ZA200407359B

ZA200407359B - Benzofuran derivatives.

Info

Publication number: ZA200407359B
Application number: ZA200407359A
Authority: ZA
Inventors: Takayuki Kawaguchi; Hidenori Akatsuka; Toru Iljima; Yasunori Tsuboi; Takashi Mitsui; Jun Murakami
Original assignee: Tanabe Seiyaku Co
Priority date: 2002-03-28
Filing date: 2004-09-14
Publication date: 2005-06-28

Description

DESCRIPTION

BENZOFURAN DERIVATIVES

TECHNICAL FIELD

The present invention relates to a Dbenzofuran derivative useful as a medicament, particularly as an inhibitor of activated blood coagulation factor X, or pharmaceutically acceptable salt thereof. e

BACKGROUND ART

In late years, as the westernization of living habit and the aging of populations, thromboembolic diseases such as myocardial infarction, cerebral infarction and peripheral arterial thrombosis increase year by year, and social importance of treatment thereof has risen more and more.

Among therapies of thromboembolic diseases, anticoagulant therapy, as well as fibrinolytic therapy and @ 20 antiplatelet therapy, takes part in medical therapy for treatment and prevention of thrombosis (Sogorinsho 41: 2141-2145, 1989). In particular, the safety sustainable to ) chronic administration and the reliable and appropriate expression of anticoagulant activity are essential in the prevention of thrombosis. A coumarin derivative, especially warfarin potassium, has often been used all over the world as only anticoagulant available orally. However, owing to the characteristics arisen from the mechanism of action, it requires long time until the drug efficacy manifests and has very long half-life in blood, although the concentration range for expression of drug efficacy is relatively narrow, and also shows significant differences in the effective dose among individuals. For these reasons, the anticoagulant ability can hardly be controlled (Journal of Clinical Pharmacology, 1992, vol. 32, pp. 196-209; NEW

ENGLAND JOURNAL OF MEDICINE, 1991, vol. 324, no. 26, pp. 1865-1875). In addition, there may be adverse drug reactions such as risk of bleeding, nausea, vomiting, diarrhea, depilation, etc., and therefore the «clinical _ i0 application thereof is very difficult and the development of anticoagulants that are useful and easy to handle has been demanded.

In addition, enhancement of blood clotting ability is one of significant causative factors of unstable angina, cerebral infarction, cerebral embolism, myocardial infarction, pulmonary infarction, pulmonary embolism,

Buerger's disease, deep vein thrombosis, disseminated intravascular coagulation, thrombogenesis after artificial heart valve displacement, reocclusion after blood @® 20 circulation reconstruction and thrombogenesis during extracorporeal circulation, etc. Therefore, a distinguished anticoagulant that shows good dose response and lower risk of hemorrhage with few side-effects, and can exert sufficient effects upon oral administration has been desired (Thrombosis Research, 1992, vol. 68, pp. 507-512).

Thrombin participates not only in the conversion of fibrinogen to fibrin, which is the final stage of the coagulation cascade, but also deeply in the activation and aggregation of blood platelets (Matsuo, O., “t-PA and Pro-

UK”, Gakusaikikaku, 1986, pp. 5-40), and an inhibitor thereof has long been the center of the research in anticoagulants as a target of development of new drugs.

However, a thrombin inhibitor shows low bioavailability upon oral administration and also has drawbacks in regard to safety such as bleeding tendency as one of side effects (Biomedica Biochimica Acta, 1985, Vol. 44, p.1201-1210), and there have been no thrombin inhibitors marketed so far, which can be orally administered.

The activated blood coagulation factor X is a key ® 10 enzyme located in the position of the common pathway of both extrinsic and intrinsic coagulation cascade reactions.

The factor Xa is located upstream from thrombin in the coagulation cascade. Therefore, the inhibition of the factor Xa is possibly more effective and specific in the inhibition of coagulation system compared to the inhibition of thrombin (Thrombosis Research, 1980, Vol. 19, pp. 339- 349).

Thus, among inhibitors of activated blood coagulation factor X, a substance, which inhibits blood coagulation @® 20 factor Xa and shows distinguished enzyme selectivity and high bioavailability, is expected to undergo control of its anticoagulant activity for a long period of time and can express superior therapeutic effect upon oral administration compared to the existing anticoagulants.

Accordingly, the development of a novel inhibitor of activated blood coagulation factor X (FXa inhibitor) that can be administered orally has been earnestly demanded.

Examples of known compounds having inhibitory effect on activated blood coagulation factor X include thiobenzamide compounds that are useful in prevention or y treatment of thrombosis (W099/42439).

The following benzofuran compounds have also been known (Indian Journal of Hetero Cyclic Chemistry, 1994, Vol. 3, pp. 3247-3252), but said literature does not mention about the inhibitory effect of the compounds on activated blood coagulation factor X. 0

IL Q

0 — NHPh 0 Il — NH ® Jr ; Gy RST nil cH, pn NnE__ cHo— Ph Cl hb

Condensed bicyclic amide compounds of the formula:

R2 R

BOSS

A? N (0) Y

X which has an activity of suppressing the growth of activated lymphocytes and are useful as a drug for ® preventing or treating autoimmune diseases are also known (WO02/12189). The W002/12189 does not mention about the inhibitory effect on activated blood coagulation factor X either. In the pamphlet, compounds having a condensed ring of pyridine and furan to which ring an amide and a carbamoyl groups are di-substituted are disclosed; however, said compounds all have a benzene ring on the nitrogen atom of the carbamoyl group, said benzene ring being substituted by X and Y simultaneously.

DISCLOSURE OF INVENTION

The present invention provides a novel benzofuran derivative having excellent inhibitory effect on activated blood coagulation factor X, or a pharmaceutically 5 acceptable salts thereof.

The present inventors have intensively studied and have found that a benzofuran derivative of the formula below has excellent inhibitory effect on activated blood coagulation factor X and have accomplished the present X ® 10 invention.

That is, the present invention is as follows: (i) A benzofuran derivative of the formula [1]: =\ R! 0 NR® ay wherein x is a group of the formula: -N= or the formula: - @® 15 CH=;

Y is an optionally substituted amino group, an optionally substituted cycloalkyl group or an optionally substituted saturated heterocyclic group:

A is a single bond, a carbon chain optionally having a double bond within or at the end(s) of the chain, or an oxygen atom;

R! is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group Or an amino group optionally substituted by a lower alkyl group;

Ring B of the formula:

is an optionally substituted benzene ring; and

R?’ is a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof. (ii) The compound according to (i), wherein Ring B is a benzene ring optionally substituted by a group (s) selected independently from a halogen atom, an optionally ® substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group, an oxy group substituted by an optionally substituted saturated heterocyclic group, a substituted carbonyl group, an optionally substituted amino group, a nitro group, a cyano group, a 4,5-dihydroxazolyl group or a group of the formula: —G=N—OH

NH; ; and the “optionally substituted cyclcoalkyl group” for Y is a [ cycloalkyl group optionally substituted by a group selected from an optionally substituted amino group, an optionally substituted group of a formula selected from the formulas:

Ny TN Ny Ny \ “Ny NS () (4 {3 LY NE ane and an optionally substituted lower alkyl group. (iii) The compound according to (ii), wherein 25° the “optionally substituted saturated heterocyclic group” for Y 1s a saturated heterocyclic group optionally substituted by a group selected from the followings:

(1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group, (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxazolyl group and a thiazolyl group,

® 10 (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group,

(11) a lower alkoxycarbonyl group,

(12) a lower alkyl group substituted by a di-lower alkylamino group, and

(13) an oxo group;

the “optionally substituted amino group” for Y is an amino [ 20 group optionally substituted by a group selected from the followings:

(1) a piperidyl group substituted by a lower alkyl group,

(2) a lower alkyl group, and

(3) a lower alkoxycarbonyl group;

the “optionally substituted amino group” as a substituent on the cycloalkyl group for Y is an amino group optionally substituted by a group selected from the followings:

(1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group,

(4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower ® 10 alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group, (14) a lower alkanoyl group,

C 20 (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxyl group, and

(23) a hydroxy-lower alkanoyl group; the “optionally substituted group of a formula selected from the formulas:

N N N N \ N—\ N

O and (> (4 (LY {oa LL] as a substituent on the cycloalkyl group for Y is a group

PY selected from the groups of the formulas:

N YN N N \ NT N

O and (> SRY ras that is optionally substituted by an oxo group; the “optionally substituted lower alkyl group” as a substituent on the cycloalkyl group for Y is a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, ® (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by a group selected from (a) a lower alkyl group, (by a lower alkoxycarbonyl group, and (c) a lower alkanoyl group; the “optionally substituted lower alkyl group” as a substituent for Ring B is a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy-

lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and ® 10 (8) a hydroxyl group; the “optionally substituted lower alkoxy group” as a substituent for Ring B is a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, ® 20 (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl-

piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group, (13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and ® 10 (14) a group of the formula: -O-NH-C(=NH)NH,; the “oxy group substituted by an optionally substituted saturated heterocyclic group” as a substituent for Ring B is an oxy group substituted by a heterocyclic group optionally substituted by an aryl group; the “substituted carbonyl group” as a substituent for Ring

B is a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower ( alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; the “optionally substituted amino group” as a substituent for Ring B is an amino group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkoxy-lower alkyl group, (3) a hydroxy-lower alkyl group, ® (4) a lower alkanoyl group, (5) a lower alkoxy-lower alkanoyl group, (6) a hydroxy-lower alkanoyl group, (7) a lower alkanoyl group substituted by a lower alkanoyloxy group, (8) a lower alkanoyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group, (9) a lower alkoxycarbonyl group, (10) a lower alkoxycarbonyl group substituted by an aryl group, (11) a carbamoyl group substituted by a lower alkyl group, (12) a lower alkylsulfonyl group, and (13) a lower alkylsulfonyl group substituted by a morpholinyl group. (iv) The compound according to (iii), wherein B is an unsubstituted benzene ring; and

Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group,

(2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxazolyl group and a thiazolyl group, (7) a lower alkanoyl group, ) 10 (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and (13) an oxo group. (v) The compound according to (iii), wherein B is an unsubstituted benzene ring; and

Y is an amino group optionally substituted by a group ® selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group. (vi) The compound according to (iii), wherein B is an unsubstituted benzene ring; and :

Y is a cycloalkyl group optionally substituted by the followings:

A) an amino group optionally substituted by the followings:

(1) a lower alkyl group,

(2) a cycloalkyl group,

(3) a hydroxy-lower alkyl group,

(4) a 1,3-dioxanyl group substituted by a lower alkyl group,

(5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by

® 10 a lower alkyl group, and (d) a lower alkoxycarbonyl group,

(6) a lower alkyl group substituted by a cyano group,

(7) a lower alkyl group substituted by a lower alkoxycarbonyl group,

(8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group,

(10) a lower alkyl group substituted by an aryl group,

(11) a lower alkyl group substituted by a pyridyl group,

(12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl

@® amino group,

(14) a lower alkanoyl group,

(15) a pyrimidinyl group,

(16) a lower alkanoyl group substituted by a morpholinyl group,

(17) a lower alkylsulfonyl group,

(18) a carbamoyl group substituted by a lower alkyl group,

(19) a carbonyl group substituted by an aryl group,

(20) a lower alkanoyl group substituted by a lower alkoxy group,

(21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group;

B) a group of a formula selected from the formulas:

Ny TN Ne Ne — ( (LL 0 8g (om L] ® that is optionally substituted by an oxo group; or

C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group. (vii) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkyl group optionally substituted by a group selected from the ® followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group,

(6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group; and

Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group ® 10 (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, _ (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and (13) an oxo group. (viii) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group,

(2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- @® 10 lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group; and

Y 1s an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group. (ix) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkyl group optionally ® substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group,

Y is a cycloalkyl group optionally substituted by the followings:

A) an amino group optionally substituted by the followings: ® 10 (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, . 20 (6) a lower alkyl group substituted by a cyano group, ® (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group,

(14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group,

K 10 (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group;

B) a group of a formula selected from the formulas:

DOOD Da (Lb and i. (Ld A that is optionally substituted by an oxo group; or ® C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (cc) a lower alkanoyl group. (x) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group,

(2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, ® 10 (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl- piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group, ® (13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C(=NH)NH,; and

Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group

(3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group,

(6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5—dihydroxaolyl group and a thiazolyl group,

(7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower ® 10 alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and (13) an oxo group. (xi) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: ® 20 (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3 a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl- piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a ® 10 lower alkanoyl group, (13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C(=NH)NH,; and

Y is an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, ® 20 (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group. (xii) The compound according to (iii), wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, @ 10 (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl- piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group, (13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a ® 20 hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C{=NH)NH,; and

Y is a cycloalkyl group optionally substituted by the followings:

A) an amino group optionally substituted by the followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (cc) a lower alkanoyl group substituted by an amino group substituted by "a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, ® 10 (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group, : (14) a lower alkanoyl group, (15) a pyrimidinyl group, ® 20 (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group;

B) a group of a formula selected from the formulas: \, NENG EG VERE (J (LL (J 9g (ows L] that is optionally substituted by an oxo group; or

Cc) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, [ (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group. (xiii) The compound according to (iii), wherein Ring B is a benzene ring substituted by a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower

[7] alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and

Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, [ i0 (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, ® 20 (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and (13) an oxo group. (xiv) The compound according to (iii), wherein Ring B is a benzene ring substituted by a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino dgroup optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-

lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl [ 10 group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and

Y is an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group. (xv) The compound according to (iii), wherein Ring B is a ® 20 benzene ring substituted by a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, : (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group,

(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and

Y is a cycloalkyl group optionally substituted by the ® 10 followings:

A) an amino group optionally substituted by the followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower ( 20 alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group,

(12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, ® 10 (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group;

B) a group of a formula selected from the formulas:

Ny ha Ny Ny Ny — Ny ® g (Ld ®, Sg LP ws that is optionally substituted by an oxo group; or

C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group. . (xvi) The compound according to (i), (ii), (iii), (iv),

(vii), (x) or (xiii), wherein the saturated heterocyclic ring is a saturated 4- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom. (xvii) The compound according to (i), (ii), (iii), (iv), (vii), (x) or (xiii), wherein the saturated heterocyclic group is imidazolidinyl, piperazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, ® 10 homopiperidyl, pyrrolidinyl, oxazolidinyl or 1, 3-dioxanyl. (xviii) The compound according to (iii), wherein the group of the formula: ==\

AT is the group of the formula: :

AI

N and the group of the formula: ® is a group of the formula:

R! is a halogen atom or a lower alkyl group;

R? is a group selected from the followings:

A) a hydrogen atom,

B) a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- ® 10 lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group;

C) a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, ® (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy-

lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl- piperazinyl group, (12) an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and(c)a lower alkanoyl group, (13) a carbamoyl group optionally substituted by a group ® 10 selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group, and (14) a group of the formula: -O-NH-C(=NH)NH,; or

D) a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by a group

CY 20 selected from (a)a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy- lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f)a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group,

(7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group;

A is a single bond; and

R® is a hydrogen atom. (xix) The compound according to (xviii), wherein Y is a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a cycloalkyl group substituted by an amino group ® 10 optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group, (3) a cycloalkyl group substituted by a group of a formula selected from the formulas:

Ny Ny Ny Ny —\ Ny

SRORGEOIS

0 that is optionally substituted by an oxo group, (4) a cycloalkyl group substituted by an amino group ® substituted by a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkanoyl group and (b) a lower alkoxycarbonyl group, and (5) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group; and

R? is a group selected from the followings: (1) a hydrogen atom, (2) a cyano dgroup,

(3) an amino group optionally substituted by a lower alkyl group, (4) a hydroxyl group, (5) a lower alkoxy group,

(6) a lower alkoxy group substituted by a lower alkoxy group, (7) a lower alkoxy group substituted by a hydroxyl group, (8) a lower alkoxy group substituted by an amino group optionally substituted by a lower alkyl group,

® 10 (9) a lower alkoxycarbonyl group,

(10) a carboxyl group, (11) an aminocarbonyl group optionally substituted by a group selected from (a) lower alkyl group, and (b) a hydroxy-lower alkyl group,

(12) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group,

(13) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group or a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group,

® (14) a lower alkyl group, (15) a lower alkyl group substituted by a lower alkoxycarbonyl group, (16) a carboxy-lower alkyl group,

(17) a lower alkyl group substituted by a carbamoyl group optionally substituted by a group selected from (a) lower alkyl group and (b) a hydroxy-lower alkyl group,

(18) a lower alkyl group substituted by a morpholinylcarbonyl group,

(19) a lower alkyl group substituted by a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group, or a lower alkyl group substituted by a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group, or {20) a hydroxy-lower alkyl group. (xx) The compound according to (xviii), wherein Y is a cycloalkyl group substituted by a group of a formula selected from the formulas:

Ny Ny Ny Ny —\ Ny o DOLD 0 that is optionally substituted by an oxo group, or a cycloalkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group; and

R? is a group selected from the followings: (1) a hydrogen atom, (2) an amino group-substituted carbonyl group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group, ® (3) a lower alkoxycarbonyl group, (4) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group, (5) a lower alkyl group substituted by a lower alkyl group-substituted carbamoyl group, (6) a carboxy-lower alkyl group, (7) a lower alkyl group substituted by a morpholinylcarbonyl group, and (8) a hydroxy-lower alkyl group.

(xxi) The compound according to (xviii), wherein Y is a cycloalkyl group substituted by an oxopyrrolidinyl group, a cycloalkyl group substituted by an oxomorpholinyl group or a cycloalkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group; and

R? is a group selected from the followings: (1) a hydrogen atom, (2) a hydroxy-lower alkyl group, ® 10 (3) a carboxy-lower alkyl group, (4) a lower alkoxy group substituted by a lower alkoxy group, or (5) a carbonyl group substituted by a group selected from (a) an amino group optionally substituted by a lower alkyl group and (b) a morpholinyl group. (xxii) The compound according to (xviii), wherein Y is a group selected from the followings: (1) a cycloalkyl group substituted by an amino group substituted by a lower alkyl group having 1 to 3 carbon ® 20 atoms, (2) a cycloalkyl group substituted by an amino group substituted by a lower alkanoyl group having 1 to 2 carbon atoms, (3) a cycloalkyl group substituted by a pyrrolidin-1-yl group optionally substituted by an oxo group, (4) a cycloalkyl group substituted by a piperidin-1-yl group optionally substituted by an oxo dgroup, (5) a cycloalkyl group substituted by a morpholin-4-yl group optionally substituted by an oxo group, (6) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group substituted by a lower alkyl group having 1 to 3 carbon atoms, or (7) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group substituted by a lower alkanoyl group having 1 to 2 carbon atoms.

(xx1ii) A compound selected from trans-5-Dimethylaminocarbonyl-3-[4- (N-formyl-N- methylamino) cyclohexylcarbonylamino] -N- (5-chloropyridin-2- yl)benzofuran-2-carboxamide;

® 10 trans-3-[4- (N-acetyl-N-methylamino)cyclohexyl-

carbonylamino] -5- (2~hydroxyethyl)-N- (5-chloropyridin-2- yl)benzofuran-2-carboxamide;

trans-~5-{(morpholine-4-ylcarbonyl)-3-[4- (2-oxo- pyrroridin-1l-yl)cyclohexylcarbonylamino] -N- (5-

chloropyridin-2-yl)benzofuran-2-carboxamide; and trans—-3-(4-dimethylaminocyclohexylcarbonylamino)—-N- (5- chloropyridin-2-yl) benzofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof. (xxiv) A benzofuran derivative having a partial

® 20 structure of the formula [1-1]: o] =) = 0] oi [1-1] oy wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof.

(xxv) A benzofuran derivative of the formula [2]: =\_R' o NR®

[2]

NH; wherein the symbols are the same as defined above, or a salt thereof. (xxvii) A pharmaceutical composition, which comprises as ® an active ingredient a compound according to any one of (i) to (xxiv) above or a pharmaceutically acceptable salt thereof. (xxvii) A method for treatment of thrombosis, which comprises administering an effective amount of a compound according to any one of (i) to (xxiv) above or a pharmaceutically acceptable salt thereof, to a patient in need thereof (xxviii) Use of a compound according to any one of (i) to (xxiv) above or a pharmaceutically acceptable salt thereof ® in treatment of patients suffering from thrombosis. (xxix) A medicament for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient a factor Xa (FXa) inhibitor showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICsp value of 100 nM or below. (xXx) A medicament for Lreatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an FXa inhibitor showing a distribution volume of 0.1-3.0 L/kg or below and an FXa inhibitory effect with the ICso value of 100 nM or below.

(xxx1i) A medicament for oral administration for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient a factor Xa (FXa) inhibitor showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICs value of 100 nM or below. (xxii) A medicament for oral administration for treatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an ) 10 FXa inhibitor showing a distribution volume of 0.1-3.0 L/kg or below and an FXa inhibitory effect with the ICso value of 100 nM or below. (xxxiii) A medicament for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient an FXa inhibitor having a partial structure of the formula:

O

I

TN i o Nee and showing a distribution volume of 0.1-3.0 L/kg and an

FXa inhibitory effect with the ICso value of 100 nM or below. (xxxiv) A medicament for treatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an FXa inhibitor having a partial structure of the formula:

0

I

NG i

Ne—( Hn and showing a distribution volume of 0.1-3.0 L/kg and an

FXa inhibitory effect with the ICs, value of 100 nM or below. (xxxV) A medicament for oral administration for treatment of thrombosis, which causes substantially no ® phospholipidosis and comprises as an active ingredient an

FXa inhibitor having a partial structure of the formula: 0 we 0 law and showing a distribution volume of 0.1-3.0 L/kg and an

FXa inhibitory effect with the ICs value of 100 nM or below. (xxxvi) A medicament for oral administration for treatment of thrombosis substantially free of ( hepatotoxicity, which comprises as an active ingredient an

FXa inhibitor having a partial structure of the formula: 0 ne 0

Ud and showing a distribution volume of 0.1-3.0 L/kg and an

FXa inhibitory effect with the ICs; value of 100 nM or below.

BEST MODE FOR CARRYING OUT THE INVENTION

The compound [1] of the present invention will be hereinafter described in detail.

The term "lower" used in the definition of the formulas herein described means unless otherwise noted a straight- or branched-carbon chain having 1 to 6 carbon atoms.

Thus, examples of “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- ® 10 butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1- methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1l-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1- ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2- trimethylpropyl, l-ethyl-1l-methylpropyl, l-ethyl-2- methylpropyl, etc. Among them, alkyl groups having 1 to 4 carbon atoms are preferred, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are ® 20 especially preferred.

The term "lower alkoxy group" means a substituent wherein an oxygen atom is bound to the above-mentioned alkyl group. Among them, alkoxy groups having 1 to 4 carbon atoms are preferred, and methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy groups are especially preferred.

Examples of "carbon chain optionally having a double bond within or at the end(s) of the chain" include "lower alkylene group", "lower alkenylene group" and "lower alkenylidene group".

Examples of “lower alkylene group” include a straight- or branched-chain alkylene group having 1 to 6 carbon atoms, specifically, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc. Among them, an alkylene group having 1 to 5 carbon atoms is preferred.

Examples of “lower alkenylene group” include a straight- or branched-chain alkenylene group having 2 to 6 carbon atoms, specifically, vinylene, propenylene, ® 10 butenylene, pentenylene, etc. Among them, an alkenylene group having 2 to 5 carbon atoms is preferred.

Examples of “lower alkenylidene group” include alkenylidenes having 2 to 6 carbon atoms, specifically, vinylidene, propenylidene, butenylidene, pentenylidene, etc.

Examples of “lower alkanoyl group” include alkanoyl groups formed by removing a "OH" group from the carboxyl group of a lower carboxylic acid, specifically, formyl, acetyl, propionyl, butyryl, etc.

The “saturated heterocyclic group” means a saturated heterocyclic group containing 1 to 4 hetero atoms selected ® independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom, preferably a 4- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom. A condensed heterocyclic ring is included. Specific examples include imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, homopiperidyl, pyrrolidinyl, oxazolidinyl, 1,3-dioxanyl, etc. Above all, piperidyl, piperazinyl, homopiperazinyl and pyrrolidinyl are preferred.

The “unsaturated heterocyclic group” means an unsaturated heterocyclic group containing 1 to 4 hetero atoms selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom, preferably a 4- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom. A condensed heterocyclic ring is included. Specific examples include ® 10 pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 4,5-dihydro- oxazolyl, thiazolyl, isothiazolyl, etc. Above all, pyridyl, pyrimidinyl, pyrazinyl, thienyl, oxazolyl, 4,5-dihydro- oxazolyl and thiazolyl are preferred.

Examples of “halogen atom” include fluorine, chlorine, bromine or iodine atom. Above all, fluorine, chlorine or bromine atom is preferred.

The term “cycloalkyl group” means a cyclic lower alkyl group, preferably a cyclohexyl group.

The term “aryl group” means a phenyl or a naphthyl ® group, preferably phenyl group.

The symbol “Y”, when A and Y are bound via a double bond, refers to the corresponding bivalent group.

The pharmaceutically acceptable salt of the compound

[1] includes a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; a salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,

tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; salt with an acidic amino acid such as aspartic acid, glutamic acid, etc.; salt with a metal such as sodium, potassium, magnesium, calcium, aluminium, etc.; salt with an organic base such as methylamine, ethylamine, ethanolamine, etc.; or a salt with a basic amino acid such as lysine, ornithine, etc.

The compound [1] of the present invention can be in o 10 the form of quaternary ammonium salt and such a quaternary ammonium salt falls within the scope of the present compound [1].

Further, the compound [1] of the present invention includes a intramolecular salt. hydrate, solvate or crystalline polymorphism, etc.

Besides, when the compound [1] has a double bond(s),: it may exist in the form of a geometrical isomer (cis, trans), when the compound [1] has an unsaturated bond such as carbonyl, it may exist in the from of a tautomerism, ) 20 when the compound [1] has an asymmetric carbon atom(s), it can exist as an optical isomer, and the present invention encompass these isomers and a mixture thereof.

Additionally, the compound [1] of the present invention encompasses a prodrug of a compound as mentioned above. Examples of a prodrug include those prepared by protecting a functional group such as an amino or carboxy group of a compound above with a conventional protecting group.

The compound of the present invention may be prepared by the following processes.

we ’ ' [Process A]

Among the compound [1] of the present invention, a compound wherein A is a single bond or a carbon chain optionally having a double bond within or at the end(s) of the chain, i.e., a compound of the formula [1-A]: 0 AS \ 7) o. SCR? * » NH Aly

I wherein A' is a single bond or a carbon chain optionally having a double bond within or at the end(s) of the chain, and the other symbols are the same as defined above, can be prepared by reacting an amino compound of the formula [2]:

Rr! 0 ST 0 L A oy [2]

NH3 sc 10 wherein the symbols are the same as defined above, with a carboxylic acid compound of the formula [3-A]:

YA'-COOH [3-A] wherein the symbols are the same as defined above, or a reactive derivative thereof at 1ts carboxyl group. [Process B]

Among the compound [1] of the present invention, a compound wherein A is an oxygen atom, or A is a single bond, and Y is an optionally substituted amino group, i.e.,

AMENDED SHEET a compound of the formula [1-B]: a / [1-B]

NH '%

Y wherein A? is an oxygen atom and the other symbols are the same as defined above, or wherein A? is a single bond and ® the other symbols are the same as defined above, can be prepared by reacting the compound [2] above with a compound of the formula [3-Bl]:

YA’-H [3—B1] wherein the symbols are the same as defined above, and a compound of the formula [3-B2]:

L'-co-1* [3-B2] wherein L' and L? are the same or different and each a leaving group.

The compound [1] can also be prepared, if necessary, ® through the mutual conversion, wherein the residue Y and/or the substituent for Ring B (R?) of resulting compound [1-A] or [1-B] 1s adequately converted into a compound [1] through the mutual conversion by alkylation, reductive alkylation, amidation, sulfonyl-amidation, amidino- etherification, arylation, reduction, dealkylation, hydrolysis, quaternary amination, formylation, pyrrolylation, protection of amino or carboxyl group and deprotection, etc. [Manufacturing Process for Starting Materials: Preparation of compound [2]]

The compound [2] can be prepared by a process comprising: converting the aldehyde group of a compound of the formula

[10]:

OH

CHO

® wherein the symbols are the same as defined above, into cyano group to give a compound of the formula [9]:

OH

CN wherein the symbols are the same as defined above, reacting the compound [9] with a compound of the formula

[8]:

T

3 C [8] ® LN

OP wherein 1° is a leaving group and P' is a protecting group for carboxyl group, to give a compound of the formula [7]:

I oT OP!

CN [71 wherein the symbols are the same as defined above, deprotecting the protecting group P' of the compound {7] to give a compound of the formula [6]:

I oT OH

CN 6) wherein the symbols are the same as defined above, reacting the compound [6], if necessary, after converting inte a reactive derivative at the carboxyl group thereof, with a compound [5]: 1 ® Ee \ /

R°NH X wherein the symbols are the same as defined above, to give a compound of the formula [4]: — 1 2 AJ oN | [4]

Ns

CN

® and subjecting the compound [4] to cyclization.

Further, the compound [4] can also be prepared by reacting a compound of the formula [9] with a compound of the formula [12]:

Ff

NTN /

X

TP (121

O wherein L* is a leaving group and the other symbols are the same as defined above.

The compound [4] can also be prepared by reacting a compound of the formula [13]: 13

CN wherein L° is a leaving group and the other symbols are the same as defined above with a compound of the formula [14]: = R' wl J

X

® Hoe [14] wherein the symbols are the same as defined above.

Further, the compound of the formula [10] can be prepared by formylating a compound of the formula [11]:

OH

[11] wherein the symbols are the same as defined above.

The Processes [A] and [B] above can be carried out in ® the following manner. [Process A]

The reaction where a compound [1-A] is prepared using a compound [2] and a compound [3-A] can be carried out in a conventional manner for amidation. That is, the reaction can be carried out by reacting a compound [2] with a compound [3-A}, a reactive derivative thereof, or a salt thereof in the presence or absence of a condensing agent, and if necessary, in the presence of an acid scavenger, in an appropriate solvent.

The condensing agent includes conventional agents such as N, N-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3- dimethylaminopropyl) carbodiimide (EDC) or a hydrochloride thereof, carbonyldiimidazole (CDI), diphenylphosphoryl- azide (DPPA), diethyl cyanophosphonate (DEPC), etc. Above all, DCC, EDC or a hydrochloride thereof is preferred.

Examples of the reactive derivative of the compound [3-A] include those conventionally used such as an acid halide, a mixed anhydride, a reactive ester, etc. Examples of an activator that can be used for converting the @® 10 compound [3-A] into the reactive derivative thereof include thionyl chloride, thionyl bromide, oxalyl chloride, N- hydroxylamines such as l1-hydroxysuccinimide, 1- hydroxybenzotriazole, etc., and phenols such as p- nitrophenol, etc. Above all, thionyl chloride, oxalyl chloride, 1-hydroxysuccinimide and 1l-hydroxybenzotriazole are preferred. The acid chloride method is especially preferable.

Examples of the salt of a compound [3-A] or a reactive derivative of the compound [3-A] include a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, ® sulfuric acid, etc. An acid scavenger 1s also usable depending on the method to be employed, which includes inorganic or organic bases.

The present reaction may be facilitated when it is carried out in the presence of a base or by using such a base as a solvent. Examples of inorganic bases include inorganic bases such as alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali earth metal carbonates (calcium carbonate, etc.), alkali metal hydrogen carbonates (sodium hydrogen carbonate,

potassium hydrogen carbonate, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.). Examples of organic bases include tri- lower alkylamines (triethylamine, tributylamine, diisopropylethylamine, etc.) , tertiary—-amines (1,4- diazabicyclo[2.2.2]octane, 1,5—-diazabicyclo[4.3.0]lnon-5-ene, 1,8-diazabicyclo[5.4.0]Jundec-7—ene, etc.), amines (N, N- dimethylaniline, N,N—diethylaniline, 4- dimethylaminopyridine, etc.), pyridine, lutidine, collidine, ® 10 etc. Above all, triethylamine, diisopropylethylamine, 4- dimethylaminopyridine, or pyridine is preferred for carrying out the reaction. The present reaction can be carried out in the presence or absence of a solvent, preferably in the presence of a solvent.

Examples of the solvent include any inert solvent which does not disturb the reaction, such as halogenated hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, 1, 2-dimethoxyethane, etc.), ® esters (ethyl acetate, etc.), amides (N,N-dimethylformamide,

N,N-dimethylacetamide, 1, 3-dimethyl-2-imidazolidinone, etc.), nitriles (acetonitrile, etc.), dimethylsulfoxide, pyridine, 2,6-luthidine, etc., a mixed solvent comprising two or more of these solvents, if necessary, and also a mixture of any one(s) of these solvents and water. It is preferred to select any appropriate solvent depending on the method used. Above all, dichloromethane, chloroform, toluene, xylene, tetrahydrofuran, dioxane, N, N- dimethylformamide, N,N-dimethylacetamide, 1l,3-dimethyl-2-

imidazolidinone, pyridine, and the like are preferred, and dichloromethane, chloroform, N, N-dimethyl formamide and pyridine are especially preferred. The present reaction can be carried out in a wide range of temperature from a temperature of under cooling to under heating. For example, the reaction can be preferably carried out at a temperature of -10°C to the boiling point of the reaction mixture, especially from under ice-cooling to 60°C. [Process B] ® 10 The process wherein the compound [1-B] is prepared by reacting a compound [2] with compounds of the formulas [3-

Bl] and [3-B2], respectively, can be carried out in accordance with a conventional method for carbonylation in the presence of an appropriate acid scavenger in an appropriate solvent.

Examples of a leaving group for a compound of the formula [3-B2] include a halogen atom. Examples of a compound [3-B2] include phosgene, triphosgene, CDI, etc., and triphosgene is preferred. [ 20 Examples of acid scavenger used in the reaction include both the inorganic and organic bases. Examples of inorganic bases include alkali metal carbonates (sodium carbonate, potassium carbonate, cesium carbonate, etc.) and alkali metal hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate, etc.). Examples of organic bases include tri-lower alkylamines (triethylamine, tributylamine, diisopropylethylamine, etc.), tertiary~ amines (1,4-diazabicyclo[2.2.2]octane, 1,5- diazabicyclo[4.3.0]lnon-5-ene, 1,8-diazabicyclo[5.4.0]- undec-7-ene, etc.), amines (N,N-dimethylaniline, N, N-

Claims

1. A benzofuran derivative of the formula [1]: —\_R! 0 NR? ar ® 5 wherein x is a group of the formula: -N= or the formula: - CH=; Y is an optionally substituted amino group, an optionally substituted cycloalkyl group or an optionally substituted saturated heterocyclic group; A is a single bond, a carbon chain optionally having a double bond within or at the end(s) of the chain, or an oxygen atom; R! is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano group Or an amino group o 15 optionally substituted by a lower alkyl group; Ring B of the formula: is an optionally substituted benzene ring; and R® is a hydrogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, wherein Ring B is a benzene ring optionally substituted by a groups) selected independently from a halogen atom, an optionally substituted lower alkyl group, a hydroxy group, an optionally substituted lower alkoxy group, an OXy group substituted by an optionally substituted saturated heterocyclic group, a substituted carbonyl group, an optionally substituted amino group, a nitro group, a cyano group, a 4,5-dihydroxazolyl group or a group of the formula: ——G=N—OH NH; ; and ® the “optionally substituted cycloalkyl group” for Y is a cycloalkyl group optionally substituted by a group selected from an optionally substituted amino group, an optionally substituted group of a formula selected from the formulas: AN \ N\ N\ N N - DOOD Ba (Ld No (_o and and an optionally substituted lower alkyl group.

3. The compound according to claim 2, wherein ® the “optionally substituted saturated heterocyclic group” for Y 1s a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group, (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxazolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfenyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and ® 10 (13) an oxo group; the “optionally substituted amino group” for Y is an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group,

(2) a lower alkyl group, and (3) a lower alkoxycarbonyl group; the “optionally substituted amino group” as a substituent on the cycloalkyl group for Y is an amino group optionally substituted by a group selected from the followings:

o 20 (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl group,

(5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group,

(6) a lower alkyl group substituted by a cyano group,

(7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl ® 10 amino group, (14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, ] 20 (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxyl group, and (23) a hydroxy-lower alkanoyl group; the “optionally substituted group of a formula selected from the formulas: Ny TN Ny Ny Ny — Ny (J (Ld () § (oma L]

as a substituent on the cycloalkyl group for Y is a group selected from the groups of the formulas: \, TN Se Nes — [ \ {4 (LD (Lo and that is optionally substituted by an oxo group: the “optionally substituted lower alkyl group” as a substituent on the cycloalkyl group for Y is a lower alkyl ® group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, and i0 (2) an oxomocrpholinyl group, and (3) an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group: the “optionally substituted lower alkyl group” as a substituent for Ring B is a lower alkyl group optionally substituted by a group selected from the followings: C (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group,

(7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group; the “optionally substituted lower alkoxy group” as a substituent for Ring B is a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, ® 10 (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a morpholinyl group, a piliperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy- ® 20 lower alkyl group,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-

lower alkyl group,

(11) a carbonyl group substituted by a lower alkyl-

piperazinyl group,

(12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group,

(13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy-

lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C(=NH)NH;; the “oxy group substituted by an optionally substituted saturated heterocyclic group” as a substituent for Ring B is an oxy group substituted by a heterocyclic group optionally substituted by an aryl group; the “substituted carbonyl group” as a substituent for Ring B is a carbonyl group substituted by a group selected from ® 10 the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, o 20 (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; the “optionally substituted amino group” as a substituent for Ring B is an amino group optionally substituted by a group selected from the followings:

(1) a lower alkyl group, (2) a lower alkoxy-lower alkyl group, (3) a hydroxy-lower alkyl group, (4) a lower alkanoyl group, (5) a lower alkoxy-lower alkanoyl group, (6) a hydroxy-lower alkanoyl group, (7) a lower alkanoyl group substituted by a lower alkanoyloxy group, (8) a lower alkanoyl group substituted by an amino group ® 10 optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group, (9) a lower alkcxycarbonyl group, (10) a lower alkoxycarbonyl group substituted by an aryl group, (11) a carbamoyl group substituted by a lower alkyl group, (12) a lower alkylsulfonyl group, and (13) a lower alkylsulfonyl group substituted by a morpholinyl group.

4. The compound according to claim 3, wherein B is ® 20 an unsubstituted benzene ring; and Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5-dihydroxazolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and ® 10 (13) an oxo group.

5. The compound according to claim 3, wherein B is an unsubstituted benzene ring; and Y 1s an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group.

6. The compound according to claim 3, wherein B is an unsubstituted benzene ring; and o 20 Y 1s a cycloalkyl group optionally substituted by the followings: A) an amino group optionally substituted by the followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group,

® i0 (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group,

(14) a lower alkanoyl group,

(15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group,

C 20 (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group,

(22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group; B) a group of a formula selected from the formulas:

Ny TN Ny Ny Ny — Ny { ) (4 () (Lo and |] that is optionally substituted by an oxo group; or C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and ® (3) an aminc group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (cc) a lower alkanoyl group.

7. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group [ selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group; and

’ Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a _ 10 pyridyl group, a pyrimidinyl group, a 4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and ® 20 (13) an oxo group.

8. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group,

(4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group; and Y is an amino group optionally substituted by a group ® 10 selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group.

9. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkyl group optionally substituted by a group selected from the followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group, o 20 (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (6) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and

(8) a hydroxyl group; and Y is a cycloalkyl group optionally substituted by the followings: A) an amino group optionally substituted by the followings: (1) a lower alkyl group, (2) a cycloalkyl group, {3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl ® 10 group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (kb) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, [ 20 (9) a lower alkyl group substituted by a carbamoyl group optionally substituted by a lower alkyl group, (10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group,

(17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (18) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group; ® 10 B) a group of a formula selected from the formulas: \, he DENG WI WERE { ) (Ld A )) (Lb and [ that is optionally substituted by an oxo group; or C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and [ (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group.

10. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group,

(5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group,

(6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group,

(8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy- ® 10 lower alkyl group,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-

lower alkyl group,

(11) a carbonyl group substituted by a lower alkyl-

piperazinyl group,

(13) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- o 20 lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C(=NH)NH;; and Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5—dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, ® 10 (11) a lower alkoxycarbonyl group, (12) a lower alkyl group substituted by a di-lower alkylamino group, and - (13) an oxo group.

11. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, ® 20 (3) a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy-

lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl-

piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group, (13) a carbamoyl group optionally substituted by a group

® 10 selected from (a) a lower alkyl group, (b) a lower alkoxy-

lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and (14) a group of the formula: -O-NH-C(=NH)NH;; and

Y is an amino group optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group.

® 20

12. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group,

(2) a lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl group, (5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group,

(6) a lower alkoxy group substituted by a lower alkoxy group, (7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group,

(9) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group, (10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group,

® 10 (11) a carbonyl group substituted by a lower alkyl- piperazinyl group, (12) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group,

(13) a carbamoyl group optionally substituted by a group selected from (a} a lower alkyl group, (b) a lower alkoxy- lower alkyl group, (c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group; and o 20 (14) a group of the formula: -O-NH-C(=NH)NH;; and Y is a cycloalkyl group optionally substituted by the followings: A) an amino group optionally substituted by the followings:

(1) a lower alkyl group,

(2) a cycloalkyl group,

(3) a hydroxy-lower alkyl group,

(4) a 1,3-dioxanyl group substituted by a lower alkyl group,

(5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group, (8) a lower alkyl group substituted by a carboxyl group, (9) a lower alkyl group substituted by a carbamoyl group ® 10 optionally substituted by a lower alkyl group,

(10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group,

o 20 (17) a lower alkylsulfonyl group,

(18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, (20) a lower alkanoyl group substituted by a lower alkoxy group,

(21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group; B) a group of a formula selected from the formulas:

\, oN Ne Nem Se § (4 LL ) (_» and |] that is optionally substituted by an oxo group; Or C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and ® (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanocyl group.

13. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- ® lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and Y is a saturated heterocyclic group optionally substituted by a group selected from the followings: (1) a lower alkyl group, (2) a lower alkyl group substituted by a pyridyl group (3) a piperidyl group substituted by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group substituted by a lower ® 10 alkoxycarbonyl group, (6) an unsaturated heterocyclic group selected from a pyridyl group, a pyrimidinyl group, a 4,5—dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl group substituted by a di-lower alkylamino group, (9) a carbonyl group substituted by a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower alkoxycarbonyl group, ( 20 (12) a lower alkyl group substituted by a di-lower alkylamino group, and (13) an oxo group.

14. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, ® 10 (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and Y is an amino greup optionally substituted by a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl group.

15. The compound according to claim 3, wherein Ring B is a benzene ring substituted by a carbonyl group ® 20 substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxy group, (c¢) a lower alkoxy- lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f) a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; and Y is a cycloalkyl group optionally substituted by the followings: ® 10 A) an amino group optionally substituted by the followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower alkyl group,

(4) a 1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkanoyl group, (c) a lower ® 20 alkanoyl group substituted by an amino group substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group substituted by a cyano group, (7) a lower alkyl group substituted by a lower alkoxycarbonyl group,

(10) a lower alkyl group substituted by an aryl group, (11) a lower alkyl group substituted by a pyridyl group, (12) a lower alkoxycarbonyl group,

(13) a lower alkanoyl group substituted by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl group substituted by a morpholinyl group, (17) a lower alkylsulfonyl group, (18) a carbamoyl group substituted by a lower alkyl group, (19) a carbonyl group substituted by an aryl group, ® 10 (20) a lower alkanoyl group substituted by a lower alkoxy group, (21) a lower alkanoyl group substituted by a lower alkanoyloxy group, (22) an aryl group substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl group; B) a group of a formula selected from the formulas: Ny TN Ny Ny \ Ny — Ny ® { ) (4 (LY (_»® and |] that is optionally substituted by an oxo group; or C) a lower alkyl group optionally substituted by a group selected from the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl group, and (3) an amino group optionally substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl group.

16. The compound according to any one of claims 1, 2, 3, 4, 7, 10 and 13, wherein the saturated heterocyclic ring is a saturated 4- to 7-membered heterocyclic group containing 1 to 4 hetero atoms selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom.

17. The compound according to any one of claims 1, 2, 3, 4, 7, 10 and 13, wherein the saturated heterocyclic group is imidazolidinyl, piperazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, homopiperidyl, pyrrolidinyl, oxazolidinyl or 1,3-dioxanyl. ( 10

18. The compecund according to claim 3, wherein the group of the formula: — 1 VR \_/ \_/ is the group of the formula: \ J" N and the group of the formula: ® is a group of the formula: R? or R? ; R! is a halogen atom or a lower alkyl group; R? is a group selected from the followings: A) a hydrogen atom, B) a lower alkyl group optionally substituted by a group selected from the followings:

(1) a lower alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy-

lower alkyl group, {(c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group substituted by a morpholinyl group, (5) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group,

® 10 (6) a pyrrolidinylcarbonyl group substituted by a hydroxy-

lower alkyl group, (7) a carbonyl group substituted by a hydroxyl group- substituted piperidyl group, and (8) a hydroxyl group;

C) a lower alkoxy group optionally substituted by a group selected from the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group,

® 20 (4) a hydroxyl group,

(5) an aminooxy group optionally substituted by a lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by a lower alkoxy group,

(7) a carbonyl group substituted by a morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a carbonyl group substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted by a hydroxy-

lower alkyl group,

(10) a pyrrolidinylcarbonyl group substituted by a hydroxy- lower alkyl group, (11) a carbonyl group substituted by a lower alkyl- piperazinyl group,

(12) an amino group optionally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and(c)a lower alkanoyl group,

(13) a carbamoyl group opticnally substituted by a group selected from (a) a lower alkyl group, (b) a lower alkoxy- ® 10 lower alkyl group, {(c) a lower alkyl group substituted by a hydroxyl group, and (d) a lower alkyl group substituted by a di-lower alkylamino group, and (14) a group of the formula: -O-NH-C(=NH)NH;; or D) a carbonyl group substituted by a group selected from the followings: (1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group optionally substituted by a group selected from (a)a lower alkyl group, (b) a lower alkoxy o 20 group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy- lower alkyl group, (e) a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group, (f)a lower alkyl group substituted by an aryl group, and (g) a lower alkyl group substituted by a pyridyl group, (4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a piperidyl group substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl group; A is a single bond; and R?® is a hydrogen atom.

19. The compound according to claim 18, wherein Y is a group selected from the followings: (1) a piperidyl group substituted by a lower alkyl group, (2) a cycloalkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower o 10 alkyl group, (b) a lower alkoxycarbonyl group, and (cc) a lower alkanoyl group, (3) a cycloalkyl group substituted by a group of a formula selected from the formulas: Ne Ne Ne — SROROROIIS 0 that 1s optionally substituted by an oxo group, (4) a cycloalkyl group substituted by an amino group @® substituted by a lower alkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkanoyl group and (b) a lower alkoxycarbonyl group, and (5) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group optionally substituted by a lower alkyl group; and R? is a group selected from the followings: (1) a hydrogen atom, (2) a cyano group, (3) an amino group optionally substituted by a lower alkyl group, (4) a hydroxyl group, (5) a lower alkoxy group, (6) a lower alkoxy group substituted by a lower alkoxy group, (7) a lower alkoxy group substituted by a hydroxyl group, (8) a lower alkoxy group substituted by an amino group optionally substituted by a lower alkyl group, (9) a lower alkoxycarbonyl group, ® 10 (10) a carboxyl group, (11) an aminocarbonyl group optionally substituted by a group selected from (a) lower alkyl group, and (b) a hydrexy-lower alkyl group, (12) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group, (13) a piperidylcarbonyl group substituted by a hydroxy- lower alkyl group or a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group, @® 20 (14) a lower alkyl group, (15) a lower alkyl group substituted by a lower alkoxycarbonyl group, (16) a carboxy-lower alkyl group, (17) a lower alkyl group substituted by a carbamoyl group optionally substituted by a group selected from (a) lower alkyl group and (b) a hydroxy-lower alkyl group, (18) a lower alkyl group substituted by a morpholinylcarbonyl group, (19) a lower alkyl group substituted by a piperidylcarbonyl group substituted by a hydroxy-lower alkyl group, or a lower alkyl group substituted by a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl group, or {20) a hydroxy-lower alkyl group.

20. The compound according to claim 18, wherein Y is a cycloalkyl group substituted by a group of a formula selected from the formulas: Ne Ne Ne ON , C000 LI ® 0 that is optionally substituted by an oxo group, or a cycloalkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group; and R? is a group selected from the followings: (1) a hydrogen atom, (2) an amino group-substituted carbonyl group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkoxy-lower alkyl group, ( (3) a lower alkoxycarbonyl group, (4) a morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a thiomorpholinylcarbonyl group, (5) a lower alkyl group substituted by a lower alkyl group~substituted carbamoyl group, (6) a carboxy-lower alkyl group, (7) a lower alkyl group substituted by a morpholinylcarbonyl group, and (8) a hydroxy-lower alkyl group.

21. The compound according to claim 18, wherein Y is a cycloalkyl group substituted by an oxopyrrolidinyl group, a cycloalkyl group substituted by an oxomorpholinyl group or a cycloalkyl group substituted by an amino group optionally substituted by a group selected from (a) a lower alkyl group and (b) a lower alkanoyl group; and R? is a group selected from the followings: (1) a hydrogen atom, (2) a hydroxy-lower alkyl group, (3) a carboxy-lower alkyl group, ® 10 (4) a lower alkoxy group substituted by a lower alkoxy group, Or (5) a carbonyl group substituted by a group selected from (a) an aminc group optionally substituted by a lower alkyl group and (b) a morpholinyl group.

22. The compound according to claim 18, wherein Y is a group selected from the followings: (1) a cycloalkyl group substituted by an amino group substituted by a lower alkyl group having 1 to 3 carbon atoms, @® 20 (2) a cycloalkyl group substituted by an amino group substituted by a lower alkanoyl group having 1 to 2 carbon atoms, (3) a cycloalkyl group substituted by a pyrrolidin-1-yl group optionally substituted by an oxo group, (4) a cycloalkyl group substituted by a piperidin-1-yl group optionally substituted by an oxo group, (5) a cycloalkyl group substituted by a morpholin-4-yl group optionally substituted by an oxo group, (6) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group substituted by a lower alkyl group having 1 to 3 carbon atoms, or (7) a cycloalkyl group substituted by a lower alkyl group substituted by an amino group substituted by a lower alkanoyl group having 1 to 2 carbon atoms.

23. A compound selected from trans-5-Dimethylaminocarbonyl-3-[4- (N-formyl-N- methylamino) cyclohexylcarbonylamino] -N- (5-chloropyridin-2- yl)benzofuran-2-carboxamide; trans-3-[4-(N-acetyl-N- ® 10 methylamino) cyclohexylcarbonylamino]-5-(2-hydroxyethyl) -N- (5-chloropyridin-2-yl)benzofuran-2-carboxamide; trans-5- (morpholine-4-ylcarbonyl)-3-[4-(2-0ox0- pyrroridin-1l-yl)cyclohexylcarbonylamino]-N-(5- chloropyridin-2-yl)benzofuran-2-carboxamide; and trans-3- (4-dimethylaminocyclohexylcarbonylamino)-N- (5- chloropyridin-2-yl) benzofuran-2-carboxamide, or a pharmaceutically acceptable salt thereof.

24. A benzofuran derivative having a partial structure of the formula [1-1]: ® lo] i) \, / 0 oy [1-1]

~. wherein the symbols are the same as defined above, or a pharmaceutically acceptable salt thereof.

25. A benzofuran derivative of the formula [2]:

—\ _R' 0 NR? NH2 wherein the symbols are the same as defined above, or a salt thereof.

26. A pharmaceutical composition, which comprises as od an active ingredient a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

27. A medicament for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient a factor Xa (FXa) inhibitor showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICs; value of 100 nM or below. pos

28. A medicament for freatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an FXa inhibitor showing a distribution volume of 0.1-3.0 L/kg or below and an FXa inhibitory effect with the ICs, value of 100 nM or below.

29. A medicament for oral administration for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient a factor Xa (FXa) inhibitor showing a distribution volume of

0.1-3.0 L/kg and an FXa inhibitory effect with the ICs value of 100 nM or below. AMENDED SHEET

39. A medicament for oral administration for treatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an FXa inhibitor showing a distribution volume of 0.1-3.0 L/kg or below and an FXa inhibitory effect with the ICso value of 100 nM or below.

31. A medicament for treatment of thrombosis substantially free of phospholipidosis, which comprises as A an active ingredient an FXa inhibitor having a partial structure of the formula: O NG 2 and showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICso value of 100 nM or below.

32. A medicament for treatment of thrombosis substantially free of hepatotoxicity, which comprises as an “v active ingredient an FXa inhibitor having a partial structure of the formula: 0) I IN ? and showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICs value of 100 nM or below. AMENDED SHEET

33. A medicament for oral administration for treatment of thrombosis substantially free of phospholipidosis, which comprises as an active ingredient an FXa inhibitor having a partial structure of the formula: O ll IN g NC—( NG » and showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICs value of 100 nM or below.

34. A medicament for oral administration for treatment of thrombosis substantially free of hepatotoxicity, which comprises as an active ingredient an FXa inhibitor having a partial structure of the formula: 0 NG i (had .€ and showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect with the ICsq value of 100 nM or below. AMENDED SHEET