AU2002346216B2

AU2002346216B2 - Fused cyclic compounds and medicinal use thereof

Info

Publication number: AU2002346216B2
Application number: AU2002346216A
Authority: AU
Inventors: Hiromasa Hashimoto; Kenji Mizutani; Atsuhito Yoshida
Original assignee: Japan Tobacco Inc
Current assignee: Japan Tobacco Inc
Priority date: 1999-12-27
Filing date: 2002-06-26
Publication date: 2005-12-08
Anticipated expiration: 2020-12-22

Description

SPECIFICATION

FUSED CYCLIC COM1POUNDS AND MEDICINAL USE THEREOF Technical Field The present invention relates to a novel fused ring compound and a pharmaceutically acceptable salt thereof useful as a therapeutic agent for hepatitis C, and to an intermediate compound for the synthesis thereof. The present invention also relates to a novel use of a certain fused ring compound or a pharmaceutically acceptable salt thereof as a therapeutic agent for hepatitis C. More particularly, the present invention relates to a therapeutic agent for hepatitis C, which contains a novel fused ring compound or a pharmaceutically acceptable salt thereof, which is effective for the prophylaxis or treatment of hepatitis C and which shows anti-hepatitis C virus (WCV) activity, particularly anti-HCV activity based on an RNA-dependent RNA polymerase inhibitory activity.

Background Art In 1989, a main causative virus of non-A noh-B, posttransfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C.

The patients infected with HCV are considered to involve several percent of the world population, and the infection with 2zs HCV characteristically becomes chronic.

HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus (from The International Committee on Taxonomy of Viruses, International Union of Microbiological Societies) Of the same hepatitis viruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system and the infection with this virus ends in an acute infection except for neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. once infected with this virus, even an adult having a mature immune system frequently develops persistent infection.

When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or hepatic cancer in a high rate. Enucleation of tumor by operation does not help much, because the patient often develops recurrent hepatic cancer due to the sequela inflammation in non-cancerous parts. In addition, there is a report on the involvement of HCV infection in dermatosis such as chronic urticaria, lichen planus, cryoglobulinemic purpura and the like (The Japanese Journal of Dermatology, 111(7), 1075-81, 2001).

lo Thus, an effective therapeutic method of hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV has been strongly demanded.

At present, a treatment with interferon is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus only in about one-third of the patient population. For the rest of the patients, it has no effect or provides, only a temporary effect. Therefore, an anti- HCV drug to-be used in the place of or concurrently with interferon is awaited in great expectation.

In recent years, Ribavirin (1-j-D-ribofuranosyl-1H-1,2,4triazole-3-carboxamide) has become commercially available as a therapeutic agent for hepatitis C, which is to be used concurrently with interferon. It enhances the efficacy of interferon but only to a low efficacy rate, and a different novel therapeutic agent for hepatitis C is desired.

Also, an attempt has been made to potentiate the immunocompetence of the patient with an interferon agonist, an interleukin-12 agonist and the like, thereby to eradicate the virus, but an effective pharmaceutical agent has not been found yet.

In addition, the inhibition of HCV growth, wherein HCVspecific protein is targeted, has been drawing attention these days.

The gene of HCV encodes a protein such as serine protease, RNA helicase, RNA-dependent RNA polymerase and the like. These proteins function as a specific protein essential for the growth of HCV.

One of the specific proteins, RNA-dependent RNA polymerase (hereinafter to be also briefly referred to as an HCV polymerase), is an enzyme essential for the growth of the virus. The gene replication of HCV having a plus-strand RNA gene is considered to involve synthesis of a complementary minus-strand RNA by the use of the plus-strand RNA as a template, and, using the obtained minus-strand RNA as a template, amplifying the plus-strand RNA.

The portion called NS5B of a protein precursor, that HCV codes for, has been found to show an RNA-dependent RNA polymerase activity (EMBO 15, 12-22, 1996), and is considered to play a central role in the HCV gene replication.

Therefore, an HCV polymerase inhibitor can be a target in the development of an anti-HCV drug, and the development thereof is eagerly awaited. However, an effective HCV polymerase inhibitor has not been developed yet, like in other attempts to develop an anti-HCV drug based on other action mechanisms. As the situation stands, no pharmaceutical agent can treat hepatitis C satisfactorily.

The following discloses known Compounds relatively similar to the compound of the present invention.

The therapeutic agents for hepatitis C, which have a benzimidazole skeleton, are known from JP-A-2001-247550 (W001/47883, EP1162196A1) and W002/04425.

These publications disclose the following J-ketoamide.

compounds J etc. and K etc., respectively, as anti-HIV agents having an integrase inhibitory activity:

CI

0 HO _oun 'sIN N= L

N-NI

compound J compound K Note that the earliest publication dates of these publications are July 5, 2001 (WO01/47883) and January 17, 2002 (W002/04425), and the priority date of the present application is June 26, 2001, antedating these publication dates.

In addition, a known therapeutic agent for hepatitis C having a benzimidazole skeleton is also disclosed in W097/36866, Japanese Patent Application.under PCT laid-open under kohyo No.

2000-511899 (EP906097) and W099/51619.

W097/36866 discloses the following compound D and the like, and HCV helicase inhibitory activity of the compounds.

Japanese Patent Application under PCT laid-open under kohyo No. 2000-511899 (EP906097) discloses the following compound E and the like, and W099/51619 discloses the following compound F and the like, in both of which a possibility of these compounds being effective as an HCV inhibitor is mentioned.

However, these publications do not include the compound disclosed in the present specification, or a disclosure suggestive thereof.

I NU NHCO CONHC/ 'II H H compound D SF NN CN PH C1 CI)' N H

H

2 NOC HO OH

HO

compound E compound F A known anti-hepatitis virus agent having a benzimidazole skeleton is disclosed in Japanese Patent Application under PCT 4 laid-open under kohyo No. 2000-503017 (W097/25316) and Japanese Patent Application under PCT laid-open under kohyo No. 10-505092 (W096/7646).

W097/25316 discloses the following compound A and the like, wherein the use thereof is for a treatment of viral infection.

The target virus is a DNA virus such as hepatitis B virus and the like. However, this publication does not include the compound disclosed in the present specification or a description regarding or suggestive of HCV.

Japanese Patent Application under PCT laid-open under kohyo No. 10-505092 discloses the following compound B and the like, wherein the use thereof is for a treatment of viral infection. The target virus is a DNA virus such as herpesvirus and hepatitis B virus. However, this publication does not include the compound disclosed in the present specification or a description regarding or suggestive of HCV.

Cl N Nl G I )C:I

N

OH

HO HO'compound A compound B The benzimidazole derivatives having an antiviral activity have been disclosed in JP-A-3-31264, US3644382 and US3778504. In addition, W098/37072 discloses, as a production inhibitor of tumor necrosis factor (TNF) and cyclic AMP, a benzimidazole derivative for the use as an anti-human immunodeficiency virus (HIV) agent and an anti-inflammation agent. W098/05327 discloses, as a reverse transcriptase inhibitor, a benzimidazole derivative for the use as an anti-HIV agent. J. Med. Chem. 697-704, 1970) discloses, as a neuraminidase inhibitor, a benzimidazole derivative for the use as an anti-influenza virus agent.

However, none of these publications includes the compound of the present invention or a description regarding or suggestive of an anti-HCV effect.

Known benzimidazole derivatives having a pharmaceutical use other than as an antiviral agent are disclosed in JP-A-8- 501318 (US5814651) and JP-A-8-134073 (US5563143). These publications disclose the following compound C and the like as a catechol diether compound, and the use thereof as an antiinflammation agent. However, neither of the publications includes the compound of the present invention, and as the action mechanism, the former discloses phosphodiesterase IV and the latter discloses TNF. These publications do not include a description regarding or suggestive of an anti-HCV effect.

Japanese Patent Application under PCT laid-open under kohyo No. 2000-159749 (EP882718) discloses the following compound i G and the like, and the use thereof for the treatment of bronchitis, glomerulonephritis and the like. However, this..

publication does not include the compound of the present invention, but discloses only a phosphodiesterase IV inhibitory and hypoglycemic action. This publication does not include a description regarding or suggestive of an anti-HC effect.

US6211177 discloses the following compound H and the like with their use as antitumor agents. However, this publication does not encompass the compound of the present invention, and does not disclose or suggest an anti-HO! effect.

H 0 -o

N

compound C compound G EtOOC- CI compound H W098/50029, W098/50030 and W098/50031 disclose benzimidazole derivatives as an antitumor agent having a protein isoprenyl transferase action. While this publication discloses a wide scope of the clams, at least it does not include a compound analogous to the compound of the present invention or a description regarding or suggestive of an anti-HO! effect.

JP-A-8-109169 (EP694535) discloses the application of a 0 tachykinin receptor antagonist to treat an inflammatory disease, C- and W096/35713 discloses the application thereof as a growth Shormone release promoter to treat a growth hormone-related O 5 disease such as osteoporosis and the like. However, none of these S publications includes a description regarding or suggestive of:an anti-HCV effect.

IND W02001/21634 discloses the following compound I in a chemical library. However, this publication does.not encompass ID lo the compound of the present invention. While it discloses an Cantimicrobial activity of certain compounds, this publication Sdoes not teach or suggest an anti-HCV effect.

00 cI cI S compound I HNf

NH

2 JP-A-53-14735 discloses a benzimidazole derivative as a brightener besides its pharmaceutical use, but this publication does not include the compound of the present invention.

Summary of the Invention O The present invention provides the following:

C)

o s 1. (4-Chlorophenyl) -5-tetrazol-5-ylbenzyloxy]phenyl}-1acid hydrochloride.

2. (4-Chlorophenyl) (isopropylcarbamoyl)benzyloxy] -2fluorophenyl}-l-piperidinobenzimidazole-5-carboxylic acid O 10 hydrochloride.

c 3. 2-[4-{2-(4-Chlorophenyl)-4-fluoro-5-(2-oxopyrrolidin-l- 0 yl)benzyloxy} -2-fluorophenyll carboxylic acid hydrochloride.

4. 2-{4-[2-(4-Chlorophenyl)-5-(4-methylpiperazin-lylcarbonyl)benzyloxy]phenyl} -1-cyclohexylbenzimidazole- carboxylic acid dihydrochloride.

5. A pharmaceutical composition comprising a compound of item 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a compound of item 2 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound of item 3 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a compound of item 4 and a pharmaceutically acceptable carrier.

Based on the findings from the preceding studies, it has been elucidated that a pharmaceutical agent having an anti-HCV Sactivity is effective for the prophylaxis and treatment of hepatitis C, and particularly an anti-HCV agent having an O s inhibitory activity on RNA-dependent RNA polymerase of HCV can be ta prophylactic and therapeutic agent effective against hepatitis C and a prophylactic and therapeutic agent for the disease caused.

by hepatitis C.

Accordingly, the present invention provides a S 10 o pharmaceutical agent having an anti-HCV activity, particularly a M pharmaceutical agent having an RNA-dependent RNA polymerase Sinhibitory activity.

SThe present inventors have made an in-depth study of compounds having an anti-HCV activity, particularly RNA-dependent if3 RNA polymerase inhibitory activity, and completed the present Sinvention.

c_ Described herein is the following to O (87).

A therapeutic agent for hepatitis C, which comprises a fused C ring compound of the following formula or a pharmaceutically acceptable salt thereof as an active ingredient:

NO

1 2

G

8 -G 7 S G9 G3 A -X [I] 7 G 6 G 6 wherein a broken line is a single bond or a double bond,

G

1 is C(-R 1 or a nitrogen atom,

G

2 is C(-R 2 or a nitrogen atom,

G

3 is C(-R 3 or a nitrogen atom,

G

4 is C(-R 4 or a nitrogen atom,

G

5

G

6

G

8 and G 9 are each independently a carbon atom or a nitrogen atom,

G

7 is C(-R 7 an oxygen atom, a sulfur atom, or a nitrogen atom optionally substituted by R 8 wherein R, R R 3 and R 4 are each independently, hydrogen atom,.

C

1 -6 alkanoyl, carboxyl, cyano, nitro, C1-6 alkyl optionally substituted by 1 to 3 substituent(s) selected from the following group A, group A; halogen atom, hydroxyl group, carboxyl, amino,

C

1 -6 alkoxy, C 1 -6 alkoxy C 1 -6 alkoxy, C 1 -6 alkoxycarbonyl and C 1 -6 alkylamino, -COORal wherein Ral is optionally substituted C 1 -6 alkyl (as defined above), C6- 14 aryl C 1 -6 alkyl optionally RNA polymerase inhibitory activity, and completed the present invention.

Thus, the present invention provides the following to (87).

s A therapeutic agent for hepatitis C, which comprises a fused ring compound of the following formula or a pharmaceutically acceptable salt thereof as an active ingredient: 2-G' e--G 1 G 2 8 o 7 3

G

9 1 6.G 4- '-G 5

-G

4

G"

x [I] wherein a broken line is a single bond or a double bond, GI is C(-R 1 or a nitrogen atom,

G

2 is C(-R 2 or a nitrogen atom,

G

3 is C(-R 3 or a nitrogen atom,

G

4 is C(-R 4 or a nitrogen atom,

G

5

G

6 Ga and G 9 are each independently a carbon atom or a nitrogen atom, 7

G

7 is C(-R 7 an oxygen atom, a sulfur atom, or a nitrogen atom optionally substituted by R 8 wherein R 2

R

3 and R 4 are each independently, hydrogen atom, Ci-6 alkanoyl, carboxyl, cyano, nitro, Ci- 6 alkyl optionally substituted by 1 to 3 substituent(s) selected from the following group A, group A; halogen atom, hydroxyl group, carboxyl, amino, C-6 alkoxy, C 1 i-6 alkoxy CI- 6 alkoxy, Ci-6 alkoxycarbonyl and C 1 i-6 alkylamino, -COORal wherein Ral is optionally substituted C 1 i-6 alkyl (as defined above), C 6 -14 aryl CI- 6 alkyl optionally substituted by 1 to 5. substituent(s) selected from the following group B or glucuronic acid residue, group B; halogen atom, cyano, nitro, Ci-6 alkyl, halogenated C 1 -6 alkyl, Ci.- alkanoyl,

-(CH

2 -COORbl, -(CH2)r-CONRblRb 2 -(CH2) r-NblRb2,

(CH

2 r-NRbl-CORb 2

(CH

2 r-NHS02Rbl, (CH 2 r-ORb,

(CH

2 r-SRbl, (C2) r-SO 2

R

b and (CH 2 r-SOzNRRb 2 wherein Rbl and Rb 2 are each independently hydrogen atom or C.-6 alkyl and r is 0 or an integer of 1 to 6, -CONRa 2 Ra 3 wherein R a2 and R 3 are each independently hydrogen atom, C1-6 alkoxy or optionally substituted C1-6 alkyl (as defined above), -C (=NR a4 NH2 wherein Ra 4 is hydrogen atom or hydroxyl group,

-NHR

a wherein Ra 5 is hydrogen atom, C 1 -6 alkanoyl or Ci-6 alkylsulfonyl, (11) -ORa 6 wherein R a6 is hydrogen atom or optionally substituted CI-6 alkyl (as defined above), (12) -S0 2 Ra 7 wherein Ra 7 is hydroxyl group, amino, Ci-6 alkyl or C 1 -6 alkylamino, (13) (ORa 31 )2 wherein R a31 is hydrogen atom, optionally substituted C 1 -6 alkyl (as defined above) or C 6 -1 4 aryl Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B or (14) heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, and

R

7 and R 8 are each hydrogen atom or optionally substituted C1-6 alkyl (as defined above), ring Cy is

C

3 cycloalkyl optionally substituted by 1 to substituent(s) selected from the following group C, group C; hydroxyl group, halogen atom, C 1 -6 alkyl and CI-6 alkoxy,

C

3 8 cycloalkenyl optionally substituted by 1 to substituent(s) selected from the above group C, or (3) )u )v )u )v )u )v )v S 0 0 0 0 0 1o- ring A

R

5 and R 6 (1) (2) (3) (4) wherein u and v are each independently an integer of 1 to 3, is

C

6 -1 4 aryl, C3-8 cycloalkyl, C3-8 cycloalkenyl or heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen .atom and a sulfur atom, are each independently hydrogen atom, halogen atom, optionally substituted C 1 -6 alkyl (as defined above) or -ORa 8 wherein R" 8 is hydrogen atom, C 1 -6 alkyl or C 6 -1 4 aryl C 1 -6 alkyl, and is hydrogen atom, halogen atom, cyano,.

nitro, amino, Ci-6 alkanoylamino,

C

1 6 alkylsulfonyl, optionally substituted Ci-6 alkyl (as defined above), C2-6 alkenyl optionally substituted by 1 to 3 substituent(s) selected from the above group A, -COORa 9 wherein Ra 9 is hydrogen atom or Ci-6 alkyl, -CONH- (CH 2 I-Ralo .wherein Ralo is optionally substituted Ci-6 alkyl (as defined above), Ci-6 alkoxycarbonyl or Ci-6 alkanoylamino and 1 is 0 or an integer of 1 to 6, (11) -ORall wherein R a l l is hydrogen atom or optionally substituted Ci-6 alkyl (as defined above) or (12) Y- B (Z)w wherein ring B is

C

6 14 aryl, C3-8 cycloalkyl or heterocyclic group (as defined above), each Z is independently a group selected from the following group D,

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the following group D, C3- 8 cycloalkyl optionally substituted by 1 to substituent(s) selected from the following group D, C6-14 aryl CI-e alkyl optionally substituted by 1 to 5 substituent(s) selected from the following group D, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the following group D, wherein the heterocyclic group has 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, or heterocycle Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the following group D, wherein the heterocycle CI-6 alkyl is CI-6 alkyl substituted by heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group D, as defined above, group D: hydrogen atom, halogen atom, cyano, nitro, optionally substituted C 1 -6 alkyl (as defined above), -(CH2)t-COR a "e (hereinafter each t means independently 0 or an integer of 1 to 6), wherein Ra 18 is optionally substituted CI-6 alkyl (as defined above), C6- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from.

the above group B wherein the heterocyclic group has 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom,

-(CH

2 t-COORa 19 wherein Ra 19 is hydrogen atom, optionally substituted C 1 -6 alkyl (as defined above) or C6- 14 aryl C 1 -6 alkyl optionally substituted by 1 to substituent(s) selected from the above group

B,

-(CH

2 )t-CONRa27R 2 8 wherein R a27 and R a28 are each independently, hydrogen atom, optionally substituted C- 16 alkyl (as defined above),

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the above group

B,

C

6 14 aryl C-s 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle Ci- 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, wherein the heterocycle CI-6 alkyl is CI-6 alkyl substituted by heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, as defined above,

C

3 8 cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

3 8 cycloalkyl CI-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, hydroxyl group or

C-

6 alkoxy,

-(CH

2 )t-C NR 33 )NH2 wherein Ra 33 is hydrogen atom, Ci-6 alkyl, hydroxyl group or Ci-6 alkoxy, (CH2)t-ORa 20 wherein R a 20 is hydrogen atom, optionally substituted Ci-6 alkyl (as defined above), optionally substituted C2- 6 alkenyl (as defined above),

C

2 6 alkynyl optionally substituted by 1 to 3 substituent(s) selected from the above group A, C6- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B,

C

6 14 aryl CI-E alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

3 8 cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, or

C

3 8 cycloalkyl C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, (CH2) t-O- (CH2)p-COR a wherein R a2 is amino, C 1 -6 alkylamino or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, and p is 0 or an integer of 1 to 6,

-(CH

2 tNRa22R 23 wherein R 22 and R a23 are each independently hydrogen atom, optionally substituted CI-6 alkyl (as defined above), C6- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B, C6-1 4 aryl Ci- 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B,

(CH

2 t-NRa 2 CO-Ra 2 4 wherein Ra2 9 is hydrogen atom, C alkyl or C wherein R is hydrogen atom, C 1 6 alkyl or C 16 alkanoyl, and R a 24 is amino,

C

1 6 alkylamino, optionally substituted Ci-6 alkyl (as defined above),

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B or heterocycle C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

-(CH

2 t-NRa29SO-Ra25 wherein R 29 is as defined above, and Ra 25 is hydrogen atom, optionally substituted CI- 6 alkyl (as defined above),

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, (CH2)t-S q-Ra 2 wherein R a25 is as defined above, and q is 0, 1 or 2,

(CH

2 t-SO2-NHRa 2 6 wherein R a26 is hydrogen atom, optionally substituted CI-6 alkyl (as defined above), C6- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, and heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, and w is an integer of 1 to 3, and Y is a single bond, CI-6 alkylene,

C

2 6 alkenylene, -(CH2)m-O-(CH2)n-, (hereinafter m and n are each independently 0 or an integer of 1 to 6),

-CO-,

-CO2-(CH2)n-, -CONH- (CH2) n-NH-, -NHC0 2

-NHCONH-,

-O-(CH

2 )n-CO-, (I11') (CH2) n-O-, -S0 2

(CH

2 )mNR a 2

(CH

2 )nwherein R 12 is hydrogen atom, optionally substituted C 1 -6 alkyl (as defined above),

C

6 14 aryl C 1 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B,

-COR

wherein R b5 is hydrogen atom, optionally substituted Ci-6 alkyl (as defined above), Cs- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B or C6-14 aryl CI- 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, -COORbs (Rb is as defined above) or -S0 2 Rb 5 (Rb 5 is as defined above), -NRal2CO- (R a12 is as defined above), -CONRl3_ (CH 2 nwherein Ra 3 is hydrogen atom, optionally substituted CI-6 alkyl (as defined above) or C6- 14 aryl CI-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, -CONH-CHRa 14 wherein R a14 is C6- 14 aryl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

(CH

2 m-CRa 5 Ra 16

(CH

2 nwherein R s 15 and Ra 16 are each independently hydrogen atom, carboxyl,

C

1 -6 alkyl, -ORb 6 wherein Rb 6 is C 1 -6 alkyl or C6- 14 aryl CI-6 alkyl, or

-NHR

b wherein Rb 7 is hydrogen atom, CI-6 alkyl, CI-6 alkanoyl or C6- 14 aryl Ci-6 alkyloxycarbonyl, or Ra 15 is optionally (CH2) B wherein ring Z' and w' are the same as the above-mentioned n, ring B, Z and w, respectively, and may be the same as or different from the respective counterparts,

-(CH

2 -NRal2_-HRal 5

(R

a12 and Ra 15 are each as defined above), -NRa7SO2wherein Ra 17 is hydrogen atom or CI-6 alkyl, -S(O)e-(CH2)m-CRal 5 Ral6-(CH 2 (e is 0, 1 or 2, R and R a 6 are each as defined above), or

(CH

2 )m-CRalRa 1 6

(CH

2 (Ra1 5 and Ra 16 are each as defined above).

The therapeutic agent of above, wherein 1 to 4 of the G 1

G

2

G

3

G

4

G

5 G G 6

G

7

G

8 and G 5 is (are) a nitrogen atom.

The therapeutic agent of above, wherein G 2 is C(-R 2 and

G

6 is a carbon atom.

The therapeutic agent of or above, wherein G 5 is a nitrogen atom.

The therapeutic agent of above, wherein, in formula the moiety i2 G 8- G 9 3-G 7 G 6 3 G'9 4.G..

is a fused ring selected from R N R2'~Jz

R'

R3 R N R ZL" R 3

R

3

R,

R N R3 RR4 and R The therapeutic agent of above, wherein, in formula the moiety 8.-G7

G

4

.G

is a fused ring selected from is a fused ring selected from

R

and and The therapeutic agent of above, which comprises a fused ring compound of the following formula [I-l]

R

1

R

7 3

R

wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof as an active ingredient.

The therapeutic agent of above, which comprises a fused ring compound of the following formula [1-2]

R'

The therapeutic agent of above, which comprises a fused ring compound of the following formula [1-31

R'

R2 N R A x [A1-3] wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof as an active ingredient.

The therapeutic agent of above, which comprises a fused ring compound of the following formula [1-4]

R

1 R 2

R

A

3 N V X [l-4] R

R

R Cy wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof as an. active ingredient.

(11) The therapeutic agent of any of to (10) above, wherein at least one of R 1

R

2

R

3 and R 4 is carboxyl, -COORa l -CONRa 2 Ra3, -SO2R a (wherein R a1 R a2

R

a3 and R a7 are as defined in

N-

0 NN-. N '-c^0 N-N N- 0 N-S V- 0 H H H or H (12) The therapeutic agent of (11) above, wherein at least one of

R

1

R

2

R

3 and R 4 is carboxyl, -COORal, -CONRa2Ra 3 or -SO 2

R

e7 wherein Ra l Ra 2 R1 3 and Ra 7 are as defined in (13) The therapeutic agent of any of to (10) above, wherein at least one of R R 2

R

3 and R' is -COOR 1 al wherein R al is glucuronic acid residue.

(14) The therapeutic agent of any of to (10) above, wherein at least one of R 1

R

2

R

3 and R 4 is heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom.

The therapeutic agent of any of to (14) above, wherein the ring Cy is cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrothiopyranyl or piperidino.

(16) The therapeutic agent of any of to (14) above, wherein the ring Cy is N)u )v wherein each symbol is as defined in (17) The therapeutic agent of any of to (16) above, wherein the ring A is Cs614 aryl.

(18) The therapeutic agent of any of to (17) above, wherein at least one substituent optionally substituted by group A is a substituent substituted by Ci-6 alkoxy Ci-6 alkoxy.

(19) The therapeutic agent of any of to (17) above, wherein the Y is -(CH 2 )m-CRa1sRa- (CH 2 wherein each symbol is as defined zo in The therapeutic agent of any of to (19) above, wherein.

at least one group represented by Z is heterocycle Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the group D.

Is (21) The therapeutic-agent of any of to (19) above, whereinat least one group represented by Z is a heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group D, wherein said heterocyclic group is selected from the following groups: Nx Ra 3 0 0

S

0 0 0--E

S-K

tE -'0 0-S

S-

X-.EZ

-N J)

,N

E--N

-N h0 0

-NW~

-N S=0 0

S'-E

2 /s 2 -N f .h 0 -N 0 0'° 0 S E2 -V(J])f

R

3 N \am wherein El is an oxygen atom, a sulfur atom or N(-R a 35

E

2 is an oxygen atom, CH2 or N(-Ra 35

E

3 is an oxygen atom or a sulfur atom, wherein each Raa 5 is independently hydrogen atom or CI- 6 alkyl, f is an integer of 1 to 3, and h and h' are the same or different and each is an integer of 1 to 3.

lo (22) The therapeutic agent of (21) above, wherein at least one group represented by Z is heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group D wherein said heterocyclic group is selected from the following groups: a\ a 0 0 2 0 -N J/ /S--E2 /S'-E2 f -N )f f and wherein each symbol is as defined in (21).

(23) The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is (CH 2 t-CONRa2 Ra28 wherein each symbol is as defined in and at least one of R a27 and R 28 is C 1 6 alkoxy.

(24) The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is (CH2)t-C(=NR 33

)NH

2 wherein each symbol is as defined in and Re33 is hydroxyl group or C 1 -6 alkoxy.

The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is -(CH2)t-O- (CH2)p-COR a2 wherein each symbol is as defined in and Ra 21 is amino.

(26) The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is (CH 2 )t-NRa 2 9CO-Ra2l 4 wherein each symbol is as defined in and R a24 is amino or C 1 -6 alkylamino.

(27) The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is -(CH2)t-NRa2 Ra2 wherein each symbol is as defined in claim 1, and at least one of

R

a 22 and R a23 is amino or Ci- 6 alkylamino.

(28) The therapeutic agent of any of to (19) above, wherein at least one group represented by group D is heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom.

(29) A fused ring compound of the following formula [II]

I

2" G 8--G 7 G G 3 '9 1'

G

4

G

G- I -Y B (Z)w III wherein the moiety 7 3 9 6

G

is a fused ring selected from R' 7 R R R' R3N R 3 R3' N R 3

N

R and R wherein R 1

R

2

R

3 and R 4 are each independently, hydrogen atom, Ci-6 alkanoyl, carboxyl, cyano, nitro,

C

1 -6 alkyl optionally substituted by 1 to.3 .substituent(s) selected from the following group A, group A; halogen atom, hydroxyl group, carboxyl, amino,

C

1 -6 alkoxy, C 1 -6 alkoxy C 1 -6 alkoxy, CI-6 alkoxycarbonyl and Cl-6 alkylamino, -COORal wherein Ra l is optionally substituted Ci- 6 alkyl (as defined above), C 6 -1 4 aryl C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the following group B or glucuronic acid residue, group B; halogen atom, cyano, nitro, CI-6 alkyl, halogenated CI-6 alkyl, CI-6 alkanoyl,

(CH

2 r-COOR b

(CH

2 -CONRbR b2

(CH

2 r-NRb 1

R

b2

-(CH

2 r-NRbl-COR b

(CH

2 r-NHS 2 Rbl, (CH 2 r-ORb

(CH

2 c-SR', (CH 2 r-SO 2 Rb and (CH 2

-SO

2 NRblRb2 wherein R bl and Rb 2 are each independently hydrogen atom or C 1 -6 alkyl and r is 0 or an integer of 1 to 6, -CONRa 2 Ra 3 wherein R a2 and R a3 are each independently hydrogen atom, Ci-6 alkoxy or optionally substituted C 1 -6 alkyl (as defined above), -C (=NRa 4

NH

2 wherein Ra 4 is hydrogen atom or hydroxyl group, (10) -NHRa wherein Ra 5 is hydrogen atom, CI-6 alkanoyl or C 1 -6 alkylsulfonyl, (11) -ORa 6 wherein R a6 is hydrogen atom or optionally substituted Ci-6 alkyl (as defined above), (12) -SO 2 Ra 7 wherein Ra 7 is hydroxyl group, amino, CI-6 alkyl or CI-6 alkylamino, (13) (ORa 31 )2 wherein Ra 31 is hydrogen atom, optionally substituted C 1 6 alkyl (as defined above) or C6- 14 aryl CI-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, or (14) heterocyclic group having 1 to 4 heteroatom(s).

selected from an oxygen atom, a nitrogen atom and a sulfur atom, and

R

7 is hydrogen atom or optionally substitute C 1 -6 alkyl (as defined above), ring Cy' is

C

3 8 cycloalkyl optionally substituted by.1 to substituent(s) .selected from the following group C, group C; hydroxyl group, halogen atom, C 1 -6 alkyl and Cl-6 alkoxy, or (2) )u0)v

S

)u >)v wherein u and v are each independently an integer of 1 to 3, ring A' is a group selected from a group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 26 cyclohexyl, cyclohexenyl, furyl and thienyl, R1' and R 6 are each independently hydrogen atom, halogen atom, optionally substituted Ci- 6 alkyl (as defined above) or hydroxyl group ring B is

C

6 14 aryl,

C

3 8 cycloalkyl or heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, each Z is independently a group selected from the following group D,

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the following group D,

C

3 8 cycloalkyl optionally substituted by 1 to substituent(s) selected from the following group D,

C-

14 aryl Ci-6 alkyl optionally substituted by 1 to substituent(s) selected from the following group D, heterocyclic group optionally substituted by 1 to substituent(s) selected from the following group D wherein the.heterocyclic group has 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, or .heterocycle Ci- 6 alkyl optionally substituted by 1 to substituent(s) selected from-the following group D wherein the heterocycle CI-6 alkyl is C 1 6 alkyl substituted by heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group.D, as defined above, group D: hydrogen atom, halogen atom, cyano, nitro, optionally substituted C 1 -6 alkyl (as defined above), t-CORale, (hereinafter each t means independently 0 or an integer of 1 to 6), wherein Ral 8 is optionally substituted Ci- 6 alkyl (as defined above), C-i14 aryl optionally substituted by 1 to substituent(s) selected from the above group B-or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B wherein the heterocyclic group has 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom,

(CH

2 t-COORal 9 wherein R a19 is hydrogen atom, optionally substituted CI-6 alkyl (as defined above) or

C

6 14 aryl Ci- 6 alkyl optionally substituted-by 1 to. 5 substituent(s) selected from the above.

group B,

(CH

2 t-CONRa 27 Ra28 wherein R a 27 and R a 28 are each independently, hydrogen atom, optionally substituted Ci- 6 alkyl (as defined above),

CG-

14 aryl optionally substituted by. 1 to substituent(s) selected from the above group

B,

C6-14 aryl Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle Ci- 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, wherein the heterocycle C 1 -6 alkyl is C 1 6 alkyl substituted by heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, as defined above, s C 3 8 cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

3 -8 cycloalkyl Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, hydroxyl group or

CI-

6 alkoxy, -(CH2)t-C(=NRa33) NH 2 wherein Ra 33 is hydrogen atom, CI-6 alkyl, hydroxyl group or CI-6 alkoxy,

(CH

2 t-ORa 20 wherein R a 2 0 is hydrogen atom, optionally substituted C 1 6 alkyl (as defined above), optionally substituted C2-6 alkenyl (as defined above),

C

2 6 alkynyl optionally substituted by 1 to 3 substituent(s) selected from the above group A,

C

6 14 aryl C-e 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle C 1 -6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

38 cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, or C3-8 cycloalkyl CI-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

(CH

2 t-O- (CH2) p-CORa 21 wherein Ra 2 l is amino, C 1 -6 alkylamino or heterocyclic group optionally substituted-by 1 to 5 substituent(s) selected from the above group B, and p is 0 or an integer of 1 to 6, a22 a3 (CH2) t-NRa22R a 2 3 wherein R a 22 and Ra 23 are each independently hydrogen atom, optionally substituted Ci-6 alkyl (as defined above),

C

6 14 aryl Cls.alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, heterocycle Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, -(CH2)t-NRa 2 9 CO-Ra 2 wherein Ra 2 is hydrogen atom, CI-6 alkyl or CI-6 alkanoyl, and Ra24 R is amino,

C

1 -6 alkylamino, optionally substituted C 1 -6 alkyl (as defined above),

CS-

14 aryl optionally substituted by 1 to substituent(s) selected from the above group B, heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, or heterocycle Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, (CH2) t-NR a29

S

O2

-R

a2 wherein R 2 z9 is as defined above, and jo R a25 is hydrogen atom, optionally substituted Ci-6 alkyl (as defined above), Cs- 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B,

(CH

2 t-S

-R

a2 wherein R a 25 is as defined above, and q is 0, 1 or 2, (CH) t-SOz-NHRa 26 wherein R 26 is hydrogen atom, optionally substituted CI-6 alkyl (as defined above),,

C

6 4 -aryl optionally substituted by 1 to substituent(s) selected from the above group B or heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the above group B, and heterocyclic group having 1 to 4 heteroatom(s) .selected from an oxygen atom, a nitrogen atom and a sulfur atom, w is an integer of 1 to 3, and Y is a single bond,

C

1 -6 alkylene,

C

2 -6 alkenylene,

-(CH

2 m-0-(CH2)n-, (hereinafter m and n are each independently 0 or an integer of 1 to 6),

-CO-,

-C02- (CH2) n-, -CONH- (CH2)n-NH-, -NHC0 2

-NHCONH-,

(CH

2 (11) -0-(CH2)n-0-, (12) -SO 2 (13) (CH 2 )-NRal2- (CH 2 )nwherein Ra 12 is hydrogen atom, optionally substituted CI-6 alkyl (as defined above),

C

6 1 4 aryl C1-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B,

C

6 14 aryl optionally substituted by 1 to substituent(s) selected from the above group B, -CORbS wherein Rb 5 is hydrogen atom, optionally substituted C1-6 alkyl (as defined above), C6-14 aryl optionally substituted by 1 to 5 substituent(s) selected from the above group B or C6-14 aryl Ci-6 alkyl optionally substituted by 1 to substituent(s) selected from the above group B, -COORbS (Rb is as defined above) or

-SO

2 Rbs (Rb 5 is as defined above), (14) -NRa1CO- (Ra 12 is as defined above),

-CONR

1 (CH2) nwherein Ra 13 is hydrogen atom, optionally substituted Ci-6 alkyl (as defined above) or C6-14 aryl Ci-6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, (16) -CONH-CHRa 14 wherein R a14 is C 6 14 aryl optionally substituted by 1 to 5 substituent(s) selected from the above group B, (17) (CH 2 m-CRalSRal 6

(CH

2 nwherein Ra 15 and Ra 16 are each independently hydrogen atom, carboxyl,

CI-

6 alkyl,

-OR

b6 wherein Rb 6 is CI- 6 alkyl or C6- 14 aryl CI-6 alkyl, or -NHRb 7 wherein Rb 7 is hydrogen atom, Ci-6 alkyl, C 1 i 6 alkanoyl or C 6 14 aryl Ci- 6 alkyloxycarbonyl, or

R

a15 is optionally

(CH

2 B wherein ring Z' and w' are the same as the above-mentioned n, ring B, Z and w, respectively, and may be the same as or different from the respective counterparts,' (18) -(CH 2 )n-NRa12-CHR a 15

(R

a 12 and R a 15 are each as defined above), (19) -NRa1 7 SO2wherein R a17 is hydrogen atom or Ci- 6 alkyl, -S(O)e-(CH 2 )m-CRalRa 16

(CH

2 (e is 0, 1 or 2,

R

a15 and R a P are each as defined above), or (21) -(CH2) -CR alRa16-(CH2)n- (Ra 15 and Ra 16 are each as defined above), or a pharmaceutically acceptable salt thereof.

The fused ring compound of (29) above, which is represented by the following formula [II-l] (Z)w [I -1] wherein each symbol is as defined in (29), or a pharmaceutically acceptable salt thereof.

(31) The fused ring compound of (29) above, which is represented by the following formula [11-2] R

I

A' (zw [I -2] X

N

wherein each symbol is as defined in (29), or a pharmaceutically acceptable salt thereof (32) The fused ring compound of (29) above, which is represented by the following formula [11-3] A' y B (Z [11-3] R N N N R 6' wherein each symbol is as defined in (29), or a pharmaceutically acceptable salt thereof.

(33) The fused ring compound of (29) above, which is represented by the following formula [11-4] N A' Y B (Z)w [I1-4] wherein each symbol is as defined in (29), or a pharmaceutically acceptable salt thereof.

(34) The fused ring compound of any of (29) to (33) above, wherein at least one of R, R 2

R

3 and R 4 is carboxyl, -COORal, -CONRa2Ra3, -SO 2 Ra 7 (wherein Ra l Ra 2

R

a 3 and Ra 7 are as defined in N- 0 N-N N 0

NSN

H H H or H or a pharmaceutically acceptable salt thereof.

1o (35) The fused .ring compound of (34) above, wherein at least one of R 1

R

2

R

3 .and R 4 is carboxyl, -COOR al or -S0 2 R wherein. R a and

R

a7 are as defined in or a pharmaceutically acceptable salt thereof.

(36) The fused ring compound of (35) above, wherein at least one of R 2

R

3 and R 4 is carboxyl or -COOR l wherein R l is as defined in or a pharmaceutically acceptable salt thereof.

(37) The fused ring compound of (36) above, wherein R 2 is carboxyl and R 3 and R 4 are hydrogen atoms, or a pharmaceutically acceptable salt thereof.

(38) The fused ring compound of any of (29) to (33) above, wherein at least one of R 2

R

3 and R 4 is -COORal wherein Ral is glucuronic acid residue, or a pharmaceutically acceptable salt thereof.

(39) The fused ring compound of any of (29) to (33) above, wherein at least one of Ri, R 2

R

3 and R 4 is heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, or a pharmaceutically acceptable salt thereof.

The fused ring compound of any of (29) to (39) above, wherein the ring Cy' is cyclopentyl, cyclohexyl, cycloheptyl or tetrahydrothiopyranyl, or a pharmaceutically acceptable salt thereof.

(41) The fused ring compound of (40) above, wherein the ring Cy' is cyclopentyl, cyclohexyl or cycloheptyl, or a pharmaceutically acceptable salt thereof.

(42) The fused ring compound of any of (29) to (39) above, wherein the ring Cy' is

N

)v wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof.

(43) The fused ring compound of any of (29) to (42) above, wherein the ring A' is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, or a pharmaceutically acceptable salt thereof.

(44) The fused ring compound of (43) above, wherein the ring A' is phenyl or pyridyl, or. a pharmaceutically acceptable salt thereof.

The fused ring compound of (44) abovej wherein the ring A' is phenyl, or a pharmaceutically acceptable salt thereof.

(46) The fused ring compound of any of (29) to (45) above, wherein at least one substituent optionaly substituted by group A is 4 substituent substituted by Ci-6 alkoxy CI-6 alkoxy, or a pharmaceutically acceptable salt thereof.

(47) The fused ring compound of any of (29) to (46) above, wherein the Y is (CH)m-0- (CH 2 -NHCOz-, -CONH-CHRa 14 (CH) m-NR a l 2 (CH) n -CONR-CH2)n-, (CH2) -CRaRa 6 (CH2) n- or -(CH2)n-NRa2-CHRa 1 (wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof.

(48) The fused ring compound of (47) above, wherein the Y is

(CH

2

(CH

2 n- or -0-(CH2) m-CRalRa 16

(CH

2 n- (wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof..

(49) The fused ring compound of (48) above, wherein the Y is

-(CH

2 )m-O-(CH 2 wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof.

The fused ring compound of any of (29) to (46) above, wherein the Y is -(CH 2 )m-CRaR a16 (CH2)n- (wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof.

(51) The fused ring compound of any of (29) to (50) above, wherein the R 2 is carboxyl, R 3 and R 4 are hydrogen atoms, the ring Cy' is cyclopentyl, cyclohexyl or cycloheptyl, and the ring A' is phenyl, or a pharmaceutically acceptable salt thereof.

lo (52) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by Z is heterocycle Ci.

6 alkyl optionally substituted by 1 to 5 substituent(s) selected from the group D, or a pharmaceutically acceptable salt thereof.

(53) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by Z is heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group D, wherein said heterocyclic group is selected from the following groups: S0. W 0 N 0 N-.E1 E

N~

0 E 0p 0 0 E 0- 0 0, ,F _0

S

k- 0 0 00.

E S--E2 Nf f N f JN\- )f -NiS=0 -NA a M h h0 N R a 3 5 N 3 3--N and

R

wherein El is an oxygen atom, a sulfur atom or N(-R 35

E

2 is an oxygen atom, CH 2 or N(.-Ra 35

E

3 is an oxygen atom or a sulfur atom, wherein each R a35 is independently hydrogen atom or Ci- 6 alkyl, f is an integer of 1 to 3, and h and h' are the same or different and each is an integer of 1 to 3, or a pharmaceutically acceptable salt thereof.

(54) The fused ring compound of (53) above, wherein at least one group represented by Z is heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group D, wherein said heterocyclic group is selected from the following groups: 0 2,S- -N f -NJ)f -N )f and wherein each symbol is as defined in or a pharmaceutically acceptable salt thereof.

The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is -(CHz)t- CONR27Ra28 wherein each symbol is as defined in and at least one of R a 27 and R a 28 is C 1 6 alkoxy, or a pharmaceutically acceptable salt thereof.

(56) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is -(CHz)t- C(=NR a33)NH2 wherein each symbol is as defined in and R a33 is hydroxyl group or C 1 -6 alkoxy, or a pharmaceutically acceptable salt thereof.

(57) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is -(CH 2 )t-O-

(CH

2 )p-COR a21 wherein each symbol is as defined in and R a21 is amino, or a pharmaceutically acceptable salt thereof.

(58) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is -(CH2)t- NRa29CO-Ra24 wherein each symbol is as defined in and Ra24 is o1 amino or Ci-6 alkylamino, or a pharmaceutically acceptable salt thereof.

(59) The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is -(CH 2

NR

2 Ra2 3 wherein each symbol is as defined in and at least one of Ra 2 and R 23 is heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from the group B, or a pharmaceutically acceptable salt thereof.

The fused ring compound of any of (29) to (51) above, wherein at least one group represented by group D is heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom,. a nitrogen atom and a sulfur atom, or a pharmaceutically acceptable.

salt thereof.

(61) The fused ring compound of the formula or a pharmaceutically acceptable salt thereof, which is selected from.

the group consisting of ethyl 2-[4-(3-bromophenoxy)phenyl] carboxylate (Example 1), (3-bromophenoxy)phenyl] carboxylic acid (Example 2), ethyl l-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5carboxylate (Example 3), ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-l- (Example 4), ethyl 2-4 4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl -l- (Example 2- 4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl -lacid (Example 6), ethyl 2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1- (Example 7), 39 ethyl 2A 4- (4-chiorophenyl) -5-methoxybenzyloxy] phenyl (Example 8), 2-14- (4-chiorophenyl) -5-methoxybenzyloxylphenyl -1acid (Example 9), ethyl 1-cyclohexyl-2- 4- -2-phenylvinyl] phenyl Ibenzimidazole- (Example 1-cyclohexyl-2-1 4- -2-phenylvinyl] phenyl carboxylic acid-(Example 11), 2- (4-benzyloxyphenyl) lo acid (Example 12), 2- (4-benzyloxyphenyl) (Example 13), 2- (4-benzyloxyphenyl) -5-cyano-1-cyclopentylbenzimidazole (Example 14), 1s 2- (4-benzyloxyphenyl) oxirne (Example ethyl 1-cyclohexyl-2-i 4-H 4- (4-f luorophenyl) thiazolyl kfethoxy] phenyl ~benzimidazole-5-carboxylate (Example 16)', 1-cyclohexyl-2-1 4- 4- (4-fluorophenyl) -2-mnethyl-5-thiazolyP methoxylphenydbenzimidazole-5-carboxylic acid (Example 17),.

ethyl 1-cyclohexyl-2- (2-fluoro-4-hydroxyphenyl) carboxylate (Example 18), ethyl 2- 4- [bis (3-fluorophenyl)methoxy] -2-fluorophenyP -1- (Example 19), 2- 4- [bis (3-fluorophenyl)methoxy] -2-fluorophenyl acid (Example ethyl 1-cyclopentyl-2- (4-nitrophenyl) (Example 21), ethyl 2- (47aminophenyl) 3o (Example 22), ethyl 2- (4-benzoylaminophenyl) carboxylate (Example 23), 2- (4-benzoylaninophenyl) acid (Example 24), ethyl 2- 4- (3-chlorophenyl) phenoxy]phenyl (Example 2-4- (3-chiorophenyl) phenoxy] phenyl acid (Example 26), ethyl (3-acetoxyphenyloxy)phenyl]-1- (Example 27), ethyl 1-cyclohexyl-2- (3-hydroxyphenyloxy) phenyl] (Example 28), ethyl 1-cyclohexyl-2- 4- (4-pyridylmethoxy) phenyloxy] phenyl K (Example 29), 1-cyclohexyl-2-1 4- (4-pyridylmethoxy) phenyloxy] phenyl K acid (Example 2- (4-benzyloxyphenyl) -1-cyclopentylbenzimnidazole (Example 31), ethyl 2- (4-benzyloxyphenyl) carboxylate (Example 32), 2- (4-benzyloxyphenyl) -1-cyclopentyl-N, carboxaxnide (Example 33), 2-(C4-benzyloxyphenyl) -1-cyclopentyl-N-methoxy-Nmethylbenzimidazole-5-carboxatide (Example 34), 2- (4-benzyloxyphenyl) -1-cyclopentyl-5- (1-hydroxy-lmethylethyl)benzimidazole (Example 5-acetyl-2- (4-benzyloxyphenyl) -1-cyclop n-tylbenzimidazole (Example 36),, 2- (4-benzyloxyphenyl) -1-cyclopentyl-N- (2-dimethylaminoethyl.) dihydrochioride (Example 37.), 2- (4-benzyloxyphenyl) (Example 38), 5-amino-2- (4-beuzyloxyphenyl) -1-cyclopentylbenzimidazole hydrochloride (Example 39), 5-acetylainino-2- (4-benzyloxyphenyl) -l-cyclopentylbenzimidazole (Example 2- (4-benzyloxyphenyl) aminobenzimidazole (Example 41), 5-sulfamoyl-2- (4-benzyloxyphenyl) -l-cyclopentylbenzimidazole (Example 42), 2- (4-tert-butylbenzyloxy) phenyll -1-cyclopentylbenziiuidazoleacid (Example 43), 2- (4-carboxybenzyloxy) phenyl] carboxylic acid (Example 44), 2- (4-chlorobenzyloxy) phenyl) carboxylic acid (Example acid (Example 46), 1-cyclopentyl-2- (4-trifluoromethylbenzyloxy) phenyl] acid (Example 47), I-cyclopentyl-2- (4-methoxybenzyloxy) phenyl] carboxylic acid (Example 48), l-cyclopentyl-2- (4-pyridylmethoxy) phenyl] carboxylic acid hydrochloride (Example 49), 1-cyclopentyl-2- (4-rethylbenzyloxy) phenyl] carboxylic acid. (Example 1-cyclopentyl-2-1 5-dimethyl-4-isoxazolyl)methoxylphenyljacid (Example 51), 1-cyclopentyl-2- (4-hydroxyphenyl) benzimidazole-5-carboxylic acid (Example 52), (4-benzyloxyphenyl) -l-cyclopentylbenzimidazol-5-yl] carbonylaminoacetic acid (Example 53), (2-chlorobenzyloxy) phenyl] carboxylic acid -(Example 54), 2- (3-chlorobenzyloxy) phenyl] carboxylic-acid .(Exam'ple 2- (4-benzyloxyphenyl) acid (Example 56), 2- (benzenesultonylamino) phenyl carboxylic acid (Example 57), 1-cyclopentyl-2- 5-dichlorophenylcarbonylauino) phenyl] acid (Example 58), 2-i (4-chiorophenyl) carbonylamino] phenyl acid (Example 59),.

2-1 4- ii(4-tert-butylphenyl) carbonylamino] phenyl -1cyclopentylbenzimidazole-5-carboxylic acid (Example 2- 4- [(4-benzyloxyphenyl) carbonylamino] phenyl acid (Example 61), trans-4- (4-benz yloxyphenyl) yllcyclohexan-1-ol. (Example 62), trans-i- (4-benzyloxyphenyl) -5-carboxybenzimidazol-1-yl] -4methoxycyclohexane (Example 63), 2- (4-benzyloxyphenyl) (Example 64), 2- 1-benzyioxycarbonyl-4-piperidyl] -1-cyclopentylbenzinidazoleacid (Example 2-[l(4-cyclohexyiphenyl) carbonylamino] -1acid (Example 66), 1-cyclopentyl-2- 5-dichlorobenzyloxy) phenyll benzimidazoleacid (Example 67), l-cyclopentyl-2- 4-dichlorobenzyloxy)phenyl]benzimidazoleacid (Example 68), 1-cyclopentyl-2- (phenylcarbamoylamino) phenyl] io carboxylic acid (Example 69), 1-cyclopentyl-2- (diphenylmethoxy) phenyl] carboxylic acid (Example 1-cyclopentyl-2- (4-phenethyloxyphenyl) acid (Example 71), trans-i- (4-benzyloxyphenyl) -5-carboxybenzimidazol-1-yl] -4tert-butylcyclohexane (Example 72), 2- (4-benzyloxyphenyl) -5-carboxymethoxy-1cyclopentylbenzimidazole (Example 73), 2- (4-benzylaminophenyl) 2o acid (Example 74), 2-14- (N-benzenesui fonyl-N-methylamino) phenyl 1-1acid (Example (N-benzyl-N-methylamino) phenyl] -1-cyclopentylbenzimidazoleacid (Example 76), 1-cyclohexyl-2- (4-phenethyiphenyl) benzimidazole-S-carboxylic acid (Example 77), 2- (1-benzyl-4-piperidyl) acid (Example 78), 2- (1-benzoyl-4-piperidyl) carboxylic acid (Example 79), 1-cyclopentyl-2- [1-(p-toluenesulfonyl) -4-piperidyl] acid (Example 1-cyclohexyl-2- 5-dichlorobenzyloxy) phenyl] carboxylic acid (Example 81), 1-cyclohexyl-2- (diphenylinethoxy) phenyl] carboxylic aci& (Example 82), 1-cyclohexyl-2- 5-di-tert-butylbenzyloxy)phenyl] acid (Example 83), 2- (4-benzyloxyphenyl) -1-(4-methylcyclohexyl) carboxylic acid (Examnple 84), l-cyclohexyl-2-A 4- (2-naphthyl) ethoxy] phenyl ~benz imidazole- carboxylic acid (Example 1-cyclohexyl-2- (l-naphthyl) methoxyphenyll carboxylic acid (Example 86), l-cyclohexyl-2- (dibenzylamino) carboxylic acid (Example 87), 2- (2-biphenylylmethoxy) phenyl] carboxylic acid (Example 88), 2-(4-berizyloxyphenyl) acid (Example 89), 1-cyclohexyl-2- (dibenzylmethoxy) phenyl] carboxylic acid (Example 2- (4-benzoylmethoxyphenyl) carboxylic acid (Example 91), 2- (4-benzyl-1-piperazinyl) carboxylic acid dihydrochioride (Example 92), 1-cyclohexyl-2- 3-diphenyipropyloxy) phenyl] benzimidazole- carboxylic acid (Example 93), (3-chloro-6-phenylbenzyloxy) phenyl] -1acid (Example 94), 2- (4-benzyloxypiperidino) acid (Example 1-cyclohexyl-2-{ 4- (phenoxy) ethoxy] phenyl carboxylic acid (Example 96), l-cyclohexyl-2- carboxylic acid (Example 97), l-cyclohexyl-2- C5-phenylpentyloxy).phenyl] carboxylic acid (Example 98), 2- (3-benzyloxy-5-isoxazolyl) carboxylic acid (Example 99), 2- (2-benzyJloxy-5-py-ridyl) acid (Example 100), 1-cyclohexyl-2-1~4- 5-trimethoxyphenyl) ethoxy] phenyl Facid (Example 101), 2- (4-benzyloxyphenyl) carboxylic acid (Example 102), 1-cyclohexyl-2-A4- (1-naphthyl) carboxylic acid (Example 103), 2- (2-benzyloxyphenoxy) phenyl] carboxylic acid (Example 104), 2- (3-benzyloxyphenoxy)phenylj carboxylic acid (Example 105), 1-cyclohexyl-2- (2-hydroxyphenoxy) phenyll carboxylic acid (Example 106), 1-cyclohexyl-2- carboxylic acid .(Example 107), 1-cyclohexyl-2- (2-methoxyphenoxy) phenyl] carboxylic acid (Example 108), 1-cyclohexyl-2- (3-methoxyphenoxy) phenyl] carboxylic acid (Example 109), l-cyclohexyl-2- carboxylic acid (Example 110), l-cyclohexyl-2- (3-propoxyphenoxy) carboxylic acid (Example 111), 1-cyclohexyl-2-1 4- (3-methyi-2-butenyloxy) phenoxy] phenyl K benzimidazole-5-carboxylic acid (Example. 112)., 1-cyclohexyl-2- (3-methyl-2-butenyloxy) phenoxy] phenyl K acid (Example 113)., 1-cyclohexyl-2- (2-isopentyloxyphenoxy) phenyl] carboxylic acid (Example 114), 1-cyclohexyl-2- (3-isopentyloxyphenoxy) phenyl carboxylic acid (Example 115), 1-cyclohexyl-2- 4- 11-dihydro-5H-dibenzo yl) ethoxylphenyl~benzimidazole-5-carboxylic Acid (Example 116), 1-cyclohexyl-2-I 4- (4-trifluoromethylphenyl)benzyloxyl phenylibenzimidazole-5-carboxylic acid (Example 11-7), 24- [bis (4-chlorophenyl)methoxy)phenyl -lZ acid (Example 118), 1-cyclohexyl-2-i 4- (4-methoxyphen'yl) ethoxyiphenylKacid (Example 119), l-cyclohexyl-2- 4- (2-methoxyphenyl) ethoxyiphenylKacid (Example 120), 1-cyclohexyl-2-A 4- (3-methoxyphenyl) ethoxy] phenyl?acid (Example 121), 2- (4-benzyloxyphenyl) acid (Example 122), 1-cyclohexyl-2- (2-phenethyloxyphenoxy) phenyl] carboxylic acid (Example 123), 1-cyclohexyl-2- (3-phenethyloxyphenoxy)phenyl] carboxylic acid (Example 124), 1-cyclohexyl-?- 2-diphenylethoxy) phenyl] carboxylic acid (Example 125), 2- (4-beozyloxyphenyl) -1-(3-cyclohexenyl) carboxylic acid (Example 126), cis-1- (4-benzyloxyphenyl) -5-carboxybenzimidazol-1-yl] fluorocyclobhexane (Example 127), 1-cyclohexyl-2- (2-phenoxyphenoxy) phenyl] carboxylic acid (Example 128), 1-cyclohexyl-2-f 4- carboxylic acid (Example 129), 2- (2R) -2-benzyloxycarbonylamino-2-phenylethoxy phenyl -1acid (Example 130)-, 1-cyclohexyl-2- 2-fluoro-4- (4-trifluoromethyiphenyl) benzyloxylphenylbenzimidazole-5-carboxylic acid (Example 131), 2- (4-benzyloxyphenoxy) carboxylic acid (Example 132), 24- [bis (4-methylphenyl)methoxylphenylY-1acid (Example 133), 2-14- [bis (4-fluorophenyl)methoxylphenyd -1acid (Example 134), l-cyclohexyl-6-methoxy-2-[4- (3-phenyipropoxy) phenyl] acid (Example 135), 1-cyclohexyl-6-hydroxy-2- (3-pheriylpropoxy) phenyl 1benzimidazole-5-carboxylic acid (Example 136), 1-cyclohexyl-6-methyl-2- (3-phenylpropoxy) phenyl]' acid (Example 137), (2-benzyloxyphenyl) ethoxylphenyli-lacid (Example 138), as 2-14- (3-benzyloxyphenyl) ethoxylphenyd -1acid (Example 139),.

(2-carboxymethyloxyphenoxy) phenyl] -1acid (Example 140), 2- (3-carboxymethyloxyphenoxy) pherxyl] -1acid (Example 141), 2- 4- (3-chioro- 6- (4-methyiphenyl) benzyloxyl phenyl K 1acid (Example 142), 2- 4- [3-chloro-6- (4-methoxyphenyl) benzyloxylphenylkacid (Example 143) 1-cyclohexyl-2-42--methyl-4- (4-trifluoromethyiphenyl)- acid (Example 144), 2-44- (4-tert-butyiphenyl) -5-chlorobenzyiloxylphenyl icyclohexylbenzimidazole-5-carboxylic acid .(Example 145), 24- (3-chloro-6-phenylbenzyloxy) -2-fluorophenyil-1acid (Example 146), 2- 4- 3-chloro-6- 5-dichiorophenyl) benzyloxy] phenyl s-iacid (Example 147), 1s 2- 4- [bis (4-fluorophenyl)maethoxyl -2-tluorophenyii-1acid (Example 148), 2- 4- (4-benzyloxyphenoxy) -2-chiorophenyl acid (Example 149), 2- 4- (4-benzyloxyphenoxy) -2-trifluoromethyiphenyl cyclohexylbenzimidazole-5-.carboxylic acid (Example. 150), 2-14- (3-chloro-6- (2-trifluoromethylphenyl)benzyloxylph-enyl acid (Example 151), 2- 44- -2-amino-2-phenylethoxylphenyl acid (Example 152), 2- (2-biphenylyloxy) phenyl] carboxylic acid (Example 153), (3-biphenylyloxy)phenyl] carboxylic acid (Example 154), 4- [2-1 (1-tert-butoxycarbonyl-4-piperidyl) methoxy~phenoxy] phenyl -1-cyclohexylbenzimidazole-5-carboxylic acid (Example 155), 2 4- 3-i (1 -tert-butoxycarbonyl -4 -piper idyl) methoxy~phenoxy) acid (Example 156), 2- 4- [3-chloro-6- 5-trimethoxyphenyl) benzyloxylphenyi>-1acid (Example 157), 2-44- (2r-biphenylyl) carboxylic acid (Example 158), 2-14- (2-biphenylylmethoxy) phenyl] carboxylic acid (Example 159), 1-cyclohexyl-2-A 4- (4-piperidylmethoxy) phenoxy] phenyl K acid hydrochloride (Example 160), 1-cyclohexyl-2-A 4- (4-piperidylmethoxy) phenoxy] phenyl K acid hydrochloride (Example 161), 2-A 4-f (2R) -2-acetylamino-2-phenylethoxyjphenyl acid (Example 162), 1-cyclohexyl-2-A 4- (4-xethyl-3-pentenyloxy) phenoxy] phenyl K acid (Example 163), 1-cyclohexyl-2- (3-iethyl-3-butenyloxy) phenoxy] pheny. K benzimidazole-5-carboxylic acid (Example 164), 2-i 4-H (23) -1-benzyl-2-pyrrolidinydrnethoxylphenylkl-cyclohexylacid hydrochloride (Example 165), 2-A 4-f3-chloro-6- (4-methylthiophenyl)benzyloxylphenyl acid.(Example 166), 2- 4- [3-chloro-6- (4-methanesulfonyiphenyl) benzyloxy] phenyl acid (Example 167), 21 4- [3-chloro-6- (2-thienyl)benzyloxylphenyl acid (Example 168),- 2-A 4- [3-chloro-6- (3-chlorophenyl)benzyloxylphenyl cyclohexylbenzimidazole-5-carboxylic acid (Example 169), 21 4- [3-chloro-6- (3-pyridyl)benzyloxylphenylkacid (Example 170), 2-1 4- [3-chloro-6- (4-fluorophenyl) benzyloxy] phenyl acid (Example 171), 2- (4-benzyloxyphenoxy) -3-fluorophenyl] -1acid (Example 172), 2- (2-bromo-5-chlorobenzyloxy) phenyl] -1acid (Example 173), 2- 4- [3-chloro-6- (4-chlorophenyl)benzyloxy] -2-fluorophenyd -1cyclohexylbenzimridazole-5-carboxylic acid (Example 174), 2-14- (l-acetyl-4-piperidy1)methoxy~phenoxylphenylj-1acid (Example 175), 2-A 4- [3-i (1-acetV1-4-piperidy1)methoxy~phenoxylpheny1K-1acid (Example 176), 1-cyclohexyl-2-i 4- (2-rpropynyloxy) phenoxy] phenyl benzimidazoleacid (Example 177), 1-cyclohexy1-2- 4- (3-pyridylmethoxy) phenoxy] phenyl K acid (Example 178), 48 2- (4-benzyloxy-2-methoxyphenyl) carboxylic acid (Example 179), 2- (2-bromo-5-methoxybenzyloxy)phenyl] -1acid (Example 180), 2- (carboxydiphenylmethoxy) phenyl] -1-cyclohexylbenzimidazoleacid (Example 181), 2-14- (4-chiorophenyl) -5-nitrobenzyloxylphenyli-1acid (Example 182), 2-14- [3-acetylamino-6- (4-chlorophenyl)benzyloxylphenyl--1cyclohexylbenzimidazole-5-carboxylic acid (Example 483), 2-1 4-12- (4-carboxyphenyl) -5-chlorobenzyloxylphenyl acid (Example 184), 2-14- (2S) -l-benzyloxycarbonyl-2-pyrrolidinyl hethoxy] phenyP -1acid (Example 185)., 2-i 2-chloro-4- (4-trifluorornethylphenyl) benzyloxyjphenyUlacid (Example 186)1 1-cyclohexyl-2-1 4- 3- (2-pyridylmethoxy) phenoxy-l phenyl acid (Example 187), 2-14- (4-chiorophenyl) -5-fluorobenzyloxy] phenyl} -1cyclohexylbenzimidazole-5-carboxylic acid (Example 188).,.

2-14- (3-carboxy-6- (4-chiorophenyl) benzyloxy] phenyl k-iacid (Example 189), 2-14- [3-carbarnoyl-6- (4-chlorophenyl)benzyloxylphenylj-1acid (Example 190), 1-cyclohexyl-2-1 4- (dimethylcarbamoylmethoxy) phenoxyl acid (Example. 191), 1-cyclohexyl-2-1 4- (piperidinocarbonylmethoxy) phenoxy] acid (Example 192), 2-14-[i (2S) -1-benzenesulfonyl-2-pyrrolidinylhnethoxylphenyii-1cyclohexylbenzimidazole-5-carboxylic acid (Example 193), 2-1 4- [1 (2S) -1-benzoyl-2-pyrrolidinylhaethoxyl phenyl4kacid-(Example 194), 2-14- (4-carbamoylphenyl) -5-chlorobenzyloxyl phenyl k-iacid (Example 195), 1-cyclohexyl-2-1 4- (dimethylcarbamoylmethoxy) phenoxy] acid (Example 196), 1-cyclohexyl-2-1 4- (pipe ridinocarbonylme thoxy) phenoxy] phenyl ~benzimidazole-5-carboxylic acid (Example 197), 1-cyclohexyl-2-A 4- 3-1 (1-methanesulfonyl-4-piperidyl) methoxy phenoxylphenylNbenzimidazole-s-carboxylic acid (Example 198) 1-cyclohexy1-2- 4- U 2-methyl-5- (4-chiorophenyl) -4-oxazolylkF acid (Example 199), 2- (3-chlorobenzyloxy)phenoxylphenylF-lacid (Example 200), 2-24- (4-chlorobenzyloxy)phenoxylphenyj -1acid (Example 201), 1-cyclohexyl-2-i 4-13- (4-fluorobenzyloxy) phenoxy] phenyl K 'a benzimidazole-5-carboxylic. acid (Example 202), 1-cyclohex y1-2- 4- (1 (2S) (4-nitrophenyl) -2-pyrrolidinylacid (Example 203), 1-cyclohexyl-2-A 4-[U (2S) -1-phenyl-2-pyrrolidinyl 6methoxy] acid hydrochloride (Example 125 204), 2A4- (1 (2S) (4 -ace tylaminophenyl) -2-pyrrolidinyl~methoxy] phenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid (Example 205), 2-1~4-US- (4-chlorophenyl) -2-methy1-4-thiazolyl~methoxylphenylKacid (Example 206), '2-14- [bis (3-fluorophenyl)methoxylphenyl acid (Example 207), 1-cyclohexyl-2-1 4- (4-chiorophenyl) -3-nitrobenzyloxylphenylKacid (Example 208), 1-cyclohexy1-2- (4-tetrahydropyranyloxy) phenoxy] phenyl K benzirnidazole-5-carboxylic acid (Example 209), 1-cyclohexyl-2-1 (4-trifluoromethylbenzyloxy) phenoxy] phenyl K acid (Example 210),' 1-cyclohexyl-2-1 4- 3- (l-methyl-4-piperidyl) methoxy~phenoxy] acid (Example 211), 2- 4- (4-tert-butylbenzyloxy) phenoxyllphenylj-1acid (Example 212), 2-i 4- (2-chlorobenzylbxy) phenoxylphenyl -1acid (Example 213), 1-cyclohexyl-2-i 4- (3-pyridyl) phenoxy] phenyl carboxylic acid-(Example 214), 2- (4-chlorophenyl)phenoxylphenylF-iacid (Example 215), 1-cyclohexyl-2- 443- (4-methoxyphenyijphenoxylphenylKacid (Example 216), 1-cyclohexyl-2- 4- H 4- (4-methanesul fonylphenyl) thiazolyl ~iethoxy] phenyl Wenzimidazole-5-carboxylic acid (Example 217), 2-14-HI4-(4-chiorophenyl) -2-methyl-5-thiazolyljmethoxylphenyij-1acid (Example 218), 24- [1-(4-chlorobenzyl) -3-piperidyloxylphenylj-1acid (Example 219), 1-cyclohexyl-2- 4- f3- (2-methy1-4-thiazolyl) methoxy~phenoxy] acid (Example 220), 1-cyclohexyl-2-1 4- [3-i 4-dimethly-5-thiazolyl)methoxy~phenoxy] acid (Example 221), l-cyclohexy1-2- 4- 5-dic-hiorophenyl) phenoxy] phenyl K benzimidazole-5-carboxylic acid (Example 222), 2-1 4- [1-(4-chlorobenzyl) -4-piperidyloxylp-enyl-lacid (Example 223), 2-14- (4-chlorobenzyloxy)piperidinolphenyjlacid (Example 224.), 2-14- (4-carbamoyl-2- (4-chlorophenyl)benzyloxylphenylacid (Example 225), 2-14- (4-chlorobenzyloxy)piperidinolphenyl acid.(Example 226), 2- 4- (2-chloro-4-pyridyl)methoxyphenoxylphenylcyclohexylbenzixuidazole-5-carboxylic acid (Example 227), 2-1 4- H (2S) (4 -dime thyl carbamayiphenyl) -2-pyrrolidinylK methoxy] phenyl k-1-cyclohexylbenzimidazole-5.-carboxylic acid- (Example 228), 24- (4-chiorophenyl) -5-ethoxycarbonylbenzyloxy] phenyl Y-icyclohexylbenzimidazole-5-carboxylic acid (Example 229), 1-cyclohexyl-2- (3-triffluoromethylphenoxy) phenyl] acid (Example 230), 1-cyclohexyl-2-i 4- H 4- (4-dimethylcarbamoylphenyl) thiazolyl ?~ethoxy] phenyl ~benzimidazole-5-carboxylic acid (Example 231), 2-i 4- (4-chlorophenyl) -5-dimethylcarbamoylbenzyloxy] phenyl V-1acid (Example 232), 2-14-H 14- (4-chiorophenyl) -2-methyl-5-pyrimidinyl~methoxylphenyl acid hydrochloride (Example 233), 2-14- (4-chiorophenyl) -3-pyridylhnethoxylphenyl cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 234), 2-A 4-H 3- (4-chiorophenyl) -2-pyridyl~methoxyjphenylkacid (Example 235), 2-A 4- (3-chiorophenyl) -4-methylamino-1, 3, 5-triazin-6- .zo yloxyl phenylk-l-cyclohexylbenzimidazole--carboxylic acid trifluoroacetate (Example 236), 24- (4-chiorophenyl) -4-(5-tetrazolyl)benzyloxylphexylk-1acid (Example 237), 2- (4-benzyloxy-6-pyrimidinyloxy)phenyl] is cyclohexylbenzimidazole-5-carboxylic acid (Example 238),.

1-cyclohexy-2-14-[4- (4-pyridylmethoxy) -6-pyrimidinyloxy] phenyl$acid (Example 239), 24- (3-chlorophenyl) -6-pyrimidinyloxy] phenyl acid (Example.240), methyl 2-14- (4-chlorophenyl) -5-methoxybenzyloxylphenylj-1- (Example 241), 2-14- (4-chiorophenyl) -5-methoxybenzyloxy] phenyl ki-cyclohexylacid hydrochloride (Example 242), ethyl 21 4- (4-chlorophenyl) pyridin-2-ylmethoxy] phenyl cyclohexylbenzimidazole-5-carboxylate (Example 243), methyl 2-IA- (2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl]-1- (Example 244), methyl 2-14- [5-tert-butoxycarbonyl---(4-chlorophenyl) benzyloxy] phenyP -1-cyclohexylbenzimidazole-5-carboxylate (Example 245), methyl 21 4- [5-carboxy-2- (4-chlorophenyl) benzyloxy] phenyl cyclohexylben zimida zol1e- 5-carboxyl ate hydrochloride (Example 246), methyl 21 4- (4-chiorophenyl) -5-methylcarbamoylbenzyloxy] phenyP-k1 -cyclohexylbenz imida.z ol1e-5- carboxyl ate (Exaniple 247), 2-14- (4-chiorophenyl) -5-methylcarbaxnoylbenzyloxy] phenyl cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 246), 2-1 4- (tert-butylsulfamoyl) (4-chiorophenyl) benzyloxyJ phenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 249), 52 2-14- (4-chiorophenyl) -5-sulfamoylbenzyloxy] phenyl k-iacid trifluoroacetate (Example 250), 2- (4-benzyloxycyclohexyl) acid hydrochloride (Example 251), 2- (2-biphenylyloxymethyl) -5-thienyl] -1acid (Example 252), 2- (2-biphenylyloxymethyl) -5-furyl] -1-cyclohexylbenzimidazoleacid (Example 253), 1-cyclohexyl-2-I 4-H[ 4- (4-f luorophenyl) thiazolyl~methoxy] phenyl }tenzimidazole-5-carboxylic acid (Example 254), 1-cyclohexyl-2-A 4-HI (4-carboxyphenyl) methoxy] phenyl Fbenzimidazole-5-carboxylic acid hydrochloride- (Example 255), l-cyclohexyl-2-12-fluoro-4- [4-f luoro-2- (3-fluorobenzoyl) acid (Example 256),, 24- (4-chlorophenyl) -5-methoxybenzyloxy] phenyl F-aacid (Example 257),.

2- 4- (4-chiorophenyl) -5-methoxybenzyloxylphenylF-3cyclohexylbenzimidazole-4-carboxylic acid (Example 258), 1-cyclohexyl-2-I 4- [3-dimethylcarbamroyl-5- (4-pyridylmethoxy) phenoxy] phenyl Fbenzimidazole-5-carboxylic acid dihydrochioride (Example 259), 23 1-cyclohexyl-2A 4- (3-carboxy-5- (4-pyridylmethoxy) phenoxyl phenyl Fbenzimidazole-5-carboxylic acid dihydroabloride (Example 260), 2-14- (4-chlorophenyl) -5-methoxybenzyloxy] phenyl F-1cyclohexylbenzirnidazole-4-carboxylic acid (Example 261), 2- 4- [3-carbamoyl-6- (4-chlorophenyl)benzyloxy] phenyl F-aacid hydrochloride (Example 262), 2-14- H 2- (4-carboxyphenyl) -3-pyridyl methoxyl phenyl F-1acid (Example 263), 2-A 4- (4-chlorophenyl) -5-methoxybenzyloxy] phenylF-i- (4tetrahydrothiopyranyl) benzimidazole-5-carboxylic acid (Example 264), 2-A (4-chlorophexyl) -5-dimethylcarbamoylbenzyloxy] phenyl acid hydrochloride (Example 265), 1-cyclohexyl-2- 4- [3-dimethylcarbamoyl-6- (4trifluoromethyiphenyl) benzyloxy] phenyl acid hydrochloride (Example 266), l-cyclohexyl-2- 4- [3-dimethylcarbamoyl-6- (4-methyithiophenyl) benzyloxy] phenyl ~benzimidazole-5-carboxylic acid hydrochloride (Example 267), io 2- 4- (4-chiorophenyl) -5-methylcarbamoylbenzyloxy] -2sfluorophenyl -l-cyclohexylbenzimidazole-5-carb.oxylic acid hydrochloride (Example 268), 2-A (4-chiorophenyl) -5-dimethylcarbamoylbenzyloxy] -2fluorophenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 269), 2-14- [3-carbamoyl-6- (4-chlorophenyl)benzyloxy] -2-f 1uorophenyl -1acid hydrochloride (Example 270), 24- [3-dimethylcarbamoyl-6- (4-methanesulfonyiphenyl) benzyloxy] phenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 271), 2-4- [3-dixnethylcarbaxaoyl-6- (3-pyridyl) benzyloxy] phenyl -1acid dihycirochloride (Example 272), 2- 4- [3-dimethylcarbamoyl-6- (4-dimethylcarbamoylphenyl) benzyloxyj phenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid (Example 273), 2-14- (4-chlorophenyl) -5-methoxybenzyloxy. phenyl k-i- (i-oxo-4tetrahydrothiopyranyl) benzimidazole-5-carboxylic acid (Example 274), 2-b4-[2- (4-chidrophenyl) -5-methoxybenzyloxylphenylk-i- 1-dioxo- 4-tetrahydrothiopyranyl) benzimidazole-5-carboxylic acid (Example- 275), 2- 4- (4-chiorophenyl) -5-methoxybenzyloxyl -2-fluorophenyl (4-tetrahydrothiopyranyl) benzimidazole-5-carboxylic acid (Example 276), 2-1 4- (4-chiorophenyl) -5-methoxybenzyloxy] -2-f luorophenyl (l-oxo-4-tetrahydrothiopyranyl) benzimidazole-5-carboxylic acid (Example 277), 2-14- (4-chiorophenyl) -5-methoxybenzyloxyj -2-f luorophenyl -1acid (Example 278), 2-14- (4-chiorophenyl) -5-dimethylsulfamoylbenzyloxy] phenyl -lacid hydrochloride (Example 279), 2-14- (4-chiorophenyl) -5-methanesulfonylbenzyloxylphenyl -1acid (Example 280), 24(4- (4-chiorophenyl) acid (Example 281), 2- 4- (4-chlorophenyl ).-5-dimethylaminobenzyloxy] phenyl -lcyclohexylbenzimidazole-5-carboxylic acid (Example 282), 2-14- (4-chiorophenyl) -5-methanesulfonylaminobenzyloxy] phenyl K acid (Example 283), 2- 4- (4-chiorophenyl) -5-diethylcarbauoylbenzyloxy) -2ifluorophenyl Kl-cyclohexylbenzimidazole-s-carboxylic acid.

(Example 284), (4-chiorophenyl) -S-isopropylcarbanoyibenzyloxy] -2fluorophenyl -l-cyclohexylbenzimidazole-s-carboxylic acid- (Example 285), 2- 4- (4-chlorophenyl) -5-piperidinocarbonylbenzyloxy] -2fluorophenyl K1-cyclohexylbenzimidazole--carboxylic acid (Example 286), 24- (4-chlorophenyl) (1-pyrrolidinyl) carbonylbenzyloxy] -2fluorophenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid (Example 287),, 2-i 4- (4-chlorophenyl) (2-hydroxyethyl) carbamoylbenzyloxy] -2fluorophenyd -l-cyclohexylbenzimiiazole-5-carboxylic acid (Example 288), 2-fl- (4-chlorophenyl) (4-hydroxypiperidino) carbonylbenzyloxy] -2-f luorophenyl kl-cyclohexylbenzimidazole-scarboxylic acid (Example 289), 2-14- (4-chiorophenyl) -S-morpholinocarbonylbenzyloxy] -2fluorophenyl -l-cyclohexylbenzimidazole-5-carboxylic acid (Example 290), 2-44- (2-(4-chiorophenyl) -5-thiomorpholinocarbonylbenzyloxyl'-2fluorophenyl Y-1-cyclohexylbenzimidazole-5-carboxyuic acid (Example 291), 2-44-(3- (carboxymethylcarbamoyl) 4 -chlorophenyl)benzyloxy] -2fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid (Exampid 292), 2-44- [2-44- (2-carboxyethyl) phenyl -5-chlorobenzyloxy] phenyl Kacid (Example 293),- 2-44- (3-chloro-6- 4 -hydroxymethylphenyl)benzyloxylphenyjj-icyclohexylbenzimidazole-5-carboxylic acid (Example 294),.

2-44- [3-chloro-6- (4-iethoxymethyiphenyl) benzyloxylphenyl iacid (Example 295), 2-44- (3-carboxyphenyl) -5-chlorobenzyloxy] phenyl Lacid (Example 296), 2-44- (4-chiorophenyl) -5-methylthiobenzyloxylphenyl -iacid (Example 297), 2-44- (4-chiorophenyl) -S-methylsulfinymbenzyloxylpheny1 -1acid (Example 298), 2-4 (4-chiorophenyl) -5-cyanobenzyloxyj phenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 299), 2-44- Ibis (2-pyridyl)methoxylphenyl-1-cycohexylbenzimidaze..-...

carboxylic acid (Example 300), 2-44- (his (4-dimethylcarbanoylphenyl) methoxy] phenyl k-iacid (Example 301), 2-4 4-(bis (2-thienyl)methoxyphenyl cyclohexylbenzindazoles.carboxylic acid (Example 302), methyl 2-14 4- 2- (4 -chiorophenyl) (dimethyl carbamoyl) ben zyloxyJ 2-fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxyiate (Example 303), sodium 2- 4- (4-chlorophe-iyl) (dimethylcarbauoyl) benzyloxy] 2-f luorophenyl K1-cyclohexylbenzimidazole-5-carboxylate (Example 304), 2-44- [5-carboxy-2- (4-chiorophenyl) benzyloxy] -2-fluorophenyl cyclohexylbenzimidazole-s-carboxylic acid (Example 305), 2-4 4- (4-carboxyphenyl) -5-methoxybenzyloxylphenyl acid (Example 306), 2-44- (4-carbamjoylphenyl) (dimethylcarbamoyl)benzyloxyj phenYl -l-cyclohexylbenzinidazole-s-carboxylic acid (Example 307), 2-14- [5-amnino-2- (4-chiorophenyl) benzyloxy] phenyl k-iacid (Example 308)., 2-f4- (4-chiorophenyl) -2-methoxybenzylsulfinylllphenylk-1acid hydrochloride (Example 309), 2- 4- (4-chiorophenyl) -2-methoxybenzylsulfonyl] phenylk-iacid hydrochloride (Example 310), 2-14- (4-chiorophenyl) -5-methoxybenzylthiojphenyl k-1cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example.

311), 24- [bis (4-carboxyphenyl)mnethoxyl -2-f luorophenyl k-1acid (Example 312), 2-4[4- (phenyl-3-pyridylmethoxy) -2-fluorophenyl] 1s cyclohexylbenzimidazole-5-carboxylic acid (Example 313), methyl 2-14- (4-chiorophenyl) (methylcarbamoyl)benzyloxy] -2fluorophenyl Y-1-cyclohexylbenzimidazole-5-carboxylate (Example 314), 2-14- [5-chlorc,-2- (4-pyridyl) benzyloxy] phenyl kcyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 315), 2-4- (4 -chlorophenyl) (benzylcarbamoyl) benzyloxy] phenylk-iacid hydrochloride (Example 316), 2- 4- (4-chlorophenyl) -5-(cyclohexylmethylcarbamoyl) benzyloxy] phenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride -(Example-317), 2- 4- [2-.(4-chlorophenyl) (4-pyridylmethylcarbamoyl) benzyloxy] phenyl k-1-cyclohexylbenzimidazole-S-carboxylic acid 3o dihyclrochloride (Example 318), 2- 4- (4-chlorophenyl) (N-benzyl-I'-methylcarbamoyl) benzyloxy] phenyl )--cyclohexylbenzimidazole-5-carboxylic acid* hydrochloride (Example 319), 2- 4- [5-dimethylaminocarbonyl-2- (4-pyridyl) benzyloxyl phenyl k-1cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example 320), 2- 4- (4-chiorophenyl) (4-methylpiperazin-1ylcarbonyl) benzyloxy) phenyl carboxylic acid dihydrochioride (Example 321), 2-1 4-12- (4-chiorophenyl) -5-IN- (3-pyridylmethyl) carbamoylkbenzyloxy] phenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 322), 2-i4- 12- (4-chiorophenyl) -5-IN- (2-pyridylmethyl) carbamoyi$benzyloxy] phenyl V1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example 323), 2-14- (4-chiorophenyl) (cyclohexylcarbamoyl)benzyloxy] phenyl K1-cyclohexylbenzinidazole-5-carboxylic acid hydrochloride- (Example 324), 2-14- (4-chiorophenyl) (2-pyridin-4-ylethylcarbamoyl) benzyloxy] phenyl K--cyclohexylbenzimidazole-5-carboxylic acid 125 dihydrochioride (Example 325), 2-14- ((4-fluorophenyl)1~4- (dimethylaminocarbonyl) phenyl kethoxy] -2fluorophenyl V1-cyclohexylbenzimidazole-5-carboxylic acid (Example 326), 2- 4- luorophenyl) (4-carboxyphenyl) m~ethoxy] -2-fluorophenyl K 1-cyclohexylbenzimidazole-5-carboxylic acid (Example 327),.

2-14-12- (4-chiorophenyl) (4-oxopiperidinocarbonyl) benzyloxy] phenyl hydrochloride (Example 328), 24- (4-chiorophenyl) -5-hydroxybenzyloxy] phenyl S-icyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 329), 24- (4-chiorophenyl) (isopropylcarbamoyl) benzyloxylphenylkacid hydrochloride (Example 330), 2- 4- (4-chiorophenyl) (N-isopropyl-N-methylcarbamoyl) benzyloxy] phenyl -l-cyclohexylbenzinidazole-5-carboxylic acid hydrochloride (Example 331), 2-4- (4-chiorophenyl). (phenylcarbamoyl) benzyloxy] phenyl S-lacid hydrochloride (Example 332), 2- 4- (4-chlorophenyl) (4-iethoxypiperidinocarbonyl) benzyloxy] phenyl S-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 333), 2-1~4- (4-chiorophenyl) -5-(3-hydroxypropyloxy)benzyloxylphenyljacid (Example 334), 2- 4- (4-chiorophenyl) (2-hydroxyethoxy)benzyloxylphenylh-1acid hydrochloride (Example 335), methyl 2- (2-bromo-S-nitrobenzyloxy) -2-f luorophenyl] -1- (Example 336), methyl 2- (4-chlorophenyl) -5-nitrobenzyloxy -2fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylate (Example lo 337), methyl 2- [4-1 5-aimirio-2- (4-chlorophenyl) benzyloxyk-2ifluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylate .(Example 338), methyl 2- [4-1 2- (4-chlorophenyl) -5-(2-oxopyrrolidin-1yl) benzyloxyS-2-fluorophenyl] carboxylate (Example 339), 2- [4-12- (4-chiorophenyl) (2-oxopyrrolidin-l-yl)benlzyloxyK-2ifluorophenyl] -1-cyclohexylbenzimidazole-S-carboxylic acid hydrochloride (Example 340), 2o 2-14- (4-chiorophenyl) 5- (4-methylpiperidin-1ylcarbonyl) benzyloxy] phenyl carboxylic acid hydrochloride (Example 341), 2-1 4- [5-acetyl-2- (4-chlorophenyl) benzyloxy] phenyl s-iacid hydrochloride-(Example 342), 2-1 4- (4-chiorophenyl) -5-I(4-hydroxypiperidin-l-ylcarbonyl) methoxy~benzyloxy] phenyl acid (Example 343), 2- 4- (4-chlorophenyl) (2-methoxyethoxy) benzyloxy] phenyl Kcyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 344), 2- 4- (4-chiorophenyl) -s-I2- (2-methoxyethoxy) ethoxyKbenzyloxy] phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 345), 2-14- (4-chiorophenyl) (isobutylcarbonyl)benzyloxylphenyl k-1acid (Example 346), 2-14-12- (4-chlorophenyl) (2-methylthiazol-4-yl)benzyloxy]acid (Example 347), 2-44- (4-chiorophenyl) 4-dihydroxypiperidin-lylcarbonyl) benzyloxy] phenyii-l-cyclohexylbenzimidazole-scarboxylic acid hydrochloride (Example 348), 2- 4- (4-chiorophenyl) (3-methyl-i, 2, yl) benzyloxy] phenyl -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 349), 2-44- (2-(4-chiorophenyl) (isopropylcarbamoyl)benzyloxylphenyl acid hydrochloride (Example 350), lo 2-44- (4-chiorophenyl) (piperidinocarbonyl)benzyloxylphenyl acid hydrochloride (Example 351), 2-44- (4-chlorophenyl) -5-4 (1-hydroxy-2-methylpropan-2yl) carbamoyl ~benzyloxylphenyl carboxylic-acid hydrochloride (Example 352), 2-44- C4-chlorophenyl) 4-dimethyl-2-oxazolin-2yl) benzyloxy) phenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 353), 2-44- (4-chlorophenyl) (4-hydroxypiperidin-1ylcarbonyl) benzyloxy] phenyl -l-cyclohexylbenzimidazole-scarboxylic acid hydrochloride (Example 354), 2-44- [2r (4-chlorophenyl) -4-4 (2-hydroxyethyl)carbamoyl benzyloxy] phenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 355), 2-44- (4-chlorophenyl) -4-4 (4-pyridylmethyl) carbamoyP benzyloxy] phenyl -1-cyclohexylbenzimidazole-5-carboxylic acid (Example 356), 2-44- (4-chlorophenyl) (dimethylcarbamoyl)benzyloxylpheny1 acid hydrochloride (Example 357), 2-4 4-[5-(2-aminothiazol-4-yl) (4-chlorophenyl)benzyloxy]phenyl ?-l-cyclohexylbenzimidazole-s-carboxylic acid dihydrochioride (Example 358), 2-44-12- (4-chiorophenyl) (4-hydroxypiperidin-lylsul fonyl) benzyloxyJ phenyl -l-cyclohexylbenz imidazole- carboxylic acid hydrochloride (Example 359)-, 2-14- (5-(dimethylcarbamoyl) (4-fluorophenyl) benzyloxy] pheny. K acid hydrochloride (Example 360)I 2-14- (dimethylcarbamoyl) (3-fluorophenyl) benzyloxy] phenyl K 1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 361), 2-14- (5-chlorothiophen-2-yl) (dimethylcarbanoyl) benzyloxy] phenyl K-5-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 362), 2-14- [2-bromo-5- (5-methyloxazol-2-yl)benzyloxylphenyl acid hydrochloride (Example 363), 2-14- [2-bromo-5- (5-methylthiazol-2-yl)benzyloxylphenylj- 1acid hydrochloride (Example.

364), 2-14- (4-chiorophenyl) (5-methyloxazol-2-yl) benzyloxy] phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 365), 2-14- (4-chiorophenyl) (5-methylthiazol-2-yl)benzyloxy] phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 366), 2-14- (4-chlorophenyl) -5-tetrazol-5-ylbenzyloxylphenyl acid hydrochloride (Example.

367), 2-14- [5-chloro-2- (4-cyanophenyl) benzyloxy] phenyl Kcyclohexylbenzimidazole-S-carboxylic acid hydrochloride (Example 368), 2-14- (5-chloro-2- (4-tetrazol-5-ylphenyl) benzyloxyjphenyl h-iacid hydrochloride (Example 369), 2-14- (4-chlotophenyl) -5-12- (4-hydroxypiperidin-1yl) ethoxy~benzyloxylphenyl acid hydrochloride (Example 370), 2-14- (4-chlorophenyl) -5-(2-oxopiperidin-i-yl~benzyloxy] -2fluorophenyl Ki-cyclohexylbenziuidazole-5-carboxylic acid hydrochloride (Example 371), 2-14- (4-chiorophenyl) (dimethylcarbamoyl) benzyloxy] -2fluorophenyl $-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 372), 2-I 4-12- (4-chiorophenyl) (N-hydroxyamidino)benzyloxy]-2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 373), 2-14- (4-chiorophenyl) 5-dihydro-5-oxo-4H-l, 2, 4-oxadiazol- 3-yl )benzyloxy],-2-fluoropheny1 carboxylic acid hydrochloride (Example 374), io 2-14- (4-chiorophenyl) (2-oxo-3-I1,2, 3, 5-oxathiadiazol-4yl) benzyloxy] -2-fluorophenyl carboxylic acid hydrochloride (Example 375), 2-A (4-chiorophenyl) 5-dihydro-5-oxo-4H-1,2, 4thiadiazol-3-yl) benzyloxy] -2-fluorophenyP -1is cyclohexylbenziiuidazole-5-carboxylic acid hydrochloride (Example 376),F 2-14- (4-chlorophenyl) (cyclopropylcarbamoyl)benzyloxy] -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 377), 2o 2-14- (4-chiorophenyl) (cyclobutylcarbamoyl)benzyloxy] -2fluorophenyl k-1-cyclohexylbenzimidazole-s-carboxylic acid hydro'chloride (Example 378), 2-14- (4-chiorophenyl) (tert-butylcarbamoyl)benzyloxy] -2fluorophenyl kl-cyclohexylbenzinidazole-5-carboxylic acid hydrochloride (Example 379), 2-14- (4-chlorophenyl) (isobutylcarbamoyl)benzyloxy] -2fluorophenyl [-1-cyclohexylbenzimidazole-s-carboxylic acid hydrochloride (Example.380), 2-14- (2-(4-chlorophenyl)-5-I (1-hydroxypropan-2-yl) carbamoyd benzyloxy] -2-f luorophenyl Kl-cyclohexylbenzimidazole-s-carboxylic acid hydrochloride (Example 381), 2-1 4-j2- (4-chlorophenyl) (methoxycarbamoyl)benzyloxyj -2fluorophenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 382), 2-14- (4-chlorophenyl) 3-dihydroxypropyl) carbamoyl k benzyloxyJ -2-f luorophenyl acid hydrochloride (Example 383), 2-14- (4-chiorophenyl) (N-ethyl-N-methylcarbamoyl) benzyloxy] 2-fluorophenylk-1-cyclohexylbenzimidazole-S-carboxylic acid hydrochloride (Example 384), 2-14- (4-chiorophenyl) -5-(N-methyl-I4-propylcarbanoyl) benzyloxyl -2-fluorophenyl acid hydrochloride (Example 385), 2-14- (4-chiorophenyl) (N-isopropyl-N--methylcarbamoyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 386), lo 2-14- (4-chiorophenyl) 6-dimethylpiperidin-1-ylcarbonyl) benzyloxyj -2-fluorophenyl acid hydrochloride (Example 387), 2-ti- (butylcarbamoyl) (4-chlorophenyl)benzyloxy] -2fluorophenyl h-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 388), 2- 4- (4-chiorophenyl) (propylcarbamoyl) benzyloxy] -2fluorophenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 389), 2-14- (4-chiorophenyl) (ethylcarbamoyl)benzyloxy] -2fluorophenyl $-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 390), 2- 4-f2- (4-chiorophenyl) -5-i(dimethylcarbatoyl) amino ~benzyloxy] -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 391), 2- 4- (4-chlorophenyl) -5.1(morpholinocarbonyl) amino ~benzyloxylj- 2-f luorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 392), (4-chiorophenyl) -5-ureidobenzyloxy] -2--fluorophenyii-1acid hydrochloride (Example 393), 2-4- (4-chiorophenyl) -5-1 (ethylcarbamoyl) amino ~benzyloxy] -2fluorophenyl )--cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 394), 2- 4- (4-chiorophenyl) -5-I(isopropylcarbamoyl) amino ~benzyloxy] 2-f luorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 395), 2-4- 4-difluorophenyl) (isopropylcarbaiuoyl)benzyloxy] -2fluorophenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid (Example 396), 2-A 4-difluorophenyl) -5-(isopropylcarbanoyl)benzyloxy] -2fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 397), 2-14- 5-dichiorophenyl) -5-(isopropylcarbamoyl) benzyloxy] -2ifluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 398), lo 2- 4- (3-chloro-4-fluorophenyl) (isopropylcarbamoyl) benzyloxyl -2-fluorophenyl acid hydrochloride (Example 399), 2-A 4-dichiorophenyl) (isopropylcarbamoyl) benzyloxy] -2ifluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acid 1s hydrochloride (Example 400), 2-4- (4-chloro-2-ifluorophenyl) (isopropylcarbamoyl) beuzyloxy] -2-fluorophenyl acid hydrochloride (Example 401), 2-14- (4-chloro-2-ifluorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 402), (4-chloro-3-ifluorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 403), 2-1 4- (4-chloro-3-ifluorophenyl) (isopropylcarbamoyl) benzyloxy] -2-f luorophenyl acid hydrochloride (Example 404), 2-1 4- 4- (methylthio) phenyi (2-oxopyrrolidin-1-yl) benzyloxy] -7 2-ifluorophenyl K1-cyclohexylbenzimidazole-5-carboxylic acid 3o hydrochloride (Example 405), 2- 4- [2-il- (methylthio)phenyl?-5- (isopropylcarbamoyl)benzyloxy] -2ifluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 406), 24- (4-chloro-2- (4-chlorophenyl) 1-dioxoisothiazolidin-2zis yl) benzyloxy] -2-ifluorophenyl carboxylic acid hydrochloride (Example 407), 2-A 4-[4-chloro-2- (4-chiorophenyl) (2-oxopyrrolidin-1yl) benzyloxyl -2-fluorophenyl carboxylic acid hydrochloride (Example 408), 2-1 4- (4-chiorophenyl) (isopropylaminosulfonyl)benzyloxy] -2fluorophenyl S-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 409), 2-A 4- (4-chlorophenyl) -5-(dimethylcarbamoyl)benzyloxyl -2- "fluorophenyl Y-1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example 410), l0 2-A 4- (4-chiorophenyl) -5-(4-hydroxypiperidin-1-ylcarbonyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 411), 2-A (4-chlorophenyl) (isopropylcarbamoyl)benzyloxy] -2- V luorophenyl S-1-cyclopentylbenzimiciazole-5-carboxylic acid hydrochloride (Example 412), 2-A (4-chiorophenyl) (isopropylcarbamoyl)benzyloxylphenylkacid hydrochloride (Example 413), 2-14- (4-chlorophenyl) -5Z- (dimethylcarbamoyl).benzyloxy] phenyl 1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example 414), 2- 4- (4-chlorophenyl) (4-hydroxypiperidin-1ylcarbonyl) benzyloxyl phenyl carboxylic acid hydrochloride (Example 415), 2-fl- (4-chlorophenyl) (isopropylcarbamoyl)benzyloxylphenyij- 1- (tetrahydrothiopyran-4-yl) benzimidazole-5-carboxylic acid hydrochloride (Example 416), 2-A (4-chiorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxy] phenyl (tetrahydrothiopyran-4-yl) acid hydrochloride (Example 417), 2-A (4-chiorophenyl) (isopropylcarbamoyl)benzyloxy] -2fluorophenyi)-1- (tetrahydrothiopyran-4-yl) carboxylic acid hydrochloride (Example 418), 2-14- (4-chiorophenyl) (2-oxopyrrolidin-l-yi)benzyloxy] -2ifluorophenyl (tetrahydrothiopyran-4-yl) carboxylic acid hydrochloride (Example 419), 2-14- (4-chlorophenyl) (isopropylcarbamoyl) benzyloxy] -2if luorophenyl 1-piper idinobenz imidazol1e- 5-carboxyl ic acid hydrochloride (Example 420), 2-14- (4-chiorophenyl)-5- (pyrrolidin-1-ylcarbonyl)benzyloxy] -2s if luorophenyl K1 I-pipe ridinoben zimida zol e- 5-carboxyl ic acid (Example 421), 2-14- [2-(4-chlorophenyl)-5- (2-imidazolin-2-yl)benzyloxy} -2fluorophenyl S-1-cyciohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example'422), 2-14- (4-chlorophenyl)-5- (2-oxooxazolidin-3-yl)benzyloxy] -2ifluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 423), 2-1 4- (4-chiorophenyl) (2-oxoimidazolidin-l-yl) benzyloxy] -2fluorophenyl $-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 424), 2- 4- (4-chiorophenyl) -5-(2-oxazolin-2-ylamino) benzyloxy) -2ifluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example 425), 2- [j2- [H (dimethylcarbamo yl) methoxy~methyl]-4- (4fluorophenyl) thiazol-5-ydmethoxylphenyl -l acid hydrochloride (Example 426), 2-14- H 4- (4-fluorophenyl) (4-hydroxypiperidinylmethyl) thiazol-5-yl 6methoxy] phenyl carboxylic acid dihydrochioride (Example 427), 2- 4-H 4- (4-ifluorophenyl.) [(carbamoylmethoxy) methyl) yl 6nethoxy] phenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 428), 24- 4--(4-fluorophenyl) (methylcarbamoyl) yl ~ethoxyJ -2-fluorophenyl acid hydrochloride (Example 429), 2-1 4- [14-7 (4-f luorophenyl) -2-1 (2-hydroxyethyl) yl 6ethoxy] -2-ifluorophenyl acid hydrochloride (Example 430), 3s 2-14- (4-fluorophenyl) (dimethylcarbamoyl) thiophen-3yl 6ethoxy] -2-ifluorophenyl acid hydrochloride (Example 431), 2- 4- K2- (4-fluorophenyl) (isopropylcarbamoyl) thiophen-3yl 6rethoxy] -2-f luorophenyl acid hydrochloride (Example 432), 2-4- [42- (4-fluorophenyl) (4-hydroxypiperidin-1ylcarbonyl) thiophen-3-yl ~ethoxy] -2-fluorophenyl -lacid hydrochloride (Example 433), 2-44- (4-chiorophenyl) (dimethylcarbamoyl)benzyloxy] -2fluorophenyl -l-cyclohexyl-5-tetrazol-5-ylbenzimidazole (Example lo 434), 2-44- (4-carboxyphenyl) -5-chlorobenzyloxy] -2-fluorophenyl hydrochloride (Example 435), 2-44- (4-chlorophenyl) (isopropylcarbamoyl) benzyloxy] fluorophenyP -1-cyclohexyl-5- 5-dihydro-5-oxo-4H-1, 2,4oxadiazol-3-yl)benzimidazole hydrochloride (Example 436), 2-A4- [5-carboxy-2-(4-chlorophenyl) benzyloxy) -2-f cyano-l-cyclohexylbenzimidazole (Example 437), 2-A 4- (4-chlorophenyl) -5-(dixethylcarbamoyl)benzyloxy] -2fluorophenyP-5-cyano-l-cyclohexylbenzimaidazole (Example 438), 2-44- UN- (4-dimethylcarbamoyl) (4-f luorophenyl) aminokmethyl] phenyl k1-cyclohexylbenzimidazole-5-carboxylic acid (Example 439), 2-15- [bis (3-fluorophenyl)methyl] -2-f luoro-4-hydroxyphenyP -1cyclohexylbenzimidazole-5-carboxylic acid (Example 440), 2-13- [bis (3-fluorophenyl)methyl] -2-fluoro-4-hydroxyphenyl k-1acid (Example 441), 2-44- [(3-dimethylcarbamoylphenyl) (4-fluorophenyl) methoxy] -2fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 442), 2-44- [43- (4-hydroxypiperidyl-1-ylcarbonyl)phenyP (4fluorophenyl) methoxy] -2-fluorophenyl carboxylic acid hydrochloride (Example 443), i-4 (4-fluorophenyl) yllmethoxy) phenyl Y-1-cyclohexylbenzimidazol-5-yl] carbonyl -I-Dglucuronic acid (Example 444), [2-A 4- [bis (3-fluorophenyl)methoxy] -2-f luoropherkyli-1carbonyl k13-D-glucuronic acid (Example 445), 2-b4- 2- (4-chiorophenyl) 1-dioxoisothiazolidin-2yl) benzyloxy] -2-f luorophenyl carboxylic acid hydrochloride (Example 446), (5-aminosulfonyl-1-cyclohexylbenzimidazol-2-yl) -3ifluorophenoxy] methyl (4-chiorophenyl) -N-isopropylbenzanide (Example 447), io 2- (4-chiorophenyl) (isopropylaminocarbonyi)berizyloxy}-2fluorophenyll -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 448), 2- (4-chlorophenyl) -4-fluoro-5- 1-dioxoisothiazolidin-2yl) benzyloxy}-2-tluorophenyl] carboxylic acid hydrochloride (Example 449-), 2- (4-chlorophenyl) (isopropylaminocarbonyl) benzyloxy ifluorophenyl] -1-cyclohexyl-4-methoxybenzimidazole-5-carboxylic acid hydrochloride (Example 450), 2- [4-f 2- (4-chiorophenyl) (N-isopropylcarbonyl-Nmethylamino)benzyloxy-2-fluorophenyl] -l-cyclohexylbenzimidazoleacid hydrochloride (Example 451), 2- [4-f 2- (4-chlorophenyl) (isopropylcarbonylamino) benzyloxy} -2fluorophenyl) -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 452), 2- [3-f (4-f luorophenyl) -2-methylthiazol-5-yllmethyl}-4hydroxyphenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid (Example 453), 2- [4-f 2- (4-chiorophenyl) -4-f luoro-5- (2-oxopyrrolidin-1yl) benzyloxy} -2-f luorophenyl] carboxylic acid hydrochloride (Example 454), 2- [4-f 2- (4-chiorophenyl) (methylsulfonylamino)benzyloxy}-2fluorophenyl] -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 455), 2- [4-f 2- (4-chlorophenyl) [N-methyl-N- (methylsulfonyl) amino] benzyloxy} -2-fluorophenyl] -1acid hydrochloride (Example 456), 2- [4-f (4-chiorophenyl) -6-(2-oxopyrrolidin-1-yl)pyridin-2yl] methyloxy} -2-fluorophenyl] carboxylic acid hydrochloride (Example 457), 2- [4-f 2- (4-chlorophenyl) (acetylaxnino~benzyloxy}-2fluorophenyl I-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 458), 2- [412- (4-chiorophenyl) (N-acetyl-N-ethylamino) benzyloxy}-2fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 459), 120 2-f4--{2-(4-chlorophenyl) (N-acetyl-N-propylamino)benzyloxy}-2fluorophenyl] -l-cyclohexylbenzitidazole-5-carboxylic acid hydrochloride (Example 460), 2- [4-112- (4-chlorophenyl) [N-ethyl-N- (methylsulfonyl) amino 1benzyloxy}-2-fluorophenyl] acid hydrochloride (Example 461), 2-f 4-f2- (4-chiorophenyl) fN- (methylsulfonyl) -Npropylamino) benzyloxy} -2-f luorophenyl] -l-cyclohexylbenzimidazoleacid hydrochloride (Example 462), 2- (4-chiorophenyl) (N-acetyl-N-methylainino) benzyloxy}-2fluorophenyl] -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 463), 2- (4-chiorophenyl) -5-EN- (ethylsulfonyl) -N-methylamino] benzyloxy} -2-fluorophenyl] acid hydrochloride (Example 464), 2- [4-f 2- (4-chlorophenyl)-5- [N-ethyl-N- (ethylsulfonyl) amino] benzyloxy} -2-f luorophenyl] acid hydrochloride (Example 465)', 2- (4-chlorophenyl) (ethylcarbonyl) -N-inethylamino] benzyloxy} -2-fluorophenyl] 3o acid hydrochloride (Example 466), 2- [4-f 2- (4-chiorophenyl) [N-ethyl-N- (ethylcarbonyl) amino] benzyloxy} -2-f luorophenyl] acid hydrochloride'(Example 467), 2- (4-chlorophenyl) -5-methoxybenzyloxy}-2-fluorophenyl] -1cyclohexylbenzimidazole-5-carboxylic acid (Example 468), 2- (4-chlorophenyl) -5-(N-acetyl-N-isopropylamino) benzyloxy} -2-fluorophenyli acid hydrochloride (Example 469), (4-chiorophenyl) -5-(2-oxopyrrolidin-1-yl)benzyloxy] -2carbonyl }-13-Dglucuronic acid (Example 470), methyl 2-14- (4-chiorophenyl) -5-methoxybenzyloxy] phenyl k-icyclohexylindole-5-carboxylate (Example 501), 2-14- (4-chiorophenyl) -5-methoxybenzyloxy) phenyl k-1-cyclohexylacid (Example 502), 2- (4-benzyloxyphenyl) -l-cyclopentyl-lH-indole-5-carboxylic acid (Example 503), .0ethyl 2- (4-benzyloxyphenyl) -3-cyclohexylimidazo pyridine- 7-carboxylate (Example 601), 2- (4-benzyloxyphenyl) -3-cyclohexylimidazo 2-alpyridine-7carboxylic acid (Example 602), (4-chiorophenyl) -5-methoxybenzyloxy] phenyl k-3-cyclohexyl- 125 3H-imidazo 5-blpyridine-6-carboxylic acid (Example 701), 2-14-f 2- (4-chlorophenyl) (isopropylcarbamoyl)benzyloxylphenylk- 3-cyclohexyl-3H-imidazo[4, 5-blpyridine-6-carboxylic acid hydrochloride (Example 702), and 2-14- (4-chiorophenyl) (pyrrolidin-l-ylcarbonyl) benzyloxy] phenyi>-3-cyclohexyl-3H-imaidazo 5-blpyridine-6-carboxylic acid hydrochloride (Example 703).

(62) The fused ring compound of the formula or a pharmaceutically acceptable salt thereof, which is selected-from the group consisting of 2-i 4- (4-chlorophenyl) (4-oxopiperidinocarbonyl) benzyloxy] phenyl V1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 328), 2-14- (4-chlorophe-yl) acid hydrochloride (Example 3o 329), 2-14-f 2- (4-chlorophenyl) (isopropylcarbamoyl) benzyloxylphenyijacid hydrochloride-(Example 330), 2-14- (4-chlorophenyl) (N-isopropyl-N-methylcarbamoyl) benzyloxyl phenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 331), 2- 4- (4-chiorophenyl) (phenylcarbamoyl) benzyloxylphenylkacid hydrochloride (Example 332), 2-4- (4-chiorophenyl) (4-methoxypiperidinocarbonyl) benzyloxyjphenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 333), 4- (4-chiorophenyl) (3-hydroxypropyloxy) benzyloxy] phenyl K acid (Example 334), 24- (4-chiorophenyl) (2-hydroxyethoxy) benzyloxylpheny-.no cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 335), methyl 2- (2-bromo-5-nitrobenzyloxy) -2-fluorophenyl] -1- (Example 336), methyl 2- [4-12- (4-chlorophenyl) -5-nitrobenzyloxyk-2ifluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylate (Example 337), methyl 2- [4-1 5-amino-2- (4-chiorophenyl) benzyloxyk-2fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylate (Examnple- 338), methyl 2-.[4A 2- (4-chlorophenyl) (2-oxopyrrolidin-lyl) benzyloxyK-2-fluorophenyl] carboxylate (Example 339), 2- [4-1 2- chiorophenyl) (2-oxopyrrolidin-l-yl)benzyloxyk-2-.

fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 340), 2-14- (4-chiorophenyl) (4-methylpiperidin-lylcarbonyl) benzyloxy] phenyl carboxylic acid hydrochloride (Example 341), 24- [5-acetyl-2- (4-chlorophenyl)benzyloxyphenylcyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 342), 2- 4- (4-chiorophenyl) (4-hydroxypiperidin-1-ylcarbonyl) methoxy~benzyloxy] phenyl acid (Example 343), 2-1 4- (4-chlorophenyl) (2-methoxyethoxy) benzyloxy] phenyl -1acid hydrochloride (Example 344), 21i4- 2- (4-chlorophenyl) -5-i2- (2-methoxyethoxy) ethoxyKbenzyloxyj phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 345), 21i4-[2- (4-chiorophenyl) (isobutylcarbonyl) benzyloxylphenyl)-1cyclohexylbenzimidazole-5-carboxylic acid (Example 346), 2-14- (4-chlorophenyl)-5- (2-methylthiazol-4-yl)benzyloxy]phenyl -l-cyclohexylbenzimidazole-5-carboxylic acid (Example 347), 2-14- (4-chiorophenyl) 4-dihydroxypiperidin-1ylcarbonyl) benzyloxy] phenyl carboxylic acid hydrochloride (Example 348), 2-1 4- f2- (4-chiorophenyl) (3-methyl-i, 2, yl) benzyloxy] phenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 349), 21i4- (4-chlorophenyl) (isopropylcarbamoyl)benzyloxylphenylK- 1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 350), 21i4- (4-chiorophenyl) (piperidinocarbonyl) benzyloxyj phenyl K acid hydrochloride (Example 351), 21i4-[2- (4-chiorophenyl) -sI (1-hydroxy-2-methylpropan-2yl) carbamoyl hoenzyloxy] phenyl carboxylic acid hydrochloride (Example 352), 2-14- (4-chiorophenyl) 4-dimethyl-2-oxazolin-2yl) benzyloxylphenyl -l-cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 353), 2-i 4- (4-chlorophenyl) (4-hydroxypiperidin-1ylcarbonyl) benzyloxyl phenyl K carboxylic acid hydrochloride (Example 354), 2-i 4- (4-chlorophenyl) -41 (2-hydroxyethyl) carbamoyl>benzyloxy] phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 355), 2-i 4- (4-chiorophenyl) -4-i (4-pyridylmethyl) carbamoylK-.

benzyloxy] phenyl $-l-cyclohexylbenzimidazole-5-carboxylic acid (Example 356), 2-14- (4-chlorophenyl) (dimethylcarbamoyl)benzyloxylphenylK7 acid hydrochloride -(Example 357)f 2-1 4- 5- (2-aminothiazol-4-yl) (4-chlorophenyl)benzyloxy] phenyl k-1-cyclohexylbenzirridazole-5-carboxylic acid dihydrochioride (Example 358), 2-14- (4-chiorophenyl) (4-hydroxypiperidin-1ylsulfonyl) benzyloxy] phenyl carboxylic acid hydrochloride (Example 359), 24- (dimethylcarbamoyl) (4-fluorophenyl) benzyloxy] phenyl acid hydrochloride (Example 360), io 2A 4- (dimethylcarbamoyl) (3-fluorophenyl)benzyloxyjphenylK7 acid hydrochloride (Example 361),1 24- (5-chlorothiophen-2-yl) (dimethylcarbamoyl)benzy loxyl phenyl k1-cyclohexylbenzixnidazole-5-carboxylic acid hydrochloride (Example 362), 24- [2-bromo-5- (5-methyloxazol-2-yl)benzyloxylphenyl acid hydrochloride (Example 363), 24- (2-bromo-5- (5-methylthiazol-2-yl)benzyloxylphenyl}-1cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 364), 2A 4- (4-chlorophenyl) (5-methyloxazol-2-yl)benzyloxyj phenyl Y-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 365), 2- 4- (4-chiorophenyl) (5-methylthiazol-2-yl) benzyloxy] phenyl K1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 366), 24- (4-chlorophenyl) acid hydrochloride (Example 367), 2- 4- [5-chloro-2- (4-cyanophenyl) benzyloxy] phenyl k-iacid hydrochloride (Example 368),F 24- (5-chloro-2- (4-tetrazol-5-ylphenyl)benzyloxy) phenyl k-icyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 369), 2-1 4- (4-chiorophenyl) -5-A2- (4-hydroxypiperidin-1yl) ethoxy~benzyloxy] phenyl acid hydrochloride (Example 370), 2-i 4- (4-chiorophenyl) (2-oxopiperidin-1-yl) benzyloxy] -2fluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 371), 2-14- (4-chiorophenyl) (dimethylcarbamoyl)benzyloxy] -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 372), .1o 2-A 4- (4-chlorophenyl) (N-hydroxyamidino)benzyloxyY.-2fluorophenyl K1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochioride (Example 373), 2-14- (4-chiorophenyl) 5-dihydro-5-oxo-4H-1, 2, 4-oxadiazol- 3-yl) benzyloxy] -2-fluorophenyl 1s carboxylic acid hydrochloride (Example 374), 2-14- (4-chlorophenyl)--5- (2-oxo-3H-1,2, 3, 5-oxathiadiazol-4yl) benzyloxyj -2-rfluorophenyl carboxylic acid hydrochloride (Example 375), 2-14- (4-chiorophenyl) 5-dihydro-5-oxo-4H-1,2, 4thiadiazol-3-yl)benzyloxy] -2-fluorophenyl$-lacid hydrochloride (Example 376), 2-14-12- (4-chlorophenyl) (cyclopropylcarbamoyl)benzyloxyl -2fluorophenyl KI-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 377), 2-i 4- (4-chlorophenyl) (cyclobutylcarbamoyl) benzyloxy] -2fluorophenyl S-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 378), 2-14- (4-chlorophenyl) (tert-butylcarbamoyl)benzyloxy] -2fluorophenyl K1-cyclohexylbenzinidazole-5-carboxylic acid hydrochloride (Example 379), 2- 4- (4-chiorophenyl) -5-(isobutylcarbamoyl) benzyloxy]-2fluorophenyl KJ-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 380), 2- 4- (4-chlorophenyl) (1-hydroxypropan-2-yl) carbamoyl K benzyloxy] -2-fluorophenyl acid hydrochloride (Example 381), 2-14- (4-chiorophenyl) (methoxycarbamoyl)benzyloxyj -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 382), 2- 4- (4-chiorophenyl) 3-dihydroxypropyl) carbamoylkbenzyloxy] -2-fluorophenyli-l-cyclohexylbenzimidazole--carboxylic acid hydrochloride (Example 383), 2-14- (4-chiorophenyl) (N-ethyl-N-methylcarbamoyl)benzyloxyj 2-fluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 384), zo 2- 4- (4-chiorophenyl) (N-methyl-N-propylcarbamoyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 385), 2- 4- (4-chlorophenyl) -5-(N-isopropyl-N--methylcarbamoyl) benzyloxy] -2-fluorophenyl 125 acid hydrochloride (Example 386), (4-chiorophenyl) 6-dimethylpiperidin-1-ylcarbonyl) benzyloxy] -2-f luorophenyl acid hydrochloride (Example 387), 2-14- (butylcarbamoyl) (4 -chiorophenyl) benzyloxyJ -2fluorophenyl K1l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 388), 2-1 4- (4-chiorophenyl) (propylcarbamoyl) benzyloxy] -2ifluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 389), 2- 4- (4-chlorophenyl) (ethylcarbamoyl)benzyloxy] -2fluorophenyl $-1-cyclohexylbenzimidazole-5-carboxyic acid hydrochloride (Example 390), 2-4- (4-chiorophenyl) -5-1 (dimethylcarbamoyl) amino~'benzyloxy] fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 391), 2A 4- (4-chlorophenyl) -S-i(morpholinocarbonyl) amino~benzyloxy] 2-f luorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 392), 2- 4- (4-chiorophenyl) -5-ureidobenzyloxy] -2-fluorophenyl Y-lcyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 393), 2- 4- (4-chiorophenyl) -5-A (ethyl carbamo yl) amino benzyloxy] -2fluorophenyl -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 394), 24- (4-chiorophenyl) (isopropylcarbamoyl) aminc~benzyloxy] 2-f luorophenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 395), 2-4- 4-difluorophenyl) -5-(isopropylcarbamoyl)benzyloxy] -2fluorophenyl Kl.-cyclohexylbenzimidazole-5-carboxylic acid (Example 396), 120 2-A 4- 4-difluorophenyl) (isopropylcarbamoyl)benzyloxy] -2fluorophenyl Kl-cyclohexylbenzimidazole-5-carboxylic acidhydrochloride (Example 397), 2-b4-(2- 5-dichlorophenlyl) -5-(isopropylcarbamoyl) benzyloxy] -2fluorophenyl kl-cyclohexylbenzimidazole-5-carboxylic acidhydrochloride (Example 398), 2-1 4- (3-chloro-4-fluorophenyl) (isopropybcarbanoyl)benzyloxyl -2-fluorophenyl acid hydrochloride (Example 399), 2- 4- 4-dichlorophenyl) -5-(isopropylcarbamoyl)benzyloxy] -2fluorophenyl Y-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 400), 2-44- (4-chlorb-2-fluorophenyl) (isopropylcarbamoyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 401), 2- 4- (4-chloro-2-fluorophenyl) -5-(pyrrolidin-l-ylcarbonyl) benzyloxyl -2-f luorophenylK- acid hydrochloride (Example 402), 2-i 4- (4-chloro-3-fluorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxy] -2-fluorophenyl 3o acid hydrochloride (Example 403), 2- 4- (4-chloro-3-fluorophenyl) (isopropylcarbanoyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 404), 2- 4- 4- (methylthio)phenyP (2-oxopyrrolidin-1-yl) benzyloxy] 2-fluorophenyl K1-cyclohexylbenzimidazole-5-carboxylic' acid hydrochloride (Example 405), 2-4 4- 4- (methylthio)phenylk-5- (isopropylcarbamoyl)benzyloxyj -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 406), 2=44- [4-chloro-2- (4-chlorophenyl) 1-dioxoisothiazolidin-2yl) benzyloxy] -2-fluorophenyl carboxylic acid hydrochloride (Example 407), 24- [4-chloro-2- (4-chiorophenyl) (2-oxopyrrolidin-1yl) benzyloxyj -2-fluorophenyl carboxylic acid hydrochloride (Example 408), 2-14- (4-chlorophenyl)-5- (isopropylaminosulfonyl)benzyloxy] -2fluorophenyl $-l-cyclohexylbenzimidazole--5-carboxylic acid hydrochloride (Example 409), 2-14- (4-chlorophenyl) -5-(dimethylcarbamoyl) benzyloxy] -2fluorophenyl k -1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example 410), 2-14- (4-chlorophenyl) -5-(4-hydroxypiperidin-l-ylcarbonyl) benzyloxy] -2-fluorophenyl acid hydrochloride (Example 411), 2- 4- (4-chiorophenyl) (isopropylcarbamoyl) benzyloxy] fluorophenyl K1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example 412), 2- 4- (4-chiorophenyl) (isopropylcarbamoyl)benzyloxylphenyl ic acid hydrochloride (Example 413), 2- 4- (4-chl'orophenyl) (dimethylcarbamoyl) benzyloxylphenyl acid hydrochloride (Example 414), 2- 4- (4-chlorophenyl) (4-hydroxypiperidin-1ylcarbonyl) benzyloxy] phenyl carboxylic acid hydrochloride (Example 415), 2-14- (4-chlorophenyl) (isopropylcarbamoyl) beuzyloxy) phenyl k 1- (tetrahydrothiopyran-4-yl) benzimidazole-5-carboxylic acid hydrochloride (Example 416), 24- C4-chlorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxy] phenyl (tetrahydrothiopyran-4-yl) acid hydrochloride (Example 417), 2-A 4- (4-chiorophenyl) (isopropylcarbamoyl)benzyloxyj -2fluorophenyl (tetrahydrothiopyran-4-yl) carboxylic acid hydrochloride (Example 418), 2- 4- (4-chiorophenyl) (2-oxopyrrolidin-l-yl) benzyloxy] -2fluorophenyl>-1- carboxylic acid hydrochloride (Example 419), 2A 4- (4-chiorophenyl) (isopropylcarbamoyl) benzyloxyl -2fluorophenyl k1-piperidinobenzimidazole-5-carboxylic acid hydrochloride (Example 420), .1a 2- 4-f2- (4-chiorophenyl) (pyrrolidin-1-ylcarbonyl) benzyloxyl -2fluorophenyl S-1-piperidinobenzimidazole-5-carboxylic acid (Example 421), 2- 4- [2-(4-chlorophenyl) (2-imidazolin-2-yl)benzyloxy] -2fluorophenyl k-l-cyclohexylbenzimidazole-5-carboxylic acid.

dihydrochloride (Example 422), 2-i 4- (4-chiorophenyl) (2-oxooxazolidin-3-yl) benzyloxy] -2fluorophenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 423), 2-1 4- (4-chlorophenyl) (2-oxoimidazolidin-l-yl)benzyloxyj -2fluorophenyl -1-cyclohexylbenzimidazole-S-carboxylic acid hydrochloride (Example 424), 2-1 4- (4-chlorophenyl) (2-oxazolin-2-ylamino) benzyloxy] -2fluorophenyl k-i-cyd'lohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example 425), 2-A 4-U[ 2- U (dimethylcarbamoyl) methoxy~methyl]1 (4fluorophenyl) thiazol-5-yl Sethoxyl phenyl acid hydrochloride (Example 426),f 2-1 4- 4- (4-fluorophenyl) (4-hydroxypiperidin-1ylmethyl) thiazol-5-yl 6methoxy] phenyl carboxylic acid dihydrochioride (Example 427), 2- 4- 114- (4-fluorophenyl) -2-f (carbamoylmethoxy)methyl yl kethoxy] phenyl -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 428), 2- 4- 4- (4-f luorophenyl) (methylcarbamoyl) yl Yethoxy] -2-fluorophenyl acid hydrochloride (Example 429), 2-14- 4- (4-f luorophenyl) -2-i (2-hydroxyethyl) yl ~ethoxy] -2-fluorophenyl acid hydrochloride (Example 430), 2-14- (4-fluorophenyl) (dimethylcarbamoyl) thiophen-3ylhethoxyj -2-fluorophenylkl1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 431), 2- 4- (4-f luorophenyl) (isopropylcarbamoyl) thiophen-3ylmethoxy] -2-f luorophenyl acid hydrochloride (Example 432), 2-fl- H 2- (4-fluorophenyl) (4-hydroxypiperidin-l1ylcarbonyl) thiophen-3-yl ~'ethoxy] -2-f luorophenyl -lacid hydrochloride (Example 433), 24- (4-chiorophenyl) (dimethylcarbamoyl)benzyloxy]--2fluorophenyl K1-cyclohexyl-5-tetrazol-5-ylbenzimidazole (Example 434), 2-14- (4-carboxyphenyl) -5-chlorobenzyloxyl-2-f luorophenyl hydrochloride (Example 435), 2- 4- (4-chlorophenyl) (isopropylcarbamoyl)benzyloxy] fluorophenyl -l-cyclohexyl-5- 5-dihydro-5-oxo0-4H-l, 2, 4oxadiazol-3-yl)benzimidazole hydrochloride (Example 436), *2A 4- [5-carboxy-2- (4-chlorophenyl) benzyloxy] cyano-l-cyclohexylbenzimidazole (Example 437), 2-14-12- (4-chlorophenyl)-5- (dimethylcarbamoyl)benzyloxy]-2fluorophenyl k-5-cyano-l-cyclohexylbenzimidazole (Example 438), 2-fl- UN- (4-dimethylcarbamoyl) (4-fluorophenyl) amino K methyl] phenyl Kl-cyclohexylbenzimidazole-5-carboxylic acid (Example 439), 2- 5- [bis (3-fluorophenyl) methyl] -2-fluoro-4-hydroxyphenyl acid (Example 440), 2-1 3- [bis (3-fluorophenyl)methyl] -2-fluoro-4-hydroxypheny]4-1acid (Example 441), 2- 4- [(3-dimethylcarbamoylphenyl) (4-fluorophenyl) methoxy] -2fluorophenyl k-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 442), 2 4- 3- (4-hydroxypiperidyl-l-ylcarbonyl) phenylj (4fluorophenyl)miethoxyl -2-fluorophenyl carboxylic acid hydrochloride (Example 443), i-I [4-(4-fluorophenyl)-2-methylthiazol-5yl] methoxy) phenyl k-1-cyclohexylbenzimidazol-5-yl] carbonyl Vp-nglucuronic acid (Example 444), [12-14- [bis (3-f luorophenyl)methoxy] -2-tluorophenylcarbonyl Kp-D-giucuronic acid (Example 445) 2-b4-f2- (4-chiorophenyl) 1-dioxoisothiazolidin-2yl) benzyloxy] -2-fluorophenyl carboxylic acid hydrochloride (Example 446), 3-f (5-aminosulfonyl-1-cyclohexylbenzimidazol-2-yl) -3fluorophenoxy] methyl (4-chiorophenyl) -N-isopropylbenzamide (Example 447), 2- (4-chlorophenyl) (isopropylarninocarbonyl)benzyloxy}-2ifluorophenyl I-l-.cyclohexylbenf'imidazole-5-carboxylic acid.

hydrochloride'(Example 448), 2- [4-{2-(4-chlorophenyl) -4-fluoro-5- 1-dioxoisothiazolidin-2yl) benzyloxyl -2-fluorophenyl] carboxylic acid hydrochloride (Example 449), 2- (4-f2- (4-chiorophenyl) (isopropylaminocarbonyl)benzyloxy}-2ifluorophenyl] -l-cyclohexyl-4-riethoxybenzimidazole-S-carboxylic acid hydrochloride (Example 450), 2- [4-f 2- (4-chiorophenyl) (N-isopropylcarbonyl-Nmethylamino) benzyloxy} -2-fluorophenyl] -l-cyclohexylbenzimidazoleacid hydrochloride (Example 451), 2- (4-chiorophenyl) (isopropylcarbonylamino)benzyloxy}-2ifluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 452), 2- [3-f (4-fluorophe nyl) -2-methylthiazol-5-yllmethyl}-4hydroxyphenyl] -l-cyclohexylbenziutidazole-5-carboxylic acid (Example 453), 2- (4-chlorophenyl) -4-fluoro-5- (2-oxopyrrolidin-lyl) benzyloxy} -2-fluorophenyl] carboxylic acid hydrochloride (Example 454), 2- (4-chiorophenyl) -5-(methylsulfonylamino) benzyloxy} -2fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 455), 2- (4-chiorophenyl) [N-methyl-N- (methylsulfonyl) amino) benzyloxy} -2-fluorophenyl] -1acid hydrochloride (Example 456), 2- [44 (4-chlorophenyl) (2-oxopyrrolidin-1-yl)pyridin-2yl] methyloxy} -2-f luorophenyl] carboxylic acid hydrochloride (Example 457), (4-chlorophenyl) (acetylaznino)benzyloxy}-2ifluorophenyl] -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 458), 2- (4-chiorophenyl) (N-acetyl-N-ethylamino)benzyloxy}-2fluorophenyl 3-l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 459), (4-chlorophenyl) (N-acetyl-N-propylamino) benzyloxy}-2fluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 460), 2- (4-chlorophenyl)-5- [N-ethyl-N- (methylsulfonyl) amino]benzyloxy} -2-f luorophenyl] acid hydrochloride (Example 461), 2- (4-chiorophenyl) -5-EN- (methylsulfonyl)-Npropylamino] benzyloxy} -2-f luorophenyl] -1-cyclohexylbenzimidazole- 5-carboxylic acid hydrochloride (Example 462), 2- (4-chiorophenyl) -5-(N-acetyl-N-methylamino) benzyloxy}-2ifluorophenyl] -1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 463), 2- (4-chiorophenyl) -5-EN- (ethylsulfonyl) -N-methylamino] benzyloxy} -2-fluorophenyl] acid hydrochloride (Example 464), 2- (4-chlorophenyl) [N-ethyl-N- (ethylsulfonyl) amino] benzyloxyl -2-ifluorophenyl] acid hydrochloride (Example 465), 2- [4-f 2- (4-chiorophenyl) (ethylcarbonyl) -N-methylamino] benzyloxy} -2-ifluorophenyl] acid hydrochloride (Example 466), 2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(ethylcarbonyl)amino]acid hydrochloride (Example 467), 2-[4-{2-(4-chlorophenyl)-5-methoxybenzyloxy}-2-fluorophenyl]-1cyclohexylbenzimidazole-5-carboxylic acid (Example 468), 2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-isopropylamino)acid hydrochloride (Example 469), {[2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2o1 glucuronic acid (Example 470), 2- 4-[2-(4-chlorophenyl)-5-( isopropylcarbamoyl)benzyloxy]phenyl 3-cyclohexyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid hydrochloride (Example 702), and 2-44-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]phenyl -3-cyclohexyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid.

hydrochloride (Example 703).

(63) A pharmaceutical composition comprising a fused ring compound of any of (29) to (62) above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(64) A hepatitis C virus polymerase inhibitor comprising a fused ring compound of any of to (28) and (29) to (62) above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

An anti-hepatitis C virus agent comprising a fused ring compound of any of to (28) and (29) to (62) above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(66) A therapeutic agent for hepatitis C comprising a fused ring compound of any of (29) to (62) above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(67) An anti-hepatitis C virus agent comprising the antihepatitis C virus agent of (65) above and at least one agent selected from the group consisting of a different antiviral agent, an antiinflammatory agent and an immunostimulant.

(68) An anti-hepatitis C virus agent comprising the antihepatitis C virus agent of (65) above and interferon.

(69) A therapeutic agent for hepatitis C comprising the hepatitis C virus polymerase inhibitor of (64) above and at least one agent selected from the group consisting of a different antiviral agent, an antiinflammatory agent and an immunostimulant.

A therapeutic agent for hepatitis C comprising the hepatitis C virus polymerase inhibitor of (64) above and (b) interferon.

o1 (71) A benzimidazole compound of the folllowing formula [III] 0 Ra38

R

OH [III] aR37 wherein Ra 36 is hydrogen atom or carboxyl-protecting group, Ra 37 is cyclopentyl or cyclohexyl, and Ra 38 is hydrogen atom or fluorine atom, or a salt thereof.

(72) A thiazole compound selected from the group consisting of 4- (4-fluorophenyl)-5-hydroxymethyl-2-methylthiazole and fluorophenyl)-5-chloromethyl-2-methylthiazole, or a pharmaceutically acceptable salt thereof.

(73) A biphenyl compound selected from the group consisting of 1- (4'-chloro-2-hydroxymethyl-biphenyl-4-yl)-2-pyrrolidinone and 1- (4'-chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone, or a pharmaceutically acceptable salt thereof.

(74) A pharmaceutical composition comprising a fused ring compound of the formula fI] of above or a pharmaceutically acceptable salt thereof and at least one agent selected from the group consisting of an antiviral agent other than the compound of above, an antiinflammatory agent and an immunostimulant.

A pharmaceutical composition comprising a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof and interferon.

(76) A method for treating hepatitis C, which comprises administering an effective amount of a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof.

(77) The method of (76) above, further comprising administering an effective amount of at least one agent selected from the group consisting of an antiviral agent other than the compound of (1) above, an antiinflammatory agent and an immunostimulant.

(78) The method of (76) above, further comprising administering an effective amount of interferon.

(79) A method for inhibiting hepatitis C virus polymerase, which lo0 comprises administering an effective amount of a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof.

The method of (79) above, further comprising administering an effective amount of at least one agent selected from the groupis consisting of an antiviral agent other than the compound of (1) above, an antiinflamrnatory agent and an inmnunostimulant.

(81) The method of (79) above, further comprising administering an effective amount of interferon.

(82) Use of a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical agent for treating hepatitis C.

(83) Use of a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof for the production of a hepatitis C virus polymerase inhibitor.

(84) A pharmaceutical composition for the treatment of hepatitis C, which comprises a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof,. and a pharmaceutically acceptable carrier.

A pharmaceutical composition for inhibiting hepatitis C virus polymerase, which comprises a fused ring compound of the formula of above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(86) A commercial package comprising a pharmaceutical composition of (84) above and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating hepatitis C.

(87) A commercial package comprising a pharmaceutical composition of (85) above and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for inhibiting hepatitis C virus polymerase.

The definitions of respective substituents and moieties used in the present specification are as follows.

The halogen atom is a fluorine atom, chlorine atom, bromine atom or iodine atom, preferably fluorine atom, chlorine atom or bromine atom.

Particularly preferably, the halogen atom is fluorine atom at R 5

R

5

R

6

R

6 group A and group C, and fluorine atom or chlorine atom at X, Z, group B and group D.

The Ci-6 alkyl is straight chain or branched chain alkyl having 1 to 6 carbon atoms, and is exemplified by methyl, ethyl, propyl,. isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl and the like.

1i Preferably, it is straight chain or branched chain alkyl having 1 to 4 carbon atoms, and is particularly preferably methyl at R a

R

a 8

R

a

R

a s

R

a16

R

a17

R

a33

R

a35

R

b and R b7 and methyl or tert-butyl at R b

R

b2 group B and group C, and methyl, ethyl, a29 propyl or isopropyl at R a2 The halogenated C1-6 alkyl is the above-defined C1-6 alkyl except that it is substituted by the above-defined halogen atom.

Preferably, it is halogenated alkyl wherein the.alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl, 1,2dichloromethyl, 2,2-dichloromethyl,,2,2,2-trifluoroethyl and the like.

The halogenated C1-6 alkyl is particularly preferably trifluoromethyl at group B.

The C1-6 alkylene is straight chain alkylene having 1 to 6 carbon atoms, and is exemplified by methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene.

The C1-6 alkylene is preferably methylene or ethylene at Y.

The C2- 6 alkenylene is straight chain alkenylene having 2 to 6 carbon atoms, and is exemplified by vinylene, propenylene, 1-butenylene, 1,3-butadienylene and the like.

The C2-6 alkenylene is preferably vinylene at Y.

The CI-6 alkoxy is alkyloxy wherein the alkyl moiety thereof is the above-defined CI-6 alkyl. Preferably, it is alkoxy wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, isopropyloxy, butoxy, isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy and the like.

The C 1 -6 alkoxy is particularly preferably methoxy at Ra 2 R a 3

R

a

R

a 2

R

a 3 group A and group C.

The Ci- 6 alkoxy Ci- 6 alkoxy is that wherein Ci- 6 alkoxy in the o0 above definition is substituted by Ci-6 alkoxy defined above and is preferably that wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms.

Specific examples include methoxymethyl, ethoxymethyl, methoxyethoxy, methoxypropoxy, isopropyloxyethoxy and the like.

The group A is particularly preferably methoxyethoxy.

The CI- 6 alkanoyl is alkylcarbonyl wherein the alkyl moiety thereof is the above-defined C 1 -6 alkyl. Preferably, it is alkanoyl wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include acetyl, .propionyl, butyryl, isobutyryl, pivaloyl. and the like.

The Ci-6 alkanoyl is particularly preferably acetyl at. R,

R

2 R 3

R

4

R

a Ra29, Rb 7 and group B.

The Ci-6 alkoxycarbonyl is alkyloxycarbonyl wherein the alkoxy moiety thereof is the above-defined Ci- 6 alkoxy. Preferably, it is alkoxycarbonyl wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms.

Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.

The CI-6 alkoxycarbonyl is particularly preferably methoxycarbonyl or ethoxycarbonyl at Ral 0 and group A.

The C 1 -6 alkylamino is alkylamino or dialkylamino wherein the alkyl moiety thereof is the above-defined C 1 -6 alkyl.

Preferably, it is alkylamino or dialkylamino wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, N-isopropyl-Nisobutylamino and the like.

The C 1 6 alkylamino is particularly preferably methylamino at Ra7, and particularly preferably dimethylamino at Ra 21 and group A, and particularly preferably dimethylamino, ethylamino or isopropylamino at Ra 4 The C 1 -6 alkanoylamino is alkylcarbonylamino wherein the o1 alkanoyl moiety thereof is the above-defined C 1 -6 alkanoyl.

Preferably, it is alkylcarbonylamino wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include acetylamino, propionylamino, butyrylamino, isobutyrylamino, pivaloylamino and the like.

The Ci-6 alkanoylamino is particularly preferably acetylamino at X and Ra 1 The CI-6 alkylsulfonyl is alkylsulfonyl wherein the alkyl moiety thereof is the above-defined C 1 -6 alkyl. Preferably, it is alkylsulfonyl wherein the alkyl moiety thereof is straight chain or branched chain alkyl having 1 to 4 carbon atoms. Examples thereof include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tertbutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

The CI-6 alkylsulfonyl is particularly preferably methylsulfonyl at X and R s The C 6 14 aryl is aromatic hydrocarbon having 6 to 14 carbon atoms. Examples thereof include phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl and the like.

The C 6 14 aryl is preferably phenyl or naphthyl, particularly preferably phenyl at the ring A, ring ring B and ring B'.

The C 3 -8 cycloalkyl is saturated cycloalkyl having 3 to 8, preferably 5 to 7, carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The C3- 8 cycloalkyl is particularly preferably cyclohexyl at the ring A, ring ring B and ring B'.

The C 3 -8 cycloalkenyl is cycloalkenyl having 3 to 8, preferably 5 to 7, carbon atoms and has at least 1, preferably 1 or 2, double bond(s). Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 2,4cyclohexadien-1-yl, 2,5-cyclohexadien-l-yl, cycloheptenyl and cyclooctenyl and the like, but do not include aryl phenyl) or completely saturated cycloalkyl.

The C 3 -8 cycloalkenyl is preferably cyclohexenyl at the ring A and ring A'.

The heterocyclic group has, as an atom constituting the ring, 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, besides a carbon atom, and includes saturated ring and unsaturated ring, monocyclic ring and fused ring having the number of ring atom constituting the ring of 3 to 14.

The heterocyclic group as a monocyclic ring includes, for example, pyridyl, pyrazinyl, pyrimidinyl,. pyridazinyl, 1,3,5triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and the like.

The heterocyclic group includes the groups of the following formulas.

N 0 0 N 0 s

N-E

3

E

0 SNo 3 0-E

,E

N El 0

N<E'

oS 0 S-E2 N\ )f -N 0 h~E 0fo ~0 Ah -N S-0 h 0 ,S-E2 f -N,.J)f hO 0 0 E N, f and and H R wherein El is an oxygen atom, a sulfur atom or N(-Ra 35

E

2 is an oxygen atom, CH 2 or N(-Ra 3

E

3 is an oxygen atom or a sulfur atom, wherein Ra 35 is independently hydrogen atom or Ci- 6 alkyl, f is an integer of 1 to 3, and h and h' are the same or different and each is an integer of 1 to 3.

Specific examples of the heterocyclic group include

H

N-

s--NH s 0 S--s 0

NH

0 0 0

NH

H

0 0

H

NH

H

__KN;

/cI H 0.

N-

s-so

H

0 0

NH

0 0

NH

0

NH

0

NH

0.

sq -Nb -b -Nj -NJ -N -N

O

o 0 0 -N3-N -NI \\J0 0_N 0

HI

and the like.

Examples of the heterocyclic group as a fused ring include quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, phthalazinyl, cirinolinyl, naphthyridinyl, 5, 6, 7,8-tetrahydroquinolyl, indolyl, benzimidazolyl, 2, 3-dihydrobenzimidazolyl, 2, 3-dihydro-2oxobenzimidazolyl, indolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl and the like.

Preferably, it is a heterocyclic group which is a membered or a 6-mexnbered monocyclic group. Examples thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, fury., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl N-N NH0 N- N-O N H a. H 0. 0, H 0. H 0 -Nt0 -c

_N-NH

0tNa- 0. a_<-k 0-1 -n a

NH

N ko

H

0

NH

0

NH

0 N H a

-NJ

0

NH

a

NH

S -s 0 k-NH 0

/S>NH

s-a -N 0

S-NH

-A-O

0

-NJ

a"s" 0 -NO 0 -N S= -N 0 s

N

SN

N

HI

and the like.

At R 2

R

3

R

4 Z and group D, tetrazolyl and 5-oxo-A 2 .o 1,2,4-oxadiazolin-3-yl are particularly preferable.

The heterocyclic group is preferably pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl which is an aromatic group, and particularly preferably pyridyl at the ring A and ring A'.

The heterocyclic group is particularly preferably pyridyl, s pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thiadiazolyl, which is an aromatic group, at the ring B and ring More preferably it is pyridyl or thiazolyl, most preferably thiazolyl.

The C 6 -1 4 aryl Ci- 6 alkyl is arylalkyl wherein the alkyl moiety thereof is the above-defined C 1 -6 alkyl and the aryl moiety is the above-defined C 6 14 aryl. Preferably, it is arylalkyl wherein the alkyl moiety thereof is straight chain alkyl having 1 to 4 carbon atoms and the aryl moiety is phenyl. Examples thereof include benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 4phenylbutyl and the like.

The C6- 14 aryl Ci-6 alkyl is particularly preferably benzyl at R a 8 and Rb 6 The glucuronic acid residue is glucuronic acid less any hydroxyl group, preferably P-D-glucuronic acid substituted at 1position.

The C 6 -1 4 aryl Ci- 6 alkyloxycarbonyl is arylalkyloxycarbonyl wherein the C 6 -1 4 aryl C 1 -6 alkyl moiety thereof is the abovedefined C6- 14 aryl Ci- 6 alkyl. Preferably, it is arylalkyloxycarbonyl wherein the alkyl moiety thereof is straight chain alkyl having 1 to 4 carbon atoms and the aryl moiety is phenyl. Examples thereof include benzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropyloxycarbonyl, 2phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl and the like.

The C 6 -1 4 aryl Ci-6 alkyloxycarbonyl is particularly preferably benzyloxycarbonyl at Rb7.

The optionally substituted C 1 -6 alkyl is the above-defined

C

1 -6 alkyl, preferably that wherein straight chain or branched chain alkyl having 1 to 4 carbon atoms is optionally substituted with 1 to 3 substituent(s), and includes unsubstituted alkyl. The substituent(s) is(are) selected from the above-defined halogen atom, hydroxyl group, carboxyl, amino, the above-defined C 1 6 alkoxy, the above-defined C 1 6 alkoxy C 1 6 alkoxy, the abovedefined C 1 -6 alkoxycarbonyl and the above-defined C 16 alkylamino.

Examples of optionally substituted C 16 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-ethylpropyl, hexyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxy- 1-methylethyl,. 1 -hydroxypropan-2-yl, 1,3-dihydroxypropan-2-yl, l-hydroxy-2-methylpropan-2-yl, carboxylmethyl, 2-carboxylethyl, methoxymethyl, methoxyethyl, 'o methoxyethoxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-dimethylaminoethyl and the like.

Preferably, the optionally substituted C 16 alkyl is methyl, l-hydroxy-l-methylethyl, carboxylmethyl or 2-dimethylaminoethyl at R 2

R

3 and R methyl or trifluoromethyl at R 5

R

5 R and 6,7 8 a5 R methyl at R R Ra3 and Rb methyl, ethyl or isopropyl at

R

24 methyl or isopropyl at Rals, methyl or ethyl at Ral, Ral 9 and R 25, methyl, carboxylmethyl or 2-dimethylaminoethyl at R,2 and Rat methyl or carboxylmethyl at Ra 6 methyl, ethyl, isopropyl, butyl or trifluoromethyl at X, methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, isopentyl, neopentyl, 1-ethylpropyl or.

carboxylmethyl at RalD, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trifluoromethyl, 2-hydroxyethyl or carboxylmethyl at all a12 R methyl or 4-hydroxybutyl at R methyl, ethyl, isopropyl, butyl, 2-hydroxyethyl, 4-hydroxybutyl, ethoxycarbonylmethyl, 2- (ethoxycarbonyl)ethyl or 2-dimethylaminoethyl at Ra 3 methyl, propyl, butyl, isopentyl, trifluoromethyl, hydroxymethyl, 2hydroxyethyl, 3-hydroxypropyl, methoxyethyl, methoxyethoxyethyl a 22 a 23 or carboxymor ethyl at R and R, methyl a26 isopropyl or tert-butyl at Ra2, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, 2-hydroxyethyl, 1-hydroxypropan-2-yl, a27 a28 1-hydroxy-2-methylpropan-2-yl or carboxylmethyl at Ra and R, and methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 2-carboxylethyl, methoxymethyl or ethoxycarbonylmethyl at Z, Z' and group D.

It is particularly preferably, trifluoromethyl at R 5 R R6 and R 6 methyl or tert-butyl at Ra26 methyl, tert-butyl, trifluoromethyl or hydroxymethyl at Z, Z' and group D, and methyl at other substituents.

The optionally substituted C 2 -6 alkenyl is that wherein straight chain or branched chain alkenyl having 2 to 6 carbon atoms is optionally substituted by 1 to 3 substituent(s), and includes unsubstituted alkenyl. The substituent(s) is(are) selected from the above-defined halogen atom, hydroxyl group, carboxyl, amino, the above-defined C 1 -6 alkoxy, the above-defined

C

1 6 alkoxy C-s 6 alkoxy, the above-defined CI-6 alkoxycarbonyl and the above-defined C 1 -6 alkylamino. Examples of optionally substituted C2-6 alkenyl include vinyl, allyl, 1-propenyl, o0 isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 2-isopentenyl, 3-isohexenyl, 4-methyl-3-pentenyl, 2-carboxylethenyl and the like.

The optionally substituted C2-6 alkenyl is preferably 2carboxylethenyl at X, and preferably 2-isopentenyl, 3-isohexenyl or 4-methyl-3-pentenyl at R a2 The optionally substituted C2- 6 alkynyl is that wherein straight chain or branched chain alkynyl having 2 to 6 carbon atoms is optionally substituted by 1 to 3 substituent(s), and includes unsubstituted alkynyl. The substituent(s) is (are) selected from the above-defined halogen atom, hydroxyl group, carboxyl, amino, the above-defined CI-6 alkoxy, the above-defined

C

1 -6 alkoxycarbonyl and the above-defined C 1 -6 alkylamino.

Examples thereof include ethynyl, 1-propynyl, 2-propynyl, 3butynyl and the like.

The optionally substituted C 2 -6 alkynyl is preferably 2propynyl at R 20 The C6- 14 aryl optionally substituted by 1 to substituent(s) selected from group B is that wherein the abovedefined C 6 14 aryl is optionally substituted by 1 to substituent(s), and includes unsubstituted aryl. The substituent(s) is(are) selected from the above-defined halogen atom, cyano, nitro, the above-defined C 1 -6 alkyl, the abovedefined halogenated CI-6 alkyl, the above-defined CI-6 alkanoyl,

-(CH

2

-COOR

b l

-(CH

2 )r-CONRb R 2 (CHz) r-NR Rb2, -(CH2) b-NRl-CORb2

(CH

2 )r-NHS 2

R

b -(CHr-OR, CH 2 )OR, H 2 r-SR b (CH2) r-SO 2

R

b and

-(CH

2 )r-S0 2 NRblRb 2 (wherein Rbl and Rb 2 are each independently hydrogen atom or the above-defined Ci-6 alkyl and r is 0 or an integer of 1 to 6).

Examples thereof include phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, 3-fluorophenyl, 4fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, pentafluorophenyl, 4-methylphenyl, 4-tertbutylphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4nitrophenyl, 4-cyanophenyl, 4-acetylphenyl, 4-carboxylphenyl, 4carbamoylphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4acetylaminophenyl, 4- (methylsulfonylamino) phenyl, 4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-methylthiophenyl, 4jo methylsulfonylphenyl, 4-aminosulfonylphenyl, 3-nitro-4methoxyphenyl and 4-nitro-3-methoxyphenyl.

The aryl moiety is preferably phenyl, the group B here is preferably the above-defined halogen atom, nitro, the abovedefined C 1 _6 alkyl, the above-defined halogenated C 16 alkyl or

-(CH

2 )r-ORbl. Examples of group B include fluorine atom, chlorine atom, nitro, methyl, tert-butyl, trifluoromethyl and methoxy.

Particularly preferably, it is fluorine atom or chlorine atom.

With regard to "Cs 6 -1 4 aryl optionally substituted by 1 to substituent(s) selected from group it -is preferably phenyl, 4-tert-butylphenyl, 4-fluorophenyl, 3-chlorophenyl, 4chlorophenyl, 4-methoxyphenyl or 4-trifluoromethylphenyl at Ra 12 Ra and Ra ,.phenyl at Ra paR22, Ra23 a26 d R, phenyl or 3fluorophenyl at Ral, phenyl or 2,4-dichlorophenyl at Ra20, phenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 3nitro-4-methoxyphenyl or 4-nitro-3-methoxyphenyl at Ra24 and phenyl or 4-methylphenyl at Ras It is particularly preferably phenyl at other substituents.

The C 6 -1 4 aryl optionally substituted by 1 to substituent(s) selected from group D is that wherein the abovedefined C6-1 4 aryl is optionally substituted by 1 to substituent(s), and includes unsubstituted aryl. The substituent(s) is(are) selected from the above-mentioned group D (substituents shown under to Examples of..group D here include fluorine atom, dhlorine atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2hydroxyethyl, methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylaminocarbonyl, isopropylaminocarbonyl, dime thyl aminocarbonyl, diethylaminocarbonyl, (2-hydroxyethyl) aminocarbonyl, (carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy, propyloxy, isopropyloxy, isopentyloxy, 2-isopentenyloxy, 3isohexenyloxy, 4-methyl-3-pentenyloxy, 2-propynyloxy, hydroxyinethyloxy, carboxylmethyloxy, (dimethylaminocarbonyl) methyloxy, amino, methylamino, dimethylamino, diethylamino, acetylamino, methylsulfonylamino, io methyithia, methylsulfonyl, methylsulfinyl, aminosulfonyl, methylazuinosulfonyl, dimethylaminosulfonyl -and tetrazolyl.

Examples Of C 614 aryl optionally substituted by 1 to substituent(s) selected from group D include phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, 3is fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,.4-chlorophenyl, 2, 4-dichlorophenyl, 3, 5-dichiorophenyl, 4-bromophenyl, 4nitrophenyl, pentafluorophenyl, 4-methyiphenyl, 4-tertbutyiphenyl, 2-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4- (hydroxymethyl) phenyl, 4- (methoxymethyl) phenyl, 4- (2carboxylethyl) phenyl, 3-carboxylphenyl, 4-carboxylphenyl, .4methoxyphenyl, 3, 4, 5-trimethoxyphenyl, 4-carbamoylphenyl, 4methylthiopheiyl, 4- (dimethylaminocarbonyl) phenyl, 4methylsulfonylphenyl, 4-acetylaminophenyl, 4-cyanophenyl, 4acetyiphenyl, 4-aminophenyl, 4-dimethylaminophenyl, 4- (methylsulfonylamino) phenyl, 4-methylsulfinylphenyl, 4aminosul fonylphenyl and 3-nitro-4-methoxyphenyl, 4-nitro-3methoxyphenyl and At Z and the aryl moiety is preferably phenyl.' The group D here is preferably the above-defined halogen 3o atom, nitro, the above-defined optionally substituted C 16 alkyl, -cooR ai, tCONRa 2 7 Ra 2 toRa"o, t-NRa 29

CO-R

24 a25 a26

-(CH

2 tS qR or (CH 2 t-S 2

-NHR

Particularly preferably, it is the above-defined halogen atom, the above-defined optionally substituted C 1 6 alkyl, a19 27a820a25 3s (CH 2 t-COOR (CH 2 tCONRa2Ra2, (CH 2 t-ORa or iCH2) t-S(O) q-R which is specifically fluorine atom, chlorine atom, bromine atom, nitro, methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl or acetylamino.

More preferably, it is fluorine atom, chlorine atom, methyl, tert-butyl, carboxyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl or acetylamino, most preferably fluorine atom or chlorine atom.

Examples of C 6 14 aryl optionally substituted by 1 substituent(s) selected from group D preferably include phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 4-tert-butylphenyl, 2-trifluoromethylphenyl, 4trifluoromethylphenyl, 4-(hydroxymethyl)phenyl, 4- (methoxymethyl)phenyl, 4-(2-carboxylethyl)phenyl, 3carboxylphenyl, 4-carboxylphenyl, 4-methoxyphenyl, 3,4,5trimethoxyphenyl, 4-carbamoylphenyl, 4-methylthiophenyl, 4- (dimethylaminocarbonyl)phenyl, 4-methylsulfonylphenyl, 4acetylaminophenyl, 4-methylsulfinylphenyl, 4-aminosulfonylphenyl, 4-cyanophenyl and 4-tetrazolylphenyl, particularly preferably 4chlorophenyl.

The heterocyclic group optionally substituted by 1 to substituent(s) selected from group B.is that wherein the.abovedefined heterocyclic group is optionally substituted by 1 to substituent(s), and includes unsubstituted-heterocyclic group..

The substituent(s) is(are) selected from the above-defined halogen atom, cyano, nitro, the above-defined C 1 6 alkyl, the above-defined halogenated C 1 6 alkyl, the above-defined C 1 6 alkanoyl, -(CH2),-COORbl, -(CH2)rCONRlRb 2

-(CH

2 rb-NRR 2

(CH

2 rNRl-CORb2, -(CH2)r-NHSO 2 Rbl CH 2 rI-OR (CH 2 r-SRbl

(CH

2 r-SO 2 R and (CH 2 r-SO2NRblRb2 wherein Rbl and Rb2 are each independently hydrogen atom or the above-defined CI-6 alkyl and r is 0 or an integer of 1 to 6.

Examples thereof-include 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 4-chloropyridin-3-yl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, 2-thienyl, 3thienyl, furyl, oxazolyl, 2-methyloxazol-4-yl, isoxazolyl, thiazolyl, 2-methylthiazol-4-yl, 2,5-dinethylthiazol-4-yl, 2,4isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, imidazolidinyl, azetidinyl, piparidyl, 3-hydroxypiperidino, 4-hydroxypiperidino, 3, 4dihydroxypiperidino, 4-methoxypiperidino, 4-carboxypiperidino, 4- (hydroxymethyl) piperidino, 2,2, 6, 6-tetramethylpiperidino, 2, 2, 6,6-tetrainethyl- 4-hydroxypiperidino, N-methylpiperidin-4 -4, N- (tert-butoxycarbonyl) pip~ridin-4-y1, N-acetylpiperidin-4-yl, Nmethyisulfonylpiperidin-4-yl, piperazinyl, 4-methylpiperazinyl, 4-methylsulfonylpiperazinyl, morpholinyl, thiomorpholinyl, 1oxothiomorpholin-4-yl, 1, 1-dioxothiontorpholin-4-yl, tetrahydropyranyl, quinolyl, isoquinolyl, quinazolinyl, lo quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, 5,6,7,8tetrahydroquinolyl, indolyl, benzimidazolyl, indolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazoiyi, o 0 N- j<N-o N 0

I

Me Et 'IQK H 0

N-

H

-KZ

M4 Me M a 0-Nt

N

0 -a

N_<N-

0 os 0 0.

-K-to _K'rko 0 -f 0

NH

Nt

H

a

NH

0 -s 0

NH

0*

NH

0

-NH

0

H

o 0 0K H_ 0 0** N N N N U

NN~

_HS/T S_-NH NH NJ -NQD -NQ N 0 N S -N AN N Me NMM N N)M 0 0 0 HI H I Me and the like.

The heterocyclic moiety is preferably a heterocyclic group which is a 5-membered or a 6-meinbered monocyclic group. Examples thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, fury., oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl, and the group B here is preferably the above-defined halogen atom, the above-defined

C

1 -6 alkyl, the above-defined halogenated C 1 6 alkyl, the above-defined

C

1 6 alkanoyl, I(CH2)r-COORbl, (CH 2 r CONRbIRb 2 or CH2) rORbl.- Examples of heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from group B preferably include piperidino, 4-methylpiperidino, 2, 6-dimethylpiperidino, 4hydroxypiperidino, 1-piperazinyl, 1- (methylsulfonyl)piperidin-4yl, l-pyrrolidinyl, inorpholino, 4-thiomorpholinyl, tetrahydropyranyl, pyridyl, thiazolyl, 100 o o- 0 \I -N b_ >-NH -N o 01 Ok:' NH S S-NK /-N NJ -NJ -N -N) -N 0 -N S0O -N NmNyMe Km N N1 O<N <NA S'N sAN M :Me ,ND N: I MMNan Me Ne /n >Me NH 0 0 Me 0 Particularly preferably, it is piperidino, 4methylpiperidino, 2, 6-dimethyipiperidino,.4-hydroxypiperidino, 1piperazinyl, 1-pyrrolidinyl, morpholino or 4-thiomorpholinyl at R a1, tetrahydropyranyl or 4-hydrox-ypiperidino at R a2, piperidino, 4-hydroxypiperidino or 3,4-dihydroxypiperidino at R azi, pyridyl or lo morpholino at R a 24 pyridyl or 4-hydroxypiperidino at Ra 25 pyridyl or thiazolyl. at R"l and at RaZ and Ra 2 it is 1- (methylsulfonyl) piperidin-4-yl, 3-hydroxypyrrolidinyl, 3- *hydroxypiperidino, 4-hydroxypiperidino, 3, 4-dihydroxypiperidino, *4-methoxypiperidino, 4-carboxypiperidino, 4- (hydroxymnethyl) piperidino, 2-oxopiperidino, 4-oxopiperidino, 2,2,6, 6-tetraxnethylpiperidino, 2,2,6, 6-tetramethyl-4hydroxyplperidino, 4-methylsulfonylpiperazinyl, 1oxothiomorpholin-4-yl or 1,1-dioxothiomorpholin-4-yl, and 2oxazolin-2-yi at R'z and R8 3 The heterocyclic group optionally substituted by 1 to substituent(s) selected from group D is that wherein the abovedefined heterocyclic group is optionally substituted by I to 101 substituent(s), and includes unsubstituted heterocyclic group.

The substituent(s) is~are) selected from the substituent(s) of the above-mentioned group D (substituents shown under to Examples of the group D here include the substituent(s) exemplified for C 6 14 aryl optionally substituted by 1 to substituent(s) selected from group D.

Examples of heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from group D include 2-pyridyl, 3pyridyl, 4-pyridyl, 3-f luoropyridin-4-yl, 3-chloropyridin-4-yl, lo 4-chloropyridin-3-yl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, 2-thienyl, 3-thienyl, furyl, oxazolyl, 2methyloxazol-4-yl, isoxazolyl, thiazolyl, 2-methylthiazol-4-yl, 2, 5-dimethylthiazol-4-yl, 2, 4-dimethylthiazol-5-yl, isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, piperidyl, N-methylpiperidin-4-yl, N- (tert-butoxycarbonyl) piperidin-4-yl, Nacetylpiperidin-4-yl, N-methylsulfonylpiperidin-4-yl, piperazinyl, inorpholinyl, thiomorpholinyl, tetrahydropyranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, phthalazinyl, cinnolinyl, 2o naphthyridinyl, 5,6,7, 8-tetrahydroquinolyl, indolyl, benzimidazolyl, indolinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl 0N 0b HN3 0 N1 -N 0 0 0. _NH. /SNH NH41 -N 0 NJ -NJ -NQ, N, 0'0 -ND 0 -N S=0

K

102 N e N Me N f Mee

H

Me N M: M Me N N 0 0 0 M H H Me and the like.

In addition, the heterocyclic group may be substituted at the 5- or 6-position of 2-pyridyl, at the 5- or 6-position of 3-pyridyl, at the 5- or 6-position of 4pyridyl, at the 4- or 5-position of 2-thienyl, or at the 2-, 4- or 5-position of 3-thienyl, by fluorine atom, chlorine atom, bromine atom, nitro, methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, lo methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl, amino or acetylamino.

At Z and the heterocyclic moiety is preferably a heterocyclic group which is a 5-membered or 6-membered monocyclic group. Examples thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, 2-oxopyrrolidinyl, 2oxopiperidyl, pyrazolyl, imidazolyl, 2-imidazolinyl, 2oxoimidazolidinyl,'1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, 2-oxazolinyl, thiazolyl, isothiazolyl, 1,1dioxoisothiazolidinyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, AK- 1,2,4-oxadiazolyl, 5-oxo-6A -1,2,4-oxadiazolyl, 5-oxo-A 2 -1,2,4thiadiazolinyl and 2-oxo-3H-1,2,3,5-oxathiadiazolinyl. The group D here is preferably the above-defined halogen atom, nitro, the above-defined optionally substituted C1-6 alkyl, a27a29a20 a29 a24

-(CH

2 -COR9, -(CH2) t-CONRa27 Ra2 (CH 2 t-OR (CH2) t NRa29 CO-Ra24

-(CH

2 -S q-Ra25 or -(CH 2 t-S02-NHRa26 Examples of heterocyclic group optionally substituted by 1 to 5 substituent(s) selected from group D preferably include piperidino, 4-hydroxypiperidino, 2-oxopiperidin-l-yl, 1piperazinyl, 1-pyrrolidinyl, 2-oxopyrrolidin-l-yl, morpholino, 4thiomorpholinyl, 4-tetrahydropyranyl, 3-pyridyl, 2-pyrimidinyl, 2-imidazolin-2-yl, 2-oxoimidazolidin-1-yl, 2-oxooxazolidin-1-yl, 103 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2methylthiazol-4-yl, 5-methylthiazol-2-yl, 2-aiinothiazol-4-yl, 3methyl-1,2,4-oxadiazol-5-yl, 1,l-dioxoisothiazolidin-2-yl, 4,4dimethyl-A 2 -oxazolin-2-yl, 2-thienyl, 5-chlorothiophen-2-yl, methyloxazol-2-yl, 5-oxo-A 2 4-oxadiazolin-3-yl, 1,2,4-thiadiazolin-3-yl and 2-oxo-3H-1,2,3,5-oxathiazolin-4-yl.

Particularly preferably, it is pyridyl, pyrimidinyl, tetrazolyl, thienyl, piperidyl, 2-oxopiperidin-1-yi, 2oxopyrrolidin-l-yl, 2-imidazolin-2-yl, 2-oxoimidazolidin-1-yl, 2io oxooxazolidin-1-yl, 2-methylthiazol-4-yl, 5-methylthiazol-2-yl, 2-aminothiazol-4-yl, 3-methyl-l,2,4-oxadiazol-5-yl, 1,1dioxoisothiazolidin-2-yl, 4,4-dimethyl-A 2 -oxazolin-2-yl, chlorothiophen-2-yl, 5-methyloxazol-2-yl, 5-oxo-M-, 2,4oxadiazolin-3-yl, 5-oxo-2-1,2, 4-thiadiazolin-3-yl or 2-oxo-3H- 1, 2,3, 5-oxathiadiazolin-4-yl, more preferably 2-oxopiperidin-1-y1, 2-oxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl, 2-oxooxazolidin-lyl or 1,l-dioxoisothiazolidin-2-yl, most preferably 2oxopyrrolidin-1-yl.

The C3- 8 cycloalkyl optionally substituted by 1 to substituent(s) selected from group C is that wherein the.abovedefined C 3 8 cycloalkyl is optionally substituted by the 1 to substituent(s) selected from hydroxyl group, the above-defined halogen atom, the above-defined C 16 alkyl and the above-defined

C

1 6 alkoxy, which may be unsubstituted. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4fluorocyclohexyl, 2-methylcyclopentyl, 3-methylcyclohexyl, 4methylcyclohexyl, 4'4-cimethylcyclohexyl, 4-tert-butylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl and 2,3,4,5,6-pentafluorocyclohexyl.

The cycloalkyl moiety is preferably cyclopentyl or cyclohexyl, particularly preferably cyclohexyl.

At the ring Cy and ring Cy', the C3- 8 cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from group C is preferably cyclopentyl, cyclohexyl, 4-fluorocyclohexyl, 4methylcyclohexyl, 4,4-dimethylcyclohexyl, 4-tert-butylcyclohexyl, 4-hydroxycyclohexyl or 4-methoxycyclohexyl, more preferably cyclopentyl or cyclohexyl, particularly preferably cyclohexyl.

The C3- 8 cycloalkyl optionally substituted by 1 to 104 substituent(s) selected from the above group B is that wherein the above-defined C3-8 cycloalkyl is optionally substituted by 1 to 5 substituent(s), and includes unsubstituted cycloalkyl. The substituents are selected from the above group B.

Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-fluorocyclohexyl, 2methylcyclopentyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 4,4dimethylcyclohexyl, 3,5-dimethylcyclohexyl, 4-tertbutylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl and 1o 2,3,4,5,6-pentafluorocyclohexyl.

Also exemplified are those wherein cyclopentyl or cyclohexyl is substituted by fluorine atom, chlorine atom, bromine atom, nitro, methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, 1i methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl or acetylamino.

At cycloalkyl moiety, it is preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. As the C3-. cycloalkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B, it.is particularly preferably cyclopropyl, cyclobutyl, cyclohexyl or 4-hydroxycyclohexyl at Ra 27 and Ra 28 The C3-8 cycloalkyl optionally substituted by'.1 to substituent(s) selected from group D, is that wherein the abovedefined C3- 8 cycloalkyl is optionally substituted by 1 to substituent(s), and includes unsubstituted cycloalkyl. The substituent(s) is(are) selected from the substituent(s) of the above-mentioned group D (substituents shown under to The group D here includes the substituents recited with regard to C6- 14 aryl optionally substituted by 1 to substituent(s) selected from group D.

Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 4-fluorocyclohexyl, 2methylcyclopentyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 4,4dimethylcyclohexyl, 3,5-dimethylcyclohexyl, 4-tertbutylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl and 2,3,4,5,6-pentafluorocyclohexyl.

The group D may be, for example, cyclopentyl or cyclohexyl substituted by fluorine atom, chlorine atom, bromine atom, nitro, 105 methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl or acetylamino.

The cycloalkyl moiety is preferably cyclopentyl or cyclohexyl, and at Z and it is particularly preferably cyclohexyl.

The optionally substituted C 3 -8 cycloalkenyl is that wherein the above-defined C 3 8 cycloalkenyl is optionally substituted by substituent(s) selected from hydroxyl group, the io above-defined halogen atom, the above-defined C 1 1- alkyl and the above-defined C 16 alkoxy, which may be unsubstituted. Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 4-fluoro-2-cyclohexenyl, 4methyl-2-cyclohexenyl, 4-methyl-3-cyclohexenyl, 2,4cyclohexadien-l-yl, 2,5-cyclohexadien-1-yl, cycloheptenyl and cyclooctenyl and the like, but do not include aryl phenyl) or completely saturated cycloalkyl.

The optionally substituted C 3 8 cycloalkenyl is particularly preferably cyclohexenyl at the ring Cy.

The C 6 -1 4 aryl.C 1 6 alkyl optionally substituted by 1 to substituent(s) selected from group B is that wherein the abovedefined C6-14 aryl C.I-6 alkyl is optionally substituted by 1 to substituent(s), and includes unsubstituted arylalkyl. The substituent(s) is(are) selected from the above-mentioned group B.

Examples thereof include benzyl, l-naphthylmethyl, 2naphthylmethyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, 3fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 3,5-dichlorobenzyl, pentafluorobenzyl, 4methylbenzyl, 4-tert-butylbenzyl, 2-trifluoromethylbenzyl, 4trifluoromethylbenzyl, 4-nitrobenzyl, 4-cyanobenzyl, 4acetylbenzyl, 4-carboxylbenzyl, 4-carbamoylbenzyl, 4-aminobenzyl, 4-dimethylaminobenzyl, 4-acetylaminobenzyl, 4- (methylsulfonylamino)benzyl, 4-methoxybenzyl, 3,4,5trimethoxybenzyl, 4-methylthiobenzyl, 4-methylsulfonylbenzyl, 4aminosulfonylbenzyl, 3-nitro-4-methoxybenzyl and 4-nitro-3methoxybenzyl.

The C 6 14 aryl CI- 6 alkyl moiety is preferably benzyl or phenethyl, particularly preferably benzyl. The group B is 106 preferably the above-defined halogen atom, nitro, the abovedefined C 1 -6 alkyl, the above-defined halogenated Ci-6 alkyl or

-(CH

2 Examples thereof include fluorine atom, chlorine atom, nitro, methyl, tert-butyl, trifluoromethyl, methoxy or trifluoromethyloxy, particularly preferably fluorine atom or chlorine atom.

The specific C6- 14 aryl C- 16 alkyl optionally substituted by 1 to 5 substituent(s) selected from group B at Ra 12 and Ra n is preferably benzyl, phenethyl, 3-chlorobenzyl, 4-chlorobenzyl, 4lo tert-butylbenzyl or 3-trifluoromethylbenzyl, it is preferably benzyl at Ral, R a19

R

a27

.R

a28

R

a31 and R it is preferably benzyl, phenethyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4chlorobenzyl, 4-tert-butylbenzyl or 4-trifluoromethylbenzyl at

R

a20 and 4-chlorobenzyl, 3,5-dichlorobenzyl or 4trifluoromethylbenzyl at Ra 2 and R23 It is particularly preferably benzyl at other substituents.

The C6- 14 aryl Ci- 6 alkyl optionally substituted by 1 to substituent(s) selected from group D is that wherein the abovedefined C6- 14 aryl CI- 6 alkyl is optionally substituted by 1 to substituent(s), and includes unsubstituted aryl. The substituent(s) is(are) selected from the substituent(s) of the above-mentioned group D (substituents shown under to Examples of group D include fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, (2-hydroxyethyl)aminocarbonyl, (carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy, isopropyloxy, hydroxymethyloxy, carboxylmethyloxy, (dimethylaminocarbonyl)methyloxy, amino, methylamino, dimethylamino, diethylamino, acetylamino, methylsulfonylamino, methylthio, methylsulfonyl, methylsulfinyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.

Examples of C6- 14 aryl C 1 6 alkyl optionally substituted by 1 to 5 substituent(s) selected from group D include benzyl, 1naphthylmethyl, 2-naphthylmethyl, phenethyl, 3-phenyipropyl, 2phenyipropyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4chlorobenzyl, 2, 4-dichlorobenzyl, 3, 5-dichlorobenzyl, 4bromobenzyl, 4-nitrobenzyl, pentafluorobenzyl, 4-methylbenzyl, 4tert-butylbenzyl, 2-trifluoromethylbenzyl, 4trifluoromethylbenzyl, 4- (hydroxymethyl)benzyl, 4- (iethoxymethyl) benzyl, 4- (2-carboxylethyl) benzyl, 3carboxylbenzyl, 4-carboxylbenzyl, 4-methoxybenzyl, 3,4, trimethoxybenzyl, 4-carbamoylbenzyl, 4-methylthiobenzyi, 4lo (dimethylaminocarbonyl) benzyl, 4-methylsulfonylbenzyl, 4- (ace tylamnino) benz yl, 4-cyanobenzyl, 4-acetylbenzyl, 4-aminobenzyl, 4-dimethylaminobenzyl, 4- (methylsulfonylamino) benzyl, 4methylsulfinylbenzyl, 4-aminosulfonylbenzyl, (3-nitro-4methoxyphenyl) methyl and (4-ni tro-3-methoxyphenyl) methyl.

At Z-and the C6.

14 aryl C1_6 alkyl moiety is.preferably benzyl or phenethyl, and the group D here is preferably the.

above-defined halogen atom, nitro, the above-defined optionally substituted C1-6 alkyl, (CH2) tCO0Ral 9

-(CH

2 CoNa 27 alR

(CH

2 tOR2 -4CH 2 tNRa2 CO-R 1CH2) tS qRa or 5-SOflpjJ&6 The C6-14 aryl 01-6 alkyl optionally substituted by 1 to substituent(s) selected from group D is preferably benzyl, 3fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3, 5-dichlorobenzyl, 4-bromobenzyl, 4-nitrobenzyl, 4-methylbenzyl, 4-tert-butylbenzyl, 2-trifluoromethylbenzyl, 4trifluoromethylbenzyl, 4- (hydroxymethyl) benzyl, 4- (methoxymethyl) benzyl, 4- (2-carboxylethyl) benzyl, 3carboxylbenzyl, 4-carboxylbenzyl, 4-methoxybenzyl, 3,4,5trimethoxybenzyl, 4-carbamoylbenzyl, 4-methylthiobenzyl, 4- (dimethylaminocarbonyl) benzyl, 4-methylsulfonylbenzyl, 4acetylaninobenzyl, 4-methylsulfinylbenzyl or 4aminosulfonylbenzyl.

It is particularly preferably the above-defined halogen atom, the above-defined optionally substituted C1_6 alkyl,

(CH

2 ),-COOR a1, (CH 2 t-CONRa2 R. a, (Cf' 2 t-OR alor -(CH 2 )t-S(O)q-R Examples thereof include fluorine atom, chlorine atom, bromine atom, nitro, methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, 108 methyithio, dimethylaminocarbonyl, methylsulfonyl and acetylamino.

It is more preferably fluorine atom, chlorine atom, methyl, tertbutyl, carboxyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl or methylsulfonyl, most preferably fluorine atom or chlorine atom.

The heterocycle C1- 6 alkyl optionally substituted by 1 to substituent(s) selected from group B is that wherein the abovedefined heterocycle C 16 alkyl is optionally substituted by 1 to substituent(s), and includes unsubstituted heterocycle C 16 alkyl.

The substituent(s) is(are) selected from the above-mentioned group B.

Examples thereof include 2-pyridylmethyl, 3-pyridylmethyl, 2-chloropyridin-4-ylmethyl, 4-pyridylmethyl, pyrrolylmethyl, imidazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 2-oxazolylmethyl, 5-isothiazolylmethyl, 2-methyloxazol-4-ylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl, 2methylthiazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl, dimethylthiazol-4-ylmethyl, 4-methylthiazol-2-ylmethyl, 2,4- 2-isothiazolylmethyl, 2pyrrolinylmethyl, pyrrolidinylmethyl, piperidylmethyl, 4piperidylmethyl, 1-methylpiperidin-4-ylmethyl, 4hydroxypiperidinomethyl, 3-hydroxypyrrolidinylmethyl, 2-(4hydroxypiperidino)ethyl, 1-(tert-butoxycarbonyl)piperidin-4ylmethyl, l-acetylpiperidin-4-ylmethyl, 1methylsulfonylpiperidin-4-ylmethyl, piperazinylmethyl, morpholinomethyl, thiomorpholinylmethyl, 1tetrahydropyranylmethyl, 2-quinolylmethyl, 1-isoquinolylmethyl and the like.

The heterocyclic moiety is preferably a heterocyclic group which is a 5-membered or 6-membered monocyclic group. Examples thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl, and the alkyl moiety thereof is preferably straight chain alkyl having 1 to 4 carbon atoms. The group B here is preferably the above-defined 109 halogen atom, the above-defined C 1 6 alkyl, the above-defined halogenated C 16 alkyl, the above-defined Cp-6 alkanoyl,

-UCH

2 )rCOORbl, -CH 2 )-CONRblRb 2 or -(CH,)r-OR.

Examples of heterocycle C 16 alkyl optionally substituted by 1 to 5 substituent(sY selected from group B preferably include 2-pyridylmethyl, 3-pyridylmethyl, 2-chloropyridin-4-ylmethyl, 4pyridylmethyl, piperidin-4-ylmethyl, l-methylpiperidin-4-ylmethyl, 2-(4-hydroxypiperidino)ethyl, 1-acetylpiperidin-4-ylmethyl, 1- (tert-butoxycarbonyl) piperidin-4-ylmethyl, 1- (methylsulfonyl) lo piperidin-4-ylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 2methylthiazolin-4-ylmethyl, 2, 4-dimethylthiazolin-5-ylmethyl and 4-methylthiazol-2-ylmethyl. Particularly preferably, it is 2pyridylmethyl,; 3-pyridylmethyl, 2-chloropyridin-4-ylmethyl, 4pyridylmethyl, piperidin-4-ylmethyl, l-methylpiperidin-4-ylmethyl, 2- (4-hydrokypiperidino) ethyl, l-acetylpiperidin-4-ylmethyl, 1- (tert-butoxycarbonyl)piperidin-4-ylmethyl, 1- (methylsulfonyl)piperidin-4-ylmethyl, 2-methylthiazolin-4ylmethyl, 2,4-dimethylthiazolin-5-ylmethyl or 4-methylthiazol-2a20 a22 a23 ylmethyl at Ra 2-pyridylmethyl at R and R and 4a22 a28 pyridylmethyl or 4-methylthiazol-2-ylmethyl at R and R The heterocycle CI- 6 alkyl optionally substituted by I to substituent(s) selected from group D is that wherein the abovedefined heterocycle C 16 alkyl is optionally substituted by 1 to substituent(s), and includes unsubstituted heterocycle CI-s alkyl.

The substituent(s) is(are) selected from the above-mentioned group D (substituents shown under to Examples of group D here include fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2hydroxyethyl, methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, (2-hydroxyethyl) aminocarbonyl, (carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy, isopropyloxy, hydroxymethyloxy, carboxylmethyloxy, (dimethylaminocarbonyl)methyloxy, amino, methylamino, dimethylamino, diethylamino, acetylamino, methylsulfonylamino, 110 methylthio, methylsulfonyl, methylsulfinyl, aminosulfonyl, methylaminosulfonyl and disethylaminosulfonyl.

Examples of heterocycle C 16 alkyl optionally substituted by 1 to 5 substituent(s) selected from group D include 2s pyridylmethyl, 3-pyridylmethyl, 2-chioropyridin-4-ylmethyl, 4pyridylmethyl, pyrrolylmethyl, imidazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl, 2-oxazolylmethyl, isothiazolylmethyl, 2-methyloxazol-4-ylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl, 2-methylthiazol-4-ylmethyl, 2-methylthiazol-S-ylmethyl, 2,5-dimethylthiazol-4-ylmethyl, 4methylthiazol-2-ylmethyl, 2,4-dimethylthiazol-5-ylmethyl, 2isothiazolylmethyl, 2-pyrrolinylmethyl, pyrrolidinylmethyl, piperidylmethyl, 4-piperidylmethyl, 1-methylpiperidir-4-ylmethyl, 4-hydroxypiperidinomethyl, 2-(4-hydroxypiperidino)ethyl, 1-(tertis butoxycarbonyl) piperidin- 4 -ylmethyl, l-acetylpiperidin-4-ylmethyl, 1-methylsulfonylpiperidin-4-yimethyl, piperazinylmethyl, morpholinomethyl, thiomorpholinylmethyl, 1tetrahydropyranyimethyl, 2-quinolylmethyl, 1-isoquinolylmethyl, and the like.

Preferable heterocyclic moiety at Z and Z' is heterocylic group which is 5-membered or 6-membered monocyclic group.

Examples of the heterocyclic moiety include-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imicazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl, and the alkyl moiety is preferably straight chain alkyl having 1 to 4 carbon atoms, particularly methyl methylene).

Preferable group D is the above-defined halogen atom, nitro, the above-defined optionally substituted CI- 6 alkyl, (CHj) t-COORal 9 -(CHj)tCONRa 27 Ra 2 -Ci 2 )toR a 2 o, (CH2) tNRa 2 9CORa 2 4 (CH2) t-S q-Ra 2 s or (CH) t-SO2-NHRa 2 6.

Preferable examples of heterocycle C 1 6 alkyl.optionally substituted by I to 5 substituent(s) selected from group D include 2-pyridylmethyl, 3-pyridylmethyl, 2-chloropyridin-4ylmethyl, 4-pyridylmethyl, piperidin-4-ylmethyl, 1rethylpiperidin-4-ylmethyl, 4-hydroxypiperidinomethyl, 2-(4hydroxypiperidino)ethyl, l-acetylpiperidin-4-ylmethyl, l-(tertbutoxycarbonyl)piperidin-4-ylmethyl, 1-(methylsulfonyl)piperidin- 4-ylmethyl, 2-thiazolylmethyl, 4-thiazolylmethyl, 2methylthiazolin-4-ylmethyl, 2,4-dimethylthiazolin-5-ylmethyl and 4-methylthiazol-2-ylmethyl.

Particularly preferred is 4-hydroxypiperidinomethyl.

The C3- 8 cycloalkyl C- 16 alkyl optionally substituted by 1 to 5 substituent(s) selected from the above group B is that wherein the above-defined C3- 8 cycloalkyl Ci-6 alkyl is optionally substituted by 1 to 5 substituent(s), and includes unsubstituted cycloalkylalkyl. The substituents are selected from the above group B.

Specific examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2- (cyclopentyl)ethyl, 2-(cyclohexyl)ethyl, cycloheptylmethyl, 4fluorocyclohexylmethyl, 2-methylcyclopentylmethyl, 3methylcyclohexylmethyl, 4-methylcyclohexylmethyl, 4,4dimethylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-tertbutylcyclohexylmethyl, 4-hydroxycyclohexylmethyl, 4methoxycyclohexylmethyl and 2,3,4,5,6-pentafluorocyclohexylmethyl.

Also exemplified are those wherein cyclopentylmethyl or cyclohexylmethyl is substituted by fluorine atom, chlorine atom, bromine atom, nito, methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl, methylsulfonyl or acetylamino.

At C3-B cycloalkyl Ci-6 alkyl moiety, it is preferably cyclopentylmethyl or cyclohexylmethyl, and at R a20

R

a27 and R a28 it is particularly preferably cyclohexylmethyl.

The carboxyl-protecting group only needs to be suitable for reaction conditions, and is capable of protecting and deprotecting and may be, for example, methyl; substituted methyl group such as methoxymethyl, methylthiomethyl, 2tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenacyl, diacylmethyl, phthalimidomethyl etc.; ethyl; substituted ethyl group such as 2,2,2-trichloroethyl, 2-chloroethyl, 2- (trimethylsilyl)ethyl, 2-methylthioethyl, 2-(ptoluenesulfonyl)ethyl, t-butyl etc.; benzyl; substituted benzyl group such as diphenylmethyl, triphenylmethyl, p-nitrobenzyl, 4- 112 picolyl, p-methoxybenzyl, 2-(9,10-dioxo)anthrylmethyl etc.; silyl group such as trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl etc.; and the like.

Preferred are industrially effective protecting groups and specifically preferred as R a36 are methyl and ethyl.

In formula X is preferably w o1 wherein each symbol is as defined above.

G

I

G

2

G

3 and G 4 are each preferably (C-R 2

(C-R

3 and (C-R 4

G

5 is preferably a nitrogen atom, and G 6

G

8 and G 9 are preferably a carbon atom. G 7 is preferably C(-R 7 or unsubstituted nitrogen atom, wherein R 7 is preferably hydrogen atom.

A preferable combination is G 2 of (C-R 2 and G 6 of a carbon atom, particularly preferably G 2 of (C-R 2

G

6 of a carbon atom and G 5 of a nitrogen atom, most preferably G 2 of (C-R 2

G

6 of a carbon atom, G 5 of a nitrogen atom and G 7of unsubstituted nitrogen atom.

In formulas and 1 to 4 of G 1 to G 9 in the. moiety 2-'G 6 G G 4. 3 9 a nitrogen atom, specifically preferably i rGe t s4G is~are) preferably a nitrogen atom, specifically preferably 113 Nz 2 2

K

R? N, N R R 4

R''

F

3 1< 3 N/

R?

4 particularly preferably

RR

more preferably

R

3

N

most preferably 114 It is also a preferable embodiment wherein the

I

39 G ,.64 moiety is aromatic ring.

RI and R 3 are preferably hydrogen atom or -OR a6 (Ra 6 is as defined above), particularly preferably hydrogen atom. R 2 is preferably carboxyl, -COORal, -CONRa 2 Ra 3

-SO

2 Ra 7 (each symbol is as defined above) or heterocyclic group having 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a sulfur atom, particularly preferably carboxyl, -COORal or -SO 2 Ra 7 more preferably carboxyl or -COORal, most preferably carboxyl. R 4 is preferably hydrogen atom.

Ral is preferably optionally substituted C- 6 alkyl.

When R 2 is carboxyl or -COORal, at least one of R 1

R

3 and R 4 is preferably hydroxyl group, halogen atom (particularly fluorine atom, chlorine atom) or -OR a6 (wherein R a6 is preferably hydrogen atom or methyl).

The ring Cy and ring Cy' are preferably cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrothiopyranyl or piperidino, particularly preferably cyclopentyl, cyclohexyl or cycloheptyl, more preferably cyclohexyl.

The ring A and ring A' are preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, cyclohexenyl, furyl or thienyl, particularly preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, more preferably phenyl or pyridyl, and most preferably phenyl.

The ring B and ring B' are preferably C1-6 aryl or heterocyclic group, specifically preferably, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl., tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or 115 thiadiazolyl, particularly preferably phenyl, pyridyl, pyrimidinyl, 1,3,5-triazinyl or thiazolyl, more preferably, phenyl, pyridyl or thiazolyl, and most preferably phenyl or thiazolyl.

With regard to R 5 and R 6 one of them is preferably hydrogen atom and the other is halogen atom, particularly fluorine atom. Alternatively, the both are preferably hydrogen atoms. When ring A is phenyl, R 5 and R 6 preferably are present at an ortho position from G 6 The same applies to R s and R 6 Y is preferably -(CH 2 )m-O-(CH 2 -NHCO2-, -CONH-CHRa 14 a 2 a13a

(CH

2 m-NRa 2

(CH

2 -CONR- (CH 2

(CH

2 m-CRa 1 5R a16

(CH

2 n- .or -(CH2) n-NRa

L

2-CHRa5- (each symbol is as defined above), more preferably, -(CH 2 (CH2)n- or -0-(CH2) mCRalSR a16

(CH

2 most preferably -(CH 2

-O-(CH

2 The 1, m and n are preferably 0 or an integer of 1 to 4, particularly preferably 0, 1 or 2, at Y. In -(CH 2 )m-O-(CH 2 m=n=0 or m=O and n=l is more preferable, most preferably m=0 and n=l. In -O-(CH 2 )m-CRal 5 Ra5l (CH 2 m=n=0, m=0 and n=l, m=l and n=0 or m=l and n=l is more preferable, most preferably m=0 and n=l.

When Y is (CH2)m-CRai5R al 6 (CH2)n-, Ra 16 is preferably hydrogen atom, Ra 15 is preferably

(CH

wherein the (B (Z)w (CH 2) -Ra (CH0) moiety is preferably symmetric. The preferable mode of n, ring B, Z and w and the preferable mode of ring Z' and w' are the same.

When ring A is phenyl, X or Y is preferably present at the para-position relative to G 6 When ring B and ring B' are phenyl, 116 Z is preferably present at the ortho or meta-position relative to Y. It is preferable that the 3-position on phenyl have one substituent or the 2-position and the 5-position on phenyl each have one substituent.

When ring B is bonded to Y as pyridin-2-yl, Z is preferably substituted at the 3-position and 6-position of pyridyl; when it is bonded to Y as pyridin-3-yl, Z is preferably substituted at the 2-position and 5-position of pyridyl; and when it is bonded to Y as pyridin-4-yl, Z is preferably substituted at o1 the 2-position and 5-position of pyridyl.

When ring B is thiazolyl, Y is preferably substituted at the 5-position, and Z is preferably substituted at the 2-position, the 4-position or the 2-position and the 4-position. Similarly, when ring B' is thiazolyl, (CH 2 is also preferably substituted at the 5-position, and Z' is preferably substituted at the 2position, the 4-position or the 2-position and the 4-position.

Z and Z' are preferably group D, "C- 14 aryl optionally substituted by 1 to 5 substituent(s) selected from group D" or "heterocyclic group optionally substituted by 1 to substituent(s) selected from group particularly preferably group D or "C6-1 4 aryl optionally substituted by 1 to substituent(s) selected from group D".

More preferably, they are the above-defined halogen atom, nitro, the above-defined optionally substituted C 1 6 alkyl,

(CH

2 t-COR a l (CH2)t-COOR 1 9 (CH2) t-CONR a 2 7R a 2 (CH) t-ORa 20 (CH2) tNR 2CO-R 4, (CH2)t-S(O)qR or (CH2) t-SO2-NR a2 6 or C6- 1 4 aryl or heterocyclic group optionally substituted by these.

With regard to Z and the preferable mode of group D that directly substitutes each ring B and ring B' and the preferable mode of group D that substitutes C6- 14 aryl, C 3 -8 cycloalkyl, C6- 14 aryl C 1 -6 alkyl or heterocyclic group are the same, wherein they may be the same with or different from each other.

Specific examples of the substituent preferably include fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, 117 carbamoylmethoxymethyl, (dimethylaminocarbonyl) methoxymethyl, acetyl, isovaleryl, carboxyl, methoxycarbonyl, ethoxycarbonyl, carbainoyl, methylaminocarbonyl, hydroxyaminocarbonyl, ethyl aminocarbonyl, propylaminocarbonyl, i sopropylaminocarbonyl, butylaxninocarbonyl, isobutylaminocarbonyl, tertbutylaminocarbonyl, (4-hydroxybutyl) aminocarbonyl, (1hydroxypropan-2-yl) aminocarbonyl, 3-dihydroxypropyl) aminocarbonyl, 3-dihydroxypropan-2-yl) aiinocarbonyl, methoxyaminocarbonyl, J 2- (methoxy) ethoxy] ethyl ~axinocarbonyl, N-ethyl -N-methyl aminocarbonyl, N-methyl -N-propyl aminocarbonyl, N-* isopropyl-N-rnethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, (2-hydroxyethyl) aminocarbonyl, (2-hydroxy- 2-methylpropan-2-yl) aiinocarbonyl, (carboxylmethyl) azinocarbonyl, hydroxyl group, methoxy, ethoxy, propyloxy, isopropyloxy, 1s butyloxy, isopentyloxy, 2-isopentenyloxy, 3-isohexenyloxy, 4methyl-3-pentenyloxy, 2-propynyloxy, tri fluoromethyloxy, hydroxymethyloxy, carboxylmethyloxy, (dimethylaminocarbonyl) methyloxy, amino, methylamino, dimethylamino, diethylamino, acetylamitno, N-acetyl-N--methylamino, N-acetyl-N-ethylamino, Nacetyl-N-propylanino, N-acetyl-N-isopropylamino, N-ethylcarbonyl- N-methylamino, N-ethyl-N- (ethylcarbonyl) amino, ureido, isopropylcarbonylauino, isobutylcarbonylamino, tertbutylcarbonylamino, (ethylamino) carbonylanino, (isopropylamino) carbonylamino, (dimethylamino) carbonylamino, (4hydroxypiperidino) carbonylamino, I (4-hydroxypiperidino) methyl] carbonylamino, [(3-hydroxypyrrolidinyl) methyl Icarbonylamino, methylsulfonylamino, isopropylsulfonylamino, N- (methylsulfonyl) N-methylamino, N- (ethylsulfonyl) -N-methylamino, N- (isopropylsulfonyl) -N-rnethylamino, N- (methylsulfonyl) -Nethylamino, N- (methylsulfonyl) -N-propylamino, N- (ethylsulfonyl) N-ethylamino, methylthio, methylsulfonyl, isopropylsulfonyl, isobutylsulfonyl, methylsulfinyl, isopropylsulfinyl, aminosulfonyl, methylaminosul fonyl, diinethylaminosulfonyl, isopropylaminosulfonyl,. tert-butylaninosulfonyl, hydroxyamidino, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chiorophenyl, 4chiorophenyl, 2, 4-difluorophenyl, 3, 4-difluorophenyl, 3,4dichiorophenyl, 3, 5-dichiorophenyl, 4-chloro-3-fluorophenyl, 4chloro-2-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4cyanophenyl, 4-me thyiphenyl, 4- ethyiphenyl, 4 -propyiphenyl, 4isopropyiphenyl, 4-tert-butyiphenyl, 2-trifluoromethyiphenyl, 4trifluoromethyiphenyl, 4- (hydroxymethyl) phenyl, 4- (2hydroxyethyi) phenyl, 4- (methoxymnethyl) phenyl, 4- (2carboxylethyl) phenyl, 4- (methoxycarbonylmethyl) phenyl, 4- (ethoxycarbonymethyl) phenyl, 4-acetyiphenyl, 3-carboxyiphenyl, 4-carboxylphenyl, 4- (methoxycarbonyl) phenyl, 4- (ethoxycarbonyl) phenyl, 4-carbamoylpheriyl, 4- (methylaminocarbonyl) phenyl, 4- (isopropylaminocarbonyl)-phenyl, 4- (dimethylaminocarbonyl) phenyl, 4- (diethylaminocarbonyl) phenyl, 4- (2-hydroxyethyl) aminocarbonyl] phenyl, 4- ((carboxylmethyl) aminocarbonyl Jphenyl, 4-hydroxyphenyl, 4methoxyphenyl, 3, 4, 5-trimethoxyphenyl, 4-ethoxyphenyl, 4propyloxyphenyl, 4-isopropyloxyphenyl, 4-butyloxyphenyl, 4isopentyloxyphenyl, 4- (2-isopentenyloxy) phenyl, 4- (3isohexenyloxy) phenyl, 4- (4-methyl-3-pentenyloxy) phenyl, (2propynyloxy) phenyl, 4- (trifluoromet-yloxy)phenyl, 4-F (hycroxymethyloxy) phenyl, 4- (carboxylmethyloxy) phenyl, 4- ((dimethylaminocarbonyl) methyloxy] phenyl, 4-aininophenyl, 4-- (methylamino) phenyl, 4- (dimethylaninophenyl), 4-.(diethylamino) phenyl, 4- (acetylamino) phenyl, N-acetyl-N-methylanino, 4- (Nacetyl-N-methylanino) phenyl, 4- (N-acetyl-N-ethylanino).phenyl, 4- (N-acetyl-N-propylamino) phenyl, 4- (N-acetyl-Nisopropylamino) phenyl, 4- (N-ethylcarbonyl-N-methylamino) phenyl, 4- [N-ethyl-N- (ethylcarbonyl) aminolphetyl, 4- (methylsulfonylaiuino)phenyl, 4- (rethylthio,)phenyl, 4- (methylsulfonyl) phenyl, 4- (methylsulfinyl) phenyl, 4- (aminosulfonyl)phenyl, 4- (methylaxninosulfonyl) phenyl, 4- (dimethylaminosulfonyl) phenyl, 4- (tert-butylaininosulfonyl) phenyl, tetrazol-5-ylphenyl, cyclohexyl, benzyl, 4-chlorobenzyl, phenethyl, benzyloxy, 4-fluorobenzyloxy, 2-chlorobenzyloxy, 3chiorobenzyioxy, 4-chlorobenzyloxy, 4-tert-butylbenzyloxy, 4trifluoromethylbeazyloxy, phenethyloxy, 2-thienyl, 2-thiazolyl, 2 -pyridyl, 3-pyridyl, 4-pyridyl, 6- fluoropyridin-3-yl, fluoropyridin-2-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl, 2-pyrixnidinyl, 5-tetrazolyl, piperidino, 2-oxopiperidin---yl, 2oxopyrrolidin-l-yl, 2-itidazolin-2-yl, 2-oxoixnidazolidin-1-yl, 2oxooxazolidinr.l-yl, 2-rethylthiazol-4-yi, 5-methylthiazol-2-yl, 119 2-aminothiazol-4-yl, 3-methyl-i, 2, 4-oxacliazol-5-yl, 1, 1dioxoisothiazolidin-2-yl, 4, 4-dimethyl-A 2 oxazolin-2-yl, chlorothiophen-2-yl, 5-methyloxazol-2-yl, 5-oxo-A 2 2,4oxadiazolin-3-yl, 5-oxo--_1, 2, 4-thiadiazolin-3-yl, 2-oxo-3H- 1,2,3, 5-oxathiadiazolin-4-yl, 4-hydroxypiperidinomethyi, piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 3, 4dihydroxypiperidinocarbonyl, 1-piperazinylcarbonyl, 1pyrrolidinylcarbonyl, morpholinocarbonyl, 4thiomorpholinylcarbonyl, phenoxy, 2, 4-dichlorophenoxy, tetrahydropyranyloxy, 2-pyridylinethyloxy, 3-pyridylmethyloxy, 2chloropyridin-4-ylmethyloxy, 4-pyridylmethyloxy, 2piperidyimethyloxy, 3-piperidylmethyloxy, 4-pip( ridylmethyloxy, 1-methylpiperidin-4-ylmethyloxy, 1-acetylpiperidin-4 -ylmethyloxy, 1- (tert-butoxycarbonyl)piperidin-4-ylmethyloxy, 1- (methylsulfonyl)piperidin-4-ylmethyloxy, 2-ntethylthiazolin-4yloxy, 2, 4-di-methyl thiazol in-5-yloxy, dimethylaminocarbonylmethyloxy, piperidinocarbonylme thyloxy, 4-hydroxypiperidinocarbonylhtethyloxy, 2-methyithiazol-4-yl, (2-methylthiazol-4yi)methyloxy, 4-di-nethylthiazoi-5-yi)methyloxy, benzoyl, 3fluorobenzoyl, 4-chiorobenzylanino, 3, 5-dichlorobenzylamino, .4trifluoromethylbenzylamino, 2-pyridylnethylauino, benzoylamino, 4-chlorobenzoylauino, 4-trifluoromethylbenzoylanino, 3, dichlorobenzoylamino, 3-nitro-4-methoxybenzoylamino, 4-nitro-3methoxybenzoylamino, 3-pyridylcarbonylamino, morpholinocarbonylamino, 2-oxazolinylamino, 4-hydroxypiperidinosulfonyl, 4methylphenyisulfonyanino, 2-thiazolylaminosulfonyl, 2-: pyridylatninosul fonyl, benzylaminocarbonyl, N-benzyl-Nmethylaminocarbonyl, (4-pyridylmethyl) aminocarbonyl or (cyclohexyhuethyl)aiinocarbonyl, 2-hydroxyethyloxy, 3hydroxypropyloxy, 2-zuethoxyethoxy, 2- (2-methoxyethoxy) ethoxy, azetidinylcarbonyl, 3-hydroxypyrrolidinyicarbonyl, 3hydroxypiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 3, 4dihydroxypiperidinocarbonyl, 4-methoxypiperidinocarbonyl, 4carboxypiperidinocarbonyl, 4- (hydroxymethyl) piperidinocarbonyl, 2-oxopiperidinocarbonyl, 4-oxopiperidinocarbonyl, 2, 6dimethylpiperidinocarbonyl, 2,2, 6, 6-tetramethylpiperidinocarbonyl, 2,2, 6, 6-tetranethyl-4-hydroxypiperidinocarbonyl, 1oxothiomorpholin-4-ylcarbonyl, 1, 1-dioxothiornorpholin-4- 120 ylcarbonyl, 1- (methylsulfonyl)piperidin-4-ylaminocarbonyl, 4methylsul fonylpiperazinylcarbonyl, 4-methylpiperazinylcarbonyl, N, N-bis (2-hydroxyethyl)aiuinocarbonyl, phenylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclohexylaminocarbonyl, 4-hydroxycyclohexylaminocarbonyl, 4methylthiazol-2-ylmethylaminocarbonyl, 2- (4-hydroxypiperidino) ethyloxy, 2-pyridylmethylaminocarbonyl, 3-pyridylmethylaminocarbonyl, N-methyl-N- (4-pyridylmethyl) aminocarbonyl, cyclohexyirnethyloxy, 4-hydroxypiperidinocarbonylmethyloxy and 4lo methylthiazol-2-ylmethyloxy.

Particularly preferable examples of the substituent include fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl, hydroxymethyl, carboxyl, carbamoyl, methylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, (2-hydroxylethyl) aminocarbonyl, (carboxymet-yl) aminocarbonyl, methoxy, 2-isopentenyloxy, 2-propynyloxy, methylthio, methylamino, dimethylamino, acetylamino, N-acetyl-Nmethylanino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, Nacetyl-N-isopropylamino, N-ethylcarbonyl-N-methylamino, N-ethyl- N- (ethylcarbonyl) amino, methylsulfonylamnino, methylsulfonyl, aminosul fonyl, dimethylaminosul fonyl, tert-butylaminosul fonyl, phenyl, 3-fluorophenyl, 4-f luorophenyl, 3-chlorophenyl, 4 r chlorophenyl, 3, 5-dichlorophenyl, 4-nitrophenyl, 4-xnethylphenyl, 4-tert-butyiphenyl, 4-trifluoromethylphenyl, 4- (methoxymethyl) phenyl, 4- (2-hydroxylethyl) phenyl, 3-carboxyiphenyl, 4carboxylphenyl, 4-me thox yphenyi, 4- carbamoylphenyl, 4methylthiophenyl, 4- (dimethylaminocarbonyl) phenyl, 4methylsulfonylphenyl, benzyl, phenethyl, benzyloxy, 4fluorobenzyloxy, 4-chlorobenzyloxy, 2-thiazolyl, 3-pyridyl, 4- 3o pyridyl, 4-pyridylmethyloxy, 2-piperidylmethyloxy, 3piperidylhtethyloxy, 4-piperidylmethyloxy, l-methylpiperidin-4ylmethyloxy, 1-acetylpiperidin-4-ylmethyloxy, 2-chloropiperidin- 4-ylmethyloxy, 1- (methylsulfonyl) piperidin-4-ylmethyloxy, 2methylthiazol-4-yl, (2-methylthiazol-4-yl)methyloxy, (2,4dimethylthiazol-5-yl) methyloxy, 5-tetrazolyl, 3-fluorobenzoyl, piperidinocarbonyl, 4-hydroxylpiperidinocarbonyl, 1pyrrolidinylcarbonyl, morpholinocarbonyl, 4thiomorpholinylcarbonyl, benzylaminocarbonyl, N-benzyl-N- 121 methylaminocarbonyl, (4-pyridylmethyl)aminocarbonyl and (cyclohexylmethyl)aminocarbonyl.

Most preferable substituents are fluorine atom, chlorine atom, methyl, hydroxymethyl, carboxyl, carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxy, methylamino, acetylamino, aminosulfonyl, dimethylaminosulfonyl, tertbutylaminosulfonyl, phenyl, 3-fluorophenyl, 4-fluorophenyl, 3chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-carboxylphenyl, 4lo methoxyphenyl, 4-carbamoylphenyl, 4-methylthiophenyl, 4- (dimethylaminocarbonyl)phenyl, 4-methylsulfonylphenyl and 2oxopyrrolidin-1-yl.

The w is preferably 1 or 2, r and t are preferably 0, 1 or 2, particularly preferably 0 or 1, more preferably 0, p.is preferably 1, and q is preferably 0 or 2.

In formula when X is -Y (Z)w wherein each symbol is as defined above and w is 2 or above, one of Z is preferably C6-14 aryl optionally substituted by 1 to substituent(s) selected from group D or heterocyclic group optionally substituted by I to 5 substituent(s) selected from group D, particularly preferably C 614 aryl optionally substituted by 1 to 5 substituent(s) selected from group D.

When ring B is phenyl, w is 2 and phenyl is bonded to Y at the 1-position, one of the most preferable embodiments is that wherein Z is bonded to the 2-position and 5-position of phenyl, Z at the 2-position is "C6- 14 aryl optionally substituted by 1 to substituent(s.) selected from group D" and Z at the 5-position is "heterocyclic group optionally substituted by 1 to substituent(s) selected from group D".

The pharmaceutically acceptable salt may be any as long as it forms a non-toxic salt with a compound of the above-mentioned formula or Such salt can be obtained by reacting the compound with an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like, or an organic acid, such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric 122 acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid, meglumine acid and the like, or an inorganic base, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and the like, or an organic base, such as methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and the like, with an amino acid, such as lysine, arginine, alanine and the like. The present invention encompasses water-retaining product, hydrate and solvate of each compound.

The compounds of the above-mentioned formula or [II] have various isomers. For example, E compound and Z compound are present as geometric isomers, and when the compound has an asymmetric carbon, an enantiomer and a diastereomer are present due to the asymmetric carbon. A tautomer may be also present.

The present invention encompasses all of these isomers and mixtures thereof.

The present invention also encompasses prodrug and metabolite of each compound.

A prodrug means a derivative of the compound of the present invention, which is capable of chemical or metabolic decomposition, which shows inherent efficacy by reverting to the original compound after administration to a body, and which includes salts and complexes without a covalent bond.

When the. inventive compound is used as a pharmaceutical preparation, the inventive compound is generally admixed with pharmaceutically acceptable carriers, excipients, diluents, binders, disintegrators, stabilizers, preservatives, buffers, emulsifiers, aromatics, coloring agents, sweeteners, thickeners, correctives, solubilizers, and other additives such as water, vegetable oil, alcohol such as ethanol, benzyl alcohol and the like, polyethylene glycol, glycerol triacetate, gelatin, lactose, carbohydrate such as starch and the like, magnesium stearate, talc, lanolin, petrolatum and the like, and prepared into a dosage form of tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like, which can 123 be administered systemically or topically and orally or parenterally.

While the dose varies depending on the age, body weight, general condition, treatment effect, administration route and the like, it is from 0.1 mg-to 1 g for an adult per dose, which is given one to several times a day.

The prophylaxis of hepatitis C means, for example, administration of a pharmaceutical agent to an individual found to carry an HCV by a test and the like but without a symptom of io hepatitis C, or to an individual who shows an improved disease state of hepatitis after a treatment of hepatitis C, but who still carries an HCV and is associated with a risk of recurrence of hepatitis.

The therapeutic agent for hepatitis C of the present invention is expected to provide a synergestic effect when concurrently used with other antiviral agents, antiinflammatory agents or immunostimulants.

The medicaments with the prospect of synergestic effect include, for example, interferon-a, interferon-p, interferon-y, interleukin-2, interleukin-8, interleukin-10, interleukin-12, TNFa, recombinant or modified products thereof, agonists, antibodies, vaccines, ribozymes, antisense nucleotides and the like.

As evidenced in the combination therapy of anti-HIV agents, which is also called a cocktail therapy, the combined use of various anti-virus agents againt viruses showing frequent genetic mutations is expected to show effect for suppressing emergence and increase of drug tolerant viruses. For example, 2 or 3 agents from HCV-IRES inhibitors, HCV-NS3 protease inhibitors, HCV-NS2NS3 protease inhibitors, HCV-NS5A inhibitors and HCV polymerase inhibitor may be used in combination. Specifically, the combined use with Ribavirin(R), interferon-a (IFN-a, Roferon(R), Intron Sumiferon(R), MultiFeron(R), Infergen(R), Omniferon(R), Pegasys(R), PEG-Intron interferon-P (Frone(R), Rebif(R), AvoneX(R), IFNsMOCHIDA(R)), interferon-o, 1-3-L-ribofuranosyl-lH- 1,2,4-triazole-3-carboxamide, 16a-bromo-3p-hydroxy-5a-androstan- 17-one, 1H-imidazole-4-ethanamide dihydrochloride, HCV ribozyme Heptazyme(R), polyclonal antibody Civacir(R), lactoferrin GPX-400, 124 (iS,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizidinium chloride, HCV vaccine (MTH-68/B, Innivax Engerix antisense oligonucleotide ISIS-14803, HCV-RNA transcriptase inhibitor VP- 50406, tetrachlorodecaoxide (high concentration Oxoferin(R)), tetrahydrofuran-3-yl (S)-N-3-[3-(3-methoxy-4-oxazol-5ylphenyl)ureido]benzylcarbamate, 4-amino-2-ethoxymethyl-a,ainterleukin-2 (Proleukin(R)), thymosin al and the like is exemplified, wherein shows product names.

Furthermore, the combined use with the compounds disclosed in JP-A-08-268890, .JP-A-10-101591, JP-A-07-069899, W099/61613 and the like as HCV IRES inhibitors; the compounds disclosed in W098/22496, W099/07733, W099/07734, WO00/09543, WO00/09558, WO01/59929, W098/17679, EP932617, W099/50230, W000/74768, W097/43310, US5990276, WO01/58929, W001/77113, W002/8198, W002/8187, W002/8244, W002/8256, W001/07407, W001/40262, W001/64678, W098/46630, JP-A-11-292840, JP-A-10-298151, JP-A-11- 127861, JP-A-2001-103993, W098/46597, W099/64442, WO00/31129, W001/32961, W093/15730, US7832236, WO00/200400, W002/8251, W001/16379, W002/7761 and the like as HCV protease inhibitors; the compounds disclosed in W097/36554, US5830905, W097/36866, US5633388, W001/07027, WO00/24725 and the like as HCV helicase inhibitors; the compounds disclosed in W000/10573, WO00/13708, WO00/18231, WO00/06529, W002/06246, W001/32153, W001/60315, W001/77091, W002/04425, W002/20497, W000/04141 and the like as HCV polymerase inhibitors; the compounds disclosed in W001/58877, JP-A-11-180981, W001/12214 and the like as interferon agonists or enhancers; and the like is also exemplified.

Inasmuch as HCV is known to be a virus associated with many genetic mutations, a compound effective for many genotypes is one of the preferable modes. If a compound ensures high blood concentration when administered as a pharmaceutical agent to an animal infected with HCV, it is also one of the preferable modes.

From these aspects, a compound having high inhibitory activity on both HCV type la and type Ib and high blood concentration, such as 2-~4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2fluorophenyl -l-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride, is particularly preferable.

Examples of the production method of the compound to be used for the practice of the present invention are given in the following. However, the production method of the compound of the present invention is not limited to these examples.

Even if no directly corresponding disclosure is found in the following Production-Methods, the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional. group with deprotect ion in a subsequent step, and changing the order of Production Methods and lo0 steps.

The treatment after reaction in each step may be conventional ones, for which typical methods, such as isolation and purification, crystallization, recrystallization, silica gel chromatography, preparative HPLC and the like, can be 1s appropriately selected and combined.

Production Method 1 In this Production Method, a benzimidazole compound isformed from a nitrobenzene compound.

Production Method 1-1 R NO 2 StepI R 2 N0N 2 Step 2 RA NH 2 Hal R 3 NH R 3

NH

R

4 (CY NH 2

R

4

R

[4] 2 R H A X 2 R Step 3 R N N6 Step 4 R N: N 11 A X

R

5

F

4

R

X CORc

C

R

6 5 6] [1 -2] wherein Hal is halogen atom, such as chlorine atom, bromine atom and the like, R"a is halogen atom, such as chlorine atom, bromine atom and the like, or hydroxyl group, and other symbols are as defined above.

Step 1 126 A compound obtained by a conventional method or a commercially available compound is reacted with amine compound in a solvent such as N,N-dimethylformamide (DMF), acetonitrile, tetrahydrofuran (THF), toluene and the like in the presence or absence of a base such as potassium carbonate, triethylamine, potassium t-butoxide and the like at room temperature or with heating to give compound Step 2 The compound is hydrogenated in a solvent such as methanol, ethanol, THF, ethyl acetate, acetic acid, water and the like in the presence of a catalyst such as palladium carbon, palladium hydroxide, platinum oxide, Raney nickel and the like at room temperature or with heating to give compound 14]. In addition, compound is reduced with a reducing agent such as zinc, iron, tin(II) chloride, sodium sulfite and the like, or reacted with hydrazine in the presence of iron(III) chloride to give compound The compound can be also obtained by reacting compound with sodium hydrosulfite under alkaline conditions.

Step 3 The compound is condensed with carboxylic acid compound in a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride, toluene and the like using a condensing agent such as dicyclohexylcarbodiimide, l-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride, diphenylphosphoryl azide and the like and, where necessary, adding N-hydroxysuccinimide, l-hydroxybenzotriazole and the like to give amide compound Alternatively, amide compound can be obtained from compound as follows. The carboxylic acid compound is converted to an acid halide derived with thionyl chloride, oxalyl chloride and the like, or an active ester mixed acid anhydride derived with ethyl chlorocarbonate and the like), which is then reacted in the presence of a base, such as triethylamine, potassium carbonate, pyridine and the like, or in an amine solvent, such as pyridine and the like, to give amide compound Step 4 127 The compound is heated in a solvent such as ethanol, methanol, toluene, DMF, chloroform and the like or without a solvent in the presence of an acid such as acetic acid, formic acid, hydrochloric acid, dilute sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid and the like, a halogenating agent such as zinc chloride, phosphorus oxychloride, thionyl chloride and the like or acid anhydride such as acetic anhydride and the like, to allow cyclization to give compound [I- 2].

lo Production Method 1-2 This Production Method is an alternative method-for.

producing compound R N0 2 Step i R 2 RN2 Step2 R Na 03 R 5 0 R 3 0 Rp ft N N

N

wherein each symbol is as defined above.

Step 1 The compound obtained in the same manner as in Step 1 of Production Method i-1 is subjected to amide condensation with compound in the same maner as in Step 3 of Production Method 1-1 to give compoud Step 2 The compound is reduced in the same maner as in Step 2 of Production Method 1i to give compound Step 3 The comound is sujected to cyclization in the sae manner as in Step 4 of Production Method 1-i to give compoud [I- 2]1 Produc tion Method 1-3 128 A [91 [41 R- [1-2]

R

or x A )-CHO R 6 or X A -COOH [11] R6 wherein R c2 is alkyl such as methyl, ethyl and the like, and other symbols are as defined above.

The compound is reacted with imidate compound in a solvent such as methanol, ethanol, acetic acid, DMF, THF, chloroform and the like at room temperature or with heating to give compound [1I-2].

In addition, compound may be reacted with aldehyde compound [10] in a solvent such as acetic acid, formic acid, acetonitrile, DMF, nitrobenzene, toluene and the like in the presence or absence of an oxidizing agent such as benzofuroxan, manganese dioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, iodine, potassium ferricyanide and the like with heating to give compound Alternatively, compound and carboxylic acid compound [11] may be heated to allow reaction in the presence of polyphosphoric acid, phosphoric acid, phosphorus oxychloride, hydrochloric acid and the like to give compound Production Method 2 In this Production Method, conversion of the substituents

R

2

R

3

R

4 on the benzene ring of benzimidazole is shown.

While a method of converting R 2 when R 1

R

3 and R 4 are hydrogen atoms is shown, this Production Method is applicable irrespective of the position of substitution.

129 Production Method 2-1 Conversion of carboxylic acid ester moiety to amide

NHRC

4 RHOOC-E [12 R N N R X

N

SN A rtep j Step 2 RC [1-2-2] [1-2-3] [I-2-1] wherein E is a single bond, (CH 2

(CH

2 or -NH- (CH 2 5 (wherein s is an integer of 1 to R0 3 Rc 4 and RC 5 are CI- 6 alkyl, and other symbols are as defined above.

Step 1 The compound obtained in the same manner as in the above-mentioned Production Method is subjected to hydrolysis in a l0 solvent such as methanol, ethanol, THF, dioxane and the like, or in a mixed solvent of these solvents and water under basic conditions with sodium hydroxide, potassium hydroxide, potassium carbonate, lithium hydroxide and the like or under acidic.

conditions with hydrochloric acid, sulfuric acid and the like to give compound Step 2 The compound is reacted with compound [12] in the same manner as in Step 3 of Production Method 1-1 to give compound Production Method 2-2 Conversion of cyano group to substituted amidino group NC R 2 x

HZN>C

[1-2-5] [1-2-41 wherein each symbol is as defined above.

The compound obtained in the same manner as in the above-mentioned Production Method is reacted with hydroxylamine in a solvent such as water, methanol, ethanol, THF, DMF and the like to give compound When a salt of hydroxylamine such 130 as hydrochloride and the like is used, the reaction is carried out in the presence of a base such as sodium hydrogencarbonate, sodium hydroxide, triethylamine and the like.

Production Method 2-3 Conversion of sulfonic acid ester moiety to sulfonic acid 0 0 60\ R5 HO0 0 AX o NG

R

[1-2-7] [1-2-6] wherein Rc 6 is Ci- 6 alkyl, and other symbols are as defined above.

The compound obtained in the same manner as in the above-mentioned Production Method is reacted with iodide salt such as sodium iodide, lithium iodide and the like, bromide salt such as sodium bromide, trimethylammonium bromide and the like, amine such as pyridine, trimethylamine, triazole and the like, phosphine such as triphenylphosphine and the like in a solvent such as DMF, dimethyl. sulfoxide (DMSO), acetonitrile, methanol, ethanol, water and the like with heating to give compound Production Method 3 This Production Method relates to convertion of the substituent(s) on phenyl group at the 2-position of benzimidazole.

This Production Method can be used even when phenyl is a different ring.

Production Method 3-1 Conversion of hydroxyl group to ether 131 2 N. R OH R :N R 4 Ro!_GI B

L(Z)W

or [1-2-8] [13]

O-RO

7 or RaLRC 7 [1-2-9] [14] wherein RC 7 is optionally substituted alkyl corresponding to Rail,

G

1 is a single bond, *-(CH 2

*-(CH

2

*-(CH

2 )n-CO- or

(CH

2 )m-CRaR a16) -(CH 2 wherein show the side to be bonded to

R

i and other symbols are as defined above.

When R c of compound [13] is halogen atom, compound [I-2-8] obtained in the same manner as in the above-mentioned Production Method is reacted with compound [13] in a solvent such as DMF, DMSO, acetonitrile, ethanol, THF and the like in the presence of.

a base such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium ethoxide, potassium tbutoxide and the like at room temperature or with heating to give compound [11-2-1].

When R c1 of compound [13] is hydroxyl group, the hydroxyl group of compound [13] is converted to halogen atom with thionyl chloride, phosphorus tribromide, carbon tetrabromide triphenylphosphine and the like and reacted with compound [1-2-8] by the aforementioned method to give compound In this case, compound may be subjected to Mitsunobu reaction with compound [13] in a solvent such as DMF, acetonitrile, THF and the like using triphenylphosphine diethyl azodicarboxylate and the like to give compound [11-2-1J.

The compound can be obtained in the same manner from compound [I1-2-8] and compound [14].

Production Method 3-2 Conversion of nitro to substituted amino group 132 [1-2-10] Step 1 1 G w [15) H 2 [NH2 Step 2N-6& [I 1-2-2] Step 3 HaIl-G (Z)w [16] or HalIIR [17] Q B (Z)w [11-2-3] or N48 [1-2-12] wherein RC8 is CI-6 alkyl, G 2 is *-(CH 2 or *-CHRa 15

G

3 is -CO-, *-CONH- or -S02-, and other symbols are as defined above.

Step 1 The nitro compound [1-2-10] obtained in the same manner as in the above-mentioned Production Method is reacted in the same manner as in Step 2 of Production Method 1-1 to give compound [I- 2-11].

Step 2 The compound [1-2-11] is alkylated with compound [15] in the same manner as in Production Method 3-1 to give compound [11-2-2].

Step 3 When G 3 of compound [16] is -CO 2 or -CONH-, compound [1-2-11] is acylated with compound [16] in the same manner as in Step 3 of Production Method 1-1 to give compound [11-2-3].

When G 3 of compound [16] is -S02-, sulfonylation is conducted using sulfonyl halide instead of acid halide used in Step 3 of Production Method 1-1 to give compound [11-2-3].

The compound [1-2-11] is acylated with compound [17] in the same manner as above to give compound [1-2-12].

133 This Production Method is applied in the same manner as above to give disubstituted compounds (tertiary amine) of compound compound [11-2-3] and compound [1-2-12].

Production Method 3-3 Conversion of carboxylic acid ester moiety to amide [1-2-14] a13 R N COORGO COOH Step 2 N-G B& (Z)w R 3 Step t 4 eR 6 (11-2-41

HN-G

4 (Z)w or a 1 3 [1-2-131 (18) (H2) T-R or

H

2 N- (CH 2

-R

1 0 [1-2-15] [19] wherein Rc 9 is Ci-6 alkyl, G 4 is #-(CH 2

#-(CH

2 )n-NH- or f#-CHRa 4 wherein shows the side that is bounded to amine and other symbols are as defined above.

Step 1 The compound [1-2-13] obtained in the same manner as in the above-mentioned Production Method is reacted in the same manner as in Step 1 of Production Method 2-1 to give compound [I- 2-14].

Step 2 The compound [1-2-14] is reacted with compound [18] in the same manner as in Step 2 of Production Method 2-1 to give compound The compound [1-2-15] is obtained from compound [1-2-14] and compound [19] in the same manner as above.

Production Method 4 In this Production Method, additional substituent(s) is(are) introduced into ring B on phenyl group that substitutes the 2position of benzimidazole. This Production Method is applicable even when phenyl is a different ring.

Production Method 4-1 134 Direct bonding of ring Z" to ring B [11-2-5] [20] [11-2-6] wherein ring Z"-M is aryl metal compound, ring Z" moiety is optionally substituted C6- 14 aryl or optionally substituted heterocyclic group corresponding to substituent Z, and the metal moiety contains boron, zinc, tin, magnesium-and the like, such as phenylboronic acid and 4-chlorophenylboronic -acid, w" is 0, 1 or 2, and other symbols are as defined above.

The compound [I1-2-5] obtained in the same manner as in the above-mentioned Production Method is reacted with aryl metal compound [20] in a solvent such as DMF, acetonitrile, 1,2dimethoxyethane, THF, toluene, water and the like in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium (II) dichloride, palladium acetate triphenylphosphine and the like, a nickel catalyst such as nickel chloride, [1,3-bis(diphenylphosphino)propane]nickel(II) chloride and the like, and a base such as potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium phosphate, triethylamine and the like at room temperature or with heating, to give compound [11-2-6].

Production Method 4-2 Conversion of hydroxyl group to ether I I 11-2-81 R NN R Ry R CNO ORclO Cy RR Cy S- [21] [11-2-7] It 1-2-8] wherein R c l 0 is -RaZ 2 or -(CH 2 )p-COR a 21 corresponding to substituent Z, and other symbols are as defined above.

The compound [11-2-7] obtained in the same manner as in the above-mentioned Production Method is reacted with compound [21] 135 in the same manner as in Production Method 3-1 to give compound [11-2-8].

Production Method 4-3 Synthesis in advance of ring B part such as compound [13] in Production Method 3-1

RCI

2 S 1 RCl 2 Step 2 [22] (m [23] [24]

Z'.

Step 3 Step 4 B B C

/Z)W

I

RI

R

R N 11H -2-9] R 3

-I

4R^

R

[1-2-8] wherein R C11 is leaving group such as chlorine atom, bromine atom, iodine atom, trifluoromethanesulfonyloxy and the like, R c12 is formyl, carboxyl or carboxylic acid ester such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl and the like, and other symbols are as defined above.

Step 1 Commercially available compound [22] or compound [22] obtained by a conventional method is reacted with aryl metal compound [20] in the same manner as in Production Method 4-1 to give compound [23].

Step 2 The compound [23] obtained in the same manner as in the above-mentioned Production Method is reduced according to a conventional method to give compound [24].

For example, compound [23] is reacted with in a solvent such as methanol, ethanol, THF and the like in the presence of a reducing agent such as lithium aluminum hydride, sodium 136 borohydride and the like under cooling to heating to give compound [24].

Step 3 The compound [24] obtained in the same manner as in the above-mentioned Production Method is reacted in a solvent such as 1,4-dioxane, diethyl ether, THF, dichloromethane, chloroform, toluene and the like with a halogenating agent, such as phosphorus pentachloride, phosphorus tribromide, thionyl chloride and the like, to give compound For an accerelated reaction, the reaction may be carried out in the presence of a tertiary amine such as DMF, pyridine and the like, or under heating.

Step 4 The compound [24] or [25] obtained in the same manner as in the above-mentioned Production Method is reacted with compound in the same manner as in Production Method 3-1 to give compound [II-2-9].

Production Method 4-4 Hal Step 1 M'*Hal step 2 (Z)w w [41] [42] B CHO [43] H Hal Step 3 B B' B B' w w' w w' [44J wherein M' is a metal such as magnesium, lithium, zinc and the like, and other symbols are as defined above.

Step 1 Commercially available compound (41] or compound [41] obtained by a conventional method is converted to aryl metal reagent by a conventional method to give compound [42].

For example, when M' is magnesium, magnesium is reacted with compound [41] in a solvent such as THF, diethyl ether, benzene, toluene and the like, preferably THF, from cooling to heating preferably at -100 0 C to 100 0 C to give compound (42].

137 Step 2 The compound [42] obtained in the same manner as in the above-mentioned Production Method is reacted with compound [43] to give compound [44].

The compound [42] is reacted in a solvent such as diethyl ether, benzene, toluene, THF and the like, preferably THF, from cooling to room temperature, preferably at -100 0 C to 30 0 C to give compound [44].

Step 3 The compound [44] obtained in the same manner as in the above-mentioned Production Method is halogenated in the same manner as.in Step 3 of Production Method 4-3 to give compound The compound [44] is reacted with thionyl chloride and is pyridine preferably in toluene solvent to give compound When compound [45] is symmetric, namely, when the ring B- (Z)w moiety and the ring moiety are the same, compound [42] is reacted with formate such as methyl formate, ethyl formate and the like, preferably ethyl formate, in a solvent such as diethyl ether, benzene, toluene, THF and the like, preferably THF, from cooling to room temperature, preferably at -100 0 C to 0 C, to give compound Production Method Method including steps to introduce a protecting group into a functional group 138 _Hal Hal R

R

0

R

lid I H Me Step 1 H Me Step 2 R 04 0 \R Y S N

NN

00 2 H COR' OH R 4 02j 1 [26] (271

N

b 1-2-101 [1-2-16] A Step 3 Step 4 Step .R -0VO °i V Y^ HNR'Z7R.

2 0

CO

0 3 C02,H [28] ONR' e [11-2-11] [(11-2-12] [11-2-13] Step 6' H0 2

C

[I 1-2-14] cONR 27

R

a z wherein R"' 3 is carboxylic acid protecting group such as tertbutyl and the like, R c14 is carboxylic acid protecting group such as methyl and the like and other symbols are as defined above.

Step 1 Commercially available compound [26] or compound [26] obtained by a conventional method is protected by a conventional method to give compound [27].

For example, when RC 13 is tert-butyl, compound [26] is converted to acid halide with thionyl chloride, oxalyl chloride and the like in a solvent such as THF, chloroform, dichloromethane, toluene and the like, and reacted with potassium tert-butoxide to give compound [27].

is As used herein, R c13 may be a different protecting group as long as it is not removed during the Step 2 or Step 3 but removed in Step 4 without affecting -CO 2

R'

4 Step 2 The methyl group of compound [27] obtained in the same manner as in the above-mentioned Production Method is converted 139 to bromomethyl with N-bromosuccinimide and N,N'azobisisobutyronitrile and reacted with compound [1-2-16] in the same manner as in Production Method 3-1 to give compound [11-2- 101.

Step 3 The compound [11-2-10] obtained in the same manner as in the above-mentioned Production Method is reacted with aryl metal compound [20] in the same manner as in Production Method 4-1 to give compound [11-2-11].

Step 4 The R c 3 of the compound [11-2-11] obtained in the same manner as in the above-mentioned Production Method is removed by a conventional method to give compound [11-2-12].

The protecting group of carboxylic acid can be removed by a conventional deprotection method according to the protecting group. In this Step, the conditions free from reaction of RC 14 are preferable. For example, when Rc 1 is tert-butyl, compound [11-2- 11] is treated with trifluoroacetic acid in a solvent such as dichloromethane, chloroform and the like to give compound [11-2- 12].

Step The compound [11-2-12] obtained in the same manner as in the above-mentioned Production Method is subjected to amide condensation with compound [28] in the same manner as in Step 3 of Production Method 1-1 to give compound [11-2-13].

Step 6 The compound (11-2-13] obtained in the same manner as in the above-mentioned Production Method is deprotected in the same manner as in Step 1 of Production Method 2-1 to give compound [11-2-14].

As used herein, R c14 is preferably a protecting group that does not react during the Step 1 through Step 5 but removed in this Step.

For example, when R' 14 is methyl, compound [11-2-13] is reacted in an alcohol solvent such as methanol, ethanol, npropanol, isopropanol and the like or a mixed solvent of alcohol solvent and water in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, 140 potassium hydroxide and the like from cooling to heating for deprotection, followed by acidifying the reaction solution to give compound [(11-2-14].

Production Method 4-6 Hal R0 1 4 0 2 C N R step 1 RC0 4 0 2 C R50 Ha Step 2 5I CY R Hal

NO

2 R 6 0 2 M Me N02 [1-2-161 [41] [I 1-2-171 Step 3 Step 4

NO

2

NH

2 Hal-(CH2)g-COCl [11-2-18] I-2-19 (42]

Z,.

R0 4 0C R Step 5 HC

R

2 ompoN obtaiNn 0th°oeetnd Q C, R& CQK R N N (11-2-20] [11-2-21] wherein g is an integer of 1 to 5, and other sunbols are as defined above.

Step 1 The compound [1-2-16] obtained by the above-mentioned 1i Production Method is reacted with toluene derivative (41] in the same manner as in Step 2 of Production Method 4-5 to give compound [11-2-17].

Step 2 The compound [11-2-17] obtained by the above-mentioned Production Method is reacted with aryl metal compound (20] in the same manner as in Production Method 4-1 to give compound (11-2- 18].

Step 3 141 The compound [11-2-18] obtained by the above-mentioned Production Method is reduced in the same manner as in Step 2 of Production Method 1-1 to give compound [II-2-19].

Step 4 The compound [11-2-19] obtained by the above-mentioned Production Method is amide condensed with compound [42] in the same manner as in Step 3 of Production Method 1-1 and subjected to cyclization in the same manner as in Step 1 of Production Method 1-1 to'give compound [11-2-20].

lo Step The compound [11-2-20] obtained by the above-mentioned Production Method is hydrolyzed in the same manner as in Step 1 of Production Method 2-1 to give compound [II-2-21].

Production Method 4-7 Hal

NO

z [46] Step 1 l2

SNO

2 [20] [47] Step 2. Step 3 Step 4 Ha l-(CH 2 g-CC [42] HO Step 5

HO

NHCO- g-Ha I tep Step 6 Hal <tt 0 Step 7 [11-2-20] [1-2-16] Step 8 HO Step 8

N

Pro [11-2-21] wherein each symbol is as defined above.

Step 1 Commercially available product or compound [46] obtained by a conventional method is reacted with compound [20] in the same manner as in Production Method 4-1 to give compound [47].

Step 2 The compound [47] obtained in the same manner as in the above-mentioned Production Method is reduced in the same manner 143 as in the above-mentioned Production Method 4-3 Step 2 to give compound [48].

Step 3 The compound [48] obtained in the same manner as in the above-mentioned Production Method is reduced in the same manner as in the above-mentioned Production Method 1-1 Step 2 to give compound [49].

Step 4 The compound [49] obtained in the same manner as in the lo above-mentioned Production Method is reacted with compound [42] in a solvent such as DMF, acetonitrile, THF, chloroform, ethyl acetate, methylene chloride and toluene to give compound To enhance the reaction selectivity for amino group, acetic acid and sodium acetate may be added in an equivalent amount ratio.

Step The compound [50] obtained in the same manner as in the above-mentioned Production Method is subjected to cyclization reaction in the same manner as in the above-mentioned Production Method 1-1 Step 1 to give compound [51].

Step 6 The compound [51] obtained in the same manner as in the above-mentioned Production Method is halogenated in the same manner as in the above-mentioned Production Method 4-3 Step 3 to give compound [52].

Step 7 The compound [52] obtained in the same manner as in the above-mentioned Production Method is reacted in the same manner as in the above-mentioned Production Method 3-1 with compound [I- 2-16] obtained in the same manner as in the above-mentioned Production Method to give compound [II-2-20].

Step 8 The compound [II-2-20] obtained in the same manner as in the above-mentioned Production Method is hydrolyzed in the same manner as in the above-mentioned Production Method 2-1 Step 1 to give compound [II-2-21].

Production Method Formation of indole ring 144 Ha tep 1 c [29] HC -C-Rcl s (31] R2 I& W Step 2 R i R| SR NH Step 3 A R N Hal Cy R3 .NH [11-2-15] R' [33] (32] wherein R C15 is protecting group such as trimethylsilyl, tertbutyldimethylsilyl, tert-butyldiphenylsilyl and the like, and other symbols are as defined above.

Step 1 The compound [29] obtained in the same manner as in the above-mentioned Production Method or conventional method is reacted with compound [30] in a solvent such as DMF, acetonitrile, 1,2-dimethoxyethane, THF, toluene, water and the like using a lo palladium catalyst such as tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, palladium acetate triphenylphosphine and the like, a copper catalyst such as copper(I) iodide and the like or a mixture thereof, and in the presence of a base such as potassium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium phosphate, triethylamine and the like to give compound [31].

Step 2 The compound [31] obtained in the same manner as in the above-mentioned Production Method is reacted in an alcohol solvent such as methanol, ethanol and the like or a mixed solvent of an'alcohol solvent and a solvent such as DMF, acetonitrile, THF, chloroform, dichloromethane, ethyl acetate, methylene chloride, toluene and the like in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, 145 potassium hydride and the like at room temperature or with heating for deprotection, and reacted with compound [32] obtained in the same manner as in Step 1 of Production Method 1-1 in the same manner as in Step 1 of Production Method 5 to give compound [33].

Step 3 The compound [33] obtained in the same manner as in the above-mentioned Production Method was subjected to cyclization in a solvent such as DMF, acetonitrile, THF, chloroform, dichloromethane, ethyl acetate, methylene chloride, toluene and the like in the presence of a copper catalyst such as copper(I) iodide and the like or a palladium catalyst such as palladium(II) chloride and the like at room temperature or with heating to give compound [II-2-15].

is Production Method 6 Formation of imidazo[1,2-a]pyridine ring 0 0 (Z step 1 ORI16 step 2 W CH YY OA N\7 OR.16 [34] HN [36] Hal .Mg R 0 Cy [37] SCy Step 4 A A Hal R [38] Step 3 [39] R NH RR C R

Y

[11-2-16] wherein R' 16 and R 17 are each independently alkyl, such as methyl, ethyl and the like, and other symbols are as defined above.

Step 1 The compound [34] obtained by the above-mentioned Production Method or a conventional method is subjected to amide 146 condensation with compound [35] in the same manner as in Step 3 of Production Method 1-1 to give compound [36].

Step 2 The compound [36] obtained by the above-mentioned Production Method is reacted with Grignard reagent [37] obtained by a conventional method to give compound [38].

Alternatively, an acid halide of compound [34] may be used instead of compound [36].

Step 3 The compound [38] obtained by the above-mentioned Production Method is subjected to halogenation by a conventional method to give compound [39].

For example, when Hal is a bromine atom, compound [38] is reacted with bromine under cooling or at room temperature in a solvent such as DMF, acetonitrile, THF, chloroform, dichloromethane, ethyl acetate, toluene and the like to give compound [39].

Alternatively, a halogenating agent such as hypohalite hypochlorite and the like), N-bromosuccinimide and the like may be used instead of bromine for halogenation.

Step 4 The compound [39] obtained by the above-mentioned Production Method is subjected to cyclization with compound [40] obtained by a conventional or known method (JP-A-8-48651) in the presence of a base such as potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like in a solvent or without a solvent at room temperature or with heating to give compound [11-2-16].

In the compounds of the formulas and a desired heterocyclic group can be formed according to a method similar to the methods disclosed in known publications. Examples of such heterocyclic group and reference publications are recited in the following.

5-oxo-A 2 -1,2,4-oxadiazolin-3-yl (or 2,5-dihydro-5-oxo-4H-l,2,4oxadiazol-3-yl), 5-oxo-A 2 -1,2,4-thiadiazolin-3-yl (or 5-oxo-4H-1,2,4-thiadiazol-3-yl), 2-oxo-A 3 -1,2,3,5-oxathiadiazolin- 147 4-yl (or 2-oxo-A 3 -1,2,4-oxathiadiazol-4-yl): Journal of Medicinal Chemistry, 39(26), 5228-35, 1996, 5-oxo-A2-1,2,4-triazolin-3-yl: J Org Chem, 61(24), 8397-8401, 1996, l-oxo-A 3 -1,2,3,5-thiatriazolin-4-yl: Liebigs Ann Chem, 1376, 1980, 3-oxo-A 4 2,4-oxadiazolin-5-yl: EP145095, 2 -1,3,4-oxadiazolin-2-yl: J Org Chem, 20, 412, 1955, 3 -1,2,4-dioxazolin-3-yl: J -Prakt Chem, 314, 145, 1972, 3-oxo-A 4 -1,2,4-thiadiazolin-5-yl: JP-A-61-275271, 5-oxo-A3-1,2,4-dithiazolin-3-yl: J Org Chem, 61(19), 6639-6645, 1996, 2-oxo-A 4 -1,3,4-dioxazolin-5-yl: J Org Chem, 39, 2472, 1974, 2-oxo-A 4 3,4-oxathiazolin-5-yl: J Med Chem, 35(20), 3691-98, 1992, 5-oxo-A 2 -1,3,4-thiadiazolin-2-yl: J Prakt Chem, 332(1), 55, 1990, 2 -1,4,2-oxathiazolin-3-yl: J Org Chem, 31, 2417, 1966, 2-oxo-A 4 -1,3,4-dithiazolin-5-yl: Tetrahedron Lett, 23, 5453, 1982, 2-oxo-A 4 3,2,4-dioxathiazolin-5-yl: Tetrahedron Lett, 319, 1968, 3,5-dioxoisooxazolidin-4-yl: Helv Chim Acta, 1 9 7 3 48, 1965, 2,5-dioxoimidazolidin-4-yl: Heterocycles, 43(1), 49-52, 1996, 5-oxo-2-thioxoimidazolidin-4-yl: Heterocycles, 5, 391, 1983, 2,4-dioxooxazolidin-5-yl: J Am Chem Soc, 73, 4752, 1951, 4-oxo-2-thioxooxazolidin-5-yl: Chem Ber, 91, 300, 1958, 2,4-dioxothiazolidin-5-yl: JP-A-57-123175, 4-oxo-2-thioxothiazolidin-5-yl: Chem Pharm Bull, 30, 3563, 1982, The Production Methods shown in the above-mentioned Production Methods 2 to 4 can be used for the synthesis of compounds other than benzimidazole of the formulas and [II], such as compounds I11-2-15] and [11-2-16].

The compounds of the formulas [II] and [III], 4-(4fluorophenyl)-5-hydroxymethyl-2-methylthiazole and 4-(4fluorophenyl)-5-chloromethyl-2-methylthiazole and production methods thereof of the present invention are explained in detail in the following by way of Examples. It is needless to say that the present invention is not limited by these Examples.

Example 1 Production of ethyl 2-[4-(3-bromophenoxy)phenyl]-l- 148 Step 1: Production of ethyl 4-chloro-3-nitrobenzoate 4-Chloro-3-nitrobenzoic acid (300 g) was dissolved in ethyl alcohol (1500 ml) and concentrated sulfuric acid (100 ml) was added with ice-cooling. The mixture was refluxed under heating for 7 hr. The reaction mixture was poured into ice-cold water and the precipitated crystals were collected by filtration to give the title compound (332 g, yield 97%).

1H-NMR (300MHz, CDC13) 8.50(1H, d, J=2.1Hz), 8.16(1H, dd, J=8.4, 2.1Hz), 7.63(1H, d, J=8.4Hz), 4.43(2H, q, J=7.5Hz), 1.42(3H, t, Step 2: Production of ethyl 4-cyclohexylamino-3-nitrobenzoate Ethyl 4-chloro-3-nitrobenzoate (330 g) obtained in the previous step was dissolved in acetonitrile (1500 ml), and cyclohexylamine (220 g) and triethylamine (195 g) were added. The 1i mixture was refluxed under heating overnight. The reaction mixture was poured into ice-cold water and the precipitated crystals were collected by filtration to give the title compound (400 g, yield. 94%).

1 H-NMR (300MHz, CDC1 3 8.87(1H, d, J=2.1Hz), 8.35-8.46(1H, m), 8.02(1H, dd, J=9.1, 2.1Hz), 6.87(1H, d, J=9.1Hz), 4.35(2H, q, J=7.1Hz), 3.65-3.50(1H, 2.14-1.29(10H, 1.38(3H, t, J=7.1Hz) Step 3: Production of ethyl 3-amino-4-cyclohexylaminobenzoate Ethyl 4-cyclohexylamino-3-nitrobenzoate (400 g) obtained in the previous step was dissolved in ethyl acetate (1500 ml) and ethyl alcohol (500 ml), and 7.5% palladium carbon (50% wet, 40 g) was added. The mixture was hydrogenated for 7 hr at atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Diisopropyl ether was added to the residue and the precipitated crystals were collected by filtration to give the title compound (289 g, yield 'H-NMR (300MHz, CDC1 3 7.57(1H, dd, J=8.4, 1.9Hz), 7.41(1H, d, J=1.9Hz), 6.59(1H, d, J=8.4Hz), 4.30(2H, q, J=7.1Hz), 3.40- 3.30(1H, 2.18-2.02(2H, 1.88-1.15(8H, 1.35(3H, t, J=7.1Hz) Step 4: Production of ethyl 3-[4-(3-bromophenoxy)benzoyl]amino-4cyclohexylaminobenzoate 149 4-(3-Bromophenoxy)benzoic acid (74 g) was dissolved in chloroform (500 ml), and oxalyl chloride (33 ml) and dimethylformamide (catalytic amount) were added. The mixture was stirred for 4 hr at room temperature. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane (150 ml). The resulting solution was added dropwise to a solution of ethyl 3-amino-4-cyclohexylaminobenzoate (66 g) obtained in the previous step in dichloromethane (500 ml) and triethylamine (71 ml), and the mixture was stirred for 1 hr at room temperature. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue for crystallization and the crystals were collected by filtration to give the title compound (129 g, yield H-NMR (300MHz, CDC13): 8.00-7.78(4H, 7.66(1H, brs), 7.37- 7.18(3H, 7.13-6.59(3H, 6.72(1H, d, J=8.7Hz), 4.50(1H, brs), 4.29(2H, q, J=7.2Hz), 3.36(1H, 2.12-1.96(2H, 1, 83- 1.56(3H, 1.47-1.12(5H, 1.37(3H, t, J=7.2Hz) Step 5: Production of ethyl 2-[4-(3-bromophenoxy).phenyl]-l- Ethyl 3-[4-(3-bromophenoxy)benzoyl]amino-4cyclohexylaminobenzoate (129 g) obtained in the previous step was suspended in acetic acid (600 ml) and the resulting suspension was refluxed under heating for 3 hr. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the precipitated crystals were collected by filtration to give the title compound (124 g, yield 99%).

H-NMR (300MHz, CDC1 3 8.51(1H, d, J=1.5Hz), 8.00(1H, dd, J=8.4, 1.SHz), 7.67(1H, d, J=8.4Hz), 7.63(2H, d, J=8.7Hz), 7.35-7.21(3H, 7.17(2H, d, J=8.7Hz), 7.14(1H, 4.42(2H, q, J=7.2Hz), 4.38(1H, 2.43-2.22(2H, 2.07-1.87(4H, 1.80(1H, m), 1.42(3H, t, J=7.2Hz), 1.40-1.27(3H, m) Example 2 Production of 2-[4-(3-bromophenoxy)phenyl]-l-cyclohexylacid Ethyl 2-[4-(3-bromophenoxy)phenyl]-1-cyclohexyl- (1.0 g) obtained in Example 1 was 150 dissolved in tetrahydrofuran (10 ml) and ethyl alcohol (10 ml), and 4N sodium hydroxide (10 ml) was added. The mixture was refluxed under heating for 1 hr. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 6N hydrochloric acid and the precipitated crystals were collected by filtration to give the title compound yield 96%).

melting point: 255-256°C FAB-Ms: 491(MH+) H-NMR (300MHz, DMSO-d 6 (12.75(1H, brs), 8.24(11, 7.96(1H, d, J=8.7Hz), 7.86(1H, d, J=8.7Hz), 7.71(2H, d, J=8.6Hz), 7.47- 7.34(3H, 7.24(2H, d, J=8.6Hz), 7.20(1H, 4.31(1H, m), 2.38-2.18(2H, 2.02-1.79(4H, 1.65(1H, 1.44-1.20(3H, m) Example 3 Production of ethyl l-cyclohexyl-2-(4- Ethyl 3-amino-4-cyclohexylaminobenzoate (130 g) obtained in Example 1, Step 3, and methyl 4-hydroxybenzimidate hydrochloride (139 g) were added to methyl alcohol (1500 ml), and the mixture was refluxed under heating for 4 hr. The reaction mixture was.

allowed to cool and the precipitated crystals were collected by filtration to give the title compound (131 g, yield 72%).

1 H-NMR (300MHz, CDCl 3 10.02(1H, brs), 8.21(1H, d, J=1.4Hz), 7.93(1H, d, J=8.6Hz), 7.83(1H, dd, J=8.6, 1.4Hz), 7.48(2H, d, J=8.6Hz), 6.95(2H, d, J=8.6Hz), 4.39-4.25(1H, 4.33(1H, q, 2.35-2.18(2H, 1.98-1.79(4H, 1.70- 1.60(1H, m), 1.46-1.19(3H, 1.35(3H, t, Example 4 Production of ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1bromide prepared from chlorotoluene (50 N-bromosuccinimide and N,N'azobisisobutyronitrile, and ethyl l-cyclohexyl-2-(4- (50 g) obtained in Example 3 were suspended in dimethylformamide (300 ml). Potassium carbonate (38 g) was added and the mixture was stirred for 1 hr at 80'C with heating. The reaction mixture was allowed to cool and then added to a mixed solvent of water-ethyl acetate. The 151 precipitated crystals were collected by filtration to give the title compound (50 g, yield 64%).

IH-NMR (300MHz, CDC1 3 8.50(1H, d, J=1.4Hz), 7.97(1H, dd, J=8.6, 1.4Hz), 7.70-7.57(5H, 7.20(1H, dd, J=8.4, 2.5Hz), 7.14(2H, d, J=8.7Hz), 5.17(2H, 4.46-4.30(1H, 4.41(2H, q, J=7.1Hz), 2.40-2.20(2H, 2.02-1.21(8H, 1.42(3H, t, J=7.1Hz) Example Production of ethyl 2- 4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl] -1- (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis- (triphenylphosphine)palladium (10 g) were suspended in 1,2dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:ethyl acetate 97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 1 H-NMR (300MHz, CDC13): 8.49(1H, d, J=1.4Hz), 7.97(1H, dd, J=8.6, 1.6Hz), 7.70-7.60(2H, 7.55(2H, d, J=8.7Hz), 4.95(2H, s), 4.48-4.28(1H, 4.40(2H, 2.02-1.20(8H, 1.41(3H, t, J=7.1Hz) Example 6 Production of 2- 4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenylkacid Ethyl 2-44-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyll-- (43 g) obtained in Example 5 was treated in the same manner as in Example 2 to give the title compound (33 g, yield 76%).

melting point: 243-244°C FAB-Ms: 571(MH+) 152 1H-NMR (300MHz, DMSO-d 6 8.32(1, 8.28(1H, d, J=8.9Hz), 8.05(1W, d, J=8.8Hz), 7.76-7.72(3, 7.58-7.46(5W, 7.40(1H, d, J=8.3Hz), 7.24(2W, d, J=8.9Hz), 5.11(2H, 4.36(1W, m), 2.40-2.15(2H, 2.15-1.95(2W, 1.95-1.75(2, 1.75- 1.55(LH, 1.55-1.15(3, m) Example 7 Production of ethyl (2-bromo-5-iethoxybenzyloxy)phenyl]-1- Ethyl 1-cyclohexyl-2-(4-hydroxyphenyl)benziiidazole-5carboxylate obtained in Example 3 and bromide were treated in the same manner as in Example 4 to give.

the title compound (59 g).

Example 8 Production of ethyl 2- 4-[2-(4-chiorophenyl)-5-methoxybenzyloxy]phenyl Ethyl 2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1obtained in Example 7 was treated in the same manner as in Example 5 to give the title compound (48 g, yield 77%).

1 H-NNR (300MHz, CDCl 3 8.49(1W, d, J=1.4Hz), 7.97(1W,.dd, J=8.6,.

1.4Hz), 7.64(1W, d, J=8.6Wz), 7.54(2W, d, 5=8.7Hz), 7.37(2W, d, J=8.6Hz), 7.31(2H, d, 5=8.6Hz), 7.25(1W, d, J=8.4Hz), 7.19(1l, d, J=2.7Hz), 7.00(2H, d, 5=8.7Hz), 6.97(1W, dd, J=8.4, 2.7Hz), 4.98(2H, 4.41(2H, q, J=7.1Hz), 4.42-4.29(1l, 3.88(3H, s), 2.40-2.20(2H, 2.01-1.88(4H, 1.83-1.73(1W, 1.42(3H, t, J=7.lz), 1.41-1.25(3H, m) Example 9 Production of 2- 4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl V acid Ethyl 2-14-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl- (52 g) obtained in Example 8 was treated in the same manner as in Example 2 to give the title compound (44 g, yield 89%).

melting point: 248-249 0

C

FAB-Ms: 568(MH+) IH-NHR (3001Hz, DMSO-d6): 8.20(1W, 7.88(1H, d, 5=8.7Hz), 7.85(1W, d, 5=8.7Hz), 7.57(6, 2H, 5=8.6Hz), 7.46(2, d, 5=8.6Hz), 7.44(2H, 6, 5=8.6Hz), 7.29(1H, d, J=8.SHz), 7.24(1l, 6, 5=2.6Hz), 153 7.11(2H, d, J=8.6Hz), 7.06(1H, dd, J=8.5, 2.6Hz), 5.04(2H, s), 4.26(1H, 3.83(3H, 2.38-2.29(2H, m) Example Production of ethyl l-cyclohexyl-2-14-[(E)-2-phenylvinyl]phenyl}- Ethyl 3-amino-4-cyclohexylaminobenzoate (500.mg) obtained in Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling.

The mixture was stirred overnight at room temperature. The o0 reaction mixture was ice-cooled and benzofuroxan (259 mg) dissolved in acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at 50°C. The reaction mixture was ice-cooled.

After 1N sodium hydroxide (0.1 ml) was added, ethyl acetate was added and the mixture was extracted. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was* purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 4:1) to give the title compound (540 mg, yield 63%).

1 H-NMR (300MHz, DMSO-d 6 8.28(1H, d, J=1.4Hz), 8.01(1H, d, J=8.7Hz), 7.90-7.80(3H, 7.75-7.65(4H, 7.50-7.25(5H, m), 4.35(2H, q, J=7.0Hz), 4.31(1H, 2.40-2.20(2H, 2.00-1.80(4H, 1.63(1H, 1.40-1.20(3H, 1.36(3H, t, Example 11 Production of 1-cyclohexyl-2-4-[(E)-2-phenylvinyl]phenylKacid Ethyl l-cyclohexyl-2- 4-[(E)-2-phenylvinyl]phenyl- (127 mg) obtained in Example 10 was treated in the same manner as in Example 2 to give the title compound (116 mg, yield 97%).

melting point: not lower than 300°C FAB-Ms: 423(MH+) 1H-NMR (300MHz, DMSO-d 6 8.25(1H, 7.96-7.29(13H, 4.33(1H, brt), 2.41-2.23(2H, 2.03-1.78(4H, 1.71-1.59(1H, 1.49- 1.20(3H, m) Example 12 Production of 2-(4-benzyloxyphenyl)-l-cyclopentylbenzinidazole-5carboxylic acid 154 In the same manner as in Examples 1 and 2, the title compound (700 mg) was obtained.

FAB-Ms: 413(MH+) H-NMR (300MHz, CDCl 3 8.60(1H, 8.04(1H, d, J=9.0Hz), 7.63(2H, d, J=8.4Hz), 7.51-7.32(6H, 7.14(2H, d, J=9.0Hz), 5.16(2H, s), 5.03-4.89(1H, 2.41-1.63(8H, m) Example 13 Production of 2-(4-benzyloxyphenyl)-l-cyclopentylbenzimidazole-5carboxamide 2-(4-Benzyloxyphenyl)-l-cyclopentylbenziiidazole-5carboxylic acid (700 mg) obtained in Example 12 was dissolved in ml), and ammonium chloride (108 mg), 1ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (390 mg), 1-hydroxybenzotriazole (275 mg) and triethylamine (0.3 ml) were added. The mixture was stirred overnight at room temperature.

Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the.residue for crystallization and the crystals were collected by filtration to give the title compound (571 mg, yield 81%).

melting point: 232-233°C FAB-Ms: 412(MH+) 1H-NMR (300MHz, CDC13): 8.23(1H, d, =1.5Hz), 7.86(1H, dd, 7.65-7.30(8H, 7.13(2H, d, J=8.8Hz), 5.16(2H, s), 4.93(1H, quint, J=8.8Hz), 2.40-1.60(8H, m) Example 14 Production of 2-(4-benzyloxyphenyl)-5-cyano-lcyclopentylbenzimidazole In the same manner as in Example 1, the title compound (400 mg) was obtained.

FAB-Ms: 394(MH+) H-NMR (300MHz, CDC1 3 8.11(1H, 7.68-7.30(9H, 7.13(2H, s), 5.16(2H, 4.94(1H, quint, J=8.9Hz), 2.35-1.60(8H, m) Example 155 Production of 2-(4-benzyloxyphenyl)-l-cyclopentylbenzimidazole-5carboxamide oxime 2-(4-Benzyloxyphenyl)-5-cyano-l-cyclopentylbenzimidazole (400 mg) obtained in Example 14 was suspended in ethyl alcohol (3 ml) and water (1.5 ml), and hydroxylamine hydrochloride (141 mg) and sodium hydrogencarbonate (170 mg) were added. The mixture was refluxed under heating overnight. The reaction mixture was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (312 mg, yield 71%).

io melting point: 225-226°C FAB-Ms: 456(MH+) H-NMR (300MHz, DMSO-de): 8.20(1H, 7.50-7.31(9H, 7.12(2H, d, J=8.7Hz), 5.15(2H, 4.94(1H, quint, J=8.7Hz), 3.61(3H, s), 3.40(3H, 2.41-1.42(8H, m) Example 16 Production of ethyl 1-cyclohexyl-2-14- [4-(4-fluorophenyl)-2methoxy] phenyl Step 1: Production of 4-(4-fluorophenyl)-5-hydroxymethyl-2methylthiazole Ethyl 4-(4-fluorophenyl)-2-methyl-5-thiazolecarboxylate (59 g) prepared by a known method (Chem. Pharm. Bull., 43(6), 947, 1995) was dissolved in tetrahydrofuran (700 ml). Lithium aluminum hydride (13 g) was added under ice-cooling and the mixture was stirred for 30 min. Water (13 ml), 15% sodium hydroxide (13 ml) and water (39 ml) were added successively to the reaction mixture, and the precipitated insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to give the title compound (37 g, yield 71%).

1 H-NMR (300MHz, CDC1 3 7.60(2H, dd, J=8.7, 6.6Hz), 7.11(2H, t, J=8.7Hz), 4.80(2H, 2.70(3H, s) Step 2: Production of 5-chloromethyl-4-(4-fluorophenyl)-2methylthiazole 4-(4-Fluorophenyl)-5-hydroxymethyl-2-methylthiazole (37 g) obtained in the previous step was dissolved in chloroform (500 ml), and thionyl chloride (24 ml) and pyridine (2 ml) were added.

The mixture was stirred for 3 hr at room temperature. The reaction mixture was poured into ice-cold water. The mixture was extracted with chloroform, and washed with water and saturated 156 brine. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (29 g, yield 76%).

1 H-NMR (300MHz, CDC13): 7.67(2H, dd, J=8.8, 5.4Hz), 7.16(2H, t, J=8.7Hz), 4.79(2H, 2.73(3H, s) Step 3: Production of ethyl l-cyclohexyl-2- 4- carboxylate 5-Chloromethyl-4-(4-fluorophenyl)-2-methylthiazole (28 g) obtained in the previous step and ethyl l-cyclohexyl-2-(4- (36 g) obtained in Example 3 were treated in the same manner as in Example 4 to give the title compound (61 g, yield 100%).

APCI-Ms: 570(MH+) H-NMR (300MHz, DMSO-d 6 8.25(1H, d, J=1.5Hz), 7.97(1H, d, J=8.7Hz), 7.86(1H, dd, J=8.6, 1.6Hz), 7.74(2H, dd, J=8.8, 7.62(2H, d, J=8.7Hz), 7.33(2H, t, J=8.9Hz), 7.22(2H, t, J=8.9Hz), 5.41(2H, 4.34(2H, q, J=7.1Hz), 4.31(1H, 2.71(3H, s), 2.40-2.15(2H, 2.05-1.75(4H, 1.55-1.15(3H, 1.36(3H, t, J=7.1Hz) Example 17 Production of l-cyclohexyl-2-44- 4- (4-fluorophenyl) thiazolyl nethoxy phenyl benzimidazole-5-carboxylic acid Ethyl 1-cyclohexyl-2- 4- [4-(4-fluorophenyl)-4-methyl-5thiazolyl hethoxy]phenyl benzimidazole-5-carboxylate (60 g) obtained in Example 16 was treated in the same manner as in Example 2 to give the title compound (39g, yield 69%).

melting point: 196-198 0

C

FAB-Ms: 542(MH+) H-NMR (300MHz, DMSO-d) 13.1(1H, brs), 8.34(1H, 8.29(1H, d, J=8.8Hz), 8.06(1H, d, J=8.7Hz), 7.80-7.72(4H, 7.36-7.31(4H, 5.46(2H, 4.38(1H, 2.72(3H, 2.45-2.15(2H, m), 2.15-1.95(2H, 1.95-1.75(2H, 1.75-1.55(1H, 1.55- 1.20(3H, m) Example 18 Production of ethyl 1-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)- 157 In the same manner as in Example 3, the title compound g) was obtained.

Example 19 Production of ethyl 2-44-[bis(3-fluorophenyl)methoxy]-2fluorophenyl Step 1 Production of 3,3'-difluorobenzhydrol To a stirred solution of magnesium strip (35.4 g) in THF (200 ml), iodine strip was added and the mixture was heated with stirring under nitrogen stream until most of color of iodine was 1o disappeared. A solution of 3-fluoro-bromobenzene (250.0 g) in THF (1000 ml) was added dropwise over 2.5 hr while the temperature of the solution was maintained at 60 0 C. After the completion of the addition of the solution, the resulting mixture was refluxed for 1 hr with heating. The resulting Grignard solution was ice-cooled and a solution of ethyl formate (63.2 g) in THF (200 ml) was added dropwise over 1 hr. After a stirring of the reaction solution for an additional 30 min, saturated aqueous ammonium chloride solution (700 ml) was added dropwise with ice-cooling and water (300 ml) was added. The mixture was stirred for 10 min.

The organic layer and water layer were separated. Water layer was extracted with ethyl acetate, and the combined organic layer was washed with 2N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated off under reduced pressure to give the title compound (156.2 g, yield 99%).

1 H-NMR (300MHz, CDCl 3 7.31(2H, td, J=7.9, 5.8Hz), 7.15-7.80(4H, 6.97-6.94(2H, 5.82(1H, d, J=3.3Hz), 2.30(1H, d, J=3.3Hz) Step 2: Production of 3,3'-difluorobenzhydryl chloride To a solution of 3,3'-difluorobenzhydrol (150.0 g) obtained in the previous step in toluene (400 ml), pyridine (539 mg) was added at room temperature. To the solution, thionyl chloride (89.1 g) was added dropwise over 1 hr at room temperature and the resulting solution was stirred for an additional 2 hr. The solution was heated so that the temperature of the solution was at 40"C, and then stirred for an additional 1.5 hr. Thionyl chloride (8.1 g) was added again and the mixture was stirred for min. To the reaction mixture, water was added. The organic 158 layer was separated, and washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, the solvent was evaporated off under reduced pressure to give the title compound (158.2 g, yield 97%).

H-NMR (300MHz, CDC1 3 7.32(2H, td, J=8.0, 5.9Hz), 7.18-7.10(4H, 7.01(2H, tdd, J=8.2, 2.5, 1.2Hz), 6.05(1H, s) Step 3: Production of ethyl 2- 4-[bis(3-fluorophenyl)methoxy]-2fluorophenyl Ethyl l-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)- (50 g) obtained in Example 18 and 3,3'-difluorobenzhydryl chloride (34 g) obtained in the previous step were treated in the same manner as in Example 4 to give the title compound (76 g, yield 99%).

FAB-Ms: 585(MH+) 1 H-NMR (300MHz, DMSO-d 6 8.24(1H, d, J=1.4Hz), 7.98(1H, d, J=8.7Hz), 7.88(1H, d, J=8.7Hz), 7.56(1H, t, J=8.6Hz), 7.50- 7.40(6H, 6.82(1H, 4.34(2H, q, J=7.1Hz), 3.95(1H, m), 2.20-2.10(2H, 1.90-1.80(4H, 1.6(1H, 1.35(3H, t, J=7.2Hz), 1.30-1.20(3H, mz) Example Production of 2-14-(bis[3-fluorophenyl]methoxy)-2-fluorophenyl -lacid Ethyl 2-A 4- [bis (3-fluorophenyl)methoxy] -2-fluorophenyl -1cyclohexylbenzimidazole-5-carboxylate (75 g) obtained in Example 19 was treated in the same manner as in Example 2 to give the title compound (48 g, yield 62%).

melting point: 242-243°C FAB-Ms: 557(MH+) H-NMR (300MHz, DMSO-d 6 8.29(1H, 8.16(1H, d, J=8.8Hz), 7.99(1H, d, J=8.7Hz), 7.66(1H, t, J=8.7Hz), 7.51-7.40(6H, m), 7.30(1H, d, J=12.1Hz), 7.20-7.14(3H, 6.88(1H, 4.07(1H, m), 2.40-2.10(2H, 2.00-1.75(4H, 1.70-1.55(1H, m), 1.50-1.15(3H, m) Example 21 Production of ethyl l-cyclopentyl-2-(4-nitrophenyl)benzimidazole- 159 In the same manner as in Example 1, the title compound (12 g) was obtained.

Example 22 Production of ethyl 2-(4-aminophenyl)-l-cyclopentylbenzimidazole- Ethyl l-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5carboxylate (12 g) obtained in Example 21 was dissolved in tetrahydrofuran (200 ml) and ethyl alcohol (50 ml), palladium carbon (50% wet, 1 g) was added. The mixture was hydrogenated for 1 hr at atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. Tetrahydrofuran was added to the residue to allow crystallization and the crystals were collected by filtration to give the title compound (11 g, yield 98%).

H-NMR (300MHz, CDCI3): 8.49(1H, d, J=1.3Hz), 7.95(1H, dd, 1.3Hz), 7.50-7.40(3H, 6.79(2H, d, J=4.6Hz), 4.97(1H, quint, J=8.9Hz), 4.40(2H, q, J=7.1Hz), 3.74(2H, brs), 2.40-1.60(8H, m), 1.41(3H, t, J=7.1Hz) Example 23 Production of ethyl 2-(4-benzoylaminophenyl)-1- Ethyl l-cyclopentyl-2-(4-aminophenyl)benzimidazole-5carboxylate (300 mg) obtained in Example 22 was dissolved in pyridine (3 ml) and chloroform (3 ml), and benzoyl chloride (127 mg) was added. The mixture was stirred for 30 min at room temperature. The.reaction mixture was concentrated under reduced pressure and water was added to the residue to allow crystallization. The crystals were collected by filtration to give the title compound (403 mg, yield 100%).

H-NMR (300MHz, CDC13): 8.58(1H, 8.00(1H, d, J=9.0Hz), 7.84(2H, d, J=7.5Hz), 7.60-7.40(6H, 7.14(2H, d, J=7.5Hz), 4.84(1H, quint, J=8.7Hz), 4.41(2H, q, J=7.5Hz), 2.20-1.30(8H, 1.41(3H, t, Example 24 Production of 2-(4-benzoylaminophenyl)-1acid Ethyl 2-(4-benzoylaminophenyl)-l-cyclopentylbenzimidazole-5carboxylate (200 mg) obtained in Example 23 was treated in the 160 same manner as in Example 2 to give the title compound (131 mg, yield melting point: not lower than 300 0

C

FAB-Ms: 426(MH+) 1 H-NMR (300MHz, DMSO-d 6 10.75(1H, 8.35(1H, s), 8.15and7.85(4H, ABq, J=8.9Hz), 8.10-7.98(4H, 7.70-7.55(3H, m), 5.02(1H, quint, J=8.7Hz), 2.36-2.15(4H, 2.14-1.95(2H, m), 1.80-1.62(2H, m) Example Production of ethyl 2- 4-[3-(3-chlorophenyl)phenoxy]phenyl -1- Ethyl 2-[4-(3-bromophenoxy)phenyl]-1- (65 g) obtained in Example 1 and 3-chlorophenylboronic acid (23 g) were treated in the same manner as in Example 5 to give the title compound (59 g, yield 1H-NMR (300MHz, CDC1 3 8.51(1H, d, J=1.8Hz), 7.99(1H, dd, J=8.7, 1.8Hz), 7.71-7.55(4H, 7.51-7.43(2H, 7.43-7.27(4H, m), 7.19(1H, d, J=8.4Hz), 7.12(1H, 4.41(2H, q, J=7.2Hz), 4.39(1H, 2.42-2.22(2H, 2.03-1.87(4H, 1.79(1H, 1.42(3H, t, J=7.2Hz), 1.39-1.29(3H, m) Example 26 Production of 2- 4- 3- (3-chlorophenyl)phenoxy]phenyld-1acid Ethyl 2- 4-[3-(3-chlorophenyl)phenoxy]phenyl k-1- (59 g) obtained in Example was treated in the same manner as in Example 2 to give the title compound (43 g, yield 76%).

melting point: 253-254°C FAB-Ms: 523(MH+) IH-NMR (300MHz, DMSO-d 6 12.82(1H, brs), 8.24(1H, d, J=1.3Hz), 7.98(1H, d, J=8.7Hz), 7.89(1H, dd, J=8.7, 1.3Hz), 7.78(1H, s), 7.72(2H, d, J=9.7Hz), 7.70(lH, 7.64-7.42(5H, 7.25(2H, d, J=8.7Hz), 7.20(1H, 4.33(1H, 2.39-2.17(2H, 2.00- 1.76(4H, 1.65(1H, 1.50-1.22(3H, m) Example 27 Production of ethyl 2- [4-(3-acetoxyphenyloxy)phenyl]-1- 161 In the same manner as in Example 1, the title compound (87 g) was obtained.

Example 28 Production of ethyl 1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)- 'Ethyl 2-[4-(3-acetoxyphenyloxy)phenyl]-l- (87 g) obtained in Example 27 was dissolved in methyl alcohol (250 ml) and tetrahydrofuran (250 ml), and potassium carbonate (31 g) was added. The mixture was stirred for 30 min at room temperature. The. insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was neutralized with 2N hydrochloric acid. The precipitated crystals were collected by filtration to give the title compound (78 g, yield 97%).

H-NMR (300MHz, DMSO-d 6 9.71(1H, 7.98(1H, d, J=8.7Hz), 7.87(1H, d, J=8.7Hz), 7.68(2H, d, J=8.6Hz), 7.24(1H, t, J=8.1Hz), 7.18(2H, d, J=8.6Hz), 6.63(1H, d, J=8.1Hz), 6.57(1H, d, J=8.1Hz), 6.51(1H, 4.38-4.23(1H, 4.35(2H, q, J=6.9Hz), .2.36-2.18(2H, 1.99-1.78(4H, 1.71-1.59(1H, 1.45-1.20(3H, 1.36(3H, t, J=6.9Hz) Example 29 Production of ethyl 1-cyclohexyl-2-14-[3-(4-pyridylmethoxy)phenyloxy]phenyl Ethyl 1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)phenyl]- (78 g) obtained in Example 28 was suspended in dimethylformamide (800 ml), and sodium hydride oil, 14 g) was added under ice-cooling. The mixture was stirred for 1 hr at room temperature. After the reaction mixture was icecooled, 4-chloromethylpyridine hydrochloride (29 g) was added and the mixture was stirred for 30 min. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture and the precipitated crystals were collected by filtration. The resulting crystals were recrystallized from ethyl alcohol to give the title compound (77 g, yield 82%).

H-NMR (300MHz, CDC13): 8.63(2H, d, J=6.0Hz), '8.51(1H, 7.99(1H, d, J=8.7Hz), 7.66(2H, d, J=8.7Hz), 7.62(2H, d, J=8.7Hz), 7.36(2H, d, J=8.7Hz), 7.31(1H, t, J=8.2Hz), 7.26(1H, 7.16(2H, d, 162 J=8.7Hz), 6.79-6.70(3H, 5.09(2H, 4.47-4.31(1H, m), 4.42(2H, q, J=7.0Hz), 2.42-2.22(2H, 2.04-1.71(5H, 1.45- 1.25(3H, 1.42(3H, t, Example Production of 1-cyclohexyl-2- 4-[3-(4-pyridylmethoxy)phenyloxy]phenyl benzimidazole-5-carboxylic acid Ethyl 1-cyclohexyl-2- 4-(43-(4-pyridylmethoxy)phenyloxy]- (60 g) obtained in Example 29 was treated in the same manner as in Example 2 to give the title o1 compound (54 g, yield melting point: 235-237°C FAB-Ms: 520(MH+) H-NMR (300MHz, DMSO-d 6 8.58(2H, d, J=6.0Hz), 8.23(1H, 7.96 and 7.86(2H, ABq, J=8.7Hz), 7.68 and 7.17(4H, A'B'q, J=8.7Hz), 7.44(2H, d, J=8.7Hz), 7.39(1H, t, J=8.3Hz), 6.90(1H, d, J=8.1Hz), 6.84(1H, 6.75(1H, d, J=8.1Hz), 5.22(2H, 4.40-4.22(1H, m), 2.40-2.19(2H, 2.00-1.80(4H, m) Example 241 Production of methyl 2-i4-[2-(4-chlorophenyl)-5methoxybenzyloxy]phenyl Step 1: Production of 3-Methoxybenzaldehyde (15 g) was dissolved in acetic acid ml), and a solution of bromine (5.7 ml) dissolved in acetic acid (15 ml) was added dropwise. The mixture was stirred overnight at room temperature and water (150 ml) was added to the reaction mixture. The precipitated crystals were collected by filtration, washed with water and dried under reduced pressure to give the title compound (21 g, yield 88%).

H-NMR (300MHz, CDC1 3 10.31(1H, 7.52(1H, d, J=8.8Hz), 7.41(1H, d, J=3.3Hz), 7.03(1H, dd, J=8.8, 3.3Hz), 3.48(3H, s) Step 2: Production of 2-(4-chlorophenyl)-5-methoxybenzaldehyde (10 g) obtained in the previous step was treated in the same method as in Example 5 to give the title compound (11 g, yield 96%).

1H-NMR (300MHz, CDC13): 9.92(1H, 7.50(1H, d, J=2.6Hz), 7.48- 7.14(6H, 3.90(3H, s) Step 3: Production of 2-(4-chlorophenyl)-5-methoxybenzyl alcohol 163 2-(4-Chlorophenyl)-5-methoxybenzaldehyde (10 g) obtained in the previous step was dissolved in tetrahydrofuran (30 ml). The solution was added dropwise to a suspension of sodium borohydride (620 mg) in isopropyl alcohol (50 ml) and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure and water was added to the residue. The precipitated crystals were collected by filtration and dried under reduced pressure. The resulting crystals were recrystallized from a mixture of methanol and water to give the title compound (9.2 g, yield 91%).

i0 1 H-NMR (300MHz, CDCI 3 7.37(2H, d, J=8.6Hz), 7.27(2H, d, J=8.6Hz), 7.17(1H, d, J=8.6Hz), 7.11(1H, d, J=2.6Hz), 6.89(1H, dd, J=8.6, 2.6Hz), 4.57(2H, 3.86(3H, s) Step 4: Production of 2-(4-chlorophenyl)-5-methoxybenzyl chloride 2-(4-Chlorophenyl)-5-methoxybenzyl alcohol (20 g) obtained in the previous step was dissolved in ethyl acetate (100 ml) and pyridine (0.5 ml), and thionyl chloride (11 ml) was added dropwise. The mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Isopropyl alcohol was added to the residue to allow crystallization. The resulting crystals were collected by filtration and dried under reduced pressure to give the title compound (16 g, yield 74%).

H-NMR (300MHz, CDCl 3 7.43-7.29(4H, 7.17(1H, d, J=8.6Hz), 7.05(1H, d, J=2.6Hz), 6.96-6.89(IH, 4.46(2H, 3.86(3H, s) Step 5: Production of methyl 2- 4-[2-(4-chlorophenyl)-5methoxybenzyloxy]phenyl 2-(4-Chlorophenyl)-5-methoxybenzyl chloride (4.0 g) obtained in the previous step and methyl l-cyclohexyl-2-(4-hydroxyphenyl)- (5.0 g) obtained in the same manner as in Example 3 were treated in the same manner as in Example 4 to give the title compound (6.0 g, yield 72%).

H-NMR (300MHz, CDCI 3 8.48(1H, 8.00-7.93(1H, 7.68- 7.62(1H, 7.54(2H, d, J=9.0Hz), 7.41-7.16(6H, 7.04-6.93(3H, 4.97(2H, 4.36(1H, 3.94(3H, 3.87(3H, 2.39- 2.21(2H, 2.02-1.88(4H, 1.85-1.45(4H, m) 164 Example 242 Production of 2-44-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyljacid hydrochloride Methyl 2-4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl l-cyclohexylbenzimidazole-5-carboxylate (5.0 g) obtained in Example 241 was treated in the same manner as in Example 2 to give the title compound (5.1 g, yield 98%).

APCI-Ms: 568(MH+) H-NMR (300MHz, DMSO-d 6 8.30(1H, d, J=1.4Hz), 8.24(1H, d, J=8.7Hz), 8.03(1H, d, J=8.7Hz), 7.72(2H, d, J=8.7Hz), 7.51- 7.39(4H, 7.34-7.18(4H, 7.11-7.03(1H, 5.08(2H, s), 4.35(1H, 3.83(3H, 2.40-2.18(2H, 2.10-1.96(2H, m), 1.93-1.78(2Hm), 1.72-1.18(4H, m) Example 243 Production of ethyl 2- 4-[3-(4-chlorophenyl)pyridin-2- Step 1: Production of methyl 3-hydroxypicolinate 3-Hydroxypicolinic acid (1.0 g) was suspended in methanol ml) and concentrated sulfuric acid (1.0 ml) was added. The mixture was refluxed under heating for 5 hr. The reaction mixture was ice-cooled, neutralized with saturated aqueous sodium hydrogencarbonate, and extracted with chloroform. The.organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (711 mg, yield 64%).

1 H-NMR (300MHz, CDC1 3 10.63(1H, 8.28(1H, dd, J=3.7, 1.8Hz), 7.47-7.35(2H, 4.06(3H, s) Step 2: Production of methyl 3-(trifluoromethylsulfonyloxy)pyridine-2-carboxylate Methyl 3-hydroxypicolinate (710 mg) obtained in the previous step and triethylamine (0.77 ml) were dissolved in dichloromethane (7 ml), and trifluoromethanesulfonic anhydride (0.86 ml) was added under ice-cooling. The reaction mixture was allowed to warm to room temperature and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

165 The solvent was evaporated under reduced pressure to give the title compound (1.2 g, yield 1H-NMR (300MHz, CDCI 3 8.80-8.73(1H, 7.75-7.70(1H, m), 7.63(1H, dd, J=8.2, 4.5Hz), 4.05(3H, s) Step 3: Production of methyl 3-(4-chlorophenyl)pyridine-2carboxylate Methyl 3-(trifluoromethylsulfonyloxy)pyridine-2-carboxylate (1.2 g) obtained in the previous step was treated in the same manner as in Example 5 to give the title compound (728 mg, yield 69%).

1 H-NMR (300MHz, CDC13): 8.73-8.66(1H, 7.77-7.68(1H, m) 7.49(1H, dd, J=7.8, 4.5Hz), 7.46-7.37(2H, 7.32-7.23(2H, m), 3.80(3H, s) Step 4: Production of [3-(4-chlorophenyl)pyridin-2-yl]methanol is Methyl 3-(4-chlorophenyl)pyridine-2-carboxylate (720 mg) obtained in the previous step was dissolved in tetrahydrofuran ml) and the solution was ice-cooled. Lithium aluminum hydride (160 mg) was added to the solution and the mixture was stirred for 1 hr. To the reaction mixture were added successively water (1.6 ml), 15% sodium hydroxide (1.6 ml) and water (4.8 The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by.

silica gel flash chromatography (developing solvent, nhexane:ethyl acetate 1:1) to give the title compound (208 mg, yield 32%).

H-NMR (300MHz, CDCI3): 8.60(1H, dd, J=4.8, 1.5Hz), 7.60-7.55(1H, 7.40-7.48(2H, 7.29-7.36(1H, 7.27-7.20(3H, 4.63(2H, s) Step 5: Production of ethyl 2- 4-[3-(4-chlorophenyl)pyridin-2ylmethoxy]phenyl [3-(4-Chlorophenyl)pyridin-2-yl]methanol (200 mg) obtained in the previous step was dissolved in chloroform (3 ml), and thionyl chloride (0.13 ml) and pyridine (catalytic amount) were added. The mixture was stirred for 1 hr at room temperature and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (3 ml), and ethyl l-cyclohexyl-2-(4- (232 mg) obtained in the same manner as in Example 3 and potassium carbonate (250 mg) 166 were added. The mixture was stirred for 3 hr with heating at 80 0

C.

The reaction mixture was then allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 1:2) to give the title compound (246 mg, yield 68%).

1H-NMR (300MHz, CDC13): 8.71(1H, dd, J=4.7, 1.4Hz), 8.49(1H, d, o1 J=2.1Hz), 7.96(1H, d, J=10.2Hz), 7.71-7.62(2H, 7.53(2H, d, J=8.7Hz), 7.45-7.34(5H, 7.04(2H, d, J=8.7Hz), 5.14(2H, s), 4.48-4.29(3H, 2.38-2.19(2H, 2.02-1.22(11H, m) Example 244 Production of methyl 2-[4-(2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl] Step 1: Production of tert-butyl 4-bromo-3-methylbenzoate 4-Bromo-3-methylbenzoic acid (25 g) was suspended in dichloromethane (200 ml), and oxalyl chloride (12 ml) and dimethylformamide (catalytic amount) were added. The mixture was stirred for 2 hr at room temperature .and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (200 ml) and the solution was ice-cooled. To the solution was added dropwise a solution of potassium tert-butoxide dissolved in tetrahydrofuran (150 ml) and the mixture was stirred for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (27 g, yield 1 H-NMR (300MHz, CDCl 3 7.83(1H, d, J=2.2Hz), 7.67-7.53(2H, m), 2.43(3H, 1.58(9H, s) Step 2: Production of methyl 2-[4-(2-bromo-5-tertcarboxylate tert-Butyl 4-bromo-3-methylbenzoate (7.0 g) obtained in the previous step and methyl l-cyclohexyl-2-(4-hydroxyphenyl)- (6.3 g) obtained in the same manner 167 as in Example 3 were treated in the same manner as in Example 4 to give the title compound (8.8 g, yield 77%).

H-NMR (300MHz, CDCl3): 8.49(1H, d, J=1.5Hz), 8.21(1H, d, J=2.1Hz), 7.97(1H, d, J=10.2Hz), 7.82(1H, d, J=10.2Hz), 7.71-7.58(4H, m), 7.16(2H, d, J=8.7Hz), 5.23(2H, 4.38(1H, 3.95(3H, s), 2.40-2.23(2H, 2.04-1.90(4H, 1.84-1.73(1H, 1.59(9H, s), 1.44-1.27(3H, m) Example 245 Production of methyl 2-44-[5-tert-butoxycarbonyl-2-(4o1 chlorophenyl)benzyloxy]phenyl carboxylate Methyl 2-[4-(2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl]- (4.5 g) obtained in Example 244 was treated in the same manner as in Example 5 to is give the title compound (3.6 g, yield 76%).

H-NMR (300MHz, CDC13): 8.48(1H, 8.27(1H, d, J=1.8Hz), 8.04(1H, dd, J=7.9, 1.5Hz), 7.96(1H, dd, J=7.0, 1.5Hz), 7.65(1H, d, J=8.6Hz), 7.55(2H, d, J=8.6Hz), 7.43-7.32(5H, 7.01(2H, d, J=8.6Hz), 4.99(2H, 4.43-4.29(1H, 3.95(3H, 2.41- 2.21(2H, 2.02-1.89(4H, 1.82-1.73(1H, 1.62(9H, s), 1.46-1.28(3H, m) Example 246 Production of methyl 2- 4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenyl hydrochloride Methyl 2-14-[5-tert-butoxycarbonyl-2-(4-chlorophenyl)benzyloxy]phenyl -l-cyclohexylbenzimidazole-5-carboxylate (3.5 g) obtained in Example 245 was dissolved in dichloromethane (35 ml), and trifluoroacetic acid (35 ml) was added. The mixture was stirred for 1 hr at room temperature and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate,-and 4N hydrochloric acid-ethyl acetate was added.

The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (3.3 g, yield 97%).

H-NMR (300MHz, DMSO-d 6 8.33(1H, d, J=1.5Hz), 8.29(1H, s), 8.24(1H, d, J=1.8Hz), 8.09-8.00(2H, 7.74(2H, d, J=8.6Hz), 168 7.61-7.44(5H, 7.24(2H, d, J=8.6Hz), 5.19(2H, 4.36(1H, m), 3.93(3H, 2.37-1.21(10H, m) Example 247 Production of methyl 2-4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]phenyl Methyl 2-4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenylhydrochloride (400 mg) obtained in Example 246 was suspended in dichloromethane (5 ml), and oxalyl chloride (0.08 ml) and dimethylformamide (catalytic o0 amount) were added. The mixture was stirred for 2 hr at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (5 ml).

The resulting solution was added dropwise to a mixed solution of aqueous methylamine solution (5 ml) and tetrahydrofuran ml) under ice-cooling. The reaction mixture was stirred for 1 hr and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water,.saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate and diisopropyl ether. The crystals were collected by filtration and dried under reduced pressure to give the title compound (335 mg, yield 86%).

H-NMR (300MHz, CDC13): 8.47(1H, 8.06(1H, d, J=1.8Hz), 7.96(1H, dd, J=8.6, 1.5Hz), 7.82(1H, dd, J=8.2, 2.2Hz), 7.64(1H, d, J=8.6Hz), 7.54(2H, d, J=9.0Hz), 7.44-7.31(5H, 6.99(2H, d, 6.35-6.26(1H, 5.00(2H, 4.35(1H, 3.95(3H, s), 3.05(3H, d, J=4.8Hz), 2.40-1.24(10H, m) Example 248 Production of 2-\4-[2-(4-chlorophenyl)-5methylcarbamoylbenzyloxy]phenyl carboxylate hydrochloride Methyl 2- 4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]phenyl -l-cyclohexylbenzimidazole-5-carboxylate (150 mg) obtained in Example 247 and tetrahydrofuran (2 ml) were treated in the same manner as in Example 2 to give the title compound (141 mg, yield 169 APCI-Ms: 594(MH+) 1 H-NMR (300MHz, DMSO-d 6 8.65-8.58(1H, 8.27(1H, d, 8.21(1H, d, J=8.2Hz), 8.15(1H, d, J=1.5Hz), 8.05-7.90(2H, m), 7.70(2H, d, J=8.6Hz), 7.56-7.43(5H, 7.21(2H, d, J=8.6Hz), 5.14(2H, 4.34(1H, 2.81(3H, d, J=4.5Hz), 2.39-1.19(10H, m) Example 336 Production of methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2- Commercially available 2-bromo-5-nitrotoluene was o1 dissolved in carbon tetrachloride (30 ml), and N-bromosuccinimide (2.9 g) and N,N'-azobisisobutyronitrile (228 mg) were added, which was followed by refluxing under heating overnight. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was is dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (30 ml) and methyl 2-(2-fluoro-4-hydroxyphenyl)-1- (3.8 g) obtained in the same manner as in Example 3 and potassium carbonate (3.8 g) were added, which was followed by stirring at 80 0 C for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (nhexane:ethyl acetate 1:1) to give the title compound (3.7 g, yield 61%).

1H-NMR (300MHz, CDC1 3 8.55-8.45(2H, 8.15-8.05(1H, m), 7.99(1H, dd, J=8.6Hz, 1.5Hz), 7.70-7.55(2H, 7.05-6.85(2H, m), 5.24(2H, 4.06(1H, 3.95(3H, 2.35-2.15(2H, 2.05- 1.85(4H, 1.80-1.70(1H, 1.45-1.20(3H, m) Example 337 Production of methyl 2-[4-i2-(4-chlorophenyl)-5-nitrobenzyloxy-2- Methyl 2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl] -1- (2.0 g) obtained in Example 336, 4-chlorophenylboronic acid (590 mg) and tetrakis(triphenylphosphine)palladium (396 mg) were suspended in 170 dimethoxyethane (40 ml), and saturated aqueous sodium hydrogencarbonate solution (20 ml) was added, which was followed by refluxing under heating for 1 hr. The reaction mixture was allowed to cool, water was added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (nhexane:ethyl acatate 2:1) to give the title compound (1.9 g, yield 'H-NMR (300MHz, CDC1 3 8.55(1H, d, J=2.3Hz), 8.49(1H, d, J=1.4Hz), 8.29(1H, dd, J=8.4Hz, 2.3Hz), 7.98(1H, dd, J=8.6Hz, 1.5Hz), 7.60- 7.30(6H, 6.85-6.70(2H, 5.03(2H, 4.02(1H, 3.95(3H, 2.35-2.10(2H, 2.05-1.70(5H, 1.40-1.20(3H, m) Example 338 is Production of methyl 2-[4-45-amino-2-(4-chlorophenyl)benzyloxy-2- Methyl 2-[4-42-(4-chlorophenyl)-5-nitrobenzyloxy-2- (1.9 g) obtained in Example 337 was suspended in ethanol (40 ml), and tin(II) chloride dihydrate (3.5 g) was added, which was followed by refluxing under heating for 30 min. The reaction mixture was concentrated under reduced pressure, 4N sodium hydroxide was added and the mixture was extracted with chloroform. The organic layer was washed with 2N sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (1.5 g, yield 82%).

1 H-NMR (300MHz, CDCl 3 8.49(1H, d, J=1.2Hz), 7.98(1H, dd, 1.5Hz), 7.66(1H, d, J=8.7Hz), 7.49(1H, t, J=8.4Hz), 7.40-7.20(3H, m),7.13(1H, d, J=8.1Hz), 6.92(1H, d, J=2.7Hz), 6.85-6.65(4H, m), 4.92(2H, 4.03(1H, 3.95(3H, 3.82(2H, brs), 2.30- 2.10(2H, 2.05-1.80(4H, 1.80-1.70(1H, 1.40-1.10(3H, m) Example 339 Production of methyl 2-[4-12-(4-chlorophenyl)-5-(2-oxopyrrolidincarboxylate Methyl 5-amino-2- (4-chlorophenyl)benzyloxy-2- (500 mg) obtained in Example 338 and triethylamine (0.14 ml) were dissolved in chloroform (5 ml), and commercially available chlorobutyryl chloride (0.1 ml) was added under ice-cooling, which was followed by stirring at room temperature for 3 hr.

Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate o1 and concentrated under reduced pressure. The residue was dissolved in dimethylformamide (6 ml) and potassium carbonate (244 mg) was added, which was followed by stirring at 80'C for 1 hr. The reaction mixture was allowed to cool, water was added and the precipitated crystals were collected by filtration to give the title compound (502 mg, yield 89%).

1 H-NMR (300MHz, CDC13): 4.89(1H, d, J=1.5Hz), 7.98(1H, dd, J=8.6Hz, 1.6Hz), 7.72(1H, d, J=2.2Hz), 7.75-7.65(2H, 7.49(1H, t, J=8.3Hz), 7.45-7.20(5H, 6.85-7.65(2H, 4.99(2H, 4.10- 3.85(6H, 2.66(2H, J=7.8Hz), 2.30-2.15(4H, 2.00-1.85(4H, 1.80-1.70(1H, 1.45-1.20(3H, m) Example 340 Production of 2-(4-chlorophenyl)-5-(2-oxopyrrolidin-lyl)benzyloxy)-2-fluorophenyll carboxylic acid hydrochloride Methyl 2-(4-chlorophenyl)-5-(2-oxopyrrolidin-lcarboxylate (200 mg) obtained in Example 339 was treated in the same manner as in Example 2 to give the title compound (182 mg, yield 87%).

Ms:638(M+1) 'H-NMR (300MHz, CDCI 3 8.28(1H, d, J=1.3Hz), 8.10(1H, d, J=8.7Hz), 8.05-7.90(2H, 7.77(1H, dd, J=8.4Hz, 2.2Hz), 7.61(1H, t, 7.55-7.35(5H, 7.00-7.20(2H, 5.09(2H, s), 4.06(1H, 3.90(2H, t, J=6.9Hz), 2.60-2.45(2H, 2.30-2.00(4H, 1.95-1.75(4H, 1.70-1.55(1H, 1.45-1.15(3H, m) Example 340-2 Step 1: Production of 4'-chloro-4-nitro-biphenyl-2-carbaldehyde 172 To a solution of 2-chloro-5-nitrobenzaldehyde (100 g) in 1,2-dimethoxyethane (1000 ml) were added 4-chlorophenylboronic acid (93 bistriphenylphosphine palladium(II) dichloride (380 mg), sodium hydrogencarbonate (68 g) and water (500 ml), and the mixture was refluxed for 1 hr. The reaction mixture was cooled to 0 C, ethyl acetate (1000 ml) was added thereto and the mixture was stirred. The aqueous layer was separated and the organic layer was washed with water (500 ml), IN aqueous sodium hydroxide solution (500 ml), water (500 ml), 28% aqueous ammonia (500 ml), o1 water (500 ml), 2N hydrochloric acid (500 ml) and saturated brine (500 ml), dried over.anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was suspended in diisopropyl ether (500 ml), filtrated and vacuum dried to give the title compound (120 g, yield 1 H-NMR (300MHz, DMSO-d 6 9.92(1H, 8.61 (1H, d, 8.53(1H, dd, J=2.6Hz, .8.5Hz), 7.82(1H, d, J=8.5Hz), 7.64(2H, d, J=8.7Hz), 7.59(2H, d, J=8.7Hz) Step 2: Production of (4'-chloro-4-nitro-biphenyl-2-yl)methanol A solution of 4'-chloro-4-nitro-biphenyl-2-carbaldehyde (120 g) obtained in the previous step in tetrahydrofuran (900 ml) was added dropwise to a suspension of sodium borohydride (47 g) in 2propanol (600 ml), over 70 min under water-cooling. The reaction mixture was stirred at room temperature for 1 hr, and 2N hydrochloric acid (185 ml) was dropwise added thereto over 40 min under water-cooling. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was suspended in 2-propanol (300 ml), and water (1000 ml) was added with stirring. After stirring the mixture for 30 min, the crystals were collected by filtration and vacuum dried to give the title compound (116 g, yield 96%).

1 H-NMR (300MHz, DMSO-d): 8.43(1H, d, J=2.5Hz), 8.19(1H, dd, J=2.6Hz, 8.4Hz), 7.57(2H, d, J=8.5Hz), 7.52(1H, d, J=8.4Hz), 7.47(2H, d, J=8.6Hz), 5.59(1H, brs), 4.48(2H, s) Step 3: Production of (4-amino-4'-chloro-biphenyl-2-yl)methanol To a suspension of (4'-chloro-4-nitro-biphenyl-2-yl)methanol g) obtained in the previous step and sodium hydrosulfite g) in N,N-dimethylformamide (4 ml) and methanol (1 ml) was added water (0.3 ml, 50 pl each time in 6 portions) every 20 min 173 at 100 0 C. Water (5 ml) was added threto at room temperature.

Cone. hydrochloric acid (2.5 ml) was added threto at room temperature. The mixture was stirred at 55°C for 2.5 hr, and a solution of sodium hydroxide (1.2 g) in water (3 ml) was added under ice-cooling. Water (5 ml) was added and the mixture was stirred at room temperature for 1 hr. The precipitate was filtrated and washed with water (3 ml). The crystals were vacuum dried to give the title compound (700 mg, yield 79%).

1H-NMR (400MHz, DMSO-ds): 7.39(2H, d, J=8.5Hz), 7.35(2H, d, J=8.5Hz), 6.90(1H, d, J=8.4Hz), 6.82(1H, 6.56(1H, d, J=8.4Hz), 5.20(2H, brs), 5.04(1H, t, J=5.4Hz), 4.29(2H, d, .J=5.4Hz) Step 4: Production of 4-chloro-N-(4'-chloro-2-hydroxymethylbiphenyl-4-yl)butyramide To a solution of (4-amino-4'-chloro-biphenyl-2-yl)-methanol (1.0 g) obtained in the previous step in tetrahydrofuran (10 ml) were added sodium acetate (390 mg) and acetic acid (0.27 ml) at room temperature.

4-Chlorobutyryl chloride (0.48 ml) was gradually added dropwise under ice-cooling. After stirring the mixture at room temperature for 30 min, water (20 ml) and ethyl acetate (20 ml) were added to the reaction mixture and the organic layer was separated. The organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml) and saturated brine (20 ml). The organic layer was dried over sodium sulfate, filtrated and the solvent was evaporated to give the title compound (1.44 g, yield 99%).

IH-NMR (300MHz, CDCI 3 7.68(1H, 7.55(1H, d, J=8.4Hz), 7.39(2H, d, J=8.5Hz), 7.28(2H, d, J=8.5Hz), 7.22(1H, d, J=8.3Hz), 4.58(2H, 3.69(2H, t, J=6.1Hz), 2.60(2H, t, J=7.0Hz), 2.22(2H, m) Step 5: Production of 1-(4'-chloro-2-hydroxymethyl-biphenyl-4yl)-2-pyrrolidinone To a solution of 4-chloro-N-(4'-chloro-2-hydroxymethylbiphenyl-4-yl)butyramide (1.44 g) obtained in the previous step in N,N-dimethylformamide (15 ml) was added potassium carbonate (710 mg) at room temperature. After stirring the mixture at 100°C for 90 min, IN hydrochloric acid (5 ml) and water (20 ml) were added at room temperature and the precipitated crystals were collected by filtration and washed with water (5 ml). The 174 crystals were vacuum dried to give the title compound (970 mg, yield 76%).

1H-NMR (300MHz, CDCl 3 7.76(1H, d, J=2.3Hz), 7.62(1H, dd, J=2.4Hz, 8.3Hz), 7.38(2H, d, J=8.5Hz), 7.29(2H, d, J=8.5Hz), 7.25(1H, d, J=8.3Hz), 4.61(2H, 3.91(2H, t, J=7.0Hz), 2.62(2H, t, J=7.8Hz), 2.18(2H, m) Step 6: Production of 1-(4'-chloro-2-chloromethyl-biphenyl-4-yl)- 2-pyrrolidinone To a mixed solution of l-(4'-chloro-2-hydroxymethylo0 biphenyl-4-yl)-2-pyrrolidinone (900 mg) obtained in the previous step in N,N-dimethylformamide (2 ml) and toluene (7 ml) was dropwise added thionyl chloride (0.26 ml) under ice-cooling.

After stirring the mixture at room temperature for 3 hr, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml), saturated aqueous sodium hydrogencarbonate (20 ml) and saturated brine (20 ml). The organic layer was dried over sodium sulfate, filtrated and the solvent was evaporated under reduced pressure to give the title compound (954 mg, yield 99%).

H-NMR (300MHz, CDC1 3 7.77(1H, d, J=2.3Hz), 7.69(1H, dd, J=2.4Hz, 8.5Hz),7.42(2H, d, J=8.6Hz), 7.34(2H, d, J=8.6Hz), 7.26(1H, d, J=8.4Hz), 4.50(2H, 3.92(2H, t, J=7.0Hz), 2.65(2H, t, J=7.8Hz), 2.20(2H, m) Step 7: Production of methyl 2-[4-{2-(4-chlorophenyl)-5-(2oxopyrrolidin-1-yl)benzyloxy}-2-fluorophenyl]-1- To a suspension of methyl l-cyclohexyl-2-(2-fluoro-4- (915 mg) obtained in Example 18 in N,N-dimethylformamide (6 ml) was added chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone (954 mg) obtained in the previous step and potassium carbonate (415 mg) at room temperature. After stirring the mixture at 100 0 C for 1 hr, IN hydrochloric acid (3 mi) and water (8 ml) were added at room temperature and the precipitated crystals were collected by filtration and washed with water (5 ml). The crystals were vacuum dried to give the title compound (1.6 g, yield 100%).

'H-NMR (300MHz, CDC1 3 8.49(1H, d, J=1.5Hz), 7.98(1H, dd, J=1.6Hz, 8.6Hz), 7.90(1H, d, J=2.2Hz), 7.72-7.65(2H, 7.49(1H, t, 175 J=8.3Hz), 7.40(2H, d, J=8.5Hz), 7.34(1H, d, J=8.7Hz), 7.31(2H, d, J=8.6Hz), 6.80 (1H, d, J=8.6Hz), 6.71(1H, d, J=11.6Hz), 4.99(2H, 4.04(1H, 3.95(3H, 3.93(2H, t, J=7.1Hz), 2.66(2H, t, J=7.8Hz), 2.30-2.15(4H, 2.00-1.85(4H, 1.80-1.70(1H, m), 1.45-1.20(3H, m) Step 8: Production of 2-[4-(2-(4-chlorophenyl)-5-(2oxopyrrolidin-1-yl)benzyloxy}-2-fluorophenyl]-1acid Methyl 2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-lyl) carboxylate (2.0 g) obtained in the previous step was suspended in methanol (4.0 ml) and tetrahydrofuran (8.0 ml), and 2N aqueous sodium hydroxide solution (2.3 ml) was added. The mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool and tetrahydrofuran (1.0 ml) and water (5.0 ml) were added.

2N Hydrochloric acid (2.3 ml) was gradually added at room temperature. After stirring the mixture at room temperature for. 2 hr, the precipitated crystals were collected by filtration and washed successively with methanol-water mixed solution ml), water (6.0 ml) and methanol-water mixed solution ml), and vacuum dried to give the title compound (1.84 g, yield 94%).

1H-NMR (300MHz, DMSO-d 6 12.75(1H, brs), 8.26(1H, 7.99(1H, s), 7.96(1H, d, J=9.0Hz), 7.89(1H, d, J=9.0Hz), 7.78(1H, dd, J=2.1Hz, 8.4Hz), 7.54(1H, t, J=9.0Hz), 7.49(2H, d, J=8.7Hz), 7.45(2H, d, J=8.4Hz), 7.38(1H, d, J=8.4Hz), 7.08(1H, dd, J=2.1Hz, 12.0Hz), 6.96(1H, dd, J=2.1Hz, 8.7Hz), 5.09(2H, 3.99(1H, 3.91(2H, t, J=6.6Hz), 2.54(2H, t, J=7.8Hz), 2.30-2.00(4H, 1.95-1.50(5H, 1.45-1.20(3H, m) Step 9: Production of 2-[4-{2-(4-chlorophenyl)-5-(2oxopyrrolidine-1-yl)benzyloxy}-2-fluorophenyl]-1acid hydrochloride To 4N hydrochloric acid (50 ml) were successively added 2- [4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2fluorophenyl]-l-cyclohexylbenzimidazole-5-carboxylic acid (10.0 g) obtained in the previous step and acetone-methyl ethyl ketone mixed solution (20 ml). The mixture was stirfed at 60 0 C for 3 hr and at room temperature for 1 hr. The crystals were 176 collected by filtration, washed twice with acetone (10 ml) and vacuum dried to give the title compound (9.62 g, yield 91%).

melting point: 243-246 0

C

Ms: 638(M+l) 'H-NMR (300MHz, DMSO-d6): 8.33(1H, d, J=1.lHz), 8.21(1H, d, J=8.8Hz), 8.02(1H, d, J=8.8Hz), 8.00(1H, d, J=2.2Hz), 7.77(1H, dd, J=2.2Hz, 8.4Hz), 7.68(1H, t, J=8.4Hz), 7.50(2H, d, J=8.4Hz), 7.45(2H, d, J=8.4Hz), 7.39(1H, d, J=8.4Hz), 7.20(1H, dd, J=2.2Hz, 12.1Hz), 7.06(1H, dd, J=2.2Hz, 8.8Hz), 5.11(2H, 4.13(1H, m), 3.91(2H, t, J=7.0Hz), 2.54(2H, t, J=8.1Hz), 2.40-2.05(4H, m), 2.00-1.75(4H, 1.70-1.55(1H, 1.50-1.20(3H, m) In the same manner as in Examples 1-30, 241-248 and 336- 340 and optionally using other conventional methods, where necessary, the compounds of Examples 31-240, 249-335, 341-471, is 701-703 and 1001-1559 were obtained. The chemical structures and properties are shown in Table 1 to 177, 185 to 212, 219 to 221 and 225 to 269.

Example 501 Production of methyl 2-44-[2-(4-chlorophenyl)-5methoxybenzyloxy]phenyl Step 1: Production of methyl 3-bromo-4-cyclohexylaminobenzoate 3-Bromo-4-fluorobenzoic acid (2.0 g) was dissolved in methanol (20 ml) and concentrated sulfuric acid (2 ml) was added.

The mixture was refluxed for 3 hr. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure.

The residue was dissolved in dimethyl sulfoxide (20 ml) and cyclohexylamine (10.3 ml) was added. The mixture was stirred overnight at 120 0 C. The reaction mixture was poured into aqueous citric acid solution (100 ml) and.extracted with ethyl acetate (100 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 10:1) to give the title compound (2.6 g, yield 92%).

177 H-NMR (300MHz, CDCI3): 8.10(1H, d, J=1.9Hz), 7.83(1H, dd, J=1.9Hz, 8.6Hz), 6.59(1H, d, J=8.7Hz), 4.73(1H, brd, J=7.3Hz), 3.85(3H, s), 3.38(1H, 2.10-2.00(2H, 1.90-1.20(8H, m) Step 2: Production of 4'-chloro-2-(4-iodophenoxymethyl)-4methoxybiphenyl 4-Iodophenol (5.0 g) was dissolved in acetone (50 ml), and potassium carbonate (4.7 g) and 4'-chloro-2-chloromethyl-4methoxybiphenyl (6.0 g) were added. The mixture was refluxed for hr. The reaction mixture was concentrated and 4N aqueous o1 sodium hydroxide solution (50 ml) was added. The precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to give the title compound (10.0 g, yield 98%).

'H-NMR (300MHz, CDC13): 7.52(2H, d, J=8.9Hz), 7.35(2H, d, 7.27-7.20(3H, 7.12(1H, 6.95(1H, d, J=8.5Hz), 6.62(2H, d, J=8.9Hz), 4.84(2H, 3.85(3H, s) Step 3: Production of [4-(4'-chloro-4-methoxybiphenyl-2ylmethoxy)phenylethynyl]trimethylsilane 4'-Chloro-2-(4-iodophenoxymethyl)-4-methoxybiphenyl (7.0 g) obtained in the previous step was dissolved in acetonitrile ml), and trimethylsilylacetylene (2.3 tetrakis- (triphenylphosphine)palladium complex (1.8 .copper(I) iodide (0.6 g) and triethylamine (50 ml) were added. The mixture was stirred overnight at room temperature and concentrated. Water ml) was added and the mixture was extracted with ethyl acetate ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml) and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 10:1) to give the title compound (5.1 g, yield 79%).

1H-NMR (300MHz, CDC1 3 7.37(2H, d, J=8.9Hz), 7.34(2H, d, J=8.2Hz), 7.28-7.21(3H, 7.13(lH,.s), 6.94(1H, d, J=8.2Hz), 6.75(2H, d, J=8.9Hz), 4.87(2H, 3.85(3H, 0.23(9H, s) Step 4: Production of methyl 3-[4-(4'-chloro-4-methoxybiphenyl-2ylmethoxy)phenylethynyl]-4-cyclohexylaminobenzoate [4-(4'-Chloro-4-methoxybiphenyl-2-ylmethoxy)phenylethynyl]trimethylsilane (5.1 g) obtained in the previous step was 178 dissolved in methanol (50 ml) and chloroform (50 ml), and potassium carbonate (2.5 g) was added. The mixture was stirred for 3 hr at room temperature and concentrated. Water (30 ml) was added and the mixture was extracted with ethyl acetate (50 ml).

The organic layer was washed with water (30 ml) and saturated brine (30 ml) and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to give white crystals (3.8 The white crystals (2.3 g) were dissolved in acetonitrile (10 ml), and methyl 3-bromo-4-cyclohexylaminoo0 benzoate (1.0 g) obtained in Step 1, tetrakis(triphenylphosphine)palladium complex (0.4 copper(I) iodide (0.1 g) and triethylamine (10 ml) were added. The mixture was stirred overnight at 100°C and concentrated under reduced pressure. Water ml) was added and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water (30 ml) and saturated brine (30 ml), and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 8:1) to give the title compound (0.9 g, yield 49%).

H-NMR (300MHz, CDC1 3 8.03(1H, 7.84(1H, d, J=8.7Hz), 7.42- 7.22(7H, 7.15(1H, 6.95(1H, d, J=8..2Hz), 6.85(2H, d, J=8.8Hz), 6.59(1H, d, J=8.8Hz), 5.07(1H, brs), 4.91(2H, s), 3.86(3H, 3.85(3H, 3.42(1H, 2.15-2.00(2H, 1.80- 1.20(8H, m) Step 5: Production of methyl 2- 4-[2-(4-chlorophenyl)-5- Methyl 3-[4-(4'-chloro-4-methoxybiphenyl-2-ylmethoxy)phenylethynyl]-4-cyclohexylaminobenzoate (0.5 g) obtained in the previous step was dissolved in N,N-dimethylformamide (5 ml), and copper(I) iodide (0.17 g) was added. The mixture was refluxed for 3 hr at 180 0 C. The insoluble materials were removed by filtration.

Water (10 ml) was added and the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with water (10 ml) and saturated brine (10 ml), and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography 179 (developing solvent, n-hexane:ethyl acetate 8:1) to give the title compound (0.27 g, yield H-NMR (300MHz, CDC1 3 8.34(1H, 7.85(1H, d, J=8.8Hz), 7.62(1H, d, J=8.8Hz), 7.40-7.18(8H, 7.00-6.94(3H, 6.48(1H, s), 4.95(2H, 4.18(1H, 3.93(3H, 3.88(3H, 2.45-2.25(2H, 1.95-1.,20(8H, m) Example 502 Production of 2-4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl 1-cyclohexyl-1H-indole-5-carboxylic acid Methyl 2- 4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl- (0.27 g) obtained in Example 501 was treated in the same manner as in Example 2 to give the title compound (0.19 g, yield 71%).

APCI-Ms: 566(MH+) 1 H-NMR (300MHz, DMSO-d 6 12.43(1H, brs), 8.20(1H, 7.79(1H, d, J=9.3Hz), 7.72(1H, d, J=9.0Hz), 7.50-7.20(8H, 7.07-7.03(3H, 6.53(1H, 5.01(2H, 4.13(1H, 3.83(3H, 2.35- 2.25(2H, 1.85-1.10(8H, m) In the same manner as in Examples 501 and 502, and optionally using other conventional methods.where necessary, the.

compound of Example 503 was obtained. The chemical structure and properties are shown in Table 207.

Example 601 Production of ethyl 2-(4-benzyloxyphenyl)-3-cyclohexylimidazo- [1,2-a]pyridine-7-carboxylate Step 1: Production of 4-benzyloxy-N-methoxy-N-methylbenzamide 4-Benzyloxybenzoic acid (5.0 g) and N,0-dimethylhydroxylamine hydrochloride (2.5 g) were suspended in dimethylformamide (50 ml), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (5.0 1-hydroxybenzotriazole g) and triethylamine (3.6 ml) were added. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (5.6 g, yield 94%).

180 1 H-NMR (300MHz, CDCl 3 7.22, 2H, d, J=8.8Hz), 7.28-7.46(5H, m), 6.97(2H, d, J=8.8Hz), 5.10(2H, 3.56(3H, 3.35(3H, s) Step 2: Production of 1-(4-benzyloxyphenyl)-2-cyclohexylethanone Magnesium (470 mg) was suspended in tetrahydrofuran (2 ml) and cyclohexylmethyl bromide (3.4 g) was added dropwise at room temperature. After the addition, the reaction mixture was stirred for 30 min at 60 0 C. The reaction mixture was allowed to cool and diluted with tetrahydrofuran (5 ml). Separately, 4-benzyloxy-Nmethoxy-N-methylbenzamide (3.4 g) obtained in the previous step o1 was dissolved in tetrahydrofuran (10 ml) and the solution was added dropwise to the reaction mixture at room temperature. The mixture was stirred for 2 hr and saturated aqueous ammonium chloride solution was added to the reaction mixture. The mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 9:1) to give the title compound (3.8 g, yield 66%).

1 H-NMR (300MHz, CDC1 3 7.93(2H, d, J=8.8Hz), 7.28-7.46(5H, m), 7.00(2H, d, J=8.8Hz), 5.13(2H, 2.76(2H, d, J=6.8Hz), 1.95(1H, 0.78-1.82(10H, m) Step 3: Production of 1-(4-benzyloxyphenyl)-2-bromo-2cyclohexylethanone 1-(4-Benzyloxyphenyl)-2-cyclohexylethanone (1.0 g) obtained in the previous step was dissolved in 1,4-dioxane (10 ml) and bromine (0.17 ml) was added. The mixture was stirred for 10 min at room temperature-. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 9:1) to give the title compound (696 mg, yield H-NMR (300MHz, CDCl3): 7.98(2H, d, J=8.9Hz), 7.28-7.48(5H, m), 7.02(2H, d, J=8.9Hz), 5.14(2H, 4.89(1H, d, J=9.3Hz), 0.86- 3.30(11H, m) 181 Step 4: Production of ethyl 2-(4-benzyloxyphenyl)-3cyclohexylimidazo[1,2-a]pyridine-7-carboxylate Ethyl 2-aminopyridine-4-carboxylate (214 mg) prepared according to JP-A-8-48651, 1-(4-benzyloxyphenyl)-2-bromo-2cyclohexylethanone (500 mg) obtained in the previous step and potassium carbonate (356 mg) were stirred for 5 hr with heating at 140°C. The reaction mixture was allowed to cool and chloroform was added. The insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was o1 purified by silica gel flash chromatography (developing solvent, n-hexane:ethyl acetate 1:1) to give the title compound (95 mg, yield 16%).

APCI-MS: 455(MH+) 1 H-NMR (300MHz, CDC1 3 8.33(1H, 8.21(1H, d, J=7.5Hz), 7.55(2H, d, J=8.7Hz), 7.25-7.50(6H, 5.13(2H, 4.41(2H, q, J=7.1Hz), 3.25(1H, 1.41(3H, t, J=7.1Hz), 1.15-2.00(10H, m) Example 602 Production of 2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2a]pyridine-7-carboxylic acid Ethyl 2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2a)pyridine-7-carboxylate (95 mg) obtained in the previous step was treated in the same manner as in Example 2 to give the title compound (33 mg, 37%).

APCI-MS: 427(MH+) 1 H-NMR (300MHz, DMSO-d 6 8.67(1H, d, J=7.3Hz), 8.08(1H, 7.25- 7.58(8H, 7.13(2H, d, J=8.7Hz), 5.17(2H, 3.23(1H, m), 1.25-2.10(10H, m) The compounds shown in Tables 213 to 218 can be further obtained in the same manner as in Examples 1 to 703 or by other conventional method employed as necessary.

The evaluation of the HCV polymerase inhibitory activity of the compound of the present invention is explained in the following. This polymerase is an enzyme coded for by the nonstructural protein region called NS5B on the RNA gene of HCV (EMBO 15:12-22, 1996).

Experimental Example [I] i) Preparation of enzyme (HCV polymerase) 182 Using, as a template, a cDNA clone corresponding to the full length RNA gene of HCV BK strain obtained from the blood of a patient with hepatitis C, a region encoding NS5B (591 amino acids; J Virol 1991 Mar, 1105-13) was amplified by PCR.

The objective gene was prepared by adding a 6 His tag Ibase pair encoding 6 continuous histidine (His)) to the 5' end thereof and transformed to Escherichia coli. The Escherichia coli capable of producing the objective protein was cultured. The obtained cells were suspended in a buffer solution containing a surfactant and 1o crushed in a microfluidizer. The supernatant was obtained by centrifugation and.applied to various column chromatographys %poly[U-Sepharose, Sephacryl S-200, mono-S (Pharmacia) inclusive of metal chelate chromatography, to give a standard enzyme product.

ii) Synthesis of substrate RNA Using a synthetic primer designed based on the sequence of HCV genomic 3' untranslated region, a DNA fragment (148 bp) containing polyU and 3'X sequence was entirely synthesized and cloned into plasmid pBluescript SK (Stratagene). The cDNA encoding full length NS5B, which was prepared in i) above, was digested with restriction enzyme KpnI to give a cDNA fragment containing the nucleotide sequence of from the restriction enzyme cleavage site to the termination codon. This cDNA fragment was inserted into the upstream of 3' untranslated region of the DNA in pBluescript SK and ligated. The about 450 bp inserted DNA sequence was used as a template in the preparation of substrate RNA. This plasmid was cleaved immediately after the 3'X sequence, linearized and purified by phenol-chloroform treatment and ethanol precipitation to give DNA.

RNA was synthesized (37 0 C, 3 hr) by run-off method using this purified DNA as a template, a promoter of pBluescript SK MEGAscript RNA synthesis kit (Ambion) and T7 RNA polymerase. DNaseI was added and the mixture was incubated for 1 hr. The template DNA was removed by decomposition to give a crude RNA product. This product was treated with phenol-chloroform and purified by ethanol precipitation to give the objective substrate

RNA.

183 This RNA was applied to formaldehyde denaturation agarose gel electrophoresis to confirm the quality thereof and preserved at iii) Assay of enzyme (HCV polymerase) inhibitory activity A test substance (compound of the present invention) and a reaction mixture (30 pl) having the following composition were reacted at 25°C for 90 min.

Trichloroacetic acid at 4°C and 1% sodium pyrophosphate solution (150 pl) were added to this reaction mixture to stop the reaction. The reaction mixture was left standing in ice for min to insolubilize RNA. This RNA was trapped on a glass filter (Whatman GF/C and the like) upon filtration by suction. This filter was washed with a solution containing 1% trichloroacetic acid and 0.1% sodium pyrophosphate, washed with 90% ethanol and dried. A liquid scintillation cocktail (Packard) was added and the radioactivity of RNA synthesized by the enzyme reaction was measured on a liquid scintillation counter.

The HCV polymerase inhibitory activity (ICs 50 of the compound of the present invention was calculated from the values of radioactivity of the enzyme reaction with and without the test substance.

The results are shown in Tables 178-184 and 222-224.

Reaction mixture HCV polymerase (5 pg/ml) obtained in i), substrate RNA (10 pg/ml) obtained in ii), ATP (50 PM), GTP pM), CTP (50 pM), UTP (2 pM), [5,6-3H]UTP (46 Ci/mmol (Amersham), pCi) 20 mM Tris-HCl (pH EDTA (1 rM), MgClz (5 mM), NaCI mM), DTT (1 mM), BSA (0.01%) Formulation Example is given in the following. This example is merely for the purpose of exemplification and does not limit the invention.

Formulation Example compound of Example 1 10 g lactose 50 g corn starch 15 g sodium carboxymethylcellulose 44 g magnesium stearate 1 g The entire amounts of and and 30 g of are kneaded with water, dried in vacuo and granulated. The obtained 184 granules are mixed with 14 g of and 1 g of and processed into tablets with a tableting machine to give 1000 tablets each containing 10 mg of 185 Table 1 Example No. 31 1H NMR(6 ppm 300MHz,CDC13 7. 81(2H, d, J=6. 6Hz), 7. 60 2H, d, 8Hz), 7. 51-7. 21 8H, 7. 11(2H, d, J=8. 8Hz) ,5.15(2H,s),4.93(1, quin t,J=8.8Hz),2.362. 32, 2. 09-2. 04 (311, 1. 1. 68 m).

Purity >9 0% (NMR) MS 369 (M+1) Example No. 32 0 Purity 9 0 (NMR) MS 441 (M+1) 11 NMR(6) ppm '300MHz,CDC13 8. 51(11, d, J=1. 5Hz), 7. 98( 11, d, J=8. 4Hz), 7. 61 d, J=8. 7Hz), 7. 56-7. 10(6H, m) 12 (2H, d, J=8. 7Hz), 5. (2H, 4. 94(1H, quint, J9 .3Hz), 4. 41(21, q, J=7. 2. 40-1. 50(8, 1. 41(3 t, JP7. Example No. Sd 0 N N PI >0INR Purity >90%q (NMR) 11 NMR(S) ppm 300MHz,CDC13 7. 84(1H, 61(2li d J=9 .0Hz), 58-7. 30(71: Z, 7.

12(2H,d, J=9.Hz), 5. 15 (2 ,s),4.94(1H,quint,J=8.71 3. 10(611, brs), 2. 40-1. 0 (8H, M) MS 440(M+1) 1 186 Table 2 Example No. 34 1H NMR(6) ppm 300MHz,CDC13 8. 20(lH, 7. 50-7.31(9H, 12(2H, d, J=8. 7Hz), 15(2H, 94(1H,quint,J 7Hz), 3.61(3H, 3. 3H,s),2.41-1.42(8H, m) Purity >90% (NMR) MS 456 (M+1) Example No.

HO N

N

Purity >90% (NMR) 18 NMR(6) ppm 300MHz,CDC13 7.91(1H. s),7.59(211, d, J=8 .7Hz), 7.49-7.30(7H, 7.

11 (2H, d,J=8.8Hz), 5. 15 (2H ,s),4.19(1H,quint J=8.8H z),2.41-2.22(2H,m), 2.13- 1.49(14H, m) MS 427 (M+1) Example No. 36 0

N

Purity 9 0% (NMR) 1H NMR(6) ppm 300MHz,CDC13 8. 40(1H, d, J=1. 4Hz), 7. 1H,dd,J=8.6, 1. 4Hz),7.61( 2H, d, J=8. 7Hz), 7.57-7. 6H, 7. 13(2H, d, J=8. 7Hz) ,5.16(2H,s),4.95(lH,quin t, J=8. 8Hz), 2. 64(3H, s),2.

54(8H,m) MS 411(M+1) 187 Table 3 Example No. 37 0

N

2HCI 1H NMR(5) ppm 300MHz,DMSO-d6 10.47(1H,brs,),9. 15(1H,b rs),8.40(111H, s),8.07(1H,d 0Hz),7. 93 (1H, d, J=8.

7Hz), 7. 77(211H, d J=8. 7Hz), 7.55-7.29(7, 5.26(2H, 93 (1H, quint, J=9. 0Hz 77-3. 63 (2H, 3. 39-3 .23(2H,m),2.84(6H,d,J=4.

8Hz), 2. 32-1. 60(81, m) Purity 9 0% (NMR) MS 483(M+1)

I

Example No.

ON 2 NN O2~%%N 0 Purity >9 0% (NMR) MS 414(M+1) IH NMR(6) ppm 300MHz,CDC13 8.69(1H,s),8. 19(1H,d, J,=9 0Hz),7.62(2H,d, J=8. 7Hz) ,7.54(1H,d J=9 0Hz),7.48 36(5H,'m, 7. 15(2H, d, J= 8. 7Hz),5. 17(2H, s),4.98(1 H, quint,J=9.0Hz),2.27-2.

07(6H,11m), 1. 82-1. 78(2H, m) Example No. 39

H

2

N

N j 0

HCI

Purity >90% (NMR) IH NMR(6) ppm 300MHz,DMSO-d6 7. 84(1H, d, J=9. OHz),7 79( 2H, d, J=8. 7Hz), 7. 52-7. 33( 8H,m),7.26(1H,d,J=9.0Hz) ,5.27(2H,s),4.92(1H, quin t J=9.3Hz),2. 19-1.70(811, m. MS 384 I 188 Table 4 Example No. 40

H

S N N Purity 9 0% (NMR) MS 426(M+1) IH NMR(6) ppm 300MHz,CDC13 7.72(1H,s), 7.60-7.35(10H 7.10(2H, d, J=8.7Hz),5 .14(2H,s),4.90(lH, uint J=8.8Hz),2. 29-2.19(2H, m) 19(3H, 19-1.74(6H m).

Example No. 41

H

Purity >90% (NMR) 1H NMR(6) ppm 300MHz,CDC13 7.66(1H,s), 7.61(2H,d,J=8 .8Hz), 7. 50-7.28(7H, 7.

12(2H,d,J=8.8Hz), 6.86(1H 15(2H,s),4.94(lH ,quint,J=8.8Hz),2.97(3H, 2. 29-1. 76(8H,m).

MS 462(M+1) Example No. 42 0 NH (S N Purity >90% (NMR) MS 448(M+) 1H NMR(6) ppm 300MHz, DMSO-d6 8. 11(1H, s),7.81(1H, d, J=8 .4Hz), 7.72 (lH, d, J=8. 4Hz) ,7.65(2H,d,J=8.4Hz),7.51 (2H, 7.43(2H, 7.37(1 H, 7.29(2H, s) 7.23 (2H, d, J=8. 4Hz), 5.22(2H, 89(1H, quintet, J=9. 2Hz), 2 1. 7 (2H,m).

189 Table Example No. 43 1H NMR(6) ppm 300MHz,DMSO-d6 8.33(1H, 08(1H, d,J=9 OHz), 7. 99(1H, d, J=9. OHz) 47-7. 41 7. 33(2H J=8. 4Hz), 5. 22(2H, s),4 .96(1H, quint, J=9. OHz), 2.

25-1. 60(8H, 30(9H11, s) Purity 9 0% (NMR) MS 469(M+1) Example No.

HOH

Purity >90% (NMR) IH NMR(6) ppm 300MHz,DMSO-d6 12.9(2H, brs), 8. 25(1H, s), 8. 00(2H, d, J=7. 8Hz), 7. 90 IH, d, J=8. 4Hz), 7. 74(1H1, d, J=8. 7Hz), 7. 67(2H, d, J=9. 0 Hz), 7.62(2H, d, J=8. 1Hz),7 .24(2H,d, J=8.4Hz),5.32(2 4. 88(1H1, quint, 0 Hz, 2.25-1. 60 (8H, m).

Ms 457(M+1) I Example No. 40 0 HO N HOPurity >0 (NM Purity 9 0% (NMR) IH NMR(6) ppm 300MHz, DMSO-d6 13.4(1H,brs),8.32(H, s), 8. 06(1H, d, J=8. 7Hz), 7. 97 1H, d, J=8. 7Hz), 7. 79 (2H, d, J=8. 8Hz), 7. 56-7. 48 (4H, m) 33 (2H, d, J=8. 8Hz), 5. 27 4.95(1H, quint, J=8 9Hz), 2. 30-1. 60 (8H, m).

MS 447 (M+1) 190 Table 6 Example No. 46 0 Purity >90 (NMR) 11 NMR(6) ppm 300MHz,DSO-d6 8.33(1H, 8.07(11, d, J=8 7Hz), 7. 98(1H, d, J=8. 7Hz) 7. 80(2H, d, J=8. 4Hz), 7. 34 d, 8. 4Hz), 7. 19(1H, d, J 6Hz), 7. 09(1H, d, J=3. 6 41 (21, s),4.95(H, intJ 8.7z),2.30-1.608 11, in).

MS 453 Example No.

0

HO

0--C 00F3 0h 1H NMR(8) ppm 300MHz,DMSO-d6 8. 33(111, 07(1H, d, J=8 4Hz), 7. 98(1H, d, J=9. 0Hz) 7. 82-7. 72 (6H, 7. 35(2 J=9. 0Hz), 5. 40(2W, s),4 .95(iH quint J=8.7Hz),2.

35-1. 608u~sH, Zi Purity >90% (NMR) MS 481(M+1) Example No. 48 0

HON

Purity >9 0% (NMR) MS 443 (M+1) 11 NMR(6) ppm 300Hz, DMSO-d6 8. 23 88(1H, d, J=8 .4Hz), 7. 70(1, i, J=8. 4Hz) 64 (2H, d, J=8. 4Hz), 7, 43 d, 4Hz), 7. 20(2, d 4Hz), 6. 98 (2H, d, J=8.

4Hz), 5. 13(2H, 4. 88 (11, quint, J8. 7Hz), 3. 77 s 2.35-1.60(8H, 191 Table 7 Example No. 49 0 HO o h HHCI Purity >90% (NMR) MS 414(M+1) 1H NMR(&) ppm 3001Hz,DMSO-dO 8. 93 (2H, d, J=6. 6Hz), 8. 1H, 8. 06-8. 04(3, 7.

97(1H d,J=8. 7Hz), 7.83(2 d, J=8. 7Hz), 7. 38(2H, d, lB 8. 7Hz), 5. 61(21, 4. 94(1 H,quint,1=8.7Hz),2.40-1.

60(8H,m).

Example No.

HO(iV-o- 0 1HNMR(6) ppm 3001Hz,DMSO-d6 8. 33 (11, 08(1H, d, J=8 .7Hz),7. 99 (1H, d, J9. 0Hz) 7. 78(2H, d, 1=8. 4Hz), 7. 39 d, J=8. 1Hz), 7. 32 (2H, d J=8. 7Hz), 7. 23 (2H, d, .P7.

8Hz), 5. 22 (2H, 4.96(1H, quint, =9.0Hz),2.32(31, s 2. 30-1. 60(8H, mn).

Purity >90% (NMR) MS 427 (M+1) Example No. 51 J1H NMR( 6) ppm 0 H,)L-l

N

HO A

NI

3001Hz,OMSO-d6 8. 31(11, 03(1H, d, J=9 .0Hz), 7. 93(1H, d, J=9. 0Hz) 7. 77(2, d, J=8. 4Hz), 7. 31 d, J8. 7Hz), 5. 07 (21 s ,4.94(11, qu in t, J1=8. 7Hz) 2. 45(1H, s) 2. 26(3M, 2 .26-1.60(8H.m).

Purity >9 0% (NMR) MS 432 (M+1) 192 Table 8 Example No. 52 0

N

H0 Purity >90% (NMR) 11 NMR(6) ppm 300MHz,DMSO-d6 12.7(111, brs), 10. 0 (1H, s), 8. 22(1H, 7. 87(11, d, J=8 6Hz), 7. 69(111, d, J=8. 6Hz) 7. 53(2H, d, J=8. 6Hz), 6. 96 (2H, d, J=8. 6Hz), 4.89(1, q uint, J=9. 0Hz), 2. 30-1. 8, i).

Ms 323(M+1) I Example No. 53 0

N

0 HQ Purity >90% (NMR) MS 470 (M+1) IH NMR(6) ppm 300MHz,DMSO-d6 9. 18(1H, t, J=5. 6Hz), 8. 34 111, 8. 04 (IH, d, J=9. 6Hz) ,7.98 (11. d, 7Hz), 7. (211, d, 7Hz). 7. 52-7. 32 5. 27(2H, 4. 95 (1 H, quint, J9. 0Hz), 3. 99(2 J=5. 7Hz), 2.40-1.60(8 inM).

Example No. 54 1H NMR(6) ppm 300MHz,DMSO-d6 8. 32(11, 8. 05(1H, d, J=8 7Hz) 7. 95 d, J=8. 7Hz) 7. 80 d, J=8. 4Hz), 7. 67 (111, t, J=4. 5Hz), 7. 56(111, t PJ=4. 5Hz), 7. 45-7. 42(2, i 35(2Hd,J=8.4Hz),5.3 1 96 (IH, quit J 9. Ollz), 2. 30-1. 60 (8H,inS Purity >90% (NMR) MS 447 (M+1) 193 Table 9 Example No.

0

N

CI

Purity 9 0% (NMR) 11 NMR(6) ppm 300MHz, DSO-d6 12.78(1R, br 24(1H, 7. 88and7. 7 2(21, ABq,J=8. 6Hz), 7. 66an d7.23 (4H, A'B'q, J=8.6Hz), 7. 58(1H, s),7.48-7.42(3H, m),5.24(1H, s),4.88(1H, qu int,J=8.8Hz),2.30-1.91(6 1.78-1. 60(2H, m) MS 447(M+1) Example No. Ob

N

H

ry

N

O 0 Purity >9 0% (NMR) 1H NMR(6) ppm 300MHz, DMSO-d6 12.89(1H, broad), 8. 18(1H, s),7.87(1H, d, J=8.4Hz),7.

74(1H,d, J=9. 2Hz), 7.67(211 J=8. 8Hz), 7. 52(2H, m),7 .45(2H, 7.38 (1H, 7. 2 3(2H, d, J=8. 8Hz), 5. 22(2H, s),4.94(11H,quintet, J=8.9 Hz), 2.16(4, 1. 98(2H, m 1.73(2H,m).

MS 413(M+) Example No. 57 0

HO

\/N

0*A.

Purity >90% (NMR) MS 462(K+1) 1H NMR(6) ppm 300MHz,DMSO-d6 10.99(1H, 8.26(1H, s) ,8 .01-7. 86(4H,m), 7. 69-7. 59 (5H, 7. 38(2H, d, J=8. 7Hz ),4.861(H, quint, J=8. 7Hz) 12-1. 90(6H, 1. 72-1.

59 (2fl, m) 194 Table Example No. 58 1H NMR(6) ppm 300MHz,DMSO-d6 12. 78(1H. 10. 69(1H, s), 8. 26-7. 72 (9H, 4. 92 (IH, quint, J=9. OHz), 2.34-1.70 6H, 1. 75-1. 61(2H, m) Purity >9 0% (NMR) MS 494 (M+1) Example No. 59 0 H

N

c I O 1H NMR(6) ppm 300MHz,DMSO-d6 10. 82(1H, 34 (1H, s),8 .14and7. 84(4H, ABq, J=8. 4H 8. 06and7. 66 (4H, A' B' q, J=8. 6Hz), 8. 06-7. 98 (4H, m) ,5.01 quint, J=9.3Hz), 2. 35-2. 15(4H, 2. 11-1. 9 6(2H, 1. 80-1. 62(2H, m) Purity >90% (NMR) MS 460 (M+1) Example No. OU 0 HOui

H

Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 10. 61(1H, s),8.32(lH, s),8 .12and7. 81(4H, ABq, 5J=8.9H 8. 03and7. 93 (2H, A' B' q, J=8.7Hz), 7. 95and7. 59 (4H, A'B'q, J=8.4Hz), 4.99 q uint, J=9. OHz),2. 33-2. 12( 4H, 2. 10-1. 93 (2H, 1.

80-1. 63 (2H, 1. 34(9H, m) MS 482 (M+1) 195 Table 11 Example No. Wi a Purity >90% (NMR) 11 NMR(6) ppm 3001iz, DMSO-d6 10. 6(LH, 34(1K, 8.

13(2H,d J=8 7Hz)X8.09-7.

98(4HHS, 7. 82 (2H d J=8 7 Hz), 7. 50-7. 35(511:, 7. 17(2H, d, J=9. 0Hz), 5. 24 (2H, OI(iH, uint,J=9 3Hz), 2. 40-1.60(8, mn).

MS 532 Example No. 62 0

OH

Purity >90% (NMR) 11 NMR( 6) ppm 300MHz,DMSO-d6 8. 32(11, 8. 26 (in, d, 1=8 7Hz), 8. 04(1 H, d, 1=8. 7Hz) 7. 77 (211,d, J=8. 4z), 7. 52 (21 d J6. 9Hz), 7. 46-7. 39 m5. i8s(2H, 4. 38(1 71(1H,i),2.60-2. 1 2.04-1.96(41,m), 1. 30-1. 20(2H, m).

443 I Example No. 63 0 H 1 N 0, Purity about MS 457 1 IH NMR(6) ppm 300MHz, DMSO-d6 8. 27(1 R, 14(IH, d, J=8 7Hz), 7. 96 d, J=8. 4Hz) 7. 71(2, d,J=9. 0Hz), 7. 51 d, J=6. 9Hz), 7. 46-7. 37 7. 30(2H, d, J=8. 4Hz ),5.25(31,s),4.39(1H m), 3. 44 (11, 3. 27(3, sS,2.

60-1. 95 (6H, 1. 25-1. 211, m).

A

196 Table 12 Example No. 64 HOyN-C 01 Purity >90% (NMR) MS 427 (u+i) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 25(111, brs), 7. 70-7. 911.i), 7. 20(21, d, J8. 7Hz) 14(I, d,J=8. 41z), 5. (211,sX,4.84(111,QUint, 3=6 .0Hz), 3. 66(2H1, 2. 30- 1.

51 (81, m) Example No. 65 0

NN

HO

1Hl NR( 6) ppm 300M~iz,DMSO-d6 '12. 641OH, brs), 8. 13 (1H, S) 7. 80(LH, d, J=7. 2Hz), 7. 59 (ill d J=8 7Hz) 7. 48-7. 5. 11(2H1, 5. 03(1 Hijint J=8 711z),4.20-4.

45-3. 90 (311, mn) 15-1. 60 (12H1,m) Purity >90% (NMR) MS 448 1) Example No. 66 0 0 Purity 9 0% (NMR) ms 508 (M 1HNWM) ppm 300MAHz, DMSO-d6 59 (11, 8. 31(111, 8 .10 (211 d, JTh8.61z), 8.03 (1 H, d J=8. 71z), 8.O00-7. 85(3 H, 7 8 (fl d J8.6Hz), 7. 1 =8.M),4.98( 111, qu int, J=8.81z), 2. 7 1-1 197 Table 13 Example No. 67

O

0

NCI

Purity >90% (NMR) MS 481(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12.81(lH,brs),8.42(1H,s) ,7.90(1H, d, J=8. 5Hz), 7.80 -7.52(6H, 7. 44 (2H, d, J= 8.6Hz), 5.25(2H, 4.88(1 H,quit, J=8. 8Hz),2.30-1.

52(8H,m) .1.

Example No. 68 0 HO Q C9 CI N Cl Purity >90% (NMR) MS 481 (M+1) 1H NMR(6) ppm 300MHIz, DMSO-d6 8.31(1H, d, J=1. 4Hz), 8.05( 1H, d, J=8.6Hz), 7.96(1H, d, J=8.6Hz), 8.86-8.61(4H,m) 51(H, d,J=6. 3Hz), 7.33 (2H, d, J=8. 8Hz), 5. 28 (2H, s 94(1H, quint, J=8. 8Hz) 31-1.60(8H, m) Example No. 69

O

HO H

-N

O

Purity >9 0% (NMR) MS. 441(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 9. 88(1H, s),9.42(lH, 8.

32(1H,s),8.09and8.02(2H, ABq, J=9. 0Hz), 7. 8 and7.78 A' B'q, J=9. 2Hz), 7.50( 2H, d, J=7. 8Hz), 7.31(2H, t, J=7. 8Hz), 7.00(1H, t, J=7. 8 Hz),5.03(H, quint,J=8.7H 2. 34-2. 17(4H, 13- 1. 96(2H, 1.83-1.64(2H, m) 198 Table 14 Example No. YU HO- N

N

Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 27(111H, d, J=1. 2Hz), 8. 04( 1H, d, J=8. 7Hz), 7.94(1H, d, J=8. 7Hz), 7. 72 (2H, d, J=8. 7 Hz), 7. 60-7. 20 (12H, m)6. 74 (1H, 4.92 (1H, quint, J=8 .9Hz), 2. 30-1. 58 (8H, m) MS 489(M+1) Example No. 71 1H NMR(6) ppm 300MHz,DMSO-d6 8.31(1H, 05 (Il, d, J=8 .7Hz), 7.97 d, J=8.7Hz) ,7.76(2H d J=8 6Hz),7.44 19(7H. m, 4.94(111, quin t, J=8. 8Hz), 4.35(2H, t, J=6 .7Hz), 3. 10(2H, t, J=6. 7Hz) ,2.32-1. 60(8H, m) Purity 9 0% (NMR) MS 427(M+1) Purity >90%

(NMR)

MS 427

(M+I)

Example No. 72 HO a NI>QtQ Purity 9 0% (NMR) MS 483(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 30(1H, 8. 25 (1H, d, J=8 7Hz), 8. 03 (1H, d, J=9. OHz) 75 (2H, d, J=8. 7Hz), 7.51 (21, d, J=7. 2Hz), 7. 46-7. 33 5.27(2H,s), 4.36(1 H, 2. 50-2. 25(2H, 2. 1 5-2. 00 (2H, 1. 95-1.85(2 H, 1. 35(1H, 1.20-1.1 0 (2H, O. 87 (9H, s).

199 Table Example No. 73 lH NM(6) ppm 300MHz,DMSO-d6 7.59(2H,d,J=8.4Hz),7.52- 7. 35 (6H, 7. 20(2H, d, J=8 .7Hz),7. 14(IH, d, J2. 1Hz) 90(1, dd, J=9. 0, 2. 4Hz) 21(2H, 4.83(11, guin t, J=8. 7Hz), 4. 70(21, 2.

30-1. 90(6H, 1. 75-1. 2H, m).

Purity (NMR) MS 443 (M 1) Example No. 74 0

HO

Purity >90% (NMR) 1H NMR ppm 300MHz,DMSO-d6 8. 27(1, 06and7. 97(2 H, ABq, J=8. 7hz), 7. 57and6.

86 (4H, A' B' q, J=8. 9Hz), 7. 4 2-7. 26(5H, 5. 04(LH, gui nt, fr9. 0Hz), 4.42(2, s),2 .32-1. 94(6H, 1. 80-1. 62 m) MS 412 (M+1) Example No.

0

HON

Purity >90% (NMR) 1 NMR(6) ppm 300MHz,DMSO-db 12. 80(1H, 26(11,s),7 .90(1H,d ,J9.2Hz),7.76-7 60 (sH, 7. 35(2H, d, J=8.

4Hz), 4. 84(LH, quint, J8. 8 Hz), 3. 23(311, 2. 32-1. (6H, 1. 78-1. 61 (2H, m) MS 476(M+1)

I

200 Table 16

I

Example No. 76

O

N N Purity 9 0% (NMR) MS 426(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 8.29(IH,s),8.07and7.49(2 H, ABq, J=8. 7Hz),7.66and7.

00 (4H, A' B' q J=7. 7Hz), 7. 3 9-7.24(5H, 5.05 qui nt, J=8. 8Hz), 4. 76(2H, 3 21 (3H, 2.35-1. 92 (6H, m 1. 81-1.62(2H, m) Example No. 77 0

N

HO Purity 9 0% (NMR) MS 425 1) 18 NMR(6) ppm 300MHz,DMSO-d6 8. 21(1IH, 7.87(1H, 7.

56and7. 43 (4H, ABq, J=8. 1Hz ),7.34-7.16(5H, 4.25(1 h, brt, J=12. 5Hz), 3. 06-2. 9 2(4H, 2.41-2. 17(2H, m), 1. 96-1. 77 1. 72-1.5 8 (1H, 1. 48-1. 15(3H, m) .7 Example No. 78.

HO

NN

Purity 9 0% (NM R) MS 404(M+1) 1 1H NMR( 6) ppm 300MHz, DMSO-d6 8. 14(111, 7.79(1H, d, J=9 .0OHz),7.57(1H, d J=8.7Hz) ,7.40-7.20(5H 4.89 (1H ,quint, J=8. 7Hz), 3.54(2H, 3. 19-2. 90(31, 2. 23- 1. 69(14H, m) 201 Table 17 Example No. 1H NMR(6) ppm 300MHz, DMSO-d6 8. 15(1H, 7.81(1H, d,J=8 .4Hz), 7. 59(1H, d, J=9. OHz) ,7.50-7. 38(5H, 5.05(1H Squint, J=9. OHz), 3.85-2.9 5(3H, 2. 20-1. 65 (14H, m) Purity >90% (NMR) MS 418(M+1) Example No. 80 HCO n

N-S=O

Purity 9 0% (NMR) MS 468(M+1) IH NMR(6) ppm 300MHz,DMSO-d6 8.17(1H, 7.84(1H, d, J=8 .4Hz), 7. 78-7. 62 (3H, 7.

49(2H, d J=8. 1Hz),5.05-4.

91 3.80-3. 70(2H, m) 30-3. 12(1H, 2. 48-2.

31(5H, 2. 15-1.60 (12H, m Example No. 81 0 HO 9 N\ o

CI

Purity >9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 12.75 brs), 8.21 (1H, d, J=1. 4Hz), 7.49(1H, d, J=8. 6 Hz),7.85(1H,dd,J=8. 6, 1.4 Hz), 7. 70-7. 55 (5H, 7. 23 (2H, d, J=8. 7Hz), 5. 25(2H, s 36-4. 15(1H, 2. 39-2 18 (2H, 2. 00-1. 78 (4H, m 1. 70-1. 57(1H, 1. 48-1 .15(3H, m) MS 495 (M+1) 202 Table 18 Example No. 6Z 1H NMR(6) ppm 300MHz, DMSO-d6 8. 27 (11, 8. 22 d, J=8 .7Hz), 8. 02 (11, d, J=8. 7Hz) 69(2H, d, J=8. 7Hz), 7. 50 (4H, 7. 45-7. 25 (8H 75(1H, s),4.21-4.23 (1H, 2. 39-2. 18(2H, 2 .10-1. 78 (4H, 1. 70-1. (4H, m) Purity >90% (NMR) MS 503 (M+1) Example No.

H1 NMR(6) ppm 300MHz, DMSO-d6 13.2(H, brs), 8.30(1H, s), 8. 23(1H, d, J=8. 8Hz), 8. 02( 1I1, d, J=8. 7Hz), 7. 74 (2H d J8. 6Hz), 7. 40-7. 33(5H, m 22 (2H, 36(1H, m),2 .50-1. 40 (10H, 1. 31 (18H

S).

Purity 9 0% (NMR) MS 539 (M+1) Example No. 84 0 Purity 9 0% (NMR) IH NMR(6) ppm mixture of isomers(cis:trans=3:I) 300MHz, DMSO-d6 8. 30 (1H, 8. 20-7. 95 (2H, 7. 72 (2H, d, J=8. 4Hz), 7.

52-7. 29 (7H, 5. 25 (2H, s) 34, 3. 40 (18, 2. 50-2.

(2H, 2. 05-1. 50 (6H, m) 14, 0. 90 (3H, d, J=6. 9, 6.

3Hz), 1. 09 (111, m).

MS 441 (M+1) 203 Table 19 Example No. 85 1H NMR(6) ppm 300MHz,DMSO-d6 8. 25(1H, 8. 14-7. 83 (6H, 7. 77-7. 44 (5H, 7. 21( 2H, d, J=7. 8Hz), 4. 44(2, br 4. 31(111, brt), 3. 56(2H, brt), 2. 20-2. 16(2H, 2. 0 0-1. 74 (4H, 1.70-1.55(1 H, 1.45-1.14(3H, m) Purity >90% (NMR) MS 491 (M+1) Example No. 86 0

O

HPi ui >0 Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 12.75(1H, s),8.23(1H, s),8 .15(1H, d, J=7. 6Hz), 8. 02-7 .53(10H, 7. 32 (2H, d, J=8 .7Hz), 5.68(2H, s),4.32(1H ,brt, J=12.2Hz), 2.41-2.20 (2H, 2.01-1. 78(4H, I .71-1.56(1H, 1. 50-1. 16 (3H, m) MS 477 I Example No. 87 H N /N Purity 9 0% (NMR) MS 516(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12.75(1H, brs), 8. 16(1H, s) 91and7. 82 (2H, ABq, J=8.

7.44and6. 86(4H, A' B' q, J=8.6Hz), 7.39-7.26(10H 4. 82 (2H, 4. 35(1H, b rt, J=12. 2Hz), 2. 35-2. 16(2 H, 1. 97-1. 75 (4H, 1. 6 9-1.56(1H, 1.45-1. 16(3 H, a) 204 Table Example No. 111 NMR( 6) ppm 30011Hz, DMSO-d6 8.311OH, 26and8. 06 (2 Hi, AEq, J=8. 9Hz), 7. 73and7.

22(4HA' B'q J=8. lHz), 7. 36 (81, Zn, 5. 10 (2H1, s), 4. 37 brt, J=12. 2Hz), 2.

38-2. 2. 10-1. 80 4H, m) 1. 70-1. 56(11H, 1.

50-1. 20(31, n Purity 90% (NMR) MS 503 (MnI) Example No. 89 1H NMR(6) ppm Purity 9 1% (HPLC) MS 427 (1+1) Example No. 1H NMR(6) pp.

30011Hz, DISO-d6 8. 40-8, 20(21,m i, 8. 04 (1H, d, J8. 4Hz), 7.65(21, d, J=8 50-7. 10 (12H1, .08(01H,m), 4.33(1H,m), 3. 0 0 2. 50-1. 10 Purity >90% (NMR) MS 5310h1+1) 205 Table 21 Example No. 91

HO

Purity about 1H NMR(6) ppm 300MHz, DMSO-d6 8. 31(1H, s),8.27(1H, d J=8 .7Hz), 8. 08-8.03 (3H, m 7.

77-7. 58(5H, 7. 31(2H, d, J=8. 7Hz), 5. 81(2H, 4.40 (1H, 2.50-1. 20(10H, m).

MS 455(M+1) Example No. 92 0 2HC

N

Purity >9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 11.8(1H, brs), 8. 07(1H, s), 7. 89(1H, d, J=8. 7Hz), 7.84( 1H, d, J=8. 4Hz), 7. 69 (2H; m) 48 (3 4. 42(2H, 4 S1((H, 3. 73(4H, m),3.4 0(4H,m),2.40-1.40(10H,m) MS 419 (M+1) Example No. V3 HO -O Purity 9 0% (NMR) MS 531 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.32(1, 8.28(1IH, d, J=8 .9Hz), 8.05 (1H, d, J=8. 7Hz) 72 (2H, d, J=8. 7Hz), 7. 38 (4H, d, J=7. 2Hz), 7.31(4H, t SJ=7. 3Hz), 7. 21-7. 17(4H, m 37(1H,m),4.26(1H, t, J =7.9Hz), 4. 01(2H, t, J=6. 2H 2. 57(2H, 2. 50-2. 2H, 2. 10-2. 00(2H, 2.

00-1. 75 (211, 1. 75-1. 1H, 1.55-1.20(3H, m).

206 Table 22 Example No. 94 0 HO N \0 0

C%

Purity 90% (NMR) MS 537(M+1) 1H NMR(5 ppm 300MHz, DMSO-d6 8.32(11,5), 8.27(1, d, J=9 .OHz),8.05(1H,d,J=-8. 7Hz) 7. 75-7. 70(3OH, 7. 56(111 d, J=8. 4Hz), 7. 55-7. 35 (61 in), 7. 22(21, d, J=8. 7Hz), *11 (2H, 4. 36(111, mn), 2. 4 0-2. 15 (2Hin) 15-1. 9 5(2 H, 1. 95-1. 75 (2H1,m), 1. 7 5-1. 55 (11, 1. 55-1. 20 (3 H, MO.

Example No.

111 NMR( 6) ppm 300Hz, DMSO-d6 12. 9(11H, brs), 8. 02 (11, s), 7. 82 (211, in), 7. 40-7. 25 (OH, m) 58 (21, s) 09 (111 m) 71(11H,im) 49(21,in., 3 .21 (2H, 2. 35-1. 30 (141,

MO.

Purity 9 0% (NMR) MS 434 1) Example No.

HO-

Purity 90% (NMR) 1H NMR 6) ppm 300MHz, DMSO-d6 8. 311H, d, J=1.311z), 8.27( 111, d, J=S. 8H), 8. 05(111,4d, J=8. MH), 7. 76 (21, d, J=8. 7 Hz), 7. 40-7. 25 (41, 7. 06 90(31,mi), 4.53-4. 26(51 in), 2. 4 0-2. 18 (2H, in), 2. 12 -1.56 1. 50-1. 19 (3H MS 457(1+1)

I

207 Table 23 Example No. ut 1H NMR(6) ppm 300MHz,DMSO-d6 8.32(1H, d, J=1. 3Hz), 8.29( 1H, d, J=8. 8Hz), 8. 05(1H, dd J=8. 8, 1. 3Hz), 8.42(2H, d, J=8. 8Hz), 7.37-7. 16(7H, m) ,4.48-4.30(1H,m),4. 12(2H J=6. 2Hz), 2. 83-2. 70(2H ,m),2.40-1.50(9H, 1.59 -1.19(3H,m) Purity >90% (NMR) MS 455 (M+1) Example No.

O0 HO 4-Q- Purity (NMR) Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 28 (1H,d, J=1. 3Hz), 8. 21( 1H,d,J=8.8Hz), 8.01 (H,d, J=10. 1Hz),7. 70(2H, d, J=8.

7Hz), 7. 33-7. 12(7H, 4 4-4.28 (1H, 4. 10(2H, t, J 3Hz), 2. 62(2H, t, J=7. 4H 2. 39-2. 15(2H, 2. 1.18(14H, m) MS 483 Example No. 99 0 .0 0 HO i r N N O' Purity >90% (NMR) MS 418 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12.93(1H, brs), 8.30 d, J=1.4Hz), 8.04(1H, d, J=8.7 Hz), 7.92(1H, dd, J=8.7,1.4- Hz), 7. 59-7. 34 7.07 (1H, 5.38(2H, 78-4 .60(1H, m),2.32-2.14(2H, m 2.03-1.28(8H, m) 208 Table 24 Example No.

100 1H NMR(6) ppm 300MHz, DMSO-d6 8.46(18, d, J=2. 1Hz), 8. 16( 1H, 8. 00 (1H, dd, J=8. 5, 2 1Hz), 7. 87(18, d, J=8. 68 d; J=8. 5Hz), 7. 30 (5H, 7. 08 (1H, d, J= 8. 5Hz), 5. 45 (2H, 4. 25-4 .08 (1H, 2. 39-2. 18(2H, m 2.00-1.75(4H,m), 1. 70-1 .55(11H. 1. 45-1. 19(3H, m Purity >90% (NMR) MS 427 (M+1) Example No. I01 1H NMR(6) ppm 300MHz, DMSO-d6 8. 33 (1H, 8. 31 (1H, d, J=6 .9Hz), 8. 06 (1H, d, J=8. 4Hz) 76and7. 29 (4H, ABq, J=8.

9Hz), 6. 68 (2H, 4. 37 (1H, 4. 35(2H, t, J=7. OHz), 3.

79 (6H, 3. 63 (3H, 3. 04 (2H, t, J=6. 9Hz), 2. 30 (2H, m 2. 04 (2H, 1. 86(2H, m), 1. 65 (1H, 1. 50-1. 15(3H, m)

H

3

C-

Purity >90% (NMR) MS 531 (M+1) Example No. 102

O

H '-CHa

H

3

C

Purity 9 0% (NMR) MS 455(M+ 1) 1H NMR(6) ppm.

300MHz, DMSO-d6 12. 88(1H, 8. 34(111, 7 .86(1H,d,J=8.5Hz),7.73(1 H, d, J=8. 5Hz), 7. 63and7. 23 (4H, ABq,'J=8. 7Hz), 7. 52-7.

(5H, 5. 22 (2H, 4. 31 (1H, 2. 39 (2H, 1. 79 (2 H, 1. 53 (2H, 1. 31(2H, 1. 11(3H, 95 (3H, s) 209 Table Example No. 103 Purity >90% (NMR) 1H NMR 6) ppm 300MHz, DMSO-d6 12. 79 (iH, brs), 8. 22 (21, s) 02-7. 78(41, mn), 7. 63-7.

42(61,mi), 7.20-7. 09(21, 43 (2H, 4. 27111, brt, J=12. 2Hz) 3. 59(2H1, s) 3 9-2. 15 (21, 1. 98-1. 72 (4 H, 1. 68-1. 59(111, mn), 1. 4 3-1. 12(3OH, mn) MS 491 Example No.

104 111 NMR(6 ppm 300Mllz,DMSO-d6 12. 75 8. 23111, 7 .94and7. 86 (2H1, ABq, J=8. 611 z) 7. 64and 7. 05(4OH, A' B'.q, J=8. 7Hz) 32-7. 09 (911,i) 13 (211, 4. 28(111, brt, J=12. 2Hz), 2. 36-2. 19(21,mi 1. 95-1. 77(4M, mn), 1. 66-1 .56(IH,in), 1. 46-1. 10(3OH,in Purity 90% (NMR) MS 519 Example No.

105 1H NR 6) ppm 300Mllz,DMSO-d6 8. 2311H, 7. 94and 7. 87 (2 11,ABq, J8. 6Hz), 7. 68and7.

17(411 A' B'q J=8 7Hlz) 4 6-7. 33(61, in,6,93and6. (211, A"B'q, J=8. 2Hz), 6. 82 111, 5. 13 (2H1, 4. 30(111 ,brt,J12.21z),2.39-2. 18 (2H, mn), 1. 98-1. 77 (41, 1 .71-1. 59(1H, 1. 48-1. (3H, in) Purity >90% (NMR) MS 519.(M±1) 210 Table 26 Example No. 106 0

O

Purity 9 0% (NMR) MS 429 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 89 (1H, brs), 9. 73 (18, s) 24 (1H, 8. 03and7. 91 211, ABq, J=8. 7Hz), 7. 66and7 04 (4H, A' B' q, J=8. 7Hz), 7.

16-7. 03 (3H, 6. 89 (2H, t, J=9. 2Hz), 4. 33 (1H, brt, J=1 2. 2Hz), 2. 40-2. 18 (2H, 2 .00-1. 78 (4H, 1. 70-1. 58 (1H, 1. 50-1. 20 (3H, m)

S

Example No. 107 1H NMR(6) ppm 300MHz, DMSO-d6 12.98 (1H, brs), 9. 82(1H, br 8. 27 (1H, 8. 09and7. 9 4 (2H, ABq, J=8. 7Hz), 7. 74an d7. 22 (4H, A' B' q, J=8. 7Hz), 7.28-7. 22 (1H, 6. 67-6.5 4 (3H, 4. 35(1H, brt, J=12 2Hz), 2. 40-2. 20 (2H, 2.

05-1. 80 (4H, 1. 72-1. 59( 1H, 1. 50-1. 21(3H, m) Purity

MS

9 0% (NMR) 429 (M+1) .1.

Example No. 108

HO

1H NMR(6) ppm 300MHz, DMSO-d6 8.24(1H, 8. 01and7. 90(2 H, ABq, J=8. 7Hz), 7. 65and7.

03 (4H, A' B' q, J=8.7Hz), 7. 3 2-7. 20 (3H, 7. 08-7. 03(1 H, 4. 32(1H, brt, J=12. 2H 3. 77 (3H, 2. 36-2. 20 2H, 2.-00-1. 78 (4H, 1.

71-1. 59(111, 1. 44-1. 11( 31, m) Purity >90% (NMR) MS 443(M+1) 211 Table 27 Example No.

109 0 HO K's tN/ Purity >90% (NMR) MS 443 1) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 75 (IH, 8. 24(1H, 7 .96and7. 87 (2H, AB, J=9. OH 7. 69and7. 19(4H, A' B' q, J=8. 6Hz), 7. 37(1H, t, J=7. I Hz), 6. 84-6. 70 (3H, 4. 31 (1H, brt, J=12. 2Hz), 3. 78 (3 H, 2. 39-2. 20(2H, 1. 9 8-1.78 (4H, 1.76-1.60(1 H, 1.48-1. 13(3H, m) Example No. 110

O

HO N Purity >90% (NMR) MS 471 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 8.31(1H, 8.26and8.04(2 H, ABq, J=8. 8Hz), 7. 75and7.

71(4H, A' B' q, J=8. 8Hz), 7. 3 2-7. 03 (4H 4. 34(1H, brt ,5J=12.2Hz), 3.94(2H, t, J=6 3Hz), 2.40-2.19(2H, 2.

11-1. 81 (4H, 1. 72-1. 16( 6H, O. 71(3H, t, J=7.3Hz) Example No. 111 0

HO

Purity >90% (NMR) MS 471 (M+1) 1H NMR(6 ppm 300MHz,DMSO-d6 8. 22 (1H, 7. 91and7. 87(2 H, ABq, J=8. 7Hz), 7. 68and7.

18(4H, A' B' q, J=8. 7Hz), 7.3 5(1H, t, J=8. 5Hz), 6. 80(1H, d, J=9. OHz), 6. 72-6. 68(2H, m),4.30(1H, brt, J=12.2Hz) 94(2H, t, J=6. 5Hz), 2. 39 18(2H, 1. 97-1. 58 (7H 1.45-1. 20(3H, 0. 97 (3H, t, 1=7. 4Hz)

I

212 Table 28 Example No. 112 LH NMR( 6) pp.

300MHz, DMSO-d6 12. 73111, 8. 2 2(11H, 7 94and7. 85 (2H1, ABq, J=9. 311 7. 6land7. 01(41, A' B'q, J=8. 6Hz), 7. 25-7. 00 (4H1, i) 5. 25 (2H1, brs), 4. 55 (21, d, J=6. 6Hz), 4. 29(11, brt, J1 2. 2Hz) 2. 38-2. 18 (2H1, mn), 1 96-1. 78(4M, 1. 70-1. 56 (1H, 1. 67(31, 1. 60 (3 H1, 1. 48-1. 15 (3H1, m) Purity 9 0% (NMR) MS 497 (M+1) Example No. lid HO 0*0 Purity 90% (NMR) 1HUNM) ppm 300MHz, DMSO-d6 12. 75(1, 8. 2 3 (1H, s),7 9Sand7. 86(28, Akq 1=8.911 z) 7. 69and7. 18 (411. A' B' q, J=8. 9Hz), 7. 35(11H, t, J=8. 3 Hz), 6. 81-6. 693OH, mu), 5. 41 (211, brs), 4. 54 (2H1, d, J=6. 6 Hz),4. 31 (11,brt, J=12. 2Hz 2. 41-2. 18 1. 98-1 .76(41,m), 1. 73(3W, s) 1.T7 0-1. 58111, in), 1.68(311, S), 1. 45-1. 17(3OH,m) MS 497 (MnI) Example No. 114 0.

HO Purity >90% (NMR) MS 499 1) 1H NOW( ppm., 300MHz, DMSO-d6 12. 73 (111,s), 8. 22 (1H, s),17 94and7. 85 (21, Aft, J=8.411 z) 7. 6Oand6. 99(411 A' B' q 1=8. 6Hz) 7. 29-7. ob (41, in 29 (ill, brt, J=12. 2Hz). 3 .99(211,t J=6 31z),2.41-2 (21, iS, 1.95-1. 76(41,.m 1. 70-1. 147M, m) 0. 76 (3 H, d,J=6.6Hz) 213 Table 29 Example No.

115 0

HO

Purity >90% (NMR) MS 499(M+1) IH NMR(6) ppm 300MHz, DMSO-d6 8.23 7.93and7. 87(2 H, ABq, J=8. 6Hz), 7.69and7.

19(4H, A' B' q, J=8. 6Hz), 7. 3 5(1H, t J=7.8Hz),6.82-6.6 9(3H, 4.30(1H, brt, J=12 .2Hz), 4. 00(2H, t, J=6. 9Hz) 38-2. 20(2H, 1. 97-1.

54(8H, 1. 47-1. 20(3H, m) 93(6H, d, J=6.6Hz) Example No. 116 0 HO Purity >90% (NMR) MS 557(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H, 8. 25(1H, d, J=8 .9Hz),8.03(111, d, J=8. 8Hz) 68(2H, d, J=8. 8Hz), 7. 24 (2H, d, J=7. 2Hz), 7.19-7. (6H, 6. 94(2H, t, J=7. 2Hz 34 4. 19(4H, brs 10(4H, brs), 2.40-2. (2H, 2.10-1. 95 (2H, 1 .95-1. 75 (2H, 1. 75-1. (11, 1. 55-1. 20 (3H, m).

Example No. 117

CF

0 HO O Purity 9 0% (NMR) MS 571(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12.8(1H, brs),8.22(1H, s), 7.98(1H, d, J=8. 7Hz), 7.87( IH, d, J=8. 6Hz), 7.80(2H, d, J=8. 2Hz), 7. 72-7. 67 (3H, m) 59(2H, d, J=8. 7Hz), 7. 54 51 (2H, 7. 42-7.41(1fI 7. 11(2H, d, J=8. .09(211, 4.27 (1H, 2. 4 0-2. 15(2H, 2. 00-1. 75 (4 H, 1. 75-1.55 (1H, 5-1. 15(3, m).

214 Table Example No. 118 0

HO

CI.

Purity >9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 13. 3(1H,brs),8.30(1H,s), 8. 25(1H, d, J=8.9Hz), 8.04( 1H, d, J=8.7Hz), 7. 72(2H, d, J=8.8Hz),7.57(4H, d,J=8.6 Hz), 7. 47(4H, d, J=8. 6Hz), 7 .33(2H, d, J=8.9Hz),6.84(1 H, 4. 33 2. 45-2. 1 0(2H, 10-1.95(2, m), 1. 95-1. 70(2H,m), 1. 70-1. (1H, 1.55-1.15(3H, m).

MS 571 Example No.

119 1H NMR(6) ppm 300MHz, DMSO-d6 8. 32-8. 30(2H, 8. 07-8.0 3(1H,m),7.74and6.90(4H,A Bq, J=8. 7Hz), 4.37(1H, m),4 .31(2H, t,J-6.8Hz), 3.74(3 H, s),3.04(2H, t, J=6. 7Hz), 2. 30(2H, 2.02(2H, 1.

86(2H, 1.63(1H, 1.55 15(3H, m) Purity >90% (NMR) MS 471 (M+1) Example No. 120 0 HO

O

N

O-CH

3 Purity 9 0% (NMR) MS 471 (M+1) 1H NMR(6). pm 300MHz,DMSO-d6 8.23(1H, 7.99(1H, d, J=8 .7Hz),7.88(1H, d,J=8.4Hz) ,7.61and7. 16(4H, ABq, J=8.

6Hz), 7. 30-7. 22 (2H, 7. 0 1(2H, d, J=8. 1Hz), 6.92(lH, t, J=7.5Hz), 4. 28(1H, 4.

25(2H,t,J=7.2Hz),3.83(3H ,s),3.07(2H, t, J=7. 1Hz),2 .28(2H, m) 2.00-1.75(4H, m) ,1.70-1. 55(1lH,m), 1.50-1.

15(3H,m) 215 Table 31 Example No. 121 O0

HOH

3 Purity >90% (NMR) MS 471 (M+1) IH NMR(6) ppm 300MHz, DMSO-d6 12. 85 (1H, brs), 8. 24(1H, s) 01(1H, d, J=8. 7Hz), 7. (1H, d, J=8. 6Hz), 7. 62and, 7 17(4H, ABq, J=8. 7Hz), 7. 24 (1H, 6. 94 (2H, 6. 82 (1 H, 4. 32 (2H, t, J=6. 7Hz), 3. 76 (3H, 3. 07 (211, t, J=6 7Hz), 2. 29 (2H, 2. 00-1.

(4H, 1. 70-1. 55(1H, m) 1. 50-1. 15(3H, m) Example No. 122 0 HO

O

SN 1H NMR(6) ppm 300MHz,DMSO-d6 12.8(IH,-brs),8.22(1H, s), 7.87(2H, 7.62(2H, d, J=8 .1Hz), 7. 60-7.20(7H, 23 (2H, 4. 46(1H, 2. -2.30(2H, 1.70-1.40(10 H, m).

Purity >90% (NMR) MS 441(M+1) Example No. 123 1H NMR(6) ppm 300MHz, DMSO-d6 8.24(1iH, 7.97(1H, d, J=9 .0Hz), 7.87 d, J=8. 4Hz) 65 (2H, d J=8. 7Hz),7.40 05 (9H, 7.03(2H, d, J= 8.4Hz),4.31(1H, 18(2 H, t, J=6.6Hz), 2.81(2H, t, J 3Hz), 2.40-2.20(2H, n), 2. 00-1. 70 (4H, 1. 70-1. 0 (1H, 1. 50-1. 05 (3H, m).

Purity >9 0% (NMR) MS 533 (M+I) 216 Table 32 Example No.

124 P N- Purity 9 0% (NMR) 1H NMR(S) ppm 300MHz, DMSO-d6 13. 1(1H,brs),8. 29(1H, s), 8. 17(1H, d, J=8.7Hz), 7. 99( 111, d, J=8. 7Hz), 7. 77(2H, d J=8. 7Hz), 7. 40-7. 20(8H, m) 84(1H, d J=9.3Hz),6.75 72(2HmZ, 4.36 (1H, 4 .22(2H, t, J=6. 8Hz), 3. 04(2 H, t, J=6. 7Hz), 2. 40-2. 15(2 H, 15-1.95(2H, 1.9 5-1. 75(2H, 1. 75-1. 55(1 H, 1. 55-1. 15 (3H, m).

MS 533(M+1)

I

Example No.

125 1H NMR(6) ppm 300MHz,DMSO-d6 8. 32(1H, 8. 28(11, d, J=8 .7Hz), 8.05(1H, d, J=9. 0Hz) 73 (2H, d, J=9. OHz), 7. 43 (4H, d J=7. 2Hz), 7. 36-7. (8H, 4. 74(2H, d, J=7. 57(1H, t, J=7.5Hz), 4. 3 8(1H, 2.40-2. 15(2H, m), 2. 15-1.95 (2H, 1.95-1. 8 (2H, 1. 85-1. 55(1H, m), 1. 55-1. 20(3H, m).

Purity 9 0% (NMR) MS 517 (M+1) Example No.

126 0 0 N Purity >90% (NMR) MS 425(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.32(1H, s),8.14(1H,d,J=8 .7Hz), 8.03(1H, d, J=8. 7Hz) 77(2H, d, J=9. 0Hz), 7. 52 -7.31(7H, 5. 74(2H, .26(2H, 4.61 (1H, 2.9 6 (1H, m),2.60-2. 10(5H, m).

217 Table 33 Example No. 127 0

N

F

Purity >90% (NMR) MS 445(M+1) Example No. 128 0

HO

Purity >90% (NMR) MS 505 (M+1) 1H NMR(6) ppm 300Hz,DMSO-d6 13.2(1H, brs),8.33(lH,s), 8. 12(1H, d, J=8. 7Hz), 7. 96( 1H, d, J=8. 8Hz), 7. 79 (2H, d, J=8.7Hz) 7. 52-7.32(7H, m) ,5.26(2H, s),4.92 d, J= 49. 4Hz), 4. 57 2.65- 2. 35(2H, 2. 25-1.50(6H, m).

1H NMR(S) ppm 300MHz,DMSO-d6 8.21(1H, 7. 92and7. 85(2 H, ABq, J=8. 6Hz), 7. 61and7.

06(4H, A' B' q, J=8. 6Hz), 7.3 6-6.91(9H, m),4.24(1H,brt J=12. 2Hz), 2. 35-2. 15 (2H, 1. 95-1. 75 1. 1. 58(1H, 1. 48-1. 14(3H, m) Example No.

129 0

HO

0 1H NMR(6) ppm 300MHz, DMSO-d6 8. 21 7. 92and7. 86(2 H, ABq, J=8. 6Hz), 7. 69and7.

22(4H,A' B'q, J=8. 6Hz), 2-7.39(1,m),7.47and7.41 (2H, A'B'q, J=8. 1Hz), 6.91 1H, d, J=8. OHz), 6. 89 (1H, d, J=8. 2Hz), 6. 75(1H, 4.36 18(1H, 2.38-2. 17(2H 1.95-1.76(4H, 1. -1.59(H, 1.44-1. 19(3H ,m) Purity >90% (NMR) MS 505 (M+1) a 218 Table 34 Example No.

130 KO N H0\ N

N-

HN 11 NMR(6) ppm 300MHz,DMSO-d6 8.27(1H,s),7.69(2H, d, J=8 .6Hz), 7.49-7.21(118, .08and5. 03(2H, ABq, J=12. 6 Hz), 5.07-4. 99(111,m), 4. 26 (2H, d, J=6. 6Hz), 2. 40-2. 18 (2H, 04-1. 77(4H, 1 .70-1.58(1H, 1.48-1.15 m) Purity >90% (NMR) MS 590(M+1) Example No. 131 1I NMR(6) ppm 300MHz,DMSO-d6 8. 29(11, 11(1H,d,J=9 .0Hz),7.96(1H, d, J8. 4Hz) ,7.80(2H d J=8 l.1Hz),7.72 -7.41(7H 7.12(1H, dJ= 12. 6Hz), 7.01(1H, d, J=8.44H 5. 12(21, 4. 06(111,m) 35-2. 10(2H, 2. 00-1.

75(4H, 1.75-1. 55(1H,m) 1. 60-1. 20(38, m).

Purity 9 0% (NMR) MS 589 (M+1) Example No.

132 0 HO N Njj /O 00 Purity 9 0% (NMR) MS 519(M+1) 1H NMR(6) ppm 300MHz,,DMSO-d6 12. 8 (1H, brs),8. 23(1H, s), 7.97(1H, d,J=8. 7Hz), 7. 87( 1H, d. J=8. 6Hz), 7.66(2H, d, J=8. 6Hz), 7. 49-7. 33(5H, m) ,7.17-7.05(6H,m),5.12(2H 31(1H,m),2.40-2. 2.05-1.20(81,m).

219 Table Example No. 133 0 Purity >90N

(NMR)

N Purity 90% (NM R) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 57(1H, 01(1UH, d, J=8 .7Hz),7.66(1H,d,J=8.7Hz) ,7.51(2H, d,J=8.7Hz),7.31 (4H, d, J=8. 0Hz), 7. 16(4H, d J=8. OHz), 7. 09(2, d, J=8.

7Hz), 6. 26(1H, 37(1H, 2. 41-2. 28(2H, m),2.33( 61H, 03-1.84(4H, 1.

77(1H, 1.45-1. 20(3H, m) MS 5310(M+1) Example No. 134 0 HO N F

F

Purity 9 0% (NMR) MS 539 (M+1) 18 NMR(6) ppm 8.59(1H1, d, J=1. 5Hz), 8. 02( IlH, dd, J=8. 7,1. 5Hz),7.68( 1H, d, J=8. 7Hz), 7. 54(21, d, J=8. 8Hz), 7. 39(4H, dd, J=8.

7, 5. 3Hz), 7. 08(4H, d, J=8. 7 Hz), 7. 05(2H, d, J=8. 8Hz),6 .29(1H, s),4.36(IH, m),2.4 3-2. 19(2H, 2. 04-1.85(4 H, 1.78(1H, 1. 45-1.2 3(3H,m).

Example No.

135 0

HOA

0

I

Purity >90% (NMR) MS 485 (M+1) IH NMR(6') ppm 300MHz,DMSO-d6 12. 34(1f, brs), 7.93(H, s) ,7.55(lH,d,J=8.6Hz),7. 33 15(6H,m),7. 11(2H, d J= 8. 6Hz),4.30-4.20(LH,im),4 .07(2H,t,J=6.3Hz),3.93(3 H, 78(2H, t, J=7. 4Hz), 2. 35-2. 19(2H, 2. 12-2. 0 0 (2H, 1. 91-1. 79(4H, m), 1. 69-1. 60(11H, 1. 47-1.2 0(3H,m) 220 Table 36 Example No. 136 0 o

HO

Purity 9 0% (NMR) MS 471 1H NMR(6) ppm 300MHz, DMSO-d6 8. 13(1H, 7.65(2H, d, J=8 .7Hz), 7.63(111H, 7.35-7.

12(71, 4. 35-4.20(111, m) 10(lH, t, J=6. 3Hz), 2. 78 (2H, t, J=7.5Hz), 2. 33-1. 78 (8H, i. 70-1. 16(4H, m) Example No.

137 0 HO 0

H

3 C N Purity >90% (NMR) MS 469 (M+1) 1H NMR ppm 300MHz, DMSO-d6 8. 24(1H, 11(IH, 7.

76 (2H, d, J=9. 0Hz), 7. 37-7.

16(7H, 4. 43-4. 30(1l, m) ,4.13(2H, t, J=6.3Hz), 2.84 68(5H, 2. 42-2. 22(2H 2. 18-1.80 (6H, 1. -1.20(4H,m) Example No. 138 S Purity >90% (NMR) MS 547(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12.73(1H,brs),8.22(1H,s) 76(l H, d, J=8. 7Hz), 7. (1H,d, J=8. 7Hz), 7.54-7.49 (4H, 7. 42-7. 21 (5H, 7 11-7. 09(3H, 6. 93 m 5. 17(2H, 4. 29(3H, m), 3. 11(2H, 2. 40-2. 20 (2H, 1. 99-1. 23 (8H, m) 221 Table 37 Example No.

139 1H NMR(6) ppm 300MHz,DMSO-d6 12.73(1H, brs), 8.22(1H, s) ,7.93(11H, d,J=8. 7Hz), 7.73 7.60-7. 57(2H,m),7 .47-6.90(1H, m),5.11(2H, s 4.33-4.28(3H, m),3.09-3 .04(2H, t, J=6.7Hz), 2. 35-2 .20(2H, 1.95-1. 10(8H, m Purity >90% (NMR) MS 547 (M+1) Example No. 140 S0OH HO N- Purity >90% (NMR) MS 487(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12.83(2H, brs),8. 22(1H, s) ,7.94(11, d, J=8. 7Hz), 7.85 (1H, d, J=8. 4Hz), 7.63-7.60 (2H, 7. 26-7.03(6H, m),4 .73(2H, 30(1H, m),2.4 0-2.15(2H,m), 2.00-1.20(8 H, m) Example No. 141 0

OOH

HOg) Q

C)

1H NMR(6) ppm 300MHz,DMSO-d6 12.87(lH,brs),8. 24(lH,s) ,7.97(H, d, J=9. OHz), 7.87 d, J=8.7Hz), 7. 69and7.

19(4H,ABq,J=8.7Hz),7.36( 1H, t, J=8. 7Hz), 6. 80-6. 72( 3H,m),4.71(2H,s),4.32(1H m),2.29(2H, 1.95-1.25 (8H, m) Purity >9 0% (NMR) MS 487(M+1) 222 Table 38 Example No. 142 0

O

ICI

-01 Purity 9 0% (NMR) MS -551(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.32(1H, s),8.27(111, d, J=8 .7Hz),8.05(1H, 76-7. 72(3H, 54(1H d,J=8. 4Hz),7.39-7.22(7H 11(1H, s),4.36(1H,m 2.35(3H,s), 2. 35-2. 15(2 H, 2. 15-1. 95(2H, 1.9 5-1. 75(2H, 1.75-1.55(1 1.55-1. 15(3H,m).

Example No.' 143 0 0 HO O N CI C Purity >90% (NMR) MS 567(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 13. 1(1H,brs),8.30(1H,s), 8.24(1H, d, J=8. 8Hz), 8.03( 1H,d, J=8. 7Hz), 7.74-7.71 3H,m),7.52(1H,d, J=8.3Hz) 7. 40-7. 36(3H, 23(2H d, J=8. 8Hz), 7. 01(2H, d, J= 8. 7Hz),5.11(2H, 35(1 H,m),3.79(3H,s),2.45-2.1 5(2H, 2. 15-1. 95(21, m), 1. 95-1. 75(2H, 1. 75-1. 1.55-1. 15(3H, m).

1H NMR(6) ppm 300MHz,DMSO-d6 13. 0(lH,brs);8.31(1H,s), 8.23(1H, d, J=8. 7Hz), 8. 04( 1H,d,J=8.7Hz),7.80(2H,11d, J=8. 3Hz), 7. 70-7. 66(311, m) 55-7. 40(4H, 7. 03-6.

95(2H,m), 5.08(2H,s),4. 03 (1H, m),2.40-2. 15(211, m),2 18(3H, s),2.05-1.70(4H, m 1. 70-1.50(1H,m), 1.50-1 .10(3H, m).

Example No.

144

CF

3 0

N

H0 Purity >90% (NMR) MS 585(M+1) 223 Table 39 Example No. 145

O

HO N

CI

Purity 9 0% (NMR) MS 593 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 31(1H,s),8.23(1H, d, J=8 .8Hz), 8. 02(1H, d, J=8. 7Hz) 73-7.71(3, 7.54(1H d, J=8. 3Hz), 7. 48(2H, d,J= 8.4Hz),7. 41-7.37(3H, ),7 .22(2H, d,.J=8.7Hz),5.13(2 H, 34(111, 2. 40-2. 2 0(2H,m),2. 15-1.95(2H,m), 1.95-1.75(2H, 1.70-1.5 (1H, 50-1.15(3H,m), 1.31(9H, s).

Example No. 146 0 HO N 0I' /0% C I c Purity >90% (NMR) MS 555(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(1H, 13(1H, d, J=8 7Hz),7. 97 (1H, d, J=8. 6Hz) ,7.76(1H, d, J=2. 1Hz), 7.63 (1H, t, J=8. 5Hz), 7. 57(1H, d d,J=8.2,2.2Hz),7.55-7. (6H, 15(1H,d, J=12. 1H 7. 02(1H, d, J=8. 6Hz), 10(2H,s), 4.07(111, 2.35 10(2H,m),,2.00-1. 70(4H 1. 70-1. 55(1H,m), 1.50 15(3H, m).

Example No. 147

CI

O CI HO rN 0 I Purity >90% (NMR) MS 605(M+1) 1H NMR(6) ppm 300MHz,CDC13 8.61(1H, s),8.04(1H,d,J=8 .7Hz),7.69(1H, d,J=8.7Hz) ,7.66(1H,d,J=2. 4Hz), 7.59 (2H, d, J=8. 7Hz), 7. 42(1H, d d, J=8.0, 2. 4Hz), 7.38(1H, t ,J=1.8Hz),?7.28(2H,d, J=1.

8Hz),7. 26(1H, d, J=8. 0Hz), 7. 03(2H, d, J=8. 7Hz), 4. 94( 2H,s),4.37(1H, 2.43-2.

21(2H, 2, 17-1. 86(4 H,m) .1.79(1H,m), 1. 43-1. 26(3H Si).

224 Table Example No. 148 0F HO 0

F

Purity 90% (NMR) MS 557(MI-'1) 111 NMR(6) ppm 300MHz, DMSO-d6 8. 21 IlH), 7. 89 (111, d, J=8 .7Hz), 7.87(11,d,J=8. 713) 63-7. 46 7. 30-7.

12(51,m),?7. 08 (111, d, J=11.

Of), 6. 81 (111, 3. 92111, m) 2. 15-2. 06 (211, rn), 1. 89- 172(41, 1. 61(11,m), 1. 4 2-1. 09 (311, m).

Y

Example No. 149 11iNMR(S Ppm 30011Hz, DMSO-d6 8.24111, d, J1. 514z),?7. 96( Ilit d, J=9. 0Hiz), 7. 88 (1H, dd J9. 0, 1. 5Hz), 7. 58 (1LH, d, J=8. 7Hz), 7. 50-7. 30(51,mi) 7. 22-7. 00 (611, rn), 5. 13 (211 3. 98-3. 80 (1H, 2. 36 10 (101-1,.m) Purity 9 0% (NMR) MS 553 (M1+I) Example No. 150 0

CF

3

HO-

1H NMR ppm 30011Hz, DMSO-d6 8. 23 (1H, 8. 95 (I11, d,J=8 4Hiz), 7. 88 (1H, d, J=8. 7Hz) .7.66(11 d J=8 52 28 (71: 7. 23 (211, d, J= 9. 3Hz), 7. 14(21,d, 3=8. 7Hz 5. 14 (2H, 3. 90-3. 72 (1 2. 20-L1 10 (10OH, m,) Purity >90% (NMR) MS 587 1) 225 Table 41 Example No. 151 HO 1

NN

b

CI

Purity 90% (NMR) 1H1 NMR(6 ppm 30014Hz, DMSO-d6 8. 18 (LH, 7. 92-7. 78(311, mn), 7. 78-7. 58 (3H, 7. 58- 7. 44(4M, mn), 7. 29 (1H1, d, J=8 *2Hz), 7. 01 (21. d, Jh8. 7Hz) 4. 88 (11, d, J=11. 8z),4. 8 0(111, d, J=11. 8Hz), 4. 22(111 2. 37-2. 16 1. 75 (41, 1. 64(11,m), 1 .48-1. 14 (311, m).

Ms 605(M+1)j__ Example No.

0 152 1H1 NMR 6) ppm 30014Hz, UNSO-dO 8. 21 mn), 7. 99-7. 80 (21, nW, 7. 63-7. 08 (91, mn), 4. 3. 98 in), 2. 20-2. 15 (21, 1. 95-1. 74(41,.m), 1. 1. 54(1OH,m), 1. 44-1. 143OH, Mn) Purity >90% (NMR) MS 456 (M4+1) Example No.

153 0 HO -aN Oi Purity 9 0% (NMR) MS 489 (1+1) 111 NMR ppm 30014Hz, DMSO-d6 8. 20(LH, 8. 93and 7. 83 (2 H, ABq, J8. 7Hz), 7. 21 20 (1 H,brt, J=12. 2Hz) 2. 32-2. 13 1. 92- 1.

74(4H, in), 1. 69-1. 58 (111, mi) 1.45-1.15(31,.) 226 Table 42 Example No.

154 11 NMR(6) ppm 300MHz,DMS-d6 8.23(1H,s),7.94and7.86(2 H, AB, J=8. 6Hz), 7. 72-7. 16 (1311, 25(2H, brs), 4. 5(2H,d,J=6.6Hz),4.31( H, brt,J=12.2Hz),2.37-2.18( 2H,m), 1.98-1.77(4H,m), 1.

70-1. 58 (1H, 1.48-1. 3H, m) Purity >90% (NMR) MS 489(M+1) 155 Example No.

0 N b., 00N Purity 9 0%o (NMR) MS ,626 (M+1) 1H NMR(6) ppm 300MHzDMSO-d6 8.21(l1H,s),7.85and7.61(2 H, ABq, J=8. 7Hz), 7. 61and6.

99(4H, A' B' q,J=8. 7Hz), 7.2 8-7. 18(1H, 25(2H, d, J =7.5Hz),7.07-6.991Hm),4 30(1H, brt, J=12. 2Hz), 3. 8 3(2Hd J=6.OHz),3.82-3.7 2(1H, 2. 68-2. 49(2H, m), 2. 39-2. 21(2H, 1. 95-1.8 0(411,m), 1.79-1.60(2H,m), 1.46-1.22(5H, 1.30(9H, s),1.00-0.82(2H, m) Example No.

156 IH NMR(6) ppm 300MHz,DMSO-dS 8.22(1H, 92and7. 86(2 H, ABq, J=8. 7Hz), 7. 68and7.

18(4, A' B'q, J=8. 7Hz), 7. 3 5(111, t,J=8. 5Hz),6. 80(111, d J=8.3Hz),6.72-6.70(2H, m.4.30(1H1, brt,J=12. 2Hz), 3.99(2H, brd,J=12. 0Hz),3.

85(2H, d, J=6. 3Hz), 2. 82-2.

62(2H,m),2.38-2.20(2H,m) 99-1. 59 (811, 1.42-1.

03(5H,m), 1.39(9H,s) Purity 9 0% (NMR) MS 626(M+1) 227 Table 43 Example No.

157 1H NMR(6) ppm 300MHz,DMSO-d6 12.78(lH, brs), 8.22(1H, s) ,7.96(1H, d, J=8. 6Hz), 7. 86 d,J=8.6Hz), 7.75(1H, d 2Hz), 7. 60(2H, d, J=8.

4Hz), 7.55(1H, dd, J=8.3,2.

2Hz), 7.48(1H, d, J=8. 3Hz), 7.18(2H,d,J=8.4Hz),6.73( 2H, s),5.08(2H, 23(1H 3. 68(9H, 2. 37-2. 17 (2H, 1. 99-1. 79 (4H,m), .65 1. 49-1. 15(3H, m Purity >9 0% (NMR) MS 627(M+1) Example No.

158 0 HO 0 0 1H NMR(6) ppm 300MHz,DMSO-d6 12. 75(1H, brs), 8. 22(IH, s) ,7.93 (2H, d, J=8. 7Hz), 7. (2H, d, J=8. 5Hz), 7.53-7. 21 94(2H, d, J=8. 7H z),4.30-4. 12(3H, 3. 2H, 2. 35-2. 15(2H,m), 1.

95-1.75(4H, 1.75-1.55( 1H, 1.50-1.10(3H, m) Purity 9 0% (NMR) -i MS 517(M+1) Example No.

159 1H NMR(6) ppm 300MHz,DMSO-d6 12.77(lH, brs), 8.22(1H, s) ,7.95 8.6Hz), 7.86(1 H, d, 8.6Hz), 7.80(1H, 7.

70-7.35(10H,m),7.27(2H,d 7Hz), 5. 30 (2H, 2 8(1H,m), 2.35-2. 15(2, m), 1.95-1.75(4H, 1.70-1.5 5(1H,m), 1.50-1.15(3H, m) Purity 9 0% (NMR) MS 503 228 Table 44 Example No.

160 1H NMR 6 ppm 300MHz, DMSO-d6 8.90(1H, brs), 8. 59(1h, brs ),8.33(1H, 18and8. 00 (2H, ABq, J=8.5Hz), 7.73and 7. 10(4H, A' B' q, J=8. 5Hz), 7 32-7. 05 (4H, 4. 35 (1H, b rt, J=12. 2Hz), 3. 86(2H, d, J 3Hz), 3. 25-3. 08 (2H, m), 2. 85-2. 66 (2H, 2. 40-2. 2 8 (2H, 2. 07-1. 14(15H, m) Purity >90% (NMR) MS 526 Example No.

1H NMR(6) ppm 300MHz, DMSO-d6 9.05(1H, brs), 8.76(lh, brs 8. 31 (18, 19and8. 00 (2H, ABq, J=8. 3Hz), 7. 79and 7. 25 (4H, A' B' q, J=8. 3Hz), 7 39(18, brs), 6. 86-6. 74 (4H 4. 37 brt, J=12. 2Hz ),3.89(2H, d J=5. OHz), 3.3 5-3. 18 (2H, 2. 98-2. 75 (2 Hm, m),2.38-2. 17 (2H, 2. 1 6-1. 15(15H, m) Purity 9 0% (NMR) MS 526(1+1) Example No.

162 HO

N

Purity >90% (NMR) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 87 (1H1, brs), 8. 58 (18, d, J=6. OHz), 8. 23(111H, 7.99 and7. 80(2H, ABq, J=8. 6Hz), 7. 61and7. 18 (4H, A' B' q, J=8 OHz), 7. 45-7. 30 (5H, 29(111, brs), 4. 26 (18, brt, J =12. 2Hz), 2. 37-2. 11(2H, m) 00-1. 71 (4H, 1. 92 (3H 1. 70-1. 52(1, 1. -1.11(3H, m) MS 498 (M+1) 229 Table Example No. 163 0

HO

Purity >90% (NMR) MS 511(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.23(1H,s),7.95and7. 86(2 H,ABq,J=8.6Hz),7.69and7.

18(4H, A'B'q,J=8.6Hz),7.3 5(1H, t, J=8. 6Hz), 6. 80(1H, 6. 72-6. 69(2H.

m),5.20(1H,t,J=3.7Hz),4.

31(1H,brt,J=12. 2Hz),3.95 (2H, t, J=6. 8Hz), 2. 49-2. 19 (4H, 1.97-1.76(4, 1 68 (3H, 1.67-1.54(1H, m 1.61(3H, 1.45-1.20(3 H, M) Example No.

164

O

Purity 9 0% (NMR) IH NMR(6) ppm 300MHz,DMSO-d6 8. 20(1H, s),7.87(2H, 7.

68and7.18(4H, ABq, J=8. 7Hz ),7.35(1H, t,J=7.9Hz),6.8 1(1H, d, J=9. 4Hz),6. 72 (1Hs 6.71(1H, d J=6. 8Hz), 4. 8 0(2H, 4.29(1H,brt,J=12 .2Hz),4. 10(1H, t,J=6. 7Hz) 2. 43 t, J=6. 7Hz), 2. 39 19(2H,m), 1. 97-1. 78(4H 1. 76(3H, 1. 70-1. 56 (1H, 1.43-1.19(3H,m) MS 497 1 Example No. 165 0 HO IN N. 0 SN'

O\

o N HCI I N o1-0 11 NMR(6) ppm 300MHz,DMSO-d6 11.21(1H,brs),8.33(1H,s) 25(1l, d, J=8. 6Hz),8.04 (1H, d,J=8. 6Hz),7. 78(2H, d ,J=8.7Hz),7.70-7.67(2H,m 7. 55-7. 42(3H, 7. 27(2 H, d J=8. 7Hz),4.73-4.30(5 H, 20-3. 97(1H,m), 3. 4 2-3. 10(2, 2.45-1.23(1 4H,m) Purity

MS

>90% (NMR) 230 Table 46 Example No.

166 18 NMR(6) ppm 300MHz,DMSO-d6 8.27(1H, 13(1H,d,J=8 4Hz), 7. 97(1H, d, J=9. 0Hz) 7.73(1H, d, J=1. 8Hz), 7.68 (2H, d, J=8. 4Hz), 7. 54(1H, d d,J=8.4,2.1Hz),7. 41-7.31 7. 19(2H, d, J=8. 4Hz ),5.10(2H 32(1H,), 2. 50(3H, s5, 2. 40-2. 15(28, 2. 10-1. 75(411, 1. 1. 55(1H, 1.55-1.10(311, M). Purity >90% (NMR) MS 583(M+t1) No. Example 167 0 Os 0 0 HO a 00C N 0 ci 1H NMR(6) ppm 300MHz,DMSO-d6 8. 25 (1H. 09(1H, d,J=8 4Hz),8.00(2H,d,J=8.4Hz) 7. 94(1H, d, J=8. 7Hz), 7. (IH, d, J=2. 1Hz), 7. 73(28, d 1Hz), 7.65(21, d, J=8.

7Hz), 7.60(1H,dd,J=8. 1,2.

1Hz), 7.44(OH, d, J=8. 1Hz), 7. 16(2H,d,J=8.7Hz),5. 13( 2H,s),4.30(1H,m),3.26(3H s),2.40-1.15(2H,m),2.05 75 1.75-1.55(111 1.55-1.15(3H,m).

Purity

MS

>90% (NMR) 615(M+1) Example No. 168 0 N ~j N s

SCI

Purity 9 (NMR) MS 543 (M+1) 1H NMR1(6) ppm 300MHz,DMSO-d6 13. 1(1H,brs),8.32(1H,s), 8.28(1H, d, J=8.8Hz),8.05( 1H,d, 8. 7Hz), 7. 80-7.75 69(1H, d, J=4. 1Hz) 7. 57(2H, 34-7. 29(3K 7.20-7. 15(1H,m),5.24 (2H, 39(1H,m), 2.45-2 20(2H, 2. 20-1.95(2H, m 1. 95-1. 75(2H,m), 1.75-1 .55(1H,m), 1.55-1.15(3H,m 231 Table 47 Example No. .169 Cl 0

C

Purity 90% (NMR) MS 571(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.31(lH, s),8.26(1H, d,J=8 .7Hz), 8.05(1H, d, J=8.7Hz) ,7.78-7.71(3H, m),7.59-7.

41(6H,m), 7.23(2H,d,J=9.0 11(2H,s),4.35(lH, m 15(2H, 2. 15-1 .95(2H, 1. 95-1.75 (2H, m 1. 75-1. 55 1.55-1 .15(3H, m).

Example No. 170

-N

0 HO O Ho'©

N

CI

Purity >9 0% (NMR) MS 538 (M+1) 1H NMR ppm 300MHz,DMSO-d6 12. 7(1H, brs), 8. 66(IH, s), 8.61(1H, m),8.21(H, 7.

92-7. 79(4H, 7. 61-7. 56( 3H, 7. 50-7.43(2H, 7.

10(2H, d, J=8. 7Hz), 5. 09 (2H ,s),4.26(1H, m),2.40-2. (2H, m),2.00-1.75(4H, I .75-1. 55 1.50-1. (3H, m).

Example No.

O

HO'-%

1H NMR(6) ppm 300MHz,DMSO-d6 8.31(lH,s),8.25(lH,d,J=8 .7Hz),8.04(H, d, J=8.7Hz) ,7.74-7. 71(3H, 7.57-7.

46(3H, m),7.39(1H, d, J=8. 1 Hz), 7.31-7.21(4H, 5. 11 (2H, 4.35(1H, 40-2 15(2H, 15-1.95(2H, m 1.95-1. 75 (2H, 1.75-1 1.55-1. 15(3H,m Purity >90% (NMR) MS 55 (M+1) 232 Table 48 Example No.

172 0

F

HO

0 Purity >90% (NMR) 1H NMR(6) ppm 300MHz, DMSO-d6 8.24(lH, 7.99(1H, d, J=8 .7Hz), 7.88 (IH, d, J=10.5Hz 7.70(1H, dd, J=11.4, 1.8H 7.48-7. 32(6H, 7. 17- 7. 09 (5H, 5. 12(2H, 4.

30(1H, 40-2. 15(2H, m) 05-1. 75 1. 75-1.

55 (1H, 1. 55-1. 20 (3H, m) MS 537 (M+1) Example No.

173 1H NMR(6) ppm 300MHz,DMSO-d6 8.33(1IH, 8.29(1H, d, J=8 .7Hz), 8. 06 (1H, d, J=8. 7Hz) 7. 82-7. 74 (4H, 7. 45 (1H dd, J=8. 4, 3. OHz), 7. 39(2H d, J=8. 7Hz),5.28 (2H, 4 .40(1H, m),2.40-2. 15(2H, m 2. 15-1. 95 (2H, 1. 95-1 1. 75-1. 55(1H, m 1.55-1.15 (3H, m).

Purity >90% (NMR) MS 540(M+1) Example No. 174 1H NMR(6) ppm 300MHz,DMSO-d6 12.80(1H, brs), 8. 26 (1H, s) ,8.01(1H, d, J=8. 7Hz), 7.85 (1H, d, J=8. 7Hz), 7.80-7.70 (IH, 7.60-7. 36(7H, 7 S18-6. 91(2H, 5. 09(21, s 4. 11-3.90 32-1 .18(14H, m) Purity >90% (NMR) MS 590(M+1) 233 Table 49 Example No. 175 0 O HO N 0 Purity >9 0% (NMR) MS 568 (M+1) IH NMR(6) ppm 300MHz, DMSO-d6 12.75 (IH, 8. 21 (1H, 7 .94and7. 85 (2H, ABq, J=8. 7H 7. 61and7. 00(4H, A'B' q, J=8. 5Hz) 31-6. 91 (2H, m) 25 (2H, d, J=7. 7Hz), 5. 41 (2H, brs), 4. 54 (2H, d, J=6. 6 Hz), 4. 35-4. 14(2H, 2. 49 -2.15(3H,m), 1. 95-1. 55(5H i. 50-1. 13(5H, -0.77(2H,m) Example No.

176 0

HO

1H NMR(6) ppm 300MHz,DMSO-d6 8.24(1H, 7. 97and7. 87(2 H, ABq, J=8. 6Hz), 7. 69and7.

19(4H, A' B' q, J=8. 6Hz), 7. 3 5(1H, t, J=8. 1Hz), 6. 81 (1H, d, J=9. 2Hz), 6. 72(1H, 6.

71(111, d, J=6. 5Hz), 4. 48-4.

20(2H, 3. 95-3. 75 (38, m) ,3.03 (1H, t, J=12. 3Hz), 2. 6 0-2. 40(1H, 2. 39-2. 15(2 H, 07-1.58(6H, 1.9 9(3H, 1. 50-1.00 (5H, m) Purity >9 0% (NMR) MS 568(M+1) 1.

177 Example No.

1H NMR(6) ppm 300MHz,DMSO-d6 12. 76(1H, s)8. 23 (1H, s),7 .96and7. 86(2H, ABq, J=8.6H 7. 69and7. 20 (4H, A' B' q, J=8. 6Hz), 7. 39(1H, t, J=8. 2 Hz), 6. 86(1H, d, J=8. 3Hz), 6 .81 (1H, 6.76(1h, d, J=8.

OHz), 4. 83 (2H, 4. 31(1H, brt, J=12. 2Hz), 2.39-2. 19( 2H, 1. 99-1. 79(4H, 1.

70-1. 58 (1H, 1. 48-1. 3H, m) Purity 9 0% (NMR) MS 467 (M+1) 234 Table Example No. ho 0 HO

N

O NQ Purity >90% (NMR) MS 520(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 85(1H, 8. 75 (1H, 8 .63(2H, d, J=3.8Hz), 8. 25(1 H, 8. 04-8. 01(2H, 8. 0 2and7.90(2H, ABq, J=8. 6Hz) 72and7. 20 (4H, A' B' q, J= 8. 6Hz), 7. 57(2H, dd, J=7. 8, OHz), 7.40(1H, t, J=8. 2Hz ),6.93(1H,d,J=8.2Hz),6.8 7(1H, 6. 77 (1H, d, J=8. 2H 5. 23 (2H, 33 (1H, br t, J=12. 2Hz), 2. 40-2. 18(2H 2. 00-1. 55(5H, 1. -1 iutau L,.

Example No. 179 HO

N

Purity >9 0% (NMR) MS 457(M+1) 1H NMR(6) ppm.

300MHz,DMSO-d6 8.32 (1H, 8.29(1H, d, J=9 .0Hz), 8. 06(1H, d, J=8. 7Hz) 61(1H, d J=8. 4Hz), 7.58 32 (5H, 6. 98(1H, d, J= 2. 1Hz), 6. 93 (1H, dd, J=8. 7, 2. 1Hz), 5. 27 (2H, 4. 16-4 .00(1H, 3. 87(3H, 2. 2 0-2. 12(2H, 02-1. 98(4 H, 1.70-1.60(1H, 2-1. 10(3H, m) Example No. 180 1H NMR 6 ppm 300MHz, DMSO-d6 8. 21(1H, s),7.91(1H, d, J=8 .6Hz),7.85 (1H, d, J=8.6Hz) ,7.63(2H, d,J=8.4Hz), 7.60 (1H, d, J9. OHz), 7. 25(2H, d J=8. 4Hz), 7. 23(1H, d, J=3.

OHz), 6. 95 (1H, dd, J=9. 0, 3.

OHz),5.19(2H 4.30(1H, 3. 78(3H, 2.40-2. 19 2H, 2. 00-1. 87 (4H, 1.

66 (1H, 1.49-1.18(3H, m) Purity >9 0% (NMR) MS 536(M+1) 235 Table 51 Example No.

181 0 HO NHO Purity >9 (NMR) Purity 9 0% (NMR) 1H. NR(6) ppm 300MHz,DMSO-d6 8.19(1H, s),7.95(lH, d, J=8 .7Hz),7.86(1H, d, J=8. 7Hz) ,7.65(4H, d, J=7.4Hz), 7.47 (2H,d,J=8.7Hz),7.44-7.27 (6H, 6.99(2H, d,J=8.7Hz ),4.20(1H,m),2.34-2. 12(2 H, 1. 98-1. 75 (4H, 1. 6 4(1H, 1.46-1. 13(3H, m).

MS 547 Example No.

182 1H NMR(6) ppm 300MHz,DMSO-d6 8.55(1H, d, J=2. 1Hz), 8.32( 1H,m, 8. 21 95(1H J=8.4Hz), 7. 86(1H, d, J= 7. 8Hz),7.68-7. 56(7H, m),7 .14(2H, d, J=8. 7Hz), 5. 21(1 H, s),4.26(H, 2.35-2.1 5(2H, 2.00-1.75(4H, m), 1. 74-1.55 (1H, 1.50-1.1 (3H,m)

NO

2 Purity >90% (NMR) MS 582 Example No.

183 NH H H CH 3 1H NMR(6) ppm 300MHz, DMSO-d6 16(lH, 25(1H, s),8 .07(1H, d, J=8. 7Hz), 7.94-7 .87(2H, 7. 71-7. 62(3H, m 7. 50-7. 42(4H, 7. 30(1 H,d,J=8.4Hz),7.14(2H,d,J =8.4Hz),5.06(2H, s),4.31( 1H, m),2.35-2. 15(2H, m),2.

05-1. 75 (4H, 1.75-1. 1H, 1.50-1. 15(3H, m) Purity

MS

9 0% (NMR) 594 236 Table 52 Example No.

184

OH

0 0 HO 0

SC

Purity 9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 13. 2(2H, brs),8.30(1H, s), 8.26(1H, d, =8.8Hz),8.04( 1H,d,J=8.8Hz), 8.00(2H,d, J=8.2Hz), 7.79(1H, 7.73 (2H, d, J=8. 7Hz), 7. 61-7. 56 (3H,m),7.44(IH,d,J=8.3Hz 23(2H, d, J=8.8Hz), 5. 1 3(2H, s),4.35(11H, m),2.45- 2. 15(2H, 15-1.95(2H, 1.95-1.75 1. 15(3H, m).

MS 581 (M+1) Example No.

185 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H,m),8.24(IH,d,J=9 .OHz), 8. 03(1H, d, J=9. OHz) 79-7. 10(9H, 5. 20-5.

07(2H,m), 4.43-4.04(4H,m) ,3.50-3. 36(2H, m),2.40-1.

19(14H, m) Purity >90% (NMR) MS 554 (M+1) Example No.

186

CF

Purity 9 0 (NMR) 1H NMR(6) ppm (DMSO-d6)6 29(1H, brs) ,8.10(1H, d, J=8. 4Hz), 7.97 (1H, d, J=8.4Hz), 7. 79(2H, d J=8.4Hz),7.74-7.67(lH,m 68(2H, d, =8.4Hz), 7.6 1(1H, d, J=8. 4Hz), 7. 57-7.5 0(2H, m),7.46-7.39(1H, m), 7. 29(1H, d,J=2. 4Hz), 7. 11( 1H, dd, J=2.4,8.4Hz), 5.12( 2H, s),3.99-3.84(1H, 2.

35-1. 72(6H, 1.68-1. 1H, 1. 42-1. 10 (3H, m) MS 605 (M+1) 237 Table 53 Example No.

187 0

HO

XgssN I O SN 0,

ON-'

Purity >90% (NMR) MS 520 (M+1) 1H NMR 6 ppm 300MHz,DMSO-d6 12. 76(1H, 8. 57(1H, d, J= 4.4Hz), 8.23(1H,s),7. 96an d7. 86(2H, ABq J=8. 2Hz), 7.

87-7. 82(1H, m, 7. 68and7. 1 2(4H, A' B' q, J=8. 6Hz), 7. 53 (2H, d, J=7. 8Hz), 7. 37(1H, t 3,J=8.3Hz), 7: 36-7. 33(1H, m ),6.90(1H,d,J=8. 3Hz), 6.8 3(1H,s),6. 74(1H, d, J=8. OH z),5.20(2H,s),4.31(1H,br t,J=12.2Hz),2.35-2. 19(2H 99-1..57(5H, 1. -1 9n1( Example No;.

188

C'

0

HO

F

Purity >9 0% (NMR) MS 555 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12. 77(1H, brs), 8. 21(1H, d, J=1,4Hz),7.92(1H,d,J =8.7 Hz), 7. 88(1H1, dd, J=8. 7, 1. 4 Hz),7.57(211, d,J=8. 7Hz), 7 .57-7. 27(7, m),7.11(2H,d J=8. 7Hz), 5. 07(2R, 2 6(lH, m),2.36-2. 16(2H,m), 1.98-1.75(4H,m), 1. 64(1H, nm), 1.49-1.17(3H,m).

Example No.

189 0 P

>N

Purity >90% (NMR) 1H NR() ppm 300N9Hz,DMSO-d6 8.32(1H, 30-8.20(2H, m),8.10-7.98(2H, r),7.74( 2H,d,J=9. 0Hz),7.60-7.46( m),7.24(2H, d,J=9. 0Hz) 19(28,s),4.44-4.30(1H 2. 40-2. 20(2H, 2. 12 -1.78(4H, 1.72-1.58(4H Mn) MS 581 I 238 Table 54 Example No.

190 1H NMR(6) ppm 300MHz, DMSO-d6 8. 36-7. 90 (5H, 7. 74 (2H, d, J=8. 6Hz), 7. 60-7. 40 7. 25 (2H, d, J=8. 7Hz), 14 (2H, 4. 45-4. 28 (1H, m) 40-2. 15 1. 75-1.

1. 55-1. 20 (3H, m) Purity >90% (NMR) MS 580 (M+1) Example No. I1i HO N N 0 N /H 3

CH

3 Purity >90% (NMR) MS 514 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 22 7. 94 d, J=8 .4Hz),7.85(1H, d, J=8. 7Hz) 61(2H, d, J;8. 7Hz), 7.25 00 (6H, 4.86(2H, 4 .30 m),2.89(3H, 2.8 0 (3H, 2. 29 (2H, 2. 00- 1.75 (4H, 1.70-1. 55 (1H, 1.50-1. 15 (3H, m) Example No. 192 II I 1H NMR(6) ppm 300MHz,DMSO-d6 8.22(1H, 7.94(1H, d, J=8 .4Hz), 7. 85(1H, d, J=8. 7Hz) 61(2H, d, J=8. 7Hz), 7. 26 01 (6H, 4. 84 (2H, s),4 .31(1H, 3. 36(4H, 2.2 9 (2H, 2. 00-1. 75(4H, m), 1. 75-1. 15 (10H, m) Purity 9 0% (NMR) MS 554 (M+1) 239 Table Example No.

193 1H NMR(6) ppm 300MHz,DMSO-d6 13.00(lH, brs),8. 29 (1H, d, J=1. 4Hz), 8.15(lH, d, J=8. 8 Hz), 7.97(1H, dd, J=1. 4Hz, 8 .8Hz), 7. 89(2H, d, J=8.8Hz) 7. 80-7. 60(5H, m) 7.25 (2H, d,J=8.8Hz),4.47-3.90(4H, m),3.20-3. 10(2H, m),2.41- 1.22(14H,m) Purity >9 0% (NMR) MS 560(M+1)

I

Example No.

194 0 H N N Purity >9 0% (NMR) MS 524(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12.80(lH,brs),8.23(lH,s) ,7.97(1H, d, J=8.5Hz), 7.87 (1H, d J=8.5Hz),7. 70-7. 17 (9H, 4.60-4. 13(4H, m),3 .72-3.40(2H, 2.40-1. (14H,m) Example No.

0

HO

ig I, I 195 1H NMR(6) ppm 300MHz,DMSO-d6 8.25 (1H, 8. 09-7. 92(5H, m),7.77(1H,s), 7.65(2H,d, J=8.4Hz), 7.59-7.51(3H, m) ,7.43(2H, d, J=8. 4Hz), 7. 17 (2H, d, J=8. 7Hz), 5. 10(2H, s ),4.30(1H,m),2.40-2. 15(2 10-1. 75 (4H, 1.7 5-1. 55 (1H, 1. 55-1. 10(3 H, m).

Purity >9 0% (NMR) MS 580(M+1) 240 Table 56 Example No.

196 0 HO H3 Put N >90%WCHN O C00 Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8.22(1H, s),7.95(1H, d, J=8 .4Hz), 7.86(1H, d, J=8.4Hz) ,7.69and7. 18(4H, ABq, J=8.

7Hz), 7. 34(1H, t, J=8. 0Hz), 6.80-6.69(3H,m), 4. 83(2H, 31(1H, m),2.98(3H, s) ,2.84(3H, s),2.29(2H,m),2 .00-1.75 (4H, 1. 70-1. (OH, i. 50-1.15(3H, m) MS 514 (M+1) Example No.

0 IO-i pg).

I

1H NMR(6) ppm 300MHz, DMSO-d6 8.23(lH, s),7.95(lH, d,J=8 .4Hz), 7.86(1H, d, J=8.7Hz) ,7.69and7.18(4H, ABq, J=8.

7Hz),7.35(1H,t,J=8.4Hz), 6. 80-6. 70(3H, 4.82(2H, s),4.31 (1H, 3.40 (4H, m) ,2.29(2H, 2.00-1. 75 (4H Sm), 1. 70-1. 15 (10H, m) Purity 9 0% (NMR) MS 554(M+1) Example No. 198 1H NMR(6) ppm 300MHz, DMSO-d6 12.75(lH, 8.23(1H, d, J= 4.4Hz), 7.95and7.86(2H, AB q, J=8. 6Hz), 7. 69and7. 19(4 H, A' B' q, J=8.6Hz), 7.36(1H J=7.8Hz),6.82(1H,d,J= 9.3Hz),6.73(H,s),6. 71(1 H,d,J=7.2Hz),4.30(1H,brt ,J=12.2Hz), 3.89(2H, d, J=6 .OHz),3.59(2H,d,J=11.7Hz 2.85(3H,s),2.73(2H, t, J =10.5Hz), 2.41-2.20(2H, m) ,1.98-1. 59 (8H, 1.46-1.

IQa(c;u Purity >90% (NMR) MS 604 (M+1) 241 Table 57 Example No. 199 HO

N

HN

N

Purity >90% (NMR) MS 542 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 8. 33(1H, 30(1H, d, J=8 9Hz), 8. 06(1H, d, J=8.7Hz) 79(2H, d, J=8.7Hz), 7. (2H, d, J=8.7Hz), 7. 61(2H, d 7Hz), 7. 39(2H, d, J=8.

8Hz),5.28(2H,s),4.39(1H, m),2.50-2. 15(2H, 2. 1.95(2H, 1.95-1.75 (2H, 1.75-1. 55 (1H, 1.55- 1.15(3H, m).

-T

Example No.

200 1H NMR(6) ppm (DMSO-d6) 6 :8.23(1H,s),7 .96(H, d, J=8.6Hz), 7.86(1 H,d,J=8.6Hz),7.69(2H,d,J =8.4Hz),7.52(1H,s), 7.50- 7.30(4H, 7. 18(2H, d, J=8 .4Hz),6.90(lH, d, J=8. 3Hz) ,6.84(1H, 6.74(1H, d, J= 8.3Hz),5.15(2H,s),4.39-4 .21(1H, 2. 39-2.18(2H, in 1.99-1. 80(4H, 1.71-1 .59(1Hm), 1.50-1. 20(3H,m Purity >90% (NMR) MS 553(M+1) Example No. 201 0 HO o O Purity >90% (NMR) MS 553 (M+1) 1H NMR(6) ppm (DMSO-d6) 6 :8.26(1H,s),8 .06(1H, d;J=8. 7Hz), 7.92(1 H, d, J=8. 7Hz),7. 72(2H, d, J 7Hz), 7. 47 (4H, s),7.38( 1H, t, J=8.2Hz), 7.20(2H, d, J=8.7Hz),6.90(lH,d,J=8.2 Hz),6.83 74(1H,d ,J=8.2Hz),5. 14(2H, s),2.4 0-2. 19(2H, 2. 04-1. 78(4 H, 1.71-1.60(IH,m), 0-1.21(3H, m) 242 Table 58 Table Example No.

202 1H NMR(6) ppm (DMSO-d6) 6:12.81(lH,brs 24(1H, 7.99(1H, d, J 7Hz), 7.87(1H, d, J=8. 7H z),7.69(2H,d J=8.6Hz),7.

53-7.47(2H,m ,7.38(1H,t, J=8. 2Hz),7.26-7. 16(4H,m) ,6.89(1lH,d,J=8.2Hz),6.82 (IH, 73(1H, d, J=8. 2Hz ),5.11(2H, s),4.40-4.21(1 H, 2.40-2. 17(2H,m), 1-1.77(4H,m), 1.71-1. 59(1 H, 1.50-1. 20(3H, m) Purity >90% (NMR) MS 537 (M+1) Example No.

203 0

HO

Nb b

NO

2 Purity 9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 12. 74(1H,brs),8.21(1H, s) 08(2H, d, J=9.0Hz), 7.93 (1H,d,J=8.7Hz), 7.85(2h,d 7Hz),7.58(2H, d,J=8.

7Hz), 7. 13(2H, d, J=8. 7Hz), 6. 83(2H, d, J=9. OHz), 4. 4. 08(4H, 3. 68-3.30(2H, 2.40-1.23(14H, m) MS 541 Example No. 204 1H NMR(6) ppm 0 300MHz,DMSO-d6 S8. 39-8.28(2H, m),8.08(1H, N d,J=8.8Hz),7.76(2H,d,J 8 HO j A 0 .7Hz),7.29(2H, d J=8.7Hz) S,7.25-7. 13(2H. 6.80-6.

60(3H, 4. 46-3.98(4H,m) ,3.51-3. 42(1H, m),3.20-3.

04(1H,m),2.39-1.20(14H,m HCI Purity 9 0% (NMR)

MS

243 Table 59 Example No. 205 0 HO -4j b 6

N

Purity >90% (NMR) MS 553 (M+1) Example No. 206

CI

O l

N

b Purity >90% (NMR) MS 558 (M+l) 1H NMR(6) ppm 300MHz,DMSO-d6 9.59(1H, brs),8.23(1H, s), 8. 04 (1H, d, J=8.4Hz), 7.90( 1H, d, J=8.4Hz), 7. 62(2H, d, J=8.7Hz), 7.39(2H,2H, d,J= 8.7Hz) 7. 18(2H, d, J=8. 7Hz) 63(2H, d, J=8.7Hz), 3.95 -3.37(4H;m),3.51-3.40(1H 3. 17-3.02 2. 39 -1.18(17H, m) 1H NMR(6) ppm 300MHz,DMSO-d6 13. 1(1H, brs), 8.33(11H,s), 8.29(1H, d, J=8.8Hz),8. 06( 1H, d, J=8. 7Hz), 7.77(2H, d, J=8.7Hz), 7.59-7.52(4H, m) ,7.35(2H, d, J=8. 8Hz), 5. 19 (2H, 4. 39(1IH, 2.71(3 H, 45-2. 20(2H, 2. 2 0-1. 95(2H, 1.95-1. 75(2 H, 1.75-1.55 5-1.15(3H, m).

Example No. 207 0 HoN\ /F HMO N'^ 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(1H, s),8.26(1H, d, J=8 .8Hz), 8.04(1H, d, J=8.7Hz) ,7.73(2H,d,J=8.8Hz),7.50 -7.41(6H,m),7.36(2, d,J= 8.8Hz), 7. 18-7. 13(2H,m),6 .84(1H, 4. 33(1H, m),2.4 0-2. 15(2H,m),2.15-1.95(2 H, 1.95-1. 75 (2H, 1. 7 5-1.55 1.55-1. 15(3 H,m).

Purity 90% (NMR) MS 539(M+1) 244 Table Example No.

208 11 NMR(6) ppm 300MHz,DMSO-d6 8. 32(1H, 8. 27 (1H, d, J=9 0Hz), 8. 07-8. 00 (3H, 7.

79-7. 70 (38, 7. 51(2H, d, J=8. 1Hz), 7. 40 (2H, d, J=8. 4 Hz), 7. 18(2H, d, J=8. 7Hz), 4 99(2H, 4. 34 (1H, 2. 4 0-2. 15(2H, 2. 15-1. 95 (2 H, mn), 1. 95-1. 75 1. 7 5-1. 55(18, 1. 55-1. 15(3 H, m).

Purity >90% (NMR) MS 582(M+1) Example No.

209 11 NMR(6) ppm 300MHz,DMSO-d6 8. 24(111, d, J=4. 4Hz), 7. 98a nd7.88(2H,ABq, J=8. 6Hz),7 S70and7. 19(4H, A' B' q, J=8.

4Hz), 7.35(1H, t, J=8. 4Hz), 6.86(1H, d, J=8. 1Hz), 6. 79( 1H, 6. 71(1H, d, J=8. 1Hz) 65-4. 53(1H, 4. 31(1H brt, J=12. 2Hz), 3. 88-3. 78 (2H, 3.48(2H, t, J-9. OHz 2. 39-2. 19(2H, 1. 02-1 71(6H, 1. 70-1. 50(3H, m 1. 46-1. 19 (3H, m) Purity

MS

>9 0% (NMR) 513 (M+1)

-P

Example No.

210 0 a HO N

N

r-sjJ

CF

3 h ~O Purity >90% (NMR) MS 587 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 75 23(111, 7 .96and7. 87(2H, ABq, J=8. 7H 7. 84-7. 66(6H, 7. 38 1, t, J=8. 4Hz), 7. 18(211, d, J=8. 4Hz), 6. 91(111, d, J=9. 0 Hz), 6. 84(111, 6. 74(1H, d J=8. 1Hz), 5. 26(2H, 4. 3 1(1H, brt, J=12. 2Hz), 2. 2. 20(2H, 1. 99-1. 76(4H, 1. 69-1. 58 1. 1. 20(3H, m) 245 Table 61 Example No. 6il 1li NMR(6) ppm 300MHz, DMSO-d6 8. 29 (1H, 8. 15and7. 47 (2 H, ABq, J=9. OHz), 7.77and7.

24(4H, ABq, J=8. 9Hz), 7.39( 1H, t, J=7. 8Hz), 6. 84(1H, d, J=9. 3Hz), 6.76(1H, s),6.75 (1H, d, J=9. 5Hz), 4. 36(1H, b rt, J=12. 2Hz), 3. 89(2H, d, J OHz), 3. 42(2H, d, J=10. 8 Hz), 3. 04-2. 88 (2H, 2. 78 60 2. 71(2H, d, J= 4. 8Hz), 2.38-2. 20(2H, m),2 .07-1. 80 1. 70-1. (1fl mI Purity >90 (NMR) MS 540 (M+1) h Example No.

212 o Purity 9 0% (NMR) MS 575 (M+1) IH NMR(8) ppm 300MHz, DMSO-d6 8. 22 (1H, 93and7. 87(2 H, ABq, J=8. 6Hz), 7.68and7.

17(4, A' B'q J=8. 7Hz),7.4 3-7. 33(5H, 87(i1H, d, J 1Hz), 7. 18(2H, d, J=8. 4H 6. 91 (1H, d, J=9. OHz), 6.

81(1H, 72(1H, d, Hz), 5. 08(2H, 4. 36(1H, b rt, J-12. 2Hz), 2.37-2. 20(2 H, 1. 98-1. 78 (4H, 6 9-1. 60 (1H, 1.41-1. 21(3 H, 1. 28 (9H, s) Example No.

213 1H NMR(6) ppm 300Hz,DMSO-d6 8. 23 (1H, 7. 95and7. 86(2 H, ABq, J=8. 4Hz), 7. 69and7.

19(4H, A' B' q, J=8. 7Hz), 7. 6 2-7. 36(5H, 6. 90(1H, d, J 1Hz), 6. 84(1H, 76( 1H, d, J=8. 1Hz), 5. 19(2H, s) 3L(1H,-brt, J=12. 2Hz), 2 .40-2. 19(2H, 1.99-1. 76 (4H, 1. 68-1. 55 (1H, I .50-1. 18(3H, m) Purity 9 0% (NMR) MS 553 (M+1) 246 Table 62 Example No.

214 1H NMR(6) ppm 300MHz,DMSO-d6 8. 94(1H, d, J=2. 1Hz), 8. 1H, dd, J=4. 8, 1. 5Hz), 8. 23( .1H, d, J=1. 5Hz), 8. 12(1H, dt 1, 2. 1Hz), 7. 93(1H, d, J=8. 7Hz),7. 87(1H,dd, J=8.

7, 1.5Hz),7. 70(1H, d,J=8. 7 Hz), 7. 67-7. 54(3, (lH, dd, J=8. 1, 4. 8Hz), 7. (2H, d, J=8. 7Hz), 7. 21(1H, m 31(1H, m),2.38-2. 19(2 2. 00-1. 78(4H,), 1. 6 1. 48-1. 22 (3H, m).

Purity 9 0% (NMR) MS 490 (M+1) Example No.

215 0 HO Purity 9 0% (NMR) MS 523(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 12. 75(1H,brs),8.23(1H, s) ,7.95(1H, d, J=8. 7Hz), 7.86 (1H, d, J=8. 7Hz), 7. 73(2H, d 4Hz), 7, 71(2H, d, J=8.

4Hz),7.63-7.39(2Hn),7.5 2(2H,d,J=8.4Hz),7.24(2H, d,J=8.4Hz),7. 18(1H,m),4.

31.(1H, 2. 39-2. 20(2H,m) 2. 00-1. 76(4H, 1. 65(1H 1.49-1. 18(3, m).

-J

Example No.

216 0

N

b Purity >9 0% (NMR) MS 519(M+1) 1H NMR(S) ppm 300MHz,DMSO-d6 12. 77(1H, s),8.23(1H,d,J= 1.4Hz), 7.95(1H, d, J=8.6Hz ),7.86(111, dd, J8. 6,1.4Hz ),7.70(2H, d,J=8. 7Hz), 7.6 4(2H, d, J=8. 8Hz), 7. 56-7. 4 8(2H,m),7.40(1H,s),7. 23( 2H, d, J=8. 7Hz), 7. 10(1H,m) 03(2H, d, J=8. 8Hz), 4. 31 (1H, 3. 80(3H, 48-2 .20(2H,i),2.00-1.88(4H,m 1. 50-1. 21(3 H,m).

247 Table 63 Example No.

217 1H NNR( 6) ppm (DMSO-d6) 6 :12. 80(LH, brs 8. 23(111, 8. 04(LH, d,J A8 6Hz) 7. 96(311, d, 1=8. 611 7. 86 (1H, d, JA8 7Hz), 7.

63 (2H, d, J8. 6Hz), 7. 25(21 d, 1=8. 6Hz), 5. 50 (2H1, 4 .36-4. 21 (1H, mn), 3.27(311, s 2. 74(311, 2. 40-2. 19 (2 1. 99-1. 79411,.m), 1. 7 1-1. 60 1. 49-1. 19 (3 H, mu) Purity >90% (NMR) MS 602 (wnl) :Example No.

218 1H NMR 6) p.

300Mflz, DMSO-d6 12. 911, brs), 8. 25 8. 04(111, d, 1=8. 7Hz), 7. 91 1H1, d, J=8. 6Hz), 7. 72(2H1, d, J=8. 5Hz),.7. 67(21,d, 1=8. 7 Hz) 7. 56 (2H1, d, 1=8. 5Hz) 7 26 (2H1, d, J=8. 7Hz), 5. 45 (2 H 4. 31(1H, 2.713OH, st, 2: 40-2. 15 (2H1, 2. 1. 80 1. 75-1. 55(11, mn), 1. 55-1. 15 (3H,m).

Purity >90% (NMR) MS 558 (u+1) 4.

-9 Example No.

219 1H NMR 6) PPM 300KHz, DMSO-d6 8. 21 (11, d, J=1. 5Hz),?7. 93( 111,d,J=9.0 Hz) 7. 84(111, dd J9.0, 1. 5z), 7.56 (2H d J=8. 7Hz), 7. 42-7. 30(411: 12 (2H, d, J=8. 7Hz), 4.53 OH1, brs), 4. 36-4. 20(11,.m) 55(21,brs), 3. 00-2. 90 111. 2. 70-2. 58 (LH, Wn, 2.

40-1. 10(181,m) Purity 90% (NMR) MS 544 1)

-I

248 Table 64 Example No.

220 0 HO b 0' Purity >90% (NMR) MS 540 (M+i) 1H NMR ppm 300MHz, DMSO-d6 12.76(lH,s),8.23(1H,s), 7 .96and7.87(2H, ABq, J=8. 9H z),7.69and7.19(4H, A'B' q, J=8. 6Hz), 7.55(1H, 7.37 t, J=8. lHz), 6.91(1IH, d ,J=7.8Hz), 6.85(1H, s),6.7 4(1H,d,J=7. 5Hz), 5.13(2H s),4.31(lH, brt, J=12.2Hz) ,2.65(3H, 2.41-2.20(2H 2.00-1.74(4H, 1.70 -1.59(1H,m), 1.58-1.20(3H ,m) Example No.

221 1H NMR(6) ppm 300MHz,DMSO-d6 8.23 (H,s),7.96and7.86(2 H,ABq,J=8.6Hz),7.69and7.

18(4H, A' B' q, J=8. 7Hz), 7. 3 7(1H, t, J=8.2Hz), 6.87(1H, d, J=8. 2Hz), 6.82(1H, 6.

d, J=8. 0Hz), 5.24(2H ,s),4.32(1H, brt, J=12.2Hz 2.58(3H,s),2.38-2. 20(2 H, 2.30(3H, 2. 00-1. 7 9(4Hm),1. 70-1.59(1H, 1.44-1. 20 (3H, m) Purity >90% (NMR) MS 554 (M+1) Example No.

222 H 1 N

O

i 91

SC

Purity >90% (NMR) 1H NMR(6) ppm 300MHz, DMSO-d6 12.88(1H1, brs), 8. 25(s, 1H) ,8.07-7.57(11H, 7. 26(2 H, d, J=8. 7Hz), 7. 24(111, m), 4.34(1H,m), 2. 30-2.20(2H, 2.03-1. 78(4H,m), 64( 1H, 1. 49-1. 19 (3H, m).

MS 557(M+ 1) 249 Table Example No.

223 0 HO

-CN

NN 0-.

Cl Purity 9 0% o (NMR) MS 544 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 10.96(1H, brs), 8.21(1H,d, J=1. 4Hz), 7.93(1H, d, J=8.7 Hz), 7. 84(1H, dd, J=8. 7,1.4 Hz), 7. 76-7.40(711, 7.18 (2H, d, J=8. OHz), 4.24-4.16 2.40-1.12(1811,m) Example No. 224 0 1 1 HO x N Nl

N

b 0 Purity >90% (NMR) MS 544(11+1) 1H NMR(6) ppm (DMSO-d6) 6 :8.22(1H,s),8 .07(1H,d,J=8.4Hz),7.92(1 H, d, J=8. 4Hz), 7. 54(21, d, J 7Hz), 7. 40(21, d, J=8. 4H z),7.30(2H,d,J=8.4Hz),7.

14(2H, d, J=8. 7Hz),4. 61(2H 48-4. 32(1H, 3. 82 (1H, brd,J=12.3Hz),3.65-3 .47(2H,m),3.10(brdd,J=8.

4, 12. 3Hz), 2. 40-2. 20(2H, m ),2.09-1.76(6H, 1.71-1 .16(6H,m) Example No.

225

CI

0 HO'- N Oj0

NH

2 600 1H NMR(6) ppm (DMSO-d6) 6 :12.83(1H,brs 10(1H,brs 01-7. 91(2H,m),7. 89-7 .82(2H,m), 7.75(1H, d, J=8.

OHz), 7. 59(2H, d, J=8. 7Hz), 7.53(4H,s),7. 46(1H, brs), 7.12(2H, d, J=8.7Hz),7.23( 211, 4.35-4.17(1H, 2.

38-2. 20 1.99-1. 79( 4H, 71-1.59(1H,m),1.

48-1. 18(3H, m) Purity

MS

>90% (NMR) 580(u+1) 250 Table 66 Example No.

226 0 Puit >90 CINMR) Purity >90% (NMR) 1I NMR(6) ppm 300MHz,DMSO-d6 8. 33and8.08(2H, ABq, J=8. 7 Hz), 8. 31 (1H, 7. 66and7.

26(4H, A' B' q, J=9. 2Hz), 7.4 2and7. 39 (4H, A'B'q, J=8. 7H 4. 57 (2H, 4.50(1H, br t,J=12.2Hz),3.85-3.62(3H 3. 28-3.16(2H, 2. 42 23 2. 14-1. 81(6 1. 72-1. 25 (6H, m) MS 544(1+1) 1 Example No.

227 0 HO t JI>--O .I Purity >90% (NMR) MS 554(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 43(1H, d, J=5. 0Hz), 8. 23( 1H, 7.96and7.86 (2H, ABq 6Hz),7. 69and7. 18(4H B'q, J=8. 6Hz), 7.57(1H, 7.47(IH, d, J=5.0 Hz), 7.

40(2H, t, J=8. 2Hz), 6. 91(1H J=8. 3Hz), 6. 85 (1H, 6 .77 (1H, d, J=7. 9Hz), 5.25(2 H, 31(1H, brt, J=12. 2H 2. 40-2. 19(2H, 1. 99- 1.75 1. 73-1. 57(1IH, 1. 49-1.19(31, m) -q Example No.

O

I

228 1H NMR(6) ppm 300MHz,DMSO-d6 12. 80(1H, brs), 8. 22(1H, s) ,7.94(1H, d, J=8. 6Hz), 7.87 (1N, d, J=8. 6Hz), 7. 60 (2H, d J=8. 7Hz), 7. 32 (2H, d, J=8.

7Hz) 7. 17(2H, d, J=8. 7Hz), 6 .70(2H, d, J=8. 7Hz), 4. 35-3 .97(4H, 3. 62-3. 11(2H, m 96(6H, 39-1. 12(1 4H, m) Purity 9 0% (NMR) MS 567 (M+1) Table 67 Example No.

229 1H NMR(6) ppm 300MHz, DMSO-d6 8. 25(1H, 8. 20 8.

04 (1H, dd, J=8. 1, 1. 8Hz), 7.

92(1H, d, J=8. 1Hz), 7.84(lH d, J=9. 9Hz), 7. 62-7. 50 (7H 12(2H, d, J=8. 14(2H, 4. 36 (2H, q, J=6.

9Hz), 4. 30-4. 20 (1H, 2. 3 8-2. 18 (2H, 1. 98-1. 18 (8 H, 1. 35(3H, t, J=6. 9Hz) Purity >90% (NMR) MS 608 (M+1) Example No.

230 0

HO

No 1H NMR(6) ppm 300MHz,DMSO-d6 8. 35(1H, s),8.27 (1H, d, J=8 .7Hz), 8.05(1H, d, J=9.OHz) ,7.87(2H, d, J=8. 7Hz),7. 74 t, J=8. 1Hz), 7. 64 (1H, d J=7. 8Hz), 7.59-7.50 (2H, m 7. 36(2H, d, J=8. 7Hz), 4. 3 9 (1H, 40-2. 15(2H, m), 2. 15-1.95 (2H, 1. 95-1.7 5(2H, 1.75-1.55(1H, m), 1.55-1.20(3H, m).

Purity about MS 481(M+1) Example No.

231 0

HO-YV

I--

1H NMR(6) ppm 300MHz DMSO-d6 12. 78 brs), 8. 23(lH, d, J=1. 5Hz), 7. 96 (IH, d, J=8. 7 Hz), 7. 87 (1H, dd, J=8. 7, 1. Hz), 7. 75 (2H, d, J=8. 4Hz), 7 .63(2H, d,J=8.4Hz),7.52(2 H, d, J=8. 4Hz), 7. 24(2H, d, J =8.4Hz), 5. 47(2H, 4. 29( 1H, 2. 97 (6H, brs), 2. 72 3H, 2. 39-2. 16(2H, 2.

00-L 78 (4H, 71-1. 59 1H, 1.49-1. 17(3H, m).

Purity about 90%(NMR) MS 595 (M+l) 252 Table 68 Example No.

232 1H NMR(6) ppm 300MHz,DMSO-d6 12.8(1H, brs), 8.22(1H, s), 7.96(lH, d, J=8. 7Hz), 7. 86( 1H, d, J=8. 6Hz), 7. 70 s) ,7.59(2H, d, J=8. 7Hz), 7. 53 -7.50(5H,m),7.42(1H, d, J= 7.9Hz), 7.12(2H,d,J=8.7Hz 11(2H, s),4.27(1H,m), 3.01(3H, brs), 2.97(3H, brs ),2.40-2.15(2H,m),2.00-1 .75(4H, 1.75-1.55(1H, 1.50-1. 15 (3H, m).

Purity 9 0% (NMR) MS 608 (M+1)

-T

Example No. 233 HO SN

HCI

Purity >90% (NMR) MS 553(M+I-HC1) 1H NMR(6) ppm DMSO-d6 13.20(1H,brs),8.99(1H,s) ,8.32(1H, s),8.25(1H, d,J= 8.8Hz), 8.04(1H, d J=8.6Hz 79-7.74(4H, m),7.60(2 H, d, J=8. 5Hz), 7. 30 (2H, d, J =8.7Hz), 5.26(2H, s),4.36( 1H, 2.72(3H, 2. 50-2.

15(2H, 2. 15-1.95(2H, m) ,1.

9 5-1.75 (2H, 1.75-1.

m1.55-1. 15(3H, m) -7 Example No. 234 HO 4N 2HCI Purity >9 0% (NMR) MS 538(M+1-2HC1) 1H NMR(6) ppm DMSO-d6 8. 77(1H, d, J=3. 6Hz), 8. 36- 8.26(3H,m), 8.08(lH, d,J=8 .8Hz), 7.79(2H, d, J=8. 7Hz) ,7.72-7.64(3H, 7.58(2H J=8. 4Hz), 7.30(2H, d, J= 8. 7Hz), 5. 26(2H, s),4.38(1 H, m),2.50-2. 15(2H, 1 5-1. 95(2H, 1.95-1. 75 (2 H, 1.75-1. 55 1. 5-1.15(3H,m).

253 Table 69 Example No. 235

CI

HO- q

-O

Purity >90% (NMR) MS APCI-Ms 538(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 12. 74(1H, brs), 8. 67 (1f, dd J=3. 1, 1. 6Hz),8. 21(11, d, J=1.6Hz),7.93(1H, d=8.6H 7. 90-7. 80(2H, 7. 7. 50(7H, 7. 09 (2H, d, J=8 .7Hz), 5. 16(2H, 26(1H Sm), 2. 40-2. 20 (2H, 2. 00 60(5H, 1. 50-1. 20(3H Sm) Example No. 236 1H NMR(6) ppm 300MHz, DMSO-d6 O 8. 40-7. 40(11 H, 2. 95, 2.

H N 81(3, each HO N- CI d J=4 7Hz), 2.40-2. 20(2H, N _N m, 2. 10-1. 80 (4H, 1 N 60 1. 50-1. 20(3H, 6 2A>U m)

-N

H

CF

3

CO

2

H

Purity >9 0% (NMR) MS APCI-Ms 555(M+1) Example No. 237 11H NMR(5) ppm Cl 300KHz, DMSO-d6 8. 21(18, 15(1H, d, J=9 O .5Hz), 8. 02 (1H, 8. 00-7.

(3H, 7.70-7. 50 (6H, m) HO N N 12 J=8. 7Hz), 5. 16 N 'N N (2H, 28(1H, m),2.40-2 NN 65 (1H, 1.50-1.20(3 H,m) Purity >90% (NMR) MS FAB-Ms 605(M+1) 254 Table Example No.

238 1H NMR( 6 ppm 300MHz, DMSO-d6 12. 80(1H, brs), 8. 54(1H, s) 25(1H, 7. 98and7. 88( 2H, Abq, J=8.6Hz),7. 76(2H, d, J=8. 6Hz), 7. 53-7. 31(3H, 6. 61(1H, 5.46(2H, s) 32 (1H, brt), 2.40-2. 2H, 2. 02-1. 79 (4H, 1.

69-1. 59(1H, 1. 48-1. 19( 3H, m) Purity >90% (NMR) MS APCI-Ms 521 (M+1)

I

Example No.

239 1H NMR(6) ppm 300MHz,DMSO-d6 12. 79(1H, brs), 8. 60(2H, d, J=1. 5Hz) 53 (1H, s),8.25 7.98and7. 85(2H, AB q,J=9.4Hz),7. 76(2H d, J=9. OHz), 7.44(4H, d, J=6 .5Hz),6. 69(1H, 53(2H 4. 32 (IH, brt), 2. 40-2.

19 (2H, 2. 03-1. 82 (4H, m) 1. 72-1. 61 m), 1.42-1.22(3H, m) Purity 9 0 (NMR) MS APCI-Ms 522(M+1)

-I

Example No. 240 1H NMR(6) ppm 300MHz, DMSO-d6 8. 90(1H, 32(1H, s),8.

28 8. 25 d, J=8. 3 Hz), 8.05(1H, d, J=8.8Hz), 7 .96(1H, s),7.93(1H, d, J=8. 8Hz), 7. 83 (1H, d, J=8. 4 Hz), 7. 68-7. 59(2H, 7. 54 (2H, d, J=8. 8Hz), 4. 37 (1H, b rt),2.30(2H, 00(2H, m 1. 88 (2H, 1. 67 (1H, 1.5-1.2 (3H, m) Purity >9 0% (NMR) MS APCI-Ms 525(M+1) 255 Table 73 256 Table 72 Ex. No. Formula MS 1007 357 (M+H) 0

N

1008 416 (M+H)

H

2 N N N N

N

6CR 3

L

1009 0 310 (M+H)

H

2 N N

I

N

1010 0 390 (M+H)

H

2 N N N 0 N 6

F

1011 0 N02 395 (M+H) H 2 N N N

N

6 1012 0 3 66 (M+H)

H

2 N N

N-

N>

OH

257 Table 73

-OH

414 (M+H) -o CH3 258 Table 74 Ex. No. Formula MS 1019 H3O 350 (M+H) 0 3 0

H

2 N NN 1020 0380 (M+H)

H

2 N

N

N0

OH

1021 OH 366 (M+H) 0 HN N

N

1022 0378 (M+H)

N

1023 0Br 402(M+H)

H

2 N N N

F

259 Table 260 Table 76 Ex. No. Formula MS 1030 O 43(M+H)

OO

AN'

b 1_ 1032 .0 307 (M+H) HP\

N

N N 1033 406 (M+H)

O

H

2 N N 0 1034 466 (M+H) 0 0-~

H

2 N I N

F/-

A N F F 1035 ,412 (NI-H) 00

N

A N 261 Table 77 406 (M+H) 417 (M+H) 1041 262 Table 78 263 Table 79 Ex. No. Fo rmfulIa M S 1048 F 374 (M+H)

FF

H2N 0

N

1049 N -398

(M+H)

t N N0

HN

1050 0 326 (M+H) hIN N s CH 3 H2N 1051 442 (M+H) 0 0 0O-CH 3

N

1052 518 (M+H) NJ\X-<N 264 Table 80 Ex. No. Formula MS 1053 442 (M+H)

H

2 N N N 0 N C8 3 1054 0 376 (M+H)

N

0 1055 0 442 (M+H) H2N Kl:N

N

/0 H3 1056 0CH 3352 (MiH)

H

2 N N

-O

N\-

1057 0 367 (Mi-H)

H

2 N /0H 1058 0 NO 2 367 (M+H) NO 2 265 Table 81 266 Table 82 Ex. No. Formula MS 1065 351 (M+H) F N

N

NO

2 1066 0 366 (M+H)

H

2 N 0 1067 o 6(MH

H

2 N NzzN N NO 2

N

d OH 1068 0 364 (M+H) H2N

N

1069 o 350 (M+H)

H

2 N 0N H2N 0OH 1070 0306

H

2

N

267 Table 83 268 Table 84 269 Table 270 Table 86 Ex. No. Formula

MS

1089 FC)351

(M+H)

HO I-Z.N

N

1090 031MH 0 OH H O

-I

1093 O 43(MeH)

HON

F

0I 271 Table 87 272 Table 88 474(M+H) 1101 0

HO

6b 273 Table 89 Ex. No. Formula MS 1106 429 (M+H) HO N

CH,

1107 4 0 467(M+H) HO-'IN 1108 o

HO

0 C 1109 o HO N O

NO

2 1110 O 441(M+H) F F

HO

1111 0 418(M+H) N1O HO N 0- 22II Kr 274 Table 0 HO _0

'N

275 Table 91 Ex. No. Formula MS 1118 519(M H) HO N

N

1119 43 (M+H

N

HO

N C H 1121 0 O-CH 3 (M-iI-) HO NN

N

1122 a-C 433(M+H) HO NN

N

HO N

O

276 Table 92 277 Table 93 1130 0 HO -111-

-NO

2 .0

CH

1133 0 HO

N

N.

b H 3

C

278 Table 94 279 Table Ex. No. Formula MS 1141 0H322(M+H) HO -r N -y

N

1142 364 (M+H) HO N N

N;

d oo 1143y 1143 0 OH 323(M+H)

"JC~N

HO .N 1144 0 363(M+H) HO N N OH N C CH 3 1145 0o 484(M+H) HO N0 0

-HH

1146 385(M+H) HO NN 0 280 Table 96 281 Table 97 474 (M+H) 0 HO 1 1153 HO N

I-

1154 282 Table 98 1160 0O

HO--N

y N 0 "J~6~ 283 Table 99 Ex. No. Formula MS 1161 468 (M+H) 0

H

HO NN

N

N.

1162 N. CH 3 4 47 (M+H) 0r HO NN

N)

N 0 1163 466(14+H) HO

N

AN 0 1164 OMe 526(M+H) o -OMe HO' NN AN 0 1165 0 420 (M-iH) 0

C

HO N N N A N (0 284 Table 100 285 286 Table 102 Ex. No. Formula MS 1178 /C,447 (M14-) HO NZ N

N)

1179 C- 3 433 (M+H) 0

C

HO N, I N 1180 509 (M+H)

HO

N 0 1181 F513 (14-H) HO IN- N) 287 Table 103 Ex. No. FruaMS 1182 N' ~497 (M+H) tN HO N

I

N0 11843jI 418 (MAH) 0 HO

N

N, 0 1185 508 (M+H) 0

HO

1186 0 C 3 408(M+H) 0 N 0N K _H 288 Table 104 441 (M+H) 504'(M+H) 289 105 Ex. No. Formula

MS

1193 0 0 o 512 (M+H) HO N 1194 0504 (14+1)

H

HO N

B

1195 516(MeH) 0

H

HO N N N N 0 1196 HO0 N-a -H 497 (M+H) 117 HO N N N-a~ 46MH N 0 1197 o 569 (t4+H)

HO'-N

XN 0 _b 290 Table 106 Ex. No. Formula MS 1199 o 483 (1+8) O H N 0 1200 0o2(MH HO N 0 1201 o 427(14+H) N H HO \NN 1 N 0 1202 -N 477 (1+8) H O N

'I

MN 0 1203 0 N 519(14+8) 1204 40044 00

HP

HO N N

N

N o 6 291 Table 107 Ex. No. Formula MS 1205 454 HO

N

N 0 1206 0 325 (M-4H) HO NN

N

1207 0 341 (M+H) HO N:N l

N

1208 0 385 (MA-H) HO N Nr N B 1209 0 363 (MiH) HO

N~

N

6 1210 a 332 (M+H)

N

HO 6N

N

292 Table 108 293 Table 109 Ex. No. Formula MS 1217 o 433(M+H)

HO

1218 o 391(M+H) HO N N F d F F 1219 0 337(M+H)

HN

O-

CH,

1220 o 385(M+H) HO N d Br 1221 0 341(M+H)

HON

1222 o 332(M+H) HO NN

N

294 Table 110 295 Table 111 0

HOH

N 0 1231 HO N 296 112 Ex. No. FruaMS 12350 0498 (M44H) N 0 QCt3 1236 476 (N-fH) 0 HON N H N0 1237 6502 (M+H)

H

1239 HO

NN

N 0 297 113 Ex. No. Formula MS 1240 o 483 (M+H) N 0 1241 0408 (M+H) O0 -OH N 0 1242 ci460(M+H) 0 HO

N

A N 0 1243 0 468 (M+H) NOk 0 1244 0 F 494 (M+H) HO N N FF 1245 HC454 (M+H) 0 HO N C\ H 3 298 114 Ex. No. Formula MS 1246 H 3 C 468 (M+Hf) 0 H HO N1- NI N 0 6 1247 o 498 (M+H) N JP< CH3 1248 0 H 482 (M+H) HO'If:NN 1249 11 HC 46'(+HI 3 00

H

HO N N K-N 0 1250 a 460 (Mr-+H) 0 0 N1

H

HO NN

N

299 115 Ex. No. FruaMS 1251 OH 442 (M+H) 0 HO

N

1252 0468 (M+H)

CH

3 0 0 1253 456 (M+H) O -\OH HO NO N

N

6 _b 1254 a494 (M+H) 0 0 HO NN

N

300 116 Ex. No. FruaMS 1255 451 (M+H)

CN

0 0 N

H

HO

NN

Ne 1256 HONO 3 468 (M+H) 1257 0 f0H 3 49 (MH 0 N

H

HO

NN-

1258 d O-H3 470 (M+H) 0 0 0

N

H

NI

301 Table 117 Ex. No. Formula MS 1259 476 (M+H} 0- 0 N

H

HO N 1260 -502 (M+H)

N

H

HO N

N

1261 jH 2 505 (M-Ui) 0 0

N

H

HO NN

N

1262 NH 2 469 CM+H) 0

N

HO N N-e

K-N

302 Table 118 1263 483 (M+H) 303 119 Ex. No. Formula MS 1267 F 494 (M+H)

F

0 0N HO N

N

1268 OH 3 454 (M+H) 00 HO N N

N

1269 48 (M+H) 0 0 HO N N Cl-i

N

1270 C3 48MH 00 HO NN

I-CN

304 Table 120 482 (M+H) 305 Table 121 Ex. No. Formula Ms 1275 N 0 H519(M+H) a >Z N o HO 11 N

XN

1276 PN427 (M+H) 0 0

N

HO'C

1277 O-CH 3 456(M+H) 0- 0

N

H

N

1278 516 (M±H) 0 0- HO N

N

___kmb 306 Table 122 o pH 3

N

H

307 Table 123

CH

3 K3C CH *jN

CH

3 308 Table 124

NQ

309 Table 125

F

-N F

H

310 126 Ex. No. FruaMS 1298 H CH3 435 (MiH) O 0

N

HO N -H

N

1299 ci488 (M+H) 0. 0 HO N N

N

1300 454 (M+H) HO N N

I-CCN

1301 54MH /\Br 0 ~0 0 N

H

HO N N 110 N 6 311 Table 127 Ex. No. Formula MS 1302 H 3 C 513(M+H) )0

HN

0- 0

O-C

3

HO

N

Ho\

N

1303 o 399(M+H) HO N

N

1304 0 530(M+H) HO N 6 0_ 1305 0 504 (MH) HK N 0 1306 0 440(M+H) HO~k N

I\N-

N 0 312 Table 128 1307 518 (M+H) 313 129 Ex. No. Formula MS 1312 /OH 3 546(M+H) 0 N 0 1313 HO/\484 (M+H) HO N HO NO 0 1314 o 517 (M+H)

SN

NtI 0 cl 1315 488 (M+H) o HO NN 1316 cl 481 (M+H) 0 0 HO ~NN Hk \d ci 314 Table 130 315 Table 131 1324 0o 4 49 (M+H) 316 Table 132 Ex. No. Formula MS 1328 o 497 (M+H) HO N 0

N

1329 0 470 (M+H) HO N 0 N

N

b HO 1330 0 530 (M+H) HO N -0

NN

b

H

1331 a502 (M+H) 0

N

H

HO N

N

1332 0 522 (M+H) HON 0

H

N N b _a 317 Table 133 Ex. No. Formula MS 1333 491 (M+H) 0 HO NN 1334 o 536(M+H) HO N 0 N j 1335 o 547 (M+H) HO N N 0

N-

1336 o 484 (M+H) HO N 0 XN 1337 0 484 (M+H) NO N 0 1338 0 498 (M+H) HO N 0 XN0 318 Table 134 319 Table 135 1346 0 HO1 320 Table 136 321 Table 137 Ex. No. Formula MS 1357 602 (M+H) HO N N 0 X-C N N I 0 1359 0 491 (M+H) HO N 0

N-

H 1\ N 1359 0491 (M+H) HO N~ 0

NN

N\

NN

C M 322 Table 136 323 Table 139 1370 1374 324 Table 140 1375 325 141 Ex. No. Formula MS 1381 0 540 (M+H) HO N 0 0 /-CH, N N- 1382 525 (M+H) HO N 0 0H

N

1383 558 (M+H) HO N- 0- 1384 0 523 (M+H) H N N 0

N-

ill 1385 539 (M+H) N N- HO

H

F F 326 Table 142 0 HO 0 HO N 4 85 (MfI-) 0 HO-1 327 Table 143 1391 328 144 Ex. No. FruaMS 1397 522 (M+H) HO IN, N 0 N

A

C4 1398 0 538 (M+H) HO N 0 IO N

F

1399 522 (M+H) HO N( N 0 [N CA 1400 0 530 (M+H) 1401 o 600

HO

00 1402 504 (M+H) HO NN 0OH H N 329 Table 145 Ex. No.FruaM 1403 534 (M+H) 1404 1 0 1475 (M+H) Ni C 1405 tA I1472 (M+H) 1406 14 55 (M-IH) i i 1407 4 69 (M+H) 1408 1547 (M+H) I L 330 Table 146 488 (M+H) 331 Table 147 332 510 (M+H) 333 Table 149 1426 511 (M+H) 334 Table 150 1436 335 151 Ex. No. Formula MS 1437 0 524 (M+H) 0 HO NN b -i 1438 o 508 (M+H) HO

N

1439 0 474 (M+H)

H

HO NN 1440 0 490 (M+H) HO 'N 1441 0 508 (M+H) HO N-

ICCN

1442 0 474 (MiH) 0 HO 1 Nt

N-

336 Table 152 1443 600 (M+H) 337 153 Ex. No.1 Formula

MS

1448 530 1449 1 .0 14 40 (M+HT- 1450 1451 1i 490 (M+H) 4 74 (M+H) 441 (M+H) 1452 1453. 508 (Mi-H) HO N N SN P ci 338 455 (M+H) 1457 516 (M+H) 339 Table 155 340- 156 Ex. No. Formula MS 1466 a4 586(M+H) 0

C-

HO N: N 0 N r b 1467 HO0 1 N518 (M+H) N0 HO N b 1469 598 (M+H) N Nl HO N N

O

b 1471 544 (M+H) NO

N

341 157 Ex. No. Formula MS 1472 440 (M+H) Nb 1473 0 H 490 (M+H) Ho NN A- N b 1474 474 (M+H) HO N- 1475 HON441 (M+H)

N

1476 -508 (M+H) HO'N\_ CI 1477 455 (M-IH) HO NN ACN N 342 Table 158 Ex. No. Formula MS 1478 522(M+H) b

U

1479 0- CF 496(M+H) HO N N C CH., b 1480 516(M+H) HO NN 1481 426(M+H)

HON

1482 F C 482 (M+H)

CH,

SN

343 Table 159 Ex. No. Formula MS 1483 o-CHi 3 486(M+fH) 00C HO N>-6

AN

1484 516(M+H)

N

1486 476 (M+H)

N

b 344 Table 160 345 T a b l e 1 6 1 Ex. No. FruaMS 1491 530

(M+H)

N

1492 598

(M+H)

ci- HO

N

ci 1493 512(M+H) AN

OH

1494544

(M+H)

HO

N

346 Table 162 Ex. No. Formula MS 1495 0 580 (M+H) HO N~

N

N 0 cti 1496 0 550 (M+H) HO A N

C-

NN-

b

CI

1497 606 (M+H) HO:C N N

CM

1498 o-CF-I 580 (M+H) N N C HO N C HO 6 4 347 Table 163 Ex. No. Formula MS 1500 H 3 C 606(M+H) Cx

N

Ho N N Cl b 1501 630 (M+H) 'o F t

-F

F

1600 (MWH) 1502 1 o t0 F

F

1503 I 0 348 164 Ex. No. Formula MS 1504 O-CH 3 630 (M+H) N HO N N F F)N N

F

1505 600 (M+H) 0N HO k N>-6 N 0)2 N F 1506 Isc 656 (M+H)

CH

3

CHS

HO N N F/ HOIC N

F

1507 o 580 (M+H)

CH

3 349 Table 165 350 166 Ex. No. Formula MS 1513 516 (M+H) HO N 11I N

__O

b 1514 572 (M+H) 0110 N 1515 O-CH, 546(M+H) 0 NN HO

N

1516 9A 516 (M-iH) HO0 1517 H 3 C 572 (M+H) CH3

HO-

351 167 Ex. No. Formula MS 1518 602 (M+H) HO N N /0

CR

3 1519 o 572 HO N NO N-0j

H

3 C

CH

3 1520 IC N628 (M+H) HO

CH,

1521 0 606 (M+H) HO N -Cl N Nd _c N c C H 3__ 352 168 Ex. No. Formula MS 1522 573 (M+H)

N-

HO I Hc CH 3 15243-ii 602 HO N HC H 3

CH

1525 572 (Mi-H) N

CH,

HO'-

CH

3

N

353 Table 169 354 Table 170 640 (M4H) -N F

F

355 Table 171 356 Table 172 1540 357 Table 173 Ex. No. Formula MS 1542 F F 627 (M+H)

F

H

1543 560 (M+H) O 0 HO O O 1544 No, 634 (M+H) 0 oo 1545 593 (M+H) HOo

N

b 358 174 Ex. No. Formula MS 1546 627 (M+H)

N

b

CI

1547 627 (M+H) 0 0i 0

HO

F

1548 560 (14+H) 0 0 N H HO H bF

N

1549 634 (M+H) 0 0t 0 HO N I -NO 2 b O-CH3 359 Table 175 360 Table 176 Ex. No. Formula MS 1554 CA 599 (M+H) 1555 F 599 (M+H)

F

0 HO

N

1556 532 (M+H) 1557 532 (M4-H) N N

H

HO

N

36.1 Table 177 362 Table 178 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitoryactivity

IC

5 0 ICso [pM] 2 0.079 67 0.26 6 0.034 68 0.28 9 0.019 70 0.19 11 0.53 71 0.62 12 0.60 77 0.51 17 0.047 81 0.18 0.042 82 0.097 26 0.033 83 0.52 0.052 85 0.17 43 0.58 86 0.13 44 0.95 87 0.80 0.40 88 0.092 46 0.47 89 0.34 47 0.54 90 0.20 48 0.44 91 0.53 49 0.94 93 0.16 0.54 94 0.084 51 1.0 96 0.25 54 0.56 97 0.16 0.36 98 0.30 363 Table 179 Ex. HCV polymerase Ex. HCV polymerase No. inhibitoryactivity No. inhibitoryactivity

IC

5 0 IAM]

IC

50 [1M] 99 0.53 120 0.16 100 0.78 121 0.19 101 0.14 122 0.51 103 0.17 123 0.10 104 0.073 124 0.091 105 0.076 125 0.12 106 0.40 128 0.14 107 0.11 129 0. 12 108 0.21 130 0.16 109 0.11 131 0.046 110 0.24 132 .0.055 111 0.14 133 0.12 112 0.11 134 0.071 113 0.071 139 0.26 114 0.56 140 0.11 115 0.17 141 0.43 116 0.37 142 0.055 117 0.075 143 0.053 118 0.14 144 0.19 119 0.13 145 0.088 364 Table 180 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitory activity ICso [JiM] IC 5 0

[JIM]

146 0.043 167 0.033 147 0.31 168 0.078 148 0.038 169 0.15 149 0. 15 170 0.048 150 0.24 171 0.050 151 0.20 172 0.10 153 0.19 173 0.14 154 0.076 174 0.030 155 0.53 175 0.29 156 0.23 176 0.053 157 0.16 177 0.077 158 0.11 178 0.052 159 0.13 179 0.63 160 0.24 180 0.11 161 0.062 181 0.71 162 0.43 182 0.021 163 0.15 183 0.017 164 0.16 184 0.018 165 0.58 185 0.11 166 0.055 186 0.37 365 Table 181 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitory activity

IC

50 IC 5 0

[M)

187 0.056 207 0.081 188 0.038 208 0.039 189 0.017 209 0. 12 190 0.020 210 0.31 191 0.43 211 0.059 192 0.22 212 0.23 193 0.13 213 0.10 194 0.52 214 0.059 195 0.023 215 0.078 196 0.20 216 0.084 197 0.11 217 0.058 198 0.044 218 0.033 199 0.11 219 0.13 200 0.10 220 0.073 201 0.14 221 0.058 202 0.095 222 0.041 203 0.063 223 0.21 204 0.16 225 0.014 205 0.077 227 0.045 206 0.05 228 .0.18 366 Table 182 Ex. HCV polymerase Ex. HCV polymerase No. inhibitoryactivity No. inhibitory activity tlM] ICso [PM] 229 0.022 257 0.074 230 0.17 259 0.10 231 0.073 260 0.27 232 0.015 262 0.013 233 0.028 263 0.035 234 0.022 264 <0.01 235 0.036 265 0.014 236 0.075 266 0.018 237 0.015 267 0.014 238 0.19 268 0.012 239 0.17 269 0.013 240 0.055 270 0.012 248 0.012 271 0.024 249 0.022 272 0.066 250 0.018 273 0.041 252 0.32 276 0.023 253 0.65 279 0.017 254 0.038 280 0.016 255 0.038 281 0.052 256 0.079 282 0.019 367 Table 183 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitory activity 50 [sM] IC 50

[I.LMI

283 0.014 300 0.045 284 0.014 301 0.017 285 0.012 303 0. 286 0.014 304 0.017 287 0.012 305 00 288 0.013 3060.1 289 01 3070.2 290 0.012 308 0.023 291 0.016310.6 292 0.015 312 0.023 293 0.034 313 0.025 294 0.032 314 0.097 295 0.045 315 0.028 296 0.034 316 0.022 297 0.022 317 0.032 298 0.011 318 0. 012 2997 0.018 319 0.030 368 Table 184 Ex. HCV polyinerase Ex. HCV polymerase No. inhibitoryactivity No. inhibitory activity 5 0 [pMJ IC 5 0 (pM) 320 0.036 328 .1 321 0.015 329 0.047 322 0.016 330 0.011 323 0.018 331 0.017 324 0.027 332 0.023 325 0.019 333 0.016 326 0.018 334 0.016 327 0.019 335 0.013 369 Table 185 Example No. 249 111 NMR(6) ppm Example No.

249 0 HO-a 1H NMR(6 ppm 300MHz, DMSO-d6 8. 02 (1H, d, J=1. 5Hz), 8. 11( IH, d, J=1. 8Hz), 7. 96-7. 81( 311, 7. 67 (111, 61-7.

49(6H, 7. 08 (2H, d, J=8. 6 Hz), 5.19(2H, s),4.25 (1H,m 17(2H, 1. 96-1 78 (4H, 1. 70-1. 56(1H, m 1. 46-1. 16(3H, 1. 11(9 H, s) Purity >9 0% (NMR) MS 672(M+1) Example No. 250 LH NMR(6) ppm Example No.

250 1H NMR 6 ppm 300MHz, DMSO-d6 8. 25 (1H, d J=1. 5Hz), 8. 16- 8. 08 (2H, 7. 99-7. 88(2H, 7. 66 (211, d, 6Hz), 7.

60-7. 48 (5H, 7. 19(2H, d, J=8. 6Hz), 5. 17(2H, 4. 31 (1H, 2 3 9 2 20(2H, 2 04-1. 79(4H, 1. 72-1. (1H, 1. 50-1. 18 (3H, m) Purity >9 0% (NMR) MS 616(M+1) Example No. 251 1H NMR(6 ppm 300MHz, DMSO-d6 cis and trans mixture 8. 13and8. 11(total IH, each 7. 90-7. 74 (2H, 7. 42- 7. 22 (511, 4. 56and4. 52 (t otal 2H, each 4. 42 (1H, brs), 3. 78-3. 0 6 (2H, m) 2. 33-1. 33 (18H, m) Purity 9 0% (NMR) MS 433 (M+1) 370 Table 186 Example No. 252

O

N i N S Purity >90%

(NMR)

1H NMR(6) ppm 300MHz,DMSO-d6 8.20(18H, d, J=1.5Hz), 7. 96( 1H, d, J=8. 6Hz), 7. 84(1H, dd ,J=8.6,1.5Hz),7. 54(2H, d J=6.9Hz),7.48-7.26(8Hm 37.09(1H, t,J=7. 3Hz),5.43 (2H, 4. 06(111, 40-2 .20(211, 01-1.80(4H,m 1.75-1. 64(1H, m),1.51-1 .28(3H, m) Ms 509(M+1) Example No.

253 0 uHO N Purity 90%

(NMR)

IH NMR(b) ppm 300MHz,DMSO-d6 8.21(1H, d,J=1. 5Hz), 7.93( 1H,d,J=8. 7Hz), 7. 85(111, dd 4, 1. 5Hz), 7.54-7.47( 2H,m), 7. 40-7. 24(6H, 7.

15(1H, d, J=3.6Hz), 7.11-7.

05(1H,m),6.81(1H,d,J=3.6 Hz), 5.26(21, 4.96(1H,m 32-2. 13(2H, 1. 95-1 72(4H,m), 1. 68-1. 55(111,m 18(3H,m) Ms 493(11M+1) Example No.

254

F

HOa

N

N'I N b 9,,OH Purity >9 0% (NMR) MS 558(M1+1) 11 NMR(6) ppm 300MHz,DMSO-d6 8. 25(1H,s),8.02(1H,d,J=8 .7Hz), 7.90(1H, dd, J=8.4,1 .4Hz), 7. 80-7. 71(21, 7.

67(211, d, J=8. 7Hz), 7. 33(2H t,J=8.7Hz),7.26(211, d,J= 8. 7Hz), 5. 46(2H, 78(2 H, 31(1H, 2. 39-2. 1 9(2H, 2. 03-1. 79(411, m), 1. 71-1. 59(1H, 1. 50-1. 1 7(3H, m)

I

371 Table 187 Example No. 255 1H NMR(6) ppm OH 300MHz,DMSO-d6 0 8.34(1H,s), 8.32(111H, d, J=8 HCI .8Hz), 8. 09-8. 03 7.

0 83 (2H, d, J=8. 3Hz), 7. 79(2H N J=8. 8Hz),7.36(211, d, J= H 0 N 8.8Hz),5.54(2H,s),4.38(1 N N 2.74(3H,s),2. 40-2.1 s 8(2H,m),2. 13-1. 96(2H, m), 1.93-1.78(2H, 1.73-1.5 7(111,m), 1.55-1. 15(3H, m) Purity 9 0% (NMR) MS 568(M+1) Example No.

256 11 NMR(6) ppm 300MHz,DMSO-d6 12. 67(1H, brs), 8. 23(1H, s) ,7.94and7.87(2H,ABq,J=8.

6Hz),7.79(1H, dd,J=8.7,5.

4Hz), 7. 62-7. 41(7H, 6. 8 0(1H, dd, J=11.9, 2.3Hz), 6.

69(1H,dd,J=8. 1,2. 20(2H, s),3.93(lH,brt,J=1 3Hz), 2. 30-2. 11(2H, brm) 1. 88-1. 74(4H, brm), 1. 64-1 .58(1H, brm), 1.41-1. 14(311 ,brm) Purity >90% (NMR) MS 585(M+1)

I

Example No. 257 0

I,,CIO

s N HO'

P

/0_ Purity 9 0% (NMR) MS 603(M+1) 11 NMR(6) ppm 300MHz,DMSO-d6 8. 19(lH,d,J=8. 7Hz),7. 93( 1H, 7. 83-7. 71(3H, 7.

50-7. 39(4H, 7. 34-7. 4H, 7. 06(1H. dd, J=8. 4, 2 .9Hz),5.09(2H, 34(H 3. 82(3H, 2. 39-2. 19 (211, 11-1. 98(2H, ),l .94-1.79(2H, 1.74-1.58 1. 52-1. 21(3H, m) 372 Table 188 Example No. 258 1H NMR(6) ppm 300MHz,DMSO-d6 7. 79(1H, d, J=6. 7Hz), 7. 56( 1H, d, J=7. 5Hz), 7. 49(2H, d, J=8. 6Hz), 7. 42 (4H, 7.32 23(3H, 7. 09-7. 03 (3H 02(2H, s),4.46(1H, m 3.82(3H, 1.95-1. 83(2 H, 1. 75-1.44 (5H, 1.3 0-1. 10(2H, 0.89-0. 71(1 H, m) Purity 9 0% (NMR) MS 567(M+1) a Example No. 259 2HCI 1H NMR( ppm 300MHz, DMSO-d6 8. 93 (2H, d, J=6. 6Hz), 8. 36( 1H, s),8.28(1H, d, J=8.7Hz) 10-8. 03(3H, 7.85(2H J=8. 7Hz), 7. 33 (2H, d, J= 8. 7Hz), 7.23(18, 7. 23(1 H, 6. 81(1H, 5. 56(2H, s),4.39(1H, 2.97, 2.92( 6H, 2. 40-2. 18(2H, 2.

16-1. 95 (2H, 1. 90-1. 2H, 1. 70-1. 55(1H, 1.

50-1.15(3H, m) Purity 9 0%(NMR) MS 591 (M+1) Example No. 260 111 NMR(6) ppm Example No.

260 1H NMR(6) ppm 300MHz,DMSO-d6 8. 93 (2H, 3Hz), 8. 1H, 8. 26(1H1, d, J=8. 7Hz) 09-8. 02 (3H, 7. 86(2H J=8.7Hz), 7. 50 s),7 .35(2H, d, J=8. 4Hz), 7. 24 (2 H, d, J=7.8Hz), 5.60 (2H, s), 4. 39 (1H, 2. 50-2. 18 (2H, 2. 15-1. 95 (21, 1. 1.75(2H, 1.70-1. 55 (1H, m) 1. 50-1. 10 (3H, m) Purity >90% (NMR) MS 564 (M+1) 373 Table 189 Example No.

261 HO o

A

1H NMR(6) pp.

300MHz,DMSO-d6 8. 22(1H, d, J=7. 8Hz), 7. 1H, d, J=6. 7Hz), 7.63(2H, d, J=9. OH),7. 51-7.38(5H,m), 7.29(1H,d,J=8.3Hz),7.23( IH, d, J=3. OHz) 7. 06(2H, d, J=9. OHz), 7.06(1H, dd, J=8.

6, 3. OHz), 5. 05(2H, 4. 41 25(1H, 3. 83(3H, s),2 .40-2. 20(2H, 03-1. 78 1.72-1.57(1H, 1 .50-1.18(3H, m) Purity >9 0% (NMR) MS 567 (M+1) 7 Example No.

262 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(1H, d, J=1. 5Hz), 8. 26( 1H, d, J=9.0Hz), 8. 19(111H, d, J=1. 8Hz), 8. 13(1H, brs), 8.

08-7. 96(2H, 7. 73(2H, d, J=9. OHz), 7. 57-7. 43(6H, m) 24 (2H, d, J=9. OHz), 5. 14 (211, 36(1H, 2. 38-2 18(2H, 12-1.97(2H,m 1. 93-1. 80(2H,m), 1.73-1 58(1H,m), 1.52-1.20(3, m Purity >90%

(NMR)

MS 580(M+1) .1.

Example No. 263

,O

H NMR( 6) ppm 300MHz,DMSO-d6 12.85(1H,brs), 8.72(111, d, J=4.8Hz),8.22(1 14 (1H,d,J=6. 3Hz),8.03and7.

76(4H, ABq,J=8.6Hz),7.93a nd7.85(211, A'B'q,J=8.6Hz) 7. 60and7. 15(4H, AB"q, J= 8.7Hz),7. 55(1H, dd, J=6. 3, 4. 8Hz), 5. 19(2H, 26(1 H,brt, J=12.6Hz),2.35-2.1 8(21, brm), 1; 95-1.77(4H, b rm), 1. 70-1. 60(1H, brm), 1.

45-1. 15(3,brm) Purity >90% (NMR) MS 548(11+1) 374 Table 190 Example No.

264 1H NMR(6) ppm 300MHz,DMSO-d6 8. 23(1H,d, J=1. OHz), 7.92( 1H, dd,J=8. 7, 1.OHz),7.87( 1H, d,J=8.7Hz),7.60(2H,d, J=8.6Hz), 7. 47(2H, d, J=8 7 Hz), 7.44(2H,d,J=8.7Hz),7 .30(lH,d,J=8.3Hz),7.23(1 H, d, J=2.6Hz), 7. 11(2H, d, J 7Hz),7.06(H, dd,J=8.7 6Hz), 5.04(2H, 4. 36( 1H, 3.83(3H, 2. 80-2.

70(4H, 2. 60-2.40(2H, m) ,2.30-2.20(2H,m) Purity 9 0% (NMR) MS 586,588(M+1) Example No.

265 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H, d, J=1. 5Hz), 8.25( 1H, d,J=9. 1Hz), 8.03(1H, dd 1.5Hz), 7. 76-7.96( 3H, 7. 55-7. 49(5H, 7.

42(lH, d, J=7.6Hz), 7. 23(2H 7Hz), 5. 15(2H, s),4 .35(1H, 3.01(3, s),2.9 7 (3H, s),2.37-2. 20 (2H, m), 2.09-1. 97 1.94-1. 8 1(2H,m), 1.72-1. 60 (1H, 1.50-1. 21(3H,m) Purity >90% (NMR) MS 608(M+1) r Example No.

266.

0

HO

HN

HCI

Purity 9 0% (NMR) MS 642 1H NMR(6) ppm 300MHz,DMSO-d6 8.27(1H, d, 5Hz),8.20( IH, d,J=9. OHz), 8. 00(IH, dd 6, 1.5Hz), 7. 82(2H, d, J=8.2Hz),7.76-7.65(5H,m) ,7.56(1H, dd, J=7.9,1.8Hz) 47(1H, d, J=7.5Hz), 7.20 (2H,d, J=8.6Hz),5.16(2H, s ),4.32(1H,m),3.02(3H,s), 2.98(3, 38-2. 19(2H, 2.07-1.95(2H, 1.93- 1. 80(2H, 1. 72-1. 58(1H, 1. 52-1. 18(3H, m) I- 375 Table 191 Example No.

267 26 IH NMR(b) ppm 300MHz, 8. 34 (21, in), 8. 03 (LH, d, J=B 3Hz),?7. 77-7. 6811, in), 7.

54 40(4M, mn), 7. 33 (2H1, d, J=8. 6Hz), 7. 24(21, d,J=9. 0 Hz) 16 (21, 4. 36(111, mn 3. 01 (31, 2. 97(311, s), 2. 40-2. 20 2. 11-1. 9 7 (2H1,rn), 1. 93-1. 81 (2H, mn), 1. 71-1.60(1OH, mn), 1. 50-1. 2 1(311, m) Purity >90% (NMR) Ms 20( 1) IExample No.

268 111 NMR( 6) ppm 300KHz, DMSO-d6 8. 67-8. 5911H, mn) ,8.301OH, 8. 13-8. 20 (2H1, 8. 02- 7. 9 2(211, mn), 7. 65(11H, t, J=8 .3Hz), 7. 56-7. 45 (51, 7.

18(11, dd, fr12.0, 2. 2Hz), 7 05(111, dd, J=8. 6, 2. 2hz), 14 4. 09(Hl,i), 2. 8 2 (31, d, J=4. 5Hz), 2. 34-2. 1 2 (211, 1. 99-1. 79(41, m), 1. 71-1. 59(11,.m), 1. 49-1. 2 1(31,.) Purity 90% (NMR) MS 612 1) Example No.

269 0 HCI HN

F

N'N

00 Purity 90% (NMR) MS 626 (M1+1) 111 NMR(6 ppm 300MHz, DM50-d6 8. 2911H, 8. 13(111, d, J=9 .0Hzt),?7. 97(111, dd, J=8. 6, 1 .5Hz), 7. 71(1OH, d, J1. 8Hz) 7.63(1Hl, t, J8. 2Hz) 7. 56 17(111, dd, J z12.' 0, 2. 2Hz),?7. 03(11H, dd, J=8. 2, 1. 8Hz), 5. 14 (2H1, s), 4. 15-4. 00(111, in, 3. 01 (31, 2. 98(3OH, 2. 32-2. 13 211, in) 1. 95-1. 79411, 1. 7 2-1. 59(111, mn), 1. 45-1. 21(3

H,.M)

376 Table 192 Example No. 270 1H NMR(6) ppm 300MHz,DMSO-d6 8.24(1H, d,J=1. 4Hz),8. 19( 1H, d, J=l. 8Hz), 8. 11(1H, br 02-7.85(3H, 7.60- 7.44(7H, 7. 10(H, dd,J= 12.0,2. Hz),6.98(1H,dd,J 1Hz),5.11(2H, s),3 .98(1H, 2.30-2.12(2H,m 1.91-1. 73(4H, 1.71-1 .58(1lH,m), 1.45-1.15(3H,m Purity 9 0% (NMR) MS 598(M+1) Example No. 271 O Purity >9 0% (NMR) MS 652 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(lH, d, J=1.5Hz), 8.24( 1H,d,J=8.7Hz),8.07-7.98( 3H, 7.80-7. 68(5H, 7.

56(lH, dd, J=8. 0, 1.8Hz),7.

47(1H, d, J=8. 0Hz),7. 21(2H d, J=8.4Hz), 5. 18(2H, s),4 .34(lH,m),3. 27(3H, 2(3H, s),2.98(3H, 2.38- 2. 18(2H, 2. 10-1.95 (2H, 1.93-1. 79(2H, 1.72- 1.59(1H,m), 1.50-1.19(3H, m) Example No. 272 1H NMR(6) ppm 300MHz,DMSO-d6 8.97(1H, d, J=1. 8Hz), 8. 1H, d, J=4.7Hz), 8.46(1lH, d, J=8.0Hz),8.39-8.26(2H, m) ,8.06(1H, d, J=8.7Hz), 7. 99 -7.64(6H, 7. 24(2H, d, J= 8.7Hz), 5.25(2H, s),4.36(1 H m) 3. 03(3H, 2.97(3H, 39-2. 19(2H, 2. 14- 1.96(2H, 1. 94-1.78(2H, 1.73-1. 60 1.21- 1.55(3H,m) Purity >90% (NMR) MS 575(M+l) 377 Table 193 Example No. 273 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H, 27(1H, d, J=8 .7Hz), 8.05(1H, d, J=8. 7Hz) 7.77-7.67(3H, m).7.58-7.

48(6H, 7.22(2H, d, J=8. 4 18(2H, s),4.35 (H,b rt,J=9.8Hz),3.06-2.88(12 H,brm),2.38-2.20(2, brm) ,2.08-1.96(2H, brm), 1.90- 1.80 (2H, brm), 1.70-1.60(1 H, brm), 1.49-1.22 (3H, brm) Purity >90% (NMR) MS 645 (M+1) Example No. 274 1H NMR(6) ppm 300MHz,DMSO-d6 mixture of cis and trans 8. 35,8. 34(1H, 8. 15-8. 1 0(2H, 7. 79-7. 70(3H, m), 7. 49(2H, d, J=8. 7Hz), 7.44( 2H, d,J=8.7Hz), 7.31(1H,d, J=8. 4Hz),7. 25-7. 19(2H, m) ,7.07(1H, d, J=8. 5Hz), 5.08 75(1H, m),3.83(3 H, s),3.70-1.90(8H, m) Purity about MS 601(M+1) Example No. 275 1H NMR(6) ppm

CI

O

,HO N V 0-- Purity >9 0% (NMR) 300MHz,DMSO-d6 8.33(1H, 13(1H,d,J=7 .5Hz), 7.93(1H, d, J=8.8Hz) 7. 74(2H, d, J=8.7Hz), 7.49 (2H, d, J=8.6Hz), 7.44(2H, d J=8.6Hz), 7.31(1H,d,J=8.

5Hz),7.25-7.15(3H,m),7.0 7(1H, d, J=8.5Hz), 5.08(2H, 98(1H, 3.83(3H, s) 65-3.45(2H, 3. 30-3.

10(2H, 3.00-2. 75 (2H, m) ,2.60-2. 30(2H, m) MS 617(M+1) 378 Table 194 Example No.

276 0F HO N Purity 90% (NMR) MS 603 (M+1) 111 NMR 6) ppm 300MHz, DMSO-d6 8. 25(111, 7. 93andl. 87 (2 H, ABq, J=9. 1Hz), 7. 55 (1H, t J=8. 6Hz),?7. 48and 7. 42 (41 B'q, J=8. GHz), 7.31 (1 H, d, J=8. 5Hz), 7. 24 (111. di, J=2 6Hz), 7. 09-6. 95 (3H, mn), (2H, 4. ii iiH, brt, J=1 4. 0Hz), 3. 84 (311, 2. 83-2 .67(4H1, brm), 2. 50-2. 32 (2H b rm), 2. 21-2. 10 (211, bin) Example No. 277

CI

HO 0 Purity 90% (NMR) MS 619 (M4+1) 111 N4R 6) ppm 300MHz, DMSO-d6 cis and trans mixture 8. 28and8. 24 (total 11,each 7. 94-7. 87(1KH, 7. 7. 41 (5H, mn), 7. 31 (LH, d, J=8 5Hz),?7. 23-7. 21(111,.m),?7 12-7. 05(21,mi), 7.00-6. 111,mi),5. O6andS. 05 (total 211,each 4. 47and4. 34 (total 111,each bins), 3. 83(3OH, 3. 12-1. 7 6(81,.> Example No. 278 o0 HOA NN\/ N0 0 Purity 90% (NMR) MS 635(14+1) 1H1 NMR(6 -ppm 300MHz, DUSO-ciS 12. 911, bins), 8. 27(11, s), 7. 97and7. 74 (21, ABq,J8. 6 Hiz) 7. 58111, t, J8.b6Hz) 7 4Sand 7. 43(411, A' B' q, J=8.

5Hz), 7. 31 11, d, J=8. 7. 22111 d J=2 6Hz),7. 1 3 -i 6. 92311, in, 5. '05(2H1, 4.

67(11, brt,J=14.211z),3.57 40 (2H, brm), 3.20-3. 05 21, bis), 2. 91-2. 70(21, hrm 2. 28-2. 11 (211, hrm) 379 Table 195 Example No.

279 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H,s),8.23(lH, d,J=8 .7Hz),8. 06-8. 00(2H, 7.

83(1H, dd, J=8. 0, 1. 8Hz), 7.

71(2H, d,J=8. 4Hz),7. 64(1H J=8.0Hz),7. 59-7.54(4H 7.22(2H,d,J=8.4Hz),5 .25(2H,s),4.33(1H m),2.6 6(3H, 2.66(3H, 2.37- 2. 19(2H, 1.93-1.80(2H, 1.70-1.59 1.47- 1.21(3H, m) Purity >9 0% (NMR) MS 644 (M+1) Example No. 280 cl

HCCI

HCI 0

HO

S- 0 Purity >9 0% (NMR) MS 615(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 32-8. 23(3H,m), 8.08-8.0 1(2H, 7. 73(2H, d, J=8.6H z),7.65(1H,d,J=8. 2Hz),7.

59-7.51(4H, 7. 25(2H, d, J=8. 6Hz),5.21(2H, s),4.34 (1H, 3.32(3H, s),2.37-2 19(2H,m),.2. 10-1.98(2H, m 1.93-1. 80 (2H, 1.71-1 60(1H, 1.51-1. 21(3H, m Example No. 281 IH NMR(6) ppm 300MHz,DMSO-d6 8. 30(1H,d,J=1. 5Hz),8.24( 1H, 14(1H, d,J=8. 6Hz) 07-7.95(2H, 7.63(1H 6Hz),7. 57-7.47(5H 16(1H, dd, J=12. 0, 2.

2Hz), 7. 03(1H, dd, J=8. 6, 2.

2Hz), 5. 17(2H, s),4.06(l1H, m),3.90(3H, 2.31-2.11( 2H, 1. 97-1. 78 (4H, 1.

71-1. 59(1H, 1.43-1. 22( 3H,m) Purity 9 0% (NMR) MS 315 380 Table 196 Example No. 282 Cl

HCI

0.

HO-T r -t

N

N> ClH

N-

Purity >90% (NMR) MS 580(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.36(1H,s), 8.35(1H, d, J=9 .3Hz),8.09(1H, d, J=9. 3Hz) ,7.78(211H, d J=8.7Hz),7.48 25(9H,a m, 5.09(2H, 4 .39(1H, 3.04(6H, s),2.4 0-2. 15(2H,m), 2. 10-1.95 (2 H, 1. 90-1. 75 1.7 0-1. 55 1. 50-1. 20 (3 H,m) Example No. 283

CI

HCI l N O 0 0 Purity 90% (NMR) MS 630 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 10.03(1H, s),8.33(1H, s),8 .29(1H, d, J=8. 7Hz), 8.06(1 H, d,J=9.0Hz),7. 74(2H,d, J 7.51-7.42(5H, 7. 37-7.30(2H, 7.22(2H, d, J=8. 7Hz), 5. 10(2H, s),4.

37(1H, 3.06(3H, s),2.40 -2.18(2H, 15-1.95(2H 1. 90-1. 80(2H, 1. 55 (IH, 1. 50-1. 20(3H ,m) Example No. 284 1H NMR(6) ppm 300MHz,DMSO-d6 CI_ 8. 30(1H, 8. 14 (1H, d, J=8 0 HCI .7Hz),7.97(1H, d,J=8.7Hz) S ,7.96-7.41(8H, m) 7.16(1H HO'/ dd, J=12. 4,2. 2Hz, 7.03(1 N N H, dd, J=8. 4, 2. 2Hz), 5. 15(2 S 15(1H,m),3.54-3. 1 N 6(4H, m),2.33-2. 13(2H,m), O 1.97-1. 79(4H,m), 1.70-1.0 2 (9H, m) Purity >9 0% (NMR) MS 654(M+1) Table 197 Example No.

285 1H NMR(6) ppm 300MHz, DMSO-d6 8. 37(1H, d, J=7. 3Hz), 8. 1H, 8. 19-8. 12(2H, 8.

02-7. 95 (2H, 7.65 t J=8.4Hz), 7. 56-7. 43(5H, m) 7. 18(1H, dd, J=12. 0, 1.8Hz 7.06(H, dd, J=8.4, 2. 1Hz 13 (2H, 4. 22-4. 03 (2 H, 2. 34-2. 13(2H, 1.9 9-1. 78 (4H, 1. 72-1. 57(1 H, 1. 44-1. 14 (3H, 1. 2 0, 1. 18(6H,each s) Purity >90% (NMR) MS 640 (M+l) Example No.

286 1H NMR(6) ppm 300MHz, DMSO-d6 8. 29(1H, 13 (H1, d, J=8 .7Hz), 7. 97(1H, dd, J=8. 7, 1 .4Hz), 7. 69-7. 40 (8H, 7.

16(1IH, dd, J=12. 0, 2. 2Hz),7 .02 (18, dd, J=8. 4, 2.2Hz), .15(2H, 4.07(1H, 3. 7 1-3. 23 (2H, 1.98-1. 71(4 H, 1. 71-1. 18 (10H, m) Purity >9 0% (NMR) MS 666(M+1) Example No.

287 1H NMR(6) ppm 300MHz, DMSO-d6 8. 29(lH, 13(1H, d, J=8 .OHz), 7.97(1H, d, J=8.4Hz) 83(1H1, 7. 68-7. 41(7H 7. 17(1H, d, J=12. OHz), 7. 03 (1H, d, J=8. 4Hz), 5. 15 2H, 4. 07 (1H, 3. 58-3.

41 (4H, 2. 34-2. 13(2H, m) 1. 97-1. 77 (8H, 1. 71-1.

58 (I 1. 49-1. 18(3H, m) Purity >9 0% (NMR) MS 652 (M+1) 382 Table 198 Example No.

288 1H NMR(6) ppm 300MHz,DMSO-d6 8.62(1N, 8.31(1H, 8.

22-8. 14(2H, 8. 99(2H, d, J=8. 7Hz), 7.66(1H, t,J=7.7 Hz), 7. 58-7. 44 (5H, 7. 19 (1H,dd,J=8.7,2.2Hz),5.14 (2H, s),4.11(l1H, 3.67-3 .49(2, 3.45-3.30 (2H, m 12(2H, m),2.00-1 .76(4H,m), 1.70-1. 58 (1H,m 1.48-1.17(3H, m)

H

OH

Purity >90% (NMR) MS 642(M+1) Example No. 289 CHCI a HCI F l 0

NO-

Purity >90% (NMR) MS 682 (M+l) 1H NMR(6) ppm 400MHz,DMSO-d6 8.28(1H, 11 d, J=8 9Hz), 7.96 d, J=8.9Hz) ,7.68(1H, s),7.62(1H,t,J= 8. 2Hz), 7. 55-7. 41 (61H,m),7 .15(1H, d, J=11. 7Hz), 7.02( 1H,d,J=8.4Hz),5.14(2H, s) 12-3. 13(6, 2.30-1.

19(13H,m) Example No. 290 1H NMR(6) ppm 400MHz,DMSO-d6 8.29(1H, 8. 15(1H, d, J=8 .6Hz), 7.98(1H, d, J=8. 8Hz) ,7.72(1H, s),7.64(1H,t,J= 8.8Hz),7.57-7.43(6H, 7 .18(H, dd,J=12.1,2.1Hz), 7.03(lH, d, J=10. 7Hz), 5.12 (2H, 15-4. 01(lH,m),3 .75-3.33(8H,m), 2.31-2.14 (2H, 1.96-1. 78 (4H, 1 .70-1. 58(1H, 1.47-1.21 (3H,m) Purity >90% (NMR) MS 668 (M+1) Table 199 Example No.

291 HC1 H-O l

OF

HNN\

'>s 1H NMR(6) ppm 400MHz,DMSO-d6 8.29(1H, 14(1, d, J=8 .9Hz), 7.97(1H, d, J=8. 6Hz) ,7.71(1H, s),7.63 t, J= 8. 2Hz),7.56-7. 42(6H, 7 .17(1H,d,J=12.3Hz),7.03( 1H, d, J=10. 7Hz), 5. 14(2H, s ),4.07(lH, m),3.96-3.52(4 H, m),2.79-2. 56(4H, 3 2-2. 14(2H, 1.97-1. 79(4 H, 1.71-1. 58 1-1.19(3H,m) Purity >9 0% (NMR) MS 684(M+1) h Example No. 292

HCI

1H NMR(6) ppm 300MHz,DMSO-d6 9.07-8.99(1H, 8.30(1H, 23-8. 12(2H, 8.04- 7. 95(2H, 7.65 t, J=8 .2Hz), 7. 60-7. 45(5H, 7.

19(1H, dd, J=12.0, 2.6Hz),7 .06(1H, dd, J=8. 6, 2. 16(2H, 18-4.02(1H, m ),3.97(2H,d J=6.0Hz),2.3 3-2.14(2H, m, 1.99-1. 79(4 1. 72-1. 59(IH, 1.4 5-1. 19(3H, m) Purity >9 0% (NMR) MS 656 (M+l) Example No.

293 0CI 0 a

C

1H NMR(6) ppm 300MHz,DMSO-d6:8.21(1H,s ),7.94and7.86(2H,ABq,J=8 .6Hz), 7. 72(H, d,J=2. 4Hz) 7.59and7. 11(4H,A' B' q, J= 8. 9Hz), 7.53(1H,dd, J=8.4, 2. 4Hz), 7.38(111H, d, J=8. 4Hz ),7.36and7.32(4H, A"Bq, J 1Hz),5.07(2H, s),4.27( 1H,brt,J=13.8Hz), 2.87(2H J=7. 8Hz), 2. 57(2H, t, J= 7. 8Hz),2. 35-2. 20(2H, brm) ,1.96-1.79(4H, brm), 1.68- 1.59(1H, brm), 1.47-1.18(3 H.brm) Purity 9 0% (NMR) MS 637(M+1) 384 Table 200 Example No.

294 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H, 25and8.03(2 H, ABq, J=8. 9Hz), 7. 73(1H, s 7. 73 (2H, d, J=8. 6Hz), 7. 5(1H, dd, J=8. 0, 2. 3Hz), 7. 4 0(4H, 7.39(1H, d, J=8. OH 7. 23 (2H, d, J=8.6Hz), 11(2H, 4. 55 (2H, 4. 36 (1H, brt, J=14. 8Hz), 2.37-2 .19(2H, brm), 2.09-1.96 (2H ,brm), 1.91-1. 79(2H, brm), 1.71-1. 59(1H, brm), 1. 50-1 .20(3H,brm) Purity 9 0 (NMR) MS 567 (M+1) Example No.

295 HO

N

1H NMR() ppm 300MHz; DMSO-d6.

8.30(1H, 8. 25and8. 04(2 H, ABq, J=8. 7Hz), 7. 74 (1H, s 7. 72 (2H, d, J=8. 7Hz), 7. 6(1H, d, J=8. 7Hz), 7. 48-7. 3 5 (5H, 7. 22 (2H, d, J=8. 7H 11(2H, s),4.46 (2H, s) 35(111, brt, J=14. 8Hz), 3 .31(3H, 2. 37-2. 17(2H, b rm), 2. 07-1. 95 (2H, brm), 1.

92-1.79(2H, brm), 1.73-1.5 6(1H, brm), 1.52-1.20 (3H, b rm) Purity >9 0% (NMR) MS 581(M+1) 9 Example No.

296 1H NMR(6) ppm 300MHz, DMSO-d6 8.21(111, d, J=1. 5Hz), 7. 98( IH, d,J=1. 2Hz),7.97-7. 91( 2H, 7. 84(1H, dd, J=8. 7, 1 7.77(1H, d, J=2.1Hz) ,7.70(1H, d, J=7. 5Hz), 7. 54(4H, 7. 43 (1H, d, J 8. 4Hz), 7. 09(2H, d, J=8. 7Hz 5.05(2H,s), 4.25(1H,brt J=14. 8Hz), 2. 36-2. 18(2H, brm), 1. 95-1. 79(4H, brm), 1 .71-1. 6(1H, brm), 1.43-1. I1 8 (3H, brm) Purity 9 0% (NMR) MS 581(M+1) 385 Table 201 Example No.

297 1H NMR ppm 300MHz,DMSO-d6 12. 7(1H, brs), 8.21(1H,s), 7.94and7.85(2H, ABq,J=8.6 Hz), 7.60-7. 55(3H, 7.49 and7. 45(4H, A' B' q,J=8. 3Hz 12(2H, d, J=8.7Hz), 5(2H, s),4.26(1H,brt,J=13 Hz),2.54(3H, 2. 38-2.

(2H, brm), 1.97-1. 80 (4H, brm), 1.71-1.59(1H, brm), 1 .47-1.20(3H,brm) Purity >9 0% (NMR) MS 583(M+1) Example No. 298

CI

0

OS=

Purity >9 0% (NMR) MS 599(M+l) 1H NMR(6) ppm 300MHz, DMSO-d6 8. 22(lH, 01(lH, s),7.

95and7.86(2H, ABq,J=8.6Hz ),7.79(1H,d,J=7.8Hz), 8(3H, t, J=7.5Hz), 7. 53(4H, 13(2H, d, 8.7Hz), 5. (2H, s),4.26(1H, brt,J=13.

8Hz), 2.83 (3H, 2.37-2.1 8(2H,brm),1.95-1.78(4H,b rm), 1.70-1. 59(1H, brm), 1.

47-1. 17(3H,brm) Example No.

299

HCI

0 HO-k N0 I' I I 1H NMR(6) ppm 300MHz,DMSO-d6 8. 43-8. 16(3H, 8. 07-7. 9 4(2H,m),7.72(2H,d,J=8.6H 7.62-7.49(5H,m),7.23( 2H, d, J=8. 6Hz), 5. 16(2H, s) 34(1H, 2. 39-2.20(2H 10-1.96(2H, 1.93 80(2H, 1.71-1. 58(1H 1.49-1. 19(3H, m)

MI

D

Purity 9 0% (NMR) MS 562(M+1) 386 Table 202 Example No.

300 1H NMR(5) ppm 300MHz,DMSO-d6:2.77(1H,b rs), 8.83(2H, d, J=1. 9Hz),8 .56(2H, dd, J=4. 9,1. 9Hz),8 .22(1H, d, 5Hz), 7.97(2 H, dt, J=7. 9, 1.9Hz), 7.95(1 H,d, J=8.6Hz), 7.87(1H, dd, J=8.6, 1.5Hz), 7.57(1H, t, j =8.7Hz), 7.46(2H, dd, J=7. 9 ,4.9Hz),7.26(H, dd, J=12.

0, 4.9Hz), 7. 14(1H, dd, J=8.

8, 2.3Hz), 6.99 (2H, s),3.94 brt), 2.26-2.09(2H, m) ,1.87-1. 73 (4H, 1.67-1.

R7(IU m 1 A9-1 19( U m\ Purity >9 0% (NMR) MS 523 (M+1) Example No.

301 HO X N 0 0 N N N-

N-

D

,N-

Purity >9 0% (NMR) MS 663 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 22(1H, s),7.95(1H, d, J=8 .7Hz), 7.87(1H, dd, Hz),7.62(4H,d,J=8.4H 55(1H, t, J=9. OHz), 7.

44(4H, d, J=8. 1Hz), 7. ,dd, J=2. 1Hz, 12.0Hz), 7. 11 (IH, dd, J=2. IHz, 8. 7Hz),6.

86(1H, s),3.94(IH, m),2.96 88(12H, s),2.35-2.00(2 H, 1. 95-1. 70(4H, 1.6 5-1.50 1.45-1.10 (3 H, m) Example No.

302 1H NMR(6) ppm 0 F SN- S S 300MHz,DMSO-d6 8. 14(1H, 88(1H,d, J=8 .4Hz); 7.68(1H, d, J=8. 7Hz) ,7.64-7.55(3H,m),7.50(1H t, J=8.7Hz), 7.22-7. 17(3H 7. 11(1H, s),7.08-7.00 (2H, 3.90(1H, 2.15-2 00(2H, 1. 95-1.50(5H, m 1.45-1. 00(3H, m) Purity 9 0% (NMR) MS 532(M+1) 387 Table 203 Example No.

303 0 0 -Sa 1H NMR ppm 300MHz,CDC13 8. 49(1H, 7. 98 (1H, dd, J= 8.6,1.5Hz),7.71(1H,d, =1 .8Hz), 7. 66(1H, d, J=8.6Hz) 55-7. 29(7H, 6. 80(1H ,dd, J=8. 2, 2. 2Hz), 6.69(1H dd, J=11.2, 2. 2Hz), 4.99(2 10-3.92(1H,m),3.9 5(3H, 3. 15(3H, 06( 31, 31-2. 14(2H, 2.

04-1. 86(4H, 1.81-1. 71( 1H, 1. 41-1. 21(3H, m) Purity >9 0% (NMR) MS 640(M+1) Example No. 304

CI

O'Na+

NN

0 0 Purity >90%

(NMR)

MS 608(M+1) mini 1H NMR( ppm 300Hz,DMSO-d6 8. 21 s),7.94(lH, d, J=8 .7Hz), 7.84(1H, d, J=9. 1Hz) ,7.70(1H,s),7.26-7.39(9H 11(2H,d,J=8.4Hz),5 .11(2H, s),4.26(lH,m),3.0 (3H, 97(3H, 38- 2.19(2H,m), 1.97-1.78(4H, 1.72-1. 57(H, 1. 48- 1. 17(3H,m) Example No. 305 1H NMR(6) ppm 300MHz,DMSO-d6 8.24(2H. s),8.03(1lH, d, J=8 .OHz), 7.96(1lH, d, J=8. 8Hz) ,7.87(1H, d,J=9. 1Hz),7. -7.46(6H,m),7.09(1H,dd,J =12.0,1.8Hz), 6.97(1H, dd, J=8.4, 1.8Hz), 5. 16(2H, s), 3.97(1H,m), 2.31-2.11(2H, 1.92-1.73(4H, 1.57(1H, 1.46-1.13(3H, m) Purity >9 0% (NMR) MS 599(M+1) 388 Table 204 Example No.

306 0

HO

1H NMR(6) ppm 300MHz,DMSO-d6 12. 84(1H1, brs), 8.21(111H, s) ,7.98-7. 84(5H, 7. 58 (2H J=8. 7Hz), 7. 54(211, d, J= 7. 8Hz), 7.34(1H,, d, J=8. 7H 7. 26(1H, d, J=2. 4Hz), 7.

13-7. 06(3H, 5. 06(2H s) ,4.26(IH, brt, J=12. 7Hz, 3 .84(3H, 2. 36-2. 17(2, b rm), 1. 99-1. 80(4H, brm), 1.

73-1. 59(1H, brm), 1. 47-1. 1 7(31H,brm) Purity 9 0% (NMR) MS 577 (M+1)

S

Example No. 307 111 NMR(6) ppm Example No.

307 1H NMR(6) ppm 300KHz, DMSO-d6 8. 22(1H, 8. 04(1H, 7.

96(2H, d, J=8. 1Hz), 7.87(2H 7.72(1H,d, J=1.2Hz), 7 .59-7. 41(7, m) 5. 12(2H, s 25 (1H, brt, J= I. 8Hz), 3.02(3H,brs),2.98(3H,brs 15(2H,brm), 1.93 76(4H, brm), 1. 71-1. 59( 1H, brm), 1.46-1. 16(3H, brm Purity 9 0% (NMR) MS 617 (M+1) Example No. 308 IH NMR( 6) ppm CI 300MHz, DMSO-d6 8. 27(111, s),8.08 (1H, d, J=9 O 0Hz), 7. 93 (1H, d, J=8. 7Hz) N ,7.65(2H,d,J=8.7Hz),7.46 HO (2H, d, J=8. 1Hz), 7. 42 (2H, d J=8. 4Hz), 7. 30-7. 04 (5H m N 5.03 (2H, 4. 32 (1H, m), 0NH 2 2. 40-2. 10 (2H, 2.05-1. 1 NH2 0(8H, m) Purity 9 0% (NMR) MS 552 (M+1) 389 Table 205 Example No. 309

HCI

HO N O

N

CI

Purity >90%

(NMR)

MS

1K NMR(5) ppm 300MHz,DMSO-d6 8. 33 (1H, 8. 15and7. 99(2 1, ABq, J8. 9Hz), 7. 84and7.

59(4, A' B' q, J=8. 3Hz), 7. 4 6 (211, d, J=8. 4Hz), 7. 22-7. 1 6(3, m) 7. 01-6. 98 (211, m), 4. 27and4. 23 A'B'q, J1 2. 9Hz), 3. 78(311, 2. 39-2 .21(211, bri), 2. 07-1.95(2K 1. 91-1. 80(2, brm), 1.72-1.59(11, brn), 1.49-1 17(3H, brm) Example No.

310

HCI

1H NMR(6) ppm 300MHz,DMSO-d6 8. 33(11, 8. O9and7. 95 (2 K, ABq, J8. 7Hz) 87and7.

71(4, A' 8' q, J8. 0Hz), 7. 4 3 (2H, d, J=7. 8Hz), 7. 15(1, d, J=8. 7Hz), 7. 07-7. 02 (4H, 4. 66(211, 4. 23(111, br t, Jl. 8Hz), 3. 76(311,s), 2 38-2. 20 (2H, brm), 2. 04-1.

93 (2H, brm), 1. 89-1. 79(211, brm), 1. 70-1. 59(1, brm), 1 .49-1. 18(3, brm) Purity >90%

(NMR)

MS 615((M+1) Example No.

311 1K NMR() ppm 300Hz, DMSO-d6 8. 30(1K, 8. 2land8. 01(2 H, AfQ, J=8. 7Hz), 7. 65(2H, d J=8. 4Hz), 7. 52-7. 41(6K, m 7.20(1H, d, J=8. 4Hz), 7. 1 4 (11, d, J=2. 7Hz), 6. 97 (1H, dd, J=8. 4, 2. 4Hz), 4. 31(111, brt, J-9. 81z), 4. 28 (2H, s), 3.78(31, 2. 37-2. 20(2H, brn), 2. 07-1. 95(2H, brm), 1 .92-1. 80(211, brm), 1. 71-1.

60(1K, brm), 1.50-1. 19(31, brm) Purity >90% (NMR) MS 583(M+1) 390 Table 206 r Example No.

312 0F 110 0 N~ N _OH 0

OH

Purity 90% (NMR) LK NMR( 6) ppm 300MHz, DMSO-d6 8. 22(1H1, 8. 12(1H, d, J=8 4Hz), 8. 00-7. 84(51, 7.

70(4OH, d, J=8. 4Hz) 7. 56 (1KH t, J=8. 6Hz), 7. 23 (11, d, J= 12.0OHz),?7. 13(1OH, d, J=8. 6K 6.-97 3. 92(11,.m) 35-2. 00 (21, mn), 1. 95- 1.

70 (411, mn), 1. 65-1. 55 (11, m,) 1. 50-1A05(3H, m,) MS 609 1)1 Example No. 313 0

F

HO 0

NN

Purity 90% (NMR) MS 522 (M+1) 1H NMR( 6) ppm 300MHz, DMSO-d6 8.89111, brs), 8, 63 (11, brs 8.24(LH, 8. 11(LH, d, J 8Hz) 99(111, di, J=8. 8 H 7.,89(111, d, J=9. 9Hz),?7.

61-7..55 7. 43 (2H, t, J=7. 34(IH, t, Jz7.2 Hz), 7.24(1, d,J.T12. 0Hz), 7. 14(111.d,J.T8. 6Hz), 6. 1K, 3. 96(LH, 2. 35-2.

05(21,mi),2. 00-1. 50(51, m) ,l1.45-1. 10(3H, m) Example No. 314

CI

1H NMR 6) ppm 300MHz, CDC13 8. 481HI d, J=1. 4Hz), 8.05( 1H-, d, J=1i. 8H), 8. 98(1H, di, J=8. 6Hz), 7. 82(111, d, J=7. 9 66(LH, d, J$8.6Hz),? 55-7. 24(6OH, mn), 6. 78(111, d d, Jt8. 6,2.6Hz), 6.69(1, d di, J=11. 6Hz), 2. 2Hz), 6. 6. 30(111, mn), 4. 99(21, 4.

021OH, in), 3. 953OH, 3. (31, d, r4. 8Hz), 2. 32-2. 13 (2H, 2. 03-1. 87(4M, 1 .81-1. 71(11,.m), 1. 46-1. 23 (3Htm) Purity 90% (NMR) MS 626 Table 207 Example No.

503 HO I N 0 Purity 9 0% (NMR) 1H NMR(6) ppm 300MHz, DMSO-d6 8. 231H, 7. 7611H, d,J=8 7Hz), 7. 58(111, d, J=8. 8Hz) 51-7. 32(7M, in, 7. 17 (21 18 (211,s), 4. 75(1H,nm),2. 3 5-2. 12(211,i),2. 10-1.85(4 H, 1. 8 0-1. 50 (2H,rm) MS 412 (M1+1) Example No. 701

CI

0

N

Purity 90% (NMR) 111 NR(6) ppm 300MHz, DMSO-d6 8. 96(1H1, 8. 50(111, 7.

77 (2H1, d, J=8. 7Hz), 7. 50-7.

40(4K,.m), 7. 30 (111, d, J=8. 4 Hz), 7. 24 (1H, d, J-2. 4Hz), 7 16 (2H1, d, J=h8. 4Hz), 7. 06(1 H, dd, J=2. 4Hz, 8. 1Hz), 5. 06 (211, 4. 31(01H, 3. 83 (3 H, 2. 80-2. 55 (2H1, mn), 2. 0 O- 1.-804K, 1. 70-1. 55(1 1. 40-71.15OH, mn) Ms 568 (4+1)I 392 Table 208 Example No. 315 HCI

N-

HO NN o> CI Purity 9 0% (NMR) MS 538(M+1) Example No. 316 HC CI N

HO

N 0) No Purity >90% (NMR) MS 670 (M+1) 1H NMR ppm 300KHz, DMSO-d6 8. 84(211, d, J=6. 3Hz), 8. 28(1 8. 17and7. 99(2, ABq, J=8 .7Hz),7.87-7. 85(3H, 7. 50(3, in), 7. 52(IH, d, J=8.

3Hz), 7. 18(2H, d, J=8. 7Hz), 22(2H,s)4.31(IH, br t, J=12. 5Hz), 2. 36-2. 18(2H, m 78(4,m), 1.70-1.5 8(1H,m),1.50-1.23(3H, m) 1H NMR 6 ppm 300kHz, DMSO-d6 9. 23(1H, t, J=6. 3Hz), 8. 29(1H, s),8.25-8.22(2H, 0),8.03(2H, d,J=7.9Hz),7.55-7.48(5, 7 .34(4H,d, J=4.4Hz),7.28-7.22 (3H,m),5.15(2H,s),4.52(2H,d ,J=5.9Hz),4.35(1H,br t,J=12. 1Hz),2.37-2.18(2H,m) 2. 08-1. 95(21, 79( 2H, 72-1.59(1I,.), 1.47-1. 19(3O,

M)

Example No. 317

HCI

1H NMR 6 ppm 300MHz,DMSO-d6 8.59(11H, t, J=5. 5Hz), 8. 28(1N, 8.2land8. 01(2H, ABq, J=8. 8 Hz),8. 16(1H, s),7.97and7.46( 2H, A' B' sJ=8.Oz), 7 71and7.

23(4H, A B'q,J=8.7Hz),7.53an d7.49(4H, A" B" q, J=9.2Hz),5 .14(2H,s),4. 34(1H,br t, 5=12. 8Hz), 3. 14(2H, t, J=6. 3 Hz), 2. 38-2. 18(2H,a),2. 07-1.

78(4H, 1. 78-1. 47(7H. 1.

47-1. 07(61H, 1. 03-0. 83(2H, m) Purity >9 0% (NMR) MS 676(M+1) 393 Table 209 Example No. 318

CI

2HCI O N SN N Purity >90%

(NMR)

MS 671 (M+1) LH NMR(6) ppm 300Hz, DMSO-d6 9.63 (IuH, t,J=4. 8Hz), 8.86and7. 97( 411, ABq, J=6. 6Hz), 8. 30(111, s), 8.27(1H, 8.23and8.03(2H,A J=8. 8Hz), 8. 09and7. 54(2 H,A"BJq, J=8.1Hz),7.73and7. 2 4(4H, B" q, J=8.8Hz),7.54a nd7.52(4H,A ""B'q,J=8.8Hz), 5. 16(2H, s)4. 78(2H, d, J=5. 6Hz ),4.35 (l1H,br t, J=11. OHz), 2. 39-2. 19(21, m) 07-1.96(211, 1.91-1. 78( 2H,m), 1. 70-1. 57(1H,m) 1. 50-1 19(3, m) Example No. 319

CI

HCI

HO~ 7 NN HO- Ns_ IN N I> 0 1H NMR( 6 ppm 300MHz,DMSO-d6 8.28(111, s),8.24and8. 03(2H, A Bq, J=9. OHz),7. 77(1H, 7.70 (2H, d, J=8. 4Hz), 7. 64-7. 10(13 H 5. 16(211, 4. 74and4. 57 (total 2H, each hr 4.34(1H, br t,J=1I.7Hz),2.90(3H,s),2.35 -2.17(2H,m),2.07-1.93(2H,m) 1.

9 3 -1.78(211,m), 1. 71-1. 57( 1H, 1. 51-1. 19(3H,m) Purity 90% (NMR) MS 684 (M+1) Example No.

320 1H NMR(6) ppm 300MHz,DMSO-d6 8.94and8.06(4H,ABq,J=6.8Hz) 8. 33(1H, 28and8. 05(2H, A'B'q, J=8. 7Hz),7.80(1H, s),7 .73and7. 22(4H, A"B"g, J=8. 7Hz ),7.63and7.57(211,A B8"q,J= 7.9Hz), 5.30(21, s),4.34(1H, b r t,J=12. 1Hz),3.04(3H, s),2.97 (3H, 2. 38-2. 18(2H, 2. -1.96(2H,m),1. 93-1. 80(2H,m) ,1.72-1.58(1H,m), 1. 52-1. 08( 3H, m) Purity 9 0% (NMR) MS 575(M+1) 394 Table 210 Example No.

321 j111.NR(S) ppm

CI

2HCI HO~ 7

N

N N- Purity >90% (NMR) 300MHz, DMSO-d6 11.1YlwHbr 8.31 (11H, 8. 23and8, 02 (2 11, AB, J=9. 0Hz), 7. 77(1H, s),7 72and7. 23 (41, A' B' q, J=8. 7Hz 59an47. 48(2, 8' 1 9Hz),7. 53and7. 51(4, A B' J=9. 0Hz), 5. 16(2H, 4. 72-2 .97(81, hr 34(1H, br t,J=L2.1Hz),2.79(31,s),2.38 -2.17(2H,m),2.07-1.93(2H,z) ,1.93-1.78(2H,m), 1. 69-1.58( IH,m), I.50-1. 10(3H,m) Ms 663 (M+1) Example No.

322 ci 2HCI 0

N

Purity >90%

(NMR)

11 NMR(B) pp.

300MHz, DMSO-d6 9. 54(1, t, J5. Hz),8.91 (1, 8. 8(111, d, J=4. 9Hz), 8. 48 11, d, J=7. 9Hz), 8. 32(1, 8.

27(1O, d, J=9. 0Hz), 8. 25(111, s) ,8.07-7. 97(311, 7. 74and7. 2 (4H, ABq, J8.9Hz),7.56-7.49 (511, 5. 16(2H, 4. 69(2H, d 1=5. 6Hz), 4. 36(11, hr t, J=12. 4Hz), 2. 37-2. 20 (2H, m) ,2.09-1. 97(2H,m), 1.91-1. 78( 2H, 70-1. 57(1, 1. 1. 17(3H, m) Ms 671

I

Example No. 323 cI 2HCI

HO~/

0N H

NO

Purity >90% (NMR) MS 671 (M+1) 1'H NMR(6) ppm 300MHz, DMSO-d6 9. 52(1H, t, J=6. 0Hz), 8. 72 d, 1=5. 3Hz), 8. 30-8. 19(411, m), 8.08(1H, d, 9Hz), 8. 0211, d, J=7. 6Hz), 7. 77-7. 64(4., m), 7. 57-7. 49 (5H, 7. 24 (2H, d, J 7Hz), 5. 16(2, 4. 77(2H, d, 1=5.'6Hz), 4. 34(11, t, 1=12. 8 Hz), 2. 36-2. 19(2H, 2. 07-1.

1.91-1.78(2H,), 1.

69-1.59(1Hm), 1.45-1.20 (3H,

M)

395 Table 211 Example No. 324 if! NMR(6) ppm Example No.

324

HCI

1H NMR(6) ppm 300MHz,DMSO-d6 8. 36(1H,d,J=7.9Hz),8.30(1H, 28and8. 05(21, ABQ, J=8. 8 Hz), 8.16(1H,s),7. 79and7. 46( 211, A'B'q,J=8.3Hz),7.74and7.

25(4H.,A'Bq,J=8.9Hz), 7. 52an d7.50(4H,A' B"'q,J=8.7Hz), 14(2H, 4.36(1H, br t,J=12. 1Hz),3.80(1H,br s),2.39-2. 18(2H, 10-1. 9 8(2H, 1.93-1.57(8H,m), 1.4 9-1.04(8H,m) Purity >90%

(NMR)

MS 662 (M+1) Example No.

325 11 NMR 6 ppm 300MHz,DMSO-d6 8.86(1H, t, J=6. 0Hz), 8. 84and8 .00(4H, ABq, J=6. 6Hz), 8. 33(1H 8. 27and8. 04(2H, A' B' q, J= 9.OHz),8. 12(1H, s),7.92and7.

46 (2H, A"B'q, J=7. 9Hz), 7. 74an d7.23(4H,A"'B'q,J=9.0Hz),7 .53and7. 49(411, J=9. 1 Hz),5.13(2H, s),4.36(1H,br t, J=12. 8Hz), 3. 70(2H, td, J=6.

8, 6. 0Hz), 3. 21(2H1, t, J=6. 8Hz) 38-2.20(2H,m), 2.09-1. 211,m), 1.91-1.77(2H,m), 1.70- 1. 59(H, m),1.49-1.20(3M,m) Purity 90%

(NMR)

MS 685 (M+1) E x a m p l e N o 3 2 1 M R p

I

I Example No. 326 1 NMR 6 ppm 300MHz,DMSO-d6 12.80(1H,brs),8.23(1H,s),7.

90(111, d, J=8. 7Hz), 7. 83 (1H, d, J=8.7Hz),7.60-7.50(5H, m),7.

39 (2H, d, J=7. 8Hz), 7. 23-7. 31,m), 7.05(1H, d, J=7. 8Hz), 6.

85(1H,s), 3.94(1H, 2.97,2.

88(6H,s),2.30-2. 10(2H, 1.

90-1.50(5H, 1.40-1.00(3H,

M)

Purity >9 0% (NMR) MS 610 (M+1) 396 Table 212 Example No. 327 0

F

HO ~A N IQ 0 0

NN

OH

Purity >90% (NMR) MS 583 111 NMR(6) ppm 300MHz, DMSO-d6 13. 20-12. 60 (2H1, brs), 8. 23(111 7. 98 (211, d, J=6. 6Hz), 7. (1H, d, J=8. 7Hz), 7. 87 d, J= 8. 7Hz), 7. 70-7. 50 (SF1, O,7. 27 20(3OH, 7. 08 (11, d, J=7. 8 Hz), 6. 901OH, 3. 931OH, 2 .51-2. 05 (2H1, 1. 90-1. 70411 10(31, m) 397 Table 213 4 3 3 12 3 6 Ex.

RR

No.R 2001 -H 4- 2002 -H 3- (-CF 3 2003 5- -H 2004 2005 2006 3- F) 4- (F) 2007 4- 4- 2008 5-H-F) 2009 6- 4- 2010 4-(-C1) 2011 2012 5H)4- (-CF 3 2013 4- (CO 2

H)

2014 4- (-CO 2 Me) .2015 5-(-F)4-(0N 2016 4- (-CONH 2 2017 4-{-CON(Me) 2 2018 5- 4- 2019 4-(-SMe) 2020 4--F (-Me) 2021 -Me) a- ~398 2022 -H 2023 2024 4-C-Cl) 2025 4-(-Me) 2026 5-C-Cl) 4-(-CF 3 2027 4-(-C02H) 2028 4-(-CO 2 Me) 2029 2030 4-(-CQNH).

2031 5-C-Cl) 4-I-CON(Me) 2 2032 5(-Cl) 3-(-OMe) 2033 4-(7SMe) 2034 (1-MB) 2035 4- -9S-Ysa 4- 6 2036 2037 4-(-Cl) 2038 5- (-NO 2 2039 4- (-N0 2 4-C-Cl) 2040 4-(-CO 2

H)

2041 5-C-Me) 4-(-CO 2 Me) 0 2042 N) 2043 5- 3 4- (-C0 2 Hj) 2044 5- (-CF 3 4-(-CO 2 Me) 2045 5- (-CF 3

N

2046 5-C-COH) 4-C-F) 2047 4-(-C0 2 H) 4-C-Cl) 2048 5-(-CO 2 Me) 4-C-F) 399 2049 5-(-CO 2 Me) 2050 5- -Ac) 4- 2051 4-(-C1) 2052 (JLNJ).) -H 2053 -LND) 4- 2054 5- ND3) 4- (-Cl) 2055 5-(iND) 4- (-ON) 2056 (i-ND) 4- (-NO 2 2057 5-(iND) 4- (-Me) 2058 5 (k-NJ) 4- (-CF 3 2059 D N) 4- (-Ac) 2060 N) 4- (-C02H) 2061 4- (-O 2 Me) 2062 5-i'ND) N) 2063 5- iND) 4-(-OON- 2 2064 4-{-CON(Me) 2) 2065 4-i-C (=NH)NH 2 5- 2066 ND) 4-(-Oe) 2067 4

-O-CH-LN))

2068 (I-NJ) 4- (-NHMe) 2069 -i-ND) 4- (-WHAc) 4 2070 5 (ILNQ 4(-i-e) 2072 5- 'nD 4- 2073 D IIN7') {--me 2 207 -(CH0 4-FsN) 20794--OH 2 1 2080 201 5- 2 2--1 2082 5- (-CONH 2 .3-H1 2083 3- CONH 2 4- C-) 208 5- -COH 2 2,3 2,5 C1)

-F

2085 5- (-CONH 2 2- 3<C1) 2086 5- (-CONH 2 4< (C1) 2087 6- (-COH 2 j2-

(-CI)

2088 3- (-COH 2 3- (-C1) 2089 3- (-CON- 2 4- (-C1) 2090 4- (-COHH 2 2091 4- (-COHH 2 4(CN) 2092 5- (-COH 2 4-(-H0 2 2093 5- (-CONH 2 4-(Me) 401 2094 5- HCONH2) 2, 6-di- (-Me) 2095 5- (-CONH 2 4- (-CF 3 2096 5- (-CONH 2 4- (-Ac) 2097 5- (-CNH 2 4- (-CO 2

H)

2098 5- (-CON?! 2 4- (-CO 2 Me) 2099 5- (-CONH 2 1

,N

2100f 5- (-CONH 2 4- (-CON! 2 2101 5- (CONH 2 3,5-di-(-CONH 2 2102 5-i(-CON! 2 4 (Me) 2 2103 5- (CONH 2 4-{f-C NH 2 2104 5-(-CONH 2 4-(-OMe) 2105 5- (-CONH 2 3, 4, 5-tri- (-OMe) 21065-( (-CON! 2 (--CH-IN~j.

21076--CN 2 4-(NHe 2108 5- (-CONH 2 4-(-NH~c) 2109 5- (-CONH 2 (-N--mgo 2110 5- (-CONH 2 4-(-SMe) 2115- (-CONH 2 2111_ 4- 2112 5- VCONHT 2 (-Me) 2113 5- (-CON! 2 .(I-N2) 0 2114 5- (-CON?! 2 2 2115 5-{-CON(Me) 2

-H

2116 5- f-CON (Me) 2 1 2117 4- (-CON (Me) 4-(-C1) 2118 5-{-CON(Me) 2 4-(-CN) 402 2119 5-{-CON(Me) 2 4-(-N0 2 2120 5-{-CON(Me) 2 4-(-Me) 2121 4-f-CON(Me) 2 1 4-(-CF 3 2122 5-(-CON(Me)2) 4-(-Ac) 2123 5-(-CON(Me) 2 4-(-CO 2

H)

2124 5-{-CON(Me)2z 4-(-CO 2 Me) 2125 5-{-CON(Me) 2

-LND

2126 5-f-CON(Me) 2 1 3--CONH 2 2127 4-f-CON(Me) 2 1 4-{-CON(Me) 2 2128 5-{-CON(Me) 2 4-{-C(=NH)NH 2 2129 5-{-CON(Me) 2 4-(-OMe) 2130 5-{-CON(Me) 2 -0-CH ND 2131 5-(-CON(Me) 2 4-(-NHMe) 2132 5-{-CON(Me) 2 A 4-(-NHAc) 2133 5-(-CON(Me) 2 Me) 2134 4-VCON(Me)} 4-(-SMe) 2135 5-{-CON(Me) 2 (-iMO) 2136 4-{-CON(Me) 2 )}H-Me 4- 0 2137 5-{-COR(Me)2} (SNH) 4- 0 2138 5-f-CON (Me) 2 2139 5-(-OMe) -H 2140 5-(-OMe) 2141 3-(-OMe) 4-(-C1) 2142 4-(-OMe) 4-(-C1) 2143 5-(-OMe) 2-(-C1) 2144 5- HOMe) 3- (-C1) 2145 T 6- 4- (-Cl) 2146 5- 4- (-CN) 2147 5- HOMe) 4-V(-NO 2 2148 5- 4- (-Me) 2149 5- C-O~e) 4- (-CE' 3 2150 5- (-OMe) 4 2151 4 OMe) 4- (-CO 2

H)

2152 4, 5-di- (-OMe) 4- (-C0 2

H)

2153 5- (-OMe) 4- (-CO 2 Me) 2154 5- (-OMe) 4( 1 ND 2i155 5- HOMe) 4- (-CONH 2 2156 5- 4-{(-CON (Me) 2 2157 5- (-OMe) 4-{-C(=NH)NH 2 2158 5-H-OMe) 4-(-OMe) 2159 5-(-OMe) 4- -o-CHj-U RD) 2160 5-HOMe) 4-(-NH-Me) 2161 5-(-OMe) 4-(-NHAc).

2162 5-(-OMe) 4 Mes 2163 5-(-OMe) 4-(-SMe) 2164 5-(-OMe) (-e 4- 2165 5-(-OMe) 0 2166 5-(-OMe)I 9N(M) 14- 0 2168 5- (-MiMe) 4- 2169 5-(-NHMe) 4-C-Cl) 2170 5-(-NHAc) 2171 5-(-NHAc) 4- -Cl) 2172 5-(-NHAc) 4-(-Ac) 2173 5-(-NHAc) 4-(-CONH 2 2174 5-(-NHAc) 4-{-CON(Me) 2 2175 5(r 4(-F) 2178 (-N-SMe) H 6 4-(-CF) H- 0 218 (-N-S-Me 4- 4H 2182 218- 4-(-Me) 218 5--SMe) 4- (-CF)

H

2186 4-N--SMe 4-(C) 2187 5( Me) 2188 5- -S e 2181 -N-S e

ND

2189 5-(-SMe) 2186 4(011 2182 -SMe 4-(-SMe) 2189 5- 0~e 2190 5-(-SMe 4-CQNH 2 2191 5-(-SMe) 4-{-CONMe) 2 405 2192 Me) 4- 2193 (Me 4- (-Cl) 2194 5-§Se) 4- (-Me) 2195 5- -S-Me 4- (-CF 3 2196 5-(-Me 4-(-Ac) 2197 4-(-CONH 2 2198 (i-Me) 4-{-CON(Me) 2} 2199 4- 2200 4- (-Cl) 2201 4- (-Me) 2202 4- (-CF 3 2203 4- (-Ac) 2204 4- (-CONH 2 0 2205 S(-Me) 4-{-CON(Me) 2 2206 (S NH 2 4- 2207 (.1s-NH) 4- (-Cl) 0 2208 (-NX 2 2, 4-di- (-Cl) 2209 S NH) 4- (-Me) 0 2210 3- (-CF 3 a 406 2211 i-NH)4 4- (-CE' 3 2212 4- (-CONH 2 0 2213 rn 4-{-CON(Me) 2 2214 S(-NH 2 4- (-Se) 2215 NtQ (A 4- Me) 221 -s-H2 5- 0 4- 0 2217 4- 0 2218 (Me) 2 4- (-Cl) 4-.

2219 N 4-(-Me) 2220 4- (-CF3)' 2221 4- (-CONH 2 5- a 2222 2 4-{-CON(Me)) 0 2223 {-9N(Me) 2 4- (-SMe) 0 2224 f t-W& s s 5- 0 4 2225 N (Me) 2 }S lie) 0 0 2226 5- {-O.(CH 2 )92-OH} 4-(-Cl) 2227 5-{-0-(CHj) 3 -OH} 4- -Cl) 2228 5 4-(-C1) 2229 4-(-Cl) 407 408

Table 214 4 3 F 5 2 0 6655 Ex. R R 2255 -H 4-H Me 2256 e 2257 -H 3- (-QF 3 2258 5-

-H

2259 4- 2260 5- 4-C(-Cl) 2261 5- 4- (-Me) 2262 4- (-CE' 3 2263 5- 4- (CO 2

H)

2264 (-CO 2 Me) 2265 5- 2265 5- 4-1-CNH 2267 5- 4--CONMe) 2 2268 5- 4-(-OMe)2 2269 4-(-SMe) 2270 5-C-F) 2271 5-C-F) 8 22721 4-C-Cl)

-H

227 5(cl) 227 4(cl) 4-(-cl) 2274 410 2276 5- 4- (-CF 3 2277 5- 4- (-CO 2

H)

2278 5- 4- (-CO 2 Me) 2279 5- 1 2280 5- (-C1)4-(CN2 2281 5- 4(-O(M)2 2282 5- (-C1)4-7Oe 22835- (Cl)4- (-SMe) 2284 5- (I-gMO) 228.5 5- 2286 5- 4- 2287 5- 4- (-C1) 2288 5- (-N0 2 4- 2289 5- (-N0 2 4- (-Cl) 2290 5- 4- (_C 2

H)

2291 5- 4 -(-CO 2 Me) 2292 5- ND) 2293 5- (-CF 3 4- (-CO 2

H)

2294 5- (-CF 3 4- (-CO 2 Me) 2295 5- (-CF 3 (-il--Nm 2296 5- (-CO 2 H) 4- 2297 4- (-CO 2 H) 4- (-C1) 2298 5- (CO 2 Me) 4- 2299 5- (-CO 2 me) 4- (-C1) 2300 5- 4- 2301 5- 4- (-Cl) 2302 (IND) -H 2303 4- 2304 ND) 4- (-Cl) 2305 5-i-ND 4- (-CN) 2306 (iND 4- (-NO2j 2307 -N-ID) 4- (-Me) 2308 5- NDN3 4 CFF3 2309 4- (-Ac) 2310 'ND) 4- (-C2H) 2311 5- ND LN) 4- -C2Me) 0 0 2312 5- ND 4- NDLNI> 2313 4- (-CONH 2 2314 5(ND) 4- {-CON (Me) 21 2315 5( I1Lnjt) 4-I-C(=NH) NH 2 0 0 2317 5- ND -0-CH 11 ND 2318 IND) 4- (-NHMe) 0 2319 5- D-i 4- (-NHAc) 2320 5- 412 2321 5- 4- (-SMe) 2322 4- SM 2323 ND( Si Me 2324 ND (JLgyN) 2325 1(LND) H(Me 2326 5- (-CONH 2

-H

2327 5- (-CONH 2 2328 4-(-CONH) 4-(-C1) 2329

-CONH

2 4-(-CN) 2330 5- (-CONH 2 4- (-N0 2 2331 5- (-CONH 2 4- (-Me) 2332 5- (-CONH 2 4-(-CF 3 2333. 5- (-CONH 2 4- (-Ac) 2334 5- (-CONH 2 4-(-C0 2

H)

2335 5- (-CONH 2 4-(-CO 2 Me) 2336 5- (-CONH 2

__AL

2337 5- (-CONE 2 4- (-CONE 2 2338 5-C-CONE 2 4-(-COI(Me) 2 2339 5- (-CONH 2 4-{-C(NH)NH 2 2340 5- (-CONE 2 4-(-OMe) 0 2341 5- (-CONE 2 -0-CH 11N 2342 5- (-CONH 2 4-(-NHMe) 2343 5- (-CONH 2 4 (-NHAc) 2345 5- (-CONH 2 4(-S Me 2345 5- -CONH2 4 (--SMe 413 2346 5- (-CONH 2 I 4_ -i- 2347 5- (-CONH 2 ~(te 2348 5- (-CONH 2 2349 5- (-CONH 2 {SNe) 2 2350 5-{-CON.(Me) 2

-H

2351 5-{-CON(Me) 2 1 4- 2352 4-{-CON(Me) 2 4-(-C1) 2353 5-{-CON(Me) 2 4-(-CN) 2354 5-{-CON(Me) 2 1 4-(-N0 2 2355 5-{-CON(Me) 2 4-(-Me) 2356 5-{-CON(Me) 2 4-(-CF 3 2357 5-{-CON(Me) 2 4-(-Ac) 2358 5-{(-CONW(Me) 2 4- (-CO 2

H)

2359 5-{-CON(Me) 2 1 4- (-CO 2 Me) 2360 5-{-CON(Me) 2 4 JLNJD 2361 5-(-CON(Me) 2 1 4- (-CON! 2 2362 5-{1-CON (Me) A 4-{--CON(Me) 2 2363 5-{-CON(Me) 2 4-{-C(=NH)NH 2 2364 5-{-CON(Me) 2 4-(-OMe) 2365 5-{(-CON (Me) 2 1} o0cx n$D) 2366 -5-{-CON(Me) 2 4- (-NH~e) 2367 5-(--CON(Me) 2 4-(-NHAc) 2368 5-{-CON(Me) 2 (N-be) 236 4- H 2369 5-{-CON(Me) 2 4-(-SMe) 414 230 5-{-CON(Me) 2 [me) 2371 5{CNM)} 4 -ie) 0 2372 5-{-CON(Me) 2 9-e 2373 5:-{1-CON (Me) 2

{-NM)

4- 0 2374 5-(-OMe) -H 2375 5-(-OMe) 2376 5-(-OMe) 4-(-Cl) 2377 5-H-OMe) 4-(-CN) 2378 5-(-OMe) 4- (-N0 2 2379 5-(-OMe) 4-(-Me) 2380 5-H-OMe) 4- (-CF 3 2381 5-(-OMe) 4-(-Ac) 2382 5-AHOMe) 4- (-CO 2

H).

2383 5-(-OMe) 4- (-CO 2 Me) 2384 5-(-OMe) N3 2385 5-H-OMe) 4- (-CONH 2 2386 5-(-OMe) 4-{(-CON (Me) 2 2387 5-(-OMe) 4-{-C(=NH)NH 2 2388 5-(-OMe) 4-(-OMe) 2389 5-(-OMe) 4 -0-cH 2 ND~ 2391 5-C-O~e) 4-(-4HAc) 2392 5-(-OMe) N M 2393 5-(-OMe) 4-(-SMe) 2394 5- (-OMe) 4(-Me 2395 5-(-OMe) -Me) a 2396 5-(-OMe) (-NH 2 2397 5-(-OMe) -N e) 2 0 2398 5-(-NHMe) 2399 5-(-NHMe) 4-(-C1) 2400 5-(-NHAc) 2401 5-(-NHAc) 4-(-C1) 2402 5-(-NHAc) 4-(-Ac) 2403 5-(-NHAc) 4-(-CONH 2 2404 5-(-NIAc) 4-{-CON(Me) 2 2405 2406 4-(-Cl) a 2407 5--N-S He~ 4-(-Me) 5- 0 2408 -N-S-Me 4- (-CF3) 2409 (-NI-Me) 4- (-C0 2

H)

a 2410 q-N)S- 4- (-CO 2 Me) H a 2411

(-ND)

H0 4 2412 (N--me 4- (-SMe) 2413 S(-Me) 2414 416 2415 5- (-SMe) 4- 2416 5- (-SMe) 4- (-CL) 2417 5- (-SMe) 4-C(-Me) 2418 5- (-SMe)4-(C3 2419 5- (-SMe) 4 2420 5- (-SMe) 4- (-CONH 2 2421 5- (-SMe) 4- (-CON (Me) 2 1 2422 5_ (A 2423 -m 4- (-Cl) 224 -i-S

M

e) 4- (-Me) 2425 (-CE' 3 24261 4- (-Ac) 2427 M 4 CONH 2 2428 s 2 1 2429 4- 5- 0 2430 (-Cl) 2431 H1-Me) 4- (-Me) 2432 (-iMe) 4- (-CF 3 0 2433 4- 2434 (-CONE 2 2435 (-.)4-{-CON(Me)2z 2436 417 2437 4

-NH

2 4-C-Cl) 0 2438 (I-NH) 4- (-Me)

U

2439 -NH 4- -CF3) 06 2440 4 (-CONH 2 a 2441 a-s9-tH. 4-(-CON(Me) 2 1 2442 (-NH 4(-SMe) 5- 0 2443 9(-NH) 2444 (-4-NH2) (-Me) a 4- 0 2445 4 0 2446 4- (-Cl) 5- 0 2447 4- (-Me) 0 2448 -S-N 4- (-CF 3 0 2449 N(e) 2 4- (-CONH 2 2450 4-(-CON (Me) 2) 5- 0 2451 -S-Na(M) 4- (-SMe) 2452 2( 0- 2453 N(ms A Me 0 4- 0 Table 215 HO0 2 C zjN 2 3 \4 26 N R Iv No.

2454 2455 2456 2- 2457 3- 3- (-Cl) 2458 3,5-di-(-Cl) 2459 3-(-CN) 2460 3- (-NO 2 3- (-N0 2 2461 3-(-Me) 2462 3- (-CE' 3 3- (-CE' 3 2463 37(-Ac) 3-(-Ac) 2464 3-(-C0 2 H) 3-(-CO 2

H)

2465 3-(-C0 2 Me) 3-(-CO 2 Me) 2466 t KDlN) 2467 3- (-CONH2) 3-(-CONH 2 2468 3- (-CONH 2 2469 3-C-CONH2) 3-(-Cl) 2470 3-(-CON(Me) 2 1 3-f-CON(Me)2) 2471 3-{-CON(Me) 2 3- (.F 2472 3-f-CON(Me) 2 1 3-(-Cl) 2473 3-{-C(=NH)NH 2 3-f-C(=NH)NH 2 2474 3-(-OMe) 3-(-OMe) 2475 N 419 2476 3- (-NHMe) 3- (-NHMe) 2477 3-(-NHAc) 3-(-NHAc) 2478 e O 3 H 3. H0 2479 3-(-SMe) 3-(-SMe) 2480 2481 3 (Ime -Me 2482 H 3- 3- H 2)/ 0 0 2483 N(Me 2 0 0 2484 3 2485 4-(-CI) 2486 4-C-CN) 2487 4-(-N0 2 4--NO 2 2488 4--C-Me).

2489 2,6-di-(-Me) 2490 4-(-CF 3 2491 4-C-Ac) 2492 4-(-CO 2 H) 4-C-C0 2

H)

2493 4- (-Co 2 Me) 4-C-CO 2 Me) 2494 D('N) 2495 4-(-CON 2 4- (-CONH 2 2496 4-(-CONH 2 2497 4-(-CONH 2 2, 3, 4, 5, 6-penta- 2498 4-(-CONH 2 4-(-Cl) 2499 4-{-CON(Me2) 4-(-CON(Me) 2 1 2500 4-{-CON(Me) 2 2501 4-{-CON(Me) 2 4-(-Cl) 420 2502 4-{-CON(Me) 2 2503 (=NH)N8 2 4 NH 2 2504 4-H-OMe) 4-H-OMe) 2505 4-H-OMe) 3,4,5-tri-(-OMe) 2506 4 CH2R-ND7 4 CH?- -NDj 2507 4-(-NHe) 4-(-NHMe) 2508 4-(-NHiAc) 4-(-NHAc) 2509 (pje)(N-N e) 2510 4-(-SMe) 4-(-SMe) 4- 4 00 2513 (-Nx 2

IN

2 4- 0 4- 0 2514 {1N(1e)8 N(Me 4- 0 0 Table 216

F

lo2i: 2 3 \4 6 1 1 6 5

R

R8 4 3 Ex. R No.

2515 -H -H 2516 2- 3- 2517 3-(-Cl) 2518 3-(-CN) 2519 3- (-N0 2 3- (-N0 2 2520 3-(-Me) 2521 3- (-CF 3 3- (-CE 3 2522 3-(-Ac) 2523 3- (-C 2 H) 3- (-C0 2

H)

2524 3-(-CQ 2 Me) 3-(-CO 2 Me) 2525 3(-LND) 2526 3- (-CONH 2 3-(-CONH 2 2527 3- (-CONH 2 2528 3-(-CONH 2 3-(-Cl) 2529 3-{-CON(Me) 2 3-(-CON(Me) 2 1 2530 3-1-CON(Me) 2 2531 3-{-CON(Me) 2 1 3-(-C1) 2532 3-{-C(=NH)NH 2 3-{-C(=NH)NH 2 2533 3-(-OMe) 3-(-OMe) 2534 (-O-CHAND) 3 (2-RCH 2ND9) 2535 3-(-NHMe) 3-(-NHMe) 2536 3-(-NHAc) 3-(-NHAc) 422 2537 -Ni-H e) (-SMe) 3- H 3- Ha 2538 3-(-SMe) 3-(-SMe) 2539 3---e-spm 2540 3- 0 2541

S[NH,)

03 0 2542 N(He),} 0 0 2543 4- 2544 4-(-C1) 2545 4-(-CN) 2546 4- (-N0 2 4- (-N0 2 2547 4-(-Me) 2548 4- (-CF 3 4- (-CF 3 2549 4-(-Ac) 2550 3- (-CO 2 H) 4- (-C0 2

H-)

2551 4- (-CO 2 Me) 4- (-CO 2 Me) 2552 (-I-NDZ

(ND

4- i 4- D 25531 4- (_COH2_ 4- __CONH 2554J 4- .COH 4--F 2556 3-{-CON(Me) 2 4-tf-CON (Me) 2 2557 3-{-CON(Me) 2 2558 4-{-CON(Me) 2 4-(-CI) 2559 NH 2 4 NH 2 }1 2560 4-(-OMe) 4-H-OMe) 2561 4 4(o-0cH2 LND3 423 2562 4- 4- (-NHMe) 2563 4 -(-NHAc) 4- (-N{Ac) 2564 2565 4-(-SMe) 4-(-SMe) 2566 A-Me)--m 2564- i-He 2567 M) (-SMe) 4- 0 4- 0 156 1 0 4- 0 424 Table 217 H%.rN Y b Py *IPR b Py :Pyridyl group Ex. IyR 2570 3-Py

-H

2571 3-Py 2572 3-Py 3- (-Cl) 2573 3-Py 3-(-Me) 2574 3-Py 3- 2575 3-Py 3-(-Ac) 2576 3 -Py 3- (-CO 2

H)

2577 3-Py 3- (-CO 2 Me) 2578 3-Py 3-(IN~D) 2579 3-Py 3- (-CONH 2 2580 3-Py 3-{--CON(Me) 2 1 2581 3-Py 4- 2582 3-Py 4-(-Cl) 2583 3-Py 4-(-Me) 2584 3-Py 4-V-C' 3 2585 3-Py 4-(-Ac) 2586 2-Py 4 -(-CO 2

H)

2587 3-Py 4- (-CO 2 Me) 2588 3-Py ND) 2589 4-Py 4- (-CONE 2 2590 3-Py 4-{f-CON (Me) 2 1 425 Table 218

F

0H 2 3 Py Pyridyl group Ex. Py V No.

2591 3-Py -H 2592 3-Py 2593 3-Py 3-(-Cl) 2594 3-Py 3-(-Me) 2595 3-Py 3- (-CF 3 2596 3-Py 3-(-Ac) 2597 3-Py 3- (-CO 2

H)

2598 3-Py 3-(-CO 2 Me) 0 2599 3-Py 1N) 3- 2600 3-Py 3- (-CONH2).

2601 3-Py 3-(-CN (Me) 2 2602 3-Py 2603 3-Py 4-(-Cl) 2604 3-Py 4-(-Me) 2605 3-Py 4-(-CF 3 2606 3-Py 4-(-Ac) 2607 3-Py 4-(-CO 2

H)

2608 3-Py 4-%-CO 2 Me)- 2609 3-Py ND 2610 3-Py 4-(-CONH 2 2611 3-Py 4-{-CON(Me)2} 426 Table 219 .7 Example No.

328 Cr 0 HC1 HO HJ 0 N NQ/ I

NNC)

1H NMR(6) ppm 300MHz,DMSO-d6 8. 29(1H, s),8.23(l1H, d, J=9. 0 Hz), 8. 02 (1H, d, J=8. 4Hz), 7. 8 0(1H, 7. 71(211H, d, J=8. 4Hz) ,7.61(1H,d,J=9. 3Hz),7. 55-7 .45(3H, m),7.46(21H, d, J=8. 1H 7. 22(2H, d, J=8. 7Hz), 5. 16 (2H, s, 4. 34(1H,m), 4. 20-3.

40(4H, 2.60-2.15(6H,m ),2 .10-1.90(2H,m), 1.85-1.70(2 H,m),11.65-1.55(111H, 1.50- 1. 10(3H, m) Purity 9 0% (NMR) MS 662 1)1 Example No. 329 ci

HC

H NH HO N>

OH

Purity 9 0% (NMR) MS 553(M+1) 1H NMR 5) ppm 400MHz,DMSO-d6 9.80(1H, brs), 8.32(1H, 8.3 0(1H, d, J=8. 8Hz), 8. 06(1H, d, J 8Hz), 7. 74 d, J=8.6Hz), 7. 48-7. 37(4H, 7. 22(1H, d, J 6Hz), 7. 17(1H,d,J=8.2Hz), 7.05(1H, d, J=2. 3Hz), 6.88(1H, dd, J=8. 3. 2. 5Hz), 5. 04 (2H, s), 4. 37 (1H, 2. 37-2. 22(21, m) 2. 11-1.98(2H,m), 1. 93-1. 81(2 1. 70-1. 58(1H, 1.56-1 .22(3H, m) .7 Example No. 330 Cl S

HC

HO- N N 2 0/- 1H NMR(6 ppm 300MHz, DMSO-d6 8. 38(1H, d, J=7. 5Hz), 8.32(1H, s),8.29(111,d,J=9.0Hz),8.16( 1H, 05(0H,d=. j9.OHz), 7.

96(H, d, J=7. 5Hz), 7.75(2H, d, J=8. 4Hz), 7. 53-7. 43(5H, m),7.

25(2H, d, J=8. 4Hz), 5.13(21, s) 4. 36(1H, m) 4. 12(111, sept, J= 6. 9Hz),2. 40-2. 15(211,m),2. 95 (2H, 1. 90-1. 75(21, m) 1.70-1.55(1H1,m),1.50-1. 311, 1. 18(6, d, J=6. 6Hz) Purity >9 0% (NMR) MS 622(M+1) 427 Table 220 Example No.

331 1IH NMR(6) ppm

CI

HCI

HO k- N i-

N

0 01$- 0 300MHz,DMSO-d6 8.31(1H, 27(1H, d, J=8.71 8. 05(1H, d, J=8. 7Hz), 7. 7. 41(91, 7.23(2H, d, J=8. 711 z),4.36(1H,m), 4.00-3.90(lH, 84(3H, brs), 2. 40-2. 15(2 H, 2. 10-2. 00(2H, 1. 95-1 .75(2H,m),1.70-1.55(lHm),1 .50-1.00(7H,m) Purity >9 0% (NMR) MS 636(M+1) 1 Example No.

SCI

HO

332 1H NMR(6) ppm 300MHz,DMSO-d6 12(1 H, 29(111Hs),8.27 10(1H, d, J=7.9Hz),8 .03(111H, d, J=8. 6z), 7.82(2H, d J=7. 5Hz), 7. 73(2H, d, J=8. 7Hz 7.56-7.52(5H,m),7.38(2H,t J=7.9Hz),7. 26(2H, d. J=8.7Hz ),7.13(1H,t, J=7.5Hz), 5.20(2 I1, 4. 35(LH, br t,J=11.7Hz),2.37-2.19(211,m) 2. 07-1. 96(21, 1. 92-1. 79( 2H,m), 1.69-1.58(1H,m), 1.50- 1. 20(3H, m) Purity 9 0% (NMR) MS 656(M+1) Example No. 333 HC

CI

O

HOPurity >90% (NMR) Purity >90% (NMR) 1H NMR(6).ppm 300MHz,DMSO-d6 8.30(1H, 24and8. 03(2H, A Bq,J=8.8Hz),7.71and7.22(4H, A'B'q, J=8. 8Hz), 7.69(1H, s),7 .52(4H, 7. 50and7. 43(211, A' B"aq, J=7. 7Hz), 5. 15(2H, s)4. (1H, br tJ=12. 11Hz),4.05-3. 15(5H,br 27(31, 39-2. 20(2H, m),2.07-1. 75(611,m), 1. 70-1.5 8(1H, m) 1. 55-1. 20(511, m) MS 678 (M+1) 428 Table 221 Example No. 334 0, HOC

N

1H NMRR(6) ppm 3001Hz, DMSO-d6 8.22(1, d, J4. 5Hz), 8. 01(IH, d, J9. 0Hz), 7. 89(111, dd, 6 1. 5Hz), 7. 61(211, d, J-8. 6Hz), 7. 50-7. 39(Off, 27(111, d, J 6Hz), 7. 22 (iH, d, J=2. 6Hz), 7. 13(2H, d, J=8. 6Hz), 7. 04(111, dd, 2, 2. 6Hz), 5. 04(211, s), 4. 28(11, 11(2H, t, J=6. 311 3. 57(2H, t, J=6. 3Hz), 2. 38- 2. 17(2H, 2. 00-1. 79(611, n), 1. 70-1. 59(1H, 1. 52-1. 16(3 H, mn) I urity >90%

(NMR)

MS 61104+1) Example No.

335

HCI

0 HO '-a N0 Pt9OH Purity >90% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 30(111, d, J=1. 5Hz), 8. 270(1H, d, J=9. 0Hz), 8. 04(1H, dd, J=8. 6 1. 5Hz), 7. 72(211, d, J=9. 0H), 7. 60-7.40(4H,m),7.32-7. 19(4 H, 7. 06(1, dd, J=8. 6, 3. 0Hz 5.08(21, 4. 36(1H, 4. 0 6(2K, t, J4. 8Hz), 3. 74(211, t, J 8H), 2. 38-2. 19(2H, 1 3-1. 97 (211, 1. 94-1. 78(2, m 1. 72-1. 59(1K, 1.52-1.

I 20(311, m) MS 597 (M+1) 429 Table 222 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitory activity ICso ICso [M] 340 0.017 360 0.014 341 0.025 361 0.028 342 0.015 362 0.020 343 0.017 363 0.11 344 0.016 364 .0.12 345 0.012 365 0.020 346 0.025 366 0.024 347 0.022 367 0.011 348 0.013 368 0.024 349 0.021 369 0.022 350 0.020 370 .0.017 351 0.019 371 0.015 352 0.013 372 0.033 353 0.023 373 0.013 354 0.013 374 0.013 355 0.015 375 0.012 356 0.016 376 0.014 357 0.019 377 0.012 358 0.017 378 0.018 359 0.015 379 0.021 430 Table 223 Ex. HCV polymerase Ex. HCV polymerase No. inhibitory activity No. inhibitory activity 50 [P±4 IC50 [JIM] 380 0.023 409 0.020 381 0.011 410 0.018 382 0.015 411 0.015 383 0.013 412 0.019 384 0.016 413 0.026 385 0.019 414 0.024 386 0.018 415 0.019 387 0.025 416 0.024 388 0.020 417 0.029 389 0.012 418 0.016 390 0.014 419 0.021 391 0.017 420 0.015 392 0.014 421 0.017 393 0.011 422 0.017 394 0.019 423 0.017 395 0.016 424 .0.020 396 0.025 425 0.026 19 0.037 426 0.053 398 0.077 427 0.020 399 0.032 428 0.026 431.

Table 224 HCV polymerase HCV polymerase Ex. inhibitory Ex. inhibitory No. activity No. activity ICso [JM] ICso [pM] 429 0.017 455 0.015 430 0.017 456 0.017 431 0.015 457 0.015 432 0.022 458 0.015 433 0.014 459 0.014 434 0.011 460 0.017 435 0.012 461 0.021 436 0.026 462 0.028 440 0.070 463 0.026 442 0.024 464 0.030 443 0.030 465 0.033 445 0.33 466 0.023 446 0.016 467 0.032 447 0.12 468 0.028 448 0.20 469 0.024 449 0.025 502 0.024 450 0.040 503 0. 196 451 0.031 601 0.32 '452 0.028 701 0.052 454 0.013 432 Table 225 Example No.

341 Hcii 0 HCI 0, HOa

NN

023- Purity 9 0% (NMR) MS 662(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 29(1. d, J=1. 5Hz), 8. 25(111H d, J=8. 7Hz), 8. 03(1H, dd, J=8 .7Hz),7.72and7.22(4H,Abq,J =8.8Hz), 7. 67 (1H, d, J=1. 7. 52(4H, 7. 49(1H, dd, J=7 1. 5Hz), 7. 43(1H, d,J=7. 911 z),4.46(1H,brs),4.35(1H br t,J=12.4Hz),3.62(1H,brs, 3 .06(lH,brs),2.79(lH,brs), 2 38-2.20(2H, brm), 2.08-1.81 (4H, brm), 1. 77-1. 52(4H, brm) 1.46-1.20(3H,brm), 1. 19-1.

00(2H, brm), 0. 94and0. 92 (tot al3H,each s) Example No.

342 ci

HCCI

0 HOI~

HO/

00 1H NMR(6) ppm 300Mz,DMSO-d6 8.28(1H, d, J=1.5Hz), 8.26(1H, d,J=1.8Hz),8.19(1lH, d.J=8. 8H z),8.07(1H,dd, J=7.7, 1.8Hz), 8.00(1H, dd,J=8. 8,1.5Hz),7.7 Oand7.22(4H,Abq,J=8.8Hz),7.

56-7. 50(1H, 7. 56(411, 17(211, 33(1, brt, J=12. Hz),2.05(3H,s),2.37-2. 20(2H brm), 2.06-1.80(411, brm), 1. 7 0-1. 60(1H, brm), 1.50-1.20(3 brm) Purity

MS

9 0% (NMR) 679 (M+1) Example No. 343. 111 NMR(8) ppm 300MHz,DMSO-d6 8.20(111, d, J=1.5Hz), 7.93(111, d, J=8.6Hz), 7.84(1H, dd, J=8.3 Hz, 1. 5Hz). 7. 57(2H, d. J=8.6Hz ),7.50-7.40(4H, 7.27(111, d J=8. 2Hz), 7. 22(1H, d, J=2. 6Hz 7. 10(2H,d,J=8.6Hz)7. 01(1H dd, J=8. 6Hz, 2. 6Hz), 5. 02 (2H, s),4.89(21, 4.78(1H, d, J=4 .1Hz),4.38-4. 18(1H,m),3.96- 3. 81(111,m), 3. 78-3. 62(2H,m), 3.27-2. 99(211,m), 2. 35-1. 15(1 4H,a) O OH Purity >90% (NMR) MS 694(M+1) 433 Table 226 Example No. 344 1H NMR(6) pp.

300MHz, DMSO-d6 8. 30(1 8. 23(111, d, J=8. 7H 8.02(1H, d, 5=8.4Hz), 7. 71( 2H, d, 5=8. 7Hz), 7. 55-7. 15(811, 7. 07(1H, dd, J=8. 4Hz, 3. OHz ),5.07(28, 4.35(1H,m), 4.1 7(2H, t, J=4. 5Hz), 3.69(21, t, J 5Hz), 3. 32(38, 40-2. 1 5(21, 2. 10-1. 80(4H, 1.7 5-1. 60(1H, 1.50-1.20(3H,m Purity >90% (NMR) MS .611(M+1) IExample No. 345 IH NMR(6) ppm 300MHz,DMSO-d6 8. 29(1H, d, J=1. SHz), 8.22(1H, d, J=8. 7Hz), 8. 01(H, d, J=8. 711 z),7.70(1H, 7Hz), 7. 7. 15(81, 7.07(1H, dd, J=8. 4 Hz, 2. 4Hz), 5.07(21, 4. 35(1 H, 17(2H, t, J=4. 2Hz), 3. 7 6(2H, t, 5Hz), 3.65-3.40(4 H, 3. 25(311, 2. 40-2. 20(2 H, 10-1.80(41,m), 1.75-1 .65(1H,m), 1.65-1.20(3H,m) o7Lo 0- Purity 9 0% (NMR) MS 655 (M+1) Example No. 346

HO-

1H NMR(6) ppm 300Mz,DMSO-d6 8. 26(1H1, d, J=1. 9Hz), 8. 23(1H, d, J=1. 5Hz), 8. 08-8. 02(2H, m), 7.91(1H,dd,J=8.7,1.5Hz) 7 6 3and7. 16(4H; Abq, 9Hzi 7.

56-7.51(5H, 5. 15(2H, 4.

29(1H, brt, J=11. 7Hz), 2. 96(21 d, J=6. 9Hz), 2. 37-2. 12(3H, a) ,2.00-1.79(4H, brm), 1.71-1.6 0(1H,bra)1.49-1.19(311,br), 0. 97and0. 95 (total6H, each s) Purity 9 0% (NMR) MS 621(M+1) 434 Table 227 7 Example No. 347 1H NMR( 6) ppm 300Hz, DMSO-d 8. 26(1H, 8.22(1H, 8. 06( 1H, 8. 05 d, J=8 OHz) 7 94and7. 85 (2H, ABq, J=8. 8HzS, .59and7. 15(4K, A' B' q, H8.6Hz 7. 52(4H, 7. 44(OH, d, Jh8.

0Hz)', 5. 12(2H, 4. 27(1, brt J=l1. 4Hz), 2. 38-2. 18(211, brm 1. 97-1. 77(41, brm), 1. 70-1.

59(111, brm), 1. 49-1. 17(3, br.

Purity >90% (NMR) Ms 634 (M+1) Example No. 348 dI HCI

HO

3 j N>J

OH

00 N

OH

Purity >9 0% (NMR) MS 680 (M+1) 11 NMR(6) ppm DMSO-d6 8. 32(111, 8. 29(11, d, Of 8. 06(111, d, J=8. 7Hz), 7. 74( 2H, d, J=9. 0Hz), 7. 72 brs), 7. 60-7. 45(5H, 7. 42(11 d J 8Hz), 7. 24(2, d, J=8. 7HzS, 5. 15(2H, 37(111, 4. 00- 3. 10(6H, 2. 40-2. 18(21, m), 2. 15-1. 95(211, 1. 90-1.80(2 H, 1. 75-1. 20(6, m) Example No. 349 1H NMR(6) ppm CI 30MHz,DMSO-d6 8.41(11, d, J=1. 5Hz), 8. 33(1), 0' HC d, J=1.Hz),8. 26(1H, d, J8. 7H 8. 18 (111 dd, J=2. 0Hz, 8. 0Hz HO' a 8. 04(1, dd, J=1. 5Hz, 9. 0Hz) 75(2H,d, J8. 7Hz), 7.63(11 /5(2H d, J=8. 1Hz), 7. 62-7. 45 (41, 26(211, d, J8. 7Hz), 5. 25(2 =N 35(H, 2. 45(3H, s),2 0, 40-2. 18(211, 2. 15-1. 95 (211 N 1. 90-1. 80(2H, 1. 75-1.

5(1, in), 1. 50-1. 20 (3M, m) Purity >9 0% (NMR) MS 619(MnI) 435 Table 228 Example No. 350

CI

HCI

N

H

Purity 9 0% (NMR) MS 622 (M+1) 1H NMR( 6) ppm 300MHz,DMSO-d6 8. 36(1H, d, J=7. 7Hz), 8.29(111, s),8.23(LH,d J=8.8Hz),8.02( 1H,d,J=8.6Hz),7.94(1H, d J=7 .9Hz),7. 84(1H, d,J=1.6Hz, 7.

80-7. 65 (3H, 7. 53(411, 15(211, s),4.34(1H,m),4. 12(1H 2.35-2.20(2H,m), 2. 60(5H,m), 1.50-1. 20(311, 1.

17(6H, d, J=6. Example No. 351 Cl 0 HC1 HO' N D 0 Purity (NMR) Purity 90% (NMR) 1H NMR ppm 300MHz,DMSO-d6 8.29(1H,s),8.24(1H,d,J=8.8H 8.02(1H, d,J=8.6Hz), 7.80- 7. 65(3H,m), 7. 55-7. 45 7.32(1H, d, J=1. 5Hz), 7.22(2H, d, J=8. 8Hz), 5. 13(2H, 4. 1H, 3. 60(2H, 3. 33(211, m) ,2.40-2. 15(2H,m),,2. 10-1. 1411, m) MS 648 1 Example No. 352 cl

HCI-

HOt

NJ-

N

/H

H

N

0

X-

1H NMR(6 ppm 300MHZ,DMSO-d6 13.20(1H, brs), 8. 30-8. 24(211, m),8.13(lH,s),8.04(1H,d,J=8 .7Hz), 7.94(1H, d, J=8. OHz),7.

75-7. 70(311, 7. 55-7. 43(511, 25(2, d, J=8. 7Hz), 5.13( 2H,s),4.36(1H,m),3.53(2H, s) ,2.40-2. 18(211,m),2.15-1.95( 211,a), 1. 90-1. 80(2, 1.75- 1. 55(1H, 1.50-1. 20(9H, m) Purity >90% (NMR) MS 652(M+1) 436 Table 229 Example No. 353 cI 2HCI 0 HO N N

-N

Purity about MS 634 (M+1) 11 NMR(6) ppm 300MHz, DSO-d6 8.41(1H, 8.33-8.29(211,m), 8. 16(18H, d, J=8. 2Hz), 8. 07(1H, d J=8.6Hz),7.77(2H, d,J=8. 711 z 7.62(1H, d, J=8. OHz), 7. 59- 7. 51(4H, 7. 28(2H, d, J=8. 8H 5. 21(2H, 56(21, s),4.

37(1H,m),2.40-2. 18(21H, 2.

15-1.95(2H, 1.90-1.80(2H, 1. 75-1.55(1H,m), 1. 50-1.2 0(911,m) Example No. 354 IH NMR 6 ppm 300MHz,DMSO-d6 8.31(1H,s),8.25 (1H,d,J=9. OH z),8.03(1H, d, J=8. 7Hz), 7. 76- 7. 71(311, 7. 51-7.47 (5H. m), 7.33(1H, 23(2H, d, J=9.OH z),5.14(2H, s),4.36(IHm),4.

02(H111, ),3.75(lH,m),3.56(1H ,m),3.22(211, 2.40-2.18(2H 15-1.95(211,m), 1.90-1.

55(5H, 1.50-1.20(5H,.m) Purity 9 0% (NMR) MS 664 (M+1) Example No. 355 1H NMR 6 ppm 300MHz, DMSO-d6 8. 62(1H, t, J=5. 7Hz), 8. 32-8. 3 O0(2H, m),8.25(1H,d J=8. 7Hz), 8.03(1H,d J=8 7Hz,7.96(1H, d,J=8. 1Hz, 7.86(1H,s),7.75( 1H, d, J=9. OHz), 7. 72(2H, d, J=9 .0Hz), 7. 55-7. 50(4H, 7. 22( 2H, d, J=9. OHz), 5. 17(2H, 4.

35(1H, 3.52(2H, t,J=6. OHz) ,3.36(2H, t,J=6. 0Hz),2.40-2.

18(2H,m),2.15-1.95(2H,m), 1.

90-1.80(2H,m), 1.75-1.55(1H, 1.50-1.20(3H,m) Purity >90% (NMR) MS 624 (M+1) 437 Table 230 Example No.

O

0 356 1H NMR(6) ppm 300Mz,DMSO-d6 9. 30(1H, t, J=5.9Hz), 8.54(2H, d, J=5. 9Hz), 8. 22(1H, 8. 02- 7. 79(5H, m) 7. 59and7. 12(4H, A Bq, J=8. 6HzS, 7.55(4H, 7.37 (2H, d, J=5. 9Hz), 5. 15(2H, 4 .54(2H, d, J=5. 7Hz), 4.26(1HI, b rt, J=12. 8Hz), 2. 36-2. 18 (2H, b rm), 1. 97-1. 78 (4H, brm), 1. 1. 60(1H, brm), 1. 47-1. 17(3H, b Purity 9 0% (NMR) MS 671(M+1) Example No.

357 S HCI HO0 N Purity 90% (NMR) Purity 9 0% (NM R) 1H NMR(6) ppm 300Mz, DMSO-d6 8.31(1H, d, J=1. 5Hz), 8.43(1H, d, J=8.4Hz), 8.03(1H, dd, 1J=8. 4 1. 5Hz), 7. 74(1H, d, J=8. 1Hz) 7. 73and7.23(4H, ABq, J=9. OHz 54-7.51(5H, 7.37(1H, d, J=1. 8Hz), 5. 14(2H, s),4.36(1H brt, J=12. IHz), 2.98(6H, brs) 37-2. 20 (2H, brm), 2. 08-1. 8 1(4H, brm), 1. 70-1. 60(1H, brm) 1. 50-1. 21(3H, brm) MS 608 (M+1) Example No. 358 1H NMR(6) ppm CI 300MHz,DMSO-d6 2HCI 8.33 (IH, 31(1H, d, J=8. 7H 0 8. 14(1H, 07(1H, d, J=8 .7Hz),7.92(1H, d J=8. 0Hz), 7.

HO 76 (2H, d, J=8. 7Hz, 7.52-7.40( 01 5H, 31-7. 26(3H, 5. 2H. 37 (1H, 2. 40-2. 18( N 2H, 15-1. 95 (2H, 1. 1. 80(2H, 1. 75-1. 55 (1H, m), S NH 2 1.50-1.20(3H,m) Purity about MS 635 (M+1) 438 Table 231 Example No. 359 1H NMR(6) ppm 300MHz, DMSO-d6 8.31(1IH, s),8.25(1H, d,J=8.7H 8. 10-7. 90(2H, 7.82 (1H, dd, J=7.8Hz, 1.8Hz), 7.72(2H, d J=9. OHz), 7.63(1H, d, J=8. 1Hz 7.23(2H,d,J=9. Hz), 5.25(2 H, 34(1H, 3.65-3. 50(1 3.20-3.05(2H 2.90-2 .75(2H, 2.40-2.15(2H, 2 .10-1. 10(12H.m) Purity 9 0% (NMR) MS 700 (M+1) Example No. 360

HCI

1H NMR(6) ppm 300MHz, DMSO-d6 8.33(1H, s),8.30(1H, d, 8.06(1H, d, J=10. 1Hz), 8.80 65 (3H, 8. 60-8. 45 (3H, m) ,7.42(lH, d, J=7.8Hz), 7.35-7.

15(4, 5.15(2H, s),4.36(lH 01. 2.97(6H, s),.2.40-2.

15(2H, 10-1.75(4H, 1.

70-1. 55(IH, 1. 50-1. 20(3H, n) Purity 9 0% (NMR) MS 592 (M+1) Example No. 361 1H NMR(6) ppm 300MHz,DMSO-d6 8.35-8. 20(2H,m), 8. 05(1H, d, J =8.7Hz), 8.80-8.65(3H, 7. 6 0-7.40(3H, 40-7.30(5H, m 17(2H, s),4.35(lH, 1, 2.97(6H, 2.40-2. 15(2H, m 2. 10-1.80(4H, 1. 70-1. (4H, m) 0 HO -a

()I

Purity >9 6% (NMR) MS 592(M+1) 439 Table 232 Example No. 362 ci

HCI

HO

7 Ny NI II S

NN

00 t, Purity 9 0% (NMR) MS 614(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.33(1H, s),8.29(1H,d, J=8. 7H 06(1H, d, J=8. 7Hz), 7. 79( 2H, d, J=9. 0Hz),7. 76(1H, d J=9 .0Hz),7. 60(iH, d, J=8. IHz 7.

53(1H, dd,J=I.7Hz,8. 0Hz), 7.3 5(2H, d, J=8. 7Hz), 6. 85-6.'80(2 H, 5. 29(21, 4. 38 (IH, m), 3. 01, 2. 96(6H, 40-2. 18(2 H, 15-1.95(211,m), 1.90-1 .80(2H,m), 1.75-1.55(1H,m), I 50-1.20(3H,m) Example No. 363 0

HCI

HO N Br N

NN

Purity 9 0% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8.28(1H, d, J=1. 3Hz), 8.20-8. 1 0(2H,m),8.98(1H,d,J=8.6Hz), 7.90-7.80(2H, 7.75 (2H, d J 7Hz), 7. 36(2H, d, J=8. 7Hz, 7. 04(1H, d, J=1. 3Hz), 5. 35(211, s),4.36(1H, 2.39(311, s),2.

35-2.15(2H, 2. 05-1. 75(4H, 1.70-1. 60(1H, 1. 50-1.2 0(311,m) Ms 586(M+1)I Example No. 364 0 HCI HOAI-) N 0 Br N I

N

0% S Purity >90% (NMR) 1H NMR 6 ppm 300MHz[,DMSO-d6 8.31(1H, 8.26(1H, d, J=8. 7H 13(1H,s),8.04(1H,d,J=9 .0Hz), 7. 90-7. 70(4H, 7. 1H, 7. 39(2H, d, J=9. 0Hz), 37(2H, 38(1H, 2.40-2.

20(2H,11m),2. 15-2.00(2H,m), 1.

95-1. 80 (2H, 1. 75-1. 60(111, m),1.50-1.20(3, m) MS 604(M+1)

I

440 Table 233 Example No.

365 IH NMR(6) ppm 300MHz, DMSO-d6 8.28(1H, s),8.23(IH,s),8. 17( 1H, d, J=8. 7Hz) 00(2H, t, J=6 9Hz), 7. 69(211, d, J-8. 4Hz), 7.

60-7. 45(5H, 7. 21(211, d, J=8 .4Hz), 7. 05(1H, s) 5. 19 (2H, s), 4. 33 (IH, 2. 41 2. 2. 20(2H, 2. 10-1. 80(411, 1. 70-1. 60(IHOm), 1. 50-1. 20(3 H, n Purity >90% (NMR) MS 618I(M+ 1) Example No. 366 1H NMR(G) ppm 300MHz, DMSO-d6 8. 26(1H, s),8.17(1H,s),8. i( 1H, d J=87Hz),7. 95(2H, d, J=9 6Hz, 7. 70-7. 40(8, 7. 19( 211, d, J=8. 4Hz) 5. 18 (2H, 4.

30(1H, 51 2. 40-2.

15(211,). 2. 05-1. 80(411, 1.

75-1. 60(111, 1. 50-1. 20(311,

M)

Purity >90% (NMR) MS 634 (M+1) Example No. 367 11 NMR(I5) ppm cI 300Mz,DMSO-d6 HCI 8. 42(0H, d, J=1. 9Hz), 8. 30(1H, 0J, 1. 5Hz), 8. 27 (0H, d, J=8. 7Hz 8.18OH, dd, J=7. 9,1. 91z),8 HO .04(11, dd, J=8. 7,1. 5Hz),. I and?. 29(411 ABq, J8. 9Hz)7. 63 (ii, ci, J7. 911, 5. 23(211, 4 H .36(1H,brt,JTh12.33Hz)237-2.

0 N 20(2H,brm),2.08-1.80(4H,brm N 5 N 1. 71-1. 60 (1I, brm), 1. 51-1.

N 21(3H,brm) Purity >90% (NMR) MS 605 (M+1) 441 Table 234 Example No. 368 1H NMR 6 ppm 300Mz, DMSO-d6 8.30(1H, d, J=1. 5Hz), 8.25(1H, d, J=8. 6Hz), 8. 04 (1H, dd, J=8. 6 5Hz) 7. 93and7. 67 (4H, ABq, J=8. 1Hz), 7.80 (1H, d, J=2. 2Hz) 72and7.21(4H, A' B' q, J=8. 6 Hz), 7. 60 (IH, dd, J=8. 1, 2. 2Hz) ,7.44(1H, d, J=8. 1Hz), 5. 13(2H ,s),4.34 brt J=11. 7Hz),2 37-2. 19(2H, brma, 2.09-1.80( 4H, bra), 1. 72-1. 60(1H, brm), 1 21 (3H, brm) Purity 9 0% (NMR) MS 562 (M+1) Example No. 369 1H NMR(6) ppm 300Mz, DMSO-d6 8.30(1H, d, J=1. 5Hz), 8. 25 (1H, d, J=8. 6Hz), 8. 16and7. 72(4H, A Bq, J=8. 4Hz), 8. L3 (111H, dd, J=8.

6, I. 5Hz), 7. 80 (1Hd, J=2. 2Hz), 7.70and7.24(4H, A' B' q, J=8. 8H 7. 61 dd, J=8. 1, 2. 2Hz), 7. 48(1H, d, J=8. 1Hz), 5. 17(2H, 4. 33(1H, brt J=12.1Hz),2.

36-2. 18(2H, brm), 2. 08-1. 77(4 H, brm), 1.69-1.57 (1H, brm), 1.

49-1.17(3H, brm) Purity 9 0% (NMR) MS 605 (M+1) Example No. 370 HCI C

OJ

Purity 9 0% (NMR) MS 680 1) 1H NMR ppm 300MHz, DMSO-d6 10. 94(1lH, brs), 8. 33(1H, 8.

27 (1H, d,J=8. 7Hz), 8. 04(1H, d, J=8. 7Hz), 7. 74(2H, d, J=8. 4Hz) 56-7. 29 (6H, 7. 23 (2H, d, J=8. 7Hz), 7. 13(111, d, J=8. 7Hz) 08(2H, 4.51 (2H, brs), 4.

36(1H, 3.94(1H, brs), 3. 3.00 3. 20-1. 20(14H, m) 442 Table 235 Example No. 371

CI-

HOI

0

F

N

Purity 9 0% (NMR) MS 652 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 31(1H, d, J1. SHz),8.17(1H, d, J=9. 0Hz), 7. 99(1H, dd, J=8. 7 Hz, 1. 4Hz), 7. 70-7. 55(2H, m),7 .50-7. 30(6H, 7.19(H, dd, J =12. OHz, 2.2Hz), 7. 06(1H, dd, J 6Hz, 2.2Hz), 5.08(2H,4. 1H, 3. 68(28, brt, J=5. 2),2.

50(21, brt, J=1. 8Hz), 2. 30-2. 1 0(2H, m),2.00-1.75(8H, 1.7 0-1. 55(1H, 1.50-1.20(3H, m Example No. 372 IH NMR(5) ppm 300Mz,DMSO-d6 8.29(1H,d,J=1.5H2),8. 11(1H, d, J=8. 6Hz), 7. 96(1H, dd, J=8. 6 7.89(1H, 7.78and7 56(4H,ABq,J=8.4Hz), 7. 69(1H 7.66(1H, t,J=8. 8Hz),7. 31 (1H,dd, J=12. 1, 2. 2Hz),7. 18(1 H,dd, J=8. 8,2.2Hz), 5. 37(2H, s 08(1H, brt, J=11. OHz),3. 0 2(311, s),2.96(311, s),2.31-2. 1 4(2H,brm),1.95-1.77(41, brm, 1.69-1. 59(31H, brm), 1.46-1.

18(3H, brm) Purity >90% (NMR) MS 626(M+1) Example No. 373 2HCI CI 0 NH2

OH

Purity >90% (NMR) MS 613(M+1) IH NMR( 6) ppm 300MHz,DMSO-d6 11.40(1H,brs),9.25(2H,brs), 8. 29(1H, d, J=1. 3Hz), 8.12-8.0 9(21, 7. 96(1H, d, J=8. 7Hz), 7.88(1H, dd, J=1. 8Hz, 8. 1Hz),7 .67-7.63(21, m),7.56(211, d,J= 8. 7Hz), 7. 51(211H, d, J=8. 7Hz),7 17(1H, d, J=12. OHz), 7.05(1H, d, J=8. 6Hz), 5.16(2H,s),4. 1H,m),2.40-2.10(2H,m),2.00- 1. 75(4H, 1. 70-1. 55(1H, m), 1. 50-1. 20(3H, m) 443 Table 236 Example No. 374

HCI

0F HOA-C N N'd o Purity >90% (NMR) MS 639 1H NMR(8 ppm 300MHz, DMSO-d6 13. 21 brs), 8. 31 (11, d, J=1 4Hlz), 8. 18-8. 15(2W, m) 7. 99 Ii, d, J=8. 7Hz), 7. 94 (1H, dd, J= 1. 8Hz, 8. 0Hz), 7. 70-7. 53 (6H1, m 7. 17 d, J=12. OHz), 7. 11-1, d,J=8. 6Hz), 5. 20 4.

2. 40-2. 10 (21, mn), 2.

00-1. 75411, 1. 70-1. 55111, in), 1. 50-1. 20(31,.m) Example NO. 375 IK NMR(6 ppm 30011Hz, DMSO-d6 8, 32(1OH, d, J=1. 5Hlz), 8. 23(LH, d, Y 511z), 8. 19(IH, d, J=9. OH 8. 03-7. 98 (21, in), 7. 68(11H, t, 1=8. 4Hz), 7. 60(IH; d, J=8. 111 7.'56 (2H1, d, 1=9. 3Hz), 7. 53 2H, d, J-9. 0Hz), 7. 22 (1 H, dd, 1= 2. 1Hz, 12. OHz), 7. 09 (111, dd, J= 2. 1Hz, 8. 41z), 5. 21 (211, 4. 1 2(111i, in), 2. 40-2. 10 2. 0 0- 1.75(41,.m), 1. 70-1. 55(111, m 1. 50-1. 20(3M,.m) Purity 90% (NMR) MS 658 (M1+1) Example No. 376. 1H- NMR(6 ppm HOJ 300MHz, DMSO-d6 H61 13. 61 (1 H, brs), 8. 34-8. 30 (2H, 0F m) /n8. 211H, d,J=8. 7Hz), 8.07 N I H1, dd, 8Hz, 8. 1lHz), 8.02(1 HO N H.dd,J1I.SHz,8.MHz), 7.6901H N v t, 4Hz), 7. 57-7. 49(51,.m) N N 7. 22 (11, dd, J=2. 7Hz, 1. Hz), N 5.19(2H,s),4.12(1H,i),2.40- N 2. 10 (2H1, 00-1. 75 (41, in), S 1. 70-1. 55(111, mn), 1. 50-1. 20 (3 Purity >90% (NMR) Hnm MS 655 (M4±1) 444 Table 237 Example No. 377

CI

HC1 0

F

HOA-NN

AN

H

N

Purity >90% (NMR) MS 638 (1M+1) 1K NMR(6) ppm 300Mz,DMSO-d6 8.60(1H,d J=4.5Hz),8. 29(1H, 5Hz, 8.14(1H,d,J=8.9H11 13(lH,d,J=1.5Hz),7.98( 1H, dd, J=8. 9, 1. 5Hz), 7. 94(1H, dd,J=8. 1, 1. 5Hz), 7. 64(1H, t,J 7Hz), 7. 52and7. 49(411, ABq, J=9. OHz), 7. 46(1H, d, J=8. 1Hz) ,7.18(1H, dd,J=12. 1,2.3Hz),7 .05(1H, dd, J=8.7,2.3Hz), 5.13 (2H, 08(1H, brt, J=12. 1H) ,2.95-2.84(1H, 2.31-2. 14( 2H, brm),1.97-1.78(4H,brm), 1 .72-1.59(1H, brm), 1.47-1.21( 3H, brm). 0.76-0.58(4H,m) Example No. 378

CI

HCI

0' F HON

H

0N Purity 9 0o% (NMR) MS 652(M+1) 11 NMR(6) ppm 300Mz,DMSO-d6 8. 77(1H, d, J=1. 4Hz), 8. 30(1H, d,J=1.4Hz),8. 16(1H,d,J=1. 811 8. 13(111, d, J=8. 4Hz),7. 98( 2H, dd, J=8. 4, 1. 8Hz), 7. 65(1H, t, J=8. 4Hz), 7. 53and7. 49(4H, A Bq,J=8. 8Hz),7.47(1H, d, J=7.7 Hz),7. 18(1H,dd,J=12. 1, 2. 2Hz 05(111H,dd, J=8. 4, 2. 13(21, 53-4.40(1l, m),4 09(1H, brt, J=12..8Hz), 2. 31-2 .02(6H, brm,), 1. 96-1. 80(4H, b rm), 1. 78-1. 60(311, brm), 1. 47- 1.21(3H,brm) Example No. 379

CI

HCI

F

HO

N

H

N

0 Purity >90 0o (NMR) MS 654(M+1) 1H NMR(6) ppm 300Mz,DMSO-d6 8.29(1H, d J=1 1Hz),8.11(1H, d, J=1. 5Hz, 8. 1(1H, d, J=8. 8H 7. 98-7.91(2H,m), 7. 89(1H, 63(1H, t, J=8. 8Hz), 7. 52a nd7. 48(411, ABq, J=8. 6Hz), 7. 44 (1H,d,J=8. IHz),7. 17(1H,dd,J =12. 1, 2.2Hz), 7.04(1H, dd, J=8 .8,2.2Hz),5. 12(211,s),4.07(1 H,brt, J=12.4Hz),2.33-2.14(2 H, brm), 1. 96-1. 79(4H. brm), 1.

70-1. 60(1H, brm), 1.48-1.21(3 H,brm), 1. 41(9H, s) 445 Table 238 Example No. 380 cl

HCI

0F HOA NN

H

00N Purity >90% (NMR) MS 654(M+1) IH NMR(6) ppm 300Mz, DMSO-d6 8. 62 (0H, t, .J5. 5Hz), 8. 30(1H d, J1. 5Hz), 8. 17(l0H, d, J=1. 8H 8. 14(11, d, J=8. 8Hz), 7. 98( 11H, dc, J=8. 1, 1.8Hz), 7. 64(1 H, t, 8Hz), 7. S2and7. 50(4, A k L=8. 8Hz),7.48(1H,d,J--8.1 Hz, 7. 18(LH, dd,PJ=12. 1, 2. 2Hz 7.05(1H, dd, J=8. 8, 2. 2Hz), .14(211, 08(1H, brt, J-12.

lHz), 3. 13(11, t,J6. 2Hz), 2.3 1-2. 14(2H, brm), 1. 97-1. 78 ,bri), 1. 70-1. 60(1, brm), 1. 4 7-1. 21 bri), 0. 92(3, s),O0 .90(3H, s) Example No. 381 0 HCI HCr HO

N'N

H

Purity >90% (NMR) MS 656(M+1) 11 NIAR(6) ppm DMSO-d6 8. 29(11, d, J=1. 5Hz). 8. 27(11, d J=8. 3z), 8.l8(111,d, J=1. 9H z, 8.13(TH, d, J. 711 01- 7. 96 (28, 7. 64 (11, t, J-8. 7 z) 7. 2and7.49(IHABq,J=8.8 Hz5, 7.49(1H, d, J=7. 9Hz), 7. 18 dd, J=12. 1, 2. 3Hz), 7. 05(1 H, dd, J-8. 7, 2. 3Hz), 5. 13(211, s 4.12-4. 00(2H, 3. 52-3. 34 2. 31-2. 14(2H,brm), 1.

97-1.79(4H,brm), 1. 71-1. 60(1 H,brm), 1. 48-1. 21(3H m) 1 17 andl.15(total3Heach S 5 Example No.

382 IH NMR(6) ppm 300Mz, DMSO-df 8. 30 d, 5Hz), 8. 13 (11, d, J=8. 8Hz), 8. 09 d, J=t. 7. 980(11, dc, J=8. 8, 1. 7. 86(1, dd, J=8. 1, 1. 5Hz), 7. 6 4(11, 1=8. 8Hz), 7. 55-7. 47 7. 17(1H, dd, J=12. 1, 2. 2Hz) 05 (1H, dd, 1=8. 8, 2. 2Hz), 14 (2H, 4.08(1H, brt, J=12. 8 Hz), 3. 75(3, 2. 32-2. 14(211 brm), 1. 96-1. 78(4, brm), 1. 7 0-1. 59(1 H, brm), 1. 47-1. 21(3H brm) Purity >90% (NMR) MS 628 (M+1) 446 Table 239 Example No. 383 1H NMR(6) ppm 300Mz,DMS0-d6 8. 57(1H, t, J=5. 5Hz), 8. 29 (H, d, J1. 4Hz), 8. 19(1 H, d, J=1. 8. 12(1, d, J=9. 2Hz), 8. 01- 7. 95(211, 7. 64 (OM, t, 8H 53and7. 50(411, Aq, 3=8. 8 Hz), 7. 48(111, d, J7. 7Hz), 7. 17 (11, dd, J=12. 1, 2. 2Hz), 7. 04(1 H, dd, J=8. 8, 2. 2Hz), 5. 14 (2H, s 4. 08(1H, brt, J=13. 9Hz), 3. 7 0-3. 66(1H, 3. 48-3. 36(311, m 3.28-3. 20(1H, 2. 32-2. 13 (21, brn), 1. 96-1. 79(41, brm), 1. 71-1. 60(1H, brm), 1. 47-1. 19 (3D, brm) Purity >90% (NMR) MS 672(M1) .3.

Example No. 384 IH NMR(6) ppm 300Mz,DMSO-d6 8. 30(111, d, J=1. 5Hz), 8. 14((IH, d, J=8. 4Hz), 7. 98(1H, dc, J=8. 4 5Hz), 7. 68(1 brs), 7. 63(1 H, t, J=8. 4Hz), 7. 51(5H, 7. 4 3(1H, d, J=8. lHz), 7. 17(1H, dd, J=12. 5, 1. 8Hz), 7. 03(1H, dc, J= 8. 4, 1. 8Hz), 4. 08(1, brt, J=1 .4Hz), 3. 50and3. 30(total2H, e ach brs),2.97(3H,brs),2.33-2.13 brm), 1.96-1.79(41, brm), 1. 70-1. 59(11, brm), 1. 47-1. 03 (6H, brn),

-N\

Purity >90% (NMR) Ms 640(M+1) Example No. 385

CI

HCI

Fh HO N 0 N Purity >90% (NMR) MS 654(M+1) 1H NMR(6) ppm 300Mz, DMSO-d6 8. 29(11, d, J=1. 5Hz), 8. 12(1K, d, J=8. 8Hz), 7. 97 (1H, dci, J8. 8 5Hz), 7. 72-7. 60 (2H, 7. 7. 16(111d, J= I1 .7Hz), 7.03(111, c, J=8. 4Hz), (2H, 4. 07 (IH, bit, J=12. Hz), 3. 44and3. 22 (totai2H, eac h 2. 97(311, brs), 2. 32-2. 13(2 H, bri), 1. 72-1. 50(3H, brm), 1.

47-1.23(3H,brm),0.93ancO.72 (total3H,each bis) Table 240 Example No.

386 1H NMR(8) ppm 300Mz, DMSO-d6 8.29(1H, d, J=1.5Hz), 8.12(1H, d, J=8. 7Hz), 7.97(IH, dd, J=8. 7 5Hz) 7. 74-7.60(2H, 7.54 42(6H, 7. 17 (IH, dd, J=12 2. 2Hz), 7. 02 (1H, dd, J=8. 3, 2. 2Hz), 5. 15(2H, 06(1H, b rt, J=12. 8Hz), 3. 92(1H, brs), 2 .85(3H, brs), 2. 32-2. 14(2H, br 1.96-1. 79 (4H, brm), 1.70-1 S59(1H, brm), 1. 46-1. 07(3H, br m),1.15(6H,brs) Purity 9 0% (NMR) MS 654(M+ 1) Example No.

387 S

HCIF

N

HO

1H NMR(6) ppm 300Mz, DMSO-d6 8. 29(1H,s), 8.14and7. 97(2H, A Bq,J=8.7Hz), 7.63(I, 63 (1H, t, J=8. 7Hz),,7. 51-7.41 (6H 7. 16(1 H, dd, J=12. 1, 1. 9Hz 02(1H, dd, J=8. 7, 1. 9Hz), S16(2H, 4.26 (2H, brs), 4.07 (1H, brt, J-12. 1Hz), 2. 32-2.14 (2H, brm), 1. 97-1. 78(5H, brm) 1 .70-1, 15(9H, brm), 1. 24(3H, s) 1. 21 (3H, s) Purity 9 0% (NMR) MS 694 (M+1) Example No. 388

CI

HC 0 0 Purity >90% (NMR) MS 654 (M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 8. 58 (1H, 8. 29(1H, 8. 8. 10(2H, 8. 05-7. 90 (2H, m), 7. 64 (IH<t, J=8. 4Hz), 7. 60-7.4 7. 15(1H, d, J=12. 3Hz) 04 (1H, d, J=8. 4Hz), 5. 13(2H 4. 08 (IH, 3.40-3. 20(2H 2. 35-2. 10(2H, 2. 00-1.

20(12H, 0. 91(3H, t, J=6. 9Hz 448 Table 241 Example No.

389 1H NMR(6) ppm 300MHz, DMSO-d6 8.60(1H, 29(1H, 8. 7. 90 (4H, 7. 64 (IH, t, J=9. OH 7. 60-7. 40 (5H, 7. 17(1H, d, J=12. 0Hz), 7. 04(IH, d, J=8. 7 Hz), 5. 13(2H, 4. 80(1H, 3 .35-3. 15(2H, 2. 30-2. 05 (2H 2.00-1. 10(10H, 91(3 H, t, Purity >90% (NMR) MS 640 1 Example No. 390 1H NMR(6) ppm 300MHz,DMSO-d6 8. 62(1H, 30(1H, s),8.20- 8. 10(2H, 8.05-7. 90 (2H, m), 7. 65(1H, t; J=8. 4Hz), 7.60-7.4 7. 18(1H, d, J=12. 0Hz) .7.05(IH, d, J=8.4Hz), 5. 14(2H 4. 09(1H1, 3.40-3. 20(2H 35-2.10(2H, 2.00-1.

(4H, 1. 75-1. 60(H, 1.

45-1. 20(3H, 1. 15(3H, t, =7 .2Hz) Purity 9 0% (NMR) MS 626(M+1) Example No. 391 HClC HO N O

ON

ON-k H

N-

Purity 9 0% (NMR) MS 641 (M+1) 1H NMR(6) ppm 400NHz, DMSO-d6 8. 54 8.31(1H, 19( 1H, d, J=8. 6Hz), 8. 01 d J=8 .6Hz), 7. 81(1H, d, J=2. 1Hz), 7.

64(1H, t, J=8. 4Hz), 7. 61(1H, dd 3Hz, 8.4Hz), 7. 47(2H, d, J 6Hz), 7. 43(2H, d, J=8. 8Hz), 7. 25 (1H, d, J=8. 4Hz), 7. 17(1H, dd, J=2. 3Hz, 12. 1Hz), 7. 05(111H, dd, J=2. 3Hz, 8. 6Hz), 5. 05(2H, s 12(1H, 96(6H, 2.4 0-2. 10(2H, 2.00-1.75 (4H, m 1. 70-1. 55(1H, 1. 50-1. (3H, m) 449 Table 242 Example No.

392 0.

1H1 NMR( 6) ppm 300~z, DMSOhd6 8.79(11, 8. 29(0H, d, J1. 13 (111, d,J=8. 811z), 7.98 1H, dd, J=8. 8,1. 5Hiz), 7. 800Hii, d, J=2, 2Hz), 7. 63(IH, t, J8. 4H 7. 61 (111, dd, J=8. 2, 2. 2H1z), 7. 47and7. 43 (411, ABq, J=8. 8Hz) ,7.26 d, JA8 2Hz) 7. 14 (111 dd, J=12. 1, 2. 2Hz), 7. 02(111, d d, J1=8. 4, 2. 2Hz) 5. 05 (211, 4 08(11, brt,J312. 1Hz), 3. 64-3 *61 (21-1, in), 3. 48-3. 45 (211, Wn, 2 .32-2. 13 (2H1, 1. 96-1. 78 4H1, 1. 70-1. 66(111, brm) 9 1 44-1. 19 (3H. brn) Purity >90% (NMR) MS 683 1) Example No. 393

CI

HCI

0F H

NH

2 Purity >90% (NMR) MS 613 (M1+1) 111 NMR( 6) ppm 400MHz, DMSO-d6 8. 94 (li, 8. 31(1ff, d J=1 OH 8.18(1 H, d, J=8. 6Qz, 8.00( 111, dd, 31I. 4Hiz, 8. 8Hz), 7. 71(1 H, d, J=2. 2Hiz), 7. 66(1, t,J=8.

6Hz), 7. 52(11, dd, 5=2. 4Hz, 8. 6 Hiz), 7. 46 (2H1, d, J=8. 6Hz), 7. 42 (211, d J=8. 2Hz), 7.24(1H4,d, J= 8. 4Q1z, 7. 16(11H, d, J=12. 1Hiz), 7. 04(111, dd, J=2. 4Hz, 8. 811z), 05 (211, 4. 13(1 H, mn), 2. 40-2 10(21i, 2. 00-1. 75 (411, rn), 1 .70-1. 55(l 1. 50-1. 20 (3H in) Example No.

HOI

0F H O

N

~394 111 NMR( 6) ppm 300MHz, DMSO-d6 8. 9311, 8. 31(1OH, d, 3=1. 411 8. 19(H1, d,J=8. 811z), 8.01 11H, d, J=8. 7Hz), 7. 71(1H, d12 .2Hz), 7. 66(1H,-tJ=8. 5Hz), 7.

51(11, dd, 3=2.2Hz, 8. 4Hz), 7. 4 6 (211, d, 3=8. 6Hz), 7. 41 (214, d, 3 7Hz), 7. 23 (IH, d, 3=8. 4Hiz), 7. 16(1H. d, J=12. 2Hz),?7. 05(1H J=8. 7H4z), 5. 05 (211, 4. 13 OH1, M) 3. 12 (2H1, q, J=7. 2Hz), 2 .40-2.1 0(2H1.m), 2. 00-1. 7 5(411 1. 70-1. 60 (111, mn), 1. 55- 1.

20(31, O,1. 06(31,t, 2Hz) Purity 90% (NMR) MS 641 (M1+1) 450 Table 243 Example No. 395 1H NMR(6) ppm 300MHz,DMSO-d6 8.83 32(1H, d J=1. 4H 8.21(1H, d, J=8.8Hz, 8.02( 1H, dd, J=1. 4Hz, 8. 7Hz), 7.71(1 H, d, J=2. 1Hz), 7.68 t, J=8.

6Hz), 7. 49(1H, dd, J=2. 2Hz, 8. 4 Hz),7.46(2H, d,J=8.4Hz),7.41 (2H, d J=8.6Hz),7.23(1H,d,J= 8.4Hz, 7.17(1H, d,J=12.2Hz), 7.06(1H, d, J=8.7Hz), 6. 30(1H, brs),5.05(2H,s),4. 14(1H, m), 3.77(1H,sept,J=6.5Hz), 2.40- 2.10(2H, 2.00-1.75(4H, m), 1.70-1.55(1H, 1.50-1.20(3 H, 1. 11(6H, d, J=6. Purity >90% (NMR) MS 655(M+1) Example No. 396 F F 0F- HO- N

"N

0 H Purity >9 0% (NMR) MS 642(M+1) 1H NMR(6) ppm 300MHz, DMSO-d6 8.37 d, J=7.3Hz), 8. s),8.15(1H,s),7.97(2H,d,J=8 .8Hz), 7. 88(1H, d, J=8.8Hz), 7.

58-7. 47 (4H, m) 7. 31 (1H, 7.

11(1H, dd, J=8.4,2.2Hz), 6. 98( 1H, dd, J=8. 5. 13(2H, s) 13(1H, q, J=6. 6Hz),3.98(1H 19(2H, 1. 86(4H, m)1.

62(lH, m)1.31(3H, 1.20(6H, d,J=6.6Hz) Example No. 397

F

HCI

0F F HO N

N

0

H

Purity >90% (NMR) MS 642 (M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.40(1H, d, J=7.9Hz), 8.28(1H, d, J=1.9Hz),8.15(1H,d,J=1.9H 11(lH, d, J=8.7Hz), 7.96( 2H, 7. 56(1H, t, J=8. 7Hz), 7.

45 (3H, 7.18(1H, 7.08(1H ,dd,J=12.1,1.9Hz),6.96(1H, d d, J=8. 3,2.3Hz), 5.09(2H, s),4 .14(1H, 4. 04(1H, m),2.23(2 1.86(3H, 1.62(1H,m), 1.33(3H, 1.20(6H, d, J=6. 4H z) 451 Table 244 Example No. 398 HCI CI 0 F CI HOAO N

H

N

0-- Purity >9 0% (NMR) MS 674 (M+1) 1H NMR(6) ppm 8. 41(1H, d, J=8. 1Hz), 8. 29(1H, d,J=1.5Hz), 8. 17(1H, d, J=1. 8H 2),8.12(1H,d,J=8.4Hz),8. 01- 7. 95(2H, mi), 7. 67-7. 62 (2H, m), 7.55-7. 51(3H, 7.19(1H, dd, J=12. 1,2. 2Hz), 7. 05(1H, dd, J= 8.8,2. 2Hz), 5. 13(2H, 4. 00(2H, 2. 32-2. 13(4H, m), 1. 71-1.60(1H,m), 1.49-1.14(3 H, 1.21(3H,s), 1. 19(3, s) I Example No. 399 1H NMR 6 ppm 300Mz,DMSD-d6 8. 39(1H, d, J=7. 7Hz), 8. 29(1H, d,J=1.5Hz),8.16(1Hd J=1. 811 8. 11(1H, 8HzS, 8. 00- 7. 95(2H, 7. 69-7. 61(2H, m), 7.54-7. 46(3H, 18(1H, dd, J=12. 1,2.2Hz),7. 04(1H,dd,J= 8. 8, 2. 2Hz), 5. 13(2H, 4.02(2H, 2.33-2. 13(2H, brm 97-1. 80(4H, 1.72-1.61 (IH, 1.44-1. 13(3H,m), 1.21 (3H, 1. 19(3H,s) Purity 9 0% (NMR) MS 658 (M+1) .3.

Example No. 400 1H NMR(6) ppm 300MHz,DMSO-d6 8. 39(111, d, J=7. 7Hz), 8.29(1H, s), 8. 17(1H,d,J=1.55Hz),8. 11(1H, d, J=8. 8Hz), 7. 98(2H, 7. 73( 211,m), 7. 64(1H, t, J=8. 4Hz), 7. 52(1H, d, J=8. OHz), 7. 46(1H, dd,J=8.4, 1. 8Hz), 7. 18(1H,dd, J=11. 9,2.0Hz),7. 05(111H, dd, J= 8.6,2.4Hz),5. 14(2H,s),4. 13( 2H, 2. 22(2H, 1. 88(411, m) 1. 64(111, 1. 34(3H, 1.20( 6H, d, J=6. 6Hz) Purity >90% (NMR) MS 642(M+1) 1 452 Table 245 Example No. 401 HCI CI F F N

N

Purity 9 0% (NMR) MS 658(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8. 38(111, d, J=7. 8Hz), 8. 28(1H, 8. 20-8. 05(21H, 8. 00-7. 9 0(2H, 7. 65-7. 30(5H, 0 9(111H, d, J=12. 3Hz), 6. 97(1H, d, J= 10. 2Hz), 5. 09(2H, 4. 20-4 .00(2H, 2. 30-2. 10(2H,1m),2 .00-1.80(4H,m),1.70-1.60(1H 1.40-1. 10(3H, 1.19(6H ,d,J=6.6Hz) Example No. 402 1H NMR(6) ppm HC 300MHz,DMSO-d6 HCI C 8.25(1H, s),8.03(1H, d, J=8. 711 z),7.91(1H,d,J=8.7Hz),7.83( 0 F F 1H,s),7.70-7.35(611H,m),7.04( HOAN 1H,d,J=12.OHz),6.93(1H,d,J= 8.4Hz),5.09(21,s),4.00(1H,m N 60-3.40(4H, m),2.30-2.10 N JJ (2H, 1.45-1. 15(3Hm) Purity 9 0% (NMR) MS 670(M+ 1) Example No. 403 HCI CI F 0 F

N

Purity >90%

(NMR)

MS 670 (M+1) 1H NMR(6) ppm 400MHz,DMSO-d6 8.25(1H,s),8.08(1H,d,J=8.4 7.92(1H, d, J=9. 2Hz), 7. 79( IH, 7. 66-7. 49(4, 7. 42( 1H, d,J=7. 6Hz), 7.31-7.28(11, 14(1H, d,J=11. 311z),6.99 (IH, d, J=8.8Hz),5.13(2H, s),4 .02(1H, m),3.54-3.33(4, m),2 .29-2. 08 (2H, 1.93-1.73(8H 1. 67-1. 52(1H,m), 1.48-1.

11(3H,.m) 453 Table 246 Example No. 404 1H NMR(6) ppm 400MHz,DMSO-d6 8.41(1H,d,J=7.6Hz),8.32(1H, d,J=1.5Hz),8.20(lHd J=8.6H 17(1H, d, J=1. 7Hz ,8.00( 1H, dt, J=8. 8Hz, 1. 5Hz), 7. 71-7 .64(2H,m),7.54(1H,dd, J=10.3 Hz, 1. 9Hz), 7. 32(1H, dd, J=8. 2H z, 1.9Hz),7.22(1H,dd,J=12. 1H z, 2. 3Hz), 7. 08(1H, dd, J=8. 6Hz 17(2H,s),4. 14(2H, 1.99-1.

70(411,m), 1. 70-1. 60(1H, 1.

46-1.20(3H,m),1.19(6H,d,J=6 .6Hz) Purity >90% (NMR) MS 658(M+1)

Y

Example No.

HCI

0 HO -a N

NII

405 1H NMR 6 ppm 300MHz,DUSO-d6 I 8. 32(H,s),8. 19(1H,d, J=9. OH 8. 03-7. 98(2H, 7. 75(1 H, dd,J=2.1Hz,8.4Hz), 7. 67(1H, t J=8. 6Hz), 7. .40-7. 36(311, m),7 32(2H, d, J=8.4Hz), 7. 19(111H, d d,J=2.1Hz,12.3Hz),7.07(1H,d d, J=2. 1Hz, 8. 7Hz), 5. 11(2H. s) 12(1H,m)4. 12(1H, m),3..90 (2H, t, J=6. 9Hz), 2. 54 (2H, t, J 8. 1Hz), 2. 50(3H, 2. 40-2. (4H, 2.00-1. 75 (411, 1.70 -1.55(11, 1.50-1. 20(3H, m) Purity >90% (NMR) MS 650((M+1) Example No. 406 11 NMR(6) ppm 300MHz,DMSO-d6 S 8. 34(1, d J=7. 7Hz), HOI 8.29(1H,s, 8. 15(1H, 11( HCI 011H, d, J=8. 8Hz), 7.97(2H11, d, J=9 F .2Hz),7.63(1H,t,J=8.8Hz),7.

H N 47-7.31(5H, 7. 18 (iH,dd, J= I 12.4,2.2Hz), 7.06(1H, dd, J=12 2. 2Hz), 5. 13(2H, 13(2 S 1.96(2H, 1.87(4H, m), N 1.62(1H,nm),1.34(3H,m),1.20( 0 H 611, d, J=6.2Hz) Purity 9 0% (NMR) MS 652(M+1) 454 Table 247 Example No. 407 HCI CI 0 F HO x N N 0

C

C0 1I

N-S=O

Purity >90% (NMR) MS 708'(M+1) 1H NMR(6) ppm 400MHz,DMSO-d6 8.32(1H, d, J=1. 4Hz), 8.20(1H, d, J=8. 8Hz), 8. 01(1H, dd, J=1. 6 Hz,8.8Hz),7.90(1H,s),7.67(1 H, t, J=8. 4Hz), 7.61(1H,s),7.5 5-7. 50(4H, 7. 21(1H, dd, J=2 .3Hz,12. 0Hz),7.06 (iH,dd,J=2 .2Hz,8. 7Hz), 5.10(2H, 11 (1H, 3. 78(2H, t J=6.7Hz),3 .47(2H,t,J=7. 4Hz, 2.54-2.48 (2H, 2. 40-2. 10(2H, 2. 00 80(4H, 1. 75-1. 55(1H, m) 1.50-1.20(3H,m) Example No. 408 111 NMR(6) ppm Example No. 408 1H NMR(6) ppm 400MHz,DMSO-d6 8.32(1H, d,J=1. 6Hz), 8.21(111, d, J=8. 8Hz), 8.02(111, dd, J=1. 6 Hz, 8.8Hz), 7.76 (11H, 7.68(1 H, t, J=8. 5Hz), 7.59(1H, 4-7. 51(4H,m), 7. 21 (1H, dd, J=2 .4Hz, 12. 1Hz),7.07(1H,dd,J=2 4Hz, 8. 8Hz), 5. 08(2, 11 3.77(21, t, J=6. 9Hz),2 .47(2H,t,J=8,0Hz),2.40-2.10 2.00-1. 80(4H, 1.70 -1.60(1H,m),1.45-1.20(3H,m) Purity >90% (NMR) MS 672 (M+1) Example No.

409

HOI

HOA-,a o UI ps 11 NMR(S) ppm 300MHz, DMS-d68.28(111, d, J=1 .5Hz),8. 20-8. 85(4 H, 7. 1H, d, J=6. 9Hz), 7. 70-7. 45(611H, 13(1H, dd,J-12. OHz, 2. 1H 7. 00(1H, dd, J=8. 7Hz), 2. 1H 22(2H, 05(iH, 3.

40-3.20(1H,m),2.30-2.10(2H, m),2.00-1.55(5H,m), 1.45-1.1 0(3H, ),1.00(6H, d,J=6.6Hz) Purity >90% (NMR) MS 676(M+1) 455 Table 248 Example No.

HCI

0 OxN Hi N I 410 1H NMR(6) ppm 300MHz,DMSO-d6 8.31(1H,s),8.00(1H, d, J=8.71 7.88(1H, d, J=8. 7Hz),7. 1H, 7.65(1H, t, J=8. 4Hz), 7.

53(2H,d, J=8.4Hz),7. 49(2H, d, J=8. 7Hz), 7. 45-7. 41(2H, m),7.

16(1, d, J=12. OHz),7. 04(1 H, d ,J=8.7Hz),5. 14(2H,s),4.68(1 H, quint,J=8.4Hz),3.02,2.98( 6H, 2.30-1.85(611,m), 1.80- 1.50(2H, in) Purity >9 0% (NMR) MS .612(M+1) Example No. 411 1H NMR(6) ppm 300MHz,DMSO-d6 8. 30(1H, 7.99(1H. d, J=9. OH z),7.87(H, d,J=8.7Hz),7.67( 1H,s),7.64(1H t J=8.7Hz),7.

53(2H, d, J=8. 7Hz, 7.49(2H,d, J=7. 5Hz), 7. 45-7. 41(2H,m), 7.

15(1H, d,J=12.3Hz), 7. 02(1H, d ,J=8.4Hz),5. 15(2H,s),4.67(1 H, quint, J=8.7Hz), 4.02(1H,m) ,3.76(1H,m), 3. 55(1H, 3. 22 2.40-1.20(12H,.m) Purity 9 0% (NMR) MS 668 (M+1) a Example No. 412 1H NMR(6) ppm 300MHz,DMSO-d6 8.38(1H,d, J=7.5Hz), 8.33(1H, s),8.16(1H,s),8.02(IH,d,J=8 .7Hz), 7. 98(1H, d, J=9. OHz), 7.

91(1H, d, J=8. 4Hz), 7. 67(1H, t, J=8. 4Hz), 7. 53(2H, d, J=8. 7Hz) ,7.48(2Hd J=8.7Hz),7.46(LH J=8. 1Hz ,7.18(1Hd,J=11.

7Hz),7.06(1H,d,J=8. 7Hz),5. 1 3(2H1, 4.70(1H, quint, J=8.4 Hz),4.13(111, sept,J=6.6Hz),2 30-1.85(61, 1.80-1. 50(2H 1. 16(6H,d,J=6.3Hz) Purity >90% (NMR) MS 626(M+) 456 Table 249 Example No. 413

HCI

OP

HO

X 0 IH NMR(6) ppm 300Mz, DMSO-d6 8. 39(1 H, d, J=7. 5Hz). 8. 31 (iM, d, J=1. 5H2), 8. 16(11, d, 9H 8. 06 (11, dc, J=8. 8, 1. 7. 99-7. 95 (2H, in), 7. 76and7. 24 (41, ABq, J=8. 9Hz), 7. 53and7. 0(4 H, A' B' q, J=9. 1Hz), 7. 46(1H d, J=8. 3Hz), 5. 14(211, 4. 94 (OH, quint, J=9. 0Hz), 4. 19-4. 0 8(1H,m),2.32-2. 11(4H, br),.2 10-1. 95 (2H, br), 1. 78-1. 62( 2H, brm), 1. 26(311, 1. 18(3, s) Purity >90% (NMR) MS 608(M+1) Example No. 414 HCI CI 0 HO

N

Purity >90% (NMR) I1H NMR(6) ppm 300Mz,DMSO-d6 8. 31(11, c, J=i. 5Hz). 8. 06 (1H, dd, J8. 7, 1. 5Hz), 7. 97(111, d, J 7Hz) 7. 75and7. 22(41, ABq J=8.9Hz 5 7.70(1, d,J=1.9z 53(11, dc, J=7. 9, 1. 9Hz), 7.

52(4, 7. 43(18, d, J=7. 9Hz) 15(2H, 93(lH, quint, J 9Hz), 3. 01(31, 2. 97(311, 2. 32-2. 11(411, bra), 2. 09-1 .94(2H, brm), 1. 77-1. 62(2H, br

M)

MS 594

I

Example No.

415 HO'a 0 0 ND-OH Purity >90% (NMR) 1H NMR(b) ppm 300Mz, DMSO-d6 8. 31(11, c, J=1. 5Hz), 8. 06(11, dd, J=8. 7, 1. 5Hz), 7. 98(11, d, J 7Hz), 7. 75and7. 22 (41 ABq, J=8. 9Hz), 7. 67 (11, d, 1=1. 7. 52(4, 7. 49 d, J=7.

9 1. 5Hz), 7. 43(JH. d, J=8. 9Hz) 16(211, s),4.93(1H, quint, J 9Hz), 3. 76(1 H, brs), 3. 55 (2 H, brs), 3. 22(21, brs), 2. 31-2.

11(4H, brm), 2. 16-1. 95 (211, bra 1. 88-1. 62 bra), 1. 48-1.

28(2H, brm) Ms 650 1 457 Table 250 Example No. 416 1HNMR(6) ppm Example No.

416 1H NMR(6) ppm 300MHz,DMSO-d6 8.38(1, d, J=7. 7Hz), 8.30(111, 20-7. 90(4H, 7. 72(2H, d, J=8. 7Hz), 7. 60-7. 40(5H, m), 7. 22 (2H, d, J=8. 7Hz), 5. 13(2H, s),4.47(1H,m),4. 15(1H,m), 2.

90-2.70(4H, m),2.60-2. 30(4H, 1.19(6H, d, J=6. Purity 9 0% (NMR) MS 640 (M+1) Example No. 417 HCI CI 0

O

N3 s 0 Purity 9 0% (NMR) MS 652(M+1) 1H NMR(6) ppm 400MHz,DMSO-d6 8.33(1H,s),8.17(11H,d,J=8. 6H 8. 10(1H, d, J=8. 6Hz),7. 82( 1H,d J=1.4Hz),7.74(2H,d,J=8 .7Hz, 7. 64(1H, dd, J=8. OHz, 1.

7Hz), 7. 55-7. 50(4H, 7. 43(1 H, d, J=7. 8Hz), 7. 24(1H, d, J=8.

7Hz), 5.16(211,s), 449(1H, m), 3. 60-3. 40(4H, 2. 90-2. 70(4 H, 2. 60-2. 30(4H, 2. 20-1 .80(4H, m) Example No. 418 1H NMR 6 ).ppm HC c 400MHz,DMSO-d6 8.34(1H,d,J=7.6Hz),8.25(1H, 0 8.11(1H, d, J=1. 3Hz), 7.90- 8. 00(311, 7. 59(1H1, t, J=8. 6H11 HO N z),7.40-7.55(5H,m),7. 12(111, S- d,J=11.9Hz),7.00(0H,d,J=8.6 N Hz),5.08(2H,s),4.30-4.10(2H H 80-2. 65(41, 2. 45-2.

N 30(2H, 1. 15(6H,d,J=4.8Hz) S 0 Purity >90% (NMR) MS 658(14+1) 458 Table 251 Example No. 419 HCI C1 0F HOA N 00 Purity >9 0% (NMR) MS 656(9+1) 1H NMR(6) ppm 400Hz,DMSO-c6 8. 30(11H 8. 05-7. 95(3H, m), 7.80-7. 75(1, 7.63(1, t, J 6Hz), 7. 55-7. 35(511, 7. 1 5(HRdd, J=12. lHz, 2. 1Hz), 7. 0 3 dd, J=8. 7Hz, 2. 3Hz), 5. (211, 4. 23(1, 3. 90(2H, t 0Hz), 2. 95-2. 70(4, 2 .60-2. 35(41, nO, 2. 30-2. 00(4 n) IExample No.

420 1H NMR(b) ppm 300Hz, DMSO-d6 8. 37(1H, d, J=7. 5Hz), 8. 28(1, d, J1. 5Hz), 8. 17(1 H, d, 8. 13 (IN d, J,8. 7Hz), 7. 97( IH, dd, J=8. 1, 1. 5Hz), 7. 94 (1H, dd, J=8. 7, 1. 5Hz), 7. 61(LH, t, j 7Hz), 7. 5 land?. 49(411, ABq, J=8. 9Hz), 7. 46 d, 1Hz) 08(I, dd, JP12. 4, 2. 3Hz), 6 .97(111, dd, J=8. 7, 2. 3Hz), 5. (2H, 4. 20-4. 08(111 3. 62 56(211 brm), 3. 13-3. 10(2H, brm), 1. 79-1. 60(311, brm), 1. 54 34(3H, brm), 1. 21(311, 1.

18(3, s) Purity >90% (NMR) MS 641 (M+1) Example No. 421 111 NMR(6.) ppm cI 300Mz, DMSO-d6 8. 24 d, J=1. 5Hz), 8. 02 (1H, d, J=8.7Hz), 7.88(111, d, 7 0 F 5Hz), 7. 82(1H, d, J=1. 9Hz), N -7.63 (IH, dd, 9, 1. 9Hz), 7. H 4(1H, t, J=8. 7Hz), 7. 50 (4H, s), A0 N 42 (IH, d, J=7. 9Hz), 7. 01(1H, dd, J=12. 0,2. 3Hz), 6. 91(1H, dd 1'7) No J=8. 7, 2. 3Hz), 5. 11 s) 3.

o 63- 3. 41 (61, 3. 07-3. 04 (21, brn), 1. 95-1. 79(4H, brm), 1. 77 57(3H, brm), 1. 50-1. 323H, Purity >90% (NMR) brm) MS 653(M.1+1) Table 252 Example No.

422 1H NMR(6) ppm 300MHz,DMSO-d6 99(211, 44(1H,s), 8. 18(1H,d,J=8. 7Hz),8 .14(1H, d, J=8. 7Hz), 7. 98(111, d J=9. OHz, 7.70-7.66(211,m),7 .57(2H, d, J=8. 7Hz),7. 54(21, d J=8. 7Hz), 7. 21(1. d, J=12. OH 7.09(1H, d, J=8.4Hz), 5. 19( 28, 4. 05(411, 40-2. 18( 2H,m),2. 15-1.80(4H, 1. 1. 55(1H, 1.50-1.20(3H,m) Purity >90%

(NMR)

MS 623(M+1) I Example No. 423 1H NMR 6 ppm 300MHz,DMSO-d6 8. 27 (1H, 05(1H, d, J=8. 7H 7.93(1H,d,J=8.77Hz), 7.90( 1H, s),7.70(1H, d,J=8. 4Hz),7.

59(1H, t, J=8. 4Hz), 7. 50(2H, d, J=9. O0Hz), 7. 45(21, d, J=8. 7Hz) ,7.41(1l, d,J=8.-4Hz),7. 12(111 d, J=12. OHz), 7.00(1H, d, J=8.

7Hz), 5. 10(211, s),4.49(2H, t, J 8Hz), 4. 14(211, t, J=8. OHz), 4. 04(1H, 2. 40-2. 10(2H, m), 2.00-1.50(5H,m),1.45-1.20(3 H, m) Purity >90% (NMR) MS 640(M+1) Example No. 424 LHNMR(6) ppm I Example No. 424 1H NMR(6) ppm 300MHz, DMSO-d6 8.30(111H, s),8.14(1H, d, J=8. 411 7. 98 (iH, d, J=9. 3Hz), 7. 89( 1H, s),7.68(1H, d J=8.4Hz),7.

62(1H,dJ=9.OHz,7.48(2H,d, J=8. 4Hz), 7. 43(2H, d, 4Hz) ,7.33(1H, d, J=8. 4Hz),7. 16(111 d, J=12. OHz), 7. 04(1H, d, J=9.

OHz), 5. 07(2H, 4. 10(1H,m), 3. 92(21, t, J=8. OHz), 3. 45(211, t, J=8. OHz), 2. 40-2. 10(21, m), 2. 00-1. 50(5H, 1. 45-1. 20(3 H,.m) Purity 9 0% (NMR) MS 639(M+1)I 460 Table 253 Example No. 425 2HCI 0 F -"aN HO

X

1H NMR(6) ppm 300MHz, DMSO-d6 9. 05(1H, 8. 30(1H, 16( 1H, d J=8.8Hz),7.99(1H,d,J=8 6Hz, 7. 72(1H, s),7.64(111, t J=8.6Hz),7.52(1H,d,J=8. 4Hz ,7.47(2H,d,J=8.7Hz),7.42(2H J=8. 6Hz),7. 25(1H, d, J=8. 4 Hz), 7.15(1H, d,J=12. 2Hz), 4(1H, d,J=8. 6Hz), 6.60(11, brs 05(2H, 4. 10(1H, 3. 6 8(2H, t J=6. 1Hz), 3. 45(2, t, J 1Hz, 2.40-2. 10(2H, 2. 0 0-1. 55(5H,m), 1.50-1.20(3H,m Purity 9 0% (NMR) MS 639 (M+1) Example No. 426

F

HCI

0 HOC N N 0 SetO,) N Nok N Purity >90% (NMR) 1H NMR 6) ppm 300MHz, DMSO-d6 8. 32(1H, 8. 24(1H, d, J=8. 711 03(1H, d, J=8. 7Hz), 7. 78- 7. 73(4H, 38-7. 32(4H, m), 5. 52 (2H, 4. 88(2H, 2H, 4.37(1, 2.92,2. 84( 611, 2.40-2.18(2H,m), 2. 1.95(2H,m), 1. 90-1. 80(2H, m), 1.75-1. 55(111, 1.50-1.20(3 H, m).

MS 643(M+1) Example No. 427

F

2HCI 0 o NNC> N N N Sr-

,N

Purity >90% (NMR) MS 641(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 11.26(1H, brs), 8.35(18H, 8.

27(lH, d, J9. OHz), 8. 05(1H, d, J=8. 4Hz), 7. 83-7. 78(4 7.

42-7. 35(41H, 5. 57(21, 4.

77, 4. 73(211, 4. 37(1H, 3.

95(1H, 3.70-3.00(4H,. 2.

40-1.00(14H,m) 461 Table 254 Example No. 428 11 NMR(6) ppm 300MHz,DMSO-d6 8.31(1H,s), 8.26(lH,d,J=9.OH z),8.04 d, J=8. 7Hz), 7. 79- 7. 73 (4H, in), 7. 38-7. 31(6H, m), 53(2H, 4. 90(2H, 4. 37( 1H, 4. 05 (2H, 2. 40-2. 18( 2H, 2. 15-1. 95(2, in), 1.90- 1. 80(2H, 75-1. 55(1H, m), 1.50-1.20(3H,m) Purity >90% (NMR) MS 615(M+1) Example No. 429 1H NMR 6) ppm 300MHz,DMSO-d6 8.88(1H, Q, J=4.5Hz),8.33(1H, d, J=1. 5Hz), 8. 18(1H, d, J=8. 7H 01(1H, dd,Jcl1. 5Hz, 8.7Hz ),7.89-7.83(2H,m),7.50-7.34 7.20(1H, dd, J=2. 1Hz, 8 .4Hz),5.61(2H,s),4. 13(1H,m) 2. 84(3R, d, J=4. 8Hz), 2. 40-2.

10(2H, 2.00-1.75(4 1.

70-1.55 1.50-1.20(3H,

M)

Purity >90% (NMR) MS 603(M+1) Example No.

430

F

HOCI

F

N-

O N H S N -OH 0H 1H NMR 6 ppm 400MHz,DMSO-d6 8. 79(IH, t, J=5. 9Hz), 8.31(1H, 15(1H, d, J=8.7Hz), 7. 99( 1H,d J=8.8Hz),7.87(lH,d J=8 .lHz, 7.85(1H,d, J=8B. 7H z, 7.

70(1H, t, J=8. 4Hz), 7.42-7. 33( 3H, 7. 18(1H, d, J=8. 8Hz), 60(2H,s),4. 11(1H, m),3.62-3.

54(4H, 2. 40-2. 10(2H, 2.

00-1. 75(4H,m), 1.70-1. 1. 50-1. 20(3H, m) Purity >90 0% (NMR) MS 633 462 Table 255 Example No. 431

F

HCI

o) F HOX O N_ 0,/ N N 1 0 Purity 9 0% (NMR) MS 616 (M+1) 1H NMR( 6) ppm 300MHz,DMSO-d6 8. 31 (1H, 8.16(0H, d, J=8.8H 7. 99 (1H, d, J=8. 7Hz), 7. 74- 7. 60(4H, 7. 37(2H, t, J=8. 8H z),7.28(1H,dd,J=2.2Hz, 12.2H 7. 14(1H, dd, J=2. 2Hz, 8. 6Hz 5.17(2H, 10(lH, 3.1 5(6H,brs),2.40-2.10(2H,m),2 .00-1.75(4H, 1. 70-1. 55(1H 1. 50-1. 15(3H, m) Example No. 432

F

HCI

0 F 0 S N Purity 9 0% (NMR) MS 630 (M+1) 1I NMR( 6) ppm 300MHz,DMSO-d6 8.45(1H, d,J=7. 7Hz), 8.32(1lH, 8. 19(1H, d, J=8. 8Hz), 8. 02- 7. 99(2H, 7. 70(11H, t, J=8. 6H 60(2H, dd, J=5. 4Hz, 8. 7Hz 7.37(2H, t, J=8. 8Hz), 7.27(1 H,dd,J=2.3Hz,12.2Hz),7. 14(1 H, dd, J=2. 2Hz, 8. 7Hz), 5. 16(2H 4. 20-4. 00(2H, in),2. 40-2.

10(2H, 2. 00-1. 75(4H, 1.

70-1.55(1H,m), 1. 50-1.20(3H, 1. 18(611, d, J=6. 6Hz) Example No. 433 1H NMR 6 ppm 300MHz,DMSO-d6 F 8.31(111, d,J=1. 4Hz), 8.15(111, HCI d,J=8.8Hz),7.98(lH,dd,J=1.4 0F Hz, 8. 7Hz), 7.68-7.60(4H, m),7 0 F .36(2H, t, tJ=8.8Hz), 7.28(1H,d HO C)IN0 d,J=2.2Hz, 12. 2Hz),7. 15(1H,d N/ S d, J=2. 2Hz, 8.6Hz), 5.17(2H, s) N ,4.10(0H,m),4.05-3.90(2H,m) 3. 85-3. 70(111,m), 3.55-3. 0 28, mn), 2. 40-2. 10(2H,m), 2. 00- 1.75(6H,m), 1.70-1.55(1H,m), 1. 50-1. 20(51, in) Purity 9 0% (NMR) 1.50-1.20H, m) MS 672 (M+1) 463 Table 256 7 Example No. 434 1H NMR(6) ppm 300Mz, DMSO-d6 8. 45(LH, d, J=1. 5Hz), 8. 26(1H d, J=8.8Hz), 8. 10(1H, dd, J=8 1. 5Hz), 7. 72 (1H, d, J=1. 7. 64(lH, t, J=8.6Hz), 7.56 48 (5H, 7. 44 (1H, d, J=J= 7. 7Hz), 7. 18(1H, dd, J=12.3, 2 .4Hz), 7.04 (1H, dd, J=8. 6, 2.4 Hz), 5.15(2H, 4.08(1IH, brt ,J=11. 7Hz), 3. 02 (3H, 2. 99 (3H, 2. 34-2. 17(2H, brm), I .97-1. 81 (4H11, brm), 1. 70-1. (1H, brm), 1. 49-1. 21(3H, brm) Purity 9 0% (NMR) MS 650 l) Example No.

435 IH NMR(6) ppm 300Mz, DMSO-d6 8.42(1H, d, J=1. 5Hz), 8.24(1H, d, J=8. 8Hz), 8. 08 (1H, dd, J=8. 8 1. 5Hz), 8. 00 d, J=8. 8Hz) 7.79(1H,d,J=7.8Hz),7.62(1H, t, J=8. 4Hz), 7. 61-7. 55 (3H, m), 7. 44 (1H, d, J=8. 1Hz), 7. 16(111H, dd, 5J=12. 1, 2.6Hz), 7.02(IH, dd J=8. 4, 2. 6Hz), 5. 12(2H, 4.

07 (IH, brt, J=12. 5Hz), 2. 33(2H ,brm), 1. 96-1. 79(411, brm), 1.7 1-1. 61 (1H, brm), 1. 49-1. 21(311 .brm) Purity 9 0% (NM R) MS 623(M+1) J Example No. 436

HCI

IH NMR(6)- ppm 300MHz, DMSO-d6 8. 41 (1H, d, J=7. 7Hz), 8. 30-8.2 6 (2H, 18(1H, d, J=1. 4Hz), 7. 99 dd, J=1. 7Hz, 8. OHz),7 .89 (1H, d, J=10. 1Hz). 7. 67 (1H, t, J=8. 8Hz), 7. 55-7. 45 (5H, m), 7.20(1H, d, J=12. 2Hz), 7. 07(1H ,dd, J=2. 1Hz, 8. 7Hz), 5. 14(2H, 4.18-4. 11(2H, 2.40-2. 1 0(2H, 00-1. 75 (4H, 1. 7 0-1. 55 (IH, 1. 50-1. 20(3H, m 1. 20 (6H, d, J=6. 6Hz) Purity >9 0% (NMR) MS 680 (M+1) 464 Table 257 I Example No.

437 4 1H NMR(6) ppm Purity >90% (NMR) MS 580(M+1) Example No. 438

CI

N N 0

N

Purity >90% (NMR) MS 607 (Me) 1H NMR(6) ppm Example No. 439.

0 HoA,

/-N

HO

N

F

IH NMR(b) ppm CDC13 8.60(1, d, J=1. 5Hz), 8. dd, 3=1. 6Hz, 8.7Hz), 7. 70(1, c J=8. 7Hz). 7. 62(2H, d J=8 2Hz 5, 7. 49(2H, d, J=8. 2Hz 5 7.31(2 H, d, J8. 8Hz), 7. 27-7. 23(2H, m 7. 06 (2H, t, J-8. 6Hz), 6.80 (2 H, d, 3=8. 8Hz)) 5. 05 (211, 4. 3 8(1, 06(6H, 2.45-2.2 0(2H, 10-1. 70 (5H, 1. 0-1. 20(3H, m) Purity >90% (NMR) 591 (M+1)

I

465 Table 258 Example No. 440 IH NMR(6) ppm 300MHz,DMSO-d6 0F 8. 20 (1H, 7.86(2H, 7. 39( Ho N 1H, d,J=7.9Hz),7.34(IH, d,J=7 OH F .9Hz), 7. 07(2H, dt, J=2. 3Hz, 8.

N 6Hz), 6. 98-6. 88(51H, 6. 83(1 H, d, J=8.3Hz), 5.91(1H, s),3.9 6(18H, 2.30-1.95(2H, 1.9 0-1.50(4H,m), 1.40-1.10(3H, m

F

Purity 9 0% (NMR) MS 557 (M+1) Example No. 441 0

N

1H NMR( 6) ppm 300MHz,DMSO-d6 8.24:(1H, d, 4Hz), 8. 01(1H, d, J=8. 8Hz), 7. 91(1H, dd, J=1. 4 Hz, 8. 7Hz), 7. 47(1H, t, J=8. 4Hz 7. 43-7. 35 (2H, 15-7. 01 (SH, 6. 92(2H, d, J=10. 4Hz), 6. 11 3. 90 (1H, 2. 1.95(2H, 1. 90-1. 50(4H, m), 1.40-1. 10(3H,m) Purity >90% (NMR) MS 557(M+1) Example No. 442

HCI

1H NMR(b) ppm 300Mz, DMSO-d6 8. 26(1H, d, J=1. 5Hz), 8. 11(1H, d, J=8. 9Hz)" 7. 96(111H, dd, J=8. 9 1. 5Hz), 7.65-7.57(5H, 7.4 7(IH, t, J=7. 7Hz), 7.35(1H, d, J 6Hz), 7. 30-7. 22 (311, 7. 1 6(1H, dd, J=8. 7, 2. 3Hz), 6.88(1 H, 4. 04 (1H, brt, J=11. 3Hz), 2. 98 (3H, s) 2. 84(3H, 2. 30-2 .10(2H, brm), 1. 94-1. 75 (4H, br 1. 68-1. 57(1H, brm), 1. 45-1 .14(311, brm) Purity 9 0% (NMR) MS 610 (M+1) 466 Table 259

I

Example No.

443 IH NMR(6) ppm 300Mz,DMSO-d6 8.23(11H, 7.98and7. 89(2H, A Bq, J=8.8Hz), 7.62-7.06(11H, m ),6.86(lH, 4. 12-3.77(2H, b rm), 3. 72 (1H, brs), 3. 69(1H, br 3.18(lH, brs), 3.05(1H, brs ),2.31-2.08(2H, brm), 1.90-1.

54 (7H, brm), 1. 48-1. 13 (5H, brm

-ND-OH

Purity >9 0% (NMR) MS 666 (M+l) Example No. 444 1H NMR( 6) ppm 300MHz, DMSO-d6 8. 36(lH, 8. 00(H, d, J=8. 7H 7. 90(1H, d, J=9. 3Hz), 7.80- 7. 70(2H, 7.63(2H, d J=8. 4H 7.32(2H, t, J=8.7Hz), 7.22( 2H, d, J=8. 4Hz), 5.62(11H, d, J=7 57(1H,brd,J=4.8Hz), 5.41(2H, s),5.31(lH, 4.29( IH, m),3.84(lH, d, J=9. 0Hz), 3.

50-3.20(3H,m),2.71(3H,s),2.

40-2.20(2H, 75-1.60(1H, 1. 50-1.20 (3H, m) S Purity >9 0% (NMR) MS 718(M+1) Example No. 445 1H NMR(6) ppm 300MHz,DMSO-d6 8. 36(H, 8.00(1H, d, J=8.7H 7.92(1H, d, J=9. 3Hz),7. 57( 1H, t, J=8. 4Hz), 7.50-7. 35 (6H, 7.25-7.05(4H, 6.82(1H, 5.62(1H,d,J=7.2Hz), 5. 56( 1H, m),5.28(lH, brs), 3.95(1H, 3.82(1H, d, J=8. 7Hz), 3. 3.20(3H, 30-2.05(2H, m), 1.90-1. 55(5H,m), 1.40-1. 10(3 H,m) Purity >9 0% (NMR) MS 733(M+l)

I

467 Table 260 Example No.

446 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(1H, 8. 13(lH, d, z),7.97(1H, d, J=9. 0Hz), 7.63( 1H, t, J=8.6Hz), 7.51-7.32(7H, 15(1H, d, J=12.0Hz), 7.03 (1H, d, J=9. OHz), 5. 10(2H, 4 .09(1H, 3.82(2H, t, J=6. 3Hz 3.56(2H,t,J=7.4Hz), 2.45(2 H, 2.40-2. 10(2H, 2.00-1 .55(5H, 1.50-1. 20 (3H, m) Purity 9 0% (NMR) MS 674 (M+1) Example No.

447 1H NMR(6) ppm 300MHz,DMSO-d6 8.36(IH, d, J=7. 7Hz),8. 14(2H, d, J=12. 1Hz), 8.08(1H, d, J=8. 7.97(1H, dd, J=1. 7Hz, 8.3Hz), 7.7 4(1H,dd,J=l.8Hz,8.4Hz), 7.58-7 .45(6H,m), 7.31(2H,s),7. 12(1H, dd,J=2.2Hz,12.1Hz),7. 00(1H, dd ,J=2.4Hz, 8.6Hz), 5. 11(2H, 4.

16(1H, 4.02(1H, 20(2H,m ),1.86(4H, 1.62(lH, 1.21( 9H,m) Purity >90% (NMR) MS 675(M+1)

J

Example No.

448 1H NMR(5) ppm 300MHz,DMSO-d6 8.29(2H, m),8.04(1H, d, J=8. .7.93(1H, dd, J=1. 5Hz,8.8Hz), 7.

60-7. 42 (8H, 7. 05 dd, J=2.

2Hz, 12. IHz), 6.95(1H, dd, J=2.4H z, 8. 6Hz), 5. 11(2H, 4. 07-3. (2H, 28-2. 19(2H, 1. 88-1 .84(4H,m), 1.67-1.62(1H,m), 1.4 0-1.26(3H, 1.04(6H, d, J=6 6H z) VAU

N-

H

Purity >90% (NMR) MS 640(M+ 1) 468 Table 261 Example No.

449 1H NMR(6) ppm 300MHz,DMSO-d6 8.31 (1H, 8.17(1H, d, J=8. 7Hz), 8.00(1H, d, J=8.7Hz), 7.78(1H, d, J =8.1Hz), 7.66(1H, t, J=8.7Hz), 5-7.45(4H, 7.40(1H, d, J=1l1.7H 19(1H,d,J=12.3Hz),7.05(1H J=8.7Hz),5.07(2H, 4. 10(1H Sm), 3. 85 (2H, t, J=6. 6Hz), 3.47(2H J=7. 5z) 2. 60-2. 50(2H, 2. 10(2H, 00-1. 80(4H, 1.

75-1.55 (1H, 1,50-1.20 (3H, m) Purity 9 0% (NMR) MS 692 (M+I) Example No. 450 HC1.

CI

0 0

F

Purity 9 0 o% (NMR) MS 670(M+1) 1H NMR(6) ppm .300MHz, DMSO-d6 8. 37 (IH, d, J=7. 8Hz), 8. 15(1H, s), 7.97(1H, d, J=9.8Hz), 7.64-7.45(8 H, 12(1H, d,J=12. 1Hz), 7. 00( 1H, d, J=8.6Hz), 5. 11(2H,s),4. 21( .3H, 4. 18-4. 05(1H, 04-3.8 9(1H, 2. 29-2.08 (2H, 1.90-1 .74(411, 1.68-1. 58(1H, 1.40 1. 17(3H, 1.20 (6H, d, J=6. 6Hz) Example No. 451

HICI

0

F

HO N Purity 9 0 (NMR) MS 654 (M+1) 469 IH NMR( ppm 300MHz, DMSO-d6 8. 29(1H, 8. 12(IH, d, J=8.8Hz), 7. 97 (1H, d, J=10. 2Hz), 7.65-7. 59( 2H, 7. 51(4H, 7. 46(2H, 7.

15(1H, d, J=12.2Hz), 7.01(1H, d, J= 8. 6Hz), 5. 15(2H, 4.13-3.98(1H 3.21(3H, 2.56-2. 42 (1H, m) 30-2. 15(2H, 1. 95-1. 77 (4H, 1. 69-1. 59 (1H, 1.45-1. 17(3 H, 0. 96(6H, d, J=6. Table 262 Example No. 452 0

HCI

HOH

I

N-

H

Purity 9 0% (NMR) MS 640 1) 111 NMR 6) ppm 300MHz, DMSO-d6 d, J=8. 7Hz), 7. 96 (1 H, d, 1=-11. 4Hz) 17. 95 (IH, 7. 72 (1H, 7Hz) 62 (1H, t, J=9. Ofz), 7.48 and 7 43 ABq, 1=8. 1Hz), 7. 31 (11, d, J=8. 4Hz), 7. 13 (1H, d, J=42.OHz), 7 *02 (11, d. J=9. 0Hz), 5. 07 (2H, 4 *14-4. oo (iu 2. 69-2. 59111, m) 30-2. 12 (2H, in), 1. 95-1. 77 (4H], 1.71-1. 57 1. 45-1. 20 (3 H, rn), 1. 12 (6H1, d, J=6. 9Hz) Example No.

453 1H NMR 6) ppm 300MHz, IIMSO-d6 11. 1 (111, brs), 8. 31 (1H1, d, J=9. 4Hz 29(111, 8.071H, d,J'10. 2H 7. 70-7. 62(3W, in), 7. 31-7. 23 (3 H, in), 4. 40-4. 231OH, 4. 24 (2H, s 2. 61(3OH, s) 2. 34-2. 14 (2H1, 1 .99-1. 72(4H1, 1. 66-1. 54 (1 H, Mi) 1. 46-1. 30 (11 in), 1. 27-1. 08(21, Mn) Purity 9 (NMR) MS 542 1) Example No.

454

HCCI

NC F i 1H NMR( 6) PPM 300MHz, DMSO-d6 8. 27(1OH, d, J=1. 4Hz), 8. 05(11, d, j 7Hz), 7. 92(11H, d, J-8. 7Hz), 7. 7 9 (1 H, d, J=7. 8Hz), 7. 5 9(111, t, J=8.

6Hz), 7. 55-7. 45 (4H, in), 7. 37(1OH, d J=11. 4Hz), 7. 14(11H, d, J--12. 1 Hz) 7. 01(1IH, d, J-8. 6Hz), 5. 04(21, s) 4. 10 (1 H, 3. 8 4(2H,. t, J=r6. 9Hz) 55-2. 45 (2H1, in, 2. 40-2. 10(411, 2. 00-1. 80411,rn), 1. 75-1. 1H, 1. 50-1. 20(3M, mt) Purity 90 (NMR) MS 656 (MnI) 470 Table 263 Example No.

455 IH NMR(6) ppm 300MHz,DMSO-d6 05(1H, brs), 8. 32(1H, d, J=1. 3H 19(1H, d, J=8. 8Hz), 8.01(1H, d, J=8. 7Hz), 7.67(1H, t,J=8. 6Hz), 7.50-7.41(5H,m),7.38-7.33(2H,m 17(1H,dd,J=2. 2Hz, 12.2Hz),7 .05(1H, dd, J=2. 2Hz, 8.7Hz), 5. 2H, 4. 12(1H, 3. 07(3H, s),2.

40-2. 10(2H,m), 2. 00-1. 80(4H, m), 1.75-1.55(1H, 1.50-1.20 (3H,

M)

Purity 9 0% (NMR) MS 648 (M+1) Example No.

456 1H NMR(6) ppm 300MHz,DMSO-d6 8.31(1H,d,lJ=1.4Hz),8. 17(1H,d,J 8Hz), 8. 00(1H, dd, J=1. 5Hz, 8. 7 Hz), 7.73(11H, d, J=2. 3Hz),7. 66(1H ,t,J=8.6Hz),7.56(1H, dd,J=2.3Hz ,8.3Hz),7. 50-7.47(4H, 7. 42(1 1, d, J=8. 3Hz),7. 19(1H, d, J=12. 2H 7. 06(111, dd, J=2. 2Hz, 8. .11(2H,s), 4.10(1H, 3.31(3H, ,s 3.03(3H, 2.40-2. 10(2H, m),2 .00-1.80(4H, 1.75-1.55(1H, m) 1. 50-1.20(3H,im)

,N-

0 //S Purity 9 0 (NMR) MS 662(M+1) Example No. 457 1H NMR(6) ppm 300MHz,DMS-d6 CI 8.41(1,. d, J=8. 8Hz), 8.28(1H, s), HI 8. 10(1H, d, J=9. 2Hz),7. 96(1H, d,J 0 F 8Hz), 7.87(1H, d,J=8.8Hz),7. 6.

HO x N 1(1H, dd, J=8. 5Hz, 8.5Hz),7. 56-7.

0 49(4H,m),7.19(1H,dd, J=2.44Hz,12 .2Hz),7. 05(1H, dd, J=2. 4Hz, 8.7Hz \N 0 ),5.18(2H, s),4.06-3. 97(4H, m),2 .62(2H, t, J=8. 1Hz), 2.28-2. 15(2H im), 2. 11-2. 01(4H,m), 1. 91-1. 87( Purity >90% (NMR) 4H, 1.64(1H, 1.43-1.23(3H, Purity 9 (NMR) m) MS 639(M+1) 471 Table 264 Example No.

458 1H NMR(6) ppm 300MHz,DMSO-d6 19(1LH, s),8.29(iH,s),8.14(1 H, d, J=8. 8Hz), 7. 98(1H, dd, J=1. 7H z, 8.7Hz), 7. 90(1H, d, J=2. 2Hz), 7.

69(tH, dd, J=2. 2Hz, 8. 4Hz), 7. 64(1 H, dd, J=8. 5Hz, 8. 5Hz), 7. 50-7. 42( 4H,m), 7.32(1H,d,J=8.4 Hz),7. 14 12. IHz),7.02(lH dd, J=2. 4Hz, 8. 6Hz), 5. 08(2H, s), 4.17-4.02(LH,m),2.30-2.18(2, m 08(3H, s) 1.87-1. 79(4H, I .68-1. 59(1H, 1. 35-1. 23(3H, m) Purity 9 0 (NMR) MS 612(M+1) Example No.

459 HC I

F.

1H NMR(6) ppm 300MHz,DMSO-d 8.29(1H.s),8.11 (ilH, d, 8Hz), 7. 96(1H, d, J=8. 6Hz), 7. 64-7. 58(2 H,m) 7. 51(4H,s),7.44(2H,s),7. 1 (1H, d, J=12. 2Hz),7. 02 (1H, d, J=8 .5H1),5. 14(2H, 4. 12-3. 95 (1H, 3.70(2H, q, J=7. 1Hz), 2. 50(3H, s),2.31-2.12(2H,m),1.92-1.82(4 H, 1.69-1. 57(1H, 1.43-1.16 (3H, 1. 05(3H, t, J=7. 1Hz) Purity 9 0% (NMR) MS 640 (M+1) Example No. 460 1 .3 c 1 8

HOI

HC- 7 0 F 2 2 HO N 0 OO HH 1 Purity 9 0% (NMR) MS 654 (M+1) H NMR(6) ppm 00MHz, DMSD-d6 28(1H, 8. 09(1H, d, J=8. 8Hz), 95(1H, d, J=10. 1Hz), 7. 64-7. 56( H, 7.51(4H, ws), 7. 44(2H, s),7 14(1H, d, J=12. 2Hz), 7. 01(lH, d, J 8. 6Hz), 5. 14(2H, 4. 12-3. 95(1 3. 64(2H, t, J=7. 2Hz),2. 50(3 31-2. 12(2H, 1. 93-1. 84 4H, 1.69-1.59(1H, 1.52-1.

7(5H, 0. 84(38, t, J-7. 3Hz) 472 Table 265 Example No. 461

HCI

O F HO N O\ 0 Purity 9 0% (NMR) MS .676 (M+1) 1H NMR() ppm 400MHz,DMSO-d6 8.30(1H, 13(1H, d,J=8.8Hz), 7.99(1H,d, J=8.8Hz), 7.69(1H, s), 7.62(1H,t,J=8.4Hz), 7.96-7.50(4 H, 7. 45(1H, d, J=8.7Hz), 7. 17(1 H, dd, J=2. 3Hz, 12. I0z), 7. 05 (IH, d d, J=2. 2Hz, 8. 7Hz), 5. 14 (2H, s),4.

07(1H, 3.73(2H, q, J=7.2Hz), 3.

05(3H,s),2.40-2. 10(2H,m),2. 00- 1.80 (4H, 1.75-1. 55 0-1. 20 (3H, 1.06(3H, t,J=7. 2Hz Example No.

462 1H NMR(6) ppm 300MHz,DMSO-d6 8.30(1H, 13(lH, d, J=8.7Hz), 7.98(1H, d, J=8. 7Hz), 7. 70(1H, d, J =1.8Hz), 7.63(1H, t, J=8.4Hz), 5-7. 50(5H, 7.43(1H, d, J=8.-1Hz 15(1H, d, J=12.0Hz), 7.02(1H, d, J=8. 7Hz), 5.13(2H, 4.07(1H, m),3.65(2H, t, J=6.6Hz), 3. 03(3H, 2. 40-2. 10(2H,m), 2. 00-1. 75(4 H, 1.70-1. 60(1H, 1.50-1. (5H. 0. 87(3H, t. Purity 9 0 (NMR) MS 690 (M+1) Example No.

463 1H NMR(G) ppm 300MHz,DMSO-d6 8.29(1H, s),8.11(1H, d,J=8. 7. 97(1H, d, J=9.9Hz), 7.65(1H, br) ,7.61(1H, d, J=8.4Hz), 7. 53-7. 42( 6H,m), 7.16(1H, dd, J=2.2Hz, 12. 1H z),7.03(1H, dd,J=2. OHz, .12(2H, 4. 04-4. 00(1H, 3. 24 2.20(2H, 1.87(7H, m),1 .64(1H, 1.41-1.28 (3H, m) Purity 9 0% (NMR) MS 626(M+1) 473 Table 266 Example No. 464 Cl

HCI

HOO I N0 0 Purity 9 0% (NMR) MS 676(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.28(1H, s),8.09(1H, d, J=8. 8Hz), 7.95(1H, d, J=8. 8Hz), 7. 73(1H, d, J 2Hz), 7.63-7.39 (7H, 7.15(1 H, dd, J=2.2Hz, 12. 1Hz), 7. 01(1H, d d, J=2. Hz, 8.6Hz), 5. 10(2H, 4.

05-3.99(1H, 3. 34(3H, 3. 23( 2H, q, J=7.2Hz), 2. 20(2H, 1. 87( 4H, 1.62(1H, 1.33(3H, 1.

24 (3H, t, J=7. 3Hz) Example No.

465 Cl 0 F HO 0 N 0 N-S 0 Purity^ 0 9 Purity >9 Q% (NMR) 1H NMR(6) ppm 300MHz,DMSO-d6 8.29(1H,d,J=1.5Hz),8. l(lH,d, J=8. 8Hz),7.98(1H,dd,J=1.4Hz,8 .4Hz),7.69(1H, d, J=2. 2Hz), 7.62 (1H, dd, J=8.6Hz, 8.6Hz), 7.56-7.

47 (5H, 7.43(1H,d,J=8. 1Hz),7 .16(1H, dd, =2.2Hz, 12. 2(1H,dd,J=2.4Hz,8.7Hz),5.13(2 H, s),4.09-4. 02(1H, 3.77(2H, q, J=6.8Hz), 3.19(2H, q, J=7.4Hz) ,2.25-2.21(2H, 1.90-1. 87(4H 1.63(1H, 1. 39-1. 33 (3H, m 1.27(3H, t, J=7.4Hz), 1.06(3H, t, J=6.9Hz) MS 690(M+1) Example No. 466 ClI

HCI

0 F HO I N 0

N

Purity >90% (NMR) MS 640(M+1) 474 1H NMR(6) ppm 300MHz,DMSO-d6 8.28(1H, 8.10(1H, d, J=8. 4Hz) ,7.96(1H, d, J=8. 4Hz), 7.64 (1H, s ),7.61(1H,d,J=8.4Hz),7.50(4H, 7.44(2H, 7.14(1H, d, J=12.

OHz), 7.02 (1H, d, J=8.4Hz), 5.12( 2H, s),4.12-3. 95 (1H, 3.23(3H 2. 32-2.06(4H, 1.94-1.77 (4H, 1.70-1.59 (1H, 1.42-1 S18(3H, 0. 96(3H, t, J=7.2Hz) Table 267 Example No.

467 1H NMR(6) ppm 300MHz,DMSO-d6 8.28(1H, 8.08(1H, d, J=8.7H z),7.95(1H, d, J=8.4Hz), 7.60( 1H, t, J=8.4Hz), 7.59 (1H, 7.

51(4H,s),7.45and7.42(2H,ABq ,J=8.1Hz), 7.14(1H, d, J=12. OH 7.00(1H, d, J=8. 4Hz), 5. 14( 2H, 12-3.95(1H, 3.70( 2H,q,J=6.9Hz),2.30-1.98(4H, 1. 94-1. 79(4H, 1.69-1.5 9 (1H, 1.45-1. 17(3H, (3H, t, J=6.9Hz), 0. 94 (3H, t, J Purity >9 0% (NMR) MS 654 (M+1) Example No.

468 1H NMR(6) ppm 400MHz,DMSO-d6 8.25(1H, 7.96(lH, d, J=8. 8H 7.90(1H, d, J=8. 8Hz), 7. 1H, t, J=8.4Hz), 7.46(2H,d,J=8 .7Hz),7. 41(2H, d, J=8.7Hz), 7.

10-7. 00(2H, 6. 98 (1H, dd,J= 2.2Hz, 8.7Hz), 5. 05(2H, 3.9 8(1H, m),3.84(3H,s),2: 30-2. 1 0(2H, 1. 90-1. 75 (4H, 1.7 0-1. 60(1H, 1.50-1. 20(3H, m Purity >90% (NMR) MS 585 (M+1) Example No..

469 1H NMR(6) ppm 400MHz,DMSO-d6 8. 26(1H, 8. 02(1H, d, J=8.8H z),7.93(1H, d, J=8.8Hz), 7.60- 7.50(6H, 7.45(1H, d, 7H 7.08(1H, dd, J=2. 3Hz, 12. OH z),6.97 dd, 2Hz, 8. 7Hz ),5.18(2H,s),4.85(1H,sept,J 6Hz), 3. 98(1H, 2. 40-2. 1 0 (2H, m),2.00-1.80(4H, 1. 7 5-1. 55(4H, 1.50-1.20(3H, m ),1.02(6H, d, J=6. 6Hz) Purity >90% (NMR) MS 654 (M+1) 475 Table 268 Example No. 470 HO 0

CI.

O 0 F I o O F HO. NNz

OH

6 Purity >9 0% (NMR) MS 814(M+1) 1H NMR(6) ppm 300MHz,DMSO-d6 8.39(1H, d, J=1.4Hz), 8. 04(1H, d, J=8.8Hz), 7. 98(1H, d, J2. 2Hz),7 .95(H, d, J=8.8Hz),7. 78(lH, dd, J=2. 3Hz,8. 5Hz),7. 57(1H, t, J=8.

6Hz), 7. 50(2H, d, J=8.8Hz), 7.45( 2H, d, J=8. 8Hz), 7. 39 d, J=8.4 Hz),7.10(lH,d,J=12.1Hz),6.98( 1H, d, J=8.6Hz), 5.65-5.60(2H, m) ,5.35(1H, d, J=4. 2Hz), 5.08(2H, s 00(1H, 3.93-3.84(3H, m), 3. 50-3. 30(4H, m) 2. 54 (2H, t, J=7.

8Hz), 2.40-2. 00 (4H, 1.95-1.7 5 1.70-1. 55(1H,m), 1.45- 1.15(3H, m) Example No.

471 1H NMR( ppm 300MHz,DMSO-d6 12.78 (1H, brs), 8. 30(1H, dd, J=0.

9Hz, 1.5Hz), 8.22 (1H, d, ,7.95(1H, d, J=1. 8Hz), 7.94(1H,.d ,J=8.4Hz), 7.85(1H, dd, 2Hz, 8. 4Hz), 6. 96(1H, dd, J=0. 9Hz, 1.8 Hz),4.46(1H,m),2.40-2.10(2H,m ),2.00-1.20(8H,m) Purity 9 0% (NMR) MS 311(M+1) 476 Table 269 Example No. 702 'Ini NMR 6) PPM 300MHz, DMSO-d6 HOI ci 8. 97(I1H, d, J=8z), 8. 521H, d, J=2. 4Hz), 8. 36(IH, d, J=7. 811 o0 8. 16(G1H, 7, 96 H, di, J=8 HO A N I 7. 55-7. 40 (5H,um), 7. 14( HO I 0. 1H,d,J=12.6Hz),7.01(LH,ddJ N H 4Hz, 1. 8Hz), 5. 11 (21, 4.

20-3. 95 2. 65-2. 45 (2H, b 0 1. 95-1. 80 (5H, 1. 20- 1. 1 O 0(31,m) Purity 90% (NMR) MS 641 1) Example No. 703 in NMR( 6) PPM 300MHz, DMSO-d6 HCI c 8. 9701H, d, J-1. 81z), 8.52 (1H, d, J= 1. 8Hz), 7. 82(1 H, 7. O F 7. 35 (711, in), 7. 1311H, d, J=42. 3 'HO N Hz), 7.OO(OH, d, J=L1.lHz),5. 1 11 4 (2H1, 3. 60-3.354OH, mn), 2. 6 N 5-2. 40 (2H1, 2. 00-2. 55 (9H, mn N231 )1.40-1. Purity >90% (NMR) MS 653 (M+1) 477 Industrial Applicability As is evident from the above-mentioned results, the compound of the present invention shows a high inhibitory Sactivity against HCV polymerase.

Therefore, the compound of the present invention can (provide a pharmaceutical agent effective for the prophylaxis or treatment of hepatitis C, based on the anti-HCV effect afforded O by the HCV polymerase inhibitory activity. When used concurrently with a different anti-HCV agent, such as interferon, and/or an IND Io anti-inflammatory agent and the like, it can provide a pharmaceutical agent more effective for the prophylaxis or Streatment of hepatitis C. Its high inhibitory activity specific to HCV polymerase suggests the possibility of the compound being a pharmaceutical agent with slight side effects, which can be used safely for humans.

This application is based on patent application Nos.

193786/2001 and 351537/2001 filed in Japan, the contents of which are hereby incorporated by reference.

It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments'of the invention.

478

Claims

1. 2-{4-[2-(4-Chlorophenyl)-5-tetrazol-5-ylbenzyloxy]phenyl}-l- 0 s cyclohexylbenzimidazole-5-carboxylic acid hydrochloride.

2. 2-{4-[2-(4-Chlorophenyl)-5- (isopropylcarbamoyl)benzyloxy]-2- acid hydrochloride. 0 10 o

3. 2-[4-{2-(4-Chlorophenyl)-4-fluoro-5-(2-oxopyrrolidin-l- c yl)benzyloxy}-2-fluorophenyl] Scarboxylic acid hydrochloride.

4. 2-{4-[2-(4-Chlorophenyl)-5-(4-methylpiperazin-l- carboxylic acid dihydrochloride.

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier. Dated this 2 4 t h day of October 2005 JAPAN TOBACCO INC. By its Patent Attorneys GRIFFITH HACK 479