CA2193223A1 - Tricyclic compounds, their production and use - Google Patents

Abstract

Tricyclic compound of formula (I'), wherein ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo; ring Q may optionally be substituted; Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mecapto group, excluding for methyl group as Y; R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof, having excellent PDGF-inhibiting activities, antihypertensive activities, activities of ameliorating renal diseases and activities of lowering lipil level.

Description

21 932~3 ~ ~096/02542 PCT/~95/01382 DESCRIPTION
Tricyclic compounds, Their production and Use Technical Field The present invention relates to a novel tricyclic compound, which is useful as a medicine having an excellent activity of inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal disease5 and lowering the cholesterol level, a process for producing the compound, and a pharmaceutical composition containing the compound.
Background Art With the progressive increase of aged population in recent years, various ischemic diseases in cerebral lS and cardiac vessels have been also increasing. As the therapeutiC agents of these diseases, calcium channel blockers or angiotensin converting enzymes (ACE) inhibitors have been widely used in the rl;ni~l field and have served to decrease cerebrovascular disturbances due to hypertension. However, the mortality from ischemic heart diseases has not yet been decreased. For improving them, it has been considered that lowering blood pressure is not sufficient but improving lipid metabolism is necessary. And, the degree of antihypertensive action is important; namely, it has been considered that, the agents which keep the elasticity of blood vessel~ are more preferable even if their antihypertensive action is milder than the agents which lower blood pressure markedly. For keeping the elasticity of blood vessels, it is necessary to positively improve vascular hypertrophy or fibrosis.
As the diseases causing~vascular hypertrophy, there are mentioned, for example, hypertension, diabetes, glomerulosClerosiS (chronic renal failure) and arteriosclerosiS- Precu~aneous transliminal coronary angioplasty (PTCA) is generally carried out in the case W096iO2s42 PCT/~9S/01382 of coronary artery obstruction caused by platelet aggregation and accumulation. In this case, however, there is often observed that endothelium is injured to causc proliferation of vascular smooth muscle toward the inside of vessels and to lead to restoerosis.
As one of the common phpn~ ~ observed in these diseases i~Pd above, the enhanced expression of platelet-derived growth factor (PDGF) or PDGF receptors (mRNA) has been reported.
More 5pecifically stating; 1) In spontaneou51y hypertensive rats (SHR) and renal hypertensive animals, expression of PDGF or PDGF receptors is enhanced, or the tyrosine kinase activity associated with PDGF
receptors is Pnh~nced (R. Sarzani et al., Hypertension, 18, III 93/1991; P. Pauletto et al., 15th International Meeting of Hypertension, Melbourne, Abstract 1197/1994; M. D. Sauro and B. Thomas, Life Sci., 53, PL371/1993). 2) In the essential hypertensive patients with diabetes, it has been observed that blood concentration of PDGF in blood is higher than normal subjects. (P. Bolli et al., 15th International Meeting of Hypertension, Melbourne, Abstract 767/1994). 3) In human atherosclerotic plaques, expression of PDGPmRNA is enhanced (T. Barrett and P. Benditt, Proc. Natl. Acad. Sci. USA, 85, 2810/1988; J. N. Wilcox et al., J. Clin. Invest., 82, 1134tl988), in the vascular smooth muscle cells of diabetic rats with arteriosclerosis, expression of PDGF
receptors is enhanced (T. Xanzaki, Y. Saitoh, Gendai Iryo (Modern Therapeutics), 23, Z614/1991). 4) In the blood vessels of balloon in~ured animals and humans r after PTCA, the expression of PDGF or PDGF receptor is enhanced (M. W. Majesky et al., J. Cell Biol., 111, 2149/1990; M. Ueda et al., Circulation, 86 (Suppl.), 1/1992). 5) In renal mesangial cells of 5/6 nephrectomized rats, a model of focal W096l02~42 ~ J,.

glomerulosclerosis, expression of PDGF is enhanced (J.
Ploege et al., ~idney Int., 41, 297/1992). 6) In mesangium proliferative nephritis (IgA nephropathy) and a model of nephritis in rats, enhancement of PDGF in ~ 5 mesangial cells is observed (R. J. Johnson et al., J.
Am. Soc. Nephrol., 4, 119/1993; H. E. Abboud et al., ~idney Int., 43, 252/1993). It is demonstrated that PDGF proliferates vascular smooth muscle cells or renal glomerular mesangial cells in vitro experiments (R.
Ross et al., Cell, 46, 155/1986); J. Floege et al., Clin. Exp. Immunol., 86, 334/1991) and in vivo experiments (A. Jawien et al., J. Clin. Invest., 89, 507/1992; Y. Isaka et al., J. Clin. Invest., 92 2597/1993; J. Floege et al., J. Clin. Invest., 92, 2952/1993). It is also reported that the action of cytokine TGF-~ (transforming growth factor ~3) is via the action of PDGF expressed by TGF-~ (E. G. Battegay et al., Cell, 63, 515/1990). Furthermore, recently there have been a number of reports that hypertensive vascular hypertrophy and cardiac hypertrophy due to congestive heart failure are suppressed by administration of ACE inhibitors or angiotensin antagonistic agent. It is considered that, also in the angiotensin-mediated vascular hypertrophy and cardiac hypertrophy, PDGF plays a role (A. J. Naftilan et al., J. Clin. Invest., 83, 1419/1989; G. H. Gibbons et al., J. Clin. Invest., 90, 456/1992). Besides, it has been known that, in respect of the proliferation of vascular smooth muscle cells or renal mesangial cells, LDL-cholesterol and PDGF mutually cooperate to enhance t the proliferation, which has been considered as one of factors causing arteriosclerosis. Therefore, drugs capable of specifically inhibiting the action of PDGF
are expected to be useful therapeutic agents of various circulatory disturbances including arteriosclerosis.
On the other hand, as the tricyclic compounds, the W096/02542 2 1 9 32 ~ 3 P~I/J~ S 1~2 ~

following compounds are disclosed in the following literatu~e references, namely, (1) J. Heterocycl.
Chem., 1972, ~ (1), p.85, (2) J. Heterocycl. Chem., 1976, 13 (5), p.l029-1031, (3) J. Mol. Struct., Perkin Trans.l, 1978, 49 (2), p415-420, (4) J. Pharm. Soc.
Jpn., 1978, 98 (5) p.631-635, (5) J. Crystallogr.
Spectrosc. Res., 1989, 1~ (1), p.l59-166, (6) Bull.
Pol. Acad. Sci., Chem., 1989, 37 (7-8), p.313-316, and (7) J. Chem. Soc., Perkin Trans. 1, 1987, (5), p.ll59-1163. However, no reports concerning the therapeutic uses of these compounds has been found yet.

Struc~ralFormula S~nbDl 15 ~ ~ Ri Rl= HorCH3 I X = OnrXa N ~

20 ~ ~ R~ Rl= HarCH3 I R2= HorC~3 N=~R2 25 ~ ,N ~
= ScH3 R2= ~rCH3 rq-~o ~ H

~ 1 93223 ~096102542 PCT/~9~101382 ~isclosure of Invention Circumstances beiny such as above, the development of novel and safely administrable therapeutic agents has been desired, which inhibit the action of PDGF.
~ 5 The present inventors have made extensive and intensive studies, and succeeded in synthesizing, for the first time, a compound of the formula:
(I')(hereinafter called the compound (I')) y wherein ring A is a nitrogen-containin~ heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo;
ring Q may optionally be substituted;
Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapts group, excluding methyl group as Y; and R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:

and the substituent on ring A, as the representative of the tricyclic condensed heterocyclic ring wherein the three kinds of rings of the pyridine ring Q, the imidazole ring and the heterocyclic ring A containing nitrogen-atom are condensed into, comprising nitrogen-~096/02~2 2 1 9 3 2 2 3 P~l/JI 7~vlJ~ ~

atom at the head of bridge in the condensed ring,espetially a cl , ulll of the formula (I) (hereinafter called the compound (I)):

~R' ( I) A~J

wherein ring A, ring Q and Rl are as defined above;
B is an optionally substituted divalent hydrocarbon;
X is a bond, an oxygen atom or a sulfur atom;
R2 is a hydrogen atom or an optionally substituted hydrocarbon group or, R and B may form a ring together with the adjacent nitrogen atom; and R3 is an electron-withdrawing group, or a salt thereof, whose characteristic feature of the chemical structure lies in the tricyclic condensed heterocyclic ring of the formula:

as mentioned above and the side-chain having an electron-wit~drawing group at the ~rminAl nitrogen, and found that the compound (I') or (I) produced thus above or a salt thereof has, unexpectedly, excellent PDGF-inhibiting action (e.g. actions of inhibiting cell proliferation or vascular constrictionl, antihypertensive action, action of ameliorating nephropathy and, further, action of lowering cholesterol level. ~he present inventors have further developed studies to accomplish the present invention.
More specifically, the present invention relates to (1) a compound (I') or a salt thereof, 096,~02s42 PCT/JP95/01382 (2) a compound as de5cribed in (l) above, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising at least one nitrogen atom, - 5 (3) a compound as described in (l) above, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising at least one electron-withdrawing group, (~) a compound as defined in (l) above, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising an amino group which is substituted with at least one electron-withdrawing group, (5) a compound as defined in (l) above, wherein Y is group of the formula:

X--B--N<~s~ ) wherein B is an optionally substituted divalent hydrocarbon group;
~ is a bond, an oxygen atom or a sulfur atom;
R2 is a hydrogen atom or an optionally substituted hydrocarbon group, or R and B may from a ring together with the ad~acent nitrogen atom; and R3- is an electron-withdrawing group; or R2 and R3~ may form a ring together with the ad~acent nitrogen atom, or a salt thereof, (6) a compound (I) or a salt thereof, ~7) a compound as described in (l) above, wherein the nitrogen atom-containing heterocycleic ring is a S- or 6 '~ ~d ring, ~ (8) a compound as described in (l) above, wherein the ring Q may optionally be substituted with l to 3 substituents selected from the group consisting of (i) halogen atom, (ii) a C14 alkyl group, (iii) a C14 2 1 ~3223 W096/02342 PCT/~951013~2 alkoxy group, (iv) a Cl4 alkylthio group, (v) a hydroxyl group, (vi) a carboxyl group, (vii) a cyano group, (viii) a nitro group, (ix) a amino group, (x) a mono- or dl- Cl4 alkyl amino group, (xi) a formyl group, (xii) a mercapto group, (xiii) a Cl4 alkyl-carbonyl group, (xiv) a Cl4 alkoxy-carbonyl group, (xv) a sulfonyl group, (xvi) a Cl4 alkyl sulfonyl group, (xvii) a ~Arh yl group and (xviii) a mono- or di- Cl4 alkyl-carbamoyl group, (9) a compound as described in (1) above, wherein the ring Q is unsuostituted, (10) a compound as described in (1) above, wherein R
is a hydrogen atom, an optionally substituted alkyl yroup, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkoxy carbonyl group, an alkyl carbamoyl group or an alkanoyl group, (11) a compound as described in (1) above, wherein R
is a hydrogen atom, a Cl6 alkyl group or a phenyl group, (12) a compound as described in (5) above, wherein R2 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group, (13) a compound as described in (3) above, wherein the electron-withdrawing group is (i) -SOzR (R is an optionally substituted hydrocarbon group), (ii) -Co-R5 ~ (R5 is a hydrogen atom or an optionally substituted hydrocarbon group), (iii) -COOR6 (R6 is an optionally substituted hydrocarbon group) (iv) -CoN(R7)R8 (wherein R and Rs respectively are a hydrogen atom or an optionally substituted hydrocarbon group, or, R and R
form a ring together with the adjacent nitrogen atom), (v) a nitro group or (vi) a cyano group, (14) a compound as described in (5) above, wherein B is a CzlO alkylene group, _ . . _ _ . _ _ _ _ _ _ _ _ ~ W096~02~42 2 ~ 9 3 2 2 3 PCT1~95101382 (15) a compound a9 described in (5) above, wherein B is a group of the formula:

- (C~2~
wherein p and q respectively are in~epPn~Pntly an integer of 0 to 5, (16) a compound as described in (5) above, wherein B is a C~8 alkylene group, (17) a compound as described in (6) above, which is one of the formula:

W096/02542 2 1 9 3 2 2 3 P~,~/J.. _._1.11iL ~

X
L (II) ~ 2 ( III ) Io X '--B--N<R~, }~ --- ' 2 ( IV) B--N<~ 5 ~ (v O~N~ ~0 ~B' N, ~ (VI) --N~ 3 ~ }~J---' R

~O961025~2 F~1/J~,~VI382 (VII') B- N<~3 or o ~,~R' . ~
~ .~ (VII") wherein Xl is an oxygen atom or a sulfur atom, and the other symbols are of the same -nings as defined in (6) or a salt thereof, (18) a cu..~uulld as described in (6) above, which is the compound (II) or (VI) or a salt thereof, (19) a compound as described in (17) above, wherein the rinq Q is unsubstituted, (20) a compound as described in (17) above, wherein i5 a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group, (21) a compound as described in (17) above, wherein is a hydrogen atom or a Cl6 alkyl group, (22) a compound as described in (17) above, wherein RZ
is a hylluy~ll atom or Cl6 alkyl group, (23) a compound as described in (17) above, wherein RZ
is a hydrogen atom, (24) a compound as described in (17) above, wherein X
is an oxygen atom, (25) a compound as described in (17) above, wherein X
is a sulfur atom, (26) a compound as described in (17) above, wherein s is a CzlO alkylene group, ..... ...... , . .. _ _ . . _ . . .. , . . _ ........ ........ ... .. .

~096/02542 2 1 9 3 2 2 3 - 12 _ PCT/JP95101382 ~

~27) a compound as described in (17) above, wherein B
is a C38 alkylene group, (28) a compound as descrLbed in (17) above, wherein the electron-withdrawing group represented by R is -SO~R
(R4~ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group), (29) a compound as described in (28) above, wherein R4 is a halogeno-CI6 alkyl group, (30) a compound as described in (1), which is 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4-8b-triaz~rPn~phthylen-3-one or a salt thereof, or 1,2-dihydro-3-methyl-1-[5-(trifluoromethanesulfonamido)pentan-1-yl]-1,4,7b-triazacylcopent[cd]inden-2-one or a salt thereof, (31) a process for producing the compound as described in (1) above, which comprises reacting a compound of the formula: :
~R' wherein the symbols are defined in (1) above, or a salt thereof, with a compound of the formula:

E -Y

~herein E~ is a leaving group and the other symbol is defined in (1) above, or a salt thereof, (32) a compound of the formula:

~ ~ 0g6102542 PCI/JP95/01382 ~N-~ ~R l b or 0 ~ ~R
h XlH
HX

~E
N

O N O

2 5 ~N~_ ~-~2 H

~096/02j42 ~ 2 ~ - 14 - PCT1~95101382 wherein Rl' i5 a halogen atom, an optLonally substituted hydrocarbon group or an acyl group, except for methyl group as R~
Rlb is a halogen atom, an optionally substituted S hydrocarbon group or an acyl group; and the other symbols are of the same meanings as defind above, or a salt thereof, (33) a composition which comprises the compound as described in (1) above, (34) a pharmaceutical composition which comprises the compound as described in (1) above, (35) a phArr~-elltical composition for suppressing platelet-derived growth factor, which comprises the compound as described in (1) above, (36) a therapeutic composition for hypertension, which comprises the compound as described in (1) above, (37) a therapeutic composition for renal diseases, which comprises the compound as described in (1) above, and (38) a composition for lowering lipid level, which comprises the compound as described in (1) above.
The term "nitrogen-containing heterocyclic ring"
used in the present specification means, for example, 5- to 10-membered ring containing, two nitrogen atoms as hetero-atoms. Among them, 5- or 6-membered ring is widely used. These ring may be saturated or unsaturated, and may contain 1 or 2 hetero atoms (e.g.
sulfur atom, oxygen atom, nitrogen atom). More specifically, for example, the following ones ~

H H
are employed. These "nitrogen-containing heterocyclic rings" may optionally be substituted with one or two of oxo or thioxo groups.
The term "divalent hydrocarbon group'' used in the _ _ _ _ _ _ .. , . ... . .. . .. _ 2 1 9322 ~
096102~42 PCTIJP9~/01382 present specification means, for example, divalent chain-like hydrocarbon groups including Cll5 alkylene groups (e.g. methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene), C2l6 alkenylene groups (e.g. vinylene, propenylene, l-butenylene, 2-butenylene, 1-pentenylene, 2-pentenylene and 3-pentenylene), C2l6 alkynylene groups (e.g. ethynylene, propynylene, l-butynylene, 2-butynylene, 1-pentynylene, 2-pentynylene and 3-pentynylene), phenylene group or a combination of them.
As substituents which the said "divalenthydrocarbon group" optionally have, mention is made of, for example, optionally substituted alkyl groups, optionally substituted aralkyl groups and optionally substituted aryl groups, and optionally substituted alkyl groups are preferable. ~he said '~phenylene group~ may be substituted As substituents which the said "phenylene group~
optionally have, mention is made of one to four selected from, for example, halogen atoms (e.g.
fluorine, chlorine, bromine and iodine), Cl4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), Cl4 alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy), C~_4 alkylthio groups (e.g.
methylthio, ethylthio, propylthio and isopropylthio), hydroxyl group, carboxyl group, cyano group, nitro group, amino group, mono- or di- Cl4 amino groups (e.g.
methylamino, ethylamino, dimethylamino and diethylamino), formyl group, mercapto group, Cl4 alkyl-carbonyl groups (e.g. acetyl, propionyl and butyryl),Cl4 alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl), sulfone group, Cl4 alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl), carbamoyl group and mono- or di- Cl4 alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-W096/02542 2 1 9 3 2 2 3 16 - PCT/~95101382 ~

diemthylcarbamoyl and N,N-diethylcarbamoyl).
The term "halogen atom" used in the present specification means, for example, fluorine, chlorine, bromine and iodine.
The "hydrocarbon group" of the term "optionally substituted hydrocarbon group" used in the present specification means, for example, alkyl group, cycloalkyl group, alkenyl group, aralkyl group and aryl group.
Examples of the substituents, which the said ~hydrocarbon group" optionally have, use is made of, the substituents which the said "alkyl group", ~cycloalkyl group", alkenyl group", "aralkyl group" and ''aryl group" optionally have.
As said "alkyl group", use is made of, for example, "straight-chain or branched Cl15 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, tetradecyl and pentadecyl.
As said ~cycloalkyl group~, use is made of, for example, "C3 ~ cycloalkyl group" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
~xamples of the substituents, which the said ~alkyl group'' and '~cycloalkyl group~ optionally have, include (i) nitro group, (ii) hydroxyl group, (iii) cyano group, (iv) carbamoyl group, (v) mono- or di- Cl4 alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethyl~rh~ yl)~ (vi) carboxyl group, (vii) C14 alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and i~o~-u~u~yuarbonyl), (viii) sulfone group, (ix) halogen atoms (e.g. fluorine, chlorine, bromine and iodine), (x) Cl4 alkoxyl groups (e.g. methoxy, ethoxy, propoxy .. . .. .. . . .... _ . _ .. ... _ . .. .. , , . _ _ _ _ '096/02s~2 r~llJl s.
_ - 17 -and isopropoxy), (xi) phenoxy group, (xii) halogenophenoxy groups (e.g. o-, m- or p-chlorophenoxy, and o-, m- or p-bromophenoxy), (xiii) Cl4 alkylthio groups (e.g. methylthio, ethylthio, n-propylthio, S isopropylthio and n-butylthio), (xiv) mercapto group, (xv) phenylthio group, (xvi) pyridylthio group, (xvii) C14 alkylsulfinyl groups (e.g. methylsulfinyl and ethylsulfinyl), (xviii) Cl_4 alkylsulfonyl groups (e.g.
methylsulfonyl and ethylsulfonyl), (xix) amino group, (xx) Cl3 acylamino groups (e.g. acetylamino and propionylamino), (xxi) mono- or di- C~ 4 alkylamino groups (e.g. methylamino, ethylamino, dimethylamino and diethylamino), (xxii) 4 to 6 membered cyclic amino groups (e.g. l-azetidinyl, l-pyrrolidinyl, piperidino, morpholino and l-piperazinyl), (xxiii) C~_3 acyl groups (e.g. formyl and acetyl), (xxiv) benzoyl group and (xxv) 5 to 10 membered heterocyclic groups (e.g. 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4-or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2, 4- or 5-oxazolyl, 1,2,3- or 1,2,4-triazolyl, lH- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl and isoquinolylindolyl).
~he said "alkyl group' optionally have 1 to 5 of these substituents at any substituable positions.
Preferable examples of the said "alkyl group"
include C~6 straight-chain or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. As the substituents which the said "C~6 alkyl groups"
optionally have, use is made of 1 to 3 of, for example, halogen atoms, C~ 4 alkoxyl group, hydroxyl group, C~ 4 alkoxy-carbonyl groups, carboxyl group, carbamoyyl ~ group, mono- or di- Cl4 alkylcarbamoyl groups and pyridylthio group.
Examples of the said "alkenyl group" include "C2~8 alkenyl groups" such as vinyl, allyl, is~L~ lyll 3-21 9322~
W096/02~2 PCTI~9~/01382 butenyl, 3-octenyl and 9-octadecenyl. As the substituents which the said "alkenyl groups" optionally have, use is made of, for example, the same ones as the above-mentioned "alkyl group" optionally have.
Preferable examples of the said "alkenyl group" S
include C26 alkenyl groups such as vinyl, allyl, 2-butenyl and 3-butenyl. As the substituents which the said "C~6 alkenyl groups" optionally have, use i8 made of, for example, the same ones as the above-mentioned ''Cl6 alkyl group" optionally have.
As the said ~aralkyl group", use is made of, for example, C7l6 aralkyl groups, which are specifically exemplified by phenyl- Cl6 alkyl groups such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl, and naphthyl- Cl6 alkyl group such as (l-naphthyl)methyl, 2-(1-naphthyl)ethyl and 2-(2-naphthyl)ethyl.
Examples of the substituents, which the said ~aralkyl group" optionally have, include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), Cl4 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl), C76 alkenyl groups (e.g. vinyl, allyl, 2-butenyl and 3-butenyl), Cl3 acyl groups (e.g. formyl and acetyl), Cl4 alkoxyl groups (e.g. methoxy, ethoxy, propoxy and iso~uLu~Uu~y)~ nitro group, cyano group, hydroxyl group, Cl4 alkoxy-carbonyl groups (e.g.
methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl), carbamoyl group, mono- or di- Cl4 alkyl-carbamoyl groups (e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethyl~rh Iyl and N,N-diethylcarbamoyl) and mono- or di- Cl4 alkenyl-r~rh yl groups (e.g. N-vinylcarbamoyl). The said r ~aralkyl group" may optionally have 1 to 4 of these substituents at any substituable position.
As the said "aryl group'', use is made of, for example, aromatic monocyclic, dicyclic or tricyclic C6 2 1 ~3223 ~I W096/02~;42 r~,~,JA ~'Il.~o~

4 aryl groups exemplified by phenyl, l-naphthyl, 2-naphthyl, phenanthryl and anthryl.
As the substituents which the said aryl group' optionally have, use is made of, besides the substituents which the said 'aralkyl group" may optionally have, oxo group. The said "aryl group" may optionally have 1 to 4, preferably 1 or 2, of these substituents at any substitutable positions. Examples of the aryl group having oxo group include benzoquinonyl, naphthoquinolyl and anthraquinonyl.
The term "electron-withdrawing group" used in the present specification is exemplified by (i) -5O2R4, (ii) -CO-R , (iii) -COOR ,(iv) -CON(R)R , (v) a nitro yroup and (vi) a cyano group, preferably -So2R4, -Co-R5-and -COOR6, especially -SO~R is commonly used. R4 stands for an optionally substituted hydrocarbon group;
R stands for a hydl~y~ll atom or an optionally substituted hydrocarbon group; R stands for an optionally substituted hydrocarbon group; R7 and R8 independently stand for a hydrogen atom or an optionally substituted hydrocarbon group, or R7 and R8 form, combined with the ad~acent nitrogen atom, an nitrogen atom-containing heterocyclic ring.
The term ~acyl group used in the present specification is exemplified by the acyl group derived from carboxylic acid, which is exemplified by alkoxycarbonyl group, alkylcarbonyl group and alkanoyl group.
As the said 'alkoxycarbonyl group~, use is made of Cl6 alkoxycarbonyl groups including, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, is~r~o~y.arbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and tert-pentyloxycarbonyl.
As the said 'alkylcarbamoyl group~, use is made of .. , , . . .. . . ~

71 ~,3~23 W096/0~42 ~ J. 1~2 mono-CI6-N-alkylc~rh yl groups, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylc~rh- yl and N-butylcarbamoyl, and di-C16-N,N-dialkylcarbamoyl groups, for example, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl and N-ethyl-methylr~rh Iyl, and 4- to 6-membered cyclic carbamoyl groups formed by combination of the dialkyl portions with each other (e.g. l-azetidinylcarbonyl, morpholinocarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinocarbonyl and 1-piperazinylcarbonyl).
In the above-mentioned formula, the ring A stands for a nitrogen-containing heterocyclic ring having two nitrogen atoms containing the nltrogen atom at the head of the bridge in the condensed ring, which be further substituted with oxo or thioxo.
Preferable examples of the ring A include 5- or 6-membered nirogen-containing heterocyclic ring optionally substituted with one or two oxo groups.
Especially, the following ones are commonly employed.

J ~ 0~0 ~la a~
In ~he above-mentioned formula, the ring Q is optionally substituted.
Examples of the substituents, which the ring Q
optionally have, include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), Cl~ alkyl groups (e.g. r methyl, ethyl, propyl, isopropyl and butyl), C~ 4 alkoxy groups (e.g. methoxy, ethoxy, propoxy and isopropoxy), Cl~ alkylthio groups (e.g. methylthio, ethylthio, propylthio and isopropylthio), hydroxyl group, carboxyl group, cyano group, nitro group, amino group, mono- or _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , 2~93223 ~0 96/02542 P~ 11J1 ,~ t lJj5 di- Cl4 alkyl amino groups (e.g. methylamino, ethylamino, dimethylamino and diethylamino), formyl group, mercapto group, Cl4 alkyl-carbonyl groups (e.g.
acetyl, propionyl and butyryl), Cl4 alkoxy-carbonyl groups (e.g. methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl~, sulfo group, C14 alkylsulfonyl groups (e.g. methylsulfonyl, ethylsulfonyl and propylsulfonyl), carbamoyl group and mono- or di- C14 alkyl-carbamoyl groups (e.g. N-methylci~rhi yl, N-ethylri~rhi 1yl, N,N-dimethylri~rhi yl and N,N-diethylcarbamoyl). One to three of these substituents may be substituted on any substitutable position on the ring Q. The ring Q is preferably unsubstituted.
In the above-mentioned formulae, Rl stands for a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or acyl group.
Preferable examples of R include a hydrogen atom, optionally substituted alkyl groups, optionally substituted alkenyl groups, optionally substituted aralkyl groups, optionally substituted aryl groups, alkoxy carbonyl groups, alkylcarbamoyl groups and alkanoyl groups; especially a hydrogen atom, C1_6 alkyl groups (e.g. methyl, ethyl, propyl, isopropyl and butyl) or phenyl group are commonly used, and, a hydrogen atom is employed most commonly.
In the above-mentioned formula, Y stands for an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapto group, excluding methyl group as Y.
Examples of the optionally substituted hydrocarbon group shown by Y include those described in respect of the above-mentioned ~optionally substituted hydrocarbon group", excluding unsubstituted methyl group.
Examples of the substituents, which the hydroxyl group or the mercapto group shown by Y optionally have, include optionally substituted hydrocarbon group, the _ . ~ _ . .. . .. ....

?~ ~322~
096/02s42 I_ groups cQmprising at least one nitrogen atom and/or the groups comprising at least one electron-withdrawing groups.
Preferable examples of the substituents, which the hydroxyl group or the mercapto group shown by Y
optionally have, include optionally substituted hydrocarbon group. As the said "optionally substituted hydrocarbon group", use is made of the same ones as the above-mentioned "optionally substituted hydrocarbon group".
Preferable examples of the substituents, which the hydrocarbon group, the hydroxyl group and the mercapto group shown by Y optionally have, include the groups comprising at least one nitrogen atom and/or the groups lS comprising at least one electron-withdrawing group, especially the groups comprising an amino group substituted with at least one electron-withdrawing group.
As ~'the group comprising at least one nitrogen atom" mentioned above, use is made of, for example, alkylAmin~A1kyl groups aralkylAminnAlkyl groups, aryl ~m i n~A 1 kyl groups, alkylaminoaralkyl groups, aralkylAmin~Aralkyl groups, arylaminoaralkyl groups, alkylaminoaryl groups, aralkylaminoaryl groups, arylaminoaryl groups, Am; n~A lkyl groups, aminoaralkyl group and aminoaryl groups.
As ~the group comprising at least one electron-withdrawing group", use is made of, for example, the hydrocarbon groups comprising at least one "electron-withdrawing group as mentioned above~.
As "the group comprising an amino group which issubstituted with at least one electron-withdrawing group~, use is made of, for example, the hydrocarbon groups comprising an amino group substituted with at least one ~electron-withdrawing group as mentioned above".

~0961025~2 2 1 9 3 2 2 3 The most preferable examples of Y include the groups represented by the formula ~ , ~
: 'n2 X--B ~

wherein the symbols are of the same meaning as defined above.
In the above-mentioned formula, B stands for an optionally substituted divalent hydrocarbon group.
Specific examples of the group include those repre5ented by (i) R ~ 3 --(C)~ --(~),--(C)~--R10 ~12 ~14 wherein m, n and o independently are integers of O to 5, R , R , R , R , R and R ;n~Pppn~pntly stand for a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, and, R9 and R10; R11 and R12;, R13 and R1; R or R and R ; R or R and R ;, or, R13 or R14 and R2 may respectively be combined to form rings, and R or R11 may be combined with R13 or R14 respectively to form rings, or (ii) - ~C~2)p~

wherein phenylene group may be substituted, and, p and q are independently an integer of 0 to 5. Examples of the optionally substituted alkyl, aralkyl or aryl group shown by R9 to R14 include those described in respect of the above-mentioned "optionally substituted hydrocarbon yroups". The rings formed by combination of R9 and R10, _ _ . ... _ _ _ _ _ _ _ _ _ _ _ _ _ _ . . . _ . . _ 2 1 9~23 W09610~2 PCT/~95/01382 R11 and R12, and R13 and R1 are exemplified by C38 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The rings formed by combination of R or R and R ; R or R and R ; or R
or R14 and R2 are exemplified by azetidinyl, pyrrolidinyl or piperidino. The rings formed by combination of R or R with R or R , respectively are exemplified by C38 cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Preferable examples of R to R14 include a hYdLUY~11 atom or C14 alkyl groups (e.g. methyl, ethyl, propyl and isopropyl), and, especially, a hydrogen atom or methyl group is commonly used.
Preferable examples of B include C210 alkylene groups (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene, heptamethylene and octamethylene), and, among them, especLally C38 alkylene groups (e.y. ethylene, propylene, butylene, pentamethylene, hexamethylene and heptamethylene) are commonly employed.
In the above-mentioned formulae, X stands for a bond, an oxygen atom or a sulfur atom. Preferable example of X is a bond.
In the above-mentioned formulae, R2 stands for a hydrogen atom or an optionally substituted hydrocarbon group, and, R and B may optionally form a ring together with the adjacent nitrogen atom.
Preferable examples of R include a hydrogen atom, optionally substituted alkyl groups or optionally substituted alkenyl groups, especially a hydrogen atom is commonly used.
In the above-mentioned formulae, R3 stands for an electron-withdrawing group, or R2 and R3 may form a ring together with the adjacent nitrogen atom.
Examples of the electron-withdrawing group include 2 1 q3223 W096/02~2 F~I/Jr--Ia~2 _ - 25 -~i) -So2R4 (R4 stands for an optionally substituted hydrocarbon group), (ii) -CO-R (R5 stands for a LUy~ll atom or an optionally substituted hydrocarbon group), (iii) -COOR (R stands for an optionally substituted hydrocarbon group), (iv) -CoN(R7)R8 (R7 and R8 each stand for a hydrogen atom or an optionally substituted hydrocarbon group, or R7 and R8 may form a ring together with the ad~acent.nitrogen atom), (v) a nitro group and (vi) a cyano group.
Examples of the electron-withdrawing group include -So2R4~, -Co-R5' and -COOR (R4~, R5' and R9- each stand for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted lS aryl group), especially -SO2R~ (R stands for anoptionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group) is commonly used among others.
Preferable examples of R4 include an optionally substituted alkyl group, especially a halogeno- Cl6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl).
Preferable examples of R include an optionally substituted alkyl group, especially a halogeno- Cl6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2-~ trifluoroethyl and 3,3,3-trifluoropropyl)~
Preferable examples of R include an optionally substituted alkyl group, especially a halogeno- C!6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl).
Preferable examples of R7 and R9 include a hydrogen atom or an optionally substituted alkyl group, especially a hydrogen atom or a halogeno- Cl6 alkyl 3 5 group (e.g. chloromethyl, trifluoromethyl, 2,2,2-2 1 ~2~
W096/02542 - 26 - pCTI~95/01382 trifluoroethyl and 3,3,3-trifluuluuLu~yl).
Examples of the ring, which R2 and R form together with the adjacent nitrogen atom, include pyrrolidine-2-one, piperidine-2-one, indoline-2-one, isoindoline-l-one, isoindoline-1,3-dione, oxazolidine-2-one, oxazolidine-2,4-dione, thiazolidine-2-one, thiazolidine-2,4-dione and 1,2-benzisothiazoLe-3(2H)-one. These rings optionally have substituents such as electron-withdrawing groups. As the said "electron-withdrawing group", use is made of, for example, theabove-mentioned "electron-withdrawing groups".
Preferable examples of the compounds (I') are shown as follows:
Compounds of the following formula or salts thereof.

2 ~ 93223 Wo 96102542 PCTIJP95/01382 ~X
(II) -'~ 2 N~ 2 1 ( I I I ) ~ R 2 1: ~R 2 ( IV) 3--N<R s 2 0 O~N~O ( v ~BI

N ~ (VI) ~ ( VI I ) B--N~, W096102542 2193223 - 28 - PCrlJP95101382 ~

~R I

~ ~ (VII') ~J ~ 7 B--N<~3 or 1 o l~R
~ (VII") wherein Xl stands for an oxygen atom or a sulfur atom, and the other symbols are of the same meaning as defined above, especially the compound (II) or (VI).
In these compounds (II) to (VII~
(1) a compound, wherein ring Q is unsubstituted, is preferable;
(2) a compound, wherein Rl stands for a hydrogen a~om, an optionally substituted alkyl group or an optionally substituted alkenyl group, is preferable, and, especially those, wherein Rl stands for a 11YdLUY~II atom or a Cl6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is commonly used;
~3) a compound, wherein R2 stands for a hydrogen atom or a Cl6 alkyl group (e.g. methyl, ethyl, propyl, isopropyl and butyl), is preferable, and, especially those, wherein R2 stands for a hydluyell atom, is commonly used;
(4) a compound, wherein Xl stands for an oxygen atom, is preferable;
(5) a compound, wherein X stands for a sulfur atom, is preferable;

(6) a compound, wherein B stands for a C2l~ alkylene _ ~ 096l02~42 F~l/JA
_ - 29 -group (e.g. ethylene, propylene, butylene, pentamethylene, hexamethylene and octamethylene), is preferable, and, especially those, wherein B stands for a C38 alkylene group (e.g. propylene, butylene, pentamethylene, hexamethylene and heptamethylene), are preferable;

(7) a compound, wherein the electron-withdrawing group shown by R3 is -sozR43 (R4- stands for an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group), is preferable; and (8) a compound, wherein R stands for a halogeno- Cl6 alkyl group (e.g. chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 3,3,3-trifluoropropyl), is preferable.
As preferable salts of the compound (I') (hereinafter included the compound (I)), mention is especially made of pharmaceutically acceptable salts and physiologically acceptable acid salts. These salts are exemplified by those with inorganic acids (e.g.
hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid) or with organic acids (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methansulfonic acid and benzenesulfonic acid). Further, when the compound (I') of the present invention has an acid group such as carboxylic group, it may optionally form a salt with, for example, an inorganic base (e.g. an alkali metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, or ammonia) or an organic base (e.g. a tri- Cl3 alkylamine such as triethylamine).
As the starting compounds for producing the target compound (I') of the present invention, similar salts to those mentioned above are employed, and they are not w096l02542 21 93~2~ 30 _ PCT/~95101382 specifically limited unless they exert undesirable influence upon the reaction.
The compound (I') or a salt thereof have, in some instances, asymmetric carbons in the molecule. When two kinds oifsterioisomers of R-configuration and S-configurated isomers, are present, each of them and a mixture of them are all included in the scope of the present invention.
Preferable practical examples of the compound (I') and salts thereof are set forth as follows:
1,2-dihydro-3-methyl-1-[4-(trifluoromethanesulfonamido) butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one 1,2-dihydro-3-methyl-1-[5-ttrifluoromethanesulfonamido) pentan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(trifluoromethanesn7~nnAmido)pentar.-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one 1,2-dihydro-3-methyl-1-[4-[(2,2,2-trifluoro)ethanesulfonamido]butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one 3-methyl-2-[4-(trifluoromethanesulfonamido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]inden 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene 4,5-dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazAArPnAphthylene 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one 4,5-dihydro-5-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triA7AA~GnA~hthylen-5-one and their salts (preferable example of the salts is hydrochloride).

096/02~2 Especially preferable practical examples of the compound (I') and salts thereof are set forth as follows;
1,2-dihydro-3-methyl-1-[5-~ 5 (trifluoromethanesulfonamido)pentan-1-yl3-1-4,7b-triazacyclopent[cd3inden-2-one, 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylen-3-one and their salts (preferable example of the salts is hydrochloride).
The compound (I') or a salt thereof of the present invention can be synthesized by the following method.

~ El-Y ~ ~r) ~X II) wherein El stands for a leaving group such as halogen (e.g. chlorine, bromine, iodine), methanesulfonyloxy and p-toluenesulfonyloxy;
the other symbols are of the same meaning as defind above.

W096/02~42 2193223 32 - r ~l/J~- IJ~2 The compound (XII) include novel compounds represented by the formula ~ Rla X~HN
or ~N ~ ~R

EIX

H

N ~ , r H

WO 96/02542 P~IIJ~ 7r ~C~ 2 wherein Rl' stands for a halogen atom, an optionally substituted hydrocarbon group or an acyl group, except for methyl group as R ;
R stands for a halogen atom, an optionally substituted hydrocarbon group or an acyl group; and the other symbols are of the same meaning as defined above, or a salt thereof.
Practically the compound (I') or a salt thereof of the present invention can be synthesized by, for example, a process for producing the compound (I') or a salt thereof which comprises reacting a compound of the formula ~B ' (XII) wherein the symbols of the same meaning as defined above, or a salt thereof, with a compound of the formula El-Y
wherein the symbols are of the same meaning as defined above, or a salt thereof. Hereinafter, in the formula containing the symbols "B" and "R2'', the symbols "B"
and "R " include the definition "R and 3 may form a ring together with the adjacent nitrogen atom~, without ~ a broken line between "B" and "R2" being indicated.
More, specifically, the compound (I) or a salt thereof of the present invention can be synthesized by, for example, the following methods.

wos~/o2s42 21 ~ P~l/J. Ia~2 1~ ~,~81 ~ X-B-N~-8Z ~ (I) ~ Bl-~-B-N<~3 ~ 3 ~XII) wherein Gl stands for a halogen (e.g. chloro, bromo or iodo) or -oR3; El stands for a leaving group such as halogen (e.g. chiorine, bromine or Lodine), methanesulfonyloxy and p-toluenesulfonyloxy; and the other symbols are of the same meaning as defined a~ove.
And, by subjecting such compounds as shown below to ring-closure reaction (e.g. ~annich reaction or dehydrative ring-closure), the compound (I) or a salt thereof can also be synthesized.

1) ~ 1 2 ~CB~ CD2~'~
N-J +
B-N<~, B~-X-B-N~

wherein ~ denotes D or 1, J stands for a hydrogen atom or a protecting group (e.g. benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl and benzyl), Rl5 stands for an optionally substituted alkyl group, and the other symbols are of the same meaning asdefined above.

~096/02!;~2 1~,IIJI 5. 1.~o2 ~ 35 -In more detail, for example, the synthesis can be carried out by the following methods.
(1) A method of producing the compound (I) or a salt thereof by allowing a compound represented by the S general formula ~_3_N~_~2 wherein the symbols are of the same meaning as defined above or a salt thereof to react with a compound represented by the general formula Gl-502-R4 (G~ stands for a halogen such as chlorine, bromine and iodine, or R4502-o-, and R4 is of the same meaning as defined above) or a salt thereof.
(2) A method of producing the compound (I) or a salt thereof by allowing a compound represented by the general formula H

25 wherein the symbols are of the same meaning as defined above or a salt thereof to react with a compound represented by the general formula R
~ -X -B-N( R

wherein ~I stands for a leaving group such as a halogen (e.g. chlorine, bromine and iodine), methanesulfonyloxy 35 and p-toluenesulfonyloxy, and the other symbols are of the same meaning as defined above, or a salt thereof.
(3) A method of producing the compound (II), (VI) or WO96/02~42 2 1 93223 P~l/J.~, J~

salts of them, which comprises subjecting a compound represented by the general formula (C~
I~-J
~2 B~

wherein j denotes 0 or 1, J stands for a hydrogen atom or a protecting group (e.g. benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl and benzyl), and the other symbols are of the same meaning as defined above or a salt thereof to trichloroacetylation, then, upon necessity, deprotection of the protecting group J, and, further subjecting the resultant compound to ring-closure reaction.
(~) A method of producing the compound (IV) or a salt thereof by subjecting a compound represented by the general formula ~ ~ ~ gl ~2C

~R~

wherein the symbols are of the same meaning as defined above or a salt thereof to Mannich reaction to cause ring closure.
(5) A method of producing the compound (V) or a salt thereof by allowing a compound represented by the 21 ~3223 _ wo96/02s42 r~ C I~&~

general formula ~ ~
CO~Cl~
~ i5 wherein Rl5 stands for a C14 alkyl group, and the other symbols are of the same meaning as defined above or a salt thereof to react with a compound represented by the general formula ~R2 H2N-B-N\

wherein the symbols are of the same meaning as defined above or a salt thereof.
These methods of producing the target compounds and those of producing the starting compounds are described as follows in further detail.
(A) method: In the case where R3 of the compound (I) is -502R, ~ Rl Gl-S~
X-B-~ Z
~rIII~
wherein Gl stands for a halogen (e.g. chlorine) or R4So2-O-, and the other symbols are of the same meaning as defined above.
(3) method: In the case where R of the c, ~uu-ld (I) is -CO-R , ~'096/02542 2 1 9 3 2 2 3 PCT/~95101382 ~2--Co--~s ~I) X--B~ R2 ~IIT~ ' wherein G7 stands for a halogen (e.g. chlorine) or R5Co-o-, and the other symbols are of the same meaning as defined above.
(C) method: In the case where R3 of the compound (I) is -COOR , ~ G~-coo-g5 X--B--N~--B~

wherein G3 stands for a halogen (e.g. chlorine) or R6CO~-O-, and the other symbols are of the same meaning as defined above.
(D~ method: In the case where R of the compound (I) is -CoN(R7)R8, ~ ~ G~--cû--N(~7)e' (I) X-B-N~-R~

wherein G stands for a phenoxy or haLogen (e.g.
chlorine), and the other symbols are of the same meaning as defined above.
(E) method:

2 ~ q32~3 096/025~2 PCTI~95/01382 ~2--E~
--B--N~
(~X) wherein El stands for a halogen (e.g. chlorine, bromine and iodine) or a leaving group such as methanesulfonyloxy and p-toluenesulfonyloxy, and the other symbols are of the same meaning as defined above.
(F) method:

--N<~3 ~XI~
--B--E
~X) wherein the symbols are of the same meaning as defined above.
(G) method:

~ E~--X--E--N~

(XII~
wherein the symbols are of the same meaning as defined above.
(H) method:

w096102542 2 1 9 3 2 2 3 PCT/~9~101382 ~

1) trichloro~ce~yl~io~
tC~ 2) de~otection ~ ) or li-J 3~ rin~-oloslLre B-~3 tXI~) wherein ~ denotes 0 or l, J stands for a hydrogen atom or a protective group of secondary amino group (e.g.
benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl and benzyl), and the other symbols are of the same meaning as defined above.
(I) method:

2 ~N--1~ rin~-closure 1 ~2 2 o B--NC~
~XV~
wherein the symbols are of the same meaning as defined above.
25 (J) method:

R ~N--B--N'Bs C~2~Z~ 5 ~XYII) ~y) ~XYI) t wherein R15 stands for an alkyl group, and the other symbols are of the same meaning as defined above.
35 (~) method: In the case where X1 of the compound (II) is a sulfur atom, ~ ~'096/02~42 2 ~ 9 3 2 2 ~ PCT/JPg~/01382 '. N~ ~ (II) --R~
(XIX) wherein X1 stands for a sulfur atom, and the other ~ symbols are of the same meaning as defined above.
(L) method: In the case where R of the compound (I) is a hydrogen atom, ~X--~--N~

wherein J1 stands for a protecting group of an amino group, and the other symbols are of the same meaning as defined above.
In the above-mentioned methods A to L, a compound, which can form a salt, may be used in the form of salt.
Examples of such a salt include those as described in the above-mentioned compound (I'). In the following description of the respective methods, of a salt of each compound may also be included.
In the reaction between the compound (XII) and the compound El-Y in the method of producing the compound (I'), one equivalent to a large excess amount (1 to 10 equivalents) of the compound E1-Y is employed relative to the compound (XII). In this case, a basic compound such as sodium hydroxide, potassium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine and 1,8-diazabicyclo[5,4,0]-7-undecene may be used in an amount of 1 to 10 ~096/02s42 2 1 9 3 ~ 2 ~ PCT1~951013~2 equivalents. The reaction temperature ranges from -20 to 200~C. Examples of the solvents to be employed include water, lower alcohols (e.g. methanol, ethanol and propanol), ketones (e.g. acetone and methyl ethyl ketone), ethers (e.g. tetrahydrofuran) and aprotic ~, polar solvents (e.g. N,N-dimethylformamide and dimethyls--lfo~ ). For the said reaction, as a reaction promotor, sodium iodide may be added in an amount ranging from l equivalent to a large excess (l to lO equivalents). The reaction time ranges usually from lO minutes to 24 hours, preferably from 0.5 to 6 hours.
In the reaction between the compound (VIII) and the compound G1-sC2-R4 in the method A, one equivalent to a large excess amount (l to lO equivalents) of the compound G1-502-R is employed relative to the compound (VIII). In this case, an inorganic base such as potassium carbonate and sodium hydrogencarbonate, or an organic base such as triethylamine, pyridine, dimethylaniline and l,4-diazabicyclo[2.2.2]octane ~DABCO) may be used in an amount of l to lO
equivalents. The reaction temperature ranges from -30 to 100~C. Examples of the solvents to be employed include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane), ethers (e.g.
diethylether and tetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate), and aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). The reaction time ranges usually from lO minutes to 24 hours, preferably from 0.5 to 6 hours.
The reaction between the compound (VIII) and the compound of G2-Co-R5 in the method B is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound Gl-SO~-R in the method A.
The reaction between the compound (VIII) and the 21 ~2~
WO 96102~2 P~ J

compound G3-CCo-R in the method C is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound Gl-5O2-R4 in the method A.
The reaction between the compound (VIII) and the compound of G -CO-N(R )R in the method D is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound &I-5O2-R4 in the method A.
In the reaction between the compound (IX) and the compound R2-EI in the method E, the compound RJ-EI is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to the compound (IX). And, a basic compound such as sodium hydroxide, potassium hydroxide, sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine and 1,8-diazabicyclo[ 5 . 4 . 0 ] - 7 -nn~PrPnP may optionally be used in an amount of 1 to 10 equivalents. The reaction temperature ranges from -20 to 200~C. Examples of the solvent to be employed include water, lower alcohols (e.g. methanol, ethanol and propanol), ketones (e.g. acetone and methyl ethyl ketone), ethers (e.g. tetrahydrofuran) and aprotic polar solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide). For the said reaction, as a reaction promoter, sodium iodide may be added in an amount ranging from 1 equivalent to a large excess (1 to 10 equivalents). The reaction time ranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6 hours.
3 0 The reaction between the compound (X) and the compound (XI) in the method F is conducted, for example, under conditions similar to those of the reaction between the compound (IX) and the compound R2-El in the method E.
The reaction between the compound (XII) and the compound (XIII) in the method G is conducted, for W096~02~2 ~ J. lJ&~

example, under conditions similar to those of the reaction between the compound (IX) and the compound R2-El in the method E.
For the trichloroacetylation of the compound (XIV) in the method H, trichloroacetyl chloride or anhydrous trichloroacetate is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to the compound (XIV). In this case, 1 to 10 equivalents of an inorganic base (e.g. potassium carbonate and sodium hydrogencarbonate) or an organic base (e.g. 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline and 1,4-diazabicyclo[2.2.2]octane) may optionally be employed.
The reaction temperature ranges from 0 to 100~C.
Examples of the solvent then employed include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane), ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate) and aprotic polar solvents (e.g.
N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). The reaction time ranges usually from 10 minutes to 100 hours, preferably from 3 to 24 hours.
The above-mentioned deprotection reactions of the protective group of secondary amino group are all ~L
se known reactions, which can be conducted in according to known conditions. For example, the benzyloxycarbonyl group or the benzyl group as the amino-protecting group can be removed by catalytic reduction (reaction temperatures ranging from room temperature to 100~C) in a solvent (e.g. alcohol, acetic acid, water, tetrahydrofuran and an appropriate t mixture of them) in the presence of a catalyst (e.g.
palladium carbon or platinum oxide). In the case of trityl group or tert-butoxycarbonyl group, it can be removed by the reaction in a solvent (e.g. water, alcohol, tetrahydrofuran and dioxane) in the presence WO 96/02542 1 ~1/J. :/~.J~,:

of an acid (e.g. a mineral acid 5uch as hydrochloric acid, phosphoric acid and 5ulfuric acid or an organic acid such as toluene5ulfonic acid, methansulfonic acid and acetic acid), at temperatures ranging from 0 to 150~C. And, in the case of tert-butoxycarbonyl group, it can be removed by processing with, for example, iodotrimethylsilane in a solvent such as chloroform.
Further, trifluoroacetyl group can be easily removed by treating with alkali (e.g. an aqueous solution of sodium hydroxide or 50dium hydrogencarbonate). The ring-closure reaction can be conducted concurrently with the reaction of removing the protecting group.
Or, after removing the protecting group, the ring-closure reaction can be conducted by using l to 10 equivalents of an inorganic base (e.g. potassium carbonate and sodium hydrogencarbonate) or an organic base (e.g. 4 -N,N-dimethylaminopyridine, triethylamine, pyridine, dimethylaniline and 1,4-diazabicyclo[2.2.2]octane. The reaction temperatures ranges from 0 to 100~C. Examples of the solvent then employed include halogenated hydrocarbons (e.g.
methylene chloride, chloroform and dichloroethane), ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g. methyl acetate and ethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). The reaction time ranges usually from 10 minutes to 24 hours, preferably from 10 minutes to 6 hours.
For the ring-clo5ure reaction by Mannich reaction using the compound (XV) and formalin in the method I, formalin is used in an amount of large excess (2 to 20 equivalents) relative to the compound (XV). The reaction temperature ranges from -20 to 150~C.
Examples of the solvent then used include water, lower alcohols (e.g. methanol, ethanol, propanol and isopropanol) and lower fatty acids (e.g. acetic acid ~7~7 ~'096~0~2 Ll 7J~ J~ o~ _ and propionic acid). The reaction time ranges usually from 10 minutes to 24 hours, preferably from 10 minutes to 3 hours.
The reaction between the compound (XVI) and the compound (XVII) in the method J is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and the compound Gl-SO~-R in the method A.
The conversion of the compound (XIX) to the thiolactam in the method K can be conducted with, for example, one equivalent to a large excess (1 to 10 equivalents) of phosphorus pentachloride relative to the compound (XIX). The reaction temperature ranges from 0 to 200~C. Examples of the solvent then employed lnclude aromatic hydrocarbons (e.g. benzene, toluene and xylene) and pyridine. The reaction time ranges usually from 30 minutes to 24 hours, preferably from 1 to 12 hours.
The reaction for removing the amino-protective group of the compound (XX) in the method L can be conducted, for example, under conditions similar to removing the amino-protecting group in the method H.
The compound (VIII) can be synthesized by, for example, the following methods.
(i) ~1 2~ 2 (X~
~--B--~' ~) wherein the symbols are of the same meaning as defined above.
The reaction between the compound (X) and the compound (XXI) is conducted under conditions similar to those of the reaction between the compound (X) and the WO 96/02~42 F_IIJ. C ~ 2 c, und (XI) in the method F.
(ii) E~--B--N~J
~' 5 ~ ~XXII) ~llIII) ~ removal of th~-(XII) prote~tiry ~roup wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XII) and the compound (XXII) is conducted under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G. And, the reaction for removing the amino-protective group is conducted under conditions similar to those of removing the protective group in the method H.
The compound (IX) can be synthesized by, for example, the following method.
~ Gl-S02-~

G ~ - CO -~s X-~-N9z ~~ G'-C00-~

(XX~II) Gl-Co-~(B7)2~
wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XXIII) and G -5O2-R4 is conducted, for example, under conditions similar to those of the reaction between the compound t (VIII) and G -SOz-R in the method A. The reaction between the compound (XXIII) and G~-Co-R5 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and GZ-Co-R5 in the method B. The reaction between the compound (XXIII) and G3-CoC-R6 is conducted, for example, under W096/02542 219~23 48 - PCTI~9~/01382 condLtions similar to those of the reaction between the compound (VIII) and G -C00-R in the method C. The reaction between the compound (XXIII) and G -Co-N(R)R3 is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G-C0-N(R )R in the method D.
The compound (X) can be synthesized by, for example, the following method.

o ~ E'--B--E' (XXIY) ~ (X) (XII) wherein the symbols are of the same meaning as defined above.
The reaction between the ~ und (XII) and the compound (XXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G.
The compound (XII) can be synthesized by, for example, the following method.

~ 15 (~V) (1~YI) wherein the symbols are of the same meaning as defined above.
The cyclization of the compound (XXV), can be conducted with one equivalent to a large excess (l to lO equivalents) of a base such as sodium hydride, potassium hydride or lithium diisopropyl amide relative to one equivalent of the compound (xxv). The reaction 2 1 93~3 096l02~42 .~lIJ. .

temperature ranges from -20 to 150~C. The solvent then employed is exemplified by ethers (e.g. tetrahydrofuran and dioxane) and aprotic polar solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide). The reaction time ranges usually from 10 minutes to 6 hours, preferably from 0.5 to 3 hours.
(ii) ~ ring-~I~s~re 2)teprotecticn N

(XXYII~ (XXYIII~
wherein the symbols are of the same meaning as defined above.
The ring-closure reaction of the compound (XXVII) is conducted, for example, under conditions similar to those of the ring-closure reaction of the compound (XV) in the method I. And, the reaction for removing the amino-protecting group is conducted, for example, under conditions similar to those of the reaction of removing the protective group in the method H.
( iii ) ~ ~1 l)trichlnro~ctyl~tion ~)dearotection ~ 1 3)ri~g-clasure tXXYII) tXXIX) wherein the symbols are of the same meaning as defined above.
The trichloroacetylation, removal of the protective group and ring-closure reaction of the compound (XXvII) are conducted, for example, under __ . . _ _ _ ___ . _ ____ WO 96/02542 2 1 9 3 2 2 3 I ~,I/J~ L

conditions similar to those for the trichloroacetylation, removal of the protective group and ring-closure reaction of the compound (XIV) in the method H.
5 (iv) ~C Cl5 ~0 ~XVI) tXXX) wherein the symbols are of the same meaning as defined above.
The ring-closure reaction of the compound (XVI), can be conducted with, for example, one equivalent to a large excess amount (1 to 100 equivalents) of aqueous ammonia relative to one equivalent of the compound (XVI). The reaction temperature ranges from 0 to 150~C. The solvent then employed is exemplified by water, lower alcohols (e.g. methanol, ethanol, propanol and isopropanol), halogenated hydrocarbons (e.g.
methylene chloride, chloroform and dichloroethane), ethers (e.g. tetrahydrofuran and dioxane), esters (e.g.
methyl acetate and ethyl acetate), and aprotic polar solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide). The reaction temperature ranges usually from 10 minutes to 24 hours, preferably from 3 to 12 hours.
The compound (XIV) can be synthesized by, for example, the following method.
(i) When j is l;

2 1 9322~
~096/02s42 r~l,J.

-B-N<~

intr0dUcti~n of ~2C
C~2--EI proteCtlve group .\N--J
(XX~I) B--~IV) wherein the fiymbols are of the same meaning as defined above.
The reaction between the compound (XXXI) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
The reaction for introducing the amino-protecting group is a E~ Se known reaction such as the above-mentioned deprotection of the amino group, which can be conducted according to known conditions.
(ii) When j is 0 and J is a hydrogen atom;
~s~~B-N~ ~ 2 E2 B~~~a ~XXX~ XXXIII) wherein E stands for, for example, a halogen (e.g.
chlorine, bromine and iodine), and the other symbols are of the same meaning as defined above.
The reaction between the compound (XXXII) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
(iii) When j is 0, and, J and R are both a hydrogen atom;

W096/02542 ~ 2 2 3 - 52 - PCT/~95/01382 ~) introduction EN
E2 cf e ~.B - N~ - ~3 ~XXII~ (XXx~

wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XXXII) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
Introduction of R is conducted, for example, under conditions similar to those of the reaction between the compound (VIII) and G1-So2-R4 in the method A, those of the reaction between the compound (VIII) and G2-C3-R5 in the method B, those for the reaction between the compound (VIII) and G3-Coo-R~ in the method C and those for the reaction between the compound (VIII) and G4-CC-7)R3 in the method D.
(iv) When j is l and R3 is a hydrogen atom;

~ ~ (XXXIY) Ec~ 2) i~trcductio~ of 33 ~zC
~, 3) introductlon o~ J
Erotectlng grDup (XXXI~
~XXX~I) The reaction between the compound (XXXI) and the compound (XXXIV) and the introduction of R3 are conducted under conditions similar to those of the reaction between the compound (XXXII) and the c ~-u--d (XXXIV) and for the Lntroduction of R described in (iii) above.

2 ~ 9 ~
~096102s42 PCTIJP95/01382 The reactions for introducing the amino-protecting group are all ~ se known ones as described above, for example, and they can be conducted according to the conditions of them.
; S The compound (XV) can be synthesized by, for example, the following methods.
(i) 2N--~--N/Bs o ~1~ (XYII) ~2G
\E' (XXXI) wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XXXI) and the compound (XVII) is conducted, for example, under conditions similar to those of the reaction between the compound (X) and the compound (XI) in the method F.
(ii) When R2 is a hydrogen atom;

~ 31 1) ~2~-B-N3 ~2C~l 2) l ~ro~u~io -~
~XX~I~ B~ R3 ~XXXYI) 30 wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XXXI) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (x) and the compound (XI) in the method F.
Introduction of R is conducted, for example, under Wo96l02~42 219 ~ 2 2 ~ r ~I/J.,~

conditions similar to those of the reaction between the ct ~ und (VIII) and Gl-502-R4 in the method A, those of the reaction between the compound (VIII) and G -Co~-R5 in the method B, those of the reaction between the compound (VIII) and G3-Coo-R6 in the method C and those of the reaction between the compound (VIII) and G'-C0-N(R7)R in the method D.
The compound (XVI) can be synthesized by, for example, the following method.

I~ tri~hloro~cetyl~tion ~' C~l 5 C0zBl 5' ~XXX~lI) (X~I~
wherein the symbols are of the same meaning as defined above.
Trichloroacetylation of the compound (XXXVIII) is conducted, for example, under conditions similar to those of trichloroacetylation of the compound (XIV) in the method H.
The compound (XXIII) can be synthesized by the following methods.
(i) ~ B - ~ ~XL) (X.~III) ~XII) 2~ o~al of the p~otecti~e g~oup wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XII) and the compound (XL) is conducted, for example, under conditions similar to those of the reaction between the compound (XII) and the compound (XIII) in the method G.

.. . . . . _ _ _ _ _, . . .

2 ~ 9~2~3 WO96102~42 E~1IJ

The removal of phthalimido group, which is the amino-protecting group, can be conducted by the reaction with hydrazine hydrate in a solvent (e.g. methanol and ethanol).
S (ii) COC~ XI~r) CO~I6 (X~I) wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XVI) and the compound (XXXIV) is conducted, for example, under conditions similar to those of the reaction between the compound (XVI) and the compound (XVII) in the method J.
The compound (XXV) can be synthesized by, for example, the following method.

-C0-CBCO~R~6 C~N~2 ~ (XLlI} ~ ~XXV) ~XLI}

wherein the symbols are of the same meaning as defined above.
For the reaction between the compound (XLI) and the compound (XLII), the compound (XLII) is used in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to o~e equivalent of the compound (XLI). The reaction temperature ranges from 0 to 200~C. Examples of the solvent then employed include water, lower alcohols (e.g. methanol, ethanol and propanol), ethers (e.g. tetrahydrofuran, dimethoxyethane and dioxane), nitriles (e.g.
acetonitrile and propionitrile) and aprotic polar _ _ . _ _ . . ..

W096,02i42 219~23 56 - pCT/~9~10l382 ~

solvents (e.g. N,N-dimethylformamide and dimethyl 5-]1fo~id~) To the reaction system, may optionally be added, as the agent for removing acid l to lO
equivalents of an inorganic base such as potassium S carbonate and sodium 1-ydluyellcarbonate, or an organic base such as triethylamine, pyridine and dimethyl~nil in~, The reaction time ranges usually from lO minutes to 7 days, preferably from one hour to two days.
The compound ~XXVII) can be synthesized by, for example, the following method.

~R 1) a~hin~t C~ 2~ introduotio~ 3~
El protec~in~ ~roup ~XXXI) wherein the symbols are of the same meaning as defined above.
The reactions for introducing primary amino group into the compound (XXXI) are all ~ç~ se known ones, which can be conducted according to known reaction conditions. For example, hexamethylene tetramine in an amount of one equivalent to a large excess (l to l0 equivalents) is used relative to one equivalent of the compound (XXXI). Examples of the solvent for this reaction include water, lower alcohols (e.g. methanol, ethanol and propanol), ethers (e.g. tetrahydrofuran, dimethoxyethane and dioxane), nitriles (e.g.
acetonitrile and propionitrile) and aprotic polar r solvents (e.g. N,N-dimethylformamide and dimethyl sulfoxide). The reaction temperature ranges from 0 to 200~C. The~quaternary amm~nium salt then formed can be hydrolyzed with an acid, such as hydrochloric acid (l ~ W096~02542 PCT/~95~1382 _ 5~ _ to 20 equivalents). The reaction temperature ranges from 0 to 100~C. The reaction time ranges usually from 10 minutes to 24 hours, preferably from l to 3 hours.
Further, the reactions for introducing a protective group into primary amino group are all ~ÇL se known ones, which can be conducted according to known reaction conditions.
The compound (XXXI) can be synthesized by, for example, the following method.
lo ~ RI 1~ i trodu tion of CO2~6 2) oonl,Te~sion to E~
~XXXYIII) wherein the symbols are of the same meaning as defined above.
The reduction of the compound (XXXVIII) is conducted by using a reducing agent, for example, a metal hydride complex compound such as sodium borohydride, lithium borohydride and aluminum lithium hydride or borane complex compounds in an amount ranging from one equivalent to a large excess (1 to 10 equivalents) relative to one equivalent of the compound (XXXVIII). The reaction temperature ranges from -20 to 100~C. Examples of the solvent employed for this reaction include alcohols (e.g. methanol and ethanol) and ethers (e.g. ethyl alcohol, tetrahydrofuran and dioxane). The reaction time ranges usually from 10 minutes to 24 hours, preferably from 0.5 to 6 hours.
The conversion of hydroxyl group to El is conducted, when El is halogen atom, by allowing 1 to 5 equivalents of a halogenating agent, for example, phosphorus halogenide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide, a mixture of red phosphorus and halogen, or 096~02s42 21q ~ ~3 - 58 - PCT/JP95101382 thionyl chlorlde to react with one equivalent of an alcohol ~c.~uund. When E is toluenesulfonyloxy group or methanesulfonyloxy group, l to 5 equivalents of toluenesulfonyl chloride or methanesulfonyl chloride is allowed to react with one equivalent of an alcohol compound. In this case, l to lO equivalents of, for example, an inorganic base such as potassium carbonate and sodium hydrogencarbonate or an organic base such as 4-N,N-dimethylaminopyridine, triethylamine, pyridine, dimethyl aniline and l~4-diazabicyclo[2~2~2]octane may optionally be used. The reaction temperature ranges from 0 to 100~C. Examples of the solvent used in this case include halogenated hydrocarbons (e.g. methylene chloride, chloroform and dichloroethane), water, ethers (e.g. diethyl ether and tetrahydrofuran), esters (e.g.
methyl acetate and ethyl acetate) and aprotic polar solvents (e.g. N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile). The reaction time ranges usually from lO minutes to lO0 hours, preferably from 3 to 24 hours.
The compound (XXXII) can be synthesized by, for example, the following method.

E2~ CO-CL2E: tXLI~) (XXXII) (7~LIII3 wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XLIII) and the compound (XLrV) can be conducted under conditions similar to those of the reaction between the compound (XLI) and the compound (XLII) in the above-mentioned method of synthesizing the compound (XXV).
The compound (XXXVIII) can be synthesized by, for example, the following method.

_ _ . . ..... .. _ . ......

? ~ 9322~
~'0 96102~42 P~I~J~

2cJ~ CO--CE~E~ (XLIV) (XLi') wherein the symbols are of the same meaning as defined above.
The reaction between the compound (XLV) and the compound (XLIV) can be conducted under conditions similar to those of the reaction between the compound (XLI) and the compound (XLII) in the above-mentioned method for synthesizing the compound (XXV).
The intP -~iate compounds for synthesizing the target compound (I') or a salt obtained by the above-mentioned methods can be isolated by the following conventional separation means, or reaction mixture per se may optionally be used, as the starting materials for the subsequent step without lsolation.
The isolation and purification of the compound ( I ' ) from the reaction mixture is conducted according to conventional separation means (for example, extraction, concentration, filtration, recrystallization, column chromatography and thin-layer chromatography).
And, in each of the above-mentioned reactions, when the starting compounds and int~ -~iAte c. uuul-ds has amino group, carboxyl group or hydroxyl group as the substituent, they may have a protective group generally used in the peptide chemistry. After completion of the reaction, the target compound can be obtained by removing the protective group upon necessity.
~xamples of the amino-protecting group include optionally substituted Cl6 alkyl carbonyl (e.g. formyl, methyl carbonyl and ethyl carbonyl), phenyl carbonyl, Cl6 alkyl-oxycarbonyl (e.g. methoxycarbonyl and 21 ~23 W096/0~42 I~l/J..

ethoxycarbonyl), phenyloxycarbonyl (e.g.
benzoxycarbonyl), C7l0 aralkyloxy-carbonyl (e.g.
benzyloxycarbonyl), trityl and phthaloyl. Examples of substituents of them include halogen atoms (e.g.
fluoro, chloro, bromo and iodo), Cl6 alkyl-carbonyl (e.g. methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro group, and the number of the substituents ranges from about l to 3.
Examples of the carboxyl-protecting group include Cl6 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl), phenyl, trityl and 8ilyl .
Pxamples of substituents of them include halogen atoms (e.g. fluorine, chlorine, bromine and iodine), Cl6 alkylcarbonyl (formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro group, and the number of the substituents ranges from about 1 to 3.
Examples of the hydroxyl-protecting group include for example, optionally substituted Cl6 alkyl (e.g.
methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl), phenyl, C7l0 aralkyl (e-g- benzyl), Cl6 alkylcarbonyl (e.g. formyl, methylcarbonyl and ethylcarbonyl), phenyloxycarbonyl, C7l0 aralkyloxy-carbonyl (e.g. benzyloxycarbonyl), pyranyl, furanyl and silyl. As the substituents mentioned above, halogen atoms (e.g. fluoro, chloro, bromo and iodo), Cl6 alkyl, phenyl, C7l0 aralkyl and nitro group were used. The number of substituents ranges from about l to 4.
And, the protecting groups can be introduced and removed by ~er se known means or those analogous thereto (for example, I.F.W. McOmie et al., PROTECTIVE
GROUPS IN ORGANIC CHEMISTRY, Plenum Press). More sprri~ic7~l1y~ those protecting groups are removed by, for example, acid, base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithincRrhRm~te, tetrabutyl ammonium fluoride orpR 1 1 R~ i llm acetate.

W096/02542 PCT/JP95/~1382 The compound (I') produced by the above-mentioned methods can be isolated and purified by a conventional : separating means such as recrystallization, distillation and chromatography. When the compound .~ 5 (I') thus obtained is in the free form, it can be converted to a salt by E~E se known means or analogous means thereto (e.g. neutralization). Conversely, when the compound (I') is obtained in the form of a salt, it can be converted to the free form or any other salt by ~er se known means or analogous means thereto.
Further, when the compound (I') is an optically active compound, it can be resolved into d-isomer and l-isomer by a conventional means for optical resolution.
lS The compound (I') and the pharmaceutically acceptable salt of the present invention have an excellent inhibiting activity of PDGF action, antihypertensive activity, ameliorating activity of renal diseases and activity of lowerLng lipid level, and are relatively less toxic. Therefore, these compounds or their salts can be safely used, in mammals (e.g. mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey and human), as therapeutic agents of, for used as hypertension, renal diseases (e.g.
acute renal failure, diabetic nephropathy and nephritis), arteriosclerotic diseases, the other cardiovasular diseases, chronic rheumatoid arthritis, cancers and hyperlipemia.
While the compound (I') or a salt thereof can be administered as it is, it is usually administered in the form of preparation formulated by a conventional method using carriers or diluents for ph~rr~e~utical preparations adequately selected from excipients (e.g.
calcium carbonate, kaolin, sodium hydrogencarbonate, lactose, starch, crystalline cellulose, talc, fine granulated sugar and porous substance), binders (e.g.

21 q32~3 ~09610~42 PCT1~9~101382 dextrin, gum, alcoholated starch, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and furfuran), disintegrants (e.g. carboxymethyl cellulose calcium, closcarmellose sodium, clospovidone, low-substituted hydroxypropyl cellulose and partial ~-starch), lubricants (e.g. magnesium stearate, calcium stearate, talc, starch and sodium benzoate), colorants (e.g. tar pigment, caramel, iron sesquioxide, titanium oxide and riboflavins), flavoring agents (e.g.
sweeteners and perfume), stabilizers (e.g. sodium sulfite) and preservatives (e.g. parabens and sorbic acid) in adequate amounts respectively. The therapeutic agent of the present invention containing the above-mentioned ph~rr~-eutical preparation contains the compound (I') or a salt thereof in a amount effective for the therapy and prophylaxis. The content of the compound (I') or a salt thereof in the pharmaceutical preparation of the present invention ranges usually from O.l to lO0 weight ~ relative to the whole weight of the ph~r~~~eutical preparation. And, the pharmaceutical preparation of the present invention may contain, as active components, medicinal components other than the compound (I') or a salt thereof. These medicinal components arQ not specifically restricted so long as the object of this invention is attained, and can be used in adequate ratios. As the said ~medicinal components", use is made of, for example, diuretic, angiotensin II receptor antagonist, calcium blocker, ACE inhibitor, kimase inhibitor, HMG-CoA reductase inhibitor and squalene synthetase inhibitor. Specific examples of the formulation include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules, granules, powdery preparations, syrups, emulsions, suspensions, injections, inhalants and ointments. These formulations are prepared by a conventional method (e.g. the method described in the W096/02542 r~llJ.,S,v.~l Japanese Pharmacopeia).
More specifically, tablets can be prepared by, for : example, the following processes:
1) the ph~rm~-~utical preparation as it is, or a homogeneous mixture of the pharmaceutical preparation with an excipient, a binder, a disintegrant or any other suitable additive, is granulated by an adequate means, to which is added, for example, a lubricant, and the whole mixture is subjected to compression molding;
2) the pharmaceutical preparation as it is, or a homogeneous mixture of the pharmaceutical preparation with an excipient, a binder, a disintegrant or any other suitable additive, is directly subjected to compression molding; or 3) the granules prepared in advance as they are, or a homogeneous mixture of the granules with a suitable additive, is subjected to compression molding. And, to this pharmaceutical preparation, a colorant or a flavoring agent may optionally be supplemented upon necessity. Furthermore, this pharmaceutical preparation may optionally be coated with a coating agent.
Injectable preparations can be provided by dissolving, suspending or emulsifying a given amount of the pharmaceutical preparation in, when using an aqueous solvent, e.g. water for in~ection, physiological saline or Ringer's solution, and, when using a water-insoluble solvent, usually e.g. vegetable oil, or by filling a given amount of the pharmaceutical preparation into a vessel, followed by sealing the vessel.
As the carriers for orally administrable preparations, use is made of substances commonly employed in the field of pharmaceutical preparations, for example, starch, mannitol, crystalline cellulose and sodium carboxymethyl cellulose. As the carriers ~= ~ ~
2 ~ 3 W096/02~42 PCT13P9~101382 for injectable preparations, use is made of, for example, distilled water, physiological saline solution, glucose solution and an agent of infusion.
Besides, additives generally employed for pharmaceutical preparations can be adequately supplemented.
The phArr~eutical preparations of this invention are relatively less toxic and useful as medicinal preparations, which have PDGF-inhibiting activity, antihypertensive activity, ameliorating activity of renal diseases and lipid lowering activity. Therefore, the pharmaceutical preparations of this invention are useful as meaicines for diseases due to these pharmacological actions. The pharmaceutical preparations of this invention can thus be used ~s the therapy or prophylaxis of, among others, hypertension, acute renal failure, diabetic nephropathy, nephritis, arteriosclerosis, chronic rheumatoid arthritis, cancers and hyperlipemia.
The dose of the pharmaceutical preparations of this invention varies with administration routes, symptoms, the age and body weight of patients and it is prefer_ble that a daily dose for treating hypertension, renal diseases or orterisderotic diseases of O.Ol to 300 mg/kg, preferably 0.2 to 50 mg/kg, more preferably 5 to 30 mg/kg for oral administration is given once or divided into several times. The administration route may be either oral or non-oral.
Best Mode for Garryin~ out the Inventio~
The experimental results showing the pharmacological ef~ects of the compound (I') or a salt thereof of this invention are described as follows:
Test ~xAmnle l Inhibitory effects on the contraction due to PDGF
~ethod: The thoracic aorta of stroke prone spontaneously hypertensive rats at ages ranging from 16 096102~2 PCT/JP9~/01382 to 36 weeks were isolated, and strip (2 mm in width, 2 cm in length) were prepared from the aorta. Each strip : was mounted in lO ml of an organ bath, which was loaded at 2 g and allowed to stabilized for 2 to 3 hours. As the nutrient, a ~rebs-Henseleit solution, bubbled with a mixture gas (95% 02, 5~ CO2), was used. At the time when the contraction response against 60 mM KCl becomes constant, each strip was applied by l.7 nM of PDGF-AB
(Cosmobio Inc.) for contraction. Observation was continued until the contraction become maximum and stable (30 to 40 minutes after application of PDGF-AB).
Then, the strips were washed, and, in about one hour later (after the tone of the vaso-contraction was recovered to the original level), lO ~l of the drug (DMSO solution) was added. Thirty minutes after drug, l.~ nM of PDGF-AB was added again and subjected to observation until the contraction became maximum. The PDGF-AB-induced contraction was isometrically recorded on a polygraph (Nihon Denki San-ei). From the contractile response of the strips to PDGF-AB in the absence or presence of drugs, % inhibition of each drug was calculated. IC5~ value for the inhibitory effects was calculated in accordance with the Filler's theorem using the least squares method. The results are shown in Table l.

w0 96~02s42 2 1 9 3 ~ ~ 3 F~/J~

Table 1 Inhibitory effects on PDGF-induced contrzction Compound IC50 (~M) (No.of Ex.) 1 2.13 3 0.29 6 1.27 8 0.31 26 0.37 2 . 26 From the Table 1, it is demonstrated that the compound (I') or a its salt o~ the present invention has an excellent action of inhibiting PDGF-induced contraction.
Test ~ nle 2 Antihypertensive action in spontaneously hypertensive rats (SHRs) 20 Method: Male SHR at ages ranging from 20 to 24 weeks were anesthetized with pentobarbital-sodium (50 mg/kg, i.p.) and, from the femoral artery of each animal, a polyethylene tube was inserted. The polyethylene tube was connected to a pressure transducer and blood pressure after oral administration of drugs was recorded continuously under non-anesthesia. The animals, after the operation, were allowed to freely access to ~r;nking water a~d eating, until administration of the drugs. The compounds were all orally administered as a suspension in gum arabic (2 ml/kg). The results are shown in Table 2.

~096/02s42 PCT~JP95/01382 - 67 _ Table 2 Antihypertensive action Compound doseblood-pressure change S (No. of Ex.~ (mg/kg) (mmHg) 1 10 -21 [after 5 hrs.]
6 lO -19 [after 4 hrs.]
11 30 -31 [after 7 hrs.]
26 10 -22 [after 7 hrs.]
27 30 -17 [after 7 hrs.]
28 30 -13 [after 3 hrs.]
-17 [after 7 hrs.]
-14 [after 2 hrs.]
37 30 -14 [after 5 hrs.]
38 30 -19 [after 4 hrs.]
-20 [after 7 hrs.]

From Table 2, in the test groups, an antihypertensive effect of about 20 mmHg as compared with the control group was observed at 2 to 7 hours after administration of the compound (I') or a salt thereof of the present invention. Therefore, the compound (I') or a salt thereof of the present invention was considered to have an excellent antihypertensive action.
Test ~m~le 3 Antiproteinuric effect in 5/6 nephrectomized rats Method: Male Sprague Dawley rats of five-week old (Japan Clea) were anesthetized with pentobarbital-sodium (50 mg/kg, i.p.), and the rlght kidney was excised by dorsal incision, and its two-thirds were cut. Two weeks later, the whole of left kidney was removed. In the Sham group, only the second operation was performed. In two weeks after the second operation, urine was collected for 24 hours under W096/02~2 ~1 9 3 2 2 3 ~I,JA l~z ~

drinking water ad libitum. Urinary albumin and total protein were quantitatively det~rm;n~d by the use of A/G B-test (Wako). On the following day of collecting urine, the blood pressure was measured by the tail cuff method. Test animals showing more proteinuria than that of Sham group were selected. Based on the amount of the proteinuria and the blood pressure level, the animals were grouped so that, the average and distribution of urinary protein and blood pressure same in each group. The drug was suspended in gumarabic/water or dissolved in water, and orally administered once a day for 6-8 weeks in a volume of 2 ml/kg. The administration was consecutively performed, and, at 2, 4, 6 and 8th weeks of treatment, urine was collected and blood pressure was measured. The vehicle group was orally administered with only water at a dose of 2 ml/kg.~ The results are shown in Table 3.
Table 3 Antiproteinurea action (Urinary protein excretion) Compound Dose Urinary protein excretion (mglday) (No.of (mglkg) Ex.) 0 2 4 6 8 (weeks) 25Control 114.41~3.1 102.5 ~56.9 220.4 group 1 3 114.5117.0 98.2 156.3 10~.8 6 10 114.1103.0 93.9 167.~ 117.3 11 ~ 10 115.169.1 62.5 170.3 125.4 30 30 3 114.198.~ 69.7 180.5 156.5 2 1 ~3~23 WO 96102542 P~/J~

Table 4 Antiproteinuric action (Urinary albumin excretion) S Compound Dose Urinary albumin excretion (mg/day) (No.of (mglkg) E~.) 0 2 4 6 8 (weeks) Control 10.0 29.2 30.6 54.Z 69.7 group 1 3 11.2 16.9 18.4 13.0 25.1 6 10 6.8 13.5 17.2 13.1 24.8 11 10 10.2 19.8 30.3 26.0 38.3 3 8.6 13.9 13.2 13.5 21.0 From Table 3, it is apparent that, from 4 weeks after renal ablation, urinary protein and urinary albumin in urea were remarkably increased. In contrast, in the test groups, no increase was observed in urinary total protein and urinary albumin. At 4th to 8th week of consecutive administration, the levels of urinary protein and albumin were significantly lower than those of the control group. Therefore, the compound (I') or a salt thereof present the leakage of 25 protein into urine, and its efficacy on the therapy of renal diseases such as glomerulosclerosis is expected.
Test ~Am~le 4 Cholesterol lowering effects in hamsters Method: Syrian hamsters of 10 weeks old were stabilized with common feed for two weeks. The animals were grouped based on the total cholesterol in blood. The vehicle (water) or drug was orally administered in a volume of 2 ml/kg for two weeks. During the period of the administration, blood was collected from retinal vessels with passage of time and the total cholesterol and triglyceride in blood were de~t~rm;nt~d. On the other hand, blood was collected from Ahdt inAl aorta on the second week after the consecutive administration of W096l02s42 ~ ? 2~ J. ,~ 2 the test compounds to determine the total cholesterol, triglyceride and HDL (high density lipid)-cholesterol in blood. Cholesterol C-test, triglyceride G-test and HDL-cholesterol E test (all manufactured by Wako Pure rh~mir~l Industries, Ltd.) were used for the determination of these parameters, respectively. The results are shown in Table 5.
Table 5 Cholesterol-lowering action Compound Dose ~ of Vehicle (No.of Ex.)(mg/kg) TC TC-HDL
1 30 64.1 68.9 3 10 82.2 79.0 6 10 89.5 84.6 8 10 81.5 77.1 26 30 74.5 72.1 28 30 65.1 61.6 81.9 77.4 From Table 5, it is apparent that, in the control group, the total cholesterol (TC) in blood increased with the passage of time. On the contrary, in the test groups, the increase of cholesterol in blood was suppressed by about 20 to 30%. On the other hand, no difference was observed HDL-cholesterol level at the second week of the consecutive administration between the vehicle group and test groups. From these results, it is apparent that the values, [total cholesterol value~ - [HDL-cholesterol value];
were lower in the test groups than that of the control group. Therefore, the compound (I') or a salt thereof act to decreafie LDL (low density lipid) and VLDL (very low density lipid~ in blood, and are useful against cardivascular diseases, for example, arteriosclerosis.

w096102542 r~ 2 The present invention provides a novel tricyclic compound and a salt thereof which have excellent PDGF-inhibiting activity, antihypertensive activity, activity of ameliorating renal diseases, and activity ; 5 of lowering lipid level, and therefore, can be safely used as, th~La~euLic agents of, for example, hypertension, renal diseases (e.g. acute renal failure, renal diabetes and nephritis), diseases due to arteriosclerosis, the other cardiovascular diseases, chronic articular rhematism, cancers and hyperlipemia.

W096/02sl2 PCT/JP95101382 The present invention will be explained in more detail by the following working examples and reference examples. These are mere examples and are not intended to restrict the present invention in any manner, and may be modified within the range of not deviating the s~ope of this invention.
In ~xamples and Reference F~mrlP~, abbreviations mean as follows.
NMR : Nuclear magnetic resonance spectrum D.~F : dimethylformamide, DMSO : dimethyl sulfoxide, Hz : herz, J : coupling constant, m : multiplet, q :
quartet, t : triplet, d : doublet, s : singlet, b :
broad, like : approximate Room temperature means 10 to 30~C.
Example 1 4,5-Dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene dihydrochloride i) Synthesis of 5-chloromethylimidazo[1,2-a]pyridine-hydrochloride To a solution consisting of 58.4 ml (800 mmol) of thionyl chloride and 100 ml of methylene chloride was added 23.68 g (160 mmol) of 5-hydroxymethylimidazo[1,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature. Then, the solvent and excess amount of thionyl chloride were distilled off under reduced pressure. To the resulting white solid residue was added 100 ml of toluene. The mixture was shaken sufficiently, then the solvent was distilled off under reduced pressure. This process was repeated twice to give 31.85 g (98.0%, white solid) of a crude product. t NMR(200MHz,D~O) 8: 5.09(2H,s), 7.49(1H,t,J=4.8Hz), 7.85(2H,d,J=4.8Hz), 7.95(1H,d,J=2.4Hz), 8.16(1H,d,J=2.4Hz).
IR(~Br): 1657, 1543, 1157 cm .
ii) Synthesis of 5-[N-[4-(trifluoromethane-096l02542 PCTIJP95/01382 sulfonamido)butan-l-yl]Am;n~ Lhyl]imidazo[1,2-a~pyridine To a suspension formed by adding 36.93 g (181.85 mmol) of 5-chloromethylimidazo[1,2-a]pyridine hydrochloride to 200 ml of acetonitrile was added 32.06 g (363.72 mmol) of 1,4-t~i~mint~hutane~ then the mixture was heated for 30 minutes under reflux. After completion of the reaction, the reaction mixture was cooled to allow 1,4-diaminobutane-dichloride to precipitate, which was collected by filtration and washed twice with 25 ml of acetonitrile. The filtrate and washings were combined, to which was added 50.68 ml (363.72 mmol) of triethylamine. The mixture was stirred sufficiently, to which was added 64.97 g (181.85 mmol) of N-phenyltrifluoromethanesulfonimide.
The mixture was stirred for two hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of chloroform. The organic layer was washed with 500 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=20:1) to give 41.60 g (65.3~, a colorless solid) as the desired compound.
NMR(200MHz,CDCl3) ~: 1.48(13H,m), 3.24(2H,br), 4.67(2H,br), 6.69(1H,d,J=6.2Hz), 7.19(lH,t,J=6.2Hz), 7.50-7.80~3H,m).
IR(~Br): 3320, 1641, 1514, 1367 cml iii) Synthesis oi 4,5-dihydro-4-[4-(trifluoro-methanesulfonamido)butan-l-yl]-3H-1,4,8b-t~ 7~ t~enaphthylene To a solution of 6.91 g (19.72 mmol) of 5-[N-[4-(trifluoromethanesulfonamido)butan-l-yl]~m i n t Lhyl]-imidazo[l,2-a]pyridine in 20 ml of acetic acid was WO96l~2~42 ~ 2 3 r "J.

added 22.1 ml (295.8 mmol) of a 37% aqueous solution of formaldehyde. The mixture was heated at 100~C for 30 minutes. The solvent was then distilled off under reduced pressure, and the residue was dissolved in 100 ml of a saturated aqueous solution of potassium hydrogencarbonate. This solution was neutralized, under ice-cooling, with lN HCl, which was subjected to extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel chromatography (eluent: chloroform/methanol = 20:1) to give 4.86 g (68.0%, pale yellow liquid product).
NMR(200MHz,CDCl3) ~: 1.76~4H,m), 2.55(2H,t,J=6.0Hz), 3.33(2H,t,J=6.0Hz), 3.97(2H,s), 4.00(2H,s), 6.55(1H,d,J=6.8Hz), 7.10(lH,dd,J=9.2,6.8Hz), 7.25(1H,s), 7.44(1H,d,J=9.2Hz).
IR(neat): 1636, 1483, 1370 cml.
iv) Synthesis of 4,5-dihydro-4-[4-(trifluoro-methanesulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylene-dihydrochloride To a solution of 3.21 g (8.87 mmol) of 4,5-dlhydro-4-[4-(trifluoromethanesulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylene in 10 ml of ethanol was added 2.0 ml of 12N HCl. The mixture was sufficiently blended. The solvent was distilled off under reduced pressure to leave 3.86 g of the desired compound (100~, colorless amorphous).
NMR(200MHz,DMSO) ~: 1.60(2H,m), 1.85(2H,m), 3.19(4H,m), 4.83(2H,s), 4.91(2H,s), 7.54(1H,m), 7.99-8.01(2H,m), 8.20(1H,s), 9.55(1H,t,J=6.0Hz).
IR(RE~r): 3463, 1662, 1459, 1440, 1373, 1190 cml.
Example 2 4,5-Dihydro-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene-dihydrochloride i) Synthesis of 5-[N-[5-~ w096/02~42 2 1 q ~ 2 ~ 3 l~l/J. '101382 (trifluoromethanesulfonamido)-pentan-l-yl]~min~ Lhyl imidazo[1,2-a]pyridine To a suspension of 10.2 g (50.0 mmol) of 5-chloromethylimidazo[l,2-a]pyridine hydrochloride in 100 ml of acetonitrile was added 10.2 g (lOO mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutes under reflux. The reaction mixture was cooled to separate 1,5-diaminopentane-dihydrochloride as precipitates, which was collected by filtration and washed lO ml of acetonitrile twice. The filtrate and the washing were combined, to which was added 14.0 ml (100 mmol) of triethylamine. The mixture was stirred sufficiently, to which was added 17.86 g (50.0 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for two hours at room temperatures. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was extracted with 250 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, dried over magnesium sulfate, then the solvent was removed under reduced pressure. The residue was purified by means of a silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 12.9 g of the object compound (71.0%, colorless Z5 solid substance).
NMR(200MHz,CDCl3) ~: 1.45(2H,m), 1.60(4H,m), 2.47(2H,t,J=6.6Hz), 3.28(2H,t,J=6.6Hz), 4.02(2H,s), 6.78(1H,d,J=7.0Hz), 7.17(1H,dd,J=7.0,9.2Hz), 7.57(1H,s), 7.58(1H,d,J=9.2Hz), 7.63(1H,s).
IR(XBr): 1637, 1481, 1637, 1295, 1188 cml ii) Synthesis of 4,5-dihydro-4-[5-(trifluoromethane-sulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene ; To a solution of 2.52 g (6.91 mmol) of 5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]~m i Lhyl]
imidazo[1,2-a]pyridine in 8 ml of acetic acid was added 7.8 ml (103.7 mmol) of a 37% aqueous solution of W096/02~42 ? ~ 9 3 ~ 2 3 76 - ~"J~, C ~

formalin. The mixture was heated at 100~C for 30 minutes. The solvent was then distilled off under reduced pressure. The residue was dissolved in 50 ml of a saturated aqueous solution of potassium carbonate.
This solution was neutralized, under ice-cooling, with -~
lN HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography to give 1.79 g of the desired compound (69.0%, colorless liquid).
NMR(200MHz,CDCl3) ~: 1.44(2H,m), 1.60~4H,m), 2.47(2H,t,J=6.6Hz), 3.28(1H,t,J=6.6Hz), 3.91(2H,s), 4.01(2H,s), 6.53(1H,d,J=6.8Hz), 7.10(1H,dd,J=9.2,6.8Hz), 7.27(1H,s), 7.39(1H,d,J=9.2Hz), 8.25(1H,br).
IR(neat): 1637, 1522, 1450, 1366, 1221 cm .
iii) Synthesis of 4,5-dihydro-4-[5-(trifluoromethane-sulfonamido)pentan-l-yl]-3H-1,4,8b-triaz~Ar~nAphthylene-dihydrochloride In a solution consisting of 10 ml of ethanol and 0.5 ml of 12N HCl was dissolved 0.88 g (2.34 mmol) of 4,5-dihydro-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene. The solvent was distilled off under reduced pressure to leave 1.05 g of the desired compound (100%, white amorphous).
NMR(200MHz,DMSO) ~: 1.39(2H,m), 1.55(2H,m), 1.83(2H,m), 3.16(4H,m), 4.85(2H,s), 4.93(2H,s), 7.54(1H,m), 8.01(2H,m), 8.19(1H,s), 9.40(1H,t,J=5.8Hz).
IR(~Br): 3431, 1662, 1549, 1440 cm .
Example 3 4,5-Dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido) butan-l-yl]-3H-1,4,8b-tri~ 7~ A ~n A phthylene-dihydrochloride i) Synthesis of 2-methyl-5-hydroxymethylimidazo[1,2-l]pyridine ~ ~096l02~2 2 ~ ~ 3 ~ ~ ~ pCT/Jp95/01382 To a solution of 8.31 g (40 mmol) of 2-methyl-imidazo[1,2-a]pyridine-5-carboxylic acid ethyl ester in 200 ml of methanol was added, under ice-cooling, 4.54 g 120 mmol) of sodium borohydride. The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was poured into 300 ml of ice-water, and the mixture was blended sufficiently, to which was then added 12N HCl until the pH of the solution reached 2.
This solution was stirred for two hours at room temperature, which was then neutralized with a 6N
aqueous solution of sodium hydroxide, followed by distilling off the solvent completely under reduced pressure. To the residue was added 300 ml of methanol.
The mixture was blended sufficiently, and insolubles were filtered off, followed by distilling off the solvent under reduced pressure to leave 5.71 g of a crude product (88~, white solid substance). The crude product was used in the subsequent reaction without purification.
NMR(200MHz,DzO) ~: 2.48(3H,s), 4.83(2H,s), 6.12(1H,br), 7.87(1H,d,J=3.0Hz), 7.71(1H,d,~=3.0Hz), 7.73(1H,s), 8.01(lH,s).
~R(KBr): 3350, 1653, 1643, 1390 cm~.
ii) Synthesis of 2-methyl-5-chloromethylimidazo[1,2-a]pyridine-hydrochloride To a mixture solution consisting of 12.0 ml (150.0 mmol) of thionyl chloride and 25 ml of methylene chloride was added, 4.87 g (30.0 mmol) of 2-methyl-5-hydroxymethylimidazo[1,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature, then the solvent and excess volume of thionyl chloride were distilled off under reduced pressure to leave a white solid matter. To the solid was added 50 ml of toluene, and the mixture was stirred sufficiently, followed by distilling off the solvent under reduced pressure. This process was 21 9~223 ~'096l02S42 PCT/~9Sl01382 repeated twice to give 6.46 g (99.0~, white solid) of a crude product.
NMR(200MHz,D~O) 8: 2.50(3H,s), 5.05(2H,s), 7.44(1H,d,J=2.8Hz), 7.75(1H,s), 7.78(1H,d,J=2.8Hz), 7.92(1H,s).
IR(~Br): 3222, 1657, 1547, 1429 cm .
iii) Synthesis of 2-methyl-5-[N-[4-(trifluoro-methanesulfonamido)butan-1-yl]~min~ thyl]imidazo[1,2-l]pyridine To a suspension of 6.52 g (30.0 mmol) of 2-methyl-5-chloromethylimidazo[1,2-a]pyridine chloride in 60 ml of acetonitrile was added 5.30 g (60.1 mmol) of 1,4-~i~minnhutane. The mixture was heated for 30 minutes under reflux. After completion of the reaction, the reaction mixture was cooled. Precipitates of 1,4-~i~minnhutane-dihydrochloride then formed were separated by filtration. The precipitates were washed with 10 ml of acetonitrile twice. The filtrate and the washings were combined, to which was added 8.4 ml (60.1 mmol) of triethylamine, and the mixture was stirred sufficiently. To this solution was added 10.73 g (30.0 mmol) of N-phenyltrifluoromethanesulfonimide, and the mixture was stirred for two hours at room temperature.
~fter comple~ion of the reaction, the solvent was distilled o~~ under reduced pressure. The residue was extracted with 150 ml of chloroform. The organic layer was washed with 150 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilllng off the solvent under reduced pressure. The residue was purified by silicagel column shromatography (eluent: chloroform/methanol=20:1) to t give 7.44 g of the desired compound (68.0%, colorless solid).
NMR(200MHz,CDCl3) 6: 1.69(4H,m), 2.44(3H,s), 2.74(2H,t,J=6.0Hz), 3.30(2H,t,J=6.0Hz), 3.97(2H,s), 6.71(1H,d,J=7.0Hz), 7.12(1H,dd,J=7.0,9.0Hz), 2 ~ 932~
~096l02~42 r_-lJ.,~ la~

7.35(1H,s), 7.47(1H,d,J=9.OHz).
IR(KBr): 1639, 1483, 1371 cm .
~ iv) Synthesis of 4,5-dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido)butan-l-yl]-3H-1,4,8b-tri~7aac~nAphthylene In 6 ml of acetic acid was dissolved 2.02 g (5.54 mmol) of 2-methyl-5-[N-[4-(trifluoromethanesulfonamido) butan-l-yl]~min~ -thyl]imidazo[1,2-a]pyridine. To the solution was added 6.2 ml (83.15 mmol~ of a 37% aqueous solution of formalin, and the mixture was heated for 30 minutes at 100~C. After completion of the reaction, the solvent was distilled off under reduced pressure.
The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized by the addition of lN HCl under ice-cooling, which was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column chromatography (eluent:
chloroform/methanol=20:1) to afford 1.45 g of the desired compound (72.0%, colorless liquid).
NMR(200MHz,CDCl3) ~i: 1.73(4H,m), 2.31(3H,s), 2.51(2H,m), 3.31(2H,m), 3.94(2H,s), 4.01(2H,s), 6.50(1H,d,J=6.8Hz), 7.07(1H,dd,J=9.0,6.8Hz), 7.36(1H,d,J=9.OHz).
IR(neat): 1643, 1506, 1454, 1367 cm .
v) Synthesis of 4,5-dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylene-dihydrochloride t In a soIution consisting of 10 ml of ethanol and 1 ml of 12N HCl was dissolved 1.41 g (3.74 mmol) of 4,5-; dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido) butan-l-yl]-3H-1,4,8b-triazaacenaphthylene. The solvent was distilled off under reduced pressure to give the desired compound (100%, white amorphous).

~V096/0~2 2 1 9 3 ~ ~ 3 PCT/JP95/01382 NMR(200MHz,DMSO) ~: 1.60(2H,m), 1.86(2H,m), 2.54(3H,s), 3.40(4H,m), 4.84(2H,s), 4.92(2H,s), 7.51(1H,d,J=6.2Hz), 7.93(2H,m), 9.53(1H,t,J=5.2Hz), IR(KBr): 3428, 1672, 1552, 1450, 1369 cm .
Example 4 4,5-Dihydro-2-ethyl-4-~5-(trifluoromethanesulfonamido) pentan-l-yl]-3H-1,4,8b-triazaacenaphthylene~dihydrochloride i) Synthesis of 2-ethyl-5-hydLu~y Lhylimidazo[1,2-a]pyridine To a solution of 5.29 g (24.24 mmol) of ethyl ester of 2-ethylimidazo[1,2-a]pyridine-5-carboxylic acid was added 2.75 g (72.72 mmol) of sodium borohydride under ice-cooling. The reaction mixture was stirred for 3 hours under ice-cooling. The reaction mixture was then poured into 150 ml of ice-water. The reaction mixture was mixed well, to which was added 12N HCl until the pH of the solution reached 2. This solution was stirred for two hours at room temperature, which was neutralized with a 6N aqueous solution of sodium hydroxide. The solvent was completely distilled off under reduced pressure. To the residue ~as added 200 ml of methanol. The mixture was mixed well, then insolubles were filtered off. The solvent was aistilled off under reduced pressure to give 2.99 g of a crude product (70~l white solid).
This crude product was used, without purification, in the subsequent reaction.
NMR(200MHz,D20) ~: 1.32(3H,t,J=7.6Hz), 2.78(2H,q,J=7.6Hz), 4.83(2H,s), 6.15(1H,br), 7.86(1H,d,J=3.0Hz), 7.74(1H,d,3.0Hz), 7.75(1H,s), t 8.00(1H,s).
IR(KBr): 3348, 1652, 1644, 1390 cm .
ii) Synthesis of 2-ethyl-5-chloromethylimidazo[ll2 a]pyridine-hydrochloride To a mixture solution consisting of 8.8 ml (120.0 2 ~ 93223 W096/02542 P~ 7 mmol) of thionyl chloride and 10 ml of methylene chloride was added, 4.23 g (24.0 mmol) of 2-ethyl-5-hydroxymethylimidazo[l,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature. Then, the solvent and excess volume of thionyl chloride were distilled off under reduced pressure. To the residual white solid was added 30 ml of toluene. The mixture was stirred well, and the solvent was distilled off under reduced pressure. This process repeated twice to give 5.44 g of a crude product (99.0~, white solid), which was used for the subsequent reaction without purification.
NMR(200MHz,D20) ~: 1.35(3H,t,J=7.6Hz), 2.85(2H,q,J=7.6Hz), 5.02(2H,s), 7.42(1H,d,J=2.9Hz), 7.75(1H,s), 7.77(1H,d,J=2.8Hz), 7.90(1H,s).
IR(~Br): 3225, 1659, 1550, 1430 cm .
iii) Synthesis of 2-ethyl-5-[N-[5-(trifluoro-methanesulfonamido)pentan-1-yl]~m i n~ ~ Lhyl]imidazo[1,2-a]pyridine To a suspension of 5.50 g (24.0 mmol) of 2-ethyl-5-chloromethylimidazo[1,2-a]pyridine-hydrochloride in 60 ml of acetonitrile was added 4.90 g (48.0 mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutes under reflux. After completion of the reaction, the reaction mixture was cooled, and then, the resulting precipitate of 1.5-diaminopentane-dihydrochloride was separated by filtration and then, washed with 10 ml of acetonitrile twice. The filtrate and the washings were combined, to which was added 6.7 ml (48.0 mmol) of triethylamine.
The mixture was 9tirred sufficiently. To this solution was added 10.29 g (28.8 mmol) of N-phenyl trifluoromethanesulfonimide, and the mixture was stirred for two hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was extracted W096l02~2 2 ~ 2 3 1 ~J/J. r l~&~ ~

with 150 ml of chloroform. The organic layer was washed with 150 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give Ç.03 g of the desired compound (64.0%, colorless solid).
NMR(200MHz,CDCl3) ~: 1.33(3H,t,J=7.6Hz), 1.29-1.63(6H,m), 2.64(2H,t,J=6.6Hz), 2.81(2H,q,J=7.6Hz), 3.29(2H,t,J=7.0Hz), 3.94(2H,s), 4.85(1H,br,NH), 6.70(1H,d,J=7.0Hz), 7.11(1H,dd,J=9.0,7.0Hz), 7.39(1H,s), 7.47(1H,d,J=9.OHz).
IR(~Br): 1645, 1480, 1361 cml. ~ ~
iv) Synthesis of 4,5-dihydro-2-ethyl-4-[5-(trifluoro-methanesulfonamido)pentan-l-yl]-3H-1,4,8b-triaza-acenaphthylene To a solution of 785 mg (2.00 mmol) of 2-ethyl-5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]~min~ thyl]imidazo[l,2-a]pyridine in 5 ml of acetic acid was added 2.25 ml (30.00 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100~C. The solvent was then distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with lN HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=20:1) to give 527 mg of the desired compound (65.2~, colorless liquid).
NMR(200MHz,CDCl3) ~: 1.29(3H,t,J=7.6Hz), 1.43(2H,m), 1.60(4H,m), 2.48(2H,t,J=7.0Hz), 2.72(2H,q,J=7.6Hz), 3.28(2H,t,J=6.8Hz), 3.91(2H,s), 4.02(2H,s), W096/02542 PCTID~5/01382 6.50(1H,d,J=7.0Hz), 7.07(1H,dd,J=9.2,7.0Hz), 7.36(1H,d,J=9.2Hz).
IR(neat): 1645, 1508, 1455, 1365 cml v) Synthesis of 4,5-dihydro-2-ethyl-4-[5-(trifluoro-methanesulfonamido)pentan-l-yl]-3H-lr4r8b-triA7~rr~
naphthylene-dihydrochloride In a mixture of 10 ml of ethanol and l ml of 12N
HCl was dissolved 542 mg (1.34 mmol) of 4,5-dihydro-2-ethyl-4-(5-trifluoromethanesulfonamidopentan-1-yl)-3H-l,4,8b-triA7~renaphthylene~ The solvent was distilled off under reduced pressure to leave 640 mg of the desired compound (100~, white amorphous substance).
NMR(200MHz,DMSO) ~: 1.37(5H,m), 1.57(2H,m), 1.85(2H,m), 2.92(2H,q,J=7.6Hz), 3.15(4H,m), 4.85~2H,s), 4.92(2H,s), 7.68(1H,d,J=6.2Hz), 7.94(2H,m), 9.43(1H,t,J=5.4Hz).
IR(RBr): 3427, 1666, 1550, 1458, 1365 cm .
Example 5 4,5-Dihydro-2-phenyl-4-[5-(trifluoromethane-sulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene-dihydrochloride i) Synthesis of 2-phenyl-5-hydroxymethylimidazo[1,2-a]pyridine To a solution of 3.14 g (11.79 mmol) of ethyl ester of 2-phenylimidazo[1,2-a~pyridine-5-carboxylic acid was added, under ice-cooling, 1.34 g (35.37 mmol) of sodium borohydride. The mixture was stirred for 3 hours under ice-cooling. The reaction mixture was poured into 150 ml of ice-water, which was sufficiently blended. To the mixture was added 12N HCl until the pH
reached 2. This solution was stirred for two hours at room temperature, which was neutralized with a 6N
aqueous solution of NaOH. The solvent was then completely distilled off under reduced pressure. To the residue was added 200 ml of methanol. The mixture was sufficiently blended, then insolubles were filtered off. The solvent was distilled off under reduced W096/02542 2 1 9 3 ~ ~ 3 PCT/JP95/01382 ~

pressure to leave 1.37 g of a crude product (52.0%, white solid). This crude product was used in the subsequent reaction without purification. -NMR(200NHz,DNSO-d6) 6: 4.95(2H,s), 6.15(1H,br), 6.90(1H,d,J=6.0Hz), 7.21-7.54(6H,m), 3.03(1H,d,J=7.0Hz), 8.45(1H,s).
IR(KBr): 3360, 1663, 1653, 1395 cml.
ii) Synthesis of 2-phenyl-5-chloromethylimidazo[1,2-a]pyridine-hydrochloride To a mixture solution consisting of 3.7 ml (50.0 mmol) of thionyl chloride and 5.0 ml of methylene chloride was added, 2.24 g (lO.0 mmol) of 2-phenyl-5-IIYILU~Y Lhylimidazo~1,2-a]pyridine with small portion.
The reaction mixture was stirred for one hour at room temperature, then the solvent and excess volume of thionyl chloride were distilled off under reduced pressure to leave a white solid. Toluene (20 ml) was added to the white solid, and the mixture was sufficiently blended, followed by distilling off the solvent under reduced pressure. This process was repeated twice to give 2.76 g a crude product (99.0%, white solid).
NNR(200NHz,DNSO-d6) 8: 5.10(2H,s), 6.95(1H,d,J=6.0Hz), 7.25-7.60(6H,m), 8.09(1H,d,J=7.0Hz), 8.51(1H,s).
IR(KBr): 3222, 1665, 1546, 1431 cm~.
iii) Synthesis of 2-phenyl-5-[N-[5-(trifluoromethane-sulfonamido)pentan-1-yl]aminomethyI]imidazo[1,2-z]pyridine To a suspension of 2.79 g (lO.0 mmol) of 2-phenyl-5-chloromethylimi~A7~[1,2-a]pyridine-hydrochloride in 35 ml of acetonitrile was added 2.04 g (20.0 mmol) of 1,5-diaminopentane. The mixture was heated for 30 minutes under reflux. After completion of the reaction, the reaction mixture was cooled. The resulting precipitate of 1,5-diaminopentane-dihydrochloride was separated by W096/02542 I~~ J

filtration and washed twice with 10 ml of acetonitrile.
The filtrate and washings were combined, to which was added 2.8 ml (20.0 mmol) of triethylamine. The mixture was stirred sufficiently, to which was added 4.29 g (12.0 mmol) of N-phenyltrifluoromethanesulfonimide, and the mixture was stirred for two hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to extraction with 100 ml of chloroform. The organic layer was washed with 100 ml of a saturated aqueous saline solution and dried over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=20:1) to give 2.66 g of the desired compound (60.3~, colorless solid).
NMR(200MHz,DMSO-d5) ~: 1.51(6H,m), 2.62(2H,t,J=6.8Hz), 3.12(2H,t,J=6.8Hz), 4.07(2H,s), 6.91(1H,d,J=6.0Hz), 7.21-7.54(6H,m), 8.02(1H,d,J=1.OHz), 8.42(1H,s).
IR(KBr): 1640, 1480, 1370 cml.
iv) Synthesis of 4,5-dihydro-2-phenyl-4-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-3H-1,4,8b-triaza-acenaphthylene To a solution of 440 mg (1.00 mmol) of 2-phenyl-5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]~minl thyl]imidazo[l,2-1]pyridine in 5 ml of acetic acid was added 1.12 ml (15.00 mmol) of a 37% aqueouS
solution of formalin. The mixture was heated for 30 minutes at 100CC. After completion of the reaction, the solvent was distilled off under reduced pressure.
he residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with lN HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure.

. .

?~ 9~3 ~096/02~42 .~IIJ. l~

The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 354 mg of the object compound (78.3~, colorless -liquid).
NMR(200MHz,CDCl3) ~: 1.24(2H,m), 1.44(4H,m), 2.39(2H,t,J=7.OHz), 3.14(2H,t,J=7.0Hz), 3.90(2H,s), 4.21(2H,s), 6.52(1H,d,J=6.8Hz), 7.12(1H,dd,J=9.2,6.8Hz), 7.33(1H,d,J=7.2Hz), 7.40-7.72(5H,m).
IR(neat): 1645, 1508, 1455, 1366 cml.
v) Synthesis of 4,5-dihydro-2-phenyl-4-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-3H-1,4,8b-triaza-acenaphthylene-dihydrochloride In a solution consisting of 5 ml of ethanol and 0.1 ml of 12N HCl was dissolved 254 mg (0.56 mmol) of 4,5-dihydro-2-phenyl-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-tri~7~rt~n~phthylene. The solvent was distilled under reduced pressure to give 295 mg of the desired compound (100%, white amorphous).
NMR(200~Hz,DMSO-d6) ~: 1.48(2H,m), 1.59(2H,m), 1.85(2H,m), 3.16(4H,m), 4.87(2H,s), 4.98(2H,s), 7.45(1H,t,J=3.6Hz), 7.61-7.70(3H,s), 7.84-7.94(4H,m), 9.38(1H,t,J=5.8Hz).
IR(~Br): 3423, 1662, 1441, 1369, 1192 cm~l.
Example 6 4,5-Dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-tr;~7~rrnArhthylen-3-one hydrochloride i) Synthesis of 5-[N-tert-butoxycarbonyl-N-[4-trifluoromethanesulfonamido)butan-1-yl]aminomethyl]-imidazo[1,2-a]pyridine To a solution of 29.10 g (83.05 mmol) of 5-[N-[4-(trifluoromethanesulfonamido)butan-1-yl]~min~ Lhyl]
imidazo[1,2-a]pyridine in 100 ml of ethanol was added dropwise, taking 10 minute, 18.13 g (83.13 mmol) of di-tert-butyl dicarbonate. The reaction mixture was 2 ~ 93223 ~ WO96/02!i42 ~ I/J~ o~

stirred for one hour at room temperature, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 26.33 g of .~ 5 the desired compound(70.4%, pale yellow solid).
NMR(2o3MHzrcDcl3) ~: 1.48(13H,m), 3.24(4H,br), 4.67(2H,br), 6.69(1H,d,J=6.2Hz), 7.19(1H,t,J=6.2Hz), 7.50-7.80(3H,m).
IR(KBr): 2978, 1691, 1516, 1379, 1228 cm .
ii) Synthesis of 3-trichloroacetyl-5-[N-tert-but carbonyl-N-[4-(trifluoromethanesulfonamido)butan-l-yl]~min( ~hyl]imidazo[1,2-a]pyridine To a solution of 7.86 g (17.44 mmol) of 5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethanesulfonamido)butan-1-yl]~m i n I thyl]imidazo[1,2-a]pyridine and 6.39 g (52.31 mmol) of 4-dimethylaminopyridine in lO0 ml of chloroform was added dropwise, taking 5 minutes, 5.84 ml (52.31 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 16 hours under reflux.
The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution and dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=lO0:1) to give 5.72 g of the desired compound (55.0%, pale yellow liquid).
NMR(200MHz,CDCl3) ~i: 1.55-1.85(4H,m), ~ 3.38(2H,t,J=7.4Hz), 3.77(2H,t,J=6.6Hz), 4.50(2H,s), 7.11(1H,d,J=6.6Hz), 7.69tlH,dd,J=8.6,7.2Hz), 7.81(1H,d,J=8.6Hz), 8.95(1H,s).
IR(neat): 2978, 1755, 1705, 1768, 1404 cml.
iii) Synthesis of 4,5-dihydro-4-[4-(trifluoro-methanesulfonamido)butan-1-yl]-3H-1,4,8b-W0961~42 2 1 9 3 ~ ~ 3 PCT1~9~1382 ., triazaacenaphthylen-3-one To a solution of 5.25 g (8.81 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(tri f luoromethanesul f onamido)butan-l-yl]aminomethyl]imidazo[1,2-a]pyridine in 25 ml of chloroform was added dropwise 2.5 ml (17.62 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 10 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate.
This solution was extracted with 250 ml of ethyl acetate. The organic layer was washed with 100 ml of a l.ON aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure.
The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 2.16 g (65.0%) of the desired compound.
NMR(200MHz,CDCl3) 8: 1.41-1.88(4H,m), 3.42(2H,t,J=6.0Hz), 3.64(2H,t,J=6.6Hz), 5.02(2H,s), 6.77(1H,d,J=7.OHz), 7.35(1H,dd,J=9.2,7.OHz), 7.54(1H,d,J=9.2Hz), 8.15(1H,s).
IR(~Br): 1641, 1542, 1369, 1189 cml.
iv) Synthesis of 4,5-dihydro-4-[4-(trifluoromethane-sulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride In a mixture of 50 ml of ethanol and 1 ml of 12N
HCl was dissolved 2.87 g (7.63 mmol) of 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one, and the solvent was distilled off under reduced pressure to leave 3.15 g of the desired compound t100%, pale yellow solid matter).
NMR(200MHz,DMSO) 8: 1.45-1.78(4H,m), 3.20(2H,dd,J=9.6,5.6Hz), 3.55(2H,t,J=6.6Hz), 5.25(2H,s), 7.43(1H,d,J=8.0Hz), 7.85(1H,d,J=8.2Hz), 2 1 932~3 ~ WO96/02542 I~,IIJ~. . I.5~,C
- 89.-7.99(1H,dd,J=8.2,8.0Hz), 8.63~1H,s), 9.44(1H,t,J=5.6Hz).
IR(~Br): 1649, 1560, 1479, 1369 cml.
Example 7 4,5-Dihydro-4-[3-(trifluoromethanesulfonamido)propan-1-yl]-3H-1,4,8b-tri~7~c~n~phthylen-3-one-hydrochloride i) Synthesis of 5-[N-[3-(trifluoromethane-sulfonamido)propan-1-yl]aminomethyl]imidazo[1,2-a]pyridine To a suspension of 6.89 g (33.9 mmol) of 5-chloromethylimidazo[1,2-a]pyridine hydrochloride in 100 ml of acetonitrile was added 5.03 g (67.9 mmol) of 1,3-~i~min~propane. The mixture was heated for 30 minutes under reflux. After completion of the reaction, the reaction mixture was cooled to cause precipitation of 1,3-diaminopropane-dihydrochloride.
The precipitate was separated by filtration and washed twice with 10 ml of acetonitrile. The filtrate and the washings were combined, to which was added 9.46 ml (67.9 mmol) of triethylamine, and the mixture was stirred sufficiently. To the solution was added 24.26g (67.9 mmol) of N-phenyltrifluoromethanesulfonimide, and the mixture was stirred for two hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was extracted with 250 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=20:1) to give 7.18 g of the desired compound (63.0~, colorless solid matter).
NMR(200MHz,CDCl3) 6: 1.82(2H,m), 2.88(2H,t,J=5.8Hz), 3.43(2H,t,J=5.8Hz), 4.00(2H,s), 4.85(1H,br), 6.73(1H,d,J=6.6Hz), 7.12(1H,dd,J=9.2,6.6Hz), W096l02~2 2 1 9 ~ ? 2 3 ~ J. ~IJ~?

7.54(1H,d,J=9.2Hz), 7.57(2H,s).
IR(RBr): 1620, 1464, 1367, 1225, 1184 cml.
ii) Synthesis of 5-~N-tert-butoxyc2rbonyl-N-[3 (trifluoromethanesulfonamido)propan-l-yl]-aminomethyl]imidazo[l,2-a]pyridine To a solution of 3.03 g (9.01 mmol) of 5-[N-[3-(trifluoromethanesulfonamido)propan-l-yl]~mint -thyl]
imidazo[l,2-a]pyridine in 20 ml of ethanol was added dropwise, taking 5 minutes, 1.~7 g (9.01 mmol) of di-tert-butyl dicarbonate. The reaction mixture was stirred for one hour at room temperature, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 3.38 g of the desired compound (86.1~, colorless liquid).
NMR(200MHz,CDCll) 5: 1.51(9H,s), 1.60(2H,m), 3.21(2H,t,J=6.2Hz), 3.41(2H,br), 4.66(2H,s), 6.88(1H,d,J=7.0Hz), 7.18(1H,m), 7.53(3H,m).
IR(KBr): 1691, 1469, 1416, 1371, 1186 cml.
iii) Synthesis of 3-trichloroacetyl-5-[N-tert-butoxy-carbonyl-N-[3-(trifluoromethanesulfonamido)propan-1-yl ] ~m i n( ~hyl]imidazo[1,2-a]pyridine To a solution of 3.15 g (7.22 mmol) of 5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfon-amido)propan-l-yl]~min~ thyl]imidazo[l,2-a]pyridine and 2.65 g (21.65 mmol) of 4-dimethylaminopyridine in 30 ml of chloroform was added dropwise, while stirring at room temperature for 3 minutes, 2.4 ml (21.65 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 15 hours under reflux. After completion of the reaction, the reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline 2 1 ~32~
~ W096/02542 r~l/J~ h~

solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.31 g of the desired compound (54.8%, pale yellow liquid).
NMR(2coMHz~cDcl3) ~: 1.21(9H,s), 1.84(2H,m), 3.35(2H,m), 3.53(2H,t,J=5.8Hz), 4.46(2H,s), 7.09(1H,d,J=7.2Hz), 7.73(1H,dd,J=8.8,7.4Hz), 7.85(1H,dd,J=7.6Hz), 8.98(1H,s).
IR(KBr): 1680, 1471, 1373, 1296, 1188 cm .
iv) Synthesis of 4,5-dihydro-4[3-(trifluoromethane-sulfonamido)propan-l-yl]-3H-1,4,8b-triaza-acenaphthylene-3-one To a solution of 1.16 g (2.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfonamido)propan-l-yl]~min~ thyl]imidazo~l,2-a]pyridine in 25 ml of chloroform was added dropwise 0.57 ml (4.00 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 15 minutes, which was then poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extractedith 150 ml of ethyl acetate. The organic layer was washed with 100 ml of a l.ON aqueous solution of sodium thiosulfate, then with 100 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroformtmethanol=20:1) to give 397 mg of the desired ~ ~ ul-d (54.8%, pale yellow solid).
NMR(2ocMHz~cDcl3) ~: 1.95(2H,m), 3.34(2H,t,J=5.8Hz), 3.73(2H,t,J=6.0Hz), 5.04(2H,s), 6.79(lH,d,J=7.OHz), 7.68(lH,br,NH), 8.13(lH,s).
IR(~Br): 1637, 1545, 1367, 1184 cm~.

W096/02542 ~ 2 2 ~ PCTI~95/01382 _ 92 -v) Synthesis of 4,5-dihydro-4-[3-(trifluoromethane-sulfonamido)propan-l-yl]-3H-1,4,8b-ri ~ 7~Ao~n;~rhthylene-3-one ~ hydrochloride In a mixture solution consisting of 5 ml of ethanol and 0.1 ml of 12N HCl was dissolved 145 mg (0.40 mmol) of 4,5-dihydro-4-[3-(trifluoromethanesulfonamido)propan-l-yl]-3H-1,4,8b-tr;A7~o~n~rhthylen-3-one. The solvent was distilled off under reduced pressure to leave 160 mg of the desired compound (100%, pale yellow solid substance).
NMR(200MHz,DMSO) ~: 1.91(2H,m), 3.26(2H,q,J=6.0Hz), 3.60(2H,t,J=7.6Hz), 5.28(2H,b), 7.46(1H,d,J=6.8Hz), 7.88(1H,d,J=8.8Hz), 8.02(1H,dd,J=8.8,6.8Hz), 8.66(1H,s), 9.52(1H,t,J=5.8Hz).
IR(KBr): 3455, 1659, 1444, 1371, 1182 cm .
Example 8 4,5-Dihydro-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride i) Synthesis of 5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-l-yl]~min~ Lhyl]-imidazo[l,2-a]pyridine To a solution of 5.00 g (13.72 mmol) of 5-[N-[5-(trifluoromethanesulfonamido)pentan-l-yl)aminomet-hyl]imidazo[l,2-a]pyridine in 25 ml of ethanol was added dropwise, taking 5 minutes, 2.99 g (13.72 mmol) of di-tert-butyl dicarbonate. The reaction mixture was stirred for one hour at room temperature, then the solvent was distllled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 5.73 g of the desired compound (90.2~, colorless liquid).
NMR(200MHz,CDCl3) ~: 1.28(6H,m), 1.48(9H,s), 3.10-3.25(4H,m), 4.68(2H,s), 6.68(1H,d,J=6.8Hz), 7.19(1H,t,J=6.8Hz), 7.57(1H,s), 7.61(1H,s), 7.75(1H,br).
IR(neat): 1699, 1512, 1471, 1419 cm1.

2 1 932?~
~ W096/02s42 PCT/JP9~101382 ii) Synthesis of 3-trichloroacetyl-5-[N-tert-butoxy-carbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl ] ~m i n~ Lhyl~imidazo[1,2-a]pyridine To a solution of 3.55 g (7.64 mmol) of 5-[N-tert-; 5 butoxycarbonyl-N-[5-(trifluoromethane-sulfonamido)pentan-l-yl]~min~ Lhyl]imidazo[1,2-a]pyridine and 2.80 g (22.92 mmol) of 4-dimethylaminopyridine in 35 ml of chloroform was added dropwise 2.6 ml (22.92 mmol) of trichloroacetyl chloride, while stirring at room temperature for 3 minutes. The reaction mixture was heated for 15 hours under reflux. The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.70 g of the desired compound (58.2~, pale yellow liquid).
NMR(2ooMHz~cDcl3) ~: 1.23(9H,s), 1.48(2H,m), 1.69(4H,m), 3.35(4H,m), 4.49(2H,s), 6.31(1H,br), 7.13(1H,d,J=7.0Hz), 7.72(1H,dd,J=8.8,7.0Hz), 7.84(1H,d,J=8.8Hz), 8.96(1H,s).
IR(neat): 1695, 1670, 1497, 1470 cm1 iii) Synthesis of 4,5-dihydro-4-[5-(trifluoro-methanesulfonamido)pentan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3-one To a solution of 1.75 g (2.87 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-l-yl]~min~ thyl]imidazo[l,2-a]pyridine in 25 ml of chloroform was added dropwise 0.82 ml (5.74 mmol) of iodotrimethylsilane at room temperature. The reaction W096/02s42 ~ 2 2 ~ PCT/~/01382 mixture was stirred for 15 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrog~n~rhonate.
This solution was extracted with 150 ml of ethyl acetate. The organic layer was washed with a l.ON
aqueous solution of sodium thiosulfate, then with 100 ml of a saturated a~ueous saline solution. The organic layer was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 706 mg of the object product (63.1~, pale yellow solid substance).
NMR(200MHz,CDCl3) ~: 1.48(2H,m), 1.71(4H,m), 3.32(2H,t,J=6.6Ez), 3.57(2H,t,J=6.8Hz), 4.99(2H,s), 6.74(1H,d,J=7.0Hz), 7.30(1H,dd,J=9.2,7.0Hz), 7.48(1H,d,J=9.2Hz), 8.07(1H,s), 8.11(1H,br).
IR(RBr): 1707, 1610, 1544, 1332, 1219 cm .
iv) Synthesis of 4,5-dihydro-4-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride In a mixture solvent consisting of 5 ml of ethanol and 0.1 ml of 12N HCl was dissolved 593 mg (1.52 mmol) of 4,5-dihydro-4-[5-(trifluoromethane-sulfonamido)pentan-1-yl]-3H-1,4,8b-triazacenaphthylen-3-one. The solvent was distilled off under reduced pressure to_leave 650 mg of the desired compound (1004, pale yellow solid).
NMR(200MHz,DMSO) ~: 1.40(2H,m), 1.60(4H,m), 3.15(4H,m), 5.27(2H,s), 1.47(1H,d,J=7.2Hz), 7.55(1H,d,J=9.OHz), 8.03(1H,dd,J=9.0,7.2Hz), 8.64(lH,s), 9.45(1H,t,J=5.4Hz).
IR(KBr): 1720, 1655, 1442, 1365, 1188 cml.
Example 9 4,5-Dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido) butan-l-yl]-3H-1,4,8b-triazaacenaphthylen-3-2 } ~3~3 O 96102542 Y~I/J~

one.hydrochloride i) Synthesis of 2-methyl-5-[N-tert-butoxycarbonyl-N-- [4-(trifluoromethanesulfonamido)butan-1-yl ] ~m i nl ~ thyl]imidazo[1,2-a]pyridine To a solution of 2.41 g (6.61 mmol) of 2-methyl-5-[N-[4-(trifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[l,2-a]pyridine in 15 ml of ethanol was added dropwise, for 5 minutes, 1.44 g (6.61 mmol of di-tert-butyl dicarbonate. The reaction mixture was stirred for one hour at room temperature, then the solvent was distilled off under reduced ---pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 2.21 g of the desired compound (72.1~, colorless liquid).
NMR(200~Hz,CDCl3) 6: 1.49(9H,s), 2.44(3H,s), 3.23(4H,m), 4.62(2H,s), 6.61(1H,d,J=6.8Hz), 7.14(1H,t,J=8.6Hz), 7.35(1H,br), 7.48(1H,d,J=8.6Hz).
IR(neat): 1686, 1510, 1467, 1367 cm .
ii) Synthesis of 2-methyl-3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-ttrifluoromethanesulfonamido)butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine To a solution of 2.90 g (6.24 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethane-sulfonamido)butan-1-yl]~min~ ~thyl]imidazo[1,2-a]pyridine and 2.29 g (18.73 mmol) o~ 4-dimethylaminopyridine in 25 ml of chloroform was added dropwise, for 3 minutes, 2.1 ml (18.73 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. The reaction mixture was then poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution and dried over magnesium sulfate, followed by distilling off the ~096l02j42 2 1 ~ ~ 2 ~ 3 P~l/J~

solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=100:1) to give 2.47 g of the desired compound (65.2~, pale yellow liquid).
NMR(2ooMHz~cDcl3) 6: 1.23(9H,br), 1.66(4H,m), 2.83(3H,s), 3.38(4H,m), 4.07(2H,s), 6.96(1H,d,J=7.0Hz), 7.60(1H,dd,J=8.8,7.0Hz), 7.75(1H,d,J=8.8Hz).
IR(neat): 1693, 1672, 1465, 1365 cm .
iii) Synthesis of 4,5-dihydro-2-methyl-4-[4-(trifluoro-methanesulfnn~mi~ln)-l-yl]-3~ 4~8b-triA7~An~n~r~h thylen-3-one To a solution of 781 mg (1.28 mmol) of 2-methyl-3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(trifluoromethanesulfonamido)butan-1-yl]~min~ ~hyl]imidazo[1,2-a]pyridine in 10 ml of chloroform was added dropwise, at room temperature, 0.36 ml (2.56 mmol) of iodotrimethylsilane. The reaction mixture was stirred for 10 minutes, which was poured into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. This solution was extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of a l.ON aqueous solution of sodium thiosulfate, then with 50 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent:
chloroform/methanol=20:1) to give 290 mg of the desired compound (58.0%, pale yellow ~olid).
NMR(200MHz,CDCl3) ~: 1.86(4H,m), 2.73(3H,s), 3.61(4H,m), 4.97(2H,s), 6.68(1H,d,J=6.8Hz), 7.28(1H,dd,J=9.2,6.8Hz), 7.41(1H,d,J=9.2Hz).
IR(KBr): 1697, 1660, 1535, 1448 cml iv) Synthesis of 4,5-dihydro-2-methyl-4-(4-trifluoro-methanesnlfnnAmidobutan-l-yl)-3H-1,4,8b-triazaace_ _ _ _ _ , .. . . , ... _ .. ....... . , _ . .. . . . . . . . _ _ _ _ ~ W096l0~42 2 1 9 3 2 2 3 P~ 1J~

naphthylen-3-one-hydrochloride 234 mg (0.6 mmol) of 4,5-dihydro-2-methyl-4-[4-: (trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one was dissolved in a mixture solvent consisting of 2 ml of ethanol and 0.05 ml of 12N HCl. The solvent was distilled off under reduced pressure to leave 256 mg of the desired compound (100~, pale yellow solid substance).
NMR(200MHz,CDCl3) ~: 1.65(2H,m), 1.81(2H,m), 2.56(3H,s), 3.15(4H,m), 5.27(1H,s), 7.47(1H,d,J=7.2Hz), 7.87(1H,d,J=g.OHz), 8.03(1H,dd,J=9.0,7.2Hz), 8.67(lH,s), 9.31(lH,br).
IR(KBr): 3428, 1716, 1664, 1444 cm .
Example lO
4,5-Dihydro-2-ethyl-4-[5-(trifluoromethanesulfonamido)-pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene-hydrochloride i) Synthesis of 2-ethyl-5-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]Rminl Lhyl]-imidazo[1,2-a~pyridine To a solution of 3.00 g (7.64 mmol) of 2-ethyl-5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 20 ml of ethanol was added dropwise, for 5 minutes, 1.67 g (7.64 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for one hour at room temperature, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 3.09 g of the desired compound (82.1%, colorless liquid).
- NMR(200MHz,CDCl3) ~: 1.21-1.45(9H,m), 1.49(9H,s), 2.82(2H,q,J=7.6Hz), 3.06(2H,br), 3.22(2H,br), 4.65(2X,br), 6.60(1H,d,J=6.0Hz), 7.13(2H,m), 7.51(1H,d,J=9.2Hz).
IR(neat): 1684, 1512, 1462, 1365 cm ii) Synthesis of 2-ethyl-3-trichloroacetyl-5-[N-tert ?~ 532~
W096102s42 PCT/~9~01382 butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)-pentan-l-yl]~min~ thyl]imidazo[l,2-a]pyridine To a solution of 2.85 g (5.79 mmol) of 2-methyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethane-sulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 3.53 g (28.g3 mmol) of 4-dimethylaminopyridine in 35 ml of chloroform was added dropwise, for 3 minutes under stirring at room temperature, 3.2 ml (28.93 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 20 hours under reflux. After completion of the reaction, the reaction mixture was poured into icQ-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=IOO:l) to give 2.04 g of the desired compound (55.2%, pale yellow liquid).
NMR(200MHz,CDCl3) ~: 1.23(9H,br), 1.43(3H,t,J=7.6Hz), 1.65(6H,m), 3.15(2H,q,J=7.6Hz), 3.34(4H,m), 4.11(2H,s), 6.94(1H,d,J=7.OHz), 7.57(1H,dd,J=8.8,7.0Hz), 7.71(1H,d,J=8.8Hz).
IR(neat): 1690, 1670, 1470, 1363 cml.
iii) Synthesis of 4,5-dihydro-2-ethyl-4-[5-(trifluoro-methanesulfonamido)pentan-l-yl]-~-1,4,8b-triazaacenaphthylen-3-one To a solution of 1.73 g (2.71 mmol) of 2-ethyl-3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-l-yl]aminomethyl]imidazo[l,2-a]pyridine in 15 ml of chloroform was added dropwise 0.80 ml (5.42 mmol) of iodotrimethylsilane at room temperature. The reaction mixture was stirred for 10 minutes, which was poured _ _ _ _ _ _ _ _ , ~ W096l02~42 2 t 93223 P~I/Jr3- IJ~2 into ice-water, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate.
This solution was extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of l.ON aqueous solution of sodium thiosulfate, then with 50 ml of a saturated aqueous saline solution. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure.
The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=20:1) to give 603 mg of the desired compound (52.3~, pale yellow solid~.
NMR(200MHz,CDCl3) ~: 1.35(3H,t,J=7.6Hz), 1.48(2H,m), 1.70(4H,m), 3.13(2H,q,J=7.6Hz), 3.33(2H,t,J=6.2Hz), 3.58(2H,t,J=6.6Hz), 4.96(2H,s), 6.68(1H,d,J=7.0Hz), 7.00(1H,br), 7.28(1H,dd,J=8.8,7.0Hz), 7.44(lH,d,J=8.8Hz).
IR(R~3r): 1700, 1650, 1537, 1446 cml.
iv) Synthesis of 4,5-dihydro-2-ethyl-4-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaace-naphthylen-3-one-hydrochloride In a mixture solvent consisting of 2 ml of ethanol and 0.05 ml of 12N HCl was dissolved 110 mg (0.26 mmol) of 4,5-dihydro-2-ethyl-4-[5-(trifluoromethane-sulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one. The solvent was distilled off under reduced pressure to leave 120 mg of the desired compound (100~, pale yellow solid).
NMR(200MHz,DMSO) ~: 1.18(3H,t,J=7.6Hz), 1.32(2H,m), 1.53(4H,m), 3.01(t,2H,J=6.2Hz), 3.42(2H,t,J=6.6Hz), 5.26(2H,s), 7.45(1H,d,J=7.2Hz), 7.86(1H,d,J=9.OHz), 8.01(1H,dd,J=9.0,7.2Hz), 8.65(1H,s), 9.32(1H,br).
IR(K~r): 3425, 1720, 1665, 1442 cml.
Example 11 4,5-Dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-WO 96102542 2 1 9 ~ ~ 2 3 ~, IlJr ~

dione~hydrcchloride i) Synthesis of 4,5-dihydro-4-[4-(trifluoromthane-sulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a solution of 5.05 g (57.3 mmol) of 1,4-~;~min~hutane and 14.81 g (114.6 mmol) of N,N-diisopropylethylamine in 200 ml of acetonitrile was added a solution of 19.22 g (57.3 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 100 ml of acetonitrile. The mixture was heated for 0.5 hour under reflux. The reaction mixture was left standing for cooling. Insolubles were then filtered off. To the filtrate was added 24.56 g (68.7 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 0.5 hour at room temperature. The solvent was distilled off. To the residue was added chloroform, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a column chromatography (eluent: ethyl acetate). The purified product was recrystallized from ethyl acetate. The crystalline product was collected by filtration, washed with ethyl acetate and dried to give 9.06 g of t~e desired compound (40.5%, colorless crystals), m.p.205.0-207.0~C.
Elemental Analysis for Cl4H~3N~04SF3:
Calcd.: C, 43.08; H, 3.36; N, 14.35.
Found : C, 43.32; H, 3.43; N, 14.30.
NMR(200MHz,CDCl3-DMSO-d6) ~: 1.60-1.92(4H,m), 3.26(2H,t,J=6.6Hz), 4.19(2H,t,J=7.OHz), 7.83(1H,dd,J=8.8,7.6Hz), 8.18(1H,d,J=7.6Hz), 8.20(1H,d,J=8.8Hz), 8.60(1H,br), 8.62(1H,s).
ii) Synthesis of 4,5-dihydro-4-[4-(trifluoromethane-sulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride 2 I q3223 ~ W096/02~42 r~l~JI7r.~

To a suspension of 204 mg ~0.52 mmol) of 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazacenaphthylene-3,5-dione in 10 ml of :~
methanol was added 0.12 ml of conc. HCl, then the solvent was distilled off. To the residue was added acetone, and the resulting solid substance was washed with acetone and dried to give 170 mg of the desired compound (76.2%, colorless solid substance), m.p.206.0-207.0~C.
Elemental Analysis for Cl4HI3N4O45F3~HCl:
Calcd.: C, 39.40; H, 3.31; N, 13.13.
Found : C, 39.42; H, 3.38; N, 12.95.
NMR(2coMHz~DMso-d6) 6: 1.50-1.80(4H,m), 3.18(2H,m), 4.04(2H,t,J=6.6Hz), 7.92(1H,dd,J=8.8,7.4Hz), 8.14(1H,dd,J=7.4,1.0Hz), 8.31(1H,dd,J=8.8,1.0Hz), 8.69(1H,s), 9.35~1H,br).
Example 12 4,5-Dihydro-4-[3-(trifluoromethanesulfonamido)propan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[3-(trifluoromethane-sulfonamido)propan-l-yl]-3H-1,4,8b-triazaacenaphthyl-ene-3,5-dione To a solution of 273 mg (3.68 mmol) of 1,3-diaminopropane and 951 mg (7.36 mmol) of N,N-diisopropylethylamine in 15 ml of acetonitrile was added a solution of 1.235 g (3.68 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo [1,2-a]pyridine in 15 ml of acetonitrile. The mixture was heated for 45 minutes under reflux. After cooling, the resulting insolubles were filtered off. To the filtrate was added 1.578 g (4.42 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added chloroform. The mixture was washed with an aqueous W096/02~2 2 ~ 9 ~ 22~ cl~o~ ~

solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), which was crystallized from ethyl acetate. The crystalline product was collected by filtration, washed with ether, and dried to give 607 mg of the desired compound (43.8%, colorless solid), m.p.169.0-170.0~C.
Elemental Analysis for Cl3HIlN4O4SF3:
Calcd.: C, 41.19; H, 2.95; N, 14.89.
Found : C, 41.19; H, 2.98; N, 14.63.
NM~(200MHz,CDCl3-DMSO-d6) ~: 2.02(2H,m), 3.34(2H,t,J=6.8Hz), 4.25(2H,m), 7.85(1H,m), 8.15-8.22(2H,m), 8.62(1H,s).
ii) Synthesis of 4,5-dihydro-4-[3-(trifluoromethane-sulfonamido)propan-1-yl]-3H-1,4,8b-triazaacenaphthyl-ene-3,5-dione-hydrochloride To a suspension of 186 mg (0.49 mmol) of 4,5-dihydro-4-[3-(trifluoromethanesulfonamido)propan-1-yl]-3H-1,4,8b-tri~z~n~rhthylene-3~s-dione in 10 ml of methanol was added 0.09 ml of conc. HCl. The solvent was distilled off. To the residue was added acetone, and the resulting solid was washed with acetone and dried to give 177 mg of the desired compound (86.8~, colorless solid), m.p.l24.0-125.0~C.
Elemental Analysis for Cl3HIlN4O4SF3 HCl:
Calcd.: C, 37.83; H, 2.93; N, 13.57.
Found : C, 37.63; H, 3.00; N, 13.23.
NMR(200MHz,DMSO-d6) ~: 1.89(2H,m), 3.28(2H,m), 4.06(2H,m), 7.92(1H,dd,J=8.8,7.4Hz), 8.14(1H,dd,J=7.4,1.0Hz), 8.30(1H,dd,J=8.8,1.0Hz), 8.69(1H,s), 9.46(1H,br).
Example 13 4,5-Dihydro-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride 2 1 93~3 ~'096l02542 PCT/~95/01382 i) Synthesis of 4,5-dihydro-4-[5-(trifluoromethane-sulfonamido)pentan-l-yl]-3H-1,4,8b-triazaacenaphthyl-: ene-3,5-dione To a solution of 1.44 g (14.1 mmol) of 1,5-: 5 diaminopentane and 3.64 g (28.2 mmol) of N,N-diisopropylethylamine in 50 ml of acetonitrile was added 4.73 g (14.1 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 50 ml of acetonitrile. The mixture was heated for 45 minutes under reflux. After cooling, the resulting insoluble5 were filtered off. To the filtrate was added 6.04 g (16.g mmol) of N-phenyltrifluoromethanesulfonimide.
The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added chloroform, and the mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a column chromatography (eluent: ethyl acetate), followed by crystallization from ethyl acetate. The crystalline product was collected by filtration, washed~with ether and dried to give 2.05 g of the desired compound (36.0%, colorless solid), m.p.l66.0-167.0~C.
Flemental Analysis for Cl5HI5N4O4SF3:
Calcd.: C, 44.55; H, 3.74; N, 13.86.
Found : C, 44.37; H, 3.79; N, 13.81.
NMR(200MHz,CDCl3-DMSO-d6) ~: 1.47-1.83(6H,m), 3.20(2H,t,J=6.6Hzj, 4.17(2H,m), 7.84(1H,dd,J=8.4,7.6Hz), 8.18(1H,d,J=7.6Hz), 8.18(1H,d,J=8.4Hz), 8.61(1H,s), 8.61(1H,br).
ii) Synthesis of 4,5-dihydro-4-[5-(trifluoromethane-sulfonamido)pentan-l-yl]-3H-1,4,8b-triazaacenaphthyl-ene-3,5-dione-hydrochloride To a suspension of 469 mg (1.16 mmol) of 4,5-dihydro-4-[5-(trifluoromethanesulfonamido)pentan-1-yl]-~ ~ n W096/02s~2 ~ ~ 7~3 Fe1/J~

3H-1,4,8b-tri~7~rPn~thylene-3,5-dione in 20 ml of methanol was added 0.19 ml of conc. HCl, then the solvent was distilled off. To the residue was added acetone, and the resulting solid substance was washed with acetone and ether, which was dried to give 461 mg of the desired compound (90.2~, colorless solid~, m.p.165.0-166.0~C.
Elemental Analysis for Cl5HI5N4O45F3 HCl:
Calcd.: C, 40.87; H, 3.66; N, 12.71.
~ound : C, 40.67; H, 3.69; N, 12.61.
NMR(200~Hz,DMSO-d6) 6: 1.26-1.74(6H,m), 3.14(2H,m), 4.01(2H,m), 7.92(1H,dd,J=8.8,7.2H~), 8.14(1H,d,J=7.2Hz), 8.31(1H,d,J=8.8Hz), 8.69(1H,s), 9.35(lH,br).
Example 14 4,5-Dihydro-4-[2,2-dimethyl-3-(trifluoromethanesulfon-amido)propan-l-yl]-3H-1,4,8b-trt~ o~n~phthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[2,2-dimethyl-3-(trifluoromethanesulfonamido~propan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a solution of 0.51 g (5.0 mmol) of 1,3-diamino-2,2-dimethylpropane and 1.29 g (10.0 mmol) of N,N-diisopropylethylamine in 30 ml of acetonitrile was added a solution of 1.74 g (5.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 15 ml of acetonitrile. The mixture was stirred for two hours. ~o the reaction mixture was added 2.68 g (7.50 mmol) of N-phenyltrifluoromethanesulfonimide.
The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added chloroform, which was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by a column chromatography (eluent: ethyl acetate) to give 1.70 g ... . _ . _ . _ . _ , , , , _ ~ W096/02542 r~l~Jr C l~OL

of the desired compound (84.5%, pale yellow solid).
NMR(200MHz,CDCl3) ~: 1.10(6H,s), 2.94(2H,d,J=6.0Hz), - 4.10(2H,s), 6.97(1H,br), 7.85(1H,dd,J=8.6,7.6Hz), 3.22(1H,d,J=7.6Hz), 8.23(1H,d,J=8.6Hz), 8.69(1H,s).
; 5 ii) Synthesis of 4,5-dihydro-4-[2,2-dimethyl-3-(trifluoromethanesulfonamido)propan-l-yl]-3H,1,4,8b-tri~7~Ar~nRphthylene-3,5-dione-hydrochloride To a suspension of 1.465 g (3.62 mmol) of 4,5-dihydro-4-[2,2-dimethyl-3-(trifluoromethanesulfon-amido)propan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 25 ml of methanol was added 0.67 ml of conc.
HCl, then the sol.vent was distilled off. To the residue was added acetone, and the resulting solid was washed with acetone and ether, dried to give 1.315 g of the desired compound (82.3%, colorless solid), m.p.196.0-198.0~C.
Elemental Analysis for Cl5HI5N4O~SF3-HCl:
Calcd.: C, 40.87; H, 3.66; N, 12.71.
Found : C, 40.92; H, 3.73; N, 12.87.
NMR(200MHz,DMSO-d6) ~: 0.95(6H,s), 3.12(2H,d,J=5.6Hz), 4.01(2H,s), 7.92(1H,dd,J=8.8,7.4Hz), 8.14(1H,dd,J=7.4,1.0Hz), 8.30(1H,dd,J=8.8,1.0Hz), 8.70(1H,s), 9.26(1H,br).
Example 15 4,5-Dihydro-2-methyl-4-[4-(trifluoromethane-sulfonamido)butan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-2-methyl-4-[4-(trifluoro-methanesulfonamido)butan-l-yl]-3H-1,4,8b-triazaace-naphthylene-3,5-dione : To a solution of 529 mg (6.00 mmol) of 1,4-~i~minrhutane and 1.55 g (12.0 mmol) of diisopropylethylamine in 20 ml of acetonitrile was added a solution of 2.10 g (60.0 mmol) of 5-ethoxycarbonyl-2-methyl-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was WO96/025.S2 E~,l/J~ _'OI.

heated for one hour under reflux. After cooling, to which was added 2.58 g (7.22 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was then stirred for two hours at room temperature.
Insolubles were filtered off, and the filtrate was ..
concentrated. To the concentrate was added chloroform, and the mixture was washed with an a~ueous solution of sodium hydrogencarbonate, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), treated with ether to give 1.04 g of the desired compound (42.8~, colorless solid), m.p.183.0-184.0~C.
Elemental Analysis for Cl5H~5N4O4SF3:
Calcd.: C, 44.55; H, 3.74; N, 13.86.
Found : C, 44.45; H, 3.79; N, 13.86.
NMR(200MHz,CDCl3-DMSO-d6) 5: 1.60-1.90(4H,m), 2.88(3H,s), 3.26(2H,m), 4.18(2H,t,J=7.0), 7.77(1H,dd,J=9.0, 7.4Hz), 8.03(1H,dd,J=9.0, l.OHZ), 8.09(1H,J=7.4, l.OHz), 8.56(1H,br).
ii) Synthesis of 4,5-dihydro-2-methyl-4-[4-(trifluoro-methanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaace-naphthylene-3,5-dione-hydrochloride To a suspension of 816 mg (2.02 mmol) of 4,5-dihydro-2-methyl-4-[4-(trifluoromethanesulfonamido) butan-1-yl]-3H-1,4,8b-tri~7~rrn~phthylene-3,5-dione in 10 ml of methanol was added 0.34 ml of~conc. HCl, and the solvent was distilled off. ~o the residue was added acetone, and the resulting solid was washed with acetone, dried to give 790 mg of the desired compound (88.8~, colorless solid), m.p.l81.0-182.0~C.
Elemental Analysis for C15H15N4O4SF3-HC1:
Calcd.: C, 40.87; H, 3.66; N, 12.71.
Found : C, 40.93; H, 3.66; N, 12.88.
NMR(200MHz,DMSO-d6) ~: 1.46-1.80(4H,m), 2.76(3H,s), 3.19(2H,m), 4.03(2H,t,J=7.0Hz), 2 ~ ~3223 W096/02~2 F~~ J~o2 7.90(1H,dd,J=8.8,7.4Hz), 8.08(1H,dd,J=7.4,1.0Hz), 8.18(1H,dd,J=8.8,1.0Hz), 9.36(1H,br).
~xample 16 4,5-Dihydro-4-[4-(tert-butoxyCarbonylamino)butan-l-yl]-; 5 3H-1,4,8b-triA7AArpnArhthylene-3l5-dione To a solution of 4.07 g (54.9 mmol) of 1,3-diaminopropane and 5.32 g (41.2 mmol) of N,N-diisopropylethylamine in 70 ml of acetonitrile was added a solution of 9.21 g (27.4 mmol) of 5-10 ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 70 ml of acetonitrile. The mixture was heated for 0.5 hour under reflux. After cooling, to which was added 23.96 g (110 mmol) of di-tert-butyl dicarbonate, stirred for one hour at room temperature. The solvent was distilled off. To the residue was added chloroform. The mixture was washed with water, then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by a column chromatography (eluent: ethyl acetate), treated with ethyl acetate and n-hexane to give 7.66 g of the desired compound (81.1%, pale yellow solid), m.p.l50.0-151.0~C.
Elemental Analysis for Cl7H~oN4O4:
Calcd.: C, 59.29; H, 5.85; N, 16.27.
Found : C, 59.20; H, 5.97; N, 16.32.
NMR(200~Hz,CDCl3) ~: 1.44(9H,s), 1.93(2H,m), 3.17(2H,m), 4.26(2H,t,J=6.6Hz), 5.14(1H,~r), 7.80(1H,dd,J=8.0,6.8Hz), 8.17(1H,d,J=8.0Hz), 8.17(1H,d,J=6.8Hz), 8.65(1H,s).
Fxample 17 ; 4,5-Dihydro-4-[4-(tert-butoxycarbonylamino)butan-1-yl]-3H-1,4,8b-triA7~ArpnArhthylene-3l5-dione To a solution of 13.56 g (153.8 mmol) of 1,4-~iAminrhutane and 15.00 g (116.1 mmol) of N,N-diisopropylethylamine was added a solution of 25.96 g (76.9 mmol) of 5-ethoxycarbonyl-3-W0961~ 2 1 9 3 2 ~ 3 trichloroacetylimidazo [1,2-a]pyridine in lS0 ml of acetonitrile. The mixture was heated for 0.5 hour under reflux. After cooling, the resulting insolubles were filtered off. To the filtrate was added 67.54 g (309.5 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for 0.5 hour at room temperature. The solvent was distilled off. To the residue was added chloroform, and the mixture was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), followed by crystallization from ethyl acetate and n-hexane.
The crystalline product was collected by filtration, washed with n-hexane and dried to give 21.72 g of the object product (78.3~, colorless solid), m.p.ll8.0-119 . 0~C .
Elemental Analysis for Cl8Hz2N4O4:
Calcd.: C, 60.32; H, 6.19; N, 15.63.
Found : C, 60.50; H, 6.16; N, 15.68.
NMR(200MHz,CDCl3) ~: 1.43(9H,s), 1.50-1.85(4H,m), 3.19(2H,m), 4.20(2H,t,J=7.2Hz), 4.63(1H,br), 7.80(1H,dd,J=8.0,6.8Hz), 8.17(1H,d,J=6.8Hz), 8.17(1H,d,J=8.0Hz), 8.65(1H,s).
Example 18 4,5-Dihydro-4-[5-(tert-butoxycarbonylamino)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a solution of 5.11 g (50.0 mmol) of 1,5-diaminopentane and 4.85 g (37.5 mmol) of N,N-diisopropylethylamine in 70 ml of acetonitrile was added a solution of 8.39 g (25.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 70 ml of acetonitrile. The mixture was heated for 0.5 hour under reflux. After cooling, the insolubles were filter~d off. To the filtrate was added 21.83 g (100 mmol) of di-tert-butyl dicarbonate, and the mixture was stirred for one hour at room temperature.

2 1 q322~
~ W09~02s42 ~ P~~
_ 109 --The solvent was distilled off. To the residue was added chloroform. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified ~- 5 by column chromatography to give 7.06 g of the desired compound (75.8%, pale brown solid), m.p.82.0-83.0~C.
Elemental Analysis for ClgH24N404:
Calcd.: C, 61.28; H, 6.50; N, 15.04.
Found : C, 60.96; H, 6.41; N, 15.06.
N~R(200MHz,CDCl3) ~: 1.43(9H,s), 1.32-1.65(4H,m), 1.75(2H,m), 3.13(2H,m), 4.18(2H,m), 4.60(1H,br), 7.79(1H,dd,J=8.8,7.2Hz), 8.16(1H,d,J=8.8Hz), 8.16(1H,d,J=7.2Hz), 8.64(1H,s).
Example 19 4,5-Dihydro-4-[4-[(2,2,2-trifluoro)ethanesulfonamido]
butane-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[4-(amino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloride To a solution of 3.58 g (lO.O mmol) of 4,5-dihydro-4-[4-(tert-butoxycarbonylamino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 30 ml of methanol was added 15 ml of conc. HCl. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue were added ethanol and ether. The resulting precipitate was collected by filtration and dried to give 3.28 g of the desired compound (99.1%, white solid), m.p.250.0-252.0~C.
Elemental Analysis for Cl3HI4N402 2HCl-0.3H20 Calcd.: C, 46.39; H, 4.97; N, 16.64.
Found : C, 46.37; H, 5.02; N, 16.51.
NMR(200MHz,D20) ~: 1.75(4H,m), 3.04(2H,m), 4.15(2H,m), 8.22(1H,dd,J=9.0,7.4Hz), 8.36(1H,d,J=9.OHz), 8.41(1H,d,J=7.4Hz), 8.85(1H,s).
ii) Synthesis of 4,5-dihydro-4-[4-[(2,2,2-trifluoro]-W096/02542 2 1 ~ 3 2 2 ~ PCTIJP95/01382 - llC -ethanesulfonamido]butan-l-yl]-3H-1,4,8b-triazaace-naphthylene-3,5-dione To a suspension of 994 mg (3.0 mmol) of 4,5-dihydro-4-[4-(amino)butan-1-yl]-3H-1,4,8b-triaz~Ac~n~phthylene-3,5-dlone-dihydrochloride in 50 ml ~, of methylene chloride was added, while stirring under ice-cooling, 1.47 ml (10.5 mmol) of triethylamine. The mixture was stirred for 5 minutes, to which was added dropwise 0.66 g (3.6 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The reaction mixture was cooled with ice for one hour, which was stirred for 19 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), followed by washing with ether and dried to give 470 mg of the desired compound (38.7%, colorless solid), m.p.l54.0-155.0~C
NMR(200MHz,CDCl3-DMSO-d6) 8: 1.58-1.90(4H,m), 3.17(2H,m), 3.84(2H,q,J=9.2Hz), 4.19(2H,t,J=7.0Hz), 7.45(1H,br), 7.83(1H,dd,J=8.6,7.6Hz), 8.17(1H,d,J=7.6Hz), 8.18(1H,d,J=8.6Hz), 8.61(1H,s).
iii) Synthesis of 4,5-dihydro-4-[4-[(2,2,2-trifluoro)-ethanesulfonamido]butan-1-yl]-3H-1,4,8b-triazaace-naphthylene-3,5-dione hydrochloride To a suspension of 440 mg (1.09 mmol) of 4,5-dihydro-4-[4-[(2,2,2-trifluoro)ethanesulfonamido]butan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 20 ml of methanol was added 0.15 ml of conc. HCl, and the solvent was distilled off. To the residue was added acetone, and the resulting solid product was collected by filtration, followed by washing with acetone and drying to give 435 mg of the de5ired compound (90.6~, colorless solid), m.p.l54.0-155.0~C.
Elemental Analysis for Cl5Hl5N4O4SF3 HC1 0-5H2O

~ W096/02s42 PCT/~9~/01382 Calcd.: C, 40.05; H, 3.81; N, 12.45.
Found : C, 40.17; H, 3.62; N, 12.47.
NMR(200MHz,DMSO-d6) 6: 1.43-1.78(4H,m), 3.03(2H,m), 4.03(2H,m), 4.35(2H,q,J=9.8Hz), 7.74(1H,br), , 5 7.96(1H,dd,J=8.8,7.4Hz), 8.15(1H,d,J=7.4Hz), 8.31(1H,d,J=8.8Hz), 8.71(1H,s).
Example 20 4-[4-[2-(trifluoromethanesulfonamido)ethan-l-yl]phenyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4-[4-[2-(trifluoromethanesulfonamido)-ethan-1-yl]phenyl]-4,5-dihydro-3H-1,4,8b-triazaace-naphthylene-3,5-dione To a solution of 1.18 g (4.4 mmol) of 4-[2-(trifluoromethanesulfonamido)ethan-l-yl]aniline and 0.68 g (5.3 mmol) of N,N-diisopropylethylamine in 20 ml of acetonitrile was added a solution of 1.53 g (4.4 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[l~2 a]pyridine. The mixture was heated for 38 hours under reflux. After cooling, and the solvent was distilled off. To the residue was added chloroform. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent:
ethyl acetate) to give 130 mg of the desired compound (6.8~, brown solid).
NMR(200MHz,CDC13) ~: 2.98(2H,t,J=6.6Hz), 3.62(2H,t,J=6.6Hz), 6.15(1H,br), 7.25(2H,m), 7.42(2X,m), 7.83(1H,dd,J=8.8,7.6Hz), 8.20(1H,dd,J=7.6,1.0Hz), 8.21(1H,dd,J=8.8,1.0Hz), 8.58(1H,s).
ii) Synthesis of 4-[4-[2-(trifluoromethane-sulfonamido)ethan-l-yl]phenyl-4,5-dihydro-3X-1,4,8b-triazaacenaphthylene-3,5-dione hydrochloride To a suspension of 130 mg (0.30 mmol) of 4-[4-[2-(trifluoromethanesulfonamido)ethan-l-yl]phenyl]-4,5-~096,~2~42 2 1 ~2~ PCT/JP9j/01382 dihydro-3H-1,4,8b-triA7arPnAphthylene-3r5-dione in 10 ml of methanol was added 0.1 ml of conc. HCl. The solvent was then distilled off. To the residue was added acetone. The resulting solid matter was collected by filtration, washed with acetone and dried to give 82 mg of the desired compound (58.2~, pale brown solid).
NMR(2ooMHzrDMso-d6) ~: 2.g3(2H,t,J=7.2Hz), 3.48(2H,m), 7.29(2H,d,J=8.4Hz), 7.42(2H,d,J=8.4Hz), 7.95(1H,dd,J=8.8,7.4Hz), 8.14(1H,d,J=7.4Hz), 8.34(1H,d,J=8.8Hz), 8.73(1H,s), 9.63(1H,br).
Example 21 4,5-Dihydro-4[5-(tert-butoxycarbonylamino)pentan-1-yl]-3H-1,4,8b-triazaacenaphthylen-5-one A solution of 7.78 g (20 mmol) of 3-[(trimethylammonio)methyl]-5-ethoxycarbony] i~ ZQ
[1,2-a]pyridine iodide, 6.07 g (30 mmol) of 5-tert-outoxycarbonylamino-1-pentylamine and 5.58 ml (40 mmol) of triethylamine was heated for 64 hours under reflux.
~he solvent was distilled off. To the residue was added methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 3.93 g of the desired compound (54.9~, a pale yellow solid).
NMR(200MHz,CDCl3)~: 1.42(9H,s), 1.27-1.85(6H,m), 3.13(2H,m), 3.61(2H,t,J=7.2Hz), 4.64(1H,br), 5.11(2H,s), 7.21(1H,dd,J=9.0, 7.0Hz), 7.43(1H,s), 7.53(1H,dd,J=7.0, l.OHz), 7.61(1H,dd,J=9.0, 7.0Hz).
Example 22 4,5-Dihydro-4[5-(trifluoromethanesulfonamido)pentan-1-yl~-3H-1,4,8b-triazaacenaphthylen-5-one i) Synthesis of 4,5-dihydro-4[5-(amino)pentan-1-yl]-3H-ll4l8b-triazaacenaphthylen-5-one dihydrochloride To a solution of 2.24 g (6.25 mmol) of 4,5-... . , . . , , , _ _ _ , ~ _ _ 2 1 q3223 W096/02542 p~

dihydro-4[5-(tert-butoxycarbonylamino)pentan-1-yl]-3H-1,4,8b-tri~7~oPn~phthylen-5-one in 20 ml of ethanol was added 20 ml of conc. HCl. The mixture was stirred for 1.5 hour at room temperature. The solvent was distilled off to leave 2.05 g of the desired compound (quant. a pale brown solid). This product was used in the subsequent reaction without further purification.
NMR(200MHz,D20)6: 1.28-1.90(6H,m), 2.94(2H,t,J=7.2Hz), 3.60(2H,t,J=7.2Hz), 5.16(2H,s), 7.75(1H,s), 7.82-7.95(3H,m).
ii) 4,5-Dihydro-4[5-~trifluoromethanesulfonamido)pentan-l-yl]-3H-1,4,8b-tr;~7aArPn~E)hthylen-5-one To a suspension of 2.05 g (6.19 mmol) of 4,5-dihydro-4[5-(amino)pentan-1-yl]-3H-1,4,8b-triazA~rPn~phthylen-5-one-dihydrochloride and 4.31 ml (30.9 mmol) of triethylamine in 10 ml of methylene chloride-N,N-dimethylformamide was added 4.42 g (12.4 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 4 hour at room temperature.
The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1), followed by recrystallization from ethyl acetate to afford 964 mg of the desired compound (39.9~, a pale yellow crystals).
NMR(200MHz,DMSO-D6): 1.38(2H,m), 1.45-1.75(4H,m), 3.15(2H,t,J=6.8Hz), 3.51(2H,t,J=6.8Hz), 5.13(2H,s), 7.26(1H,dd,J=9.0, 7.0Hz), 7.39(1H,dd,J=7.0, l.OHz), 7.47(1H,s), 7.66(1H,dd,J=9.0, l.OHz), 9.33(1H,br).
Example 23 4,5-Dihydro-4[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-5-one A solution of 778 mg (2.0 mmol) of 5-ethoxycarbonylimidazo[1,2-a]pyridin-8-ylmethyl W096l02~42 2 1 9~3 Y~l/J~ _. Ia~ ~

trimethylammonium iodide, 616 mg (2.4 mmol) of 4-trifluoromethanesulfonamido-l-butylamine and 1.12 ml (8.0 mmol) of triethylamine in 40 ml of acetonitrile was heated for 14 hours under reflux. The solvent was distilled off. To the residue was added chloroform, and washed with water. The aqueous layer was further extracted with chloroform. The chloroform layers were combined, and dried over anhydrous magnesium sulfate.
The solvent was distilled off. The residue was crystallized from chloroform. The crystalline product was collected by filtration, washed with chloroform and dried to afford 141 mg (18.8%, colorless crystals) of the desired cDmpound.
Elemental Analysis Calcd for Cl4Hl5N4035F3:
Calcd.: C, 44.68; H, 4.02; N, 14.89 Found : C, 44.93; H, 3.89; N, 15.13.
NMR(200MHz,CDCl3-DM5O-d6)5: 1.58-1.90(4H,m), 3.27(2H,m), 3.64(2H,m), 5.15(2H,s), 7.22(1H,dd,J=9.0, 7.0Hz), 7.46(1H,s), 7.51(1H,dd,J=7.0, l.OHz), 7.62(1H,dd,J=9.0, l.OHz).
Pxample 24 1,2-Dihydro-3-methyl-1-[3-(trifluoromethanesulfonamido) propan-l-yl]-1,4,7b-triazacyclopento[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[3-(trifluoro-methanesulfnn~mirln)propan-l-yl~-1,4,7b-triazacyclo-pentlcd] inden-2-one To a solution of 1.16 g (5.04 mmol) of 1-[3-(amino) propan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento[cd]inden-2-one and 1.05 ml (7.53 mmol) of triethylamine in 60 ml of methylene chloride was added, while stirring under ice-cooling, 1.71 g (6.06 mmol) of trlfluoromethane sulfonic acid anhydride. The mixture was stirred for 30 minutes at the same temperature_ The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried .... , . _ _ ... .. . . ~ _ _ _ _ _ ~096/0~42 - 115 - I ~ I ~J~ 2 over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by means of a column chromatography (eluent: ethyl acetate) to give 1.15 g of the desired compound (63.0~, pale brown solid), m.p.l68.0-169~C.
NMR(200MHz,CDC13) 5: 2.08(2H,m), 2.85(3H,s), 3.33(2H,m), 4.26(2H,m), 6.88(1H,d,J=7.4Hz), 6.97(1H,br), 7.58(1H,d,J=8.6Hz), 7.78(1H,dd,J=8.6,7.4Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[3-(trifluoro-methanesulfonamido)propan-l-yl]-1,4,7b-triazacyclo-pent[cd]inden-2-one-hydrochloride To a suspension of 866 mg (2.39 mmol) of 1,2-dihydro-3-methyl-1-[3-(trifluoromethanesulfon-amido)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 20 ml of methanol was added 0.24 ml of conc.
HCl. The solvent was then distilled off. To the residue were added ethanol, acetone and ether. The resulting solid was washed with ether and, then dried to give 844 mg of the desired compound (88 6~, pale yellow solid), m.p.l45.0-146~C.
Elemental Analysis for C13Hl3N4O35F3-HCl:
Calcd.: C, 39.15; H, 3.54; N, 14.05.
Eound : C, 39.13; H, 3.47; N, 14.05.
NMR(200MHz,DMSO-d6) ~: 2.02(2H,m), 2.78(3H,s), 3.30(2H,m), 4.14(2H,t,J=7.0Hz), 7.52(1H,d,J=7.8Hz), 7.74(1H,d,J=8.6Hz), 8.12(1H,dd,J=8.6,7.8Hz), 9.55(1H,br).
Example 25 1,2-Dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)-ethanesulfonamido]propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)ethanesulfonamido]propan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 0.43 g (1.87 mmol) of 1-[3-2 ~ ~3~2~
WO 96/02542 I_IIJ~

(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopenttcd]inden-2-one and 0.39 ml (2.80 mmol) of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.41 g (2.26 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 412 mg of the desired compound (58.6~, white powdery).
NMR(200MHz,CDC13) 6: 2.09(2H,m), 2.84(3H,s), 3.25(2H,m), 3.85(2H,q,J=9.OHz), 4.25(2H,m), 6.28(1H,br t,J=6.0Hz), 6.88(1H,d,J=7.4Hz), 7.56(1H,d,J=8.6Hz), 7.77 (lH,dd,J=8.6,7.4Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)ethanesulfonamido]propan-l-yl]-1,4,7b-triazacyclopento[cd]inden-2-one-hydrochloride To a solution of 405 mg (1.08 mmol) of 1,2-dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)-ethanesulfonamido]propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added 0.11 ml of conc. HCl, then the solvent was distilled off. To the residue were added ethanol, acetone and ether. The resulting solid was washed with ether and dried to give 436 mg of the desired compound (98.2%, white solid), m.p.l57.0-158.0~C.
Elemental Analysis for Cl4HI~N40~5F3~HCl:
Calcd.: C, 40.?3; H, 3.91; N, 13.57.
Found : C, 40.85; H, 3.97; N, 13.38.
NMR(200MHz,DMSO-d6) 6: 1.99(2H,m), 2.79(3H,s), 3.14(2H,m), 4.12(t,J=7.0Hz), 4.41(2H,q,J=lO.OHz), 7.55(1H,d,J=7.6Hz), 7.76(1H,d,J=8.6Hz), 7.92(1H,br), 8.15(1H,dd,J=8.6,7.6Hz).

. _ . . . _ _ .

2 ~ 9~2~3 WO 96/02542 F~11J. 7~.'01382 _ 117 --Example 26 1,2-Dihydro-3-methyl-1-[5-(trifluoromethanesulfon-amido)pentan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride - 5 i) Synthesis of 1,2-dihydro-3-methyl-1-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclo-pent[cd]inden-2-one To a solution of 1.512 g (5.85 mmol) of 1-[5-(amino)pentan]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.23 ml (8.82 mmol) of triethylamine in 35 ml of methylene chloride was added, while stirring at room temperature, 2.51 g (7.03 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 14 hours at the same temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.236 g of the desired compound (54.1~, pale yellow solid substance).
Elemental Analysis for Cl5HI7N~O3SF3:
Calcd.: C, 46.15; H, 4.39; N, 14.35.
Found : C, 46.29; H, 4.38; N, 14.41.
N~R(200MHz,CDCl3) ~: 1.50(2H,m), 1.74(2H,m), 1.90(2H,m), 2.77(3H,s), 3.33(2H,t,J=6.4Hz), 4.10(2H,t,J=6.6Hz), 6.82(1H,d,J=7.6Hz), 7.45(1H,d,J=8.6Hz), 7.71(1H,dd,J=8.6,7.6Hz) ii) Synthesis of 1,2-dihydro-3-methyl-1-[5-(trifluoro-methanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclo-pento[cd]inden-2-one-hydrochloride ; To a suspension of 1.195 g (3.06 mmol) of 1,2-dihydro-3-methyl-1-[5-(trifluoromethanesulfon-amido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of methanol was added 0.31 ml of conc.
HC1, the solvent was distilled off. To the residue was added acetone and ether. And the resulting solid was W096l02~42 2 ~ ~3~ r-llJ. - .5~ ~

washed with ether, dried to give 1.190 g of the desired compound (91.0%, white solid), m.p.l49.0-150.0~C.
Elemental Analysis for Cl5HI7N40~5F3-HCl:
Calcd.: C, 42.21; H, 4.25; N, 13.13.
Found : C, 42.03; H, 4.14; N, 13.22. - :
NMR(200MHz,DMSO-d6) ~: 1.37(2H,m), 1.55(2H,m), 1.78(2H,m), 2.78(3H,s), 3.11(2H,m), 4.07(2H,t,J=7.0Hz), 7.52(1H,d,J=7.8Hz), 7.74(1H,d,J=8.6Hz), 8.11(1H,dd,J=8.6,7.8Hz), 9.33(1H,br).
Example 27 1,2-Dihydro-3-methyl-1-[5-[(2,2,2-trifluoro)-ethanesulfonamido]pentan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[5-[(2,2,2-trifluoro)ethanesulfonamido]pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.630 g (6.31 mmol) of 1-[5-(amino)pentyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.32 ml (9.47 mmol) of triethylamine in 30 ml of methylene chlori~e was added, while stirring under ice-cooling, 1.38 g (7.56 mmol) of 2,2,2-trifluoroethanesulfonylchloride. ~he mixture was stirred for 30 minutes at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.669 g of the desired compound (65.4~, pale brown solid substance).
NMR(200MHz,CDCl3) ~: 1.49(2H,m), 1.70(3H,s), 1.88(2H,m), 2.80(3H,s), 3.19(2H,m), 3.80(2H,q,J=9.OHz), 4.07(2H,t,J=6.4Hz), 5.87(1H,br t, J=6.0Hz), 6.82(1H,d,J=7.6Hz), 7.47(1H,d,J=8.6Hz), 7.71(1H,dd,J=8.6,7.6Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[5-[(2,2,2-2 1 932?3 ~ W096/02s42 PCT/JP9~/01382 trifluoro)ethanesulfonamido]pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a solution of 1.485 g (3.67 mmol) of 1,2-dihydro-3-methyl-1-~5-[(2,2,2-trifluoro)ethanesulfon-S amido]pentan-1-yl]-1,4,7b-triazacyclopento[cd]inden-2-one in 30 ml of methanol was added 0.37 ml of conc.
HCl, was the solvent was distilled off. To the residue was added ethanol, acetone and ether, and, the resulting crystals were washed with ether, followed by lO drying to give 1.632 g of the desired compound (quantitative, colorless crystals), m.p.143.0-145.0~C.
Elemental Analysis for C16HIgN403SF3-HCl-HzO:
Calcd.: C, 41.88; H, 4.83; N, 12.21.
Found : C, 41.73; H, 4.79; N, 12.18.
15 N~R(200MHz,DMSO-d6) ~: 1.25-1.60(4H,m), 1.77(2H,m), 2.77(3H,s), 2.96(2H,m), 4.07(2H,t,J=6.8Hz), 4.33(2H,q,J=lO.OHz), 7.49(1H,d,J=7.4Hz), 7.72(1H,br), 7.73(1H,d), J=8.8Hz), 8.08(1H,dd,J=8.8, 7.4Hz).
Example 28 20 1,2-Dihydro-3-methyl-1-[6-(trifluoromethanesulfon-amido)hexan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-~6-(trifluoro-methanesulfonamido)hexane-1-yl~-1,4,7b-triazacyclo-25 pent[cd]inden-2-one To a solution of 770 mg (2.83 mmol) of 1-[6-(amino)hexane-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.59 ml (4.23 mmol) of triethylamine in 25 ml of methylene chloride was added, while stirring at room temperature, 1.21 g (3.39 ; mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 14 hours at the same temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to W096/0X~2 ~1~ 3 2 .2 3 P~IIJ

give 633 mg of the desired compound (55.4~, pale yellow solid).
NMR(200MHz,CDCl3) 6: 1.31-1.73(6H,m), 1.87(2H,m), 2.81(3H,s), 3.31(2H,t,J=6.4Hz), 4.09(2H,t,J=7.2Hz), 6.82(1H,d,J=7.6Hz), 7.50(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6,7.6Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[6-(trifluoro-methanesulfonamido)hexan-1-yl]-1,4,7b-triazacyclo-pent[cd]inden-2-one-hydrochloride To a suspension of 623 mg (1.54 mmol) of 1,2-dihydro-3-methyl-1-[6-(trifluoromethanesulfonamido) hexan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added 0.16 ml of conc. HCl and, then, the solvent was distilled off. To the residue were added acetone and ether. The resulting solid was washed with ether, dried to give 570 mg of the desired compound (83.9%, pale yellow solid).
NMR(200M~z,DMSO-d6) 6: 1.25-1.56(6H,m), 1.75(2H,m), 2.75(3H,s), 3.11(2H,m), 7.46(1H,d,J=7.8Hz), 7.70(1H,d,J=8.6Hz), 8.05(1H,dd,J=8.6,7.8Hz), 9.31(lH,br).
Example 29 1,2-Dihydro-3-methyl-1-[6-[(2,2,2-trifluoro)ethanesulfonamido]hexan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[6-t(2,2,2-trifluoro)ethanesulfonamido]hexan-l-yl]-1,4,7b-triaza-cyclopent[cd]inden-2-one To a solution of 676 mg (2.48 mmol) of 1-[6-(amino)hexyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.52 ml (3.73 mmol) 7 - of triethylamine in 30 ml of methylene chloride was added, while stirring under ice-cooling, 0.55 g (3.01 mmol) of 2,2,2-trifluoroethanesulfonylchloride, and the mixture was stirred for 30 minutes at the same temperature range. The reaction mixture was washed 2 ~ 932~3 W096/02~2 PCT1~95101382 with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 802 mg of the desired compound (77.2~, pale brown solid).
NMR(200MHz,CDCl3) ~: 1.30-1.68(6H,m), 1.86(2H,m), 2.82(3H,s), 3.18(2H,m), 3.81(2H,q,J=9.OHz), 4.07(2H,t,J=6.8Hz), 5.48(1H,br t,J=6.0Hz), 6.81(1H,d,J=7.4Hz), 7.50(lH,d,J=8.6Hz), 7.71(1H,dd,J=8.6,7.6Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[6-[(2,2,2-trifluoro)ethanesulfonamido]hexan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a solution of 702 mg (1.68 mmol) of 1,2-dihydro- 3-methyl-1-[6-[(2,2,2-trifluoro)ethanesulfon-amido]hexan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of methanol was added 0.17 ml of conc. HCl, then the solvent was distilled off. To the residue were added acetone and ether. The resulting crystals were washed with ether and dried to give 718 mg of the desired compound (94.1%, colorless crystals), m.p.141.0-143.0~C.
Elemental Analysis for C17H2lN403SF3-HCl:
Calcd.: C, 44.89; H, 4.87; N, 12.32.
Found : C, 44.79; H, 4,83; N, 12.41.
NMR(200MHz,DMSO-d6) ~: 1.22-1.50(6H,m), 1.76(2H,m), 2.78(3H,s), 2.96(2H,m), 4.07(2H,t,J=7.0Hz), 4.33(2H,q,J=lO.OHz), 7.53(1H,d,J=7.8Hz), 7.71(1H,br), 7.75(1H,d,J=8.6Hz), 8.12(1H,dd,J=8.6,7.8Hz).
~ Example 30 1,2-Dihydro-3-methyl-1-[4-(trifluoromethanesulfon-; amido)butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a solution of 7.05 g (28.9 mmol) of 1-[4-(amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-~'096/0~42 ~19~ PCT1JP95101382 triazacyclopent[cd]inden-2-one and 8.04 ml (57.7 mmol) of triethylamine in 300 ml of methylene chloride was added, while stirring at room temperature, 20.62 g (57.7 mmol) of N-phenyltrifluoromethanesulfonimide.
The mixture was stirred for 8 hours at the same ~ ~ure. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give a solid, washed with ether to afford 6.17 g of the desired compound (56.8%, pale yellow solid substance), m.p.195.0-196.0~C.
Elemental Analysis for C14HI5N4O3SF3:
Calcd.: C, 44.68; H, 4.02; N, 14.89.
Found : C, 44.68; H, 3.95; N, 15.02.
NMR(200MHz,CDCl3) ~: 1.78(2H,m), 2.02(2H,m), 2.77(3H,s), 3.44(2H,t,J=6.2Hz), 4.14(2H,t,J=6.6Hz), 6.82(1H,d,J=7.6Hz), 7.41(1H,d,J=8.8Hz), 7.70(1H,dd,J=8.8,7.6Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(trifluoro-methanesulfonamido)butan-l-yl]-1,4,7b-triazacyclo-pent[cd]inden-2-one-hydrochloride To a suspension of 5.00 g (13.3 mmol) of 1,2-dihydro-3-methyl-1-[4-(trifluoromethanesulfonamido)-butan-1-yl]-1,4,7b-triazacyclopento[cd]inden-2-one in 100 ml of methanol was added 1.33 ml of conc. HCl, then the solvent was distilled off. To the residue were added methanol and ether, and the resulting solid was collected by filtration, washed with ether and dried to give 5.38 g oi the desired compound (98.2~, colorless solid) .
NMR(200MHz,DMSO-d6) 5: 1.58(2H,m), 1.83(2H,m), 2.80(3H,s), 3.19(2H,m), 4.11(2H,t,J=6.8Hz), 7.57(1H,d,J=7.8Hz), 7.77(1H,d,J=8.6Hz), 8.16(1H,dd,J=8.6,7.8Hz), 9.40(1H,br).
Example 31 2 1 93~23 W096l02~42 r~ CI~

1,2-Dihydro-3-methyl-1-[4-(methanesulfonamido)butan-1-yl]-ll4/7b-triazacyclopent[cd]inden-2-one~hydro~hlori~
i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(methane-sulfonamido)butan-l-yl]-l~4~7b-triazacyclopento[cd]
inden-2-one To a solution of 977 mg (4.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 607 mg (6.0 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 836 mg (4.8 mmol) of methanesulfonic acid anhydride. The mixture was stirred for one hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous sodium hydrogencarbonate. The solvent was distilled off, and the residue was recrystallized from methylene chloride-ethanol to give 827 mg of the desired compound (64.2%, colorless crystals), m.p.183.0-184.0~C.
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(methanesulfonamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one hydrochloride To a suspension of 500 mg (1.55 mmol) of 1,2-dihydro-3-methyl-1-[4-(methanesulfonamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 20 ml of methanol was added 0.17 ml of conc. HC1. The solvent ~as then distilled off. The residue was washed with ether to give 555 mg of the desired compound (99.6%, colorless solid), m.p.l66.0-167.0~C.
N~R(200MHz,DMSO-d6) ~: 1.53(2H,m), 1.82(2H,m), 2.79(3H,s), 2.86(3H,s), 2.96(2H,m), 4.09(2H,t,J=6.8Hz), 7.00(1H,br), 7.56(1H,d,J=7.6Hz), 7.76(1H,d,J=8.6Hz), ~.15(1H,dd,J=8.6,7.6Hz).
Example 32 1,2-Dihydro-3-methyl-1-[4-(benzamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-Wo96lo2~42 2 ~ 23 124 - PCT1~95101382 ( h~n 7 ami~n)butan-1-yl]-1,4,7b-triazacyclopent-[cd]inden-2-one To a solution of 2.44 g (10.0 mmol) of 1-[4-(amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 2.09 ml (15.0 mmol) of triethylamine in 80 ml of methylene chloride was added, while stirring under ice-cooling, 1.39 ml (12.0 mmol) of benzoyl chloride. The mixture was stirred for 0.5 hour at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:
ethyl acetate/ethanol = 10:1).
NMR(200MHz,CDCl3) 5: 1.74(2H,m), 1.95(2H,m), 2.80(3H,s), 3.55(2H,m), 4.12(2H,t,J=6.8Hz), 6.75(1H,br), 6.87(1H,d,J=7.4Hz), 7.33-7.54(4H,m), 7.69(1H,dd,J=8.6,7.4Hz), 7.75-7.85(2H,m).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(benzamido)butan-1-yl]~1,4,7b-triazacyclopent-[cd]inden-2-one-hydrochloride To a solution of 3.06 g (8.78 mmol) of 1,2-dihydro-3-methyl-1-[4-(b~n7~m;~ )butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 50 ml of methanol was added 0.88 ml of conc. ~Cl, then the solvent was distilled off. The residue was crystallized from methanol-acetone. The crystals were collected by filtration and washed with acetone to give 2.90 g of the object product (85.8%, colorless solid), m.p.173.0-175.5~C.
Elemental Analysis for C~oH20N4O~-HCl~O.2H20:
Calcd.: C, 61.84; H, 5.55; N, 14.42.
Found : C, 61.82; H, 5.48; N, 14.34.
NMR(200MHz,DMSO-d6) ~: 1.60(2H,m), 1.82(2H,m), 2.77(3H,s), 3.31(2H,m), 4.12(2H,t,J=6.8Hz), 7.37-7.50(3H,m), 7.54(1H,d,J=7.6HZ), 7.73(1H,d,J=8.8Hz), _ .. . . _ .. . .. . . .. . .. .. .. .

2~932~
W096/02~2 PCT/~95/01382 ~ - 125 -7.81(2H,m), 8.10(1H,dd,J=8.8,7.6Hz), 8.48(1H,br).
Example 33 1,2-Dihydro-3-methyl-1-[4-(trifluoroacetamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride S i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(trifluoroacetamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.71 g (7.0 mmol) of 1- [ 4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.46 ml (10.5 mmol) of triethylamine in 50 ml of methylene chloride was added, while stirring under ice-cooling, 1.76 g (8.4 mmol) of trifluoroacetic acid anhydride. The mixture was stirred for 3 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was crystallized from chloroform-ethanol-ether. The crystals were collected by filtration and washed with ether to give 0.986 g of the desired compound (41.4%, pale yellow crystals).
NMR(200MHz,CDC13) ~: 1.73(2H,m), 1.93(2H,m), 2.82(3H,s), 3.48(2H,m), 4.12(2H,t,J=6.8Hz), 6.83(1H,d,J=7.4Hz), 6.91(1H,br), 7.50(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6,7.4Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(trifluoro-acetamido)butan-l-yl]-1,4,7b-triazacyclopento-[cd]inden-2-one-hydrochloride To a solution of 978 mg (2.87 mmol) of 1,2-dihydro-3-methyl-1-[4-(trifluoroacetamido)butan-1-yl]-; 1,4,7b-triazacyclopent[cd~inden-2-one in 15 ml ofmethanol was added 0.29 ml o~ conc. HCl. The solvent was then distilled off to give 1.084 g of the desired compound (100%, pale yellow solid).
NMR(2o3MHzlDMso-d6) ~: 1.56(2H,m~, 1.77(2H,m), 2.78(3H,s), 3.22(2H,m), 4.10(2H,t,J=6.8Hz), W096l0~2 2 1 9 3 2 2 3 r ~l/J~

7.54(1H,d,J=7.8Hz), 7.75(1H,d,J=8.6Hz), 8.13(1H,dd,J=8.6,7.8Hz), 9.44(1H,br).
Example 34 1,2-Dihydro-3-methyl-1-[4-(bPn7~n-~ulfonamido)butan-l-yl]-1,4,7b-triazacyclopento[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(benzenesulfonamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.22 g (5.0 mmol) of 1-t4-(amino) butan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento[cd]inden-2-one and 0.77 ml (6.0 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 1.07 g (6.0 mmol) of benzenesulfonyl chloride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was cryst~lli7ed from methylene chloride-ether.
The crystals were collected by filtration, which was washed with ether to give 1.09 g (56.8%, grayish white solid) of the desired compound.
NMR(200MHz,CDCl3) ~: 1.60(2H,m), 1.92(2H,m), 2.81(3H,s), 3.05(2H,m), 4.07(2H,t,J=7.0Hz), 4.94(1H,br), 6.82(1H,d,J=7.4Hz), 7.39-7.69(4H,m), 7.71(1H,dd,J=8.8,7.4Hz), 7.80-7.90(2H,m).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(benzene-sulfonamido)butan-l-yl]-1,4,7b-triazacyclopento-[cd]inden-2-one-hydrochloride To a suspension of 961 mg (2.50 mmol) of 1,2-dihydro-3-methyl-1-[4-(benzenesulfonamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 0.42 ml of conc. HCl, and the solvent was distilled off. The residue was washed with acetone to give 1.013 g of the desired compound (96.3%, 2 1 ~2~
W096/02542 r~-~J~ _ I
~ - 127 -colorless solid), m.p.163.0-164.0~C.
Elemental Analysis for Cl9H20N4O3S-HCl:
Calcd.: C, 54.22; H, 5.03; N, 13.31.
Found : C, 53.86; H, 5.04; N, 13.15.
NMR(200MHz,DMSO-d6) ~: 1.43(2H,m), 1.75(2H,m), 2.77(2H,m), 2.79(3H,s), 4.03(2H,t,J=6.8Hz), 7.46-7.60(4H,m), 7.64(1H,br), 7.70-7.81(3H,m), 8.13(1H,dd,J=8.6,7.6Hz).
Example 35 10 1~2-Dihydro-3-methyl-l-[4-(ethanesulfonamido)butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(ethanesul-fonamido)butan-l-yl)-1,4,7b-triazacyclopento[cd]inden-2-one To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopento[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.~2 ml (6.5 mmol) of ethanesulfonyl chloride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride-ether to give 1.32 g of the desired compound (78.6~, pale brown crystals).
NMR(2ooMHz~cDcl3) ~: 1.36(3H,t,J=7.4Hz), 1.69(2H,m), 1.97(2H,m), 2.82(3H,s), 3.03(2H,q,J=7.4Hz), 3.22(2H,m), 4.12(2H,t,J=7.0Hz), 4.57(1H,br), 6.86(1H,d,J=7.6Hz), 7.50(1H,d,J=8.8Hz), 7.72(1H,dd,J=8.8,7.6Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(ethanesul-fonamido)butan-l-yl]-1,4,7b-triazacyclopento[cd]inden-2-one-hydrochloride To a suspension of 1.166 g (3.47 mmol) of 1,2-dihydro-3-methyl-1-[4-(ethanesulfonamido)butan-1-yl]-W096/02s42 2 ~ 9 3 2 2 3 PCT1~95/01382 1,4,7b-triazacyclopent[cd]inden-2-one in 20 ml of methanol was added 0.4 ml of conc. HCl. The solvent was then distilled off. and the residue was washed with ether to give 1.275 g of the desired compound (98.7~, pale brown solid), m.p.144.0-145.0~C.
Elemental ~nalysis for C~H20N4O35-HCl:
Calcd.: C, 48.32; H, 5.68; N, 15.03.
Found : C, 47.94; H, 5.62; N, 14.84.
NMR(200MHz,DMSO-d6) ~: 1.17(3H,t,J=7.2Hz), 1.52(2H,m,), 1.82(2H,m), 2.80(3H,s), 2.96(2H,q,J=7.2Hz), 4.09(2H,t,J=6.8Hz), 7.04(1H,br), 7.57(1H,d,J=7.8Hz), 7.77(1H,d,J=8.8Hz), 8.16(1H,dd,J=8.8,7.8Hz).
Example 36 1,2-Dihydro-3-methyl-1-[4-(propan-1-ylsulfonamido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(propan-1-ylsulfonamido)butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.73 ml (6.5 mmol) of propan-l-ylsulfonyl chloride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene nhlnri~ - methanol - ether to give 1.313 g of the 7 desired compound (75.0%, pale brown crystals), m p.150.0-151.0~C.
NMR(200MHz,CDCl3) ~: 1.06(3H,t,J=7.4Hz), 1.60-2.05(6H,m), 2.82(3H,s), 2.98(2H,m), 3.22(2H,m), 4.12(2H,t,J=7.0Hz), 4.48(1H,br), 6.86(1H,d,J=7.4Hz), , . . . , . . _ . . .. _ .. , _ . . . . .. . .. .. , . _ . .

7.50(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6,7.4Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(propan-1-ylsulfonamido)butan-l-yl]-1,4,7b-triazacyclopento-[cd]inden-2-one-hydrochloride To a suspension of 1.16 g ~3.31 mmol) of 1,2-dihydro-3-methyl-1-[4-(propan-1-ylsulfonamido)-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 0.4 ml of conc. HCl. The solvent ==
was distilled off to give 1.28 g of the desired compound (100%, pale brown solid).
NNR(200MHz,DMSO-d6) ~: 0.95(3H,t,J=7.4Hz), 1.43-1.90(6H,m), 2.79(3H,s), 2.93(2H,m), 4.09(2H,t,J=6.8Hz), 7.02(1H,br), 7.56(1H,d,J=7.8Hz), 7.76(1H,d,J=8.6Hz), 8.15(1H,dd,J=8.6,7.8Hz).
Example 37 1,2-Dihydro-3-methyl-1-[4-(methoxycarbonylamino)butan-l-yl]-1,4,7b-triazacyclopento[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(methoxycarbonylamino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.50 ml (6.5 mmol) of methyl chlorocarbonate. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous c magnesium sulfate. The solvent was distilled off, and the residue was recrys~lliz~ from methylene chloride - methanol - ether to yive 1.192 g of the desired compound (78.9~, colorless crystals), m.p.l75-176~C.
NMR(200MHz,CDCl~) ~: 1.62(2H,m), 1.90(2H,m), W096/0~2 219 ~ 2 2 3 s ~l/Js ~a~

2.83(3H,s), 3.26(2H,m), 3.66(3H,s), 4.10(2H,t,J=7.0Hz), 4.85(lH,br), 6.84(lH,d,J=7.4Hz), 7.50(lH,d,J=8.6Hz), 7.22(1H,dd,J=8.6,7.4Hz).
ii) Synthesis of 1,2-dihydro-3-methyl-1-[4-(methoxy-carbonylamino)butan-1-yl]-1,4,7b-triazacyclopento-[cd]inden-2-one-hydrochloride To a suspension of 1.069 g (3.54 mmol) of 1,2-dihydro-3-methyl-1-t4-(methoxycarbonylamino)butan-1-yl]-1,4,7b-triazacyclopenttcd]inden-2-one in 30 ml of methanol was added 0.4 ml of conc. HCl. The solvent was distilled of~ to give 1.19 g of the desired ~ound (99.4%, colorless crystals), m.p.l60.0-163.0~C.
Example 38 1,2-Dihydro-3-methyl-1-t4-t(2,2,2-trifluoro)ethanesulfonamido]butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-[(2,2,2-tri~1uoro)ethanesulfonamido]butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 5.58 g (22.8 mmol) of 1-t4-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 4.78 ml (34.3 mmol) of triethylamine in 200 ml of methylene chloride was added, while stirring under ice-cooling, 5.0 g (27.4 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The mixture was stirred for one hour at the same temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium 5ulfate. The solvent was distilled oi~, and the residue was purified by means of a column chromatography (eluent: ethyl acetate/ethanol=10:1), followed by crystallization from ethyl acetate-n-hexane. The crystals were collected by filtration, washed with n-hexane to give 3.89 g of the desired compound (43.6~, colorless crystals), W096/02542 P~l/J~ S la8 _ - 131 -m.p.165.0-166.0~C.
Elemental Analysis for Cl5HI7N4O3SF3:
Calcd.: C, 46.15; H, 4.39; N, 14.35.
Found : C, 46.15; H, 4.39; N, 14.52.
ii) Synthesi5 of 1,2-dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)ethanesulfonamido]butan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a solution of 840 mg (2.15 mmol) of 1,2-dihydro-3-methyl-1-[3-[(2,2,2-trifluoro)-ethanesulfonamido]butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added 0.22 ml of conc. HCl. The solvent was distilled off, and the residue was washed with acetone-ether to give 915 mg of the desired compound (99.7%, colorless solid), m.p.ll6.0-118~C.
Example 39 1,2-Dihydro-3-methyl-1-[3-(methanesulfonamido)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[3-(methanesulfonamido)propan-1-yl]-1,4,7b-triazacyclopent[cd~inden-2-one To a solution of 800 mg (3.47 mmol) of 1-[3-(amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.73 ml (5.24 mmol) of triethylamine in 20 ml of methylene chloride was added, while stirring under ice-cooling, 726 mg (4.17 mmol) of methanesulfonic acid anhydride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride - ethanol - ether to give 634 mg of the desired compound (59.2~, pale yellow crystals).
ii) Synthesis of 1,2-dihydro-3-methyl-[3-(methanesulfonamido)propan-l-yl]-1,4,7b-.... , . ,, . . . _ _ _ _ _ _ _ _ . . _ W096/02s42 2 1 9 ~ 2 2 3 PCTI~95/01382 triazacyclopent[cd]inden-2-one.hydronhlnri~i To a suspension of 500 mg (1.62 mmol) of 1,2-dihydro-3-methyl-1-[3-(methanesulfonamido)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 0.18 ml of conc. HCl. The solvent was distilled off to give 557 mg of the desired compound (99.6%, pale yellow crystals), m.p.184.0-185.0~C.
Elemental Analysis for Cl3HI6N4O35-HCl:
Calcd.: C, 45.28; H, 4.97; N, 16.25.
Found : C, 44.99; H, 4.95; N, 16.16.
NNR(200MHz,DMSO-d6) ~: 1.98(2H,m), 2.78(3H,s), 2.89(3H,s), 3.06(2H,m), 4.13(2H,t,J=7.0Hz), 7.12(1H,br), 7.54(1H,d,J=7.8Hz), 7.75(1H,d,J=8.6Hz), 8.14(1H,dd,J=8.6,7.8Hz).
Example 40 1,2-Dihydro-3-methyl-1-~3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 3,3-dimethyl-1,5-pentanediol To a solution of 13.38 g (83.5 mmol) of 3,3-dimethylglutaric acid and 90 ml (60 mmol) of methanol in 200 ml of 1,2-dichloroethane was added 4.18 ml of conc. sulfuric acid at room temperature. The mixture was heated for 16 hours under reflux. The reaction mixture was cooled, to which was added water. The organic layer was separated, washed with an aqueous solution of sodium hydrogencarbonate and dried. The solvent was distilled off, and the residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=2:1) to give ethyl 3,3-dimethyl glutarate.
This product was added, at room temperature, to a suspension of 3.80 g (100 mmol) of lithium aluminum hydride in 250 ml of tetrahydrofuran. The mixture was stirred for 16 hours. Water was added to this mixture until excess amount of lithium aluminum hydride was 2~3~23 ~096/0~42 ~ J.
~ - 133 -~r~ - C ed. The organic layer was dried, and the resulting precipitate was filtered off. The solvent was then distilled off to give 10.62 g of the desired compound (96.2~, white crystals).
NMR(200~Hz,CDCl3) ~: 0.95(6H,s), 1.58(4H,t,J=7.0Hz), 3.74(4H,t,J=7.0Hz).
ii) Synthesis of l-benzyloxymethoxy-3,3-dimethyl-5-pentanol To a solution of 7.93 g (60 mmol) of 3,3-dimethyl-1,5-pentandiol and 10.45 ml of diisopropylethylamine in 120 ml of dichloromethane was added, at room temperature, 8.35 ml (60 mmol) of benzylchloromethylether. The mixture was stirred for 3 hours, to which was added a saturated aqueous solution of sodium hydLoy~llcarbonate~ The mixture was extracted with dichloromethane. The extract was dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=2:1) to give 5.50 g of the desired compound (36.3%, colorless oil)~
NMR~200MHz,CDCl~) ~: 0.95(6H,s), 1.53-1.63(4H,m), 3.61-3.76(4H,m), 4.61(2H,s), 4.75(2H,s), 7.35-7.37(5H,m).
IR(neat): 3425, 2933, 1454, 1380, 1110, 1043, 787, 698 cm~l .
iii) Synthesis of 1-(3,3-dimethyl-5-benzyloxymethoxy-pentyl)phth~l imi ~
To a solution of 5.50 g (21.8 mmol) of 3,3-dimethyl-5-benzyloxymethoxy-1-pentanol and 3.14 ml (22.5 mmol) of triethylamine in 100 ml of dichloromethane was added, at 0~C, 1.74 ml (22.5 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes at room temperature, to which was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane. The extract was dried, followed by distilling off the solvent to give 3,3-dimethyl-5-W096/0~42 2 I q 3 2 2 3 PCT/JP9jlO1382 benzyloxymethoxy-l-methanesulfonyl -oxy~entane.
NMR(200MHz,CDCl3) ~: 0.97(6H,s), 1.61-1_78(4H,m), 2.98(3H,s), 3.58-3.66(2H,m), 4.29(2H,t,J=8.0Hz), 4.59(2H,s), 4.74(2H,s), 7.32-7.42(5H,m).
IR(neat): 2933, 1479, 1356, 1174, 951, 737, 699 cm 1.
To a solution of the above-mentioned product in 80 ml of N,N-dimethylformamide was added, at room temperature, 3.70 g (20 mmol) of phthalimide potassium salt. The mixture was stirred for 4 hours at 80~C.
The reaction mixture was cooled and, then, the solvent was distilled off. The residue was dissolved in a mixture of dichloromethane and a saturated aqueous solution of sodium hydLuy~ncarbonate. The organic layer was separated, washed with water and dried, followed by distilling off the solvent. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate = 5:1 - 2:1) to give 5.85 g of the desired Ll und (70.3%, colorless oily).
NMR(200MHz,CDCl3) ~i: 1.02(6H,s), 1.58-1.68(4H,m), 3.64-3.75(4H,m), 4.61(2H,s), 4.76(2H,s), 7.30-7.37(5H,m), 7.68-7.72(2H,m), 7.81-7.85(2H,m).
IR(neat): 2954, 1770, 1714, 1400, 1369, 1045, 719, 698 cm iv) Synthesis of 1-(3,3-dimethyl-5-hydlL~y~l:llLyl) phth~l imir~r~, To a solution of 5.70 g (14.9 mmol) of 1-(3,3-dimethyl-5-benzyloxymethoxypentyl)phth~l imi~ in 70 ml of methanol was added 3.75 ml (45 mmol) of conc. HCl.
The mixture was stirred for 3 hours at 60~C. The reaction mixture was cooled, and the solvent was distilled of~ The residue was dissolved in lOO ml of water, to which was added 30 ml of lN aqueous solution of sodium hydroxide. The mixture was extracted with dichloromethane. The extract solution was dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: n-2 1 ~3~3 Wog~/02s42 PCT~JP9~101382 _ - 135 -hexane/ethyl acetate = 2:1 - 1:2) to give 3.63 g of the desired compound (93.2%, white solid).
NMR(200MHz,CDCl3) ~: 1.02(6H,s), 1.56-1.67(4H,m), 3.67-3.78(4H,m), 7.69-7.73(2H,m), 7.82-7.86(2H,m).
IR(KBr): 2954, 1772, 1713, 1400, 1365, 719 cml.
v) Synthesis of 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(phthalimido)pentan-1-yl]-1,4,7b-triazacyclopento-[cd~inden-2-one To a solution of 1.57 g (6.0 mmol) of 1-(3,3-dimethyl-5-hydroxypentyl)phthalimide and 0.92 ml (6.6 mmol) of triethylamine in 30 ml of dichloromethane was added, at 0~C, 0.51 ml (6.6 mmol) of methanesulfonyl chloride. The mixture was stirred for 30 minutes at room temperature, to which was added a saturated aqueous solution of sodium hydrogencarbonate. The mixture was extracted with dichloromethane. The extract was dried, followed by distilling off the solvent to give l-(3,3-dimethyl-5-methanesulfonyloxypentyl)phthalimide.
NMR(200MHz,CDCl3) 8: 1.05(6H,s), 1.56-1.65(2H,m), 1.81(2H,t,J=7.8Hz), 3.70(3H,s), 3.65-3.74(2H,m), 4.36(2H,t,J=7.8Hz), 7.69-7.73(2H,m), 7.82-7.86(2H,m).
IR(neat): 2962, 1770, 1714, 1344, 1171, 947, 716, 527 To a suspension of 0.24 g (6.0 mmol) of sodium hydride (60% despersion in oil) in 30 ml of N,N-dimethylformamide was added, at room temperature, 1.04 g (6.0 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopento[cd]indene.
The mixture was stirred for 10 minutes. To this mixture was added the above-mentioned product. The mixture was stirred for 2 hours at 100~C. The reaction mixture was cooled, which was then poured into water, extracted with ethyl acetate. The organic layer was washed with water, dried, distilled off the solvent.
The residue was purified by column chromatography W0 96~02~42 2 1 q ~ 2 2 3 r~

(eluent: ethyl acetate - ethyl acetate/ethanol = 9:1) to give 1.32 g of the desired compound (52.8%, pale yellow oil).
NMR(200MHz,CDCl3) 5: 1.41(6H,s), 1.67-1.89(4H,m), 2.82(3H,s), 3.73-3.82(2H,m), 4.11-4.20(2H,m), 7.02(1H,d,J=7.4Hz), 7.49(1H,d,J=8.8Hz), 7.70-7.78(3H,m), 7.84-7.88(2H,m).
IR(RBr): 2966, 1709, 1626, 1406, 1371, 775, 752, 717 cm~l -vi) Synthesis of 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 1.25 g (3.0 mmol) of 1,2-dihydro-3-methyl-[3,3-dimethyl-5-(ph~h~li m i d~ ) pentan- 1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of ethanol was added, at room temperature, 0.44 ml (9.0 mmol) of hydrazinemonohydrate. The mixture was heated under reflu~. The reaction mixture was cooled, and the resulting precipitates were filtered off. The solvent was distilled off. The residue was dissolved in chloroform. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate, dried, distilled off the solvent to give 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(amino)pentan-1-yl]-1,4,7b-triazacyclopenttcd]inden-2-one.
NMR(2ooMHz~cDcl3) ~: 1.05(6H,s), 1.49-1.58(2H,m), 1.69-1.78(2H,m), 2.75-2.83(4H,m), 4.02-4.11(2H,m), 6.78(1H,d,J=7.4Hz), 7.48(1H,d,J=8.6Hz), 7.04(1H,d,J=7.4,8.8Hz).
To a solution of the above-mentioned product and 0.56 ml (4.0 mmol) of triethylamine in 25 ml of acetonitrile was added, at 0~C, 1.43 g (4.0 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 12 hours at room temperature. To the reaction mixture was added water, to extracted with chloroform.---The extract solution was dried, the ~ 1 93~2~
W096/02542 ,_"J,,~

solvent was distilled off. The residue was purified by column chromatogr-aphy to glve 1.03 g of the desired : compound (82.1%, pale yellow foam).
NMR(200MHz,CDCl3) 5: 1.07(6H,s), 1.72-1.81(4H,m), - 5 2.81(3H,s), 3.36-3.44(2H,m), 4.01-4.11(2H,m), 6.83(1H,d,J=7.8Hz), 7.34-7.38(1H,m), 7.51(1H,d,J=9.2Hz), 7.73(1H,dd,J=7.6,8.8Hz),;
vii) Synthesis of 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a solution of 1.03 g (2.46 mmol) of 1,2-dihydro-3-methyl-1-[3,3-dimethyl-5-(trifluoromethanesulfonamido)pentan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 0.29 ml (3.5 mmol) of conc. HCl. The solvent was distilled off, and the residue was recrystallized (solvent: ethanol/diethylether) to give 0.928 g of the desired compound (82.9%, pale yellow powdery substance), m.p.162.0-165.0CC.
Elemental Analysis for Cl7H2lN4O35 HCl:
Calcd.: C, 44.89; H, 4.87; N, 12.32.
Found : C, 44.86; H, 4.89; N, 12.43.
NMR(200MHz,CD30D) ~: 1.10(6H,s), 1.62-1.84(4H,m), 2.92(3H,s), 3.22-3.32(2H,m), 4.14-4.22(2H,m), 7.56(1H,d,J=7.8Hz), 7.80(1H,d,J=8.8Hz), 8.32(1H,t,J=8.0Hz).
Example 41 3-Methyl-2-[4-(trifluoromethanesulfonamido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]inden-hydrochloride i) Synthe5is of 3-methyl-2-[4-(trifluoromethane-: sulfonamido)butan-l-ylthio]-1,4,7b-triazacyclopento[cd]indene To a solution of 1.30 g (5.0 mmol) of 3-methyl-2-[4-(amino)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene and 0.84 ml (6.0 mmol) of triethylamine in 40 ml of methylene chloride was added, W096~1542 2 1 q 3 2 2 3 PCr/.lP95/01382 while stirring at room temperature, 1.97 g (5.5 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 18 hours at the same temperature. The reaction mixture was washed with an a~[ueous solution of S sodium hydLu~ullcarbonate/ dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 883 mg (45.1%, pale brown solid).
NNR(200MHz,CDCl3) ~: 1.85(2H,m), 2.19(2H,m), 2.90(3H,s), 3.37(2H,m), 3.64(2H,t,J=6.0Hz), 7.76(1H,d,J=7.8Hz), 7.89(1H,d,J=7.6Hz), 7.99(1H,dd,J=7.8,7.6Hz), 9.01(1H,br).
ii) Synthesis of 3-methyl-2-[4-(trifluoromethane-sulfonamido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene hydrochloride To a suspension of 873 mg (2.22 mmol) of 3-methyl-2-[4-(trifluoromethanesulfonamido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene in 10 ml of methanol was added 0~23 ml of conc. HCl. The solvent was then distilled off. The residue was recrystallized from ethanol-ether to give 762 mg of the desired compound (79.996, colorless crystals), m.p.129.0-131.0~C.
Elemental Analysis for Cl4HI5N4O25~F3-HCl:
Calcd.: C, 39.21; H, 3.76; N, 13.06.
Found: C, 38.92; H, 3.80; N, 13.33.
~xample 42 4,5-Dihydro-4-[4-(methanesulfonamido)phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[4-methanesulfonamido) phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a suspension of 877 mg (3.0 mmol) of 4-[4-tamino)phenylmethyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione and 0.63 ml (4.5 mmol) of triethyla-mlne in methylene chloride (60 ml) was added dropwise 0.30 ml (3.9 mmol) of methanesulfonyl 2 ~ ~3223 W096I02542 ~ J- _ I
_ - 139 -chloride while stirring at room temperature. The mixture was stirred for 72 hours at room temperature.
The solvent was distilled off. To the residue was added chloroform, washed with lN-HC1, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: chloroform/methanol=20:1) to afford 274 mg of the desired compound (24.7%, a pale yellow solid).
NMR(200MHz,CDCl3-DMSO-d6)~: 2.89(3H,s), 5.30(2H,s) 7.23(2H,m), 7.51(2H,m), 7.83(1H,dd,J=9.0, 7.2HZ), 8.17(1H,d,J=9.OHz), 8.18(1H,d,J=7.2Hz), 8.63(1H,s), 9.33(lH,br).
ii) Synthesis of 4,5-dihydro-4-[4-(methanesulfonamido) phenylmethyl]-3H-1,4,8b-triazAAr~nAphthylene-3,5-dione-hydrochloride To a suspension of 248 mg (0.67 mmol) of 4,5-dihydro-4-[4-(methanesulfonamido)phenylmethyl]-3H-1,4,8b-triA7~r~nAphthylene-3~5-dione in 15 ml of methanol was added 0.09 ml of conc. HCl. The solvent was distilled off. To the residue was added acetone.
The resulting solid was washed with acetone and dried to afford 273 mg of the desired compound (100%, a colorless solid).
Example 43 4,5-Dihydro-4-[4-(trifluoromethanesulfonamido) phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[4-(trifluoromethane sulfonamido)phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a suspension of 1.46 g (5.0 mmol) of 4-[4-(amino)phenylmethyl]-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione and 1.05 ml (7.5 mmol) of triethylamine in methylene chloride (100 ml) was added dropwise, while stirring under ice-cooling, 1.01 W096l02~2 2 1 9 3 2 ~ 3 140 - PCT/~9~01382 ml (6.0 mmol) of trifluoromethanesulfonic acid anhydride. The mixture was stirred for one hour at room temperature. The reaction mixture was washed with lN-HC1, and dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was eluted by column chromatography (eluent:chloroform/ethyl acetate=1:1) to afford 502 mg of 4,5-dihydro-4-[4-bis(trifluoromethane sulfonyl)imido)phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione (18.1%, a pale reddish brown solid).
NMR(200NHz,CDCl3)~: 5.40(2H,s), 7.35(2H,m), 7.74(2H,m), 7.81(1H,dd,J=9.0, 7.2Hz), 8.18(1H,d,J=9.OHz), 8.19(1H,d,J=7.2Hz), 8.67(1H,s).
and was further elution (eluent:chloroform/ethyl acetate=l:l) afforded 137 mg of the desired compound (6.5%, a pale brown solid).
NMR(200MHz,CDCl3)8: 5.35(2H,s), 7.24(2H,m), 7.59(2H,m), 7.81(1H,dd,J=9.2, 7.2Hz), 8.18(1H,d,J=9.2Hz), 8.19(1H,d,J=7.2Hz), 8.66(1H,s).
ii) Synthesis of 4,5-dihydro-4-[4-(trifluoromethane sulfonamido)phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride To a suspension of 129 mg (0.30 mmol) of 4,5-dihydro-4-[4-(trifluoromethanesulfonamido) phenylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 10 ml of methanol was added 0.04 ml of conc. HCl.
The solvent was distilled off. To the residue was added acetone. The resulting solid was washed with acetone and dried to afford 141 mg of the desired compound (100~6, a pale brown solid).
NMR(200MHz,DMSO-d6)8: 5.21(2H,s), 7.20(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.94(1H,dd,J=8.8, 7.2Hz), 8.17(1H,d,J=7.2Hz), 8.33(1H,d,J=8.8Hz), 8.73(1H,s), 11.78(lH,br).
Example 44 ~096/02~2 PCT/~95101382 4,5-Dihydro-4-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3H-1,4,8b-triA7~Ar~nAphthylene-3~5-dione To a suspension of 10.59 g (30.3 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine ; 5 and 5.09 g (39.4 mmol) of diisopropylethylamine in 200 ml of acetonitrile was added 4.15 g (36.3 mmol) of 4-Ami -thylpiperidine. The mixture was stirred for 20 hours at room temperature. To the reaction mixture was added dropwise 15.87 g (72.7 mmol) of di-tert-butyl dicarbonate, and the mixture was stirred for one hour at room temperature. The solvent was distilled off.
To the residue was added methylene chloride. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=20:1), and treated with ethyl acetate and n-hexane to afford 9.10 g (78.1~, a pale yellow solid) of the desired compound.
NMR(200MHz,CDCl3)~: 1.22-1.48(2H,m), 1.45(9H,s), 1.57-1.73(2H,m), 2.05(1H,m), 2.55-2.75(2H,m), 3.98-4.22(2H,m), 4.12(2H,d,J=7.0Hz), 7.81(1H,m), 8.13-8.21(2H,m), 8.65(1H,s).
Example 45 4,5-Dihydro-4-[1-(trifluoroacetyl)piperidin-4-ylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione i) Synthesis of 4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaacenaphthylene-3,5-dione-dihydrochloride To a suspension of 7.99 g (20.8 mmol) of 4,5-dihydro-4-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 50 ml of ethanol was added dropwise 25 ml of conc.HCl.
The mixture was stirred for two hours at room temperature. The resulting crystalline precipitates were collected by filtration, washed with ethanol and then with ether to afford 7.07 g (87.4%, a colorless _ . _ _ _ _ _ _ _ _ _ _ . . .. . . . . .

W096/0~4z 2 t q 3 2 ~ ~ r~ l/J~ o~ ~

solid substance) of the desired compound Elemental Analysis Calcd for Cl5Hl6N404-2HCl-2H20:
Calcd.: C, 47.75; H, 5.88; N; 14.85 ~-Found : C, 47.91; H, 5.49; N, 14.84 NMR(200MHz,D70)h: 1.47-1.72(2H,m), 1.89-2.06(2H,m), 2.21(1H,m), 2.96(2H,m), 3.44(2H,m), 4.12(2H,d,J=7.2Hz), 8.26(1H,dd,J=9.0, 7.2Hz), 8.40(1H,d,J=9.OHz), 8.44(1H,d,J=7.2Hz), 8.89(1H,s).
ii) Synthesis of 4,5-dihydro-4-[1-(trifluoroacetyl) piperidin-4-ylmethyl]-3H-1,4,8b-triA7~ n~phthylene-3,5-dione To a suspension of 1.08 g (2.77 mmol) of 4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-triazaace-naphthylene-3,5-dione-dihydrochloride in 100 ml of acetonitrile were added 1.93 ml (13.9 mmol) of triethylamine, 2.0 g (16.4 mmol) of 4-dimethylaminopyridine and 5.25 g (25.0 mmol) of trifluoroacetic acid anhydride. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added ethyl acetate - tetrahydrofuran. The mixture was washed with an aqueous solution of sodium hydrogencarbonate, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate), which was then recryst~ 7~d from ethyl acetate to afford 862 mg (81.7%, a colorless crystals) of the desired compound.
Elemental Analysis Calcd for Cl7Hl5N403F3:
Calcd.: C, 53.69; H, 3.98; N; 14.73 Found : C, 53.62; H, 3.96; N, 14.69 NMR(200MHz,CDCl3)~: 1.50(2H,m), 1.84(2H,m), 2.24(1H,m), 2.77(1H,m), 3.09(1H,m), 4.03(1H,m), 4.15(2H,d,J=7.2Hz), 4.54(1H,m), 7.82(1H,dd,J=9.0, 7.4Hz), 8.19(1H,d,J=7.4Hz), 8.20(1H,d,J=9.OHz), 8.67(1H,s).
Example 46 4,5-Dihydro-4-[1-(trifluoromethanesulfonyl)piperidin-4-w096/02s42 ylmethyl]-3H-1~4~8b-triazaacenaphthylene-3~5-diOne To a suspension of 1.95 g (5.0 mmol) of 4,5-dihydro-4-(piperidin-4-ylmethyl)-3H-1,4,8b-tri ~7~r~n~phthylene-3,5-dione-dihydrochloride in 50 ml of acetonitrile were added 3.5 ml (25.0 mmol) of triethylamine and 8.93 g (25.0 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 66 hours at room temperature. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), which was recryst~ ed from ethyl acetate - ethanol to afford 1.32 g (63.2~, a colorless crystals) of desired compound.
NMR(200MHz,CDCl3)~: 1.56(2H,m), 1.83(2H,m), 2.13(1H,m), 3.01(2H,m), 3.97(2H,m). 4.16(2H,d,J=7.2Hz), 7.82(2H,dd,J=8.8, 7.2=Hz), 8.19(1H,d,J=7.2Hz), 8.20(1H,d,J=8.8Hz), 8.67(1H,s).
Example 47 3-Methyl-1-[5-(trifluoroacetamido)pentyl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentyl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring under ice-cooling, 1.43 ml (12.0 mmol) of trifluoroacetic acid ethyl ester. The mixture was stirred for one hour at the same temperature. The solvent was distilled ofi.
To the residue was added ethyl acetate -tetrahydrofuran. The mixture was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent:
ethyl acetate), which was recryst~lli7ed from ethyl W096l02~42 21q3~2~ r~llJA ~ CIJ~ ~

acetate - n-hexane to afford 2.57 g (72.6%, a pale yellow crystals) of the desired compound.
NMR(200MHz,CDCl3)~: 1.44(2H,m), 1.75(2H,m), 1.92(2H,m), 2.82(3H,s), 3.39(2H,m), 4.11(2H,t,J=6.6Hz), 6.83(1H,d,J=7.4Hz), 6.92(1H,br), 7.51(1H,d,J=8.6Hz), 7.74(1H,dd,J=8.6, 7.4Hz).
Example 48 3-Methyl-1-[4-(pentafluoropropanoylamino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 2.44 g (10.0 mmol) of 3-methyl-1-[4-(amino)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of ethyl ester of pentafluoropropionlc acid. The mixture was stirred for 14 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with water, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate), and recrystallized from ethyl acetate - hexane to afford 1.53 g (39.1%, a colorless crystals) of the desired compound.
Elemental Analysis Calcd for Cl6HI5N4O~F5:
Calcd.: C, 49.25; H, 3.87; N; 14.35 Found : C, 49.15; H, 3.91; N, 14.21 NMR(200MHz,CDCl3)~: 1.73(2H,m), 1.92(2H,m), 2.82(3H,s), 3.50(2H,m), 4.13(2H,t,J=6.8Hz), 6.84(1H,d,J=7.4Hz), 7.05(1H,br), 7.50(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6,7.4Hz).
~xample 49 3-~ethyl-1-[5-(pentafluoropropanoylamino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 2.58 g (10.0 mmol) of 3-methyl-1-[5-(amino)pentan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2 1 9322~
~0~6/02s42 PCT1~9~01382 2-one and 1.81 ml (13.0 mmol) of triethylamine in 100 ml of acetonitrile was added, while stirring at room temperature, 2.31 g (12.0 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 4 hours at the same temperature. The solvent was distilled off. To the residue was added methylene chloride, and the mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 2.04 g of the desired compound (50.4~, a pale yellow solid).
NMR(200MHz,CDCl3)~: 1.43(2H,m), 1.75(2H,m), 1.90(2H,m), 2.82(3H,s), 3.41(2H,m), 4.10(2H,t,J=6.6Hz), 6.83(1H,d,J=7.4Hz), 7.11(1H,br), 7.51(1H,d,J=8.6Hz), 7.74(1H,dd,J=8.6, 7.4Hz).
Example 50 3-Methyl-2-[5-(trifluoromethanesulfonamido)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene To a solution of 500 mg (1.82 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]
indene in 30 ml of acetonitrile were added 0.51 ml (3.66 mmol) of triethylamine and 1.302 g (3.66 mmol) of N-phenyltrifluoromethanesulfonamide. The mixture was stirred for two hours at room temperature. The solvent was distilled off. To the residue was added methyIene chloride, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 608 mg (8Z.1%, a pale yellow solid) of the desired compound.
NMR(2ooMHz,cDcl~)~: 1.55-1.85(4H,m), 1.97(2H,m), 2.90(3H,s), 3.39(2H,m), 3.50(2H,t,J=7.0Hz), 7.69(1H,d,J=7.8Hz), 7.73(1H,d,J=8.0Hz), 7.95(1H,dd,J=8.0, 7.8Hz).
Example 51 3-Methyl-2-[5-(trifluoroacetamido)pentan-1-ylthio]-W09610~2 2 1 ~3~2~ 146 -1,4,7b-triazacyclopent[cd]indene To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]
indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 171 mg (1.20 mmol) of ethyl ester of trifluoroacetic acid. The mixture was stirred for 15 hours at room temperature. The solvent was distilled off. To the residue was added ethyl acetate, which was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 267 mg (72.0~, a pale yellow solid) of the desired c~ uulld.
NMR(200MHz,CDCl3)~: 1.50-2.10(6H,m), 2.90(3H,s), 3.42(2H,m), 3.52(2H,t,J=7.0Hz), 6.56(1H,br), 7.67(1H,d,J=7.8Hz), 7.73(1X,d,J=8.0Hz), 7.95(1H,dd,J=8.0, 7.8Hz).
Example 52 _ 3-Methyl-2-[5-(pentafluoropropanoylamino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene To a solution of 275 mg (1.00 mmol) of 3-methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]
indene in 30 ml of acetonitrile were added 0.19 ml (1.36 mmol) of triethylamine and 231 mg (1.20 mmol) of pentafluoropropionic acid ethyl ester. The mixture was stirred for 15 hours at room temperature, and the the solvent was distilled off. To the residue was added ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 245 mg (58.1~, a pale brown solid) of the desired cl ~uulld.
NMR(200MHz,CDCl3)~: 1.50-1.80(4H,m), 1.96(2H,m), 2.90(3H,s), 3.44(2H,m), 3.52(2H,t,J=7.0Hz), 6.68(1H,br), 7.67(1H,d,J=7.8Hz), 7.73(1H,d,J=8.0Hz), 7.95(1H,dd,J=8.0,7.8Xz).

2~ 9322~
096/02542 PCT1~9~/01382 _ - 147 -Example 53 3,4-Dihydro-3-[5-(tert-butoxycarbonylamino)pentan-1-yl]-1,3,7b-triazacyclopent[cd]inden-4-one To a suspension of 29 mg (0.077 mmol) of 3,4-dihydro-3-[5-(ph~h~limi~)pentan-l-yl]-lr3/7b-triazacyclopent[cd]inden-4-one in 5 ml of ethanol was added 24 mg (0.048 mmol) of hydrazinemonohydrate. The mixture waE stirred for three hours under reflux.
After cooling, the solvent was distilled off. To the residue was added 2 ml of chloroform. To the mixture were added 80 mg (0.37 mmol) of di-tert-butyl dicarbonate and lO0 mg (0.99 mmol) of triethylamine, and stirred for 14 hours at room temperature. The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol=lO:1) to afford 18 mg (67.4~, a colorless solid) the desired compound.
NMR(200MHz,CDCll)~: 1.30-1.82(6H,m), 1.44(9H,s), 2.98(lH,m), 3.13(2H,m), 4.46(lH,m), 4.58(lH,br), 6.90(1H,dd,J=7.0, 1.2Hz), 7.15(1H,s), 7.17(1H,dd,J=9.2, 7.0Hz), 7.40(1H,dd,J=9.2, 1.2Hz).
~xample 54 3,4-Dihydro-3-[5-(trifluoromethanesulfonamido)pentan-l-yl]-1,3,7b-triazacyclopent[cd]inden-4-one To a solution of 18 mg (0.052 mmol) of 3,4-dihydro-3-[5-(tert-butoxycarbonylamino)pentan-1-yl]-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of methanol was added 1 ml of conc.HCl, and the mixture was stirred for 15 minutes at room temperature. The solvent was distilled off. To the residue was added toluene. The solvent was further distilled off. To the residue were added 3 ml of acetonitrile, 0.2 ml (1.43 mmol) of triethylamine and 100 mg (0.28 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 14 hours at room temperature. The solvent W096/02~2 21~3223 P I~J ~ 0 was distilled off. To the residue was added chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=lO:l) to afford 13 mg (66.0~, a colorless solid) of the desired compound.
NMR(2ooMHz~cDcl3)~: 1.35-1.85(6H,m), 3.05(lH,m), 3.33(2H,m), 4.43(1H,m), 6.53(1H,br), 6.97(1H,dd,J=7.0, l.OHz), 7.16(1H,s), 7.23(1H,dd,J=9.0, 7.0Hz), 7.43(1H,dd,J=9.0, l.OHz).
Pxample 55 4,5-Dihydro-4-(4-trifluoroacetamidobutan-l-yl)-3H-1,4,8b-tri~7~ct~n~rhthylene-dihydrochloride i) Synthesis of 5-[N-(4-trifluoroacetamidobutan-1-yl) ~m; nt -thyl]imidazo[1,2-a]pyridine A suspension of 38.94 g (179.36 mmol) of 5-chloromethylimidazo[l,2-a]pyridine-hydrochloride and 31.62 g (358.73 mmol) of 1,4-tli~inthutane in 500 ml of acetonitrile was heated for one hour under:reflux with stirring. The reaction mixture was cooled to room temperature, and 1,4-diaminobutane-dihydrochloride formed as precipitate was filtered off. To the filtrate were added 21.34 ml (179.36 mmol) of trifluoroacetic acid ethyl ester and 30 ml (215.23 mmol) of triethylamine. The mixture was stirred for one hour at room temperature. The solvent was then distilled off under reduced pressure. The residue was extracted with 500 ml of dichloromethane. The organic layer was washed with 350 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified ky silica gel column chromatography (eluent;dichloromethane:methanol=20:1) to afford 29.38 g (52.1~, a pale yellow liquid) of the disired compound.
N~R(200MHz,CDCl3)~: 1.65(4H,m), 2.73(2H,t,J=6.2Hz), 2~32~3 096l02s42 ~IJ.~51~1382 3.37(2H,m), 4.04(2H,s), 6.78(1H,d,J=7.OHz), 7.18(1H,dd,J=9.2Hz,7.0Hz), 7.57(1H,d,J=9.2Hz), 7.67(1H,s), 7.69(1H,s), 7.88(1H,brs,NH).
IR(Neat): 1714, 1558, 1207, 1153 cm ; 5 ii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamido butan-1-yl)-3H-1,4,8b-triazaacenaphthylene To a solution of 3860 mg (12.28 mmol) of 5-[N-(4-trifluoroacetamidobutan-1-yl)~m i n~ Lhyl]imidazo[1,2-a]
pyridine in 15 ml of acetic acid was added 13.8 ml (184.21 mmol) of a 37% aqueous solution of formalin.
The mixture was heated for 30 minutes at 100~C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water.
To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 150 ml of dichloromethane. The organic layer was washed with 200 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent;
dichloromethane:methanol=20:1) to afford 2890 mg of the desired compound (72.0%, a white solid).
NMR(200~Hz,CDC13)~: 1.69(4H,m), 2.53(2H,m), 3.40(2H,m), 3.99(2H,s), 4.14(2H,s), 6.55(1H,d,J=6.8Hz), 7.12(1H,dd,J=9.2Hz, 6.8Hz), 7.39(1H,s), 7.45(lH,d,J=9.2Hz), 8.14(lH,brs,NH).
IR(~Br): 1707, 1562, 1260, 1140 cml.
iii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamido butan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride To a solution of 1100 mg (3.37 mmol) of 4,5-dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H,1,4,8b-tri~r~ n~phthylene in 20 ml of ethanol was added 0.70 ml (8.43 mmol) of 12N hydrochloric acid. The mixture was stirred for one hour at room temperature. The resulting precipitates were collected by filtration, ~096/02542 2 I q 3 2 2 3 PCT/~95101382 washed with a small volume of ethanol and ether, and dried to afford 1160 mg of the desired compound (86.2%, a white crystals).
NMR(200MHz,DMSO-d6)~: 1.50-1.82(4H,m), 3.04(2H,m), 3.23(2H,m), 4.64(2H,s), 4.70(2H,s), 7.48(1H,d,J=7.4Hz), 7.95-7.99(2H,m), 8.12(1H,s), 9.05(1H,t,J=5.2Hz).
IR(~Br): 1716, 1549, 1224, 1186, 1149 cm .
Example 56 4,5-Dihydro-4-(4-trifluoroacetAmi~inhutan-l-yl)-3H-1,4,8b-triazaacenaphthylene-3-one-hydrochloride i) 5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamido butan-l-yl)~m i nl Lhyl]imidazo[1,2-a]pyridine To a solution of 29.38 g (93.47 mmol) of 5-[N-(4-trifluoroA~ tAmidobutan-yl)aminomethyl]imidazo[1,2-a]
pyridine in 200 ml of ethanol was added 20.40 g (93.47 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for one hour at room temperature. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 30.12 g of the desired c~ ~u~ d (77.8%, a colorless li~uid).
NMR(200MHz,CDCl3)~: 1.35-1.50(13H,m), 3.26(4~,m), 4.71(2H,s), 6.69(1H,d,J=6.6Hz), 7.20(1H,t,J=8.8Hz), 7.59-7.80(3H,m).
IR(Neat): 17I3, 1686, 1556, 1147 cm1.
ii) Synthesis of 3-trichloroacetyl-5-[N-tert-butoxy carbonyl-N-(4-trifluoroacetamidobutan-1-yl ) Am i n~ Lhyl]
imidazo[l,2-a]pyridine To a solution of 7.69 g (18.56 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-1-yl)amino methyl]imidazo[l,2-a]pyridine and 10.20 g (83.52 mmol) of 4-(N,N-dimethylamino)pyridine in 100 ml of THF was added 6.21 ml (55.67 mmol) of trichloroacetyl chloride.
The reaction mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-096l0~2 I~-/J, I~B~

water, and extracted with 100 ml of ethyl acetate. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure.
The residue was purified by silica gel column chromatography (eluent; chloroform) to afford 4.98 g of the desired compound (48.0%, a pale yellow amorphous).
NMR(2coMHzlcDcl~ 1.26(9H,s), 1.68(4H,m), 3.43(4H,m), 4.51(1H,s), 4.68(1H,s), 6.95(1H,brs,NH), 7.11(1H,d,J=7.0Hz), 7.65-7.78(2H,m), 8.69(0.5H,s), 8.97(0.5H,s).
IR(~Br): 1701, 1514, 1178, 1153 cm'.
iii) Synthesis of 4,5-dihydro-4-(4-trifluoroacetamido butan-l-yl)-3H-1,4,8b-triazaacenaphthylen-3-one To a solution of 2.60 g (4.64 mmol) of 3-trichloro acetyl-5-[N-tert-butoxycarbonyl-N-(4-trifluoroacetamidobutan-l-yl)aminomethyl]imidazo[1,2-a]pyridine in 20 ml of ethanol was added 1.90 ml (23.22 mmol) of 12N HCl. The mixture was stirred for one hour at room temperature. The solvent and excess volume of hydrochloric acid were distilled off under reduced pressure. The residue wa5 dissolved in a mixture of 20 ml of purified water and 20 ml of ethanol. To this solution was added a 2N aqueous solution of sodium hydroxide to neutralize. This solution was extracted with 100 ml of dichloromethane. The organic layer was washed with lO0 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 1.26 g of the desired compound (75.9~, pale yellow amorphous).
NMR(2ooMHz~cDcl3)~: 1.74(4H,m), 3.48(2H,m), 3.63(2H,m~, 5.03(2H,s), 6.77(1H,d,J=7.0Hz), 7.28(1H,brs,NH), 7.34(1H,dd,J=9.2Hz, 7.0Hz), 8.15(1H,s).

W096/02~2 ~32~3 152 ~ IJr~ 5~2 IR(RBr): 1702, 1643, 1207, 1159 cm iv) Synthesis of 4,5-dihydro-4-(4-trifluoroacetAmi~lnhutan-l-yl)-3H-1,4,8b-triazaacenaphthylen-3-one~hydrochloride To a solution of 1.13 g (3.32 mmol) of 4,5- , dihydro-4-(4-trifluoroacetamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one in 20 ml of ethanol was added 0.42 ml (4.98 mmol) of 12N hydrochloric acid. The mixture was concentrated under reduced pressure. The resulting crystals was collected by filtration, which was washed with a small volume of ethanol and ether to afford S60 mg of the desired compound (44.8%, a white crystals.
NMR(200~Hz,D~SO-d6)6: 1.63(4H,m), 3.27(2H,m), 3.53(2H,m), 5.25(2H,s), 7.43(1H,d,J=7.4Hz), 7.85(1H,d,J=8.2Hz), 8.02(1H,dd,J=8.2,7.4Hz), 8.61(1H,s), 9.06(1H,t,NH,J=5.4Hz).
IR(KBr): 1709, 1653, 12SS cml.
~xample S7 4,5-Dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride i) Synthesis of 5-[N-(4-pentafluoropropionamidobutan-1-yl)~min Lhyl]imidazotl,2-a]pyridine A suspension of lS.13 g (69.69 mmol) of S-chloromethylimidazo[l,2-a]pyridine-hydrochloride and 12.29 g (139.38 mmol) of 1,4-~i~min~hutane in 150 ml of acetonitrile was heated for one hour under reflux while stirring. The reaction mixture was cooled to room temperature. The resulting precipitates of 1,4-~i~min~hutane-dihydrochloride were filtered off. To the filtrate were added 20.61 ml (139.38 mmol) of ethyl ester of pentafluoropropionic acid and 19.43 ml (139.38 mmol) of triethylamine. The mixture was stirred for one hour at room temperature. The solvent was then distilled off under reduced pressure, and the residue was extracted with 200 ml of dichloromethane. The 2 ~ 93223 W096/02~42 I~l/J.

organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent. The residue was purified by silica gel column chromatography (eluent;
dichloromethane:methanol=20:1) to afford 13.61 g of the desired Cl Ju~,d (53.6%, a pale yellow liquid).
NMR(200MHz,CDCl3)~: 1.54-1.75(4H,m), 2.72(2H,t,J=6.6Hz), 3.39(2H,q,J=6.6Hz), 4.03(2H,s), 6.78(1H,d,J=6.8Hz), 7.17(1H,dd,J=9.OHz, 6.8Hz), 7.54(1X,d,J=9.OHz), 7.64(1H,s), 7.69(1H,s), 8.32(lH,brs,NH).
IR(Neat): 1710, 1550, 1221, 1161 cm .
ii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropion amidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene To a solution of 2620 mg (7.19 mmol) of 5-[N-(4-pentafluoropropionamidobutan-l-yl)~min~ ~hyl]imidazo[1,2-a]pyridine in 10 ml of acetic acid was added 8.1 ml (107.88 mmol) of a 37%
aqueous solution of formalin. The mixture was heated for 30 minutes at 100~C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to afford 2250 mg of the desired compound (83.2%, a pale yellow liquid).
NMR(200MHz,CDCl3)~: 1.64-1.74(4H,m), 2.53(2H,m), 3.42(2H,m), 3.97(2H,s), 4.10(2H,s), 6.54(1H,d,J=6.8Hz), 7.11(1H,dd,J=9.2,6.8Hz), 7.34(1H,s), 7.41(1H,d,J=9.2Hz), 8.63(1H,brs,NH).
IR(Neat): 1718, 1545, 1221, 1169 cml.
iii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropion W096/02542 - 2 1 9 3 ~ ~ 3 , ~l/J~ - .s&2 amidobutan-l-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride To a solution of 2230 mg (5.93 mmol) of 4,5-dihydro-4-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylene in 35 ml of ethanol was added 1.22 ml (14.31 mmol) of 12N hydrochloric acid.
The mixture was stirred for one hour at room temperature. The resulting precipitates was collected by filtration, washed with a small volume of ethanol and ether, and dried to afford 2120 mg of the desired compound (76.9~, white crystals).
NMR(200MHz,CDCl3)~: 1.23-1.34(2H,m), 1.36-1.93(2H,m), 3.20-3.30(4H,m), 4.85(2H,s), 4.94(2H,s), 7.54(1H,m), 8.00(2H,m), 8.21(1H,s), 9.66(1H,t,NH,J=5.4Hz) IR(Neat): 1712, 1549, 1223, 1167 cml.
Example 58 Synthesis of 4,5-dihydro-4-(4-pentafluoropropi-lnAmir!~hutan-l-yl)-3H-1,4,8b-triaz;t;t~ n~rhthylen-3-one~hydrochloride i) Synthesis of 5-[N-tert-butoxycarbonyl-N-(4-penta fluoropropionamidobutan-1-yl)~m i n( Lhyl]imidazo[1,2-a]
pyridine To a solution of 12.41 g (34.06 mmol) of 5-[N-(4-pentafluoropropionamidobutan-l-yl)aminomethyl]imidazo [1,2-a]pyridine in 100 ml of ethanol was added 7.44 g (34.06 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent;dichloromethane:methanol=20:1) to afford 11.78 g of the desired compound (74.5%, a colorless liquid).
N~R(2ocMHzlcDcl3)~: 1.22-1.72(13H,s), 3.06-3.53(4H,m), t 4.71(2H,s), 6.70(1H,d,J=6.6Hz), 7.20(1H,t,J=8.6Hz), 7.45-7.95(4H,m).
IR(Neat): 1712, 1687, 1523, 1221, 1165 cm1.

WO96/02542 P_-/J. --IJ~

ii) Synthesis of 3-trichloroacetyl-5-[N-tert-butoxy carbonyl-N-(4-pentafluoropropionamidobutan-l-yl)amino methyl]imidazo[l,2-a]pyridine To a solution of 11.78 g (25.36 mmol) of 5-[N-tert-butoxycarbonyl-N-(4-pentafluoropropi~nAm;~nhutan-1-yl)~min~ ~hyl]imidazo[1,2-a]pyridine and 13.94 g (114.36 mmol) of 4-(N,N-dimethylamino)pyridine in 250 ml of chloroform was added 8.50 ml (76.09 mmol) of trichloroacetyl chloride. The mixture was heated for 16 hours under reflux. The reaction mixture was poured into ice-water, and extracted with 100 ml of chloroform. The organic layer was washed with 200 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 6.80 g of the desired compound (44.0~, a pale yellow liquid).
NMR(2ooMHz~cDcl3)~: 1.00-1.45(9H,s), 1.55-1.80(4H,m), 3.25-3.55(4H,m), 4.51(2H,s), 7.10(1H,d,J=7.4Hz), 7.72(1H,t,J=8.8Hz), 7.83(1H,d,J=8.6Hz), 8.97(1H,b).
IR(Neat): 1724, 1678, 1670, 1219, 1157 cm .
iii) Synthesis of 4,5-dihydro-4-(4-pentafluoropropion amidobutan-l-yl)-3H-1,4,8b-tri~7a~ n~rhthylen-3-one To a solution of 5.00 g (8.2 mmol) of 3-trichloro acetyl-5-[N-tert-butoxycarbonyl-N-(4-pentafluoropropion amidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in lO0 ml of ethanol was added 3.4 ml (41.0 mmol) of 12N
hydrochloric acid. The mixture was stirred for one hour at room temperature. The solvent and an excess volume of hydrochloric acid were distilled off under reduced pressure. The residue was dissolved in a mixture of 50 ml of purified water and 50 ml of ethanol. The solution was neutralized with 2N aqueous solution of sodium hydroxide. This solution was extracted with 150 ml of dichloromethane. The organic W096l02~2 2 1 q3~23 156 - I_~/J.. ~

layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2.11 g of the desired compound (66.1~, a pale yellow solid).
NMR(200MHz,CDCl3)~: 1.62-1.85(4H,m), 3.42-3.54(2H,m), 3.55-3.68(2H,m), 5.02(2H,s), 6.76(lH,d,J=7.0Hz), 7.27-7.56(1H,m), 7.52(1H,brs,NH), 7.53(1H,d,J=9.2Hz), 8.15(1H,s).
IR(KBr): 1702, 1646, 1543, 1220, 1161 cm .
iv) Synthesis of 4,5-dihydro-4-(4-pentafluoropropion amidobutan-1-yl)-3H-1,4,8b-triazaacenaphthylen-3-one-hydrgchlnri~
To a solution of 840 mg (2.15 mmol) of 4,5-dihydro-(4-pentafluoropropionamidobutan-1-yl)-3H-1,4,8b-triA7n~r~n~phthylene-3-one in 15 ml of ethanol was added 0.27 ml (3.23 mmol) of 12N hydrochloric acid.
The mixture was concentrated under reduced pressure.
The resulting crystalline precipitates were collected by filtration, and washed with a small volume of ethanol and ether to afford 662 mg of the desired compound (72.1%, white crystals).
NMR(23oMHzlDMso-d6)~: 1.58(4H,m), 3.26(2H,m), 3.55(2H,t,J=6.2Hz), 5.24(2H,s), 7.42(1H,d,J=7.4Hz), 7.84(1H,d,J=9.2Hz), 7.99(1H,dd,J=7.4,9.2Hz), 8.63(1H,s), 9.59(1H,t,NH,J=5.4Hz).
IR(RBr): 1718, 1636, 1548, 1224, 1163 cm~l.
Example 59 Synthesis of 1-(1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-triazacyclopent[cd]inden-2-one i) Synthesis of l-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl p-toluenesulfonate To a sslution of 10.18 g (50.58 mmol) of (S)-1-.... .. ~

W096/02~2 butoxycarbonylprolinol and 8.00 g (101.16 mmol) of pyridine in 100 cc of dichloromethane was added 9.64 g ~ (50.58 mmol) of p-toluenesulfonyl chloride. The reaction mixture was stirred for two hours at room temperature, to which was added 100 cc of dichloromethane. The mixture was washed with 200 cc of purified water, then with 200 cc of a saturated aqueous saline~solution. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=l:l) to afford 15.28 g of the desired compound (85.0%, a colorless liquid).
NMR(200MHz,CDCl3)~: 1.37(9H,s), 1.78-1.93(4H,m), 2.44(3H,s), 3.25-3.31(2H,m), 3.89-4.09(3H,m), 7.34(2H,d,J=8.0Hz), 7.77(2H,d,J=8.0Hz).
IR(Neat): 1722, 1666, 1166 cml.
ii) Synthesis of l-(l-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-triazacyclopent[cd]
inden-2-one To a solution of 5.85 g (33.81 mmol) of 3-methyl-2~-1,4,7b-triazacyclopent[cd]inden-2-one in 100 cc of DMF was added, while stirring under ice-cooling, 1.35 g (33.81 mmol) of sodium hydride (purity 60%) under the atmosphere of argon. The mixture was stirred for 30 minutes under the atmosphere of argon. To the reaction mixture was added at 0~C, under the atmosphere of argon, a solution of 14.42 g (40.57 mmol) of 1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl p-toluenesulfonate in 10 cc of DME. The mixture was heated for 3 hours at 100~C under the atmosphere of argon. The reaction mixture was poured into ice-water, and extracted with 500 cc of ethyl acetate. The organic layer wa5 washed with water three times, and further with 300 cc of a saturated aqueous saline 2 1 q322~ ' W096/02~2 PCTIJP95101382 solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to afford 7.54 g of the desired S compound (64.9~, a pale yellow liquid~. ;
NMR(200MHz,CDCl3)~: 1.48(9H,s), 1.89(4H,m), 2.83(3H,s), 4.23(3H,m), 7.10(d,J=7.4Hz) and 6.79(d,J=7.4Hz) for lE, 7.49(1H,d,J=8.8Hz), 7.70(1H,dd,J=7.4,8.8Hz).
IR(Neat): 1710, 1679, 1166 cm .
Example 60 1,2-Dihydro-3-methyl-1-(1-trifluoromethanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-(2-(S)-lS pyrrolidin-2-ylmethyl-1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride A solution of 3.42 g (10 mmol) of 1-(1-tert-butoxycarbonyl-2-(S)-pyrrolidin-2-ylmethyl)-3-methyl-2H-1,4,7b-tri~zacyclopent[cd]inden-2-one in a mixture of 25 cc of ethanol and 2 cc of lN hydrochloric acid was stirred ~or one hour at room temperature. The solvent was distilled of~ under reduced pressure. To the residue was added 20 cc of toluene. The solvent was distilled of~ under reduced pressure. This procedure was repeated twice. The residue was dried sufficiently to afford 4.11 g of a crude product (100~, a while solid). This crude product was used in the subsequent reaction without purification.
NMR(200MHz,D2O)~: 1.74-2.38(4H,m), 2.83(3H,s), 3.17-3.40(2H,m), 4.00(1H,m), 4.49(2H,d,J=6.4Hz), 7.52(1H,d,J=8.0Hz), 7.75(1H,d,J=8.8Hz), 8.23(1H,dd,J=8.0Hz, 8.8Hz).
IR(RBr): 3433, 1720, 1646, lS91 cml.
ii) Synthesis of 1,2-dihydro-3-methyl-1-(1-trifluoro methanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopent[cd]inden-2-one .

:=
2 ~ 932~
W09~02s42 ~ v.

To a saspension of 786 mg (2.5 mmol) of 1,2-dihydro-3-methyl-1-(2-(5)-pyrrolidin-2-ylmethyl)-; 1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride in 15 cc of acetonitrile was added, while stirring under ice-cooling, 1.4 cc (10.0 mmol) of triethylamine, followed by addition of 5.14 g (6.25 mmol) of N-phenyltrifluoromethanesulfonimide. The reaction mixture was stirred for two hours at room temperature.
The solvent was distilled off under reduced pressure.
The residue was purified by silica gel chromatography (eluent: ethyl acetate) to afford 751 mg of the desired compound (80.2%, a pale yellow liquid).
NMR(2ooMHzlcDcl3)5: 2.09(1H,m), 2.82(3H,s), 3.59(2H,m), 4 34(3H,m), 7.02(1H,d,J=7.6Hz), 7.53(1H,d,J=8.6Hz), 7.78(1H,dd,J=7.6, 8.6Hz).
IR(Neat): 1729, 1650, 1385 cml iii) Synthesis of 1,2-dihydro-3-methyl-1-(1-trifluoro methanesulfonyl-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride In a solvent consisting of 20 cc of ethanol and 0.1 cc of 12N hydrochloric acid was dissolved 800 mg (2.14 mmol) of 1,2-dihydro-3-methyl-1-(1-trifluoromethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopenttcd]indene. The solvent was distilled off under reduced pressure. The residue was dried to afford 880 mg of the desired compound (100%, a white solid).
NMR(200MHz,DMSO)~: 1.98-2.18(5H,m), 2.85(3H,s), 3.50(2H,m), 4.19(2X,m), 7.58(1H,d,J=7.6Hz), 7.81(1H,d,J=8.4Hz), 8.25(1H,dd,J=7.6,8.4Hz).
IR(KBr): 1733, 1651, 1385 cm Example 61 1,2-Dihydro-3-methyl-1-[1-(2,2,2-trifluoroethanesulfonyl)-2-(s)-pyrrolidin-2-ylmethyl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[1-(2,2,2-W096/02542 ~ ,J~ la~

trifluoroethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl]-1,4,7b-triaz~cyclopent[cd]inden-2-one To a suspension of 786 mg (2.5 mmol) of 1,2-dihydro-3-methyl-1-(2-(S)-pyrrolidin-2-ylmethyl)-1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride in 15 cc of dichloromethane was added, while stirring under ice-cooling, 1.4 cc (10.0 mmol) of triethylamine, and added 0.33 cc (3.0 mmol) of 2,2,2-trifluoroethAn~sulfonyl choride. The reaction mixture was stirred for one hour at room temperature. The solvent was then distilled off under reduced pressure.
The residue was purified by silica gel chromatography (eluent: ethyl acetate) to afford 651 mg of the desired compound (67.1%, a white solid).
NMR(200MHz,CDCl3)~: 2.00(3H,m), 2.26(1H,m), 3.21-3.58(2H,m), 3.86(2H,q,J=9.2Hz), 4.12-4.34(3H,m), 7.10(lH,d,J=7.6Hz), 7.52(1H,d,J=8.6Hz), 7.77(1H,dd,J=7.6,8.6Hz).
IR(Neat): 1731, 1651, 1358 cm1 ii) Synthesis of 1,2-dihydro-3-methyl-1-[1-(2,2,2-trifluoroethanesulfonyl)-2-(S)-pyrrolidin-2-ylmethyl]-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride In a solvent consisting of 20 cc of ethanol and O.1 cc oi lZN hydrochloric acid was dissolved 626.1 mg (1.61 mmol) of 1,2-dihydro-3-methyl-1-[1-(2,2,2-trifluoroethanesulfonyl]-2-(S)-pyrrolidin-2-ylmethyl]-1,4,7b-triazacyclopent[cd]inden-2-one. The solvent was distilled off under reduced pressure. The residue was dried to afford 685 mg of the desired compound (100%, a white solid).
NMR(200MHz,DMSO-d6)~: 1.89-2.07(4H,m), 2.85(3H,s), 3.44(2H,m), 4.16-4.38(3H,m), 4.48(2H,g,J=lO.lHz), 7.60(1H,d,J=8.0Hz), 7.81(lH,d,J=8.OHz), 8.26(1H,t,J=8.0Hz).
IR(~Br): 1738, 1650, 1589, 1358 cml.
~xample 62 2 1 ~32~3 w096102542 PCT1~ 1382 4,5-Dihydro-4-[2-[4-(trifluoromethanesulfonamido)phenyl]ethan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione-hydrochloride i) Synthesis of 4,5-dihydro-4-[2-[4-(trifluoromethane sulfonamide)phenyl]ethan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a suspension of 1.53 g (5.0 mmol) of 4,5-dihydro-4-[2-[4-(amino)phenyl]ethan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione and 1.05 ml (7.5 mmol) in methylene chloride (150 ml) was added dropwise, while stirring under ice-cooling, 1.21 ml (7.2 mmol) of trifluoromethanesulfonic acid anhydride. The mixture was stirred for 14 hours at room temperature. The reaction mixture was washed with lN-HCl, which was dried over anhydrous magnesium sulfate.
The solvent was distilled off, and the residue was eluted by column chromatography (eluent: ethyl acetate/methylene chloride = 1:1) to afford 245 mg of 4,5-dihydro-4-[2-[4-[bis(trifluoromethanesulfonyl)imido]phenyl]ethan-l-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione (8.6%, a pale yellow solid).
NMR(200MHz,CDCl3)8: 3.10(2H,m), 4.43(2H,m), 7.34(2H,d,J=8.4Hz), 7.49(2H,d,J=8.4Hz), 7.80(1H,dd,J=8.8, 7.6Hz), 8.16(1H,dd,J=7.6, l.OHz), 8.18(1H,dd,J=8.8, l.OHz), 8.67(1H,s).
IR(KBr): 1710, 1666, 1632, 1444, 1340, 1290, 1223, 1163, 1128 cm~l And further elution (eluent: ethyl acetate/methylene chloride = 1:1) afforded 77 mg of the desired compound (3.5~, a pale yellow solid).
NMR(200MHz,DMSO-d6)~: 2.90(2H,m), 4.22(2H,m), 7.20(2H,d,J=8.4Hz), 7.33(2H,d,J=8.4Hz), 7.91(1H,dd,J=8.8, 7.4Hz), 8.13(1H,dd,J=7.4, l.OHz), 8.31(1H,dd,J=8.8, l.OHz), 8.67(1H,s).
~ Br): 1707, 1662, 1633, 1510, 1371, 1340, 1284, ~096/0~42 2 1 9 ~ 2 2 ~ P~l/J. _ l3~2 1209, 1167, 1137 cm~l ii) Synthesis of 4,5-dihydro-4-[2-[4-(trifluoromethane sulfonamido)phenyl]ethan-l-yl]-3H-1,4,8b-tri~7~r~n~phthylene-3,5-dione-hydrochloride To a suspension of 59 mg (0.13 mmol) of 4,5-dihydro-4-[2-[4-(trifluoromethanesulfonamido)phenyl]ethan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 5 ml of methanol was added 0.05 ml of conc. hydrochloric acid.
The solvent was distilled off to afford 64 mg of the desired compound (100%, a pale yellow solid).
NMR(200MHz,DMSO-d6)~: 2.91(2H,m), 4.22(2H,m), 7.21(2H,d,J=8.4Hz), 7.34(2H,d,J=8.4Hz), 7.93(1H,dd,J=8.8, 7.4Hz), 8.14(1H,dd,J=7.4, l.OHz), 8.32(1H,dd,J=8.8, l.OHz), 8.69(1H,s).
IR(~Br): 3099, 1724, 1681, 1649, 1348, 1209, 1144 cm Example 63 3,4-Dihydro-3-[5-(tert-butoxycarbonylamino)penten-1-yl]-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one To a suspension of 355 mg (0.91 mmol) of 3,4-dihydro-3-[5-(phthalimido)pentan-1-yl]-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one in 15 ml of ethanol was added 229 mg (4.57 mmol) of hydrazinemonohydrate. The mixture was stirred for two hours while heating under reflux. A~ter cooling the resulting precipitates were filtered off, and the filtrate was concentrated. To the concentrate was added 30 ml of chloroform. To the mixture were added 1.00 g (4.58 mmol) of di-tert-butyl dicarbonate and 0.38 ml (2.73 mmol) of triethylamine.
The mixture was stirred for one hour at room temperature. The reaction mixture was washed with water ~nd dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol =
10:1) to afford 244 mg of the desired compound (74.4%, a pale yellow foam).

WO9G/0~2 PCT/~9~0l382 , NMR(2coHHzlcDcl3)6: 1.20-1.80(6H,m), 1.44(9H,s), 2.07(3H,s), 3.02(1H,m), 3.10(2H,m), 4.34(1H,m), 1 4.54(1H,br), 6.98(1H,dd,J=6.8, 1.2Hz), 7.16(1H,dd,J=9.0, 6.8Hz), 7.32(1H,dd,J=9.0, 1.2Hz).
: 5 Example 64 3,4-Dihydro-2-methyl-3-[5-(trifluoromethanesulfonamido) pentan-l-yl]-1,3,7b-triazacyclopent[cd]inden-4-one To a solution of 228 mg (0.64 mmol) of 3,4-dihydro-3-[5-(tert-butoxycarbonylamino)pentan-1-yl]-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one in 5 ml of methanol was added 5 ml of conc. hydrochloric acid.
The mixture was stirred for 30 minute at room temperature. The solvent was distilled off. To the residue was added toluene, and the solvent was distilled off. To the residue were added 20 ml of acetonitrile, 0.89 ml (6.39 mmol) of triethylamine and 1.14 g (3.19 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 20 hours at room temperature. The solvent was distilled off. To the residue was added chloroform. The mixture was washed with water and dried over magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 13 mg of the desired compound (5.2%, a pale yellow solid).
NMR(200MHz,CDCl3)~: 1.20-1.80(6H,m), 2.08(3H,s), 3.02(1H,m), 3.18(2H,m), 4.33(1H,m), 7.02(1H,dd,J=6.8, 1.2Hz), 7.19(1H,dd,J=9.0, 6.8Hz), 7.32(1H,dd,J=9.0, 1.2Hz), 8.64(1H,br Example 65 4,5-Dihydro-4-(3-trifluoromethanesulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylene-dihydrochloride i) Synthesis of 3-carbomethoxy-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1 -yl ) am i nl ~ thyl]imidazo[1,2-a]pyridine W096/02~2 2 1 9 3 ~ 2 ~ PCT/~9~01382 To a solution of 581 mg (1.00 mmol) of 3-tr;nhlnrn acetyl-5-[N-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 5.0 ml of methanol was added 0.46 ml (2.00 mmol) of a 25%
methanol solution of sodium methylate. The mixture was stirred for 10 minutes at room temperature. The reaction mixture was poured into ice-water, which was neutralized with lN HC1. The mixture was extracted with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated a~ueous saline solution, and dried over magnesium sulfate. The solvent was distilled o~f under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
chloroform) to afford 462 mg of the desired compound (93.4%, a pale yellow liquid).
N~R(200HHz,CDCl3)~: 1.32(9H,s), 1.83(2H,m), 3.35(2H,brs), 3.49(2H,t,J=6.0Hz), 3.93(3H,s), 4.85(2H,s), 6.84(1H,d,J=7.2Hz), 7.49(1H,t,J=7.2Hz), 7.70(1H,d,J=8.8Hz), 8.36(1H,s).
IR(Neat): 1699, 1680, 1512, 1471, 1419 cm ii) Synthesis of 3-hydroxymethyl-5-tN-tert-butoxycarbonyl-N-(3-trifluoromethanesulfonamidopropan-1-yl)aminomethyl]imidazotl,2-a]pyridine To a solution of 396 mg (0.80 mmol) of 3-carbo-methoxy-5-tN-tert-butoxycarbonyl-N-(3-trifluoromethane-sulfonamidopropan-l-yl)Amin~ thyl]imidazotl,2-a]pyridine in a mixture of 5.0 ml of TXF and 1.0 ml of methanol was added, at room temperature, 87.12 mg (4.00 mmol) of lithium borohydride with small portions. The mixture was heated for 30 minutes under reflux. The reaction mixture was cooled to room temperature, and poured into ice-water. The mixture was neutralized with lN HCl, and extracted with 50 ml of chloroform.
The organic layer was washed with 50 ml of a saturated a~ueous saline solution, which was dried over magnesium 21 ~32~3 ~ ~'096/02~42 r~l/Jr ,so~

sulfate. The solvent was then distilled off underreduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol =20:1) to afford 269 mg of the desired compound (72%, a pale yellow liquid).
NMR(200MHz,CDCl3)~: 1.40(9H,s), 1.83(2H,m), 3.35(2H,t,J=6.4Hz), 3.49(2H,t,J=6.4Hz), 4.90(2H,s), 5.18(2H,s), 6.59(1H,d,J=7.4Hz), 7.12-7.25(1H,m), 7.42-7.52(2H,m).
IR(Neat): 1695, 1497, 1470 cml iii) Synthesis of 4,5-dihydro-4-(3-trifluoromethane-sulfonamidopropan-1-yl)-3H-1,4,8b-triazaacenaphthylene To a solution of 233 mg (0.50 mmol) of 3-hydroxymethyl-5-[N-tert-butoxycarbonyl-N-(3-trifluoro-methanesulfonamidopropan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 5.0 ml of chloroform was added 0.36 ml (2.50 mmol) of trimethylsilyl iodide. The mixture was stirred for 18 hours at room temperature. The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted of the desired compound with 50 ml of chloroform. The organic layer was washed with 50 ml of a saturated aqueous saline solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol =20:1) to afford 109 mg of the desired compound (62.8%, a pale yellow liquid).
NMR(200MHz,CDCl3)~: 1.82(2H,m), 2.68(2H,m), 3.43(2H,m), 3.91(2H,s), 4.01(2H,s), 6.53(1H,d,J=6.8Hz), 7.10(1H,dd,J=9.2,6.8Hz), 7.27(1H,s), 7.39(lH,d,J=9.2Hz), 8.27(lH,brs,NH) IR(Neat): 1637, 1552, 1450, 1363 cm~
iv) Synthesis of 4,5-dihydro-4-(3-trifluoromethane sulfonamidopropan-l-yl)-3H-1,4,8b-2 1 93~23 W096/02542 r~llJI 5 triazaacenaphthylene-dihydrochloride To a solution of 248 mg (0.72 mmol) of 4,5-dihydro-4-(3-trifluoromethanesulfonamidopropan-l-yl)-3H-1,4,8b-tri~zAArPnArhthylene in 5.0 ml of ethanol was added 0.18 ml (2.16 mmol) of 12N HCl. The mixture was stirred, and concentrated under reduced pressure.
resulting precipitates were washed with a small volume of ethanol and ether to afford 253 mg of the desired compound (84.2%, a white solid).
NMR(200MHz,DMSO-d6)5: 2.02(2H,m), 3.17(4H,m), 4.85(2H,s), 4.93(2H,s), 7.54(1H,m), 7.99-8.02(2H,m), 8.19(1H,s), 9.39(1H,t,NH,J=5.6Hz) IR(Neat): 3430, 1660, 1550, 1441 cm Example 66 4,5-Dihydro-4-[4-(2-trifluoromethanesulfonamidoethan-1-yl)phenyl]-3H-1,4,8b-triazaacenaphthylen-3-one-hydrochloride i) Synthesis of 5-[N-[4-(2-trifluorommethanesulfon-amidoethan-yl)phenyl~aminomethyl]imidazo[1,2-a]pyridine A solution of 6.51 g (30.00 mmol) of 5-chloromethylimidazo[l,2-a]pyridine, 8.05 g (30.00 mmol) of l-amino-4-(2-trifluoromethanesulfonamidoethan-l-yl)benzene and 8.4 ml (60.00 mmol) of triethylamine was heated for 3 hours under reflux. The reaction mixture was cooled to room temperature to cause formation of triethylamine hydrochloride, which was filtered off.
The filtrate was concentrated under reduced pressure, and the concentrate was extracted with 150 ml of chloroform. The organic layer was washed with 150 ml of a saturated aqueous saline solution. The organic layer was drled over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:ethanol=20:1) to afford 9.11 g of the desired compound (76.2%, a colorless liquid).
NMR(200MHz,CDCl3)~: 2.37(2H,brs), 3.45(2H,t,J=8.2Hz), 2 1 932~3 ~ W096/02~i42 4.77(2H,brs), 6.48(2H,d,J=8.4Hz), 6.64(2H,d,J=8.4Hz), 6.85(1H,d,J=6.8Hz), 7.21-7.29(1H,m), 7.74(1H,d,J=7.6Hz), 7.77(1H,s), 7.89(1H,s).
IR(Neat): 1628, 1518, 1387 cm .
r S ii) Synthesis of 5-[N-tert-butoxycarbonyl-N-t4-(2-trifluoromethansulf~n~mi~ethan-l-yl)phenylAminl Lhyl]
imidazo[l,2-a]pyridine To a solution of 2130 mg (5.35 mmol) of 5-[N-[4-(2-trifluoromethansulfonamidoethan-l-yl)phenyl]~m; n~ Lhyl]imidazo[1,2-a]pyridine in 30 ml of ethanol was added 1167 mg (5.35 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate : ethanol = 20:1) to afford 2.0 g of the desired compound (75.0~, colorless amorphous).
NMR(200NHz,CDCl3)~i: 1.50(9H,s),2.39(2H,brs), 3.48(2H,t,J=8.0Hz), 4.78(2H,brs), 6.50(1H,brs,NH), 6.75(2H,d,J=8.4Hz), 6.84(1H,d,J=7.0Hz), 7.15(2H,d,J=8.4Hz), 7.25-7.29(1H,m), 7.75(1H,d,J=8.4Hz), 7.77(1H,s), 7.92(1H,s).
IR(Neat): 1710, 1630, 1522, 1390 cm iii) Synthesis of 3-trichloroacetyl-5-[N-tert-butoxy carbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-1-yl) phenyl]aminomethyl]imidazo[l,2-a]pyridine To a solution of 2.00 g of 5-[N-tert-butoxycarbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-l-yl)phenyl]
Aminl Lhyl]imidazo[1,2-a]pyridine and 1.47 g (12.04 mmol) of 4-(N,N-dimethylamino)pyridine in 20 ml of chloroform was added dropwise 1.34 ml (12.04 mmol) of trichloroacetyl chloride at room temperature. The reaction mixture was heated for 18 hours under reflux.
The reaction mixture was poured into ice-water. The mixture was neutralized with a saturated aqueous W096/02~2 ~ 3 2 ~ 3 PCT/JP95/01382 solution of sodium hydrogencarbonate, and extracted with 100 ml of chloroform. The organic layer was washed with 100 ml of purified water three times and ~' further with 100 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to afford 1415 mg of the desired compound (54.8%, a yellow liquid).
NMR(200MHz,CDCl3)~: 1.23(9H,s), 2.38(2H,brs), 3.48(2H,t,J=8.0Hz), 4.58(2H,brs), 6.52(1H,brs,NH), 6.80(2H,d,J=8.4Hz), 7.24(1H,d,J=7.0Hz), 7.19(2H,d,J=8.4Hz), 7.76-7.80(1H,m), 7.81(1H,d,J=8.4Hz), 8.96(1H,s) IR(KBr): 1710, 1690, 1525, 1360 cm iv) Synthesis of 4,5-dihydro-4-[4-(2-trifluoromethane sulfonamidoethan-l-yl)phenyl]-3H-1,4,8b-triazaacenaphthylen-3-one To a solution of 644 mg (1.00 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-[4-(2-trifluoromethanesulfonamidoethan-l-yl)phenyl]~m ~ n- ~ thyl]imidazotl,2-a]
pyridine in 5 ml of chloroform was added dropwise 0.29 ml (2.00 mmol) of trimethylsilyl iodide at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, and poured into ice-water.
The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 50 ml of chloroform for extraction of the desired compound. The organic layer was washed with 50 ml of a saturated aqueous saline solution, and dried over magnesium sulfate. The solvent was distilled off under reduceL pressure. The residue was purified by silica gel co~lumn chromatography (eluent;
chloroform:methanol=20:1) to afford 195.7 mg of the desired compound (46.1%, a pale yellow solid).

21 932~3 ~ WO96l02542 r~J.,'~Is~2 _ 169 -NMR(200MHz,CDCl3)~i: 2.36(2H,brs), 3.45(2H,t,J=8.0Hz), 5.08(2H,s), 6.51(1H,brs,NH), 6.85(2H,d,J=8.4Hz), 6.89(2H,d,J=7.0Hz), 7.19(2H,d,J=8.4Hz), 7.34-7.40(1H,m), 7.75(1H,d,J=8.4Hz), 8.12(1H,s) : 5 IR(RBr): 1708, 1661, 1535, 1430 cml v) Synthesis of 4,5-dihydro-4-[4-(2-trifluoromethane sulf-n~mi~lr~than-l-yl)phenyl]-3H-l~4~8b tri~ 7~ ~r~n~rhthylen-3-one-hydrochloride To a solution of 85 mg (0.2 mmol) of 4,5-dihydro-4- [4-(2-trifluoromethanesulfonamidoethan-l-yl)phenyl]
3H-1,4,8b-triazaacenaphthylen-3-one in 5.0 ml of ethanol was added 0.04 ml (0.5 mmol) of 12N HCl. The mixture was stirred at room temperature, and concentrated under reduced pressure. The resulting precipitates were collected by filtration, and washed with a small volume of ethanol and ether to afford 64 mg of the desired compound (69.4%, a pale yellow solid).
NMR(200MHz,DMSO-d~)~: 2.22(2H,brs), 3.38(2H,t,J=6.8Hz), 5.28(2H,s), 7.25(2H,d,J=8.4Hz), 7.49(2H,d,J=7.2Hz), 7.59(2H,d,J=8.4Hz), 7.94-8.00(1H,m), 8.35(1H,d,J=8.4Hz), 8.72(1H,s) IR(KBr): 1720, 1665, 1443, 1385 cm Example 67 1-[1-(tert-~utoxycarbonyl)piperidin-4-ylmethyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 735 mg (4.24 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of DMF was added, while stirring under ice-cooling, 187 mg (4.68 mmol) of 60 % sodium hydride (dispersion in : oil). The mixture was stirred for 20 minutes at the same temperature. To the mixture was added a solution of 1.18 g (4.24 mmol) of 4-bromomethyl-1-tert-butoxycarbonylpiperidine in 5 ml of DMF. The mixture was stirred for one hour at 100 ~C. After cooling, the reaction mixture was poured into water and extracted W096l0~42 2 ~ 9 3 2 2~ 170 - F~llJ. S. iJO~ ~

with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 988 mg of the desired compound (62.8 %, pale yellow solid).
NNR(200MHz,CDC13)~: 1.41(2H,m), 1.45(9H,s), 1.71(2H,m), 2.11(1H,m), 2.68(2H,m), 2.83(3H,s), 3.95(2H,d,J=7.2Hz), 4.15(2H,m), 6.79(1H,d,J=7.6Hz), 7.50(1H,d,J=8.6Hz), 7.72(1H,dd,J=8.6, 7.6Hz).
Example 68 1,2-dihydro-1-[1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl]-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) synthesis of 1,2-dihydro-1-(piperidin-4-ylmethyl)-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 3.65 g (9.85 mmol) of l-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 30 ml of methanol was added 15 ml of conc. HCl. The mixture was stirred for 1.5 hours at room temperature. The solvent was distilled off. To the residue was added chloroform and 2N agueous solution of sodium hydroxide to make ~lk~l in~. The mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 2.316 g of the desired compound (86.9 %, pale yellow solid). This product was used in the subsequent reaction without further purification.
ii) Synthesis of 1,2-dihydro-1-[1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl]-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.09 g (4.03 mmol) of 1,2-dihydro-l-(piperidin-4-ylmethyl)-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 0.84 ml (6.03 mmol) of triethylamine in 30 ml of methylene chloride was 2~ 93223 W096/02542 - 171 - r~l/J~ J~

added 1.73 g (4.84 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was ; stirred for 14 hours at room temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate. The solvent was disti-lled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 522 mg of the desired compound (32.2 ~, pale yellow solid).
NMR(2ooMHz/cDcl3)6: 1.50(2H,m), 1.87(2H,m), 2.20(1H,m), 2.83(3H,s), 3.02(2H,m), 3.99(2H,d,J=7.0Hz), 4.00(2H,m), 6.77(1H,d,J=7.4Hz), 7.51(1H,d,J=8.6Hz), 7.73(1H,dd,J=8.6, 7.4Hz).
iii) Synthesis of 1,2-dihydro-1-[1-(trifluoromethanesulfonyl)piperidin-4-ylmethyl]-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride To a suspension of 494 mg (1.23 mmol) of 1,2-dihydro-l-[l-(trifluoromethanesulfonyl)pip.or;~lin_4_ ylmethyl]-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 15 ml of methanol was added 0.13 ml of conc.
HCl. The solvent was distilled off. The residue was treated with acetone and diethylether to give S26 mg of the desired compound (97.6 ~, colorless solid).
m.p. 150-152~C
Elemental Analysis for Cl6HI7N403SF3-HCl-H~O:
Calcd.: C, 42,06; H, 4.41; N, 12.26 Found : C, 42.07; H, 4.27; N, 12.07 NMR(200MHz,DMSO-d~)~: 1.38(2H,m), 1.84(2H,m), 2.16(lH,m), 2.79(3H,s), 3.14(2H,m), 3.84(4H,m), 7.57(1H,d,J=7.6Hz), 7.76(1H,d,J=8.4Hz), 8.14(1H,dd,J=8.4, 7.6Hz).
Example 69 [l-(tert-Butoxycarbonyl)piperidin-4-yl]-l~2-dihydr 3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one The title compound was synthesized in the same manner as example 67.

W096,02~42 2t~3~ 172 - PCTIJP9~101382 NMR(200MHz,CDCl~ 1.52(9H,s), 2.00(2H,m), 2.17(2H,m), 2.83(3H,s), 2.94(2H,m), 4.37(2H,m), 4.72(1H,m), 6.90(1H,d,J=7.8Hz), 7.50(lH,d,J=8.4Hz), 7.69(1H,dd,J=8.4, 7.8Hz).
Example 70 -.
1-[2-[1-(tert-Butoxycarbonyl)piperidin-4-yl]ethan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]
inden-2-one The title compound was synthesized in the same manner as example 67.
NMR(200MHz,CDCl3)~: 1.18(2H,m), 1.46(9H,s), 1.50(1H,m), 1.70-1.86(4H,m), 2.68(2H,m), 2.83(3H,s), 4.11(4H,m), 6.?8(1H,d,J=7.6Hz), 7.50(1H,d,J=8.6Hz), 7.71(1H,dd,J=8.6, 7.6Hz).
Example 71 1,2-Dihydro-1-[2-[1-(trifluoromethanesulfonyl) piperidin-4-yl]ethan-1-yl]-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride The title ~ uul~d was synthesized in the same manner as Example 68.
m.p. 169-170~C
Elemental Analysis for C17HlgN4O3SF3-HCl:
Calcd.: C, 45.09; H, 4.45; N, 12.37 Found : C, 44.95; H, 4.42; N, 12.13 NMR(200MHz,DMSO-d6)~: 1.23(2H,m), 1.58(1H,m), 1.76(2H,m), 1.91(2H,m), 2.75(3H,s), 3.11(2H,m), 4.10(2H,t,J=7.2Hz), 7.46(1H,d,J=7.6Hz), 7.70(1H,d,J-8.8Hz), 8.04(1H,dd,J=8.8, 7.6Hz).
Example 72 1,2-Dihydro-3-methyl-1-[4-(N-methyl-N-trifluromethane sulfoneamide)butan-l-yl]-1,4,7b-triazacyclopent[cd]
inden-2-one-hydrochloride i) Synthesis of 1,2-dihydro-3-methyl-1-[4-(N-methyl-N-tri~ Ehanesulfonamide)butan-l-yl]-1,4,7b-triazacyclopent[cd]indene-2-one To a solution of 1.129 g (3.0 mmol) of 1,2-. . . ~

~ ~'O96102542 ,~,I/J~,;, IJ~

dihydro-3-methyl-1-[4-(trifluoromethanesulfonamide)butan-l-yl]-1,4,7b-; triazacyclopent[cd]inden-2-one in 30 ml of DMF was added, while stirring under ice-cooling, 144 mg (3.6 .- S mmol) of 60 ~ sodium hydride (dispersion in oil).
The mixture was stirred for 15 minutes at the same temperature. To the mixture was added 0.56 ml of methyl iodide. The mixture was stirred for 14 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 170 mg of the desired compound (14.5 ~, pale brown solid).
NMR(2ooMHzrcDcl3)5: 1.65-2.02(4H,m), 2.83(3H,s), 3.01(3H,d,J=1.2Hz), 3.42(2H,m), 4.13(2H,t,J=6.8Hz), 6.85(1H,d,J=7.4Hz), 7.51(1H,d,J=8.6HZ), 7.73(1H,dd,J=8.6, 7.6Hz).
ii) Synthesis of l~2-dihydro-3-methyl-l-[4-(N-meth N-trifluoromethanesulfonamide)butan-l-yl)-1,4,7b-triazacyclopent[cd]indene-2-one-hydrochloride To a solution of 168 mg (0.43 mmol) of 1,2-dihydro-3-methyl-1-[4-(N-methyl-N-trifluoromethene sulfonamide)butan-1-yl]-1,4,7b-triazacyclopent[cd]
indene-2-one in 5 ml of methanol was added 0.05 ml of conc. kCl. The solvent was distilled off. The residue was washed with acetone to give 163 mg of the desired compound (88.6 ~, yellow solid).
m.p. 133-135~C
Elemental Analysis for Cl5Hl7N4O35F3-HCl:
Calcd.: C, 42.21; H, 4.25; N, 13.13 Found : C, 42.09; H, 4.26; N, 12.95 NMR(200MHz,DMSO-d6)~: 1.58-1.85(4H,m), 2.78(3H,s), 2.99(3H,d,J=1.2Hz), 3.40(2H,m), 4.12(2H,t,J=6.4Hz), 7.53(1H,d,J=7.6Hz), 7.74(1H,d,J=8.6Hz), W096/0254Z 2t q~223 .~l/Ji~ [,~h~ ~

8.11(1H,dd,J=8.6, 7.6Hz).
Example 73 1-[4-(tert-Butoxycarbonylamino)butan-l-yl]-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one To a solution of 1.67 g (8.87 mmol) of 4-tert-butoxycarbonylamino-1-butylamine and 1.53 g (11.8 mmol) of N,N-diisopropylethylamine in 30 ml of acetonitrile was added 1.762 g (5.91 mmol) of 5-chloro-3-trichloroacetylimidazo[1,2-a]pyridine. The mixture was heated for 17 hours under reflux with stirring. The solvent was distilled off. To the residue was added chloroform. The residue was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to give 453 mg of 5-[4-(tert-butoxycarbonylamino)butan-1-ylamino]-3-[4-(tert-butoxycarbonylamino)butan-1-yl~i~rhi yl]imidazo[1,2-a]pyridine(14.8 %, pale brown solid) as fration 1, NMR(200MHz,CDCl3)~: 1.44(18H,s), 1.40-2.00(8H,m), 3.05-3.32(6H,m), 3.49(2H,m), 4.83(2H,br), 5.90(1H,d), 6.99(1H,d,J=8.6Hz), 7.03(1H,br), 7.31(1H,dd,J=8.6, 7.8Hz), 8.06(1H,s), 8.87(1H,br).
and to give 583 mg of the disired compound (29.8 ~, pale brown solid) as fraction 2, NMR(200MHz,CDCl3)~: 1.43(9H,s), 1.62(2H,m), 1.91(2H,m), 3.22(2H,m), 4.12(2H,t,J=7.2Hz), 4.89(1H,br), 6.96(1H,d,J=7.4Hz), 7.63(1H,d,J=8.8Hz), 7.77(1H,dd,J=8.8, 7.4Hz), 8.33(1H,s).
and was eluted (eluent: ethyl acetate/ethanol=10:1) to give 508 mg of 5-chloro-3-[4-tert-butoxycarbonylamino) butan-1-ylcarbamoyl]imidazo[1,2-a]pyridine(23.4 ~, pale brown solid).
NMR(2coMHz/cDcl3)~: 1.43(9H,s), 1.50-1.80(4H,m), 3.19(2H,m), 3.52(2H,m), 4.64(1H,br), 6.52(1H,br), 6.98(1H,dd,J=7.2, l.OHz), 7.28(1H,dd,J=9.0, 7.2Hz), ~ W096102542 2 1 9 3 2 ~ 3 PCT1~9~01382 7.63(1H,dd,J=9.0, l.OHz), 7.86(1H,s).
Example 74 , 1,2-Dihydro-1-[4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopent[cd]inden-2-one-hydrochloride i) Synthesis of 1-[4-(amino)butan-1-yl]-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride To a solution of 548 mg (1.66 mmol) of 1-[4-tert-butoxycarbonylamino)butan-l-yl]-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one in 10 ml of methanol was added dropwise 10 ml of conc. HCl. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue was added acetone.
The resulting solid was collected by filtration and washed with acetone to give 400 mg of the desired compound (79.5 %, grayish white solid).
Elemental Analysis for C1zH14N4O 2HCl:
Calcd.: C, 44.87; H, 5.65; N, 17.44 Found : C, 45.27; H, 5.48; N, 17.56 N~R(200MHz,D~O)~: 1.75(2H,m), 1.95(2H,m), 3.02(2H,m), 4.22(2H,t,J=6.8Hz), 7.58(1H,d,J=7.8Hz), 7.88(1H,d,J=8.8Hz), 8.32(1H,dd,J=8.8, 7.8Hz), 8.71(1H,s).
ii) synthesis of 1,2-dihydro-1-[4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopent[cd]indene-2-one To a suspension of 350 mg (1.15 mmol) of 1-[4-(amino)butan-l-yl]-1,2-dihydro-1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride was added 0.64 ml (4.62 mmol) of triethylamine. The mixture was stirred for 10 minutes at room temperature.
To the mixture was added 619 mg (1.73 mmol) of N-phenyltrifluoromethanesulfonimide. The mixture was stirred for 66 hours at room teperature. The solvent was distilled off. The residue was purified by column chromatography(eluent: ethyl acetate) to give 97 mg of the desired compound (23.2 %, colorless solid).

W096l0~42 2193223 - 176 - ~ J- c ~

NMR(200MHz,CDCl3-DMSO-d6)~: 1.70(2H,m), 1.97(2H,m), 3.27(2H,m), 4.12(2H,t,J=7.0Hz), 6.98(1H,d,J=7.4Hz), 7.65(1H,d,J=8.6Hz), 7.81(1H,dd,J=8.6, 7.4Hz), 8.33(1H,s), 8.70(1H,br).
iii) Synthesis of 1,2-dihydro-1-[4-(trifluoromethanesulfonamide)butan-l-yl)-1,4,7b-triazacyclopent[cd]inden-2-one-dihydrochloride To a suspension of 89 mg (0.25 mmol) of 1,2-dihydro-1-[4-(trifluoromethanesulfonamide)butan-1-yl)-1,4,7b-triazacyclopent[cd]inden-2-one in 5 ml of methanol was added 0.05 ml of conc. HCl. The solvent was distilled off. To the residue was added acetone, and the solvent was distilled off to give 98 mg of the desired compound (100 %, coloress solid).
NNR(200MHz,DMSO-d6)6: 1.59(2H,m), 1.84(2H,m), 3.19(2H,m), 4.12(2H,t,J=6.8Hz), 7.57(1H,d,J=7.6Hz), 7.84(1H,d,J=8.6Hz), 8.15(1H,dd,J=8.6, 7.6Hz), 8.84(1H,s), 9.39(1H,brt,J=5.6Hz).
Reference Example 1 5-~thoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine To a solution of 25.22 g (0.133 mol) of 5-ethoxy-carbonylimidazo[1,2-a]pyridine and 48.60 g (0.398 mol) of 4-dimethylaminopyridine was added dropwise 72.33 g (0.398 mol) of trichloroacetyl chloride. The mixture was heated for 63 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=l:1) to give 33.10 g of the desired compound (77.4%, yellow solid).
NMR(200~Hz,CDCl3) ~: 1.40(3H,J=7.2Hz), 4.46(2H,q,J=7.2Hz), 7.57-7.72(2H,m), 7.98(1H,dd,J=3.0,2.0Hz), 8.84(1H,s).

2 1 ~32~
096/02~2 PCT/~9~101382 Reference Example 2 5-Ethoxycarbonyl-2-methyl-3-trichloroacetylimidazo[1,2-a]pyridine To a solution of 8.03 g (39.3 mmol) of 5-ethoxy-r 5 carbonyl-2-methylimidazo[1,2-a~pyridine and 14.41 g (118 mmol) of 4-dimethylaminopyridine in 80 ml of chloroform was added dropwise 21.45 g (118 mmol) of trichloroacetyl chloride. The mixture was heated for 15 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, drid over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:
ethyl acetate/n-hexane=2:1) to give 8.29 g of the desired compound (60.3%, pale yellow solid).
NMR(200MHz,CDCl3) ~: 1.45(3H,J=7.2Hz), 2.65(3H,s), 4.49(2H,q,J=7.2Hz), 7.40(1H,dd,J=8.8,7.2Hz), 7.77(1H,dd,J=7.2,1.2Hz), 7.84(1H,dd,J=8.8,1.2Hz).
Reference Example 3 5-Amino-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine-hydrochloride To a suspension of 43.7 g (0.40 mol) of 2,6-diaminopyridine in 400 ml of ethanol was added 131.7 g (0.8 mol) of ethyl 2-chloroacetoacetate. The mixture was heated for 18 hours under reflux. After cooling, the resulting crystals was collected by filtration, washed with ethanol and ether successively to give 58.4 g of the desired compound (57.1%, pale yellow crystals).
NMR(200MHz,D~O) ~: 1.41(3H,t,J=7.2Hz), 2.61(3H,s), 4.42(2H,q,J=7.2Hz), 6.53(1H,d,J=8.2Hz), 6.87(1H,d,J=8.2Hz), 7.68(1H,t,J=8.2Hz).
Reference ~xample 4 1,2-Dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 4.8 g (120 mmol) of sodium Wog610~2 2 ~ 3 P~IIJ.,3v~

hydride (60~ dispersion in oil) in 60 ml of DMF was added 10.23 g (40 mmol) of 5-amino-3-ethoxycarbonyl-2-methylimidazo[l,2-a]pyridine-hydrochloride with small ,' portions. The mixture was stirred for 0.5 hour, then S for 0.5 hour at 100~C, which was left standing for cooling. To the reaction mixture was added 60 ml of water. The mixture was washed with chloroform, to which was added, while stirring at room temperature, conc. HCl to make the pH of the solution 8. The resulting precipitate was collected by filtration, washed with water and ether, successively to give 5.97 g of the desired compound (86.1~, pale brown solid).
NMR(200MHz,DMSO-d6) 6: 2.65(3H,s), 6.94(1H,d,J=7.4Hz), 7.48(1H,d,J=8.6Hz), 7.76(1H,dd,J=8.6,7.4Hz), 12.1(lH,br).
~eference Example 5 1,2-Dihydro-3-methyl-1-[S-(phthalimido)pentan-l-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DMF was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 8.89 g (30 mmol) of N-(5-bl~ ~el~Lyl)phth~l im;~ in DMF (20 ml). The mixture was stirred for 1.5 hour at 110~C. After cooling, the reaction mixt~re was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol = 10:1) to afford 6.93 g of the desired compound (59.4%, pale brown solid).
N~R(200MHz,CDCl3) ~: 1.46(2H,m), 1.76(2H,m), 1.91(2H,m), 2.80(3H,s), 3.68(2H,t,J=7.0Hz), ~ W096l02~42 PCT/~9~/01382 4.05(2H,t,J=7.2Hz), 6.83(1H,d,J=7.4Hz), 7.58(1H,d,J=8.6Hz), 7.70(1H,dd,J=8.6,7.4Hz), 7.66-7.85(4H,m).
Reference Example 6 1~2-Dihydro-3-methyl-l-[6-(phthalimido)hexan-l-yl]
1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 5.20 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 60 ml of DME was added, while stirring under ice-cooling, 1.44 g (36 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a D~F solution (20 ml) of 9.31 g (30 mmol) of N-(6-bromohexyl)phthalimide. The mixture was stirred for 1.5 hour at 110~C. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (eluent: ethyl acetate/ethanol = 10:1) to give 3.47 g of the desired compound (28.7%, pale brown solid). NMR(200MHz,CDCl~) ~: 1.33-1.56(4H,m), 1.68(2H,m), 1.85(2H,m), 2.82(3H,s), 3.67(2H,t,J=7.2Hz), 4.04(2H,t,J=7.2Hz), 6.78(1H,d,J=7.4Hz), 7.47(1H,d,J=8.6Hz), 7.69(1H,dd,J=8.6,7.4Hz), 7.67-7.76(2H,m), 7.78-7.88(2H,m).
Reference Example 7 1,2-Dihydro-3-methyl-1-~3-(phthalimido)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of D~E was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 20 minutes at the same temperature. To the reaction mixture was added 13.14 g (50 mmol) of N-(3-W096~02542 2 ~ q 3 2 ~ 3 r~llJ~ 75. ~

b~ Lu~yl)phth~limi~e~ The mixture was stirred for 7 hours at 100~C. After cooling, the reaction mixture was poured into water, which was subjected to extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and, the solvent was then distilled off. The residue was crystallized from methylene chloride - ethanol to give 5.72 g of the desired c ~-und (31.7%, pale brown solid substance).
NMR(200MHz,CDCl3) ~: 2.29(2H,m), 2.81(3H,s), 3.85(2H,t,J=7.0Hz), 4.16(2H,t,J=7.2Hz), 6.86(1H,d,J=7.4Hz), 7.48(1H,d,J=8.6Hz), 7.79(1H,dd,J=8.6,7.4Hz), 7.66-7.76(4H,m).
Reference Example 8 1,2-Dihydro-3-methyl-1-[4-(phthalimido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-~ethyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of DMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 14.10 g (50 mmol) of phthalimide, which was stirred for 6 hours at 100~C. After cooling, the reaction mixture was then poured into water, extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate, the solvent was distilled o~f. The residue was purified by column chromatography (eluent: ethyl acetate) to give 11.43 g of the desired compound (61.1%, pale yellow solid).
NMR(200MHz,CDCl3) ~: 1.70-2.00(4H,m), 2.81(3H,s), 3.76(2H,t,J~6.6Hz), 4.12(2H,t,J=6.8Hz), 6.85(1H,d,J-7.6Hz), 7.47(1H,d,J=8.6Hz), 7.69(1H,dd,J=8.6,7.6Hz), 7.65-7.88(4H,m).
Reference ~xample 9 1-[5-(Amino)pentan-l-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one ... . . _ .. . . .. . .

~ W096l02542 2 1 9 3 2 2 3 pCT/~95/01382 To a suspension of 6.26 g (16.1 mmol) of 1,2-dihydro-3-methyl-1-[5-(ph~h~limi~ln)pentan-l-yl]-lr4r7b triazacyclopent[cd]inden-2-one in 120 ml of ethanol was added 2.42 g (48.3 mmol) of hydrazine monohydrate. The mixture was heated for two hours under reflux. After cooling, the resulting precipitates were filtered off.
The filtrate was concentrated to give the residue, water was added, extracted with chloroform (three times). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off to give 3.31 g of the desired compound (79.6%, pale yellow solid substance).
NMR(2coMHzrcDcl3) ~: 1.34-1.60(6H,m), 1.88(2H,m), 2.70(2H,t,J=6.8Hz), 2.83(3H,s), 4.07(2H,t,J=7.2Hz), 6.79(1H,d,J=7.4Hz), 7.48(1H,d,J=8.6Hz), 7.70(1H,d,J=8.6,7.4Hz).
Reference Example 10 1-[6-(Amino)hexan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 2.94 g (7.31 mmol) of 1,2-dihydro-3-methyl-1-[6-(phthalimido)hexan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 80 ml of ethanol was added 1.10 g (22.0 mmol) of hydrazine.monohydrate. The mixture was heated for 2 hours under reflux. After cooling, the resulting precipitates were filtered off.
The filtrate was concentrated to give the residue, water was added, extracted with chloroform (three times). The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to glve 1.50 g of the desired compound (75.4%, pale yellow solid).
NMR(200MHz,CDCl3) ~: 1.25-1.52(8H,m), 1.86(2H,m), 2.68(2H,m), 2.83(3H,s), 4.06(2H,t,J=7.2Hz), 6.79(1H,d,J=7.4Hz), 7.48(1H,d,J=8.6Hz), 7.70(1H,dd,J=8.6,7.4Hz).
Reference Example 11 W096l02~2 2 T ~ 3 2 2 3 ~ J~ ~

1-[3-(Amino)propan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 3.47 g (9.63 mmol) of 1,2-dihydro-3-methyl-1-[3-(phth~l;mirlo)propan-l-y~ 4~7b triazacyclopent[cd]inden-2-one in 70 ml of ethanol was added ~ 45 g (29.0 mmol) of hydrazine monohydrate. The mixture was heated for 2 hours under reflux. After cooling, and the resulting precipitate~ were filtered off. The filtrate was concentrated to give the residue, water was added, extracted with chloroform (three times). The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 1.68 g of the desired compound (75.8%, pale yellow solid substance).
NMR(200MHz,CDCl3) ~: 1.48(2H,br), 1.98(2H,m), 2.78(2H,t,J=6.6Hz), 2.83(3H,s), 4.18(2H,t,J=6 8Hz), 6.86(1H,d,J=7.4Hz), 7.49(lH,d,J-8.8Hz), 7.70(1H,dd,J=8.8,7.4Hz).
Reference Example 12 1-[4-(Amino)butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 5.99 g (16.0 mmol) of 1,2-dihydro-3-methyl-1-[4-(phthalimido)butan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 150 ml of ethanol was added 2.40 g (48.0 mmol) of hydrazine monohydrate. The mixture was heated for one hour under reflux. After cooling, and the resulting precipitates were filtered off. The filtrate was concentrated to give the residue, water was water, extracted with chloroform (three times). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled-off to give 3.17 g of the desired compound (81.1%, pale yellow solid).
- NMR(200MHz,CDCl3) ~: 1.37(2H,br), 1.56(2H,m), 1.91(2H,m), 2.77(2H,t,J=7.0Hz), 2.83(3H,s), 4.09(2H,t,J=7.OHz), 6.81(1H,d,J=7.4Hz), . , . _ . _ . . _ . . _ . . . _ . _, _ .

2 1 9322~
W096/02~2 PCT/JP95/01382 7.49(1H,d,J=8.8Hz), 7.71(1H,dd,J=8.8,7.4Hz).
Reference Example 13 1,2-Dihydro-3-methyl-1,4,7b-triazacyclopento[cd]indene-2-thione r 5 A mixture of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 24.27 g (60 mmol) of a Lawesson's reagent in 200 ml of pyridine was stirred for 5 hours at 100~C. After cooling, the resulting precipitates were collected by filtration, washed with pyridine and ether in that order to give 6.90 g of the desired compound (72.9~, brown solid substance). This compound was used, in the subsequent reaction without further purification.
NMR(200MHz,DMSO-d6) 8: 2.75(3H,s), 7.24(1H,d,J=7.6Hz), 7.68(1H,d,J=8.4Hz), 7.93(1H,dd,J=8.4,7.6Hz).
Reference Example 14 3-Methyl-2-[4-(phthalimido)butan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene A mixture of 5.68 g (30 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd~indene-2-thione, 8.47 g (30 mmol) of N-(4-bromobutyl)phthA1imi~P and 6.27 ml (45 mmol) of triethylamine in 150 ml of DMF was stirred for 2 hours at 100~C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract solution was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was cryst~1li7ed from chloroform-ethanol to give 7.39 g of the desired compound (63.1~, pale brown solid) NMR(200MHz,CDCl3) 8: 1.96(4H,m), 2.89(3H,s), - 3.56(2H,m), 3.77(2H,m), 7.62-7.75(4H,m), 7.76-7.85(2H,m), 7.92(lH,m).
Reference Example 15 2-[4-(Amino)butan-1-ylthio]-3-methyl-1,4,7b-triazacyclopent[cd]indene To a suspension of 3.90 g (10.0 mmol) of 3-methyl-W096102~2 2 ~ 184 - PCTI~9~/01382 [4-(phth~limi~)butan-l-ylthio]-l~4~7b-triazacyclopent[cd]indene in 70 ml of ethanol was added 1.50 g (30.0 mmol) of hydrazine monohydrate. The ,~
mixture was heated for 2 hours under reflux. After cooling the resulting precipitates were filtered off.
The filtrate was concentrated to give the residue, water was added, extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 1.89 g of the desired compound (72.7%, pale brown solid) NMR(200MHz,CDCll) 8: 1.51(2H,br), 1.69(2H,m), 1.96(2H,m), 2.79(2H,t,J=6.8Hz), 2.90(3H,s), 3.54(2H,t,J=7.2Hz), 7.66(1H,d,J=8.0Hz), 7.71(1H,d,J=7.8Hz), 7.93(1H,dd,J=8.0,7.8Hz).
Reference Example 16 4-[4-(Amino)phenylmethyll-4,5-dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a solution of 1.47 g (12.0 mmol) of 4-aminobenzylamine and 1.68 g (13.0 mmol) of N,N-diisopropylethylamine was added a solution of 3.50 g(10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stIrred for 7 hours at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and dried to afford 2.586 g of the desired compound (86.7%, a yellow crystals).
Blemental Analysis Calcd for Cl6HlzN~O2:
Calcd.: C, 65.75; H, 4.14; N, 19.17 Found : C, 65.53; H, 3.94; N, 19.19 NMR(200NHz,DMSO-d6)~: 4.99(2H,br), 5.03(2H,s), 6.47(2H,d,J=8.4Hz), 7.10(2H,d,J=8.4Hz), 7.89(1H,dd,J=8.8, 7.4Hz), 8.12(1H,dd,J=7.4, l.OHz), 8.28(1H,dd,J=8.8, l.OHz), 8.66(1H,s).
Reference Bxample 17 4-[2-[4-(Amino)phenyl]ethan-1-yl]-4,5-dihydro-3H-, . .... ..

W096/02542 ~l/J.,~

1,4,8b-tr;~7~c~n~phthylene-3,5-dione To a solution of 1.63 g (12.0 mmol) of 2-[4-(amino)phenyl]ethylamine and 1.68 g (13 mmol) of N,N-diisopropylethylamine in 40 ml of acetonitrile was added a solution of 3.50 g (10.0 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 10 ml of acetonitrile. The mixture was stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with acetonitrile and dried to afford 1.03 g of the desired compound (33.6%, a yellow crystals). The filtrate was concentrated. The residne was crystallized from acetonitrile-methylene chloride.
Crystalline precipitatse were collected by filtration, washed with acetonitrile to afford 1.60 g of the desired compound (52.1%, a yellow crystals).
NMR(200MHz,DMSO-d6)~: 2.71(2H,m), 4.12(2H,m), 4.89(2H,br), 6.51(2H,m), 6.92(2H,m), 7.90(1H,dd,J=8.8, 7.4Hz), 8.13(1H,dd,J=7.4, 0.8Hz), 8.29(1H,dd,J=8.8, 0.8Hz), 8.66(1H,s).
Reference ~xample 18 3-Methyl-2-[5-(ph~h~l;m;d~)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene To a suspension of 2.03 g (10.7 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-thione in 50 ml of N,N-dimethylformamide were added 3.18 g (10.7 mmol) of N-(5-bromopentyl)phthalimide and 2.24 ml (16.1 mmol) of triethylamine. The mixture was stirred for two hours at 100~C. After cooling, the resulting precipitates were collected by filtration, washed with N,N-dimethylformamide, ethanol, and diethylether, successively, dried to afford 3.44 g of the desired compound (79.3%, a pale brown solid).
NMR(2ooMHzlcDcl3)~: 1.48-1.88(4H,m), 1.96(2H,m), 2.89(3H,s), 3.51(2H,t,J=7.2Hz), 3.73(2H,t,J=7.0Hz), 7.62-7.87(6H,m), 7.94(1H,dd,J=8.0, 7.8Hz).

W096/0~42 2 1 q 3 2 2 3 ~ . /J., A~

Reference Example l9 3-Methyl-2-[5-(amino)pentan-1-ylthio]-1,4,7b-triazacyclopent[cd]indene To a suspension of 2.50 g (6.2 mmol) of 3-methyl-2-[5-(ph~h~limi~)pentan-l-ylthio]-l/4/7b triazacyclopent[cd]indene in 50 ml of ethanol was added 928 mg (18.5 mmol) of hydrazinemonohydrate. The mixture was heated for two hours under reflux. ~fter cooling, the resulting precipitates were collected by filtration and washed with ethanol. The filtrate and washing were combined and concentrated to give the residue. Water was added, extracted with methylene chloride, dried over anhydrous magnesium sulfate. The solvent was distilled off to afford 1.197 g of the desired compound (70.6%, a greenish brown solid).
NMR(200MHz,CDCl3)~: 1.44(2H,br), 1.56(4H,m), 1.93(2H,m), 2.73(2H,m), 2.91(3H,s), 3.54(2H,t,J=7.2Hz), 7.67~1H,d,J=7.8Hz), 7.73(1H,d,J=8.0Hz), 7.94(1H,dd,J=8.0, 7.8Hz).
Reference ~xample 20 3-Dimethyliqmin~ thyl-5-ethoxycarbonylimidazo[1,2-a]
pyridine To a solution of 1.90 g (10.0 mmol) of 5-ethoxycarbonylimidazo[1,2-a]pyridine in 40 ml of acetonitrile was added 2.41 g (13.0 mmol) of N,N-dimethylmethyl~n~i ium iodide. The mixture was heated for two hours under reflux. The solvent was distilled off. To the residue was added methylene chloride. The mixture was washed with an aqueous solution of s-odium thiosulfate and an aqueous solution of sodium hydrogencarbonate, successively, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate) to afford 1.496 5 of the desired compound (60.6~, a pale yellow solid).
This product was recrystallized from ethyl acetate to W096l02542 r~ L

afford the desired compound (colorless crystals), m.p.117.0-118.0~C.
Elemental Analysis Calcd for Cl3HI7N3O2:
Calcd.: C, 63.14; H, 6.93; N, 16.99 Found : C, 63.09; H, 6.68; N, 16.94 NMR~200MHz,CDCl3)6: 1.45(3H,t,J=7.2Hz), 1.96(6H,s), 3.72(2H,s), 4.45(2H,q,J=7.2Hz), 7.20(1H,dd,J=8.8, 7.0Hz), 7.28(1H,dd,J=7.0, 1.6Hz), 7.59(1H,s), 7.78(1H,dd,J=8.8, 1.6Hz).
IR(KBr) : 1718, 1714, 1626.
Reference Example 21 5-Ethoxycarbonylimidazo[1,2-a]pyridin-3-ylmethyl trimethylammonium iodide To a solution of 6.15 g (24.9 mmol) of 3-dimethyl ~min~ thyl-5-ethoxycarbonylimidazo[1,2-a]pyridine was added a solution of 3.71 g (26.1 mmol) of methyl iodide in 5 ml of acetonitrile. The mixture was stirred for 66 hours at room temperature. The solvent was distilled off, to give 10.50 g of the desired compound (quantitative, a yellow solid). This product was used in the subsequent reaction without further purification.
NMR(200MHz,DMSO-d6)6: 1.42(3H,t,J=7.2Hz), 2.94(9H,s), 4.57(2H,q,J=7.2Hz), 5.13(2H,s), 7.55(1H,dd,J=9.0, 7.2Hz), 7.82(1H,dd,J=7.2, 1.4Hz), 8.06(1H,dd,J=9.0, 1.4Hz), 8.09(1H,s).
Reference Example 22 5-Ethoxycarbonyl-3-nitroimidazo[1,2-a]pyridine To a solution of 19.02 g (0.10 mol) of 5-ethoxy-carbonylimidazo[1,2-a]pyridine in 50 ml of conc.
sulfuric acid was added dropwise, while stirring under ice-cooling, 40 ml of conc. nitric acid. The mixture was stirred for 20 minutes at the same temperature.
The reaction mixture was poured into ice-water, which was neutralized with a 10~ aqueous solution of NaOH.
The resulting precipitates were collected by w0 96~0~2 2 1 9 ~ ~ 2 ~ P ~/~r il~

filtration, washed with water and dried to afford 20.38 g of the desired compound (86.6%, a pale yellow solid).
NMR(200MHz,CDCl3)~i: 1.41(3H,t,J=7.2Hz), 4.48(2H,q,J=7.2Hz), 7.62-7.74(2H,m), 7.98(1H,m), 8.55(1H,s).
Reference Example 23 3-Amino-5-ethoxycarbonylimidazo[1,2-a]pyridine To a solution of 2.35 g of 5-ethoxycarbonyl-3-nitroimidazo[1,2-a]pyridine in 100 ml of ethanol was added 10% Pd-~ (wet, 470 mg). The mixture was stirred for 110 hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with ethanol. The filtrate and the washing were combined, and the solvent was distilled off. The residue was purified by column chromatography (eluent:
ethyl acetate) to afford 891 mg of the desired compound (43.4%, a dark reddish oil).
NMR(200MHz,CDCl3)/ii: 1.46(3H,t,J=7.2Hz), 4.22(2H,br), 4.48(2H,q,J=7.2Hz), 7.04(1H,dd,J=8.8, 7.2Hz), 7.24(1H,s), 7.54(1H,dd,J=7.2, 1.2Hz), 7.74(1H,dd,J=8.8, 1.2Hz).
Reference Example 24 3,4-Dihydro-1,3,7b-triazacyclopent[cd]inden-4-one To a suspension of 343 mg (8.58 mmol) of 60~
sodium hydride (dispersion in oil) in 3 ml of DNF was added, while stirring at room temperature, a solution of 880 mg (4.29 mmol) of 3-amino-5-ethoxycarbonylimidazo[1,2-a]pyridine in 5 ml of DME.
~he mixture was stirred for 30 minutes at 100~C. After cooling, the reaction mixture was poured into ice-water, washed with ethyl acetate. The aqueous layer was neu~rAli7ed by the addition of 6N-HCl. The resulting precipitates were collected by filtration, washed with water, and dried to afford 100 mg of the desired compound (14.7%, a brown solid). The filtrate was extracted with chloroform, dried over anhydrous 2 1 ~322 ~
~09~02542 magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1~ to afford 27 mg of the desired compound (4.0%, a yellow solid) NNR(2o3NHz~cDcl3)5: 7.67(1H,s), 7.75(1H,dd,J=8.6, 7.0Hz), 7.99(1H,d,J=7.0Hz), 8.08(1H,d,J=8.6Hz), 9.92(lH,br).
Reference Example 25 3,4-Dihydro-3-[5-(phthalimido)pentan-1-yl]-1,3,7b-triazacyclopent[cd]inden-4-one To a suspension of 81 mg (0.51 mmol) of 3,4-dihydro-1,3,7b-triazacyclopent[cd]inden-4-one in 1 ml of DMF was added, while stirring under ice-cooling, 25 mg (0.63 mmol) of 60~ sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added a solution of 151 mg (0.51 mmol) of N-(5-bL~ ~e~Lyl)phth~limi~ in 1 ml of DMF. The mixture was stirred for two hours at 110~C. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent:
ethyl acetate/ethanol=10:1) to afford 40 mg of the desired rl ~_ ~ (20.9~, a colorless solid).
NMR(200MHz,CDC13)~: 1.30-1.85(6H,m), 2.95(1H,m), 3.71(2H,t,J=7.0Hz), 4.44(1H,m), 6.88(1H,d,J=7.0Hz), 7.16(1H,dd,J=9.2, 7.0Hz), 7.16(1H,s), 7.38(1H,d,J=9.2Hz), 7.67-7.90(4H,m).
Reference Example 26 5-Ethoxycarbonyl-2-methyl-3-nitroimidazo[1,2-a]pyridine To a solution of 1.02 g (5.0 mmol) of 5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine in 2.5 ml of conc. sulfuric acid was added dropwise, while stirring under ice-cooling, 2.0 ml of conc. nitric W0 96/02542 2 ~ ~ 3 ~ 2 ~ . 5. ~

acid. The mixture was stirred for 10 minutes at the same temperature. The reaction mixture was poured into ice-water, whose pH was adjusted to 3-4 with a 10%
aqueous solution of NaOH. The resulting crystalline precipitates were collected by filtration, washed with water and dried, followed by further purification by column chromatography (eluent: ethyl acetate) to afford 752 mg of the desired compound (60.4~, a yellow solid).
NMR(200MHz,CDCl3)~: 1.41(3H,t,J=7.2Hz), 2.81(3H,s), 4.46(2H,q,J=7.2Hz), 7.58-7.68(2H,m), 7.84(1H,m).
Reference Example 27 3-Amino-5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine To a solution of 300 mg of 5-ethoxycarbonyl-2-methyl-3-nitroimidazo[1,2-a]pyridine in 20 ml of methanol was added 10~Pd-C (wet, 90 mg). The mixture was stirred for two hours at room temperature under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate and the washing were combined, and the solvent was filtered off. The residue was purified by column chromatography (eluent:
ethyl acetate) to afford 184 mg of the object product (69.7~, an orange solid) NMR(200MHz,CDCl3)~: 1.46(3H,t,J=7.2Hz), 2.45(3H,s), 4.02(2H,br), 4.48(2H,q,J=7.2Hz), 6.99(1H,dd,J=8.8, 7.2Hz), 7.52(1H,dd,J=7.2, 1.2Hz), 7.66(1H,dd,J=8.8, 1.2Hz).
Reference Example 28 3,4-Dihydro-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one To a suspension of 610 mg (15.3 mmol) of 60~
sodium hydride (dispersion in oil) in 5 ml of DME was added, while stirring at room temperature, a solution of 1.67 g (7.62 mmol) of 3-amino-5-ethoxycarbonyl-2-methyl-imidazo[1,2-a]pyridine in 5 ml of DMF. The mixture was stirred for 10 minutes, then for 30 minutes _ W O 96/02542 P~r/JP95/01382 at 100~C. After cooling, the reaction mixture was poured into ice-water, and washed with chloroform. To the aqueous layer was added 6N-HCl to adjust the pH to 5-6. The resulting precipitates were collected by filtration, washed with water and diethyl ether, successively, and dried to afford 3S7 mg of the desired compound t27.0%, a brown solid).
NMR(200MHz,CDCl3)~: 2.02(3H,s), 7.02-7.40(3H,m), 10.45(lH,br).
Reference Example 29 3,4-Dihydro-3-[5-~phthalimido)pentan-1-yl]-2-methyl-1,3,7b-triazacyclopent~cd]inden-4-one To a suspension of 277 mg (1.60 mmol) of 3,4-dihydro-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one in 3 ml of DMF was added, while stirring under ice-cooling, 77 mg (1.93 mmol) of 60~ sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 521 mg (1.76 mmol) of N-(5-bromopentyl)phthalimide. The mixture was stirred for one hour at 110~C. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract solution was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 410 mg of the desired compound (66.0%, a pale brown solid).
NMR(200MHz,CDCl3)6: 1.25-1.80(6H,m), 2.06(3H,s), 2.99(1H,m), 3.67(2H,t,J=7.0Hz), 4.31(1H,m), 6.94(1H,dd,J=6.8, 1.2Hz), 7.13(1H,dd,J=9.0, 6.8Hz), 7.29(1H,dd,J=9.0, 1.2Hz), 7.66-7.90(4H,m).
Reference Example 30 4,5-Dihydro-3H-1,4,8b-triazaacenaphthylene-3,5-dione To a solution of 2.64 g (7.55 mmol) of S-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine W096l02s42 2 1 9 3 2 2 3 PCT/JP9S/01382 in 20 ml of acetonitrile was added 2.5 ml of 25%
aqueous ammonia. The mixture was stirred for 5 hours at room temperature. The resulting crystals were collected by filtration and washed with acetonitrile to S give 393 mg of the desired compound (27.8%, pale brown solid).
NMR(2ooMHzrDMso-d6)~: 7.84(1H,dd,J=8.8, 7.4Hz), 8.01(1H,dd,J=7.4, l.OHz), 8.22(1H,dd,J=8.8, l.OHz), 8.53(1H,s).
R~fPr~nre Example 31 5-[2-[4-(Amino)phenyl]ethan-l-ylamino]-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine A mixture of 4.07 g (17.1 mmol) of 5-chloro-3-ethoxycarbonyl-2-methylimidazo[7,2-a]pyridine, 3.48 g (25.6 mmol) of 2-(4-aminophenyl)ethylamine and 4.41 g (34.1 mmol) o~ N,N-diisopropylethylamine in 60 ml of acetonitrile was heated for 64 hours under re~1ux with stirring. After cooling, the solvent was distilled off. To the residue was added chloroform. The residue was washed with water and dried ~ver anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent:
chloroform/methanol=30:1) and recrys~ 7~d from ethyl acetate-n-hexane to give 4.37 g of the desired compound (75.7~l pale brown crystals).
NMR(200MHz,CDCl3)6: 1.44(3H,t,J=7.2HZ), 2.66(3H,s), 2.95(2H,m), 3.42(2H,m), 3.62(2H,br), 4.39(2H,q,J=7.2Hz), 5.95(1H,dd,J=8.0, 1.2Hz), 6.65(2H,m), 6.91(1H,dd,J=8.4, 1.2Hz), 7.15(2H,m), 7.33(1H,dd,J=8.4, 8.0Hz), 8.75(1H,br).
~eference ~xample 32 1-[2-[4-(Amino)phenyl]ethan-l-yl]-ll2-dihydro-3-meth 1,4,7b-triazacyclopent[cd]inden-2-one To a suspension of 80 mg (2.0 mmol) of 60% sodium hydride (dispension in oil) in 10 ml of DMF was added, while stirring at room temperature, 338 mg (1.0 mmol) 2 ~ 932~3 ~ W096~2~2 PCT/~9~/01382 _ - 193 -of 5-[2-[4-(amino)phenyl]ethan-l-ylamino]-3-ethoxycarbonyl-2-methylimidazo[1,2-a]pyridine. The mixture was stirred for 30 minutes. The reaction mixture was poured into water, extracted with ethyl acetate. The extract was washed with an aqueous saline solution, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 151 mg of the desired compound (51.7%, pale brown solid).
NMR(200MHz,CDC13)~: 2.82(3H,s), 3.01(2H,t,J=7.0Hz), 3.61(2H,br), 4.21(2H,t,J=7.0Hz), 6.39(1H,d,J=7.4Hz), 6.55(2H,m), 6.93(2H,m), 7.41(1H,d,J=8.6Hz), 7.58(1H,dd,J=8.6, 7.4Hz).
Reference Example 33 5-Chloro-3-trichloroacetylimidazo[1,2-a]pyridine To a solution of 45.77 g (0.30 mol) of 5-chloroimidazo[l,2-a]pyridine and 120.9 g (0.99 mol) of 4-dimethylaminopyridine in 500 ml of chloroform was added dropwise 163.5 g (0.90 mol) of trichloroacetyl chloride. The mixture was heated for 43 hours under reflux. After cooling, the reaction mixture was washed with an aqueous solution of sodium hydlu4ullcarbonate, dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexan=1:1) to give 7.41 g of the desired compound (8.3~, pale brown solid).
NMR(200MHz,CDCl3)~: 7.24(1H,dd,J=7.4, 1.2Hz), 7.58(1H,dd,J=8.8, 7.4Hz), 7.82(1H,dd,J=8.8, 1.2Hz), 8.79(1H,s).
Reference Example 34 N-(5-Imidazo[1,2-a]pyridylmethyl)hexamethylenetetraminium-chloride To a suspension of 5.78 g (28.46 mmol) of 5-chloromethylimidazo[l,2-a]pyridine hydrochloride and ~'096/0X~2 2 ~ ~ 3 2 2 3 P~ IJ6~

4.79 g (34.16 mmol) of hexamethylenetetramin in 100 ml of acetonitrile was heated for 30 minutes under reflux.
The reaction mixture was cooled to room temperature.
The resulting precipitates were collected by filtration, washed with 20 ml of acetonitrile and 20 ml of ether, and dried under reduced pressure to give 8.61 g of the desired ~ompound (98.6 ~, white solid).
NMR(200MHz,DMSO-d6)~: 4.41-4.78(12H,m), 5.40(2H,s), 7.30(1H,d,J=7.0Hz), 7.48(1H,dd,J=8.6, 7.0Hz), 7.83-7.89(2H,m), 8.68(1H,s).
IR(KBr): 2831, 1460, 1375 cm Reference Example 35 5-(tert-Butoxycarbonylamino)methylimidazo[1,2-a]pyridine To a solution of 20 ml of purified water, 100 ml of ethanol and 24 ml of 12N HCl was added 8.61 g (28.06 mmol) of N-(5-imidazo[1,2-a]pyridylmethyl)hexamethylenetetraminium-chloride. The reaction mixture was stirred for 12 hours at 50~C. The reaction mixture was concentrated to 30 ml of volume under reduced pressure. The resulting precipitates anmmonium chloride were collected by filtration. The filtrate was completely concentrated under reduced pressure. To the residue was added 50 ml of purified water and 50 ml of THF, to give the homogeneous solution. To the solution was added 12 ml (84.18 mmol) o~ triethylamine and 7.35 g (33.67 mmol) of di-tert-butyl dicarbonate. The mixture was stirred for one hour at room temperature. To the reaction mixture was added 100 ml of purified water and 100 ml of ethyl acetate, and the mixture was extracted. The organic layer was washed with 100 ml of a saturated saline, dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
chloroform/methanol=20:1) to give 4.20 g of the desired 096l02542 I~

c ~_ ' (60.5~, white solid).
NMR(200MHz,CDCl3)6: 1.47(9H,s), 4.61(2H,d,J=6.0Hz), 5.13(1H,brs), 6.76(1H,d,J=6.6Hz), 7.18(1H,dd,J=8.8, 6.6Hz), 7.61(1H,d,J=8.8Hz), 7.69(2H,s).
IR(KBr): 1707, 1450, 1269, 1167 cm Reference Example 36 4,5-Dihydro-4-(tert-butoxycarbonyl)-3H-1,4,8b-~riR7~enaphthylen-3-one To a solution of 989 mg (4.0 mmol) of 5-(tert-butoxycarbonylamino)methylimidazo[l,2-a]pyridine and 2200 mg (18.0 mmol) of 4-(N,N-dimethylamino)pyridine in 25 ml of chloroform was added dropwise 1.34 ml (12.0 mmol) of trichloroacetyl chloride at room temperature.
The reaction mixture was heated for 5 hours under reflux. The reaction mixture was poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 100 ml of chloroform for extraction of the desired compound. The organic layer was washed with 100 ml of a saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent:
chloroform:methanol=20:1) to give 492 mg of the desired compound (45.0~, pale yellow solid).
NMR(200MHz,CDCl3)6: 1.58(9H,s), 5.28(2H,s), 6.92(1H,d,J=7.0Hz), 7.45(1H,dd,J=9.2, 7.0Hz), 7.65(1H,d,J=9.2Hz), 8.39(1H,s).
IR(~Br): 1714, 1515, 1309, 1149 cm Reference Example 37 4,5-Dihydro-3H-1,4,8b-triazaacenaphthylene-3-one-hydrochloride To a solution of 95.7 mg (0.35 mmol) of 4,5-dihydro-4-(tert-butoxycarbonyl)-3H-1,4,8b-tri~7~c~n~rhthylen-3-one in 100 ml of ethanol was added 0.09 ml (1.05 mmol) of 12N HCl. The mixture was w0 96~02s42 2 ~ ~ 3 ~ 2 3 r~l~J. ~8~ ~

stirred for one hour at room temperature. The resulting crystalline precipitates were collected by filtration, washed with a small volume of ethanol and ether and dried to give 56.1 mg of the desired compound (76.4%, white solid).
NMR(200MHz,DMSO-d6)~: 5.12(2H,s), 7.44(1H,d,J=7.4Hz), 7.85(1H,d,J=9.2Hz), 7.99(1H,dd,J=9.2, 7.4Hz), 8.50(1H,brs), 8.62(1H,s).
IR(KBr): 1677, 1479, 1360 cm 10 Preparation Example 1 (as one coated tablet) (1) Compound of Example 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg A mixture of 10.0 mg of the compound of Example 1, 60.0 mg of lactose and 35.0 mg of corn starch was granulated through a 1 mm mesh screen, using 0.03 ml of an aqueous solution of 10 weight % gelatin (3.0 mg in terms of gelatin), which was dried at 40~C and screened again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The core tablet thus obtained was coated with a suspension of sucrose, titanium dioxide and talc in gum arabic, which was polished with bees wax.
Preparation Example 2 (as one tablet) (1) Compound of Example 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg A mixture of 10.0 mg of the compound of Example 1 and 3.0 mg of magnesium stearate was granulated with 0.07 ml of an aqueous solution of soluble starch (7.0 mg in terms of soluble starch), which was dried and, then mixed with 70.0 mg of lactose and 50.0 mg of corn .. .. . _ ... .. . . . .. .. . _ _ _ _ _ _ _ _ _ ~ W096~02s42 2 1 9 3 2 2 3 ~ J~

starch. The mixture was compressed to obtain a tablet.
Preparation Example 3 (l) Compound of Example l 5.0 mg (2) Common salt 20.0 mg (3) 3istilled water to make the whole volume 2 ml In distilled water were dissolved 5.0 mg of the compound of Example l and 20.0 mg of common salt. To the solution was added distilled water to make the whole volume 2.0 ml. The solution was subjected to filtration, which was filled into a 20 ml-ampoule under sterile conditions. The ampoule was sterilized and sealed to provide an injectable solution.
Industrial APplicability The present invention relates to a novel tricyclic compound, which is useful as a medicine having an excellent activity of inhibiting platelet-derived growth factor (PDGF), antihypertensive activity, ameliorating activity of renal failure and lowering the cholesterol level, a process for producing the compound, and a pharmaceutical composition containing the compound.

Claims

1. A compound of the formula:

wherein ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo;
ring Q may optionally be substituted;
Y is an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted mercapto group, excluding methyl group as Y; and R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group, or a salt thereof.
2. A compound of claim 1, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising at least one nitrogen atom.
3. A compound of claim 1, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising at least one electron-withdrawing group.
4. A compound of claim 1, wherein Y is a hydrocarbon group, a hydroxyl group or a mercapto group, each of which optionally has a substituent comprising an amino group which is substituted with at least one electronwithdrawing group.
5. A compound of claim 1, wherein Y is a group of the formula:

wherein B is an optionally substituted divalent hydrocarbon group;
X is a bond, an oxygen atom or a sulfur atom;
R2 is a hydrogen atom or an optionally substituted hydrocarbon group, or R2 and B may form a ring together with the adjacent nitrogen atom; and R3a is an electron-withdrawing group; or R2 and R3a may form a ring together with the adjacent nitrogen atom.
6. A compound of the formula:

wherein ring A is a nitrogen-containing heterocyclic ring, having two nitrogen atoms as the hetero-atoms, which is optionally substituted with oxo or thioxo;
ring Q may optionally be substituted;
B stands for an optionally substituted divalent hydrocarbon group;
X is a bond, a oxygen atom or a sulfur atom;
R1 is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an acyl group;
R2 is a hydrogen atom or an optionally substituted hydrocarbon group, or R2 and B may form a ring together with the adjacent nitrogen atom; and R3 is an electron-withdrawing group, or a salt thereof.
7. A compound of claim 1, wherein the nitrogen-containing heterocyclic ring is a 5- or 6-membered ring.
8. A compound of claim 1, wherein the ring Q may optionally be substituted with 1 to 3 substituents selected from the group consisting of (i) halogen atom, (ii) a C1-4 alkyl group, (iii) a C1-4 alkoxy group, (iv) a C1-4 alkylthio group, (v) a hydroxyl group, (vi) a carboxyl group, (vii) a cyano group, (viii) a nitro group, (ix) a amino group, (x) a mono- or di- C1-4 alkyl amino group, (xi) a formyl group, (xii) a mercapto group, (xiii) a C1-4 alkyl-carbonyl group, (xiv) a C1-4 alkoxy-carbonyl group, (xv) a sulfonyl group, (xvi) a C1-4 alkyl sulfonyl group, (xvii) a carbamoyl group and (xviii) a mono- or di- C1-4 alkyl-carbamoyl group.
9. A compound of claim 1, wherein the ring Q is unsubstituted.
10. A compound of claim 1, wherein R1 is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an alkoxy carbonyl group, an alkyl carbamoyl group or an alkanoyl group.
11. A compound of claim 1, wherein R1 is a hydrogen atom, a C1-6 alkyl group or a phenyl group.
12. A compound of claim 5, wherein R2 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group.
13. A compound of claim 3, wherein the electron-withdrawing group is (i) -SO2R4 (R4 is an optionally substituted hydrocarbon group), (ii) -CO-R5 (R5 is a hydrogen atom or an optionally substituted hydrocarbon group), (iii) -COOR6 (R6 is an optionally substituted hydrocarbon group), (iv) -CON(R7)R8 (wherein R7 and R8 respectively are a hydrogen atom or an optionally substituted hydrocarbon group, or, R7 and R8 form a ring together with the adjacent nitrogen atom), (v) a nitro group or (vi) a cyano group.
14. A compound of claim 5, wherein B is a C2-10 alkylene group.
15. A compound of claim 5, wherein B is a group of the formula:

wherein p and q are independently an integer of 0 to 5.
16. A compound of claim 5, wherein B is a C3-8 alkylene group.
17. A compound of claim 6, which is are of the formula:

, , , , , , or wherein X1 is an oxygen atom or a sulfur atom, and the other symbols are of the same meanings as defined in claim 6, or a salt thereof.
18. A compound of claim 6, which is one of the formula or wherein X1 is an oxygen or a sulfur atom, and the other symbols are of the same meanings as defined in claim 6, or a salt thereof.

19. A compound of claim 17, wherein the ring Q is unsubstituted.
20. A compound of claim 17, wherein R1 is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group.
21. A compound of claim 17, wherein R1 is a hydrogen atom or a C1-6 alkyl group.
22. A compound of claim 17, wherein R2 is a hydrogen atom or a C1-6 alkyl group.
23. A compound of claim 17, wherein R2 is a hydrogen atom.
24. A compound of claim 17, wherein X1 is an oxygen atom.
25. A compound of claim 17, wherein X1 is a sulfur atom.
26. A compound of claim 17, wherein B is a C2-10 alkylene group.
27. A compound of claim 17, wherein B is a C3-8 alkylene group.
28. A compound of claim 17, wherein the electron-withdrawing group represented by R3 is -SO2R4a (R4a is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aralkyl group or an optionally substituted aryl group).
29. A compound of claim 28, wherein R4a is a halogeno-C1-6 alkyl group.
30. A compound of claim 1, which is 4,5-dihydro-4-[4-(trifluoromethanesulfonamido)butan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one or a salt thereof, or 1,2-dihydro-3-methyl-1-[5-(trifluoromethanesulfonamido)pentan-1-yl]-1,4,7b-triazacyclopento[ed]inden-2-one or a salt thereof.
31. A process for producing a compound of claim 1, which comprises reacting a compound of the formula:

wherein the symbols are as defined in claim 1, or a salt thereof with a compound of the formula:

wherein E1 is a leaving group and the other symbol is as defined in claim 1, or a salt thereof.
32. A compound of the formula:

, or , , , , , wherein R1a is a halogen atom, an optionally substituted hydrocarbon group or an acyl group, except for methyl group as R1a;
R1b is a halogen atom, an optionally substituted hydrocarbon group or an acyl gorup; X1 is an oxygen atom or a sulfur atom and the other symbols are of the same meanings as defined in claim 6, or a salt thereof.
33. A composition which comprises a compound of claim 1.
34. A pharmaceutical composition which comprises a compound of claim 1.
35. A pharmaceutical composition for inhibiting platelet-derived growth factor, which comprises a compound of claim 1.
36. A therapeutic composition for hypertension, which comprises a compound of claim 1.
37. A therapeutic composition for renal diseases, which comprises a compound of claim 1.
38. A composition for lowering lipid level, which comprises a compound of claim 1.
39. Use of a compound of claim 1 for manufacturing a pharmaceutical composition.
40. Use of a compound of claim 1 for manufacturing a platelet-derived growth factor inhibitor.
41. Use of a compound of claim 1 for manufacturing a therapeutic composition for hypertension.
42. Use of a compound of claim 1 for manufacturing a therapeutic composition for renal diseases.
43. Use of a compound of claim 1 for manufacturing a composition for lowering lipid level.
44. Use of a compound of claim 32 in the preparation of a compound of claim 1.
44. A method for treating a diseases derived from platelet-derived growth factor which comprises administering an effective amount of a compound of claim 1 together with a pharmaceutecally acceptable carrier or diluent to mammals.
46. A method for inhibiting platelet-derived growth factor which comprises administering an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent to mammals.
47. A method for treating hypertension which comprises administering an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent to mammals.
48. A method for treating renal diseases which comprises administering an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent to mammals.
49. A method for lowering lipid level which comprises administering an effective amount of a compound of claim 1 together with a pharmaceutically acceptable carrier or diluent to mammals.