86 920 M + 1 I-282 A 2.99 908 M + 1 I-283 A 2.79 891 M + 1 I-284 A 2.84 880 M + 1 I-285 A 3.16 966 M + 1 I-286 A 2.20 930 M + 1 I-287 A 2.86 908 M + 1 I-288 A 2.80 880 M + 1 I-289 A 2.77 897 M + 1 I-290 A 2.65 891 M + 1 I-291 A 2.95 908 M + 1 I-292 A 3.05 904 M + 1 I-293 A 2.73 920 M + 1 I-294 A 3.11 974 M + 1 I-295 A 2.80 897 M + 1 I-296 A 2.97 908 M + 1 I-297 A 2.74 897 M + 1 I-298 A 2.85 900 M + 18 I-299 A 3.26 980 M + 1 I-300 A 3.11 902 M + 1 I-301 A 2.89 952 M + 1 I-302 A 2.91 952 M + 1 I-303 A 2.87 899 M + 1 I-304 A 2.90 899 M + 1 I-305 A 2.45 891 M + 1 I-306 A 1.82 728 M + 1 I-307 A 2.02 893 M + 1 I-308 A 2.34 836 M + 1 I-309 A 2.17 789 M + 1 I-310 A 2.45 761 M + 1 I-311 A 2.30 757 M + 1 I-312 A 2.23 624 M + 1 I-313 A 1.94 668 M + 1 I-314 A 2.27 782 M + 1 I-315 A 1.87 756 M + 1 I-316 A 2.09 726 M + 1 I-317 A 2.09 730 M + 1 I-318 A 2.12 779 M + 1 I-319 A 2.12 799 M + 1 I-320 A 1.69 767 M + 1 I-321 A 1.93 756 M + 1 I-322 A 3.16 940 M + 1 I-323 A 2.41 930 M + 1 I-324 A 3.15 1011 M + 1 I-325 A 3.20 999 M + 1 I-326 A 3.16 985 M + 1 I-327 A 3.19 999 M + 1 I-328 A 3.19 999 M + 1 I-329 A 3.04 971 M + 1 I-330 A 3.22 1013 M + 1 I-331 A 3.09 985 M + 1 I-332 A 3.08 985 M + 1 I-333 A 3.16 985 M + 1 I-334 A 2.69 899 M + 18 I-335 A 2.55 842 M + 1 I-336 A 2.54 856 M + 1 I-337 A 2.69 899 M + 18 I-338 A 3.42 961 M + 1 I-339 A 2.69 933 M + 1 I-340 A 3.21 958 M + 1 I-341 A 2.48 911 M + 1 I-342 A 2.50 911 M + 1 I-343 A 3.29 1014 M + 1 I-344 A 2.58 900 M + 1 I-345 A 2.23 911 M + 1 I-346 A 2.28 911 M + 1 I-347 A 3.07 895 M + 1 I-348 A 2.52 875 M + 1 I-349 A 2.65 889 M + 1 I-350 A 3.08 946 M + 1 I-351 A 3.10 946 M + 1 I-352 A 3.01 919 M + 1 I-353 A 2.82 971 M + 18 I-354 A 3.15 1000 M + 1 I-355 A 2.42 948 M + 1 I-356 A 2.81 891 M + 1 I-357 A 3.01 932 M + 1 I-358 A 3.09 911 M + 1 I-359 A 3.04 911 M + 1 I-360 A 3.11 932 M + 1 I-361 A 3.12 932 M + 1 I-362 A 2.66 897 M + 1 I-363 A 2.85 911 M + 1 I-364 A 3.17 960 M + 1 I-365 A 2.94 970 M + 1 I-366 A 2.58 840 M + 1 I-367 A 2.22 876 M + 1 I-368 A 1.69 846 M + 1 I-369 A 3.29 972 M + 1 I-370 A 3.05 932 M + 1 I-371 A 2.13 932 M + 1 I-372 A 2.91 897 M + 1 I-373 A 2.92 897 M + 1 I-374 A 2.96 911 M + 1 I-375 A 2.95 911 M + 1 I-376 A 3.06 919 M + 1 I-377 A 2.74 947 M + 1 I-378 A 2.73 943 M + 1 I-379 A 2.87 957 M + 1 I-380 A 3.03 907 M + 1 I-381 A 2.89 880 M + 1 I-382 A 3.10 961 M + 1 I-383 A 2.89 904 M + 1 I-384 A 2.72 941 M + 1 I-385 A 2.79 884 M + 1 I-386 A 3.11 916 M + 1 I-387 A 3.06 932 M + 1 I-388 A 2.56 930 M + 1 I-389 A 2.49 930 M + 1 I-390 A 2.71 946 M + 1 I-391 A 3.12 945 M + 1 I-392 A 2.57 884 M + 1 I-393 A 3.28 958 M + 1 I-394 A 2.72 885 M + 1 I-395 A 2.72 885 M + 1

TABLE-US-00111 TABLE 111 No. method RT MS I-397 A 2.74 934 M + 1 I-398 A 2.83 899 M + 1 I-399 A 2.78 898 M + 1 I-400 A 2.87 913 M + 1 I-401 A 2.93 913 M + 1 I-402 A 2.82 926 M + 1 I-403 A 2.36 909 M + 1 I-404 A 2.76 931 M + 1 I-405 A 2.76 931 M + 1 I-406 A 3.18 960 M + 1 I-407 A 2.86 947 M + 1 I-408 A 2.82 948 M + 1 I-409 A 2.81 882 M + 1 I-410 A 2.87 883 M + 1 I-411 A 2.47 855 M + 1 I-412 A 2.80 869 M + 1 I-413 A 2.48 935 M + 1 I-414 A 2.44 968 M + 1 I-415 A 2.66 968 M + 1 I-416 A 2.40 947 M + 1 I-417 A 2.50 961 M + 1 I-418 A 2.96 918 M + 1 I-419 A 2.56 879 M + 1 I-420 A 3.17 970 M + 1 I-421 A 3.37 994 M + 1 I-422 A 3.37 946 M + 1 I-423 A 2.55 981 M + 1 I-424 A 3.15 970 M + 1 I-425 A 2.45 981 M + 1 I-426 A 3.43 1008 M + 1 I-427 A 3.24 1000 M + 1 I-428 A 3.58 974 M + 1 I-429 A 2.39 1003 M + 1 I-430 A 3.22 986 M + 1 I-431 A 3.00 987 M + 1 I-432 A 3.50 1022 M + 1 I-433 A 2.83 878 M + 1 I-434 A 3.25 1039 M + 1 I-435 A 3.15 958 M + 1 I-436 A 2.92 933 M + 1 I-437 A 2.92 933 M + 1 I-438 A 2.83 923 M + 1 I-439 A 2.84 961 M + 1 I-440 A 2.98 989 M + 1 I-441 A 2.89 939 M + 1 I-442 A 2.80 974 M + 1 I-443 A 2.72 934 M + 1 I-444 A 2.94 959 M + 1 I-445 A 2.69 936 M + 1 I-446 A 2.74 942 M + 1 I-447 A 2.81 956 M + 1 I-448 A 2.96 894 M + 1 I-449 A 2.78 905 M + 1 I-450 A 3.02 904 M + 1 I-451 A 3.27 972 M + 1 I-452 A 3.07 929 M + 1 I-453 A 2.79 941 M + 1 I-454 A 3.21 988 M + 1 I-455 E 2.21 933 M + 1 I-456 A 3.50 972 M + 1 I-457 A 3.36 946 M + 1 I-458 A 3.86 1017 M + 1 I-459 A 3.48 974 M + 1 I-460 A 3.20 944 M + 1 I-461 A 3.43 960 M + 1 I-462 A 3.26 932 M + 1 I-463 A 3.39 958 M + 1 I-464 A 2.77 934 M + 1 I-465 A 2.85 904 M + 1 I-466 A 2.80 914 M + 1 I-467 A 2.75 917 M + 1 I-468 A 2.90 876 M + 1 I-469 A 3.06 890 M + 1 I-470 A 2.80 897 M + 1 I-471 A 3.45 1002 M + 1 I-472 B 2.63 888 M + 1 I-473 B 2.78 904 M + 1 I-474 B 2.72 902 M + 1 I-475 B 2.76 904 M + 1 I-476 A 2.63 875 M + 1 I-477 B 2.47 982 M + 1 I-478 B 2.91 876 M + 1 I-479 B 3.06 890 M + 1 I-480 A 3.12 959 M + 1 I-481 A 2.74 1041 M + 1 I-482 A 2.74 933 M + 1 I-483 A 2.91 916 M + 1 I-484 A 2.97 930 M + 1 I-485 A 3.14 958 M + 1 I-486 A 2.84 981 M + 1 I-487 A 3.09 947 M + 1 I-488 A 3.22 918 M + 1 I-489 A 2.63 905 M + 1 I-490 A 3.06 934 M + 1 I-491 A 3.20 922 M + 1 I-492 A 3.01 894 M + 1 I-493 A 3.15 922 M + 1 I-494 A 3.00 905 M + 1 I-495 A 2.29 859 M + 1 I-496 A 2.39 860 M + 1 I-497 A 2.43 802 M + 1 I-498 A 2.41 808 M + 1 I-499 A 2.67 886 M + 1 I-500 A 2.28 883 M + 1 I-501 A 2.30 859 M + 1 I-502 A 2.46 841 M + 1 I-503 A 2.51 841 M + 1 I-504 A 2.42 859 M + 1 I-505 A 2.36 858 M + 1 I-506 A 2.43 871 M + 1 I-507 A 2.81 908 M + 1 I-508 A 3.18 986 M + 1 I-509 A 3.23 996 M + 1 I-510 A 3.12 918 M + 1 I-511 A 2.72 906 M + 1 I-512 A 2.60 981 M + 1 I-513 A 2.81 943 M + 1 I-514 A 3.35 1014 M + 1 I-515 A 2.62 976 M + 1 I-516 A 2.38 812 M + 1 I-517 A 2.49 826 M + 1 I-518 A 3.01 934 M + 1 I-519 A 3.10 948 M + 1 I-520 A 3.25 1039 M + 1 I-521 A 2.54 642 M + 1 I-522 A 3.25 930 M + 1 I-523 A 3.24 930 M + 1 I-524 A 3.10 908 M + 1 I-525 A 3.30 922 M + 1 I-526 A 3.15 958 M + 1 I-527 A 2.87 882 M + 1 I-528 A 2.85 880 M + 1 I-529 A 3.10 966 M + 1 I-530 C 3.06 966 M + 1 I-531 A 3.15 940 M + 1 I-532 A 2.98 904 M + 1 I-533 A 3.13 918 M + 1 I-534 A 3.03 904 M + 1 I-535 A 3.35 946 M + 1 I-536 A 2.46 931 M + 1 I-537 A 3.15 972 M + 1 I-538 E 2.31 947 M + 1 I-539 E 2.53 973 M + 1 I-540 A 3.27 972 M + 1 I-541 A 2.65 993 M + 1 I-542 A 2.78 932 M + 18 I-543 A 2.96 908 M + 1 I-544 A 3.04 924 M + 1 I-545 A 2.99 904 M + 1 I-546 A 2.91 935 M + 1 I-547 A 3.07 924 M + 1 I-548 A 2.51 906 M + 1 I-549 A 2.99 904 M + 1 I-550 A 2.99 904 M + 1 I-551 A 2.72 891 M + 1 I-552 A 2.87 934 M + 1 I-553 A 2.95 950 M + 1 I-554 A 2.86 920 M + 1 I-555 A 2.63 906 M + 1 I-556 A 3.14 918 M + 1 I-557 A 2.51 891 M + 1 I-558 A 3.20 996 M + 1 I-559 A 2.55 905 M + 1 I-560 A 2.77 950 M + 1 I-561 A 2.68 906 M + 1 I-562 A 2.65 906 M + 1 I-563 A 3.11 924 M + 1 I-564 A 3.15 982 M + 1 I-565 A 2.88 915 M + 1 I-566 A 2.92 920 M + 1 I-567 A 2.96 935 M + 1 I-568 A 2.83 941 M + 1 I-569 A 2.91 896 M + 1 I-570 A 2.78 894 M + 1 I-571 A 3.20 996 M + 1 I-572 A 3.31 1010 M + 1 I-573 A 2.15 726 M + 1

TABLE-US-00112 TABLE 112 No. method RT MS I-574 A 2.68 933 M + 1 I-575 A 3.08 976 M + 1 I-576 A 3.23 930 M + 1 I-577 A 3.23 930 M + 1 I-578 A 2.55 960 M + 1 I-579 A 3.24 1014 M + 1 I-580 B 2.59 963 M + 1 I-581 A 3.12 940 M + 1 I-582 A 3.33 954 M + 1 I-583 A 2.65 974 M + 1 I-584 A 2.81 988 M + 1 I-585 B 2.76 981 M + 1 I-586 B 2.62 933 M + 1 I-587 A 2.74 947 M + 1 I-588 A 3.13 989 M + 1 I-589 A 2.82 923 M + 1 I-590 A 2.72 961 M + 1 I-591 A 2.69 947 M + 1 I-592 A 2.72 960 M + 1 I-594 A 2.99 959 M + 1 I-595 A 3.05 989 M + 1 I-597 A 3.28 960 M + 1 I-598 A 2.99 904 M + 1 I-599 A 3.18 918 M + 1 I-600 A 3.00 973 M + 1 I-601 A 2.76 986 M + 1 I-602 A 1.62 945 M + 1 I-603 A 2.93 904 M + 1 I-604 A 2.70 925 M + 1 I-605 A 2.69 925 M + 1 I-606 A 3.14 989 M + 1 I-607 A 2.75 966 M + 1 I-608 A 2.89 980 M + 1 I-609 B 2.32 940 M + 1 I-610 B 2.58 948 M + 1 I-611 B 2.48 939 M + 1 I-612 B 2.71 983 M + 1 I-613 A 2.85 959 M + 1 I-614 A 2.94 939 M + 1 I-615 A 2.96 939 M + 1 I-616 A 3.13 953 M + 1 I-617 A 2.81 972 M + 1 I-618 A 3.30 960 M + 1 I-619 A 2.95 920 M + 1 I-620 A 2.80 929 M − 1 I-621 A 2.81 929 M − 1 I-622 A 2.92 954 M + 1 I-623 A 2.83 940 M + 1 I-624 A 2.88 940 M + 1 I-625 A 2.81 951 M + 1 I-626 A 3.17 935 M + 1 I-627 A 3.06 967 M + 1 I-628 A 3.38 949 M + 1 I-629 A 2.95 954 M + 1 I-630 A 2.89 940 M + 1 I-631 A 2.86 940 M + 1 I-632 A 2.97 954 M + 1 I-633 A 2.66 909 M + 1 I-634 A 2.32 871 M + 1 I-635 A 2.63 961 M + 1 I-636 A 2.91 1000 M + 1 I-637 A 3.05 958 M + 1 I-638 A 3.08 970 M + 1 I-639 A 3.15 984 M + 1 I-640 A 2.95 985 M + 1 I-641 A 2.99 997 M + 1 I-642 A 3.06 1011 M + 1 I-643 A 3.01 972 M + 1 I-644 A 3.04 984 M + 1 I-645 A 3.11 897 M + 1 I-646 A 2.90 911 M + 1 I-647 A 3.06 934 M + 1 I-648 A 2.82 947 M + 1 I-649 A 2.77 947 M + 1 I-650 A 3.08 940 M + 1 I-651 A 2.79 948 M + 1 I-652 A 2.70 941 M + 1 I-653 A 2.97 985 M + 1 I-654 A 3.18 982 M + 1 I-655 A 2.80 917 M + 1 I-656 A 2.99 967 M + 1 I-657 A 3.00 967 M + 1 I-658 A 3.15 981 M + 1 I-659 A 3.16 981 M + 1 I-660 A 2.34 841 M + 1 I-661 A 2.49 875 M + 1 I-662 A 3.11 908 M + 1 I-663 A 2.71 871 M + 1 I-664 A 2.65 983 M + 1 I-665 D 2.88 875 M + 1 I-666 A 2.76 958 M + 1 I-667 A 3.19 944 M + 1 I-668 A 3.19 944 M + 1 I-669 A 2.90 961 M + 1 I-670 A 2.81 882 M + 1 I-671 A 3.29 1025 M + 1 I-672 A 3.15 973 M + 1 I-673 A 3.30 1057 M + 1 I-674 A 3.33 1016 M + 1 I-675 A 3.15 940 M + 1 I-676 A 2.89 945 M + 1 I-677 A 2.54 973 M + 1 I-678 A 3.10 974 M + 1 I-679 A 2.82 975 M + 1 I-680 A 2.14 988 M + 1 I-681 A 2.99 987 M + 1 I-682 A 2.95 959 M + 1 I-683 A 2.79 977 M + 1 I-684 A 2.85 1033 M + 1 I-685 A 2.85 984 M + 1 I-686 A 3.02 998 M + 1 I-687 A 2.62 935 M + 1 I-688 A 2.79 983 M + 1 I-689 A 2.70 973 M + 1 I-690 A 2.96 1001 M + 1 I-691 A 2.92 1001 M + 1 I-692 A 3.42 1031 M + 1 I-693 A 2.94 946 M + 1 I-694 A 2.72 949 M + 1 I-695 A 3.10 983 M + 1 I-696 A 3.28 997 M + 1 I-697 A 3.00 917 M + 1 I-698 A 3.00 917 M + 1 I-699 A 3.24 989 M + 1 I-700 A 2.93 990 M + 1 I-701 E 2.35 1003 M + 1 I-702 A 2.96 962 M + 1 I-703 A 3.15 955 M + 1 I-704 A 3.03 962 M + 1 I-705 A 2.87 930 M + 1 I-706 A 3.03 944 M + 1 I-707 A 3.22 955 M + 1 I-708 A 3.08 960 M + 1 I-709 A 3.08 931 M + 1 I-710 A 3.10 931 M + 1 I-711 A 3.12 931 M + 1 I-712 A 2.96 968 M + 1 I-713 A 2.97 967 M + 1 I-714 A 2.81 1042 M + 1 I-715 A 2.98 1056 M + 1 I-716 A 2.81 947 M + 1 I-717 A 2.82 947 M + 1 I-718 A 2.92 947 M + 1 I-719 A 2.37 967 M + 1 I-720 A 3.10 1009 M + 1 I-721 A 3.34 1043 M + 1 I-722 A 3.29 1034 M + 1 I-723 A 3.10 930 M + 1 I-724 A 3.24 1056 M + 1 I-725 A 3.03 973 M + 1 I-726 A 3.00 931 M + 1 I-727 A 3.36 970 M + 1 I-728 A 2.84 988 M + 1 I-729 A 2.70 988 M + 1 I-730 A 3.10 1002 M + 1 I-731 A 2.86 1001 M + 1 I-732 A 2.77 963 M + 1 I-733 A 2.40 1016 M + 1 I-734 A 2.38 1016 M + 1 I-735 A 3.08 910 M + 1 I-736 A 2.65 961 M + 1 I-737 A 3.03 981 M + 1 I-738 A 2.73 983 M + 1 I-739 A 2.49 499 M/2 + 1 I-740 A 2.86 988 M + 1 I-741 A 2.65 988 M + 1 I-742 A 2.65 973 M + 1 I-743 A 2.82 1001 M + 1 I-744 A 2.82 987 M + 1 I-745 A 2.96 961 M + 1 I-746 A 2.95 961 M + 1 I-747 A 3.08 961 M + 1 I-748 A 2.85 951 M + 1 I-749 A 2.82 951 M + 1 I-750 A 3.05 1001 M + 1 I-751 A 3.19 931 M + 1 I-752 A 3.19 931 M + 1

TABLE-US-00113 TABLE 113 No. method RT MS I-753 A 2.80 953 M + 1 I-754 A 2.67 962 M + 1 I-755 A 2.82 975 M + 1 I-756 A 3.24 995 M + 1 I-757 A 2.89 997 M + 1 I-758 A 2.75 1010 M + 2 I-759 A 2.75 976 M + 1 I-760 A 3.32 1077 M + 1 I-761 A 3.49 1091 M + 1 I-762 A 2.93 977 M + 1 I-763 A 3.78 1116 M + 1 I-764 A 3.22 924 M + 1 I-765 A 3.22 924 M + 1 I-766 A 2.97 974 M + 1 I-767 A 2.79 976 M + 1 I-768 A 2.84 990 M + 1 I-769 A 3.18 938 M + 1 I-770 A 3.18 938 M + 1 I-771 A 2.15 759 M + 1 I-772 A 3.24 954 M + 1 I-773 A 3.71 996 M + 1 I-774 A 2.86 984 M + 1 I-775 A 3.19 982 M + 1 I-776 A 3.28 997 M + 1 I-777 A 3.59 980 M + 1 I-778 A 3.10 941 M + 1 I-779 A 2.73 948 M + 1 I-780 A 2.62 859 M + 1 I-781 A 2.67 857 M + 1 I-782 A 2.36 842 M + 1 I-783 A 2.75 781 M + 1 I-784 A 3.06 1058 M + 1 I-785 A 2.65 970 M + 1 I-786 A 2.88 935 M + 1 I-787 A 2.50 891 M + 1 I-788 A 2.61 890 M + 1 I-789 A 1.88 1013 M + 1 I-790 A 3.21 987 M + 1 I-791 A 2.83 961 M + 1 I-792 A 2.43 1084 M + 1 I-793 A 2.98 987 M + 1 I-794 A 3.22 1051 M + 1 I-795 A 3.35 1029 M + 1 I-796 A 2.92 947 M + 1 I-797 A 3.04 961 M + 1 I-798 A 2.85 917 M + 1 I-799 B 2.51 917 M + 1 I-800 A 2.88 917 M + 1 I-801 B 2.67 932 M + 1 I-802 A 3.01 860 M + 1 I-803 A 2.96 860 M + 1 I-804 A 2.99 860 M + 1 I-805 A 2.97 878 M + 1 I-806 A 2.35 847 M + 18 I-807 B 2.46 861 M + 1 I-808 A 3.10 1049 M + 18 I-809 A 2.81 954 M + 18 I-810 B 2.59 907 M − 1 I-811 B 2.49 793 M − 1 I-812 B 2.56 843 M + 23 I-813 A 2.51 824 M + 1 I-814 A 2.44 883 M + 1 I-815 B 2.68 917 M + 1 I-816 A 2.60 770 M + 1 I-817 B 2.52 847 M + 23 I-818 A 2.24 839 M + 1 I-819 A 2.70 863 M + 1 I-820 A 2.92 905 M + 1 I-821 A 2.74 996 M + 1 I-822 A 2.93 1010 M + 1 I-823 A 2.52 906 M + 1 I-824 B 2.62 884 M − 1 I-825 B 2.92 909 M − 1 I-826 B 2.75 877 M + 1 I-827 A 2.58 879 M + 1 I-828 A 2.68 884 M + 1 I-829 B 2.77 889 M + 1 I-830 B 2.54 804 M − 1 I-831 A 2.82 826 M + 1 I-832 B 2.61 835 M + 1 I-833 A 2.36 880 M + 18 I-834 B 2.51 831 M − 1 I-835 A 3.06 891 M + 1 I-836 A 3.01 881 M + 1 I-837 B 2.44 859 M − 1 I-838 A 2.56 918 M + 1 I-839 B 2.23 823 M + 1 I-840 A 2.44 853 M + 1 I-841 B 2.67 906 M − 1 I-842 A 2.24 839 M + 1 I-843 A 2.57 888 M + 1 I-844 A 2.78 908 M + 1 I-845 A 2.93 907 M + 1 I-846 A 2.76 908 M + 1 I-847 A 2.84 1030 M + 1 I-848 B 2.62 870 M − 1 I-849 B 2.67 903 M − 1 I-850 B 2.79 883 M − 1 I-851 A 2.99 926 M + 1 I-852 A 2.91 876 M + 1 I-853 A 2.91 906 M + 1 I-854 A 2.66 933 M + 1 I-855 A 2.70 946 M + 1 I-856 A 2.81 919 M + 1 I-857 A 2.92 945 M + 1 I-858 A 3.05 959 M + 1 I-859 A 2.80 972 M + 1 I-860 A 1.55 931 M + 1 I-861 A 2.80 945 M + 1 I-862 A 2.73 958 M + 1 I-863 A 2.87 897 M + 1 I-864 A 3.00 920 M + 1 I-865 A 2.89 883 M + 1 I-866 A 2.80 883 M + 1 I-867 A 2.83 883 M + 1 I-868 A 3.00 944 M + 1 I-869 A 3.03 956 M + 1 I-870 A 3.10 970 M + 1 I-871 A 2.90 971 M + 1 I-872 A 2.94 983 M + 1 I-873 A 3.01 997 M + 1 I-874 A 2.96 958 M + 1 I-875 A 2.99 970 M + 1 I-876 A 3.06 984 M + 1 I-877 A 2.75 868 M + 1 I-878 A 2.77 868 M + 1 I-879 A 2.81 947 M + 1 I-880 A 2.81 916 M + 1 I-881 A 3.04 930 M + 1 I-882 A 2.60 920 M + 1 I-883 A 3.01 896 M + 1 I-884 A 2.69 935 M + 1 I-885 A 2.79 970 M + 1 I-886 A 3.15 910 M + 1 I-887 A 3.13 910 M + 1 I-888 A 2.18 745 M + 1 I-889 A 2.78 856 M + 1 I-890 A 2.87 906 M + 1 I-891 A 2.76 949 M + 1 I-892 A 2.86 975 M + 1 I-893 A 2.79 961 M + 1 I-894 A 3.28 960 M + 1 I-895 A 3.17 964 M + 1 I-896 A 3.26 960 M + 1 I-897 A 2.48 841 M + 1 I-898 A 2.63 858 M + 1 I-899 A 2.62 855 M + 1 I-900 A 2.99 912 M + 1 I-901 A 2.72 836 M + 1 I-902 A 3.19 966 M + 1 I-903 A 2.79 910 M + 1 I-904 A 2.97 987 M + 1 I-905 B 2.68 890 M + 1 I-906 B 2.70 890 M + 1 I-907 A 2.97 907 M + 1 I-908 A 2.95 891 M + 1 I-909 A 2.99 932 M + 1 I-910 A 3.88 1130 M + 1

Test Example 1: HIV-Protease Inhibitory Activity Assay

[1168] The HIV-1 PR assay was performed by using a FRET (Fluorescence Resonance Energy Transfer) peptide substrate (AnaSpec, Inc., Fremont, Calif.). Initially in the intact FRET peptide, the fluorescence of HiLyte Fluor 488 is quenched by QXL 520. Upon substrate cleavage by PR, the fluorescence is recovered and can be monitored. Test compounds diluted in DMSO was plated to the wells of 384-well plate. Then, mixed with assay buffer (0.1 mol/L NaAc containing 0.5 mol/L NaCl, 1 mmol/L EDTA, 1 mmol/L DTT, and 0.05% Tween 20, pH 4.8) in the presence or absence of HIV-1 PR (0.83 ng), and let it stand for 5 minutes at room temperature. Background fluorescence intensity was measured and let it stand for another 15 minutes at room temperature. The enzyme reaction was started by adding substrate diluted in assay buffer at final concentration of 2 μmol/L, and let it stand for 60 minutes at room temperature. After 60 minutes, the fluorescence intensity was measured. Fluorescence intensity was measured with excitation and emission wavelengths of 485 nm and 535 nm, respectively.

[1169] IC.sub.50 values were determined using non-linear regression four-parameter logistic equation,

y=A+((B−A)/(1+((C/x)̂D)))

[1170] where A=minimum inhibition, B=maximum inhibition, C=log IC.sub.50, D=slope factor, x=concentration of compound and y=% inhibition.

Test Example 2: Protein Binding Test

[1171] Unbound ratios of the present invention compounds in the sera of some animal species, fu (%), were evaluated.

[1172] Assay condition: Evaluation method; Equilibrium dialysis method, Reaction time; 24 hours, Reaction temperature; 37° C., Assay concentration; 2 μg/mL

[1173] A solution of the compound was added to each serum and mixed to prepare the serum samples with above concentration. The serum sample was put into one side of an equilibrium dialysis apparatus with dialysis membrane and phosphate buffered saline (PBS) was also put to another side of the apparatus. The apparatus was incubated at 37° C. for 24 hours. After incubation, the serum and PBS samples were collected and the compound concentrations in both samples were measured by LC/MS/MS. Fu was calculated by dividing the concentration in PBS by the concentration in the serum.

Test Example 3: Evaluation of Total Body Clearance (CLtot)

[1174] (Study design and method)

Animal: Rat, Sprague-Dawley (SD)

[1175] Animal care condition: Rats were allowed free access to the sterilized tap water and the solid laboratory food.
Dose: Intravenous administration with designated doses was selected. (Doses were changed depending on compounds.) [1176] 0.5-10 mg/kg (n=2-3)
Preparation of dosing formulation: The dosing solution was prepared by dissolving in an adequate solvent.
Administration method: The dosing solution was injected into the tail vein by a syringe with a needle
Blood sampling: The blood was collected at the scheduled time and obtained the plasma. Plasma concentrations of the compound were measured by LC/MS/MS.
Statistical analysis: Area under the plasma concentration-time curve (AUC) of the compound was calculated by pharmacokinetic analysis software, WinNonlin™ and CLtot was calculated by dividing the dose by AUC.

[1177] The results of Test example 1, 2 and 3 were shown below.

TABLE-US-00114 TABLE 114 No. IC50 (nM) I-1 1.29 I-2 1.05 I-3 1.02 I-4 1.69 I-5 1.15 I-6 1.36 I-7 2.31 I-8 11.6 I-9-1 1.53 I-9-2 1.56 I-10-1 5.17 I-10-2 4.47 I-11 1.40 I-12 1.82 I-13 0.74 I-14 1.70 I-15 2.27 I-16 2.22 I-17 1.24 I-18 1.63 I-19 1.18 I-20 1.77 I-21 1.39 I-22 0.99 I-23 3.38 I-24 1.39 I-25 2.07 I-26 2.01 I-27 3.70 I-28 1.63 I-29 1.41 I-30 3.67 I-31 0.73 I-32 1.37 I-33 0.72 I-34 1.28 I-35 2.85 I-36 1.88 I-37 2.22 I-38 3.85 I-39 1.79 I-40 1.90 I-41 1.11 I-42 23.4 I-43 2.00 I-44 1.09 I-45 2.57 I-46 1.86 I-47 5.41 I-48 2.01 I-49 2.50 I-50 1.13 I-51 2.65 I-52 2.34 I-53 0.83 I-54 1.24 I-55 7.34 I-56 1.21 I-57 1.07 I-58 1.11 I-59 1.19 I-60 1.60 I-61 1.90 I-62 0.82 I-63 0.89 I-64 1.30 I-65 1.28 I-66 0.84 I-67 1.88 I-68 1.83 I-69 1.17 I-70 1.06 I-71 1.77 I-72 1.45 I-73 4.73 I-74 1.71 I-75 1.19 I-76 1.35 I-77 2.16 I-78 1.00 I-79 1.74 I-80 1.75 I-81 1.88 I-82 3.32 I-83 1.32 I-84 4.12 I-85 1.33 I-86 1.76 I-87 1.32 I-88 0.86 I-89 1.11 I-90 1.32 I-91 1.35 I-92 1.88 I-93 0.99 I-94 40.2 I-95 2.09 I-96 2.14 I-97 0.82 I-98 2.18 I-99 0.81 I-100 1.98 I-101 2.15 I-102 3.83 I-103 3.75 I-104 4.02 I-105 2.42 I-106 2.57 I-107 2.37 I-108 1.12 I-109 1.20 I-110 1.67 I-111 1.48 I-112 1.07 I-113 1.84 I-114 3.08 I-115 1.16 I-116 0.87 I-117 0.75 I-118 0.87 I-119 1.23 I-120 0.94 I-121 0.97 I-122 1.02 I-123 1.00 I-124 0.89 I-125 1.58 I-126 0.76 I-127 1.14 I-128 2.19 I-129 3.09 I-130 1.12 I-131 2.12 I-132 2.66 I-133 1.53 I-134 2.04 I-135 6.80 I-136 1.40 I-137 3.99 I-138 2.66 I-139 0.78 I-140 1.42 I-141 1.74 I-142 1.72 I-143 0.99 I-144 0.80 I-145 0.81 I-146 0.92 I-147 1.01 I-148 1.16 I-149 1.27 I-150 0.93 I-151 1.88 I-152 1.15 I-153 1.08 I-154 1.87 I-155 1.37 I-156 1.30 I-157 1.22 I-158 0.88 I-159 1.07 I-160 0.96 I-161 0.94 I-162 0.96 I-163 1.10 I-164 2.07 I-165 3.21 I-166 8.83 I-167 7.10 I-168 1.83 I-169 0.88 I-170 0.91 I-171 0.94 I-172 1.02 I-173 1.69 I-174 2.08 I-175 2.00 I-176 1.01 I-177 3.17 I-178 3.14 I-179 1.10 I-180 2.71 I-181 7.46 I-182 1.44 I-183 2.39 I-184 1.64 I-185 1.71 I-186 2.14 I-187 2.21 I-188 2.22 I-189 2.53 I-190 5.59 I-191 2.22 I-192 2.27 I-193 3.48 I-194 1.63 I-195 2.15 I-196 7.42 I-197 1.94 I-198 1.95 I-199 2.35 I-200 5.08 I-201 10.2 I-202 12.1 I-203 5.02 I-204 2.04 I-205 2.03 I-206 3.38 I-207 2.10 I-208 1.86 I-209 3.07 I-210 2.15 I-211 11.7 I-212 2.86 I-213 1.76 I-214 1.89 I-215 2.01 I-216 1.93 I-217 1.95 I-218 1.95 I-219 2.06 I-220 2.08 I-221 2.11 I-222 2.90 I-223 1.97 I-224 1.96 I-225 2.31 I-226 4.48 I-227 3.26 I-228 3.98 I-229 3.70 I-230 6.34 I-231 3.91 I-232 4.10 I-233 6.22 I-234 3.50 I-235 3.56 I-236 2.90 I-237 3.56 I-238 2.52 I-239 2.74 I-240 2.02 I-241 2.95 I-242 3.11 I-243 4.24 I-244 2.01 I-245 2.01 I-246 2.07 I-247 2.25 I-248 2.26 I-249 2.26 I-250 2.20 I-251 2.30 I-252 4.22 I-253 2.59 I-254 2.64 I-255 2.39 I-256 2.82 I-257 4.98 I-258 5.23 I-259 10.9 I-260 2.96 I-261 3.55 I-262 3.95 I-263 3.41 I-264 3.53 I-265 5.07 I-266 2.61 I-267 2.40 I-268 4.46 I-269 3.41 I-270 3.38 I-271 2.23 I-272 2.11 I-273 2.25 I-274 2.11 I-275 2.11 I-276 2.16 I-277 1.94 I-278 1.83 I-279 1.60 I-280 3.24 I-281 2.95 I-282 4.04 I-283 2.28 I-284 2.98 I-285 7.76 I-286 2.06 I-287 2.02 I-288 2.19 I-289 2.40 I-290 2.08 I-291 3.54 I-292 2.68 I-293 1.90 I-294 3.92 I-295 2.19 I-296 1.91 I-297 1.82 I-298 2.29 I-299 16.5 I-300 4.78 I-301 3.14 I-302 2.28 I-303 1.86 I-304 1.98 I-305 1.99 I-306 1.89 I-307 1.87 I-308 1.91 I-309 2.00 I-310 1.96 I-311 1.88 I-312 1.58 I-313 1.81 I-314 1.93 I-315 1.98 I-316 1.85 I-317 1.86 I-318 1.63 I-319 2.09 I-320 1.95 I-321 1.90 I-322 10.5 I-323 2.41 I-324 19.6 I-325 31.7 I-326 9.19 I-327 10.4 I-328 12.8 I-329 7.67 I-330 40.6 I-331 12.3 I-332 7.39 I-333 11.0 I-334 1.91 I-335 1.81 I-336 2.13 I-337 2.03 I-338 4.70 I-339 1.83 I-340 5.60 I-341 1.89 I-342 2.06 I-343 15.9 I-344 2.83 I-345 1.82 I-346 1.98 I-347 4.40 I-348 1.96 I-349 2.33 I-350 5.32 I-351 5.09 I-352 4.22 I-353 3.09 I-354 44.2 I-355 2.35 I-356 3.30 I-357 4.41 I-358 3.89 I-359 3.77 I-360 4.54 I-361 6.22 I-362 3.07 I-363 3.36 I-364 5.39 I-365 3.20 I-366 2.72 I-367 2.61 I-368 2.11 I-369 15.8 I-370 5.02 I-371 10.5 I-372 3.26 I-373 2.92 I-374 4.35 I-375 3.87 I-376 9.86 I-377 5.40 I-378 4.10 I-379 4.42 I-380 5.51 I-381 4.69 I-382 7.26 I-383 6.47 I-384 6.62 I-385 1.25 I-386 5.89 I-387 5.49 I-388 1.53 I-389 1.79 I-390 1.84 I-391 3.94 I-392 2.40 I-393 14.5 I-394 1.64 I-395 1.86 I-396 2.76 I-397 2.64 I-398 1.67 I-399 1.94 I-400 1.69 I-401 1.77 I-402 1.89 I-403 2.30 I-404 1.88 I-405 2.42 I-406 1.89 I-407 3.77 I-408 1.80 I-409 2.45 I-410 1.99 I-411 1.30 I-412 1.51 I-413 1.84 I-414 1.71 I-415 2.55 I-416 1.63 I-417 1.64 I-418 2.21 I-419 1.83 I-420 13.1 I-421 14.7 I-422 8.58 I-423 2.80 I-424 5.41 I-425 2.65 I-426 8.10 I-427 10.4 I-428 15.9 I-429 2.21 I-430 17.5 I-431 3.72 I-432 8.42 I-433 2.49 I-434 1.98 I-435 6.27 I-436 3.17 I-437 4.42 I-438 2.55 I-439 3.45 I-440 4.50 I-441 2.61 I-442 2.95 I-443 1.88 I-444 5.10 I-445 2.78 I-446 2.12 I-447 2.37 I-448 2.31 I-449 2.19 I-450 2.68 I-451 9.46 I-452 2.60 I-453 2.63 I-454 5.51 I-455 2.38 I-456 13.6 I-457 5.63 I-458 51.0 I-459 18.4 I-460 3.58 I-461 7.09 I-462 3.33

TABLE-US-00115 TABLE 115 No. IC50 (nM) I-463 5.13 I-464 2.52 I-465 2.97 I-466 4.28 I-467 2.42 I-468 5.60 I-469 5.16 I-470 2.67 I-471 4.69 I-472 2.27 I-473 2.71 I-474 2.14 I-475 2.42 I-476 1.99 I-477 2.00 I-478 2.25 I-479 2.49 I-480 2.36 I-481 3.72 I-482 2.27 I-483 2.75 I-484 2.43 I-485 2.28 I-486 4.59 I-487 3.03 I-488 2.20 I-489 1.81 I-490 2.01 I-491 1.92 I-492 1.84 I-493 2.43 I-494 1.46 I-495 1.48 I-496 1.81 I-497 1.96 I-498 1.83 I-499 1.73 I-500 1.78 I-501 1.82 I-502 1.87 I-503 1.68 I-504 1.93 I-505 1.55 I-506 1.70 I-507 1.85 I-508 8.48 I-509 1.96 I-510 10.6 I-511 2.14 I-512 1.63 I-513 1.76 I-514 6.21 I-515 2.79 I-516 2.29 I-517 2.56 I-518 5.63 I-519 8.93 I-520 5.26 I-521 2.84 I-522 13.6 I-523 9.44 I-524 5.03 I-525 5.75 I-526 6.47 I-527 1.99 I-528 2.36 I-529 4.98 I-530 8.31 I-531 6.98 I-532 4.14 I-533 10.6 I-534 4.11 I-535 43.1 I-536 2.10 I-537 5.50 I-538 2.86 I-539 2.91 I-540 27.8 I-541 2.34 I-542 1.34 I-543 2.14 I-544 3.65 I-545 1.85 I-546 1.86 I-547 2.28 I-548 1.49 I-549 1.55 I-550 1.75 I-551 1.34 I-552 1.41 I-553 1.92 I-554 1.77 I-555 1.68 I-556 5.45 I-557 1.67 I-558 4.99 I-559 1.87 I-560 1.65 I-561 1.35 I-562 1.98 I-563 2.13 I-564 14.2 I-565 1.75 I-566 1.61 I-567 3.12 I-568 1.54 I-569 2.22 I-570 1.87 I-571 22.2 I-572 30.0 I-573 1.39 I-574 2.93 I-575 8.32 I-576 4.95 I-577 6.47 I-578 2.39 I-579 4.38 I-580 3.23 I-581 4.02 I-582 9.36 I-583 1.96 I-584 2.30 I-585 11.1 I-586 2.72 I-587 1.71 I-588 3.29 I-589 3.48 I-590 2.82 I-591 3.16 I-592 3.19 I-593 1.71 I-594 3.95 I-595 2.17 I-596 1.54 I-597 7.37 I-598 2.12 I-599 2.46 I-600 5.07 I-601 3.26 I-602 3.67 I-603 3.65 I-604 2.19 I-605 1.96 I-606 2.25 I-607 1.80 I-608 2.01 I-609 1.90 I-610 2.16 I-611 1.95 I-612 2.11 I-613 2.55 I-614 2.91 I-615 3.37 I-616 4.20 I-617 3.13 I-618 6.83 I-619 2.48 I-620 2.22 I-621 1.84 I-622 3.71 I-623 4.24 I-624 3.77 I-625 5.07 I-626 4.58 I-627 4.06 I-628 5.03 I-629 2.35 I-630 2.11 I-631 1.93 I-632 3.81 I-633 2.48 I-634 2.26 I-635 2.10 I-636 4.37 I-637 4.45 I-638 6.95 I-639 3.93 I-640 5.07 I-641 5.26 I-642 4.65 I-643 3.57 I-644 6.68 I-645 2.51 I-646 2.92 I-647 2.59 I-648 2.31 I-649 2.25 I-650 4.31 I-651 2.00 I-652 2.46 I-653 3.69 I-654 8.75 I-655 51.0 I-656 6.57 I-657 8.14 I-658 13.7 I-659 9.51 I-660 2.12 I-661 2.35 I-662 2.51 I-663 2.80 I-664 1.86 I-665 51.0 I-666 4.70 I-667 7.95 I-668 7.06 I-669 8.54 I-670 2.67 I-671 34.8 I-672 2.05 I-673 2.81 I-674 4.89 I-675 13.4 I-676 2.42 I-677 2.32 I-678 5.48 I-679 2.82 I-680 2.10 I-681 7.97 I-682 4.37 I-683 5.74 I-684 2.83 I-685 2.98 I-686 3.60 I-687 2.48 I-688 2.59 I-689 2.01 I-690 7.70 I-691 6.44 I-692 26.1 I-693 3.30 I-694 2.27 I-695 4.07 I-696 12.2 I-697 2.90 I-698 3.80 I-699 10.3 I-700 2.02 I-701 1.49 I-702 2.15 I-703 4.60 I-704 2.39 I-705 4.87 I-706 6.62 I-707 12.1 I-708 1.65 I-709 7.20 I-710 4.26 I-711 8.10 I-712 2.02 I-713 1.69 I-714 4.50 I-715 5.31 I-716 3.95 I-717 2.77 I-718 3.97 I-719 1.90 I-720 2.42 I-721 2.24 I-722 5.07 I-723 1.65 I-724 1.83 I-725 2.17 I-726 2.82 I-727 3.38 I-728 2.96 I-729 1.64 I-730 2.84 I-731 1.96 I-732 3.26 I-733 6.24 I-734 15.4 I-735 1.56 I-736 1.73 I-737 1.99 I-738 1.80 I-739 1.93 I-740 1.60 I-741 2.07 I-742 2.08 I-743 2.32 I-744 2.14 I-745 3.39 I-746 2.81 I-747 4.35 I-748 2.39 I-749 2.33 I-750 4.60 I-751 15.7 I-752 13.3 I-753 2.39 I-754 2.49 I-755 2.69 I-756 3.46 I-757 3.02 I-758 1.62 I-759 2.55 I-760 3.38 I-761 6.76 I-762 6.23 I-763 3.07 I-764 2.81 I-765 2.96 I-766 3.28 I-767 3.29 I-768 2.95 I-769 5.98 I-770 5.56 I-771 2.00 I-772 21.0 I-773 51.0 I-774 6.26 I-775 3.64 I-776 6.40 I-777 51.0 I-778 13.8 I-779 2.74 I-780 1.64 I-781 1.02 I-782 1.02 I-783 6.62 I-784 7.30 I-785 2.46 I-786 5.25 I-787 1.97 I-788 2.11 I-789 1.82 I-790 1.76 I-791 51.0 I-792 25.0 I-793 17.7 I-794 38.4 I-795 0.73 I-796 1.02 I-797 0.85 I-798 0.99 I-799 3.35 I-800 2.22 I-801 0.84 I-802 1.22 I-803 1.12 I-804 1.69 I-805 3.53 I-806 1.06 I-807 0.86 I-808 2.67 I-809 1.30 I-810 1.03 I-811 0.81 I-812 0.97 I-813 1.06 I-814 0.75 I-815 1.63 I-816 5.78 I-817 1.56 I-818 0.64 I-819 0.72 I-820 0.94 I-821 2.24 I-822 2.08 I-824 1.01 I-825 1.02 I-826 1.18 I-827 0.81 I-828 0.96 I-829 1.20 I-830 0.83 I-831 1.49 I-832 1.16 I-833 1.54 I-834 1.15 I-835 2.81 I-836 1.76 I-837 0.82 I-838 0.76 I-839 0.74 I-840 0.71 I-841 2.21 I-842 0.69 I-843 1.33 I-844 1.01 I-845 0.85 I-846 1.20 I-847 3.38 I-848 0.89 I-849 0.78 I-850 1.03 I-851 2.57 I-852 1.99 I-853 1.98 I-854 3.16 I-855 2.66 I-856 2.64 I-857 3.41 I-858 4.23 I-859 3.41 I-860 3.56 I-861 2.80 I-862 2.61 I-863 2.55 I-864 2.25 I-865 2.21 I-866 2.57 I-867 2.64 I-868 4.30 I-869 6.45 I-870 9.33 I-871 4.93 I-872 4.99 I-873 8.43 I-874 5.12 I-875 6.78 I-876 7.13 I-877 2.12 I-878 2.94 I-879 3.78 I-880 4.70 I-881 5.89 I-882 2.28 I-883 2.15 I-884 2.03 I-885 3.48 I-886 3.68 I-887 2.85 I-888 2.10 I-889 1.49 I-890 1.74 I-891 2.88 I-892 4.06 I-893 5.83 I-894 20.4 I-895 6.59 I-896 16.7 I-897 2.46 I-898 1.78 I-899 1.46 I-900 2.90 I-901 2.34 I-902 6.83 I-903 2.23 I-904 3.69 I-905 51.0 I-906 51.0 I-907 1.27 I-908 1.21 I-909 3.25 I-910 7.84

TABLE-US-00116 TABLE 116 No. rat_CLt (mL/min/kg) rat_fu (%) I-1 0.542 <0.1 I-2 5.11 <0.1 I-6 1.22 <0.1 I-7 0.238 <0.1 I-10-2 0.092 <0.1 I-12 2.9 <0.1 I-13 1.09 <0.1 I-15 4.86 <0.1 I-19 1.7 <0.1 I-29 1.54 <0.1 I-30 1.52 <0.1 I-37 0.784 <0.1 I-39 0.363 <0.1 I-43 3.19 <0.1 I-44 0.535 <0.1 I-45 1.71 <0.1 I-47 3.51 <0.1 I-48 2.28 <0.1 I-49 2.23 <0.1 I-51 1.47 <0.1 I-55 0.752 <0.1 I-74 3.88 <0.1 I-79 3.15 <0.1 I-82 0.285 <0.1 I-83 0.362 <0.1 I-84 0.117 <0.1 I-85 5.54 <0.1 I-86 1.09 <0.1 I-88 2.5 <0.1 I-93 2.22 <0.1 I-94 2.02 <0.1 I-98 0.933 <0.1 I-99 0.576 <0.1 I-101 0.985 <0.1 I-102 4.24 <0.1 I-104 0.07 <0.1 I-105 2.29 <0.1 I-106 3.49 <0.1 I-113 1.18 <0.1 I-119 2.29 <0.1 I-120 1.48 <0.1 I-125 3.89 I-127 7.74 <0.1 I-131 2.27 <0.1 I-132 0.376 <0.1 I-134 3.92 <0.1 I-137 1.5 <0.1 I-138 1.6 <0.1 I-139 0.286 <0.1 I-140 0.111 <0.1 I-145 1.29 <0.1 I-146 0.584 <0.1 I-147 1.68 <0.1 I-148 2.5 <0.1 I-165 1.08 <0.1 I-166 0.194 <0.1 I-168 5.68 <0.1 I-175 4.44 <0.1 I-181 0.117 <0.1 I-182 3.84 <0.1 I-188 2.47 <0.1 I-190 1.4 <0.1 I-195 6.74 <0.1 I-197 3.81 <0.1 I-205 1.68 <0.1 I-206 0.162 <0.1 I-211 3.07 <0.1 I-212 3.97 <0.1 I-214 0.297 I-228 0.144 <0.1 I-231 1.02 <0.1 I-234 1.49 <0.1 I-235 4.05 <0.1 I-236 0.763 <0.1 I-237 1.1 <0.1 I-238 3.05 <0.1 I-240 4.5 <0.1 I-241 0.404 <0.1 I-242 0.408 <0.1 I-243 0.477 <0.1 I-247 0.148 <0.1 I-248 2.47 <0.1 I-252 0.113 <0.1 I-253 4.65 <0.1 I-255 0.455 <0.1 I-256 3.83 <0.1 I-260 0.801 <0.1 I-261 2.78 <0.1 I-262 0.343 <0.1 I-265 4.01 <0.1 I-267 5.01 <0.1 I-268 0.0553 <0.1 I-271 2.42 <0.1 I-272 0.715 <0.1 I-274 0.659 <0.1 I-275 2.12 <0.1 I-277 0.512 <0.1 I-287 2.73 I-292 0.166 <0.1 I-297 3.54 <0.1 I-304 0.41 <0.1 I-305 1.55 I-334 3.87 <0.1 I-338 5.7 <0.1 I-343 3.31 <0.1 I-347 5.18 <0.1 I-348 0.585 <0.1 I-349 0.71 <0.1 I-351 3.08 <0.1 I-352 3.26 <0.1 I-353 4.97 <0.1 I-354 0.0682 <0.1 I-357 1.55 <0.1 I-362 4.62 <0.1 I-363 3.39 <0.1 I-365 0.119 <0.1 I-371 4.69 I-372 0.868 <0.1 I-374 3.94 <0.1 I-376 0.485 <0.1 I-378 0.173 <0.1 I-379 0.173 <0.1 I-380 0.702 <0.1 I-384 0.253 <0.1 I-386 4.96 <0.1 I-389 14 <0.1 I-391 10.3 <0.1 I-396 0.0572 <0.1 I-399 0.487 I-405 3.27 <0.1 I-406 4.61 <0.1 I-407 0.31 I-409 0.873 I-410 1.07 I-415 0.66 <0.1 I-418 1.49 <0.1 I-434 1.73 I-436 1.72 I-440 0.871 I-448 5.28 I-449 11.1 I-450 3.7 I-451 0.211 I-453 0.593 I-454 4.02 I-455 0.236 I-465 0.675 I-466 1.75 I-467 2.36 I-471 2.17 I-473 1.22 I-474 1.28 I-475 2.28 I-480 0.0997 I-481 3.29 I-483 2.41 I-484 1.58 I-485 0.45 I-487 3.16 I-488 0.501 I-490 0.88 I-491 3.32 I-492 17.3 I-507 1.61 I-509 0.377 I-510 1.08 I-513 3.23 I-514 3.01 I-519 0.429 I-520 0.0285 I-522 0.144 I-524 0.23 I-525 0.127 I-526 0.632 I-528 4.05 I-530 1.57 I-531 0.0543 I-532 0.551 I-537 0.328 I-538 0.598 I-539 0.156 I-540 1.5 I-541 0.195 I-545 1.15 I-550 5.29 I-552 0.985 I-555 5.98 I-560 4.5 I-561 4.48 I-563 0.883 I-566 0.727 I-567 2.81 I-574 1.01 I-575 0.267 I-578 3.16 I-579 1.66 I-580 0.0683 I-581 0.204 I-582 0.179 I-583 0.107 I-584 0.77 I-585 0.0436 I-586 2.51 I-588 0.291 I-589 0.311 I-594 0.106 I-596 0.213 I-598 0.532 I-599 0.479 I-600 0.104 I-601 0.164 I-602 0.0667 I-603 5.83 I-606 2.2 I-607 0.797 I-608 0.826 I-613 0.0573 I-614 0.146 I-617 0.098 I-618 1.78 I-623 1.83 I-625 0.0688 I-627 0.0474 I-631 0.699 I-632 0.176 I-636 0.372 I-637 0.503 I-638 0.802 I-648 0.783 I-649 0.622 I-651 0.536 I-652 0.641

TABLE-US-00117 TABLE 117 No. rat_CLt (mL/min/kg) rat_fu (%) I-662 1.11 I-664 1.5 I-666 0.668 I-674 0.0392 I-676 0.145 I-679 1.65 I-680 2.77 I-689 0.385 I-693 0.247 I-701 2.71 I-704 0.724 I-714 0.0783 I-719 0.066 I-720 0.0677 I-722 0.0366 I-726 0.212 I-727 0.0528 I-736 0.0528 I-742 5.03 I-780 2.23 <0.1 I-781 5.37 <0.1 I-782 1.16 <0.1 I-786 4.34 <0.1 I-788 3.87 <0.1 I-798 4.54 <0.1 I-799 0.324 <0.1 I-807 0.61 <0.1 I-808 1.86 <0.1 I-825 5.22 <0.1 I-826 0.823 <0.1 I-827 4.21 <0.1 I-832 4.09 <0.1 I-835 1.63 <0.1 I-836 4.31 <0.1 I-841 2.38 <0.1 I-847 6 <0.1 I-851 0.298 <0.1 I-852 2.25 I-856 0.0831 I-857 0.132 I-858 0.142 I-859 0.2 I-860 0.0981 I-861 0.0804 I-862 0.14 I-867 0.372 I-869 1.15 I-877 2.31 I-882 0.26 I-890 0.652 I-903 0.0436 <0.1 I-907 0.73 <0.1 I-908 0.63 <0.1

Reference Example

[1178] The results of measurements of HIV protease inhibitory activity, serum protein binding rate and total body clearance of Darunavir according to the description of Test Example 1, 2 and 3.

[1179] Enzyme inhibitory activity: 1.05 nM

[1180] Serum protein binding rate: 9.71%

[1181] Total body clearance: 35.5 mL/min/kg

[1182] The compounds of the present invention are having excellent long acting performance in blood without decreasing drug efficacy drastically in comparison with Darunavir from the above results.

[1183] Further useful for medicine can be examined by the following tests etc.

Test Example 4: CYP Inhibition Test

[1184] Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation (CYP3A4) as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a compound of the present invention was assessed.

[1185] The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenytoinmephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; concentration of a compound of the present invention, 1, 5, 10, 20 μmol/L (four points).

[1186] Each five kinds of substrates, human hepatic microsome, or a compound of the present invention in 50 mmol/L Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and, after the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and toltributamide hydroxide (CYP2C9P metabolite), mephenytoin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

[1187] Addition of only DMSO being a solvent dissolving a compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution and IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.

Test Example 5: Metabolism Stability Test

[1188] Using commercially available pooled human hepatic microsomes, a compound of the present invention was reacted for a constant time, and a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.

[1189] A reaction was performed at 37° C. for 60 minutes or 120 minutes in a CO2 incubator in 30 μL of William's Medium E containing 0.5 mg protein/mL of human liver microsomes (final concentration 1×10.sup.6 cells/mL). After the reaction, 30 μL of the reaction solution was added to 120 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.

Test Example 6: CYP3A4 Fluorescent MBI Test

[1190] The CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound of the present invention by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylcoumarin (HFC) emitting fluorescent light.

[1191] The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25° C. (room temperature); CYP3A4 content (expressed in Escherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25 μmol/mL (at 10-fold dilution); test drug concentration of a compound of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six points).

[1192] An enzyme in a K-Pi buffer (pH 7.4) and a solution of a compound of the present invention as a pre-reaction solution were added to a 96-well plate at the above composition of the pre-reaction, a part of it was transferred to another 96-well plate so that it was 1/10 diluted with a substrate and a K-Pi buffer, NADPH as a co-factor was added to initiate a reaction as an index (without preincubation) and, after a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. In addition, NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index. After a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC which is a metabolite was measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).

[1193] Addition of only DMSO which is a solvent dissolving a compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution, and IC.sub.50 was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. When a difference between IC.sub.50 values is 5 μmol/L or more, this was defined as (+) and, when the difference is 3 μmol/L or less, this was defined as (−).

Test Example 6-2: CYP3A4(MDZ) MBI Test

[1194] CYP3A4(MDZ) MBI test is a test of investigating mechanism based inhibition (MBI) ability on CYP3A4 inhibition of a compound by enhancement of a metabolism reaction. CYP3A4 inhibition is evaluated using 1-hydroxylation reaction of midazolam (MDZ) by pooled human liver microsomes as an index.

[1195] The reaction conditions were as follows: substrate, 10 μmol/L MDZ; pre-reaction time, 0 or 30 minutes; substrate reaction time, 2 minutes; reaction temperature, 37° C.; protein content of pooled human liver microsomes, at pre-reaction time 0.5 mg/mL, at reaction time 0.05 pmg/mL (at 10-fold dilution); concentrations of the compound of the present invention, 1, 5, 10, 20 μmol/L (four points).

[1196] Pooled human liver microsomes in a K-Pi buffer (pH 7.4) and a compound of the present invention solution as a pre-reaction solution were added to a 96-well plate at the composition of the pre-reaction. A part of pre-reaction solution was transferred to another 96-well plate, and 1/10 diluted by a substrate in a K-Pi buffer. NADPH as a co-factor was added to initiate a reaction as an index (without preincubation). After a predetermined time of a reaction, methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. On the other hand, NADPH was also added to a remaining pre-reaction solution in order to initiate a preincubation (with preincubation). After a predetermined time of a preincubation, a part was transferred to another 96-well plate, and 1/10 diluted by a substrate in a K-Pi buffer in order to initiate a reaction as an index. After a predetermined time of a reaction, methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After centrifuged at 3000 rpm for 15 minutes, 1-hydroxymidazolam in the supernatant was quantified by LC/MS/MS.

[1197] The sample adding DMSO to a reaction system instead of compound of the present invention solution was adopted as a control (100%) because DMSO was used as a solvent to dissolve a compound of the present invention. Remaining activity (%) was calculated at each concentration of the compound of the present invention added as the solution, and IC.sub.50 value was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. Shifted IC value was calculated as “IC of preincubation at 0 min/IC of preincubation at 30 min”. When a shifted IC was 1.5 or more, this was defined as (+). When a shifted IC was 1.0 or less, this was defined as (−).

Test Example 7: Fluctuation Ames Test

[1198] Mutagenicity of compounds of the present invention was evaluated.

[1199] 20 μL of freezing-stored rat typhoid bacillus (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and this was cultured before shaking at 37° C. for 10 hours. 9 mL of a bacterial solution of the TA98 strain was centrifuged (2000 x g, 10 minutes) to remove a culturing solution. The bacteria was suspended in 9 mL of a Micro F buffer (K.sub.2HPO.sub.4: 3.5 g/L, KH.sub.2PO.sub.4: 1 g/L, (NH.sub.4).sub.2SO.sub.4: 1 g/L, trisodium citrate dehydrate: 0.25 g/L, MgSO.sub.4.7H.sub.2O: 0.1 g/L), the suspension was added to 110 mL of an Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL). The TA100 strain was added to 120 mL of the Exposure medium relative to 3.16 mL of the bacterial solution to prepare a test bacterial solution. Each 12 μL of DMSO solution of a compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as a negative control, and 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain, 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under the non-metabolism activating condition, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strain, 20 μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain under the metabolism activating condition as a positive control, and 588 μL of the test bacterial solution (a mixed solution of 498 μl of the test bacterial solution and 90 μL of S9 mix under the metabolism activating condition) were mixed, and this was shaking-cultured at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to a compound of the present invention was mixed with 2300 μL of an Indicator medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL was dispensed into microplate 48 wells/dose, and this was subjected to stationary culturing at 37° C. for 3 days. Since a well containing a bacterium which has obtained the proliferation ability by mutation of an amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the bacterium proliferation well which has turned to yellow in 48 wells per dose is counted, and was assessed by comparing with a negative control group. (−) means that mutagenicity is negative and (+) is positive.

Test Example 8: hERG Test

[1200] For the purpose of assessing risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (IKr), which plays an important role in the ventricular repolarization process, was studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel.

[1201] After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), IKr induced by depolarization pulse stimulation at +40 mV for 2 seconds and, further, repolarization pulse stimulation at −50 mV for 2 seconds, was recorded. After the generated current was stabilized, extracellular solution (NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH.sub.2PO.sub.4: 0.3 mmol/L, CaCl.sub.2.2H.sub.2O: 1.8 mmol/L, MgCl.sub.2.6H.sub.2O: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4), in which the compound of the present invention had been dissolved at an objective concentration, was applied to the cell at room temperature for 10 minutes. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (DataXpress ver.1, Molecular Devices Corporation). Further, the % inhibition relative to the tail peak current before application of the compound of the present invention was calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess influence of the compound of the present invention on IKr.

Test Example 9: Solubility Test

[1202] The solubility of the compound of the present invention was determined under 1% DMSO addition conditions. A 10 mmol/L solution of the compound was prepared with DMSO, and 2 μL of the solution of the compound of the present invention was added, respectively, to 198 μL of JP-1 solution (water were added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL) and JP-2 solution (1 volume of water were added to 1 volume of the solution which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate to reach 1000 mL). The mixture was shaked for 1 hour at a room temperature, and the mixture was filtered. The filtrate was ten-fold diluted with methanol/water=1/1(v/v), and the compound concentration in the filtrate was measured with LC/MS or SPE/MS by the absolute calibration method.[0404]

Test Example 10: Powder Solubility Test

[1203] Appropriate quantity of the compound of the present invention was put in a suitable container and 200 μL of JP-1 solution (water was added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL), JP-2 solution (500 mL of water was added to 500 mL of phosphate buffer with a pH of 6.8) or 20 mmol/L sodium taurocholate (TCA)/JP-2 solution (JP-2 solution was added to 1.08 g of TCA to reach 100 mL) was independently added to each container. When total amount was dissolved after adding the test reagent, the compound of the present invention was added appropriately. After sealing and shaking at 37° C. for 1 hour, solution was filtrated and 100 μL of methanol was added to 100 μL of each filtrate to dilute two-fold. The dilution rate was changed as necessary. After checking that there is no bubble and deposit, the container was sealed and shaken. The compound of the present invention was measured using HPLC by absolute calibration curve method.

Formulation Example

[1204] The following Formulation Examples are only exemplified and not intended to limit the scope of the invention.

Formulation Example 1: Tablets

[1205] The compounds of the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to give a suitable size of granules. Next, calcium stearate is added to the granules, and the mixture is compressed and molded to give tablets.

Formulation Example 2: Capsules

[1206] The compounds of the present invention, lactose and calcium stearate are mixed uniformly to obtain powder medicines in the form of powders or fine granules. The powder medicines are filled into capsule containers to give capsules.

Formulation Example 3: Granules

[1207] The compounds of the present invention, lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.

Formulation Example 4: Orally Disintegrated Tablets

[1208] The compounds of the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.

Formulation Example 5: Dry Syrups

[1209] The compounds of the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.

Formulation Example 6: Injections

[1210] The compounds of the present invention and phosphate buffer are mixed to give injection.

Formulation Example 7: Infusions

[1211] The compounds of the present invention and phosphate buffer are mixed to give injection.

Formulation Example 8: Inhalations

[1212] The compound of the present invention and lactose are mixed and crushed finely to give inhalations.

Formulation Example 9: Ointments

[1213] The compounds of the present invention and petrolatum are mixed to give ointments.

Formulation Example 10: Patches

[1214] The compounds of the present invention and base such as adhesive plaster or the like are mixed to give patches.

INDUSTRIAL APPLICABILITY

[1215] The compound of the present invention has protease inhibitory activity and/or cell growth inhibitory activity against virus especially HIV or resistant virus. Therefore, it is useful for treatment or prevention against a variety of disease relating to protease or virus infections (ex. AIDS). Especially, it is useful for long acting injection of pharmaceutical active ingredient.