AU6445899A - Tricyclic benzazepine vasopressin antagonists - Google Patents

Description

S&F Ref: 387830D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: American Cyanamid Company Five Giralda Farms Madison New Jersey 07940-0874 United States of America Jay Donald Albright, Aranapakam Mudumbai Venkatesan and Efren Guillermo Delos Santos Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Tricyclic Benzazepine Vasopressin Antagonists The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c Title: TRICYCLIC BENZAZEPINE VASOPRESSIN

ANTAGONISTS

1. Field cf the Invention This invention relates to new tricyclic nonpeptide vasopressin antagonists which are useful in 15 treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in .o disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

2. Background of the Invention .Vasopressin is released from the posterior pituitary either in response to increased plasma osmolarity detected by brain osmoreceptors or decreased 25 blood volume and blood pressure sensed by low-pressure volume receptors and arterial baroreceptors. The hormone exerts its action through two well defined receptor subtypes: vascular V1 and renal epithelial V2 receptors. Vasopressin-induced antidiuresis, mediated by renal epithelial V2 receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure.

Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased. Vi antagonists may decrease systemic vascular resistance, increase cardiac output and prevent 1 i vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induce increases in total peripheral resistance and altered local blood flow, V l antagonists may be therapeutic agents. V 1 antagonists may decrease blood pressure, induced hypotensive effects and thus be therapeutically useful in treatment of some types of hypertension.

The blockage of V2 receptors is useful in treating diseases characterized by excess renal reabsorption of free water. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific receptors on renal collecting tubule cells. This binding stimulates adenylyl cyclase and promotes the cAM?-mediated incorporation of water pores into the luminal surface of these cells. V2 antagonists may correct the fluid *o retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia.

Elevated vasopressin levels occur in congestive heart failure which is more common in older patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopressin levels, a V2 antagonist may be beneficial in i 25 promoting free water excretion by antagonizing the action of antidiuretic hormone, On the basis of biochemical and pharmacological effects of the hormone, antagonists of vasopressin are expected to be therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding and abnormal states of water retention.

2

~I

The following prior art references describe peptide vasopressin antagonists: M. Manning et al., Med. Chem., 382(1992); M. Manning et al., J. Med.

Chem., 3, 3895(1992); H. Gavras and B. Lammek, U.S. Patent 5,070,187 (1991); M. Manning and W.H. Sawyer, U.S. Patent 5,055,448(1991) F.E. Ali, U.S. Patent 4,766,108(1988); R.R. Ruffolo et al., Drug News and Persoective, 217, (May) (1991). P.D.

Williams et al., have reported on potent hexapeptide oxytocin antagonists Med. Chem., 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to Vi and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., r. J. Pharmacol, 05. 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP 0514667-Al; EPO 382185-A2; W09105549 and U.S.5,258,510; WO 9404525 Yamanouchi Pharm.Co.,Ltd., WO 9420473; WO 9412476; WO 9414796; Fujisawa Co. Ltd., EP 620216-A1 Ogawa et al, (Otsuka Pharm. Co.) EP 470514A disclose carbostyril derivatives and pharmaceutical .31 25 compositions containing the same. Non-peptide oxytocin and vasopressin antagonist have been disclosed by Merck and Co.; M.G. Bock and P.D. Williams, EP 0533242A; M.G.

Bock et al., EP 0533244A; J.M. Erb, D.F. Verber, P.D.

Williams, EP 0533240A; K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the prevention of preterm labor, B.E. Evans et al., Z. Med. Chem. 3919(1992), Med. Chem., 36 3993(1993) and references 3 therein. The compounds of this invention are antagonists of the peptide hormone oxytocin and are useful in the control of premature birth.

The present invention relates to novel tricyclic derivatives which exhibit antagonist activity at VI and/or V2 receptors and exhibit invv vasopressin antagonist activity. The compounds also exhibit antagonist activity at oxytocin receptors.

SUMIARY OF THE INVENTION LO This invention relates to new compounds selected from those of the general formula I: P /R :9 Fnrmula T Wherein Y is (CH2)n, 0, S, NH, NCOCH3, N-lower alkyl (Cl-C3), CH-lower alkyl CHNH-lower alkyl (C1-C3), CHNH2, CHN~lower alkyl (CI-C3)]2, CHO-lower alkyl(Cl-C3), CHS-lower alkyl (Cl-C3), wherein n is an integer from 0-2: A-B is

-(CH

2

)M-N

1 3

N-(CH

2 m -4 f( N wherein m is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, m may also be zero and when n i-s zero, m may also be three, provided also that when y is -(CH2)n and n is 2, m may not also be two.

RI is hydrogen, halogen (chlorine, bromine, fluorine, iodine), Oh, -S-lower alkyl(Cl-C3), -SH, -SO lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3; lower alkyl(Cl-C3); 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl (Cl-C3), N-[lower alkyl(C'L-C3fl2, -SO2NA'2; -SO2NH lower alkyl(Cl-C3) or -SO2N[lower alkyl (Cl-C3) ]2; R2 is hydrogen, CIL, Br, F, -OH, lower alkyl(Cl-C3), :9 0-lower alkyl(C2.-C3), or RI and R2 taken together are methylenediLoxy or ethylenedioxy; R3 is the moiety: 0 -CAr wherein Ar is a moiety selected from the moiety j

A

R

R

3 H C O, 5 0 :9 a a N---rX -Rio R4 is hydrogen, lower alkyl(Cl-C3); -CO-lower alkyl (CIL-C3) R5 and R7 are selected from hydrogen, (Cl-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R6 is selected from moieties of the formula: -6 1 4 -NCOAr',

-NCOCH

2 Ar' -NCON-Ar, I

I

-N-SO 2 Ra

-NCO(CH

2

I

NA

-cycloakl, N-SO 2

CH

2 1

I/

RR,

0 000 0 0*0* *0*0 *00* 0 0**0

S

SO

0.500.

0000 0 02 I II I-N-P 0- 15 l~v~c 2R 0~R2

-N-PI

II

-M\O2-bwe- a Ikoe1 3

-'CS)

I 2

Z

0

II

-NHi-C-O-luw erlky l(C 3 -C)straighlt or branched 0 11 -NH-C-lowver alkyl(C 3-C 8 )straight or branched, 0

II

-NI--C-O-loiver alkenyl(C C 8 )straight or branched, 0 11 -NH-C-lowver alkenyl(C.

1

-C

8 )straight or branched, wherein cyciloalkyl is defined as C3 to C6 cycloa1Jky1, cyclohiexenyl or cyclopenteny.; Ra is hydrogen, CH3, C2H;, moieties of the formulae: (CI-1)q--N (CH N 0 (C1- No 0Sb 0 00

S

0600

-(CH

2 )20-lower alkyi(Cl-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, CH3 or -C2Hr,; a moiety of the formula: -X-RlO; wherein Rio is lower alki-l(03-C8), lower alkenyl (C3-CB) (CH 2 )p-cycloalkyl (C3-C6),

-(CH

2 /A

RI;

4cf-y

N

R.

R

0 and p is zero to three: X is 0, S, NH, NCH3,

I

C=0 or abond and R; and R7 are as previously defined a moiety off the formula: N- COJ wherein J1 is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, CD-lower alkyl(Ci-Cs) branched or unbranched, -0-lower alkenyl(C-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophiene, the moieties

R

8 s o N or wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: Dz: -9wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally-, substituted with halogen, (Cj-Ci)lower alkony, -CO-lower alkyl( Ci1-C3) CHC'. (Cl-3--)lowEr alko -C-22-lower alkyl(Ci-C-0 and Fa and Rb, are as hereinbefore defined; a moiety selected from those of the formulae: N COCHAr' 0 -0-C-lowver,1kvI (C 1 -C 3 N Rb -S-lowver cilkvl(C 1

-C

3

NHCH

2 )q -CON RLb Rb NH(J N.'R N\b wherein F, i15 selected from halogen, (Ci-Ci)lower alkyl, -0-lower alkyl(Ci-C3,) and CH, Rb is as nereinbefore defined; Ar' is a moiety selected from the groucp

RS

R,

S

R8 and R9 are independently hydrogen, lower alkyl (Cl-C3); 0-lower alkyl(Cl-Ci) S-lower alkyl(Cl-C3), -CF3, -CN4, -011, -SCF3, -OCF3, halogen, N02, amino or NH lower alkyl(Cl-C3), -N-[lower alkyl(CI-C3)12, -N(Rb) (CH2)q-N(Rb)2; W' is 0, S NH, N-lower alkyl(Cl-C3), NCO-lower alkyl(Cl-C3) or NSO2-lower alkyl(Cl-C3) or NS021ower alkyl(Cl-C3); is selected from the moieties x Dx Sx As.

N

11 and tle moiety z represents: phenyl or substituted phenyl optionally substituted by one or two substituents selected from (Cl-C3) lower alkyl, halogen, amino, (C1-C3) lower alkoxy, or (Cl-C3) lower alkyl amino; a aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; a 5 or 6-membered aromatic 1 (unsaturated) heterocyclic ring having two nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3) lower alkyl, formyl, a moiety of the formula:

(CH

2 qN halogen or (CI-C3) lower alkoxy. For example, the fused heterocyclic ring may be represented by furan, pyrrole, pyrazole, thiophene, thiazole, oxazole, imidazole, pyrimidine or pyridine ring which may be substituted or unsubstituted.

12 DETAILED DESCRIPTION OF THE INVENTION Within the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R3 is a moiety:

O

II

CAr and Ar is selected from the moiety:

R

N

R

7 wherein R5, R6 and R7 are as hereinbefore defined.

Especially preferred are compounds wherein R3 is the moiety: 0

II

-CAr and Ar is selected from the moiety: NICORB and R6 is NHCOAr' and Ar' is 13

R

8 wherein R8, Ro, R25 and WI' are as hereinbefore defined.

Also especially broadly preferred are compounds wherein Y in Formula I is -(CH2)n- and n is zero or one; A-B is (CH 2)ni- N N (CH2) Mand R4, R5, R6, R7, R8, P9 and Rio are as hereinbefore defined; and m is an integer from 1-2.

The most broadly preferred of the compounds of Formula I are Lhose wherein Y is (CI2)11- and n is one: A-B is -(CH 2-I 2

N

3 or N (CH 2

M

R 3 ;m is one or two R3 is the moiety: 0 11 -CAr 14 fe--,N.

Ar is NIC2R 2 5 and R6 is -NCOAr', or -NCOCH 2 Ar', -NON -Ai I Ib

-NCO(CH

2 2 -cycloalkyl,

R

and Ar' is a moiety: aX. .a.a a a a a. a a a. a a Cycloalkyl Ra, Rb and W' are as previously defined and RB and R9 are preferably ortho CF3, Cl, OCH3, CH3, SCH3 30 or OCF3 substituents or Ar' is a disubstituted derivative wherein Ra and R9 are independently Cl, OCH3, CH3 and F.

The most highly broadly preferred of the compounds of Formula I are those wherein Y is -(CH2)n-, n is zero or one and thle imoiety zO represents a phenyl, substituted phenyl, thiophene, furan, pyrrole or a pyridine ring; A-B is -(Cl-I 2

N

I 3 N-(CH 2 i-n R 3 0 m is one when n is one and m is two when n is zero; R3 is the moiety: 0 11 CAr wherein Ar is f.

*5 S S S. S S

S

S. S S

S

S

/Nl-JCOR~ 25 id

R-

and R6 is selected from the group 16 Ia -NCOAr',

R

I\XXa where Ar' is selected from the moieties:

N.N

and Ra, Rb. RI, R2, R4, R5, R6, R7, R8. Ra, R25 and W' are as previously defined.

Most particularly preferred are compounds of the formulae: and R21

S

S.

5 0

SO

*0 S

S

*5 S S. 55

S

S

wherein m is an integer one or two; Pl and P2 are as previously defined; 30R3 is the moiety: 300 CAr 35 wherein Ar is selected from moieties of the formulae: 17 NI-2OR~ anid N 6 R-

P

7 R6 is -NCOAr', NCO(CH29n cycloalkyl, I

I

R, Rol NCOCH2 Ar', -X-RI 0 RA R b wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties: R 5

R

8

N

R

9 Ce,. Ra is independently selected from hydrogen, CH-3 or -C2HS; and R5, R7, R8, R9, R10, R25, X and W' are as hereinbefore defined.

too:#*Also particularly preferred are compounds of the formulae:

H

N-N

Y' N

M

wherein m is an integer one or two; R1 and R2 are as previously defined; R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formulae: NHCOR~ and6 R6 is

S

0 0* 0000 0000 0000 00*0 00 0 0 0000 -NCOAr', Ra -NCONAr', I I R~ R b NC0(CH 2 )n cycloalkyl, NCOCH 2 Ar',

R&

-X-R

10 00 0 0* 00 000000 0 *.00 0 000000 0 19 M 0 I1 -NH--C-0-lower alkyl(C 3

-C

8 straight or branched 0 11 -NH-C-lower alkyl(C 3

-C

8 straight or branched, 0 11 -NH-C-0-lower alkenyl(C 3

-C

8 )straight or branched, 0 1I -NH-C-lower alkenyl(C 3

-C

8 )straight or branched, wherein cycloalky. is defined as C3 to 06 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:

R

5

RR

,R N

R

9 Ra is independently selected from hydrogen, CH3 or and R5, R7, R8, R9, R10, R251, X and W' are as hereinbefore defined.

Compounds of this invention may be prepared as shown in Scheme 7 by reaction of tricyclic derivatives of Formula J and 21 with a substituted or unsubstituted 6-nitropyridine-3-carbonyl chloride -I to give the intermediates LL and at Reduction of the nitro group in intermediates aa and c~ gives the 6-amino-3pyridinylcarbony]l derivatives -Ea and -E]2 The reduction of the nitro groip in intermediates 5 A and 5,1 may be .*:**carried out under catalytic reduction conditions (hydrogen-Pd/C; Pd/C-hydrazine-ethanol) or under 20 chemical reduction conditions (SnCl2-ethanol; Zn-acetic acid; TiCl3) and related reduction conditions known in the art for converting a nitro group to an amino group.

The conditions for conversion of the nitro group to the amino group are chosen on the basis of compatibility with the preservation of other functional groups in the molecule.

Reaction of compounds of Formula 6a and bh with aroyl chlorides, heteroaroyl chlorides, arylsulfonyl chlorides, diarylphosphinyl chlorides, diphenoxyphosphinyl chlorides, alkyl (C3-C8) carbonyl chlorides, alkenyl(C3-C8)carbonyl chlorides, alkoxy(C3-C8)carbonyl chlorides, alkenyloxy(C 3 -CS)carbonyl chlorides, alkyl(C3-C8)sulfonyl chlorides, alkenyl(C3-C8)sulfonyl chlorides cycloalkylcarbonyl chlorides, arylcarbamoyl chlorides or heteroarylcarbamoyl chlorides as illustrated in Scheme 1, gives the novel compounds 8. and tb of this invention. The reactions may be carried out in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine, diisopropylethylamine or pyridine at 0°C to 50 0 C. If more than one aroyl, heteroaroyl or arylsulfonyl group, etc. is introduced during the reaction, mild base treatment (NaOH, KOH etc.) in a lower alkanol removes the second such group to give the products 8a and 8b.

o 21 o a Scheme 1 Rl

R

1 Y Y

-I

zO y zOR2 (C N

H

H

3a 3b CI 0 R ~N 4 zO R 2 zO

A

(C mN -C) =0

R

5 NR 7R 5 NR7 N N N* N -22 m I Scheme 1 (CGnt'da Ri F 7 Ar'CQCI Ar'CH 2

COC

cycloolkyl(CH 2 )nCOCI Ar'NCOCI

S

a a a a R 6 -NHCOAr'; -NHCO INAr t

-NHCQ(CH

2 )ncycloalkyl;

-NHCOCH

2 Ar' 23 Scheme 1 (Contd.

alkyl(C 3

'C

8

)COCI

alky!(C 3 -Ce)O-COCI alkeny(C 3 .Ca)-COCI alkenyl(C 3 'Ce)-OCOCI alkyl(C 3

-CS)SO

2

CI

alkenyl(C 3 -CB)So 2

CI

R 2 R 7 7 R 0 .0.000 0 2 0

II

2 24 Scheme 1 (Cont'd.) 0 0 N-N

R

7 b R6 *NHCOalkenyl(C 3

-C

8 -NHCOalkyI(C 3 -0 8

-NHCO

2 alkyI(C 3 -Cs).

NHSO

2 alkyI(C 3

-C

8

-NHCO

2 alkenyl(C.-C.)

-NHSO

2 alkenyl(C 3

C,)

0NS 2 /NQC

N-'

_N*2 P Aq F p1 0 -NHP

R

7 Reaction of tricycl~ic derivatives of Formula _E and fk with either a carbamoyl derivative a or a isocyanate derivative 2 gives compounds (Scheme 2) of Formula 12, and 1.1,b which are vasopressin antagonists and/or oxyt-ocin antagonists of Formula I wherein R6 is -NHCONAr' R b and Rb is H, CH3 or *see .06.* 26 66".

***06 Schemne 2 2 1 C1-C-NAr' or R b j 0=0 NAr' RI RI zO z mN-() =0 R R F 5 N 75 N N NHCONMr NHCONAr' 30 Reaction of tricyclic derivatives of Formula l and .1b with a 6-chioro or a 6-fluoropyridinjne-3carbonyl chloride 12 gives intermediates Ila, and 11h.

(Scheme 3).

0*000 *000: a. a Scheme 3

H

7 CI (F) 12 CI (F) al (F) 0O 4 4 4.

S 4 *00 S

S

.4 4 S S. ~k *4 54 4* 4 S. 9 5* a.

4.5.55 5

S

13a 13b The intermediates 1_3A and ib~ may be reacteLwith RlOX- (JA) wherein Rio is as previously defined and X is 0, S, NH or NCH3 to give derivatives of 1_5a and 2,12b as shown in Scheme 4.

28- I R 10

X-

14

R

1

RRI

R

5 'N X-R 0 N XR The compounds of Formula I wherein Y, A-B, Z, RI, R2 arnd R3 are as defined and the R3 (-COAr) aryl group is

N

2 9 wherein R6 is as previously defined may be prepared as shown in Scheme 5 by first synthesizing the pyridinyl moieties 1a which are to be attached to the tricyclic benzazepine units.

R

H-0- 6

N

R

7 16 The preformed pyridinyl moieties 1 may be activated for coupling by reaction with peptide coupling reagents or preferably activated by conversion to the pyridine-3-carbonyl chlorides 17. The coupling may be carried out in inert solvents such as chloroform, dichloromethane, tetrahydrofuran, dioxane, toluene and the like in the presence of a tertiary amine such as triethylamine. The reactions may also be carried out in pyridine and related alkyl pyridines.

3

I

aphem C1 0

R

5

NR

7 R 6 The starting materials )A and lb in Scheme 1 can be made by literature methods. For example, intermediate 6ll1-dihydro-5H-dibenz~b,elazepines and substituted derivatives are prepared according to literature procedures: L.I1. Werner, et al., C£he.,_a,74-80 (1965); A.W.H. Wardrop et al., C. SQ.Perkins Trans 1, 1279-1285 (1976).

Substituted 5, ll-dihydrodlibenzfb,elazepin-6one are prepared by literature procedures: J. Schmutz 31 et al., Helv. Chim. Acta., 4A, 336 (1965); and reduced to substituted 6,11-dihydro-5H-dibenz[b,e]azepines with lithium aluminum hydride, borane, borane-dimethylsulfide and agents know to reduce an amide carbonyl to a methylene group. Intermediate 10,11dihydrodibenz[b,f] [1,4]thiazepines are prepared by literature procedures for example, see K. Brewster et al., J. Chem. Soc. Perkin I, 1286 (1976). Reduction of either dibenz[b,f][1,4]oxazepines Wardrop et al., J. Chem. Perkin Trans. 1279 (1976)] and dibenz[b,f] [1,4]oxazepin-11(10H)-ones and dibenz[b,f][1,4]thiazepin-ll (10H)-ones J. Schmutz et al., Helv. Chim. Acta.,48, 336 (1965); may be carried out with lithium aluminum hydride in inert solvents such as dioxane and the like. The tricyclic 6,7-dihydro-5Hdibenz[b,d]azepine intermediates of Formula 32 may be prepared by the literature procedures: T. Ohta et al., Tetrahedron Lett., 26, 5811 (1985); Wiesner et al., J.

Amer. Chem. Soc., 7, 675 (1955); or derivatives may be prepared by coupling procedures illustrated in Scheme 7.

The reduction of nitro compounds of structure type 31 followed by ring closure, affords lactams 22 which are reduced to give tricyclic azepines of Formula 33.

5,11-Dihydro-6E-pyrido[3,2-c][1]benzazepines 0 25 are prepared by literature procedures J. Firl et al., Liebias A=a. Chem. 469, (1989). 11E-Pyrido[2,3b] [1,4]benzcdiazepin-6(5H) ones have been reported by Liegeois et al., Med. Chm 36, 2107 (1993) and these derivatives are reduced to 11i-pyrido[[2,3- 30 b] [1,4]benzodiazepines. The synthesis of tricyclic 1,4,5,10-tetrahydropyrazolo-[4,3-c][l]benzodiazepine and the 3-chloro derivative have been reported Palazzinc, et al., Heterocycliz Chem., 26, 71 (1989). 4,10-Dihydro-5H-thieno[3,2-.] [lbenzazepine 21.

and 9,10-dihydro-4H-thieno[2,3-][1]benzazepine 21b may be prepared by coupling tributyltin derivatives 19 and 32 with 2-nitrobenzyl bromide in the presence of tetrakis(triphenylphosphine) palladium(0) as shown in Scheme 6.

Following coupling of intermediate 24 to give the tricyclic azepine 25, the nitro group is reduced to give the 6-aminonicotinoyl derivative 26. The derivative 26 is then reacted with the appropriate acid chlorides as illustrated in Scheme L to give the products 27 and 27a.

Also depicted in Scheme 7 is the synthesis of intermediate tricyclic azepine 30 and 33. The tricyclic O lactam derivatives 29 and 2 may be prepared by reduction of nitro intermediates 28 and 31, followed by ring closure of the corresponding amino derivatives.

These tricyclic lactam intermediates 29 and 2a may be reduced with lithium aluminum hydride (LAH) or borane to give the tricyclic azepines 32 and 3..

*o e 33 Scheme 6Q 0s SnBu 3 Sn Bu 3 F \0

N

H+

Zn: HOAc

*CHO

0 H N02

LAH

0 0 0000 9 0* 009900 9**00* Zn: HOAc Sl;

N

21a 21b 34 Scheme7 S NH-

(H

2 2 a

,R

""I

BH

3 S(C O 3 2 Cu/A

CNPI

-N2 Pd/C

H

'V

N0 2 0@ a..

35 Scheme 7 (Continued) Ar'COCI or Ar'CH 2

COCI

Ar' I CoCI NH 2 cycloalIkylI(C H 2 nCOCI Rb Rll- Ar', Ar'-CH 2 Ar'Ncycloalkyl(CH 2 )nl- 0 11

NHC-R

11 36 9 9 Schemp, 7 (Continued) 7 Ri11a alkyl(0 3 -0C 8

)CO-

0 11 aikyl(C 3 -C 8

)O-C-

alkenyl(C 3 -C0 8

)CO-

alkenyl( 3 -C 8

)COCO-

alkyI(C 3

CB)SO

2 alkenyl(C 3

-C

8 )S0 2 NHRiia 0 n 2 -a 0 11 2 A A

A.

A S

A

A A CH SO2

F

0- 37 Scheme 7 (Continued)

H

2 9 Pd/C Ring close N2 O-alkyl

LAH

o r BH 3 y 0-al kyl 31 Pd/C, H 2 ring closure

OS

0* *0 S 0 *500 *5 S S ewe.

S.C.

a.

04 45 f

S*

*0500*

S

38 LAH 0 or N BH N HO 3 H Ar'COCI 0 F zO N 0 Ar' 34 Tricyclic intermediates 42 for the synthesis of selected vasopressin antagonists of this invention wherein Y in Formula I is -CH2- and m is one, may be prepared as shown in Scheme 8. Suitable l-nitro-2chloro or l-nitro-2-bromo heterocycles 35 undergo S 25 halogen exchange when reacted with a alkyllithium reagent such as t-butyllithium, a-butyllithium or nbutyllithium to give intermediates 12 which react with anhydrides of Formula Ia. R12 is ter.-butyl, secondary butyl, n-butyl, 2,6-dimethylpiperidine or a hindered 30 non-nucleophilic dialkylamine. The nitro products 31 are reduced with hydrogen and a suitable catalyst or chemically reduced (Zn-acetic acid, TiC13 etc.) to the amino intermediates AQ. Ring closure to the cyclic lactams j1 is conveniently carried out by heating in xylene or an inert solvent at 100°C to 200 0 C. The 39 cyclic lactams of structure type 41 are readily reduced by borane in tetrahydrofuran, borane-dimethylsulfide in tetrahydrofuran or lithium aluminum hydride in a suitable solvent such as dioxane to give the tricyclic compounds A2.

Alternatively phenyllithium derivatives 37b, which are prepared by lithiation of protected benzaldehyde derivatives or by lithiation of 2-chloro or 2-bromo protected benzaldehyde derivatives, are reacted with derivatives 38b wherein Z is as previously defined.

Derivatives 38b are prepared by standard procedures such O as ring closure of l-amino-2-carboxy heteroaromatic compounds or l-amino-2-benzoic acid derivatives, with acetic anhydride (Scheme 8).

e 40

R

1 2 Li R C or Br NO 2 3,R =H 0 0 R 2 a7b

IR

R- 2 3a Li 0K CH 3 38b~

WO

2

I

00 2

H

41 1

NH

2 CO 2

H

O R

R,

O zO N

N

H O H 41 42 Alternatively, as shown in Scheme 9, some of the tricyclic derivatives of structural type 42 may be prepared by "palladium" type coupling or "copper" induced coupling of halogenated derivatives _U to give tricylic lactams 44. Reduction of the lactam carbonyl group gives the intermediates A2. Coupling of halogen derivatives A5 to effect ring closure with activated copper or "palladium' type reagents which induce aryl coupling gives lactams A6. Borane reduction of lactams A4 gives derivatives A4. Ullmann cross couplings of 30 halogenated hetterocycles and 2-bromonitrobenzenes and related cross couplings by low valent palladium species such as [Pd(PPh3)4] and PdCl2(PPh3)2 are known synethetic procedures; N. Shimizu et al., Ttrahedrn Lett. 3, 3421 (1993) and references therein; N. M. Ali et al., Tetrahedron, 37, 8117 (1992) and references 42therein; J. Stavenuiter et al., Heterocycles, 2& 2711 (1987) and references therein.

Scheme 9 zo ~CH 2 Br(or 1I)F N1

H

0 H 0 44 42 H 0

H

H 4 47 Tetralhydro-1H-1-benzazepin-5-ones a5. and the tetrahydro-1H-1-benzazepin-2,5-diones U~ are useful ccmpounds for the synthesis of intermediate tricyclic heterocyclic structures .52 and 54 (Scheme 10) The t etrahydrobenzazepin -5 -ones U5. and Ua may be formulated to give hydroxymethylene derivatives .or reacted with 43 either the Vilsmeier reagent or the N, Ndimethylformamide dimethyl acetal to give the dimethylamilomethylefle derivatives. The construction of heterocyclic rings from a-hydroxymethylefleketones by reactions with hydrazine, N-methylhydrazile, hydroxylane or formamidine to give pyrazoles, Nmethylpyrazoles, oxazoles or pyrimidines respectively, is a standard literature procedure. See Vilsmeier formylation Tetrahedron, A.2, 4015-4034 (1993) and references therei.n and ring formations J.Heterocyclic Chm. 20, 1214 (1992) and references therein.

Substituted and unsubstituted tet-rahydrobenzazenifl- 2 -ones are known compounds which are prepared by reaction of a-tetralones with sodium azide under acidic Conditions. Chem. ~.456 (1937); Terhdc _A2, 180-7 (1993)]J (Schmidt reaction).

Reduction of tetrahydrc-1H-beflzazepin- 2 -ones grives the tetrahydro-1H-beflzazepines -4i which acylation gives compounds 492. Oxidation of N-acyl tetrahydro-lHbenzapines of type 49. to give the 5-one derivatives is a known oxidative procedure; R. Augustine and W. G Pierson, 2. Cb. .3A, 10'70 (1969).

The synthesis of 3, 4-dihydro-1A=-1-beflzazepinehas been reported as well as the 025 conversion cf 3,4-dihnydrc-l'-1-benzazepine-2,5-diones to 4- [(dimethy', lamino) methylenel 4-di-hydro-lli-1benzazepi~dne-2, 5-diones with LI, Ll-dimet hylformamfide, :dimethylacetal: Chen and N. W. Gilman, Heterccyc-i 4- Chm, 663 (1983)13. The preceding reference describes the synthesis of 2-methyl-5,7dihydropyrirnido 5, I1jbenzazepin-6 (6l1) -ones which may be reduced to remove the lactam carbonyl group to give tricyclic derivatiLves of structural type 54 wherein Z is a pyrimidine ring.

-44 Scheme 1Q No 2

H

4-)NB

I

RIS

6

H

5

C-O)

2 0 0 a;Rl (CH 3 3

CCO

0 b; Rl 5

=C

6

H

5

-CH

2 Ac-

(CH

3 2

S=O

E\

3

N

c; Rl. R 1 a,b,c KMnO 4

S

S

S.

S S 55 5 S S *5

SSSSSS

S S 5-1 a, b, c (Continued) 45 Scheme 10 (Cont'd.) 2 (R 1 5 Ri 0 CHN(CH 3 2

R

2

N

R 1 0* a a H 0 46

I

Scheme 11

Y-

H

N0 2 zO NO2 N0 2 4*7 Scheme 11 (Cont'd.) Rl Rl

Y

Y

mN =0

NN

NH 2 5aCICOR 25 57 4 48

RR

zR2 z OR n =0 0c- 2 NHCCp7 N NC2 9*59a 305HO~NO~ S48 The compounds wherein the aryl group in the R3 moiety -COAr is

R

NHCOR,

R

7 are prepared as shown in Scheme 11. The tircyclic derivatives 3a and 3b are reacted with a substituted or unsubstituted 4-nitrobenzoyl chloride 55 to give the derivatives 56a and 5f. Reductions of the nitro group in derivatives 56a and 56b gives the 4-aminobenzoyl intermedites 5a and 5,b which are then reacted with an acid chloride represented by formula .5 to give the products 5a and -b.

The compounds wherein the aryl group in the R3 moiety -COAr is

X-RIO

R7 are prepared by reactin of tricyclic azepines 3a and a with a substituted benzoyl chloride illustrated by structural formula 60 (Scheme 12) to give the products 61a and 61b. In a similar manner reaction of heteroaroyl chlorides 62, or 64 with the tricyclic 20 azepines 3a and 3b gives the products .5a and wherein the aryl groups are as illustrated in Scheme 13.

49 4 49 e o* Scheme 12

R-

yXR1

R

y Y zO R 2 zOCH 20=00 25 X- R 1 10 X- Rio Scheme 13i 0 ci

-RX-

0 '14 X- RI 0 0 N- X-RI 0

R

2

Y\

O

Ar

I

S

3 X- RI 0 0 Reference Example 1 6. 11-Dihvdro-5H-dibenz[b. elazepilne A mixture of 48.52 g (0.20 mol) of 2aminobenzophenone-2'-carboxylic acid and 500 ml of xylene is refluxed for 67 hours, cooled to room temperature and filtered. The solid is washed with ,cyJene to give 43.3 9 of 6,ll-dione as light tan crystals, m.p. 245-248*C. To 51 4.46 g (0.020 mol) of the preceding compound in 25 ml of tetrahydrofuran is added 12 ml (0.12 mol) of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran.

An additional 10 ml of tetrahydrofuran is added and the mixture is stirred overnight and then is refluxed (solids dissolve) for 4 hours. The solution is cooled and 15 ml of methanol added dropwise. The mixture is concentrated under vacuum, 50 ml of 2N sodium hydroxide is added and the mixture refluxed for 2 hours. The solid is filtered, washed with water, air dried and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 3.25 g of crystals, m.p. 117-1220C.

Reference Example 2 2-Chlorc-5H-dibenzfb.e1azeine-6. 11-dione Chlorine gas is bubbled into a mixture (partial suspension) of 1.0 g (450 mmol) of dibenz[b,e]-azepine-6,11-dione in 50 ml of glacial acetic acid. The temperature of the mixture rises to 38 0 C. On standing, as the temperature of the solutions decreases, a white solid precipitates. The mixture is filtered to give 0.40 g of solid (mixture of starting material and product in ratio of The filtrate on standing gives 0.10 g of product as crystals, m.p. 289- 293 0

C.

52 o o o o* *oo Reference Example 3 10.11-Dihvdro-N.N-dimethvldibenzfb. fl l.41oxazenine-2sulfonamide To 5.88 g of 10,11-dihydro-N,N-dimethyl-l1oxodibenz[b,f][l,4]oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred overnight and then refluxed for 2 hours. The mixture is chilled, diluted with 10 ml of methanol and then concentrated, methanol added again and the mixture concentrated. To the mixture is added 20 ml of 2N NaOH and the mixture refluxed for 2 hours. The mixture is O extracted with dichloromethane, the extract dried (MgSO4) and filtered. The filtrate is passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give 4.8 g of crystals, m.p. 99-102 0

C.

Recrystallization from diisopropylether-dichloromethane gives 3.96 g of crystals, m.p. 109-110 0

C.

Mass Spectrum (FAB) 305(M H).Anal.Calc'd. for C15H16N203S:C,59.2; H,5.3; N,9.2; S,10.6.

Found: C,57.6; H,5.2; N,8.9; S,10.1.

Reference Example 4 6-dihvdroohenanthridine To a hot (70 0 C) solution of 2.62 g (17 mmol) of 6(5H)-phenanthridinone in 120 ml of acetic acid is added chlorine gas for 10 minutes. The solution is allowed to cool to room temperature and the mixture filtered. The crystals are filtered to give 1.35 g of crystals, m.p. 310-3180C.

To the preceding compound (1.57 g) in 25 ml of tetrahydrofuran is added 12 ml of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 18 hours, cooled and 15 ml of methanol 35 is added. The mixture is concentrated under vacuum and ml of 2 N sodium hydroxide added. The mixture is 53 *000 refluxed for 2 hours and the solid filtered off and washed with water and air dried to give the product as a solid.

Reference Example 9-Chloro-5H-dibenz b.e!azepin-6.11-dione A mixture of 11.15 g of 6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70 0 C) is added chlorine gas. Chlorine is bubbled throughout the solution until a precipitate begins to form. The mixture is allowed to cool to room temperature and is filtered to give 7.3 g of product, m.p. 290 0 C to 2950C.

Reference Exame 6 9-Chloro-6.11-dihydrc-5H-dibenz b.elazepine To a mixture of 7.28 g [b,e]azepin-6,11-dione in 25 ml of tetrahydrofuran under argon is added 8.5 ml of 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture is stirred 18 hours at room temperature, 30 ml of tetrahydrofuran added and the mixture refluxed for 3 hours (solids dissolved). The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 ml of 2 N NaOH. The mixture is refluxed overnight and filtered.

The solid is extracted with dichloromethane and the extract is washed with 2 N citric acid, water and dried (Na2SO4). The solvent is removed to give 4.2 g of solid which is triturated with ethyl acetate-hexane to 30 give crystals, m.p. 1370C to 1410C.

SReference Exampre 7 ll-rihvdrodibenz bf 1 4tia eon To a mixture of 3.3 g of 10,11-dihydro-lloxodibenz[b,f] [l,4]th-iazepine in 25 ml of tetrahydrofuran is added 4.0 ml of 10 molar boranedimethylsulfide in tetrahydrofuran. The mixture is 54 0:i stirred at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional 30 ml of methanol is added and the solvent removed to give white crystals. A sample is purified by chromatography on silica gel with hexane-chloroformethyl acetate as solvent to give white crystals, m.p. 145-148*C.

The following compounds are prepared as described in Reference Example 7.

Reference Example 8 4-Meth1li 0-11-dihydrodibenz rb. fI! ~1 4thiazegine Reference Exarn. le 9 4 -Chi c-0, -dihvdrcdibenz fb. f I 1 4 1th 4azeipine Reference 2-Methvl-'0.11-dih-vdrodibenz Tb. fifl.4 1 thipzepine Referene~ ExamI21P 11 11-dihvdrodibenzfb~ flI .41thiazecine Reference Examp 12 2-Methoxvl0.U1-dihydrcdibenz Tb. fi r1,41thiazein~e Reference Examiple 13 8-Chl r-0. 1-dihydrodibenz rb. f 111 r4 1 hiazepine Reference Exape 16 4. 8-Dichihro-10.11-dihvdrodibenz Tb. fi1. 41thiazepine Reference Example 8-Ch2.orc,-4-rmethv1-10. 11-dihvdrodibenz Tb. fl i. 41azl~n Reference Examiple 16 8-Methoxv-10, 1-dihvdrcdibenz 1.4lthiazepine :Reference Examn1e 17 I-Chloro -4-mejhyl-10.11dihvdrcoiibenz Tb. fi 1. 41 thiazeroine Off* The following compounds are prepared as described in Reference Example 3.

Refpr Dcp ExamRP1 18 2-h 0 -ibd dbn b f 1 41 -xazeniae 0 *5

S

S

S

S

Reference Example 19 2-Methvl-l0.11-dihvdrodibefb.El -rl.41-oxazeroine Reference Examp~le 4-Chloro-10.l1-dihvdrodibelzfb.fl rl.41-oxazepjnnp Reference Example 21 3-Methyl-lO. l1-dihydrodibenzfb. fl rl.41-oxazepine Reference Examole 22 7-Chlorog-10,1l-dihydrodibenzlfb. fi f1.4 1 -oxazerfine- Reference Examjple 23 8-Chlcrc-lO. 2-dihvZdrodibenz lb. ff1 !1-c:azerine Reference ExamL) 24 2.4-Dichloro-10.11-dihvdrodibenzfb.fl1 4-mzepn Reference Example 4. 8-Dichic rc10 1'-dihvd,,rodibenz.fb. ff1K. 4 1 -oxaz7epine Reference Example 26 4-Chlorc-8-mrethyl-10.11-dihvdpdibenzfb.ff 1 [,41- Reference Examole 27 4-Methvl-7-chlcro-10.11-dihvdrodibefb. ff1[.41oae~n Reference Examiple 28 I-Chicro-4-methvl-10.1l-dihdrodbefl. flf .41- Reference Ezamnle 29 2-Fluoro-lO,. :iihvdrodibenz lb. ff1 r4lxazepine Reference Exampl,- e N- (2-Iodophenvl)-2-icdonhenvlacetamide A solution off 13.32 g (0.05 mol) off 2iodophenylacetic acid in 75 ml thionyl chloride is reffluxed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2iodophenylacetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture f 100 m-2 of toluenedichioromethane is added 11 g (0.05 mol1) of 2iodoaniline and (0.10 mol) off dii-sopropylethylamine.

56 The mixture is stirred at room temperature overnight and the solvent removed. The residue is dissolved in dichloromethane and the solution washed with 1N HC1, saturated sodium bicarbonate, brine and dried (Na2SO 4 The solvent is removed and the residue recrystallized from methanol-ether to give 16.0 g of light brown crystals, m.p. 160 0 -163 0

C.

Reference Example 31 2-Iodo-N-(2-iodophenvl)benzeneethanamine To a suspension of 1.39 g (3 mmol) of 2-iodo- N-(2-iodophenyl)benzeneacetamide in 30 ml of tetrahydrofuran-dichloromethane is added 3.75 ml O of 2.0 molar borane-dimethylsulfide in tetrahydrofuran.

The solution is stirred 1 hour at room temperature and then relfuxed for 16 hours. The mixture is cooled and water slowly added dropwise until gas evolution ceases.

The volatile are removed under vacuum and the aqueous residue made alkaline with 2N sodium hydroxide. The mixture is extracted with ether (50 ml) and the extract is washed with brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad is washed with ether and the filtrate evaporated. The residual solid is washed with isooctane to give 1.20 g of white solid.

Recrystallization from diethylether/hexane gives white O crystals.

Reference Example 32 N-(4-Nitrobenzoyv-N-(2-iodophenyl)-2iodobenzeneethylamine 30 To a solution of 0.90 g of 2-iodo-N-(2iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under 35 vacuum. The residue is dissolved in ethyl acetatedichloromethane and the solution washed with 1N 57 9 .,.go HC1, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.

Reference Example 33 ?.4-Dihydr--1-l-bena2eazeDine-2.5-dione To a solution of 225 ml of glacial acid and ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heated at 100 0 C for 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloromethane-hexane to give 20.1 g of 3-(2nitrobenzoyl)acrylic acid as white crystals, m.p. 153- 158 0 C. A solution of the proceeding compound (9.0 g) in ml of ethanol and 1.6 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30 pounds per square inch of hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatographed on silica gel with hexane-ethyl acetate as solvent to give 4.0 g of 3-(2-aminobenzoyl)propionic acid as an orange solid, m.p. 103 0 -107 0 C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml of diethoxyphosphinyl cyanide in 20 ml of dichloromethane is stirred at room temperature for 30 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2 H citric acid, 1M NaHC03, brine and dried (Na2SO4). The solvent is ":removed and the residue purified by chromatography over silica cel with ethyl acetate-hexane as solvent to give 0.190 g of light brown crystals, m.p. 168 0 -170 0

C.

58 I .L -CR- I J .I-CIILLI-J. J 4- (Dimethylamino)methvlenel-3.4-dihvdro-lH-1- A mixture of 0.250 g (1.43 mmol) of 3,4dihydro-l-l-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,H-dimethylformamide, dimethylacetal is heated at 90 0 C for 1.5 hour. The mixture is cooled, diluted with diethyl ether and filtered. The solid is washed well with diethyl ether and dried to give 0.26 g of tan crystals, m.p. 2030-205OC.

Reference Example 2-Methyl-6.

7 -dihydrc-5H-Dvrimidof5.4-dl llbenzazepine To a solution of 0.308 g (3.26 mmol) of acetamidine hydrochloride in 15 ml of methanol under argon is added 0.176 g of (3.26 mmol) of sodium methoxide and the mixture stirred for 5 minutes. To the mixture is added 0.50 g (2.17 mmol) of 4- [(dimethylamino)methylene]-1,2,3,4-tetrahydro-5i-land the mixture stirred at room temperature overnight. The mixture (containing thick precipitate) is diluted with 3 ml of methanol, chilled and filtered. The filtrate is concentrated to dryness.

The residue and original solid are combined and chloroform added. The mixture is washed with water, the organic layer is treated with activated carbon and then filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated to give 0.41 g of crystals, m.p. 257 0 -258 0

C.

The preceding compound is heated with 30 equivalents of lithium hydride in dioxane for 24 hours to give the product as a solid.

Reference Example 36 -Dihvdroovridor2.3-b1fl.41benzothiazepine To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 ml of ethanol and 11 ml of water is added portion wise 12.72 g of solid sodium 59- M M bicarbonate. After the complete addition, the mixture is stirred for 15 minutes and 10.0 g of 2-chloro-3nitropyridine added portionwise. The mixture is refluxed for 2 hours, cooled and then concentrated in vacuo. The residual aqueous solution is diluted with ml of water, acidified with 2N HCI and extracted twice with 250 ml of ethyl acetate. The extract is concentrated under vacuum to give a yellow solid residue. The residue is dissolved in a minimum of ethyl acetate by heating on a steam bath. The solution is cooled overnight and filtered to give 2.5 g of starting O material. The filtrate is concentrated, chilled and filtered to give 12.5 g of 2-(3-nitro-2pyridinylthio)benzoic acid as a yellow solid. The preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml of ethanol is shaken in a Parr hydrogenator under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with 200 ml of dichloromethane. The combined filtrate is evaporated in vacuo to give a solid. The solid is triturated with ethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g) is again hydrogenated with Pd/C (0.50 g) in 50 ml of ethanol and 30 ml of acetic acid under 45 psi of hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with methanol. The combined filtrate is concentrated in vacuo to give 1.6 g of solid. This solid in 25 ml of N,N-dimethylformamide is again reduced with 0.80 g of Pd/C under 45 psi of hydrogen to give 30 0.57 g of solid. Recrystallization from ethyl acetate gives 0.28 g of 2-(3-amino-2-pyridinylthio)benzoic acid.

The preceding compound (0.20 g) is heated in 2hydrcxypyridine at 170 0 C to give 5, 6-dihydropyrido[2,3h][1,4]benzothiazepine as a yellow solid. The preceding 35 compound is reacted with borane-dimethylsulfide as 60 oo* described for Reference Example 3 to give the product as a solid.

Reference Example 37 2-Nitro-2''-carboxy-diphenvlamine A stirred solid mixture of 13.7 g of anthranilic acid, 20.2 g of Q-bromonitrobenzene, 13.8 g of anhydrous potassium carbonate and 0.1 g of copper metal is heated at 200 0 C in an oil bath. The reaction mixture is heated for 2 hours, cooled and the solid washed with ether (3 X 100 ml). The solid is dissolved in hot water and filtered. The filtrate is acidified with 40 ml of HC1 and the resulting solid is collected Sand dried to give 20.5 g of the desired product as a solid, m.p. 262-265 0

C.

Reference Example 38 2-.Ainc-2'-carboy-diphen.ylamine A solution of 7.3 g of 2-nitro-2'-carboxydiphenylamine in 50 ml of methanol containing palladium-on-carbon is hydrogenated under 42 pounds of pressure for 24 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated to dryness in vacue to give 6.6 g of the desired product as a solid, m.p. 72-75 0

C.

Reference Example 39 5.11-Dihvdro-!0H-dibenzbh.el r1.41diazepine--one O A mixture of 6.6 g of 2-amino-2'carboxydiphenylamine in 300 ml of xylene is heated at reflux for 20 hours. The xylene is evaporated in vacuo to a residue which is evaporated from 210 ml of toluene in vacuo to a residue which is evaporated from 50 ml of chloroform to give a residue. The residue is dissolved in 10 ml of tetrahydrofuran and added to 400 ml of icecold hexane. The resulting solid is collected, to give 4.3 g of the desired product as a solid, m.p. 121-123 0

C.

61 o Reference Example 5.11-Dihvdro-10H-dibenzrb.el l.41diazepine To a stirred solution of 4.3 g of 5,11dihydro-10-dibenz[b,e][1,4]diazepin-ll-one in 50 ml of tetrahydrofuran, under nitrogen and cooled to OOC is added 4.0 ml of a 10 molar solution of dimethyl sulfideborane complex in tetrahydrofuran. The ice bath is removed after 30 minutes and the reaction mixture stirred at room for 18 hours. The reaction mixture is cooled in an ice bath and 30 ml of anhydrous methanol added dropwise and evaporated to dryness in vacuo.

Another 30 ml of methanol is added and evaporated to a residue. The residue is quenched with 30 ml of sodium hydroxide followed by heating at 110 0 C for minutes and cooling to room temperature. The reaction mixture is diluted with 200 ml of water and extracted with methylene chloride (3 x 100ml). The combined extracts are washed with 1N HCI, water and 0.5 N NaOH.

The organic layer is dried and evaporated in vacuo to give 3.2 g of the desired product, m.p. 114-116 0

C.

Reference Example 41 SH-Diben:b.elazepine-6.11-dione A mixture of 2.50 g of 2-aminobenzophenone-2'carboxylic acid in 50 ml of xylene is stirred at reflux for 23 hours. The mixture is filtered to give 1.82 g of the desired product as a solid.

Reference Example 42 2-Chlorc-5H-dibenz [b.elazepine-6. 1-dione A mixture of 1.0 g of 30 6,11-dione in 50 ml of acetic acid is stirred while chlorine is bubbled into the reaction mixture until saturated. The temperature increases to 38 0 C. After standing, a precipitate forms and is filtered, washed with hexane and air dried to give 0.62 g of solid which is purified by chromatography to give the desired product as a solid, m.p. 289°-293°C.

62 Reference Examole 43 2-Chloro-6.11-Dihvdro-5H-dibenz hb.elazepine To a mixture of 7.28 g of 2-chloro-51dibenz[b,e]azepine-6,11-dione in 25 ml of anhydrous tetrahydrofuran, under argon, is added dropwise 8.5 ml of (10 M) boron-dimethyl sulfide in tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is heated at reflux for 3 hours and cooled to room temperature. While stirring, 25 ml of methyl alcohol is carefully added, followed by 100 ml of 2 N NaOH. The reaction mixture is heated at reflux for 24 hours and the solid collected. The solid O is dissolved in methylene chloride and washed with 2 N citric acid, water and dried (Na2S0 4 The volatiles are evaporated i vacuo to give 4.16 g of a residue which is crystallized from ethyl acetate-hexane to give 2.05 g of the desired product as a crystalline solid, m.p. 137-141 0

C.

Reference Example 44 2-r2-(Tributylstannvl)-3-thienv!-l.3-dioxolane To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78 0 C and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture :.is warmed to room temperature and the solvent 30 evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiC1) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, given 34.16 g of the desired product.

63 Reference Examole 2-f2-_ 2-Nitrophenvl)methyll-3-thienyl-1.3d ioxolane A mixture of 2-[2-(tributylstannyl)-3thienyl]-1,3-dioxolane (8.8 gms, 20 mmols), 2nitrobenzyl bromide (4.5 gms, 22 mmol) and tetrakis (triphenylphosphine)-palladium (200 mg) is refluxed in degassed toluene for 16 hours under a nitrogen atmosphere. At the end, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth. The toluene is removed by concentrating at reduced pressure and the product isolated by silica gel column chromatography by elution with 30% ethyl acetate: hexane to give 4.5 gms of the desired product as viscous liquid. Mass Spectrum; M+292 Reference Example 46 4,10-Dihyvdr-5H-thienfo3.2-c' r!lbenzazepine A stirred solution of 4 gms of nitrophenyl)methyl]-3-thienyl]-i,3-dioxolane in acetone ml) and acetic acid (90% 50 ml) is heated to 60 0

C.

Zinc dust (10 gms) is slowly added and after the addition, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water.

The organic layer is dried (Na2S04) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate: hexane to give 2.0 g of the desired product as a pale yellow crystalline solid, m.p. 86 0 C. Mass Spectrum; 30 M+202.

Reference Exam-p 47 4.?ni hvrr methvl -2thienvl oxazole To a solution of 4,5-dihydro-4,4-dimethyl-2- (2-thienyl)-oxazole (4.5 gms 25 mmol) in anhydrous ether az -70 0 C, n-butyl-lithium (2.5 molar solution in hexane, 64 11 ml) is added drop by drop under N2 atmosphere. The reaction mixture is stirred at -78 0 C for 45 minutes and tri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour and quenched with water.

The reaction mixture is extracted with ether, washed well with water, dried and concentrated. The product obtained is pure enough for further transformation. The oil product, 4,5-dihydro-4,4-dimethyl-2-[3- (tributylstannyl)-2-thienyl]-oxazole is mixed with 2nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis (triphenylphoshine)-palladium 200 mg) for 16 hours.

At the end reaction mixture is cooled to room temperature and filtered. Toluene is removed under reduced pressure and the product is isolated as brown oil by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 5.7 g of the desired product. Mass Spectrum; M+316.

Reference Example 48 9.10-Dihydro-4H--hion [3.2-c f!Ibenzazeoin-1O-one A solution of 4,5-dihydro-4,4-dimethyl-2-[3- [(2-nitrophenyl)methyl]-2-thienyl]oxazole 5 gms is refluxed in acetone/water (3:1 100 ml) containing 1 N HC1 (30 ml) for 24 hours. The reaction mixture is concentrated and the residue is dissolved in glacial acetic acid (100 ml). The acetic acid is stirred at 70 0 C and zinc dust (10 gm) is slowly added. Stirring is continued at 70 0 C for 6 hours. At the end, the reaction 30 mixture is cooled to room temperature and filtered.

Acetic acid is removed under reduced pressure and the residue is extracted with chloroform. The chloroform layer is dried and concentrated to give 2.9 gms of the desired product as a brown solid.

35 Mass Spectrum: M+215.

*a ••go ooo *Qo 0- Reference Example 49 9,10-Dihydro-4H-thienof2. 3-c1r11benzazepine A stirred solution of 2.0 g of 9,10-dihydro- 4a-thieno[2,3-c][1]benzazepin-10-one and lithium aluminum hydride (500 mg) in tetrahydrofuran is refluxed for 4 hours. At the end, reaction mixture is carefully quenched with ice cold water and extracted with chloroform. The organic layer is washed well with water and dried over anhydrous Na2SO4, filtered and concentrated. The product is purified by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 1.2 g of the desired product as a bright yellow solid. Mass Spectrum M 202.

Reference Example 2-Methylfurane-3-carbonyl chloride A mixture of 4.0 g of methyl-2-methylfurane-3carboxylate, 30 ml of 2 N NaOH and 15 ml methanol is refluxed for 1.5 hours. The solvent is removed under vacuum to give a solid. The solid is extracted with dichloromethane (discarded). The solid is dissolved in water and the solution acidified with 2 N citric acid to give a solid. The solid is washed with water and dried to give crystals 1.05 g of crystals of 2-methylfuran-3carboxylic acid. The preceding compound (0.95 g) and 3 ml of thionyl chloride is refluxed for 1 hour. The solvent is removed, toluene added (20 ml, three times) and the solvent removed to give the product as an oil.

Reference Example 51 S2- 2- (Tribu avl -thienvl 1 3-dioxolane 30 To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxclane in 100 ml of anhydrous ether, n-buyl-lithium (1.48 N, ir hexane, 74.3 ml) is added dropwise under nitrogen at room temperature.

*After being refluxed for 15 minutes, the reaction 35 mixture is cooled to -78°C and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is 66 added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCI) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, giving 34.16 g of the desired product.

Reference Example 52 Methyl 6-aminoovridine-3-carboxvlate Dry methanol (400 ml) is cooled in an ice bath and HC1 gas is bubbled into the mixture for 25 minutes.

To the MeOH-HCl is added 30 g of 6-aminopyridine-3carboxylic acid and then the mixture is stirred and heated at 90 0 C for 2 hours (all the solid dissolved).

The solvent is removed under vacuum and the residual solid dissolved in 100 ml of water. The acidic solution is neutralized with saturated sodium bicarbonate (solid separated) and the mixture chilled and filtered to give g of white crystals, m.p. 150 0 -154 0

C.

Reference Example 53 6-f(5-fluoro-2-methvlbenzovl)aminolDvridine-3-carboxylic acid To a mixture of 4.5 g of methyl 6-aminopyridine-3-carboxylate and 5.53 ml of triethylamine in 40 ml of dichloromethane (cooled in an ice bath) is added 6.38 g of 5-fluoro-2-methylbenzoyl chloride in ml of dichloromethane. The mixture is stirred at room temperature under argon for 18 hours and an additional 3.4 g of 5-fluoro-2-methylbenzoyl chloride added. After 30 stirring at room temperature for 3 hours, the mixture is e*as filtered to give 3.0 g of methyl 6-[[bis(5-fluoro-2methylbenzoyl)]amino]pyridine-3-carboxylate. The filtrate is concentrated to dryness and the residue triturated with hexane and ethyl acetate to give an 35 additional 9.0 g of bis acylated compound.

67 A mixture of 12.0 g of methyl 6-[[bis 'fluoro-2-methylbenzoyl) I amino) pyridine-3-carboxylate, ml of methanol-tetrahydrofuran and 23 ml of 5 Nj NaOH is stirred at room temperature for 16 hours. The mixture is concentrated under vacuum, diluted with 25 ml of water, cooled and acidified with 1 N HC1. The mixture is filtered and the solid washed with water to give 6.3 g of the product as a white solid.

As described for Reference Example 53, but substi-:uting the appropriate aroyl chloride, heteroaroyl chloride, cycloalkanoyl chlorides, phenylacetyl chlorides and related appropriate acid chlorides, the f ollowi'ng 6-1 (aroylaminolpyridine-3-carboxylic acids, 6- (hetero-ar-oy-) ami-nojpyridi-ne-3-carb-oxyli:c acids and related (acylated)aino)pyri-dine-3-carboxylic acids are prepared.

Reference Example 54 C(3-Methvl-2-thienvlcarbonvi)aminoliovridine-3carboxylic aci~d Reference Examolje 6- (2-Methvl-3-thienvlcarbonvZ) am~novridine-3carboxylic aci-d Reference rxamTple 56 (3-Methvl1-2-furanvlcar-bonvl)aminolrovridine-3carbom%''ic acid Refereance Example 57 lr (2-Methvl -3-furanv! carbonv! ami nclovridine-3carboxvlic acid Reference ExamI2> 58 f 1 eth1g -,r Reference E.xamni= 5;9 6-f (2 -Met hy Iber- cy'D amino 1 nvri ne-3-carbcyy lic acid ReferencP Example= :35 6-r(2-chicrobenzo-vl) aminci-cvr 4 in-3-carboxylic- afcid -68 Reference ExaMn~1e 61 6-F (2-rF'uorobeflzovl) aMino1t~yri~ine-3-carboxylic- acidl Reference Ex~ample 62 6-f (2-Chlr-o-4-fluorobenzovl)aminol]2yridine-3-carboxylic Reference Exampe 63 6- r(2. 4-Dichlorcbenzovl) amrinolpvridine-3-carboxylic acid Reference ExamRle 61 6-f (4-Chlorc-2-fluorobenzovl)aminolovridine-3-carboxylic acid Reference Examole 6- r(3.4. 5-Trimetho:-~benzv)amincivrid ne-3-;carboxvlic Reference. Example 66 6- (2.4-Difluorobenzov1)aminc1rvridine-3-carboxvlic acid Reference Examole 67 6-f (2-1:ro-nobenzov1)arninolpvridine-3-carboxvlic acid Reference Example 68 6- r (2-Ch or--nit robenzov 1 1amiflc 1 vrijdine- 3-carbxv 1 ic id Refer'once Example 69 G- r(Te~rahvdrcfturanyl-2-ca.rbonv1l aminoiovridine-3carboxylin acid Reference E:xarno'e 6- r(Te-rahyvdrcthienvl-2-carbollamino nvridine-3carlboxvlir acid :Reference ExaMole 71 6- r (Cclohe,-vl carbonyl) amifcl ori dine- 3--carboxvl ic acid Reference 7xami~le 72 Reforence E:xamnle 73 69. r (5-Fiuo,.,ro-2-mTethylbenzeneA cetyl) amiIi~pri ine- 3carboxvlic acid -69 Reference Example 74 Reference Examnple 6-E (cvclcentvlcarbonvl)aminoln',ridine-3-carbcxylic acid Reference Example 76 6-r4 ,lhz;actlaioprdielcrov4 acid- Reference Exarnole 77 6-f (3-Meshvl-2-thienv lacetvl) aminolovridine-3-carboxylic ai Reference Ezamipie 78 6-F (2-Methv1-3-ffiienylapet..')minolrpyridq'ne-3-carbpxvljc Refer--nce Exarro0 7)9 6-..r(3-Methvl1-2-f,-ranvlaCerylIaminolxovridine-3-carboxvlic ac.id, rn.p. 288-290 0

C

-r(2-Methvyl-'-frnlacetvl,-) aniiprvridino-3-carbcxvlic Reference Exam~lo 81 ~r (A-Met-hvl,-2-tetrahvdrctheni acetvl amino!vrii ne-3carboxylic acid Reference Exammle 82 .9 25 .30 .35 carboxylic a,4 Reference ExaMn1e 83 F 5 -D ichl1c'rc.ben z oy1) ani n o in-- c a rh oxyc a c jd Reference~ Emant'lp 84 F- 5-D-,chi orobenzoyU ami no 1 '.ridine-3-carboxvli acid Reference Exam-oe 06-' (2-Met hv2 -4-cn' r:cbenzcvl )amino ',vrij4 ne-3-carboxylic Reference E>:amu2.e 8E 6-f imethvlben-zoyl)amino1r,,:'rdine-"-car-bo.xvlic'7 A-i d Reference Examr~le 87 6-r(-ehc e..,,~r~~ol~r-zin---carboxylic acidj 70 Reference ExamRnre 88 6-Fr (2-Trif luoromethoxyvbenzofl) aminol Rvridine.-3carboxylic acid Reference Example 89 E-t 4 -Chloro-2-methoxvbenzovl)aminolpyridine-3carboxylic acid Reference Examplen 6- T2- (Triflucromethvl)benzoil aminclpyridine-3carboxylic acid Reference Example 91 9~-r(2 i- A- .9 a a.

a a.

a a a. a. a Reference ExaMple 92 6-!f C--Dimethv.lbenzcy1) arrincol 2ridine-3-carboxyl ic acid PRefe.rence ExaMpLe q3 6-F(-ehlhi-e olamnl~rdn-3croyi acid Reference vzamrple 94 6- r (tri f uoromethvl) benzovl) amino I yridine- 3-carboxylic acid ReferePnce Example 6-Fr 3-Di chi orobenzcvl)amino I oridin-3-carboxyl ic acid Reference Example 96 6- r (4 -FluorcQ-2-methylbenzovi )amino 1 tvr4 dine- 3-arbczyylic Reference Zxairple 97 E-r(2. 3.%TPrichcrcbelzcvl)amincoipvridine-?-carbcxvlic Reference Examle 98 6- f (5-F1uorc-2-chlcZQobenzc,.1) arinoQ-lovridine-3-cprboxylic 30 Reference Examyle 99 E- F (2-Fl (tri-fliunormethyl )benzol) amnho I vridine- 3-carboxylic acid -71 Reference Example 100 6-F (5-Fluioro-2-methylbel~oyl) aminolipvridine-3-carbonvl chloride A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)aminolpyridifle-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thiony. chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml o-f toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.

As described for Reference Example 100, the following 6- (acyl)amino)pyri.dine-3-carbonYl chlorides are prepared.

Reference Examnl1e 101 25 30 35 6-f (3-Mlethvl-2-- thieflvlcarbonvl) aminol~ovridine-3-carbonv1 Reference Examplo 102 6-f (2-Methv1-3-thienV1icarbonv1~aminolOpyrdie3-carbonyl chloride Reference Examc1'p !03 Reference Examclne 104 Reference Exainnle 105 2~MehvlbflZO-hp chlrid Referen e Exar;c1 107 6-f (2-Chlorobenzoyl) amincl1),vridine-3-carbonvI chloride, white crystals 72 Reference ESAmole 108 6-F (2-Fluorobenzovl)amincl'vridine-3-carbonvl chloride Reforence Example 109 6-r (2-Chloro-4-fluorobenazovl) aminolovridine-3-cprbonvI chori ret Reference Examole 110 6-r (2.4-Dichlorcbenzoyl) aminoliovridine-3-carbonyl Reference Example Ill 6-F (4-Chloro-2-Fluo,-obenz,,'1 aminolo~vridine-3-carbcnyl Reference Examrole 112 6-F 4.5-Trirethcxvbenzcvl)aminolbpvridine-3-carbonvI chl cridei Reference Example 113 6- 4-r)ifll~orcbenzovl) amino~ovridine-3-carbonvlI chicride Reference Examrle 114 6- r(2-;romobenzov!) amrinol pyridine-3-carbonvI chloride Reference Example 115 6-r(2-Chloro-4-nitrobenzovfl amgino Lovrid~ne-3-carbonvl chlnride RL,'frenae Example 116 6-r (Tetnrahydrcfuranyl-2-carbonyl)aminorvridine-3carbonyl chloride .9 Reference Emam;ole 117 6-r~(Te,:rahvdrcthienv1-2-carbonvl) amino 1 ovridincarbonyl chloride Reference Examole 118 6-f (C\'clohexvlcarbonvl)arinolpvridine-3-carbonvI chicrvide Referenza 7mamnle 119 6-F (Cvz'olhem-3-enecarbonvl) aMinoloyridine- 3-car-bon I.

-73 Reference Example 120 6-fr (2-Methvlbeflzeneacetvl) amino I pridine-3-carbcanvl Reference Examole 121 6-r (2-Cc robenzefeacetyl )amiflpyridife- 3 -carbol I Refprence Examvle 122 E- .r (Cyclgipentvicarbofll) aming Ipyridine-3-carbonl chicride Reference rxample 123 6- r (Cvc ohex',lac--yl) ami novridine -carbcPnvl chloride Reference Example 124 (3-Mehv--t-hieovlacetvV) amrnirl:criine-3-carbonVI Roference Examp'le 125 6-r'(2Mehv-3-hienlpt--vl)mO1Plvr:idine-3-carbonyI Reference Example 126 clrd Reference Examip1e_127 6- (-Metv I-3--Ftranvlacetvl) ainolvridine-3-carbonvl chloride Reference Fzamp~le 128 G-f' (2Meh1!-5-flu-robenzefeacel) amino! Lvridine- 3 carbonvi chlori.de Peferen-c- Pxamnl10 129 6- r 1 -2 -trahvdirothi enlv!acer v minc-luvr- dine-3carobonvi chioride Reference Examcle 130 carbon 1 chlcride Reference Examcle 131 6- r 5- .c i:r b n ol)a i o n -a b chloride -74 Reference ExamRle 132, 6- r 5-ichlorobenzovl) aminolRvridine-3-carbonvI Reference Example 133 6-F 2Mtv--hnnpzy~aicTviie3c~ov chicridp Referen-e Exam~voe 134 3-DiMethvlbenzovl) amrino ovridine-3-cprbonvl chloride Reference ExAm~lo 135 6-F (2-Methoxvb-nrzovlaminpILvrdin-3-carbonyI chloride Reference-E'xaMple 136 E- Jr(2-Tri fluorornet-honbenzovI) ami no bo\r4dine-l-rarbonyl chloride Reference Exarn~le 137 6- (4-C:h 1 orc-2-rnethomybenzo vl) a~inclpvridine-3-carbonvl Reference Example 138 6- rF2-(Trifluorom~e- vl )benzovllarninolpyvridine-3-carbonyl clrd Reference Examrole 139 see *535 0* 6r 6-Di chi 'rc-benzovl)l anino I vridine-3-carboayvL Reference Ex'amp~le 140 F(2. 6-Di.methvlbenZovi) aminolr;',ridine-3-carbonvI Referenca Exanmlo 141 6- r(2-Me!thylthicbenzovl) arninolpvridine-3-carbonv:I ch.lnride Refer-nce rx.amlo 142 6r(4-Flucrc"-2- f lu' crrethy1)benzo%,l) amino I vrldine- 2-ca'-bonv! c~ 1 ~de Reference Examolp 143 6- 3-Dich.lorobenzoyvl amnoILoyridine-3-carbonvlI 75 Reference Exampl1e 194 (4-~Fiorc-2-TflthvlbeflZOvllaminolipvridine-3-carbony1 clo~ride Referenc- Examnle 145 6-f §-TrichiiorobenlZo%,l)aT!UfoiO%ridine-3-carbonvl R-Ference Exarmil 146 r(5-1 uc~o- 2 obenzov 1) ami no I pvridine,- 3-ca rbonvl chlo-ride Refe.rence Examiple. 141 6--r (2-luorc- ft-ifuoromnethvl)bpnflovl)ainoIlPvrid'-ne- 3-carbonv1c! od As described for Reference Example 53, the following bis acflated products (Table A) are prepared and purified by silica gel chromatography. These compounds are then hydrolysed to the acids (Table B) as described in Reference Example 53.

0

CH

3 RC R3 9**6 Ref. RI R2 R3 R4 x M .Ex 148 CH3 H H H F 388 149 CH3 H H F H 424 150 CH3 F H H H. 426 151 H OCH 3 OCH3 OCH3 I H 540 152 Ci H H H H 430 153 F H F H H 396 154 Br H H H H 520 155 C1 H F H H 412 156 Ph H H H H 512 157 C- H H Br H 474 158 CH3 HH F I Br 159] CH3 H H H I Br 468 M+ is molecular ion found from FAB mass spectrum 77 Ref.- R1 R2 R3 R4 X

M

Ex No. 160 CH3 H H H H 256 161 CH3 HH F H 274 162 CH3 F H H H 274 163 H OCH3 OCH3 OCH3 H 332 164 Cl H H H -H 276 165t F H F H H 278 166 Tr4___ H H 322 167L Cl W F H H 294 168 Ph H H -H 318 169 Cl H HBr H 3__5__5 170 CR3 Hj H H Br CH3 Br H336 M+ is molecular ion found from FAB mass spectrum.

Rei-fre Eaamp 1 172 ;;-krinc-b-rmolvrdine-' -arhoxv acid To a stirred solution of 6-aminonicotinic acid (13.8 g, 0.1 mole) in glacial acetic acid (100 ml), bromine (16 g, 5 ml, 0.1 mole) in acetic acid (20 ml) is added slowly. The reaction mixture is stirred for 8 hours at room temperature and the acetic acid is removed under reduced pressure. The yellow solid residue is dissolved in water and carefully neutralized with NH4OH. The separated solid is filtered and washed with water to give 18 g of solid; mass spectrum: 218 30 R 0a -Fe-n- 173 c-mn---rmprdn--abxl acid g, 50 mmclI) is dissolved in saturated methanolic RdI (100 ml) and refluxed for 24 hours. The solvent, 35 methanol, is re-moved under reduced pressure and the residue is dis-solved in ice cold water. The aqueous 78 solution is neutralized with 0.1 N NaOH and the solid which separates is filtered; washed well with water and air dried to yield 10 g of product as a solid: mass spectrum 231 Reference ExamPle 174 6-f(2-Methylbenzeneacetvl)aminoDpvridine-3-carboxylic acid To a cooled mixture of 5.0 g methyl 6aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropylethylamine in 40 ml of dichloromethane is added a solution of 12.2 g of 2-methylbenzeneacetyl chloride in ml of dichloromethane. The mixture is stirred under argon at room temperature overnight. The mixture is diluted with 200 ml of dichloromethane and 50 ml of water and the organic layer separated. The organic layer is washed with 50 ml each of 1 M NaHC03, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (9.0 g) is chromatographed on a silica gel column with hexane-ethyl acetate as eluent to give 8.6 g of solid. This solid, mainly methyl 6-[[bis(2-methylbenzeneacetyl)]amino]pyridine-3-carboxylate, is dissolved in 60 ml of tetrahydrofuran-methanol and 23 ml of 5 N NaOH added to the solution. The mixture is stirred at room O temperature overnight and the mixture concentrated under vacuum. Water (25 ml) is added and the mixture is stirred and acidified with cold 1 N HC1. The mixture is chilled and the solid filtered and washed with water to give 5.9 g of off-white solid.

Reference Examole 175 6-[(2-tM-ethvlbenzeneacetyl)aminolovridine-3-carbonvl chloride A mixture of 4.5 g of 6-[(2-methylbenzene- 35 acetyl)amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 1 hour and then con- 79 ;e gee•* e• centrated to dryness under vacuum. To the residue is added 20 ml of toluene and the solvent removed under vacuum. The addition and removal of toluene is repeated and the residual solid dried at room temperature under vacuum to give 5.3 g of dark brown solid.

Reference Example 176 1l.!'-Biphenvl -2-Biphenvlcarbonvl chloride A mixture of 5.6 g of [l,l'-biphenyl]-2carboxylic acid and 29 ml of thionyl chloride is heated on a steam bath for 0.5 hour and the volatiles removed under vacuum. Toluene (40 ml) is added (twice) and the solvent removed under vacuum to give 6.8 g of a yellow oil.

Reference Example 177 Methyl bis(fl.1'-biphenvll-2- L-carbonvl)1aminoloyridine-3-carboxylate To a chilled solution of 2.64 g of methyl 6aminopyridine-3-carboxylate and 5.5 ml of diisopropylethylamine in 30 ml of dichloromethane under argon is added 6.8 g of [l,1'-biphenyl]-2-carbonyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature 2 days and then diluted with 120 ml of dichloromethane and 50 ml of water. The organic layer is separated, washed with 50 ml each cf 1 M NaHC03 and brine and dried (Na2S04). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give a solid. Crystallization from ethyl acetate gives 6.2 g of white crystals, m.p. 180-188 0

C.

30 Reference Examnle 178 r (rl. 1'-biDhenv 1-2-vlcarbonvl) aminolpyridine-3carbcyvlic acid To a chilled (0 0 C) mixture of 6.0 g of methyl 6-[[bis[(1,l'-biphenyl]-2-ylcarbonyl)]amino]pyridine-3- 35 carboxylate in 40 ml of methanol and 30 ml of tetrahydrofuran is added slowly 18 ml of 2 N NaOH. The 80 *i mixture is stirred at room temperature overnight and brought to pH 5 with glacial acetic acid. The mixture is concentrated, acidified to pH 2-3 with 1 N HC1 and extracted with 250 ml of ethyl acetate. The extract is washed with 50 ml of brine, dried (Na2SO4) and the solvent removed under vacuum. The residual white solid is triturated with 15 ml of ethyl acetate to give 3.35 g of white crystals, m.p. 215-217 0

C.

Reference Example 179 6-fl.l'-biohen!v1-2-vlcarbonyl)aminopovridine-3-carbonyv chloride A mixture of 1.9 g of 6-[([1,1'-biphenyl]-2ylcarbonyl)amino]pyridine-3-carboxylic acid and 9 ml of thionyl chloride is refluxed for 1 hour and then concentrated to dryness under vacuum. Toluene (15 ml) is added (twice) to the residue and the solvent removed under vacuum to give 2.1 g of a light brown oil.

Reference Example 180 6- (Cvclohexvlcarbonvl)aminolyvridine-3-carboxylic acid To a chilled solution of 5.0 g of methyl 6-aminopyridine-3-carboxylate and 12.6 ml of diisopropylethylamine in 50 ml of dichloromethane under argon is added a solution of 9.7 ml of cyclohexylcarbonyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature overnight and diluted with 200 ml of dichloromethane and 60 ml of water. The organic layer is separated, washed with 60 ml of brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 12.8 g of a solid.

The above solid (12.0 g) in a mixture of 150 ml of tetrahydrofuran-methanol is chilled (0 0

C)

and 62 ml of 2 N sodium hydroxide added. The mixture is stirred at room temperature for 3 hours, neutralized 35 with 10 ml of glacial acetic acid and concentrated under vacuum. The mixture (containing solid) is acidified to 81

C

pH 1 with 1 N HC1 and extracted with 250 ml of ethyl acetate and twice with 100 ml of ethyl acetate. The combined extract is washed with 100 ml of brine, dried (Na2SO4) and concentrated to a white solid. Trituration with hexane gives 6.5 g of product as a white solid.

Reference Example 181 Methyl-2- (4-ethoxy-oobutvl)aminclbenzoat.

A mixture of 19.2 g of methyl 2-aminobenzoate and 9.6 g of ethyl g-bromobutyrate is heated at 80-85 0

C

for 24 hours, cooled to room temperature and filtered.

The solid is washed with CH2C12 and the filtrate washed with 1NHC1, H20, INNaHCO3 and brine. The solvent is removed to give an oil. The oil is distilled and the fraction boiling at 45-75 0 C and 130-1600C were collected and discarded. The residue is the product (55.4 g of oil) Reference Example 182 Methyl 2- N-(4-ethoxy-4-oxobutvl)-N-(2methylphenvlsulfonyvlamino)benzoate A mixture of 2.65 g of methyl 2-[(4-ethoxy-4oxobutyl)amino]benzoate, 2.0 g of 2-methylphenylsulfonyl chloride and pyridine is heated on a steam bath for 16 hours. The mixture is concentrated under a vacuum (remove pyridine) and 1N HC1 added. The mixture is extracted with dichloromethane and the extract washed with INHC1, H20, 1 M NaHC03, brine and dried (Na2SO4).

The solution is filtered through a thin pad of hydrons magnesium silicate and the filtrate evaporated to give 3.8 g of solid which is crystallized from ethanol to 30 give crystals, m.p. 100-102oC.

Reference Example 183 Methyl and Ethyl 1.2-Dihydrc-5-hvdroxy-l- (4methylchenl)sulfonyl 1 -3H-l-benzazepine-4-carboxvlate To a mixture of 0.448 g of potassium ert- 35 butoride in 2 ml of tetrahydrofuran; cooled to OOC is added 0.838 g of methyl 2-[N-(4-ethoxy-4-oxobutyl)-N-(2- 82 o** *o o ftoo M- M methylphenylsulfonyl)amino]benzoate in 12 ml of tetrahydrofuran. The mixture is stirred at 0 0 C for 4 hours (under argon), poured into water and neutralized with 2N citric acid. The mixture is extracted with dichloromethane and the extract washed with H20, brine and dried (Mg S04). The extract is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness to give 0.59 g of product (a mixture of methyl and ethyl esters).

Reference Example 184 1.2.3.4-tetrahydrc-1-f 2-methylphenvl)sulfonvly-5H-1- A 30 g sample of a mixture of methyl and ethyl 1,2-dihydro-5-hydroxy-l-[(4-methylphenyl)sulfonyl]-3H-lbenzazepine-4-carboxylate in a mixture of 171 ml of concentrated hydrochloric acid and 171 ml of glacial acetic acid is refluxed 24 hours. An additional 170 ml of concentrated hydrochloric acid is added and the mixture refluxed for 24 hours. The mixture is concentrated under vacuum to near dryness, diluted with water and the solution brought to pH 8 with saturated NaHCO3. The mixture is extracted with dichloromethane and the extracted washed with H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give 12.0 g of a brown oil.

Reference Example 185 4-r(Dimethylamino)methylenel-1.2.3.4-tetrahydro-l- r2- 0* 30 A mixture of 1.89 g of 1,2,3,4-tetrahydro-l- [(2-methylphenyl)sulfonyl-5i-l-benzazepin-5-one and 2.47 ml of ter-butoxy-bis(dimethylamino)methane (Bredericks reagent) in 10 ml of dichloromethane is heated under argon on a steam bath for 16 hours. The 35 mixture is concentrated to dryness under vacuum and the residue dissolved in CH2C12. The solution is filtered 83 oooo through a thin pad of hydrous magnesium silicate and the pad washed with 5% ethyl acetate in CH2C12. The filtrate is concentrated to dryness and the residue (1.96 g) crystallized from CH 2 Cl2-hexane to give 0.85 g of crystals, m.p. 180-185 0 C. A second crop of crystals (0.85 g) is recovered from the mother liquors and an additional 0.30 g is recovered from washing the pad of hydrous magnesium silicate with ethyl acetate.

Reference ExamPle 186 4.5.6-tetrahvdr-6f (2methyvlhelnv1)su-,1fvony vrazol4,3-di 1 .benzazePine A mixture of 1.55 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-!-[(2-methylphenyl)- 0.25 ml of hydrazine and 60 ml of ethanol is refluxed on a steam bath under argon for 2 hours. After standing overnight at room temperature, the solvent is removed under vacuum. The residue is dissolved in CH2C12 and the solution washed with water, brine and dried ((Na2S04). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give 1.4 g of crystals, m.p. 76-79 0

C.

On a larger scale reaction with 18.29 g of 4- [(dimethylamino)methylene]-1,2,3,4-tetrahydro-l- (2methylphenyl)sulfonyl]-5H-i-benzazepin-5-one the product in CH2C12 is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate is concentrated to give 16.5 g of product (one spot by thin layer chromatography (silica 30 gel) with hexane-ethyl acetate Reference Examle 187 1.4.5. r e-TetrahydrCVrjzo 4 -dl benzazein SA mixture of 1.0 g of 1,4,5,6-tetrahydro-6- [(2-methylphenyl)sulfonyl]pyrazolo[4,3-)[ 1]benzazepine in 60 ml of 40% (V/v)H2S04 in glacial acetic acid is heated at 60 0 C for 12 hours or until the tosyl group is 84 removed. The mixture is poured into 100 ml ice and water with cooling. Solid NaOH is added portionwise (temperature kept below 30 0 C) with efficient stirring and the pH brought to 8. The mixture is extracted with ethyl acetate and the extract dried (Na2S04) and the solvent removed to give a solid.

Reference Example 188 10.11-Dihvdrobenzfb.flf !l41oxazepine To a slurry of 7.35 g of lithium aluminum hydride 100 ml of tetrahydrofuran is added in portions 10.0 g of dibenz[b,f][1,4]oxazepin-10(l1H)-one. An additional 100 ml of tetrahydrofuran is added and the 8 mixture is refluxed for 6 hours and then stirred at room temperature overnight. To the chilled mixture is added dropwise 7.5 ml of H20, 7.5 ml of 15% NaOH and three ml portions of H20. The mixture is filtered and the filter cake washed with tetrahydrofuran and dichloromethane. The filtrate is concentrated to dryness under vacuum to give 10.1 g of solid. The solid is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter cake is washed with dichloromethane and the filtrate concentrated to dryness to give 8.9 g of solid. Crystallization from dichloromethane-hexane gives 7.5 g crystals, m.p. 69- O 71oC.

Reference Example 189 Pyridof2,3-bl l.41benzoxazepin-6(5H)-one A mixture of 21.4 g of phenyl salicylate, 30 25.71 g 3-amino-2-chloropyridine and 20 ml of 1,2,4trichlorobenzene is refluxed for 1 hour under argon and the liberated phenol and HC1 simultaneously distilled (from the refluxing mixture) and collected in a solution of IN NaOH. The hot mixture is poured into 200 ml of 35 ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried.

85 «e *o *oo Recrystallization from methanol DMF gives 6.0 g of product, m.p. 268-270 0

C.

Reference Example 190 5.6-Dihvdropyrido[2.3-b[1l.41benzoxazepine A mixture of 2.8 g of pyrido[2,3-b][1,4] 10 ml of tetrahydrofuran and 3 ml of 10M borane-dimethylsulfide in tetrahydrofuran is stirred at room temperature overnight and then refluxed for 3 hours. To the mixture is added dropwise under argon, 5 ml of methanol. The solvent is removed under vacuum and methanol added. The solvent is removed under vacuum and 12 ml of 2V NaOH added to the residue. The mixture is refluxed for 2 hours and extracted with ethyl acetate. The extract is washed with 2. citric acid, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue is chromatographed on a column x 18") of silica gel (320 g) with hexane-ethyl acetate as solvent to give 0.78 g of crystals, m.p. 172-174 0

C.

Reference Example 191 N-(2-Hydrox::vhenv1) -2-chlcrc-3-cvridinecarboxamide As described in 1. Med. Chem., 27, 519 (1994), a solution of 1.09 g of 2-aminophencl in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g of 2-chloropyridine-3carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed 30 for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallizaticn from 2-propancl gives crystals, m.p. 145-146oC.

86 eo a.

a Reference Examole 192 Pyridof2.3-blr,.51benzoxazepin-5(6H)one A mixture of 13.0 g of h-(2-hydroxyphenyl)-2chloro-3-pyridinecarboxamide and 2.82 g of sodium methoxide in 100 ml of N, N-dimethylformamide is refluxed under argon for 3 hours. Sodium methoxide (0.50 g) is added and the mixture refluxed 2 hours and then stirred at room temperature for 2 days. The solvent is removed under high vacuum and the red-brown residue triturated with cold methanol. The mixture is filtered and the solid washed with chilled methanol to give 5.0 g of white solid, m.p. 250-253 0

C.

Reference Example 193 5.6-Dihvdroovrido 2.3-bl1 To a stirred slurry of 0.886 g of lithium aluminum hydride in 20 ml of tetrahydrofuran is added 1.65 g of pyrido[2,3-b][1,5] benzoxazepin-5(6H)-one in portions. The mixture is diluted with 30 ml of tetrahydrofuran and refluxed under argon for 18 hours.

To the mixture is added 1 ml of water, 1 ml of 15% NaOH and three one-ml portions of H20 and the mixture is filtered. The solid is extracted with dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness to give crystals, m.p. 125-129 0

C.

O Reference Examole 194 9. !1-Dihdrc-4H-thienof2.3-cl r benzazeoine To a solution of 9.0 g at 4,5-dihydro-4,4dimethyl-2-(2-thienyl)oxazole in 200 ml of 30 tetrahydrofuran, cooled to -78 0 C, is added 20 ml of a 2.5 molar solution of n-butyl lithium in hexane. The mixture is stirred -78 0 C for 15 minutes and at OOC for 30 minutes. To the stirred solution is added 6.0 g of 2-methylbenzoxazepine-4-one. The mixture is stirred at 35 room temperature for 16 hours quenched with ice cold water and extracted with chloroform. The extract is 87 concentrated to dryness and 100 ml of 40% H2S04 is added. The mixture is refluxed for 4 hours, cooled to room temperature and filtered to give 9,10-dihydro-4,10dioxo-4H-thieno [1]benzazepine. The solid is washed with water to give 2.5 g of crystals. The solid is dissolved in 100 ml of dry tetrahydrofuran and 1.0 g of lithium aluminum hydride added. The mixture is refluxed for 16 hours, chilled and ice cold water is added dropwise. The mixture after dilution with water is extracted with chloroform-methanol and the extract dried (MgSO4). The solvent is removed and the O residue chromatographed over silica gel with ethyl acetate-hexane as solvent to give 1.8 g of solid; Mass spectrum 202 (M H).

Reeferenc Eample 195 Methyl 4-f (!r.,'-ipheny11-2-carboonvl)aminol- 3 methovvbenzoate A mixture of 10.0 g of [l,1'-biphenyll-2carboxylic acid in 75 ml of methylene chloride and 12.52 g of oxalyl chloride is stirred at room temperature for hours. The volatiles are evaporated in yac= to give 11.06 g of an oil. A 2.16 g portion of the above oil in ml of methylene chloride is reacted with 1.81 g of 0 25 methyl 4-amino-3-methoxybenzoate and 1.30 g of N,Ndiisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 3.20 g of the desired product as a crystalline solid, m.p. 115-1170C.

88 Reference Example 196 Methyl 4-f l. '-Biphenvll-2-carbonvl)amino-2chlorobenzoate A solution of 2.37 g of [1,1'-biphenyl]-2carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4 -amino-2-chlorobenzoate and 1.49 g of N,Ndiisopropylethylamine in 50 ml of methylene chloride.

The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHC03 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 1.1 g of the desired product as a crystalline solid, m.p. 132-134 0

C.

M+H=365 Reference Example 197 4-1rl..'-Biphenyll-2-carbonyl)aminol- 2 -chlorobenzoic

A

A mixture of 3.0 g of methyl biphenyl]-2-carbonyl)amino]-2-chlorobenzoate in 75 ml of absolute ethanol and 2.0 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in at 80 0 C to give 0.1 g of the desired product as a crystalline solid, m.p. 217-219 0

C

Reference Example 198 4-1( l f '-Biohenvl1- 2 -carbonvl)-aminol-3-methoxvbenzovl Chloridp A solution of 2.69 g of 4 -[([l,l'-biphenyl]-2carbonyl]amino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour 89 oo under Argon. The volatiles are removed in vacuo to give a residue which is stirred with hexane to give 2.58 g of crystalline solid, m.p. 121-123°C. M+=361.

Reference Example 199 Methyl 4- 1 -ipohenyl P-2-carbcnyl) amino 1benzoate A mixture of 10.0 g of [1,l'-biphenyl]-2carboxylic acid in 75 ml of methylene chloride and 12.52 g of oxalyl chloride is stirred at room temperature for 18 hours. The volatiles are evaporated in vacuo to give 11.66 g of an oil. A 7.5 g portion of the above oil in O 25 ml of methylene chloride is added dropwise to a solution of 4.53 g of methyl-4-aminobenzoate and 4.3 g of N,N-diisopropylethylamine in 100 ml of methylene chloride at 0°C. The reaction mixture is stirred at room temperature for 18 hours and washed with water, and saturated aqueous NaHC03 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 8.38 g of the desired product as a crystalline solid, m.p. 163-1650C.

Reference Example 200 4-r f(!.,1'-Biiphenvl-2-carbonvl)aminolbenzcic Acid A 3.15 g sample of methyl 4-[([1,1'-biphenyl]- 2-carbonyl)amino]benzoate is refluxed for 8 hours in 100 ml of ethyl alcohol and 2.5 ml of 10N sodium hydroxide.

The cooled reaction mixture is acidified with acid]) and the desired product collected and dried to give 2.9 30 g of the desired product as a solid m.p. 246-2490C.

M+H=318.

Reference Example 201 4-f (rl 1' -iDhenvl -2-arbonvl)amino benzovl Chloride A mixture of 1.39 g of 4- ([1,1'-biphenyl)-2- .carbonyl)amino]benzoic acid in 2.0 ml of thionyl 90 oo chloride is heated on a steam bath for 1 hour. Cold hexane is added and the crystalline solid collected and dried to give 1.34 g of the desired product, m.p. 118- 120 0

C.

Reference Example 202 2-(Phenvlmethvl)benzovl Chloride A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.74 g of the desired product as an oil. M+=227 as methyl ester.

Reference Example 203 Methyl 4-rr2-(Phenvlmethvl)benzovllaminolbenzoate To 3.03 g of methyl 4-aminobenzoate and 3.12 g of N,N-diisopropylethylamine in 75 ml of methylene chloride is added 5.54 g of 2-(phenylmethyl)benzoyl chloride and the reactants stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138-139 0

C.

Reference Example 204 Sodium 4-r 2-(Phenvlmethyl)benzovllaminolbenzoate A mixture of 4.90 g of methyl 30 (phenylmethyl)benzoyl]amino]benzoate in 100 ml of absolute ethanol and 3.50 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. The aqueous phase is filtered and the resulting solid collected and dried give 4.25 g of the desired product m.p. 340-346 0

C.

91- N M Reference Example 205 4-f 2-(Phenv1methyvlbenzov11aminolbenzcic Acid A mixture of 4.0 g sodium (phenylmethyl)benzoyl]amino]benzoate is suspended in water and the pH adjusted to 5 with acetic acid. The solid is collected by filtration and dried at 80 0 C in vacuo to give 3.75 g of the desired product, 246-2470C.

M'=332.

Reference Example 206 O) 4-f 2- (Phenylmethyl) benzoYv1 ]airlbenzoy! Chloride A mixture of 2.0 g of (phenylmethyl)benzoyl]amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour.

The volatiles are evaporated in vacuo to give 1.53 g of the desired product as an oil. M+=346 as methyl ester.

Reference Example 207 Methyl 4-r (2-Phenvlmethyl)benzovl1aminol-2-chlorobenzoate A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of methyl 4-amino-2-chlorobenzoate and 1.65 g of N,Ndiisopropylethylamine by stirring at room temperature 30 for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-1350C. M+=380.

92 Reference Example 208 Methyl 4-fr(2-Phenvlmethyl)benzovllaminol-3methoxybenzoate A solution of 2.85 g of 2- (phenylmethyl)benzoyl chloride in 25 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-3-methoxybenzoate and 1.61 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHC03 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 2.2 g of the desired product as a crystalline solid, m.p. 129-1310C. M+=376.

Reference Example 209 2-Chloro-4-r (2-Phenvlmethyl)benzovlaminolbenzoic Acid A mixture of 2.8 g of methyl 2-chloro-4-[[(2phenylmethyl)benzoyl]aminobenzoate in 75 ml of absolute ethanol and 1.84 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride.

The aqueous phase is acidified with acetic acid and the O resulting solid collected and dried in vacuo at 80°C to give 2.6 g of the desired product as a crystalline solid, m.p. 184-187 0 C. M

H

366.

30 Reference Example 210 3-Methovy-4-r r (2-phenvymethvy)benzovl1aminolbenzeic Acid A mixture of 2.05 g of methyl phenylmethyl)benzoyl]amino]-3-methoxybenzoate in 75 ml of absolute ethanol and 1.4 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene 93 9 chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vaclu at 80 0 C to give 1.87 g of the desired product as a crystalline solid, m.p. 176-1780C. M+H=362.

Reference Example 211 3-Methox-4-F'(2-ohenvlmethl)benzovllaminolbenzovI Chloride A mixture of 1.71 g of 3-methoxy-4-[[(2phenylmethyl)benzoyllamino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 1.7. g of the desired product as a crystalline solid, m.p. 130-135 0 C. M+=376 as the methyl ester.

Reference ExamDle 212 14'-(Trifluoromethl)-1,1'-biphenv1l-2-carbonvl Chloride A mixture of 5.0 g of 4'- (trifluoromethyl)[1,1l'-biphenyl]-2-carboxylic acid in ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 5.36 g of the desired product as a colorless oil. MI=280 as methyl ester.

Reference Example 213 Methyl 4-rUf4'-(triflucrmethvhyl)FlA!'biohenv 1 carbonyl) aminolbenzoate A solution of 3.13 g of (trifluoromethyl)[1,1'-biphenyll-2-carbonyl chloride in ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-aminobenzoate and 1.43 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, -94a V saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 3.36 g of the desired product as a crystalline solid, m.p. 164-165 0 C. MI=396.

Reference Exampl- 214 3-Moy~ov-4-Tr (ruoromethy1) l'-bpheny''-2carhony!)aminolbenzoyl Chloride A mixture of 2.0 g of 3-methoxy-4-[([4'- (trifluoromethyl) [1,1'-biphenyl]-2carbonyl)amino]benzoic acid in 20 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 1.92 g of the desired product as a crystalline solid, m.p. 136-138 0

C.

Reference Example 215 3-Mo-hov-4 fA' -t ri uoromethy1 V1. 1 -biheny' -2carbonyl)aminolbenzoic Acid A mixture of 3.78 g of methyl 3-methoxy-4- [([4'-trifluoromethyl) [(1,1'-biphenyl]-2carbonyl)amino]benzoate in 75 ml of absolute ethanol and 2.20 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80 0 C to give 3.49 g of the desired product as a crystalline solid, m.p.

30 213-215 0

C.

Rpferp xampla 216 M-1-hy1 3-Math--y-&-r fliinromc3,thyl) n biphenvyll-?-carbonyl)aminlbanzoate A solution of 3.56 g of (trifluoromethyl) [1,1'-biphenyll-2-carbonyl chloride in 95 ml of methylene chloride is added dropwise to an ice cold solution of 1.81 g of methyl 4-amino-3methoxybenzoate and 1.62 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 3.9 g of the desired product as a crystalline solid, m.p. 112-113 0

C.

Reference Example 217 O 2-Chlorc-4-r (triflucromethv1) r. 1 '-biPhenvy1-2carbonyl)aminolbenzov Chloride A mixture of 1.39 g of 2-chloro-4-[((4'- (trifluoromethyl) [1,1'-biphenyl]-2carbonyl)amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The reaction mixture is concentrated to a residue in vacuo to a residue. Cold hexane is added to the residue and the solid collected and dried to give 1.39 g of the desired product.

Reference Example 218 O 25 2-fChoro-4-f (4'-(trifluoromethvl) Il.1'-biphenvyl-2carbonvylaminolbenzoic acid A mixture of 3.83 g of methyl 2-chloro-4- ([4'-(trifluoromethyl) [1,1'-biphenyl]-2carbonyl)amino]benzoate in 75 ml of absolute ethanol and 30 2.20 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried Ji vacuc at 80 0 C to give 3.42 g of the desired product as a crystalline solid, m.p.

187-189 0

C.

96 00o0 0 Reference Example 219 Methyl1 2-Chlorg-4-f (f4'-QtriflU~romethVl) tl-l'biphenvll-2-crbOnvl)arinolbenzoate A solution of 3.56 g of (triflUoromethYl) [1,1 '-biphenyl3-2-carboflYl chloride in ml of methylenle chloride is added dropwise to an ice cold solution of 1.86 g of methyl 2-chloro-4aminobenzoate and 1.6 g of N,N-diisopropylethYlamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried (Na2SO4) The organic layer is passed through a pad of hydrous magnesium silicate(3X) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132 0

C.

Reference Example- 22 4 -r(r4'-(TrifluoromethyI)f1.I'bip~henyllcarbonvl) aminolbefl~oiC Acid A mixture of 3.0 g of methyl (trifluororethYl) 1'-biphenyll- 2 carbonyl)amfifolObenzoate in 75 ml of absolute ethanol and ml of 10 N sodium hydroxide is heated on a steam 0 25 bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in va-u at 80 0 C to give 2.93 g of the desired product as a crystalline solid, m.p.

243-245'C. M'=385.

97 0 0 0 9 Reference Example 221 Methyl 6-r r 3 -(2-Methvlpyrdinv1)cpr-bonvllAmino-piin 3-carboxy late To a stirred solution of 3 g of methyl 6aminopyridine-3-carboxylate and 4 ml of N,Ndiisopropylethylamine in 100 ml of methylene chloride is added drop~wise a solution of 6.4 g of 2-methylpyridine- 3-carbonyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 2 hours and quenched with water. The organic layer is washed with water, dried(MgSO4), filtered and evaporated ,La vacuo to a residue which is stirred with ether and the resulting solid collected and air dried to give 6.8 g of the desired product. M+=390.

Reference Example 222 6- r r 3- (2-methyloyridinvl) carbonyl Iaminol pyridine-3carboxylic Acid To a solution of 6.5 g of methyl methylpyridinyl) carbonyl]aminoljpyridine-3-carboxylate in 100 ml of 1:1 tetrahydrofuran:methyl alcohol is added ml of 5N NaQH. The reaction mixture is stirred overnight and evaporated ia vacuo to a residue. The 925 residue is dissolved in water and neutralized with acetic acid. The separated solid is filtered and airdried to give 3.0 g of the desired product. M+=257.

Reference Examiple 223 too:~ Methyl 6- 1'-Biphenvll-2-carbonvl)amin.-l-o~vridin--3abxlt too. To a solution of 1.5 g of methyl 6aminopyridine-3-carboxylate in 100 ml of methylene chloride is added 3 ml of N,N-diisopropylethylamine at room temperature. To the stirred reaction mixture is slowly added a solution of 2.5 g of L[,1-biphenyl)-2carbonyl chloride. The reaction mixture is stirred at -98 0-S room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo to a solid residue. The residue is stirred with ether, filtered and dried to give 3.0 g of the desired product:M*=332.

Reference Example 224 6-r(fl. l'-Bihenyl1-2-c3rbonvl)amino1pyridine-3carboxylic Acid To a stirred solution of 2.5 g of methyl 6- [([1,1'-Biphenyl)-2-carbonyl)amino]-pyridine-3carboxylate in 50 ml of 1:1 tetrahydrofuran:methanol is 0 added 10 ml of 5N sodium hydroxide and the mixture stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in water and neutralized with acetic acid.

The separated colorless solid is'filtered and air dried to give 2.0 g of the desired product:M+=318.

Reference Example 225 Methyl 2-(2-Pvridinyl)benzoate A mixture of 12 g of methyl 2- (iodomethyl)benzoate, 20 g of n-butyl stannane and 2 g of tetrakis(triphenylphosphine)palladium are refluxed in degassed toluene for 48 hours. The reaction mixture is concentrated in yacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 5.5 g of the desired product as an oil. M'=213.

30 Reference Examole 226 2- (2-Pvridinvl benzoic Acid A mixture of 3.0 g of methyl 2-(2pyridinyl)benzoate and 600 mg of sodium hydroxide in ml of 9:1 methanol:water is refluxed for 4 hours. The 35 reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution 99 is neutralized with glacial acetic acid and the resulting product filtered, washed with water, and dried to give 2.5 g of the desired product:M+1=200.

Example 1 N-r[-(Dibenz b. f1 l,41oxazepin-10(11H)-vlcarbonyl)-2pyridinyl -5-fluoro-2-methylbenzamide To a stirred solution of 0.39 g of 10,11dihydrodibenz[b,f][1,4]-oxazepine, 1.1 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6- [(5-fluoro-2-methylbenzoyl)amino]-pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours, and diluted with 50 ml of dichloromethane and 20 ml of water. The organic layer is separated, washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate is concentrated to dryness under vacuum. The residue is chromatographed on silica gel with ethyl acetate-hexane as solvent to give a solid. Crystallization from ethyl acetate gives 0.335 g of off-white crystals, m.p.

180-186 0

C.

Example 2 N-(r5-r(9. Dihvdr.-4H-thieno2..3-c 1 benzazepin-9yl) carbonvl -2-cvridinyl 1 fluoro-2-methyvbenzanide As described for Example 1, 9,10-dihydro-4-ithieno[2,3-c] [1benzazepine in dichloromethane, in the presence of triethylamine is reacted with 2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to 30 give the product as a non-crystalline yellow solid.

100

S

o o go *o* (J.10-Dihydro-5H-thielor3. 2-cIfl Illbengzzpine-Svicarbonv I) -9--tvridinyl I-5-f luoro-2-methylbenzamide As described for Example 1, a mixture of 4,10dihydro-5H-thielo 2-c] [1 )benzazepine and triethylamine in dichioromethane is reacted with 6- [(5-fluoro-2methylbenzoyl) aminolpyridine-3-carbonyl chloride to give the product as a solid.

px'ridinv! flucrc-2-methvl benzamide As described for Example 1, 5,6-dihydropyrido[2,3-b) (lL,4]benzoxazepine is reacted in dichioromethane, in the presence of triethylamine, with (5-fluoro-2-methylbelzoyl)amiflpyridine-3-carboflYl chloride to give the product as white crystals, m.p.

187-189 0

C.

N-T.5;-(Pvridof2.3-b1 '1.5benzoxazeroin-6(5H)-vlcarbonyl)- 2-tvridinv1 -5-flujoro-2-methvlbenzamide As described for Example 1, 5,6-dihydrot2,3bi (1,.5]benzoxazepile reacted with 6- [(5-fluoro-2methylbenzoyl)amrinolOdichloromet"hane in the presence of triethylamine to give the product as a non-crystalline 25 solid.

N-!S-f .'-Dihvdcr-5F,-dibenzfb.elazein-5-v1lJcarbonll- 2-pvridiflvl 1--fluoro-2-rethvlbenzamide As described for Example 1, 6,l1-dihydro-5Hdibenz~b,elazepine is reacted In dichioromethane in the presence of -triethylamine, with 6-t(5-fluoro-2methylbenzoyl) ami-nolpyridine-3-carbonyl chloride to give the product as a solid.

-101- N-!5-r4. 5-Dihvdro-2-methvlpvrazoclo 3-di rllbenzazpin- 6 (2H) carbonv! -2-ipvridinl 1- 5- luoro-2-nethl- As described for Example 1, 2,4,5,6-tetrahydro-2-methylpyrazolo[4,3-d) [l]benzazepine is reacted in dichloromethane, in the presence of triethylamine, with (-,Fluoro-2-methylbenzoyl)aminolpyridile-3carbonyl chloride to give the product as a solid.

(E.7-Dihydiro-5H-diben-lb~dlaze~ifl-5-vl)carbcnvll- 2-nvriodinvl -5-fluorc-2-mrethvlbenzamide As describe for Example 1, 6,7-dihydro-5Hdibenz~b,djazecine is reaction in dichloromethane in the p~resence of triethylamine, with 6-1(5-fluoro-2-methylbenzoyl)amninolpyriLdine-3-carbonyl chloride to give the product as a solid.

(4.5-Dihvdrc-EH-thiencr3.2-d1 rllbenzazenin-_6vl) a b n i -l l c o- -e h l e z m d As described for Example 1, 4,5-dihydro-61Pthieno[3,2-d] [1jbenzazepine is reacted in dichioromethane, in the presence c' triethylamine, with 6- [(5-flucro-2-methylbeflzoyl)aminolpyridifle-3-carbonYI chloride to give the product as a solid.

N-r5-1 10-Dihydroc.4!9-thienor3, 2-c! f21benzazerin-4vl) carbonyl I J, rdinl1 -5-f iucrO 2TethV, ben zamide As described for Example 1, 5, 10-di4hydro-4fithieno[13,2--i [2]benzazepine in dichloromethane in the presence of triethylanine is reacrted with 96-[(5r-fluoro- 2-methy,,lbenzoyl) aminolpyridine-3-carbonYl; chloride to give the product as a solid.

102 Example 11 N-15f(4.5-ihvdrovrazolof4.3-dl1r11benzazegin-6(1H)v1)carbonv11-2-ovridinvl1-5-fluor-2-methy1benzamide To a solution of 0.20 mol of 1,4,5,6tetrahydropyrazolo[l4, 3 [llbenzazepine, 0.80 mol of triethylamine is added 0.42 mol of 6-[(5-fluoro-2methylbenzoyl)amino]pyridine-3-carbonyl chloride in ml of dichloromethane. The mixture is stirred under argon for 16 hours and diluted with dichloromethane (25 ml). The mixture is washed with H20), 1MNaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue in methanol-tetrahydrofurane(1:l) stirred with 1NNaOH for 5 hours. The mixture is neutralized with acetic acid and the solvent removed. To the residue is added H20 and the mixture extracted with ethyl acetate. The extract is washed with H20, 1NHC1, 1MNaHCC3 and dried (Na2SO4). The solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.

ExamRle 12 N-f5r(6,11 2-pyridinvl l r 1.1'-ihenv1 -2-carboxamide To a chilled (OOC) solution of 0.293 g of 6,11-dihydro-5-dibenz[b,e]azepine and 625 mL triethylamine in 3.5 ml of dichloromethane is added a solution of 0.657 g of 6-[([1,1'-biphenyll-2-ylcarbonyl)amino]- 3 pyridinecarbonyl chloride in 1.5 ml of dichloromethane.

The mixture is stirred under argon at room temperature for 16 hours and diluted with 40 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate con- 35 centrated to dryness under vacuum. The residual solid is chromatographed on silica gel with ethyl acetate- -103hexane(l:l) as solvent to give the product as a glass.

Crystallization from ethyl acetate gives 0.395 g of white crystals, rn.p. 134-142 0

C.

N-fr--fr 4. S-D,'hvdro.-2-methyloyrazo Ior 4.3-dl rFllben zazer7P-Dn 6(2H)-yl)carbonv1l-2-ipyridinvl r!i-biphenvil-? carbox.amide As described for Example 12,2,4,5,6tetrahydro-2-methylpyrazolo[4, 3-dJ tljbenzazepine is reacted with 6-[(-l41'biphenyl]-2-ylcarbonyl)amino]-3pyridinecarbonyl chloride to give the product as a solid.Examcle 14 2-tvrdinv1' r 1 1'-biphenv391-2-carboxamide As described for Example 12, 6,7-dihydro-5Hdibenz[b,d'lazepine is reacted with ([1,l'-biphenylj- 2-ylcarbonyl) amino) -3-pyridinecarbonyl chloride to give the product as a solid.

Examnle N-rS-[ (4,5-'ihvdr:o-6?i-thienor3,2-d1 rllbenzazepin-6vl) carbcnvl 1 -2-pyridinyl If!, I-tinhenvlI'I-2-carboxanide As described for Example 12, 4,5-dihydro-6Hthieno[3,2-d] jl~benzazepiJne is reacted with biphenyl]1-2-ylcarbonyl)aminol-3-pyridi;4necarbonyI chloride to give the product as a solid.

Examnle 14 1ODihdrc-4-~-b~inor.2-l 2lbenzazepin-4yl) carbonvl 1-2-pyridin'v11. 1'-bi~henv1 'I-2-carboxamide As described for Example 12, 5,10-dihydro-4Hthienc[3,2-c] k'2]benzazepi-ne is reacted with -iphenylJ-2-yl-carbny.) amino]-3-pyrid-inecarbonyl chloride togive the product as a solid.

104 10-Dihydro-4H-thielof 2 3 -CI ril-benzazfepin-9vl)carbonv11-2-ipvridinyll1ri. 1'-biphenvl1-2-Carbnyarnide As described for Example 12, 9,10-dihydro-4Hthieno[2,3-.I][l]benzazepine is reacted with biphenyl] -2-ylcarbony-) amino I-3-pyridinecarbonyl chloride to give the product as a solid.

10-Dihvdr-~-5iH-thieflor3.

2 -c 1 v1~carbornv11-2-Dvr~dilil r. i'izhenvll1-2-carb~oxamide As described for Example 12, 4,1O-dihydro-5jithieno[3,2-cj [l]benzazepine is reacted with bip~henyl) -2-ylcarbonyl) amino] -3-pyr-idinecarbolyl chloride to give the product as a solid.

Example 19 v1~carbcm-vl-2-vridinlll I..1 -bipheflvll-2-carboxamfide As described for Example 11, 1,4,5,6tetrahydropyrazolo[ 4 3 -I (l~benzazepine is reacted with (El, 1tbiphenyl3-2-ycarboflyl)ainfo-3-pyridinecarbonyl chloride to give the product as a solid.

11-Dihvdrc-SH-o~vridor2. 3-b1 r.51benzodiazeJin7 c-arbonyl -2-c~yridinvly1 2-mnethylIfurafe-3-carboxamide To a cooled (0 0 C) solution of 0.296 g ofIL 6,11dihydro-5.w-pryrido[2,3-b] (1,5lbenzodiazepile and 624 mL of triethylamine in 3 ml] of dichloromethane i4s added a solution of 6-t (2-methyl-3-furanY'Lcarbonyl)amino>- 3 pyridinecarbonYl chloride in 4 ml of dichloronethale.

The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaHICO3 and the mixture extracted with ethyl acetate. The extract is washed with H20, 1M NaHCO3 brine and dried (Na2SO4) The solvent is removed under 35 vacuum and the residue chroinatographed on silica gel 105 with ethyl acetate-hexane as solvent to give the product as a solid.

methylfurane-1-carboxanide As described for Example 20, 5,6-dihydrophenanthridine is reacted with 6- [(2-methyl-3-furanylcarbonyl)aminol- 3-pyrz..c-inecarbonyl chloride to give the product as a solid.

Examcle 22 Dhd2!O-~ezbe rl.41dizpipn-10vl)carbonv1 1 -9-DvridinvUl-2-re'thv1,f--rane-3-carboxamide As described for Example 20, 5,71l-dihydro-101:dibenz~rb-,el W'-4]d'azer-ine is reacted with (2-methyl- 3-furanvlcarbony!-ami: no)-3-pyri-dinecarbonyl chloride to give the product as a solid.

Ezamoip 23 N-[5-r(5.11-Dihvdro-10H-dibenzrb~e1 r1.4!dipzep2in-10yl)carbonvl'-2-orirdinv ll rl.1 '-biohenvll-2-carboxanide As described for example 12, 5,11-dihydro-10jidibenzr~b,e)[1,4]diazepine is reacted with biphenyl-27-ylc-arbonyl) amino) -3-pyri-dinecarbonyl chloride to give the product as a solid.

Examale 24 5 (4 Biox-y) ben zov I- 6. 11'- ih-ydr, d~benz Fb.el azer-ine To a solution of 6,11-dih-,ydro-5li-dihydro-5Hdibenz[t,e]azepine (0.12 g, 0.6 mmol) in methylene chloride (2 ml1) is added triethylamine (0.12 g, 1.2 mmolj, -followed by 4-butoxybenzoy'L chloride (0.15 g, 0.72 mmol) The resulting mixture is s'tirred at room temperature for 2 hours, and then treated with 4 ml of IN NaOH. The mixture is extracted with ethyl acetate an th etract is washed with IN sodium hydroxide and brine (5 ml), dried over anhydrous sodium sulfate, and filtered through hydrous magnesium -106silicate. The fitrate is evaporated, arnd the crude material is triturated with isoctane to give 0.24 g of white solid; Mass spectrum 372(MH+) F~xamle lo-cr.1',Biphenv1ll--ylcarbonyl)-.1'-dihvdro-l10Fd~ben,7o-fb.ep 141diaie]2inpe To a cooled (0 0 C) solution of 0.5 g of 5,11dihydrc-10O.-dibeflzo~b,e][1,4]diazePile in 50 ml of CH-2C12 and 12 ml disopropylethylamiie is added dropwise a soluti-on of 0.67 g of [.,'-biphenyl)-4carbonyl chloride in 50 ml oZE CH2Cl2. The mixture is stirred at room temperature for 16 hours. An additional S0.3 q c-f [:!,1)j-biphenyll-4-carbonyl- chloride in 30 ml of CH2Cl2 is added and the mixture stirred at room temperature 16 hours. The volatiles are removed under vacuum and the residue dissolved in 150 ml of CHCl3.

The solution is washed with 50 ml of H20, dried (Na2SO4) arid the solvent removed. The residue is chromatographed on silica gel with ethyl acetate-hexane and ethyl acetate-hexane as solvent to give 0.816 g of solid, m.p. 1,52C-154OC; Mass spectrum (),377 1.1 -B5iphenyll -4-vlc-arbonvl) -10. 11dihvdrcdibenz fb. fl 1. 4lozazepine To a cooled (0 0 C)solution of 1.0 g off 10,11dihydrodibeflz~b,fLrlj,4]oxazepile and 7 ml of triethylamine in 30, ml of CH2CI12 under argon is added dropwise 2.0 g Of [1,l'-bipherylV,4-carbonyl chloride.

The mixture is stirred at room temperature for 16 hours and d-iluted with 50 ml of CHCl3. The mixture is washed with 30 m-1 each Of H-20, 2NHC1, H20, saturated NaHCO3, and dried (Na2SO4) Solvent is removed under vacuum to give 1.6 g of a yellow solid, m.p. 930-95oC; Mass spectrum 3-78 (MH 4 -107- 9-U1l. 1 -Biihenv11-4-vlcarbonyl)-9. 10-dihvdro-4Hrhieno f2, 3-cl r1lbenzazejpin~e As described for Example 26, 9,10-dihydro-411thieno[2,3-cJ[ljbenzazepine is reacted with biphenyl]-4-carbonyl chloride to give the product as a yellow solid; Mass spectrum (CT) 381 (MT).

5-U1l. 2'-Biphenvll--4-vlcarbcnvl)-6.-7-dihvdrc-5Hdibenz Fb. dl azeo-ne As described for Example 26, 0'7-dihydro-5Hdibenz[b,d~azepine is reacted with (1,1'-biphenyl]-4carbonyl chloride to give the product as a solid.

Exarmole 29 6-(ri.i1'-io:hernv1 1 -4-vlcarbonflI5.11-dihvdro-6H- Py.-ido!2. 3-e 1 Fllbenzazepinea As described for Example 26, 5,111-dihydro-6Hpyrido[2,3-e] [1]benzazepine is reacted with biphenyll-4-carboiyl chloride to give the product as a solid.

(FL 2'-Bip~henvll-4-vlcarbonv2)-5. 6-dihydropyridor2, 3bIF!.41benzfothiazeiojne As described for Example 26, 5,6dihydropyri.do[2,3-b] [1,4]jbenzozh. ,iazepine is reacted with [1.1-biphenyl]-4-carbonyl chloride to give the product as a solid.

Example 3l K. 2 '-rhenyl 1 -4-vicarbonvl)-20. 11- ~dihydr b, f 1 4 rlt!biqzepine As described for Example 26, 10,11dihydro[b,f] [1,43-tb-hiazep~ine is reacted with bipenll--crbovlchloride to giv the product as a V: solid.

9. 108 (4-BpriZovlbeflzoyl) -10.11dihvdrodibenz fb. flr 1.41 oxazepine As described for Example 26, 10,11dihydrodibenz~b,fM[1,4oxazepile is reacted with 4- (benzoyl)beizoy chloride to give the product as an offwhite, m.p. 1030 106 0 C; Mass spectrum 406 (MHt).

(4-BenZoylbenzoy1 5. 6. 11. 12te, rahydrodibenz rb. fiazocine As described for Example 26, 5,6,11,12tetrahydrodibenz~b,flazocile is reacted with 4- (benzoyl)beflzoyl chloride to give the product as a solid, m.p. 890-920oO, Mass spectrum 418('fl-) Eape3 10-f4-(Benzovlbenzoy')-10.11-dhvdjrorb~fl '1.Hlthiazepine As described for Example 26, 10,11dihydrofb,f] [l,4]thiazepine is reacted with 4-(benzoyl chloride to give the product as a solid.

Faoe3 5-r4- (Benzc'ylbenazovlI-5. 6-dihvdrcovyridoF2. .3b 1 r .411bnzothiazeuine As described for Example 26, 5,6dihydropyri-dof2, 3-b] [1,4jjbenzothiazepifle is reacted with 4-(benzoyl)benzoy. chloride to give the product as a solid.

EXamv1--36 6- r(4-Benzcvlbenz0V1l 15. 11-dihydro- 6H-rovridof2. 3-el-llenzazepine As described for Example 26, 5,11-dihydro-6jipyrido[2,3-.] [l1benzazepile is reacted with 4a. (benzoyl)beflzoyl chloride to give the product as a solid.

a~a -109- 5-r(4-Benzovlbenzovl) 13-6. dibenz rb. dlaz--yine As described for Example 26, 6,7-dihydro-5jidibenz(b,dlazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.

q- (4-Benzovlbenzcvl) 1-9k 10-dihvdro-4Hthienor2. 3-c' r11benzaze~iinP_ As described for Example 26, 9,10-dihydro-4iithieno[L2, 3-c] '1ibenzazepine is reacted with 4- (benzoyl)benzoyl chloride to give the product as a solid.

Exam;ple 'IQ 5- (4-Benzovibenzoy1il-4.10-dihvdrc-5H-thienorj._2ci 'Abenzazenine As described for Example 26, thieno[3, 2-c] ~1]benzazepine is reacted with 4- (benzoyl')benzoyl chloride to give the product as a solid.

Ex'amzole -Bionhnv-'l-4-ylcarbonpjy)-4. thieno f3,2-cl r1lbenzazepinea As described fo Example 26, 4,l0-diJhydro-5H- 25 thienol,.3,2-c] (1]'lbenzazepine is reacted with 11biphenyll-4-carbonyl chloride to give the product as a sclid.

Exanole 41 l.'-Bihenvl-4-vcaronvi-1.4,5.6tetrahvdrcpyrazoplcr4.3-cE 'libenzazepine As described fcr Example 26, 2 mniol of 1,4,5, 6-tetrahydropyrazolo[4,3-d] '..3Ibenzazepine is reacted with 5 mmol of [(,1'-bipheny1]-4-carbonyl chloride. The product is stirred in methanol with 2N *35 NaOH ffcr 16 hours and the mixture concentrated and extracted with ethylI acetate. The extract is washed .i -110 with 1 M citric acid, NaHCO3, H20, dried (Na2SQ4) and the solvent removed to give the product of the example as a solid.

Exmple 42 Nr4-, 1bn~ei-(Hv,')abonvl-3-hlrohflyll rl '-biheriv11-2- Carboxamidie As described for Example 11, 6-(2-chloro-4- 6-tetrahydropyrazolo(4,3d](l)benzazepile is reacted with [l,1'-biphenyl]-4carbonyl chloride to give the product as a solid.

E'camplIP 43 0 NftA f ydrcpyraznoor4A'-di r, lbanzaein-- yl1---h' c.~1rnphernyl (din~yl nno)sridnrcarboamidp As described for Example 11, 6-(2-chloro-4aminobenzoyl)-l, 4 5 6-tetrahydropyrazolo24,3d)benzazepile is reacted with 2- (dimethlamino)pyridiie- 3-carbonyl chloride to give the product of the example as a solid.

N-f4 S '-jhdrya-n ,id 1 bnzazeir'-6(1 4 y 1 ca'-hcnvl 1 1pnyl1-2-fdimethylailO~Oyridifl-- 3 rahxmidp As described for Example 1-1, aminobenzoyl)-1, 4 6-tetrahydropyrazolo-[4, 3d~benzazepine is reacted with 2-(dimethylaminopyridile- 3-carbonyl chloride to give the product as a solid.

__rha_-z y' I-~~dPl To a cooled (OOC) and stirred solution of 0.246 g of 5,6,l',12-te-trahydrodibenz~b,f'jazocine 695 mL of triethylanuine in 5 ml of dichloromethane is added 0.586 g of 6-[(5--fluoro-2-methylbelzoyl)anfopyridine- 3 *:carbonyl chloride. The mixture is stirred 16 hours under argon, diluted with 50 ml of dichioromethane and ml of water, and the organic layer separated. The organic layer is washed with 20 ml each of NaHCO3, brine and dried (Na2SO4) The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue (450 mg) is chromatographed on silica gel preparative plates to give a solid. Crystallization from ethyl acetate gives C.20 g of white crystals, m.p. 1980 200 0

C.

Exarno1p 46 N-r4-(Dibenzyfb.f1 Fi,L1oazein-i0(11H'-vlcarbonvl)p~henvl 1 rI. I'-bithenvl)-2-carboxamide To a mixture of 0.197 g of 10,11dihydrodibenzlb,fl..-4)oxazepine and 0.402 g of 4- 1'-biphenyljl-2-car-bony'l)aminolbenzoyl chloride in ml of dichloromethane (cooled in ice bath) is added dropwise 0.154 g of N,N-diisopropylethylamine in 2 ml of dichioromethane. The mixture is stirred at room temperature under argon for 2 hours. The mixture is poured into water and the organic layer separated. The organic extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4) The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concerntrated to dryness to give 0.65 g of solid. The solid is purified by thick layer chromatography on silica gel with hexane-ethyl acetate as solvent to **:give 0.110 g of a glass, m.p. 107o-l-22oC. Anal.

Found: C, 80.8; H, 4.9; Examrzle 47 N-r4-(Dibe-,,nzrb.fl r.41oxazetin-10(1H-ylcarbonvl)- 3 chloro-,;henl 1binhenv11'-2-carbcxamide A mixture of 0.263 g of 10,11-dihydro-10(4amino-2-chlorobenzoyl)dibenz~b, 4loxazepine, 0.195 g of [l,il-bipheny)-2-carbonyl chloride and 0.116 g of ,V--dii4sopropylethylamine in 7 ml of dichloromethane is -112 stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane.

The extract is washed with 21 Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate (pad washed with dichloromethane). The filtrate is concentrated to dryness to give a yellow solid. The solid is purified by chromatography on thick layer silica gel plates with hexane-ethyl acetate as solvent to give 0.12 g of 113 *o a yellow glass, m.p. 145 0 C-18SOC: Anal.found: C, 73.6; H, 4.6; N,5.0; Cl, 6.4.

E'imp~p 48 rl.41oxaz7epin-1o(M!-flvlcarbonvf -2pyridiny''-5-fluorg-2-methlbe'zamide As described for Example 46, 10,11dihydrodibenz[b,f](l,4)oxazepine is reacted in dichloromethane with 2- fluorobenzoyl) amino) -5-pyridinylcarbonyl chloride in the presence of" N,N-dii'-sopropylethylamine to give the product as crystals. m.p. 180 0 C-186 0

C.

As described for Example 46 the following compounds can be prepared.

N-r4-(Dibenzfb. rl.4loxazepin-lOflH)-ylcarhonyblpevy1 (2-1vri diny' bh'izamide Example pheny 1 '2 (I-pviiv' )h ny bzaide Examplp 52 N-r4-DibnFb.f1 fli4lox.azei'-'Q(1i')-vlcarbonyl)chlorcpheny,1'-2- (2-t'hieniv1) benzamTidie :ExamI2lA 53 N-4- r1n~b-I~f.41oxa-zepirn-!'e( 1 1H)-ylcarbony1,)-3c -i1 nr 1on y h i P n 1 bez am ide As described for Example 48 the following compounds can be prepared.

114- (Dibenz rrb.f I r I. 4oxazepin-1 0(11H)-vlIcarbonl1) -2pvridinvll -2-chloro-S-fluorobenzamide N-f5-(Dib2enzrb.fl fi4loxazepin-10(11H)-vlcarhonvl)-2pvridin vl -eh2-netlbenzamiezm rl41oxazerii-10(11H)-\'1carbonv1)-2- ~vRygdinv1 1 -2-Mh lxbenzamid2 rL.41oxazelpin-10(11rn-vlcarbonv1)-2pridiivi -2-hlodimethvridinvicenarnaide N-r5-(Dibenzfrb.f' fl.41oxazevin-10(i1H)-vlcarbonyl)-2- -2v- ciethlaminydox -3-zvide~abxmd fl.4lxazepin-10(11H)-vcarbonvH)-2p2yridinvl' N-r5-(Dibenzfb~fr.1xzli-01!)vcroy)2 p~riivrl--dimet' i. 1-iphnvl--vdycarboxamid f1.41oxazei10(11H)-v1carbonfly12v-idin,,,11-2-fluor-5-chloro1benzamnide r.4oaze2in-10(11H)-yicarbonv1)-2rvr 4dinvl 1 (-ovridinvlbenzanide -115- N-rS-(Dibenzrb.f' f1.41oxaze~in-10OU1H)-vlcarbonv12- Ryridinyl 1 (4 -ovridinvl)benzamiLLe N-[5-(?~vridoF2.3-b' rl.51benzo 2-pyridinyl 1 ri. 1 'binhenvl' -2-carb1oxanide A mixture of 0.198 g of 5,6-dihydropyrido[2,3- 1a) 5]benzoxazepine, 0. 155 g of LI, 1diisopropylethylamine and 0.404 g of 6-[([l,l'biphenylj- 2-carbonyl)aminolpyridine-3-carbonyl chloride in 12 ml of dichioromethane is stirred at room temperature for hours. The mixture is poured into water and extracted with dichioromethane. The extract is washed with 2N Na2CO3,H20, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The solid is dissolved hexane-ethyl acetate and the solution filtered through a thin pad of hydrous magnesium silicate. The pad is washed with hexane-ethyl acetate and the filtrate concentrated to dryness to give a glass, m.p.107 0 C-114 0 C Anal. Found: C, 74.4; H, 5.7; N, 8.8 N-r4-(Pvridor2.3-bl !1.51benzoxazeoin-6(5H"-vlcarbonv1)- 3-chlcroiphenvi' rl.l'-biphe,-nvll'-2-carboxamide A mixture of 0.198 g of 5,6-dihydropyrido[2,3- 0.155 g of jdiisopropylethylamine and 0.444 g of 4-[U[1,l-biphenyl]- 2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichlor-omethane is stirred at room temperature for *hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2Ni Na2CO3, H20, brine and dried (Na2SO4) The solution is passed through a thin pad of hydrous magnesium silicate.

The filter pad is washed with 50 ml of hexane-ethyl acetate and the filtrate concentrated to dryness.

-116- The residue is triturated with ether to give a solid, m.p. 205-217 0 C. Anal. Found: C, 72.3; H, 4.2; N, 7.9; Cl, 6.7.

As described for Example 66, the following compounds can be prepared.

(Pvridcr2.3-b1 r2.51benzoxazelin-6(5H)-vlcprbonvl)- 3-o,vr-idinvlr1.1lbiphenvil-2-carboxpnide N-f5-(Pvridor2.3-bl r2.51benoxazein-6(5H-vlcarbonyl1- 2-ovridiny1 -2-chlorobenzpmide ExamoDle N-r5- (Pvridor2.3-bl 2-tvridinvl 1-2-chlorc-5-fluorobenzamidle N- r5- (Pvridor2,3-b 1 [1.51benzoxazeoin-6(5H)-vlcarbonv1)- 2-ovridinvil -2-hvdroxvbenzamide EaRe7 N-r5-(Pyridor2.3-bl r1.51benzoxazepin-6(5H)-vlcarbon1',- 2-rvrfrdinv1 2. N-r5-(P\Tridor2. 3-b- [1.51benzoxazeoin-6(5H)-vlcarbonv1)- 2-ov,,ridirnvil-2-methvlbenzamide N-r5-(Pvr-idor2.3-bl r2.5'-benzoxazepin-6(5H)-vlcarbonvl)- 2-Dv-ridinvl-2- (dimethylamino) benzamide N-r5- (Pyridor2. 3-birj 2-p2yridinvyl-2- (methvlamino~benzamidle (?vlridor2.3-b1 r.51benzoxazepin-6(5H)-vlcarbon1'i- 2-r~vridinv11 (aminomethyl)benzaMide 117 N- r5- (Pvridcr2. 3-b rl.51benzoxaze~in-6(5H)-ylcarbonvlD- 2--ovridinvl -2-methoxvbenzamide N-f5- (Pvridor2,.'3-bl rl.5lbe!nzoxazep~in-f3(5H)-vlcarbonvD)- 2-ovriciinvll-2-chloro-5-flucrobenzamide N-f5--(?yridof2. 3-b 1 r1.51benzoxpzepi4n-6(5H)-vlcarbonvl)- 2-r'vridinvll -2-methvl-3-flucroberizamide N-t5-(Pvridor2.3-b1 r2.51bezoazepin-6(5H-vlcarbonvD)- 2-rvridinyll -2-fluoro-6-chicorobenzamide N~r5~P~ri2r2.3-l 2-ovridinvl-2. 6-dichlcrobe,-nzamide FExamle-82 N-r5-(Pvrido[2.3-b1 r1.51benzoxazeipin-6(5H)-vlcarbonvl)- 2-Rvridinvl 1-2. N-r5-(?vriclor2.3-bl [l.51benzoxazein-6(5H)-vlcarbonvl)- 2-nvricdinv1 -2-chloro-3-ipvridinvlcarboxamide N-r5-(Pvridior2.3-b21ri.51benzoxazetin-6(5H)-vlcarbonyl)- 2-ovyridinyl (methvlamino) -3-rwvridinylcarboxamiie Eave-- N-rS,-(Pvridcr2.3-b' f1.51benzoxazepin-r-6(5!-)-vlcarbonv1)- 2-,oyridirwi 1-2 (dimethvlamino) -2 -vridin\'lcarboxamidie ExaMnle 86 N!-r5-(P\'ridor2. 3-b I l.51benzoxazerin-6-(5H)-vlcarbonvl)- 2-,ovridi nyll (aminomet-hyl 4-ryr4 dinvlcarboxamide Examiple 87 N-[5-(Pvrid--cr2.3-bi !1.51benzcoxa,,e~oi-6(5H)-vlcarbolvl)- 2-pvridinvl1-2-(dimethylamfino)-4toYridiflvlcarb~oxamide As described for Example 67, the following compounds can :be prepared.

118a Ct 9400.

apPTru? 9**q@SZ-C Z=LLua43Q 0 lz)0 apal~ q :U OLL-, -L AUa L0: 0 4 ,3p~~ulpzuE~* (S~TT4E -Z -(I~oqav)TX-iiS9-UT~azv~zuq~g'I LqE'ZopT-Z~j3VCC 86 GPTW~ua4(A~a~-4-Z-Z-LA~aqTALqa..- L6 aTQI duX3 5R7 aPpuuzu(Tga(Lju4-Z)- L f ST~~gaPWXq;'Z--LLAa4L~-,L' J~lO I-T qZd-t6 J 16 alfw~

OT

-([UqU L-H 1 gud~xzuqgll-E'jop~IAd)-Vi-N LJUtUL- LA~ag I I L j AaTU 14C-r4aW- -l T4) -(Aoa T-Higu;azxz~qgljC-E ZjopIwad)-VJ-N e~~ai- ai w=7 CA~U~- N-r4- (pyridof2. 3-b I r I, 5bgnzoxazevin-6 3-chlorolphenyl (3-pvridinvl) berzamide N- (p\'rido r2.3-bl ri, 51benzoxazepin-6 (5H) lcarhcnvl1 3-chlorovhenv11-2- (4-ovridinvl)benzamide Examyle 101 N-[r4- (Pvrido f2. 3-bl 51benzoxazevin-6 (5E) -vlcarhonyl) 3-chlcrophenyll (3-furanvl~benzpmide ExamL~1e 102 N-r4-(Pyridor2. 3-bi ri.51bepnzoymaze-p in6(5H).vlcrronv1)- 3-methvlphenvll ri.1'biphenvyll-2-carboxanicle Examiple 103 (Pvrido r2. 3-bl r 1,51 benz~e6(!vuin-E SH) prbonbon1) 3-methvlo~henvil (t3-thienvlI)benzamide Examole 104 N-r4-(?D.ridcf2.3-b1 3-methvlo~henyl (2-pvyridinvl) benzamiie Example =0 N-F4-(Pyvrido[2.3-bl I5bnoae~n6-S)vcroy) 3-mnethyp~henvi 1-2- (3-ovyridinvl benzamide Examvle 106 N-f4-(Pvridor2.3-b 1 fl.51benzoxazeoin-6(5H)-vicarbonv1)- 3-methylohenv,1'-2- (4-ovridinvIbenzamide Examiple 107 N-r4-(Pyridor2-.3-bl r2.5]1benzoxazepin-6(51-n-vlcarbonv1)- 3-methylohenyvl1-2- (9-furan,'1 ~benzamide Example 108 N-r4-(Pvridor2,3-bl rl.5lben.zoxazeoin-6(S).vlcarbonyl)- 3, 6-dimethvlohen2.'-2- (2-thiie-nvl)berizamide As described for Example 67, the following compounds can be prepared.

120 N-r4-(Pvridof2.3-bl r1.51benZoxazepin-6(5H)-vlcarb~nvl)- 3-fluo-6-m'gihv1phenv11 rl. -bi~henv11 -2-carboxarnide N-r4-(?Vridor2,3-bl ri.5lbenzoxpzetine-6(SH"-vlcarbonvl)- 3. 6-dichloroohenv1i fl.1'-bihhenvll-2-garboxamide N-r4-(Pvridor2.3-b' ri.51benzoxgze~pin-6(5H)-vlcarbgnl)- 3-fluoro~henv1' ti.' -bir.henvll-2-cprboxamide N-r4-(Pvrido[2.3-blr 2henvll r 1.''-bilhhenvl 1-2-carboxamide N-r4-(Pvrickn2.3-b1 r1.51be)nzo>:aze,ir-6C5H)ylcarbonv11-Oheflvil-2- (2-thienvl)belzamfide N-r4-(Pvricdor2.3-1 1. 51benzoxazernin-6(5H)vicarbonyl -p2henvi 1-2- (3-thienvi Ibenzamide N-r4-(Pvridor2.3-bl rl.51lbenzoxazepin-6(5H)vicarbonvl) -nhenv1 (2-thienvi)benzamide N-r4-(Pvridpf2.3-hl f.51benzoxazepin-6(5H)-vlcarboflYl)- 3-fluorcphbenvll1-2- hinvl)benzarnide Examvie 117 N-r4-(Pvridor2. 3-blr F1Sbenzoxpzerpin-6(5H,)vlcarbonyl) -phenvll-2- (3-t-hienv1) bonzamide N-f4-(PvridtoE2.3-bl r.51benz.omvaZepin-6(5H)vlcarbonv1)Phenl2-2-av1)belzamide N-r4-(Pvri-dcr2. 3-b' vicarbonvi) -phenvl1 (2-pvyridinvl)beflzamide N-r4-tpvr-idcr2. 3-b' fl.5]ben-cxazepifl-6-(5H)yvlcrarbonvl) -ohenvll (-pvridinv1~beflzamida 121 Ni-f4-(pvridioT2.3-bl fl.51benzoxazelin-6(5H)- V I arhonyl) -phenvl11-2- (4 -vridinv') ben zamide N-r4- (?vridjo[2.3-bl ri.51ber'7oxepin-6(5Hi)-vicarbonv1)mehv--flurrohenyl .l---(-biphnv1'-2-enarboxmi N-r4--(Pvridot2. 3-b' f.51benzoxazepif-E(5)-vl-arbonVyl3 2ehv-methyipo~henvi 1-2i- 2-furanl berarbide~l Examiple 125 N-r4-(Pvridc12.3--b 1 K.5-berizoxazeipin-6(5H)-v2-carbonv1)- 32-methvl-henlyll-2- (-furanvl)benzamide N-ri- (vridor2l.3- 1 153 -diethyi~henvil (3-ovdl)benzamide 20N-f4-(Pvridor2.3 -bl ~.51benzoxaze-Tifl-6(5H)-y1carbonfl)- 3. -dimchlvropheflv1l-2- (-~ridirnvl)benzamfide Examole 128 N-r4-(pvridor2.3-b1 l.51,benzcxazetin-6(5H)vicarbonvl)-ohenvi' (3-furanvl,) benzamide ExarnP1e 129 N-r4-(Pvridor2.3-bl 5benzoxazeo~in-6(5H)-vlcarboflyl)- 3-flurcrpheny'-2- (2-thieinvl)benzamide N-FS(?vrdof23-b 1 Example 130 N-r-(Driof23-brn41benoazei4n-5(6H)-'1carbonyl)- 2-,ovridifly1'l-5-fluorO-2-e, hlbelzamide As described for Example 46, the reaction of 6-dihydropyrido[ 2 1 3-a] 4)benzoxazepine (1 mmol) with 2-i (2-methyl-5-fluorobelzo~yl) amino] chloride (1.0 rrizno) in dichioromethane in the presence of hl,p.diisopropy2lethylamine (3 mmol) gives the product as a glass.

22 Examle 131 N-rs-(pvridor2.3-bl r1.41ben zxazevin-5(6H -vlcarbpnv1) 2-pyridinyl' 1 -bihenvli-2-carboxamide As described for Example 66., the reaction of 5,6-dihydropyrido[2,3-bl 1,4lbenzoxazepine (0.198 g) with 6-f([l,1'-biphenyl]-2-carbonyl)amino]pyridife-3carbonyl chloride (0.404 g) in dichoromethane in the presence of U,V-diisopropylethylamine (0.155 g) gives the product as a solid.

Examle 132 N-r4-(Pyridof2,3-blr1.4lbenzoxpzeoin-5(6H)-vlcarbcnyl'- 3 -chlorohhenyll i.1 bipenvll-2-carboxamide 0 As described for Example 66, reaction of 0.198 g of 5,6-dihydropyrido[2,3-b] [l,4)berzoxazepine with 0.444 g of 4-[(t1,1'-biphenyl]-2-carbonyl)amino)-2chlorobenzoyl chloride in dichioromethane in the presence of ILV-diisopopylethylamine gives the product as a solid.

Example 133 N-r4-(6.11-Dihvdrpovridr2.3-bl l.51benzodipzepin-6(SH)vlcarbonvl)-henvl'rl.l '-biphenvl'-2-carboxanide To a mixture of 10.55 g of 6,11dihydropyrido[2,3-bl[1,5]benzodiazepin-5(EH)-Ofe in ml of tetrahydrofuran is added 15 ml of 10 molar boranedimethylsulfide in tetrahydrofuran. The mixture is stirred at room temperature 2 hours and then refluxed (under argon) for 4 hours. An additional 40 ml of tetrahydrofuran is added and the mixture refluxed overnight. To the cooled mixture is added 12 ml of methanol and the solvent removed. To the residue is 9. added 30 ml of 2Ni NaOH and the solution refluxed 2 hours under argon. The mixture is extracted with ethyl acetate and the extract washed with 2N citric acid. The aqueous layer is made basic with 2N NaOH and extracted with ethyl acetate. The extract is washed with brine and dried (Na2SO4). The solution is filtered 123 .0 through a thin layer of hydrous magnesium silicate and the filtrate concentrated to dryness to give 4.65 g of brown solid. The solid is purified by chromatography on silica gel to give the product as a solid. A 4.85 g sample of crude product is triturated with ether to give 2.68 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine as a solid.

A mixture of 0.296 g of 6,11dihydropyrido[2,3-b][1,5]benzodiazepine, 0.604 g of 4- [([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride and 0.232 g of N1,N-diisopropylethylamine in 6 ml of dichloromethane is stirred at room temperature for hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with saturated NaHCO3, H20,brine and dried (Na2S04). The solution is filtered through a thin pad of hydrous megnesium silicate and the filtrate concentrated to dryness. The residue is purified on thick layer silica gel plates with hexane-ethyl acetate as solvent to give the product as a solid which is crystallized from ethyl acetate to give off-white crystals, m.p. 220 0

C-

221oC.

Example 134 N-r4-(6.11-Dihvdrovri'do 2.3-bI !l.51benzodiazepin-E vlcarbonvl)-3-chloroDhenvyl fi.

l '-biphen

V

y 1 -2-carboxamide A mixture of 0.197 g of 6,11-dihydropyrido [2,3-b [1,5]benzodiazepine, 0.444 g of biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of N,N-diisopropylethylamine in 8 ml of 30 dichloromethane is stirred at room temperature for hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with saturated NaHCO3, H20, brine and dried (Na2SO4). The 4 solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer 124 **to 0 silica gel plates with hexane-ethyl acetate to give 0.160 g of solid, m.p. 1470C-1650C.

Anal Found: C, 72.1; H, 5.1; N, 9.1; Cl, 6.3.

Examiple 135 Nr4-(E.11 -DihvdroDvr do[2.

3 -bl rI.5benzodiazepin-6(5H1vlcarbonvl)-ohenvl ril i-biphenylP-2-carboxamide.

hydrochloride Hydrogen chloride (gas) is bubbled into 50 ml of anhydrous chilled methanol for 15 minutes. A 25 ml sample of the methanolic hydrogen chloride is added to 0.30 g of j-[4-(6,1-dihydropyrido[2,3bi t,5]benzodiazein-6(5i)-ylcarbonyl)phenyl][1,1biphenyl)-2-carboxamide. The mixture is stirred at OOC for 0.5 hours and allowed to warm to room temperature.

The solvent is removed and the solid dried under vacuum to give 0.31 g of solid, m.p. 1950C-2100C.

As described for Example 134, the following compounds can be prepared by reaction of 6,11dihydropyrido[2,3-b][1,5]benzodiazepine with the appropriate substituted or unsubstituted [(arylcarbonyl)amino]benzoyl chloride or the appropriate substituted or unsubstituted[(arylcarbonyl)amino pyridinylcarbonyl chloride.

Examvle 136 N- f 4- (.1DihyAronvridr2.3-b! 1. vlcrbonvl)--chloroOhell-2- (2-thienvl)benzamide FxamiDle 137 11 ihvLrovr id2.3-b! r 5lbenzodiazefn-6 vlcarbonvyl)3-chicroohenvil-2-(3-t-hienylbenzamide Example 138 N- r4-( -1Dhvdr o)yridor 2 3 b 151 benzodiazepin- vlcarbofvl- -chloro-6-TethVohenlV'-2--(2tbhenvl)benzamide -125 N-r4-(6,11-Dihvdrop-vrido[2.3-b1 rl.51benzodipazepin.6(5H)vlcarborivl)-phenvll-2- (2-thienvl~benzamidie N-f 11-Dihvdropyri do f2. 3-bl f! .';Ibenzodia zepin-6(SH)vlcarbonyl) -toheny11-2- (3-thienvl)benzamide N-rA-(6.11-Dihvdro-ovridor2.3-b1 I.-5lben~zodiazeipin-6(SH)vlcarbonyl)-3-rnethvlr-henvll-2- (2-thienvl'ibenzamide Example 1_42 1-Dihvdrpvrilo r2, 3-b!l. S>lbenzodi vicarbonyl)-3. 6-dimethyl1phenv1'-2-(2-thienvlbenzamide N- r4- '-Dhvd:-r~ri do(2, 3-b If!. Sibenzodiazevir'-6C5H) vlcarbonv1)-l-methylphenv!1 li. 1 -bio~henvil-2-carboxanide Example 144 N-r4-(6,11-Dihvdroovridor2.3-bl rl.5,lbenzodiazeipin-6(5H)ylcarbonvl)-3.6-drnethvlohenjfl ii -bip~henvll-2caroxmide xmpp14 N-F4-(6-.11-D)ihvdr-opvridof2.3-bl rl5lbenzodiazepin-6(5H)vlcarbonvl)-3. 6-dichlcro~henv1 l. 1'bip2henvll-2carboxamide Exar~lp 146 N-r4-(3.::--Dihvdiroovridof2,3-b rl,51benzodiaze~in-6(5H)ylcarbonv' '-3-nmethv1-6-chlorcphenv11 ri. 1-biphenvll-2- N-r4-(6.1l-Dihvdr"ovRyidor2.3-bl r',5lbenzodiazeoin-6A5H)vlcarbonv1)-3-ch-,horo-E-fluororhenyvi '-bi~henv1)-2carboxamide *.00 Exammlp 148 Krr),r-c 'f.5 1 ylcarbonvl)-2-methyvlhenvll fi '-bihen11-2-carboxanide -126too.

o* N--r4-(6.11-Dihvdropvridor2.3-b1 ylcarbonv1)-2-chloro~heny11 Ii ''I-bi~henvll-2-cp~rbpxpmide N-F4- 11-Dihydrolpvridor2. 3-b Ir, vicarboivl) -ohenyl 1-2- (2-Dyvridinyfl benzprnidem 151 N-re- 11-Dihydropyridor2.3-hl rl.51benzodipzegin-6(5H)vlcarbcnyl) -T~henv1 (3-t~vridinyl) berizaride Exam~1e 152 N-r4-(6.11-Dihvdroppvridof2.3-bl rl.51benzpdipzer.ip-6(5H)vicarbonvl) -1henvll-2-(4-ovridinv1l)benzamide- Examvle 153 -ivroE1dr23bf.5 1 b vlcarbonv1)-3-chlorop~henv11-2-(2-pvridinv1)benzamideP N-r4- 11-Dihvdropyridor2.3-bl-rl.51benzodiazepin-6(5H)vlcarbonyl)-3-chloro~henvll-2- 3 -ovridinvl,benzanide N-[4-(6.11-Djhvdrppvridor2.3-bl rl.51benZodiazein-65H)vlcarbonvl)-3-chlhrchenl-2-(4-rwvridinvl)benprnide N-r4-(6.11-Dihydrorvridof2.3-b1 rl.51benzodiaze~in-6(5H)vlCar-bonv1)-3-re-h1Thenv1-2-(2-oYridinvbenzamide Exarnyle 157 N-r4-(6.11-Dihydrocvri-dor2.3-blrl.51benzodiazepin-6(5H)ylcarbonv1)-3-methv1phenvll-2- 3 -o~vridinvl)benzanide N-r4- 11-Di'hydrol~yrdof2.3-b1rl.Slbenzodiaze~ini7-E(5H)vlcarbonv1)-3-nret-hy1henvil-2-(4-vidny'benzanide Exmi 159 N-r4- 11-Dihvdrotvridcr2. 3-b' 14.51benzdiazei,-(5).

vicarbonvi) -3-rnethvi-E-flucoophenyl-2- (2thienvi ben.7amido 127- N-r4- 1-Dihvdrnrpvridof2.3-b I fl, Slberzodiazepin-6 (SH) v Icarbonv)-3. 6-dimethvliQhenvl1 (2-RvricinyI) benzamide N- r4- 1 -pihvdrpyvri do f2,3-bl ri. 51ben? odi azep~in-6(51) vlcarbonvl) 6-cdimgthvjThenv1'-2- (3-pvridinvl)benzamide N-f4- LI1-Dihvdrctovridor2.3-bI Fl,5!benzodipzelin-6(5H)vlcarbonyl -3 6-direthylphetnvi 1-2- (4-p2yridinvl berizaride Nl-r4-(6,II-Dihydrpovridor2.3-b' N- f4 1 1 ihydrcr~yrjdof2. 3-h' 1 ,51 benzcdipazepin- 6(5H) vlca rbonv1' -h rpey -2-rethy 1thiopvridine- 3carboxarnide Example 165 N-r4-(6.12.-Dih3vdroovridor2.3-bI t1.5'benzodiazepin-r(5JHBvicarbonv1l-3-merh1Ohelv11-2-rethvl1Dvridinle- 3 a-bxmd N-r4-(6.11-DihydroTvridof2.3-b1 vlcarbonvi) -3,;6-dIirethy1rhenv1 1 I 2-methy 1pvri dine- 3- Exanole 1E7 N-r4- 112-hvdr-Ooy-idor2.3-b 1 vlcarlbcnvl) -ohenv1 I -2-Tretbvlroyridi ne-3-carboxamfide ExamoJle 168 N-r4-(6.u.-Dihvdrcpoyridor2.3-bi ylcar:bonyl) -3-chlcrophenv2.'-2-methv1~pvridifle-3- Examioig269 N-r4-(6.11-rihvdrcrnyridor2.3-bI i1benzodiazeipin-6(5H)vicarbl a3c~rc- 6-methvlpbelV21-2-f ucropyridile- 3 carboxamide -128- N-r4-(6;.11-Dihvdrop~vridor2.3-b1 fl.51benzodi a2in-6(5H)vlcarbonvi) -3-chlgrop~henvi -2-fluoropvridine-3vicrbnv) 3-riehv~hnv'1 2-hxaomriin-3 10N-r4-(6,21-Dihvdropovridor2.3-bl11.'51benzodiazepin-6(5H)vicarboni) -3 -dmethvkhenv1 -2-choro~ridine-- N-r4-(6,:!-Dihvdroopvridcr2.3-b' vicarbZonvi) -3hev 1 -dietvmevpyidin--chcrarOdiniezz carboxaide N-r4-(6-.12-Dihvirocyvridor2.3-bl f.51benzodipazepin-6(5H)- ~vcarbonvi-)h n-3-pr hnl -3-mehy1cvrbdine-2 N-r4-(6..11-Dihydroovridor2.3-b1 r.51benzodiazepin-6(5H)~vlcarbonvl) ;hlorophenv1 -3-mehlrvridine-2- N-r4-(.11-DihvdcrorDvridor2.3-blrf2.5benzdiaze~in-6(SH)vlcarbonv1)-2-nyridilvli rli biphenv2.-',--Carboxamide, in.p. 278OC-281 0

C

(611-DihydroPyrid~r2.3-bl r.5benzodipzepin-6(5H)vicarbonvi) -2-t)yridinll1-2-(2-thienvl) benzainide 1-ivloyio2ibri.Sbenzodiazepin-6(5H)y2.carbonvl) -2-pvridir'V11-2- (3-thienvl-)benzamfi-da N-rS-(6 11-Dihvd-olDvridor2.3-b-l r.51benrzodiazepin- 6 vicarboflyl) -2-rpvridinv1' fluorobenzamide -129- N-r5-(6.11-Dihvdrot~vri'dor2.3-b1 f1.51benzodiipzepin-6(5H)vlcarbonvl) -2-o~vridinvll -2-(2-pvri-dirvl) benzaMidie N-r5-(6j11-Dihvdroovridor2.3-bl r1.5lbenzodiazepin-6(5H)vlcarbonvi) -2-tpvriciinv1' -2 (3-ovridinvl benzamide (6,I1-Dihydroovridor2. 3-bl vlcarbcnvl) -2-Dvridinj. 1-2- (4-,ovridinvl) benzarnide xml18 N- 5-(E.11-Dihvdronrwridof2A3-blrfL5lbenzcdiazepin-6(5H)vicarbcnvl)-2-cvridinvll-2-(2-fu-ranvllbenzamide Examr'le 1.84 N-r5-(e.-Dihirct,vri4dor2, -l15bezdae~n65) vicarbonvl) -2-,ovridinvP U3-furanvl)benzamiie N-r5-(6j11-Dihvdrot~yridor2.3-b1 r1.51benzodiazep)in-6(5H)vlcarbonvl)-2-tpvr~dinvll-3-chloroovr-idine-2-carboxamide N-f5-(6.11-Dihvdrc]2vridof2.3-b1 rl,51benzodiazepin-6(5H)ylcazbonvl)-2-Dvyriciinvil-2-methvlovr~dine-3-carboxamide N-r5-(6.11-Dihyciroo~vridor2.3-bl fI..5!benzodiazeipin-6(5H)vlcarbonvl) -9-ovr~dinyl 1-5-flucr--2-Tn.ethvlbenzamide Eal 8 N-r5-(E.1-DihydrcDyridor2.3-bl r:.51-benzodiazerin-6(5H)vicarbonvl) -2-rvridinv1 1-2-chlorobenzamide .*Example 189 :N-F-.611-Dihdroviiof2.3-bl1.lbe-zodiazepin-6(H.

vlicarbonvl)-2-ovriciinvll-2-chloc',-5-f'uorobenzanide N-rS-(E.11-Dihvdrcovridof2,3-bl r1.51benzodipzep2in-CE5H)vlcaprbonvi -2)-ovr~din2. 1-2-me 1 i' benzaMide Exam~ole 191 N-f5-(6,11-Dihvdrp .ridof2.3-b1 vlcarbonvl) -2-o~vridinvil -130- N-r5-(611-iJhdpnvridor2-1 [1.Slbenzodiazejin-6(5H)vlcarbognvfl 2-2vridinv11-2-chlorO-4flurobelzamide N-r5-(E.:'-rDihvdrot~Vridc-T2.3-bI rl.S1benzodiaze~in-6(5H)vlcarbonyl)-2-,ovridiny1' -2-chor-g-fluorobenzamide ''-Dihvdrcpvridor2. 3-bi rl.51benzodiaze~in-6(5H)vlcarbon'.y1-2-r~vridinv1l -2-methvl-3-fluorobezam~ide Ea~p 9 N-f5-(E.1DihvdrotoVridof2.3-blrl.51benzodiazeipin-6(5H)v"lcarbonyl) -2-cvridinv1 1-2-hydroxvbenzamide N-5(.'Dhdor,*io23b vicarbonvl) -2-cvridinv.1-2-acetvloxybenzarnide Exarnole 197 N-r5-(6.11Dihvdroorrdor2.3- l '.51benzocizenin-6(5H)vlcarbonyl) -2-vridinv1 1 -2-arinobenzamide N-r5-(6-11-DihydroDyridof2.3-bl t.5benzodiazein-6(5HYvlcarbonyl)-2-D~yridifvl- 2 -(methylamino) enzamide N-r5-1 .2A-DihydroPyridor2.3-bl l.5benzodiazepin-6(5H)vlcarzbony.) -2-ovridinvl 1-2- (direthvlarnino) benzarnide TE xample 200 N-r5--(-'s.-DihvdiroR:ridor2.3-bI [.5benzodiazepifl-6(5H)vicarbonyl) -2-1pridinv11-2-afiflomfethylbeflzamide N-S(,1 ivfcyrdr.- l.51benzodliazeoif-6(5H)ylcarbonv)-2V)rifll- 2 -(diethvlamin)elzamride Examp1e 202 rr5- (611-pjhvdrcvridn F2, 3-bl r. Sbenzodia7ze~ii-6 (5H) vlngrbonyl)-2-p-vridinyl1 -2- (dirnthylamiflomethyl) benzarnide 131- N-fS-(6.11-DihvdrrVridor2.3-bl vlcarbonvl) -2-Doyridinvi 1-2- (Methylthio) benzamide Example 204 N-r5-(6.11-Dihvdrppvridor2.3-b1 rl.5lbenzoaIiaze~i-6(5H)vlcarbonyl) -2-pyridinvill-2-chlorons'ridine-3-carboxarnide N-F5-(6.11-Dihydrnpvridor2.3-b1 ylcarbonvl) -2-rvridinvll -2-fluoroipvridine-3-carboxanide 10Exml20 N-r5-(6.11-Dihvdrcoovr-idof2.3-bl rl.51benz.odipzepin-6(5H)vlcarbonvi) -2-12yridinvyll-2-mothoxvr'vridine-3-carboxamide N- 5(6. 11-Dihvdrorvridof2.3-b1 vlcar-bonvl)--2-ovyridinyll -2-methvlthiop~vridine-3carboxamide N-r5-(6.11-Dihvdropov-rdorf2.3-b1 rl.5]kenzodiazelin-6(5H)vicarbcnvl) -2-ovyridinvll-2-aminorvridine-3-carboxanide Eall 0 N-rE,-(6.11-Dihvdropvyridof2.3-b1 rl.5lbenzodiazeipin-6-5H,ylcarbonvl) -2-pyridinvyl- 2-methylamino-tpvridine-3- N-r5-(6.11-Dihvdropvridor2.3-b1 FT.5lbenzodiazepin-6(5H)vlcarbonv.) -2-pvridjinvil-2- (direthlarin)pvridine-3- *Example211.

N-r5-(6.2J-Dihvdropyridor2.3-bl fl.51lbenzodiazepin-6(5H)vlcarbonvl) -2-vridinyllthiorhene-2-carboxamide iv F,,io2.lb(.l.benzodiazeipin-6 vlcarbonvl)-?2rpvridinvil1thioph,,ene-3-carboxamide N-r5 -(6.1!2Dihydro-avrido-f2,3-bl !,15benzodipzeipin-6(5H)vicarbonvl) -2-ovyridiinvll furane-2-carboxamide -132 ~4 N-r5-(6o.11-Dihvdiro~pyridor2.3-bI rl.51benzodiaze~in-6(5H)ylcarbonvl) -2-ovridinvll-2m yti~en--abxmd N-r5-t6.11-Dihvdror~vridor2.3-b1 tl.51benzodiazepin-6i5H)ylcarbcnvl) -2-Tvridinv1 1 -3-methvlthiophene-2-carboxamide !(6,1-Dihvdropyridor2,3-b [l.51benzodiaze~ir-6(5H)vlcarbonvi) -2-Drirdinvl-2-chlorothio~hene-3-caroxanide xme21 N-r5-C6.1l-DihvdroP~v-idof2.3Ab1 T1.51benzodi.azepin-6(5H)yICarbonvl-2-Rvridinl1-2-methvlthio]phene-3-carboxamide -10M-dibenzrb.el f1.41d-iaze~in-1OylI)carbonvll-3-chloro]henlll .1 '-biphenvll-2carboxamide A mixture of 0.196 g of 5,11-dihydro-10Hdibenzo[b,e)E1,4]diazepile, 0.155 g of N_,jdiisopropylethylamile and 0.444 g of biphenyl) -2-carbonyl) amino) -2-chlorobenzoyl chloride in 12 ml of dichioromethane is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N K 2 C03,H20,brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness and the residue triturated with ether and the ***solvent removed. The residue is triturated with dichioromethane to give 0.31 g of solid, m.p. 158 0

C-

1840C. Anal. Found for C33H24C1N302 1/2 H20; C,73.7; H, 4.6; N,7.5; Cl,6.9.

*As described for Example 218, the following compounds can be prepared by the reaction of 5,11dihydro-l0li-dibenz el[l, 4]diazepine with the appropriate substituted or unsubstituted [(aryla. -133carbonyl)amilo]beflzoyl chloride or the appropriate substituted or unsubstituted t (arylcarboriyl) aminolpyridinylcarbolyl chloride.

N- r4-r 11-Dihvdrc-10H-dibenflZ .e I! f41diazepin-10vllcaronvi-helll [1.1 -biphenv1l-2-Carboxamid-e 00 to 0 00 0* 0 0 0 0 *000 9000 0000 0000 00 00 0 *.00 0000 00 00 0004 00 0. 0 *0 0 *0 *0 000000 0 0000 0 0 0000 000000 0 N-r4-r('ll.1-Dihydro-10+-dibenlfb.e1 rl.4ldiaze~in-10vliarbonll-3-rolthyliphenYll rl.i'-biphenvll-2- 1l.-ihvdro1j0H-d2benz Fb~e) rl. 41diapepin-l0vl)ca-bcnv1l-3. 6-dimethvlohen2l r' '-bipohenvll-2wi- rA-r tc; iinvvir-OH-dibenz rb~ei rl41diazepin-10vllcarbonvll-3l-hlor~henvll 2 -(2-thienvlbenzamfide 1L~hydrc-l 0H-dibenzrb .el rl4ldiazepin-10vl)carbonl--hlorolhenvl- 2 -(-thien'vl)benzamfide Examvle ~224~ N-4!5.1 hyrl.OHdbn~l~I141dciazein-10yl)carbonvll-3-chloroiphefvl- 2 V -furarivl)benzamfide Example-225 N-r4-r(5, 1 1-phvd-r10H-dibeflZt--erI1.41diazelpin-iO vl)carbonyl1-3-chloror>hefll- 2 -(2-furanvl)beznzaMide N-4 5"Oi t-O-citnr~ l.4diazep-ifl-l0ca-bonvl 1 -methyilnheflyll (2-hienvl)benzamide 30 Exm~le-2 N- 11Dhd:- -ie~befi.4d'aeipinl-10vi) cqbonivl' methvlphevil- 2 -(3-thienvl)b2enzamfide ExamRle 228 N-r 4 -f(5,1l-Dihvdrnl0Hdibelzrb.el fl,4dipze~ifi-IO- 35 vl)carbofy1mtVLhnl ar~112Crboxamide -134- N-r4-r~(5.11-D~ihvdro-1OH-dibelzrb.ei fi.41diaze~in-10vl)carbonyll-3. 6-dimethyiphenvill f.l1 -bit~henyl-2- E~ml 3 N-r44f 11-Dihvdrco-10H-cdibenflb.e1 f1.41diazepin-10vl nrhnnv1-3-nethv1-6-chlororhenvlV 1. '-bi~henvll-2- N,,-r4-r(5.11-pihvdrp-10H-dibenzrb.e' rl.41dipzenin-10vi)carbofll1-3-chlcrc:,6-fluoro~hfll r. 1'-biohenvll-2- S

S.

S S S S *5 9 *5S* S S 5v S. S S S *5 vl~arbonll-2-ncahboheflil i '-ihnv'2 N-r4-rU5.i1-Dihvdiro-10H-d4ibenzfb.el f.41diaze~in-10)carbonvr1 -3-clo-2-meth~ylhflvi.11 bien envvl~crbonll-2 chlrboxhefidei''b~hnl 2 N-r4-r(5.11-Dihdr-10-dibefb.el fl.4ldiazepin-10vlcrvl)cabo3~-hr v1'-me (2-yriinvll.'bflzamide vVcabov1boelvi-'-3-midifV)efgm Exampe234 N-r4-r (5.11-Dihvcdc%-0H-dibenzrb.el f.41diazein-10yl) carbonvll-2-Orthenyll (-~rlid-invienypllide 35N-r4 f f5,lI -Dihvdr-10M!-dlibenzrb.el fl.41diazein-lOvi)crbon1l3ChorhelV2-(2vrdifvi)benzamide 135 Exampl~e 239 N- f(5, 1 -Dihvdro-10H-dibenz fb.e I rl. 41diazepil-10vl) carbonv II -3--ch Ioropheny 1 1-2- (3-rwridinvl) ben7amide Exampe 240 N-4F(,11Lyro11-iezr~ ri.41diazeipin-10carbcnv. 1 -3-chloroheni 1 (4-rpyridinv I) benzapmidje Examipip 241 N- r(,11D~dc Hdbn~~ rl.41diazep-in-1vl)carbonyl'-3-methvlohenv1'-2- (2-pvyridinylbenzamide Examole 242 N-r4-F 1 -Dihvdr, -lOH-dibenzfb~e. 1 rl.41diazepin-10yl) carbon,,, I!-3-met by oheny.I-?- (3-,ovridinvl) ben zamide Examipip 243 vl)carbonvli-3-methvlophenvll-2-(4-ovyriciinvl)benzamide Examole 244 llDihvdrt-~10H.dibenzfbe1rl.41diazepi-10vi) carbonvi 1-3.6-dimethvlohenvi 1-2- (2pvridinvl) benzamide 20Exml24 N- r4- f 11-Dibhvdro-10M-Slibenz Ib.el i I41diazeTp-10vi) carbcnvl,, 1 6-dirnethylphenvll-2- (3pyriciinvi) benzamide N-[4-r 5, 11-Dhdr-lM-dbenzfb.e Il f4dae!-10yl) carbonyl 1-3. 6-dirnethylphenyvll1-2- (4- 12y'diny!) benz.amide Examole 247 11 -L vrc-0-dibenzrb~e1 rl.41diazeipin-lQv1)cgrbcn%,Klohenvl' -2-phenyimethyl)benzamide Examole 248 f4- r 5, 1 -Dihydr HO-dbn--1 vl)carbonvlohenvl' (3-chlorcr'henvimethvl)benzamide ExamoLe 249 35 N-r4-r(5. vr-0idbnfb,el !1.4idiazepin-l0 vl) carbonyil -3-chicroohenvil-2- (Lhenvlmethvl) berizamide -136

I

ie 11 -ih-vdro-1oH-rifbenz rbe I fl. 41di vi) carbonvill-3-chlorophenl1-2-rethoxvpvyridine-- Examvl~e- 252 N-4-r(5.11-Dihvdrc -10H-dIibenzrb.el f.4ldiazet'in-10v) caronl-3-methv1roihenv1 1 m thvlpjovridie-3- Examole 253 N-r 4 -r(5 ,11-Dihvdc-IOH-djben-fb.e' fL4lciazet~ln-10- 15vi)carbonvi1-3m-ethylihefl-i)3m-thvl~vridine 2 3 yd-IO b!zh~li.4diazepifl-10carbonvi' -3-methylphenyll ehyrvridinle-3- N-4r511Dh or0-ienf~ll41diazep2i-10vi) caronil- 3 -mthvhef9l~21oroDpvidine 3 ivrcIrfibnre l.4diazepif-iOvi) carbonyl' -e~v-gcloo hni-2-chloroloyridile- 3-carboxam~ide 6 30 N-f- CS1~ivdrc-IOH-ibeflzfb ml !I4dazpnvl)carbonvl-2Pvridinvil fi. 1?]iheflV12carboxa ide.

m.p.280 0 C-285 0

C

(.11DihvdrO-40!&-dibenlZ .e1 fl,41diazeinifl-10 vi) carboyl 1 v-riinvl -9 (2thi env!) benl-7amide 6 137 N-r5-r(5.11-Qihvdro-10H-dibenzrb~el fi.4ldipzepin-10vl) carbonv1'-2-12yridinvi1-2- (3-t-hienvl)benzanide N-5r51-hd -0-iezLerl.41dlazepir- 10vl)carbonvil-2-ovridinyi 1 -2-(2-furanwl) )benzamtidef_ N- r 5- r(5, i2-Dihvdro-1OH-di-benzfb.ei rl.4]diazeli-10vl)carbonvll-2-r'vriciinvPl-2- (3-ovridinvl)benzprnido hvdiro -1!--dibenzrb.e lfi41diazepin-10vl)carbonvll-2-ovridin2.

1 -2-(3-ov.,ridinvl)benzrnide Examtle 264 ihd Vdiazein-0 1y- I carbonv 1 -2vvjinl (-yianv) benzamide 20N-r5-(5i1D~hydrc-I0Hbzbi,fe.1r.41dizeTin- 10-vl.carbonv1'-2-cvridinv1'-2- (2-fur~anvl)benzarnide Ex:ample 265 Icarbony -2-p\yridny l-2-nvyrnvl~ -enami Examnp1p 267 caarbonyide Example 268 ~i rNr (S hydrc-'0H--,I4ben- r! i 41 ni azevin- Iarbonyil -2-pyrid!inv1'-2-nt-hy1-5--Fuorohenamnide -138 N-15-1 (5,11-Dihvdro- IOH-dibenz rb.el rl1.4ldipaz-epin- 1 0-vi carbonvi 1-2-,ovridinvll1- 2 -Chlorobenzamidie N-r- 5 1-iyj:- Hdbn be l. 41ldia zepin- 10-v1l carbonvil -2-!2vrfiinyl I- 2 Exam~le2272 N-r-r(,1 Dhdc1Hdlpzf) elj. 41di azepincarboivil 2 -2vridinvll-2-methvlbenzamide Example 273 N-r5-rt5.11-Dihvdro-lOH-dibenzfb.e fL.4ldiazepin- 1O-y', carbonyl I -?-rDvridinvl 1 N- N Ndbn b el 1. 4 1dipzepin- 10-vl)carbonvll-2-1Pyridinvll-2-chloro-4-fluonrnbenzpmide Eam~e275 N-r5-f(,l1!-Dihvdro-lOH-dibenzfb.el rl.41diazepin- 10-vl)carbonvll-2-pvyridinvll-2-chloro-6-fluorobenzpmide N-f5-f (5.11-Dihvdro-IOH-dibenzrb.elrl,4'diazeyincarbonvi 1-2-o~vridinl 1-2-methvl-3-flunorobenzanide 11-Dihvdro-IQH-dibenz rb.el rl.41diazepin- 1 Q-vl) carbonvl 1 -2-vridinv1 1-2-hvdroxvbenzamiie Example 278 (5.1l-Dihvdro-10H-dibenzfb.el fl.41diazepin- 1O-vI) carbonyl -2-oyvridinvl 1-?-acetvloxvbenzanide (5.11-Dihvdrn-l0HT-dibenzfb.e1 fl.41diaze~in- 30 1 carbon\'l 1-2-2vridinil 1-2-aminobenZamide N-rB-r (5r.ll-Dihydro-1OH-dibenzfb.el l.41diapeincarbonvll-2-oyvridinvil-2- (met-hvlamino)benzaMiie N-5r(- -iyrQIHdbn he l r4]dia.epin- 10-vl)-carbonvi-2-~vridill-2-(aminoethv)belzamfide -139 Exam~2l28 N-r5-f(5.11-Dihydro-10H-dibenzrb.el F2.4ldiazeoinlo-vl' carbonvi 1-2-i~yridinv1 1-2- (direthylamino) benzarnide N-r5-r(5.1:1-Dihvdrp-10H-dibeizrb,,e1 r1.41diazeipin-10-vl1 carbonvl-2-ovridinvl 1-2-chloroovridine-3-carboxanide (5.12-Dihvdrc-OM-dibenzrb.el rl.4ldiazeipin-10-vl) carbonvi 1--2--pyridinvl 1-2-fluororovridine-3-carboxamide Exml 8 carbonv11-2-iDvridinv!1-2-methoxvcvridifle-3-Carboxamide Example 266 10-vl) carbonvll-2-loyridinvyt--2-(mrnthvlthio)ipvridine-3- N-r5-r(5.11-Dihvdr 10H-dibenzrb.e1 rl.41diazetpin-10-vl) carbonv 1 -2-,oyriiinvJ. 1-2-arninoovridine-3-carboxanide mml28 (5.1'-Dihydr, -10q1-dibenflzb~e rl,41diazepin-10-vl) carbonvi'-2-r)vridinv1'-2-(met'hV,,lmilo)P~vridifle- 3 Exarno1e 289 N-F5-f(5,11-Di-hvdrc- 1QH diben-zF,e' ,141diazevirn-10-v1) carbonvl 1 -2-ovridinvl 1 1-2- (dimethvlamino) tvridine-3- Exarnolg 290 (5.11-Dihvdr 10M-dibenflb,e 1 rl,41dipze-oin-10-v') carbonv11-2rvridin112methVlthiihen--3crboxamide -140- N-r4-r (6.11-0ihvdro-5SM-dibenzfb.elazepin-5;-vl) carbonv11-ohenv1 ri. 1 -biiphenyll-2-carboxamipei A mixture of azepine (0.195g), 4 -[Ul1,1'-biphenyl]-2-carbonyl)amino] benzoyl chloride (0.41g) and 0.155 g of diisopropylethylamine in 12 ml of dichioromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichioromethane.

The extract is washed with H120, saturated NaHCO3, brine and dried (Na2SO4) The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with dichloromethane. The filtrate is concentrated to-dryness to give 0.66 g of a yellow solid. Chromatography on thick layer silica gel plates with hexane-ethyl acetate gives crystals 165g) (from dichloromethane-ethyl acetate), m.p.

224 0 C-225 0

C

N-f4-r (6.1-Dihvdro-5.H-dibnzrb.elazein-5.vl) carbonv1'-3-chloro]Rhenvl1 l. 1'-bilhhenvll-2-carboxamide A mixture of 0.195 g of 6,11-dihydro-5iidibenz~b,elazepine, 0.444 g of 4-H([1,1'-biphenyl]-2carboriyl)arino-2-chlorobenzoyl chloride and 0.155 g of H,V--diisopropylethylamine is stirred at room temperature for 3 hours. the mixture is poured into water and extracted with dichloromethane. The extract is washed with H120, Saturated NaH-C03,H20, brine and dried (Na2SO4) The solvent is removed and the residue chromatographed on thick layer silica gel plates with solvent hexane-ethy'l acetate to give 0.32 g of crystals, m.p. 120 0 C-125 0

C.

As described for Example 302, the following compounds can be prepared by reaction of 6,11-dihydro- 5.1-dibenz~b,e~azepine with the appropriate substituted or unsubstituted 4-i (arycarbonyl)amino]benzoyl chloride 141 or the appropriate substituted or unsubstituted 6- [(arycarbonyl) aminolpyridine 3-carboflyl chloride Examole 303 N-f4-r (61-i~dc5 dhn7fheIazti--l car.bonvloheflvll-?-(2-thienyl)benzamide Exam! 1e 304 N-r4-r(61-ivr-Hdbezbeaei--l carbonyllohenflvlb 2 (3-thilenvl)beflzamide carbonvllIchenl! 3 -dchi nhel1~- 2 t hiev !)-ben zam.ide Examr'le 306 l-phydr-5 -dib-n r0 e 1 carbonvlPI-'-ch1croohefnl I 2 (2-thienvl 12elzamide Examole 307 N-r4-r 12-Ehivrc-5H-dibeflZrb.elazerifl-5-Vi) carbonvl1-3-chloro~ohfnl1- 2 -(3-thienvl)belzamfide Examotl e -308 N-r4-1 (6,11-Dihvdro-5-dibenzb.&plzeOJ.P. ;vl) carbonvl 1-3chorEieth\'1Ophevi 1 2 2thienvl) enzamidap ExvamTpl1e -30 9 carbcnvl I -0-Y'3hel 1- 2 (-thienp.V) benzamilde- Exarmle 310 N-f4r (6 1---iv r idb n f~ lz~i -l *carbonv! 9-iinetb+-v1hernv 1 (2-hienl) beflzpride :Examolle 3'1 i<!-r4-r (11-7ihvdr-5H-dib--.rb~e'azeoin5Yl) carbcnvY'-3-met-hvlhenllfl.1 'bohenv11-2-carboYamfide Examnle 31 rc-r(6 1 1 -hdrc- 5H-d en-, ri, I azienv-a- -142- Exam~ie 313 N-r4-r 11-Dihvdro-5H-dibenzfb.elazepThi-5-vlI carbonvll-3-methvl-6-chlorop2henvll Ti. 1 -bipherivil-2carboxamide Exmple 14 N-r4-r 11-Dihvdro-5H-dibenzr)b.elaze~in-5-vl) carbonvPl-3-chloro-6-methvlhhenvll i1 -bioherivll-2caror~11--mehv~hen1 1 roi -ihev'2eabxmd Nr4-r 11-Dihyvdro-5H-dibenzrb.elazeyin-5-vl) carbonvy 1 -2-mehy'rohenv11 fI.1 -biphenv1l-2-carboxamide N-I>4-t(6. 11-Dihvdrc-5H-dibenzrb.elazein-5-v1' cabrbo-2cnv 1 hen1 (-bidinvl berArne i N-r4--r(6.11-Dihvdro-5H-dibenzrb.elaze~il-5-vi) carbonyll'Phenyll-2- (2-ryridinv1'JbenzamTide N-f4-T 12-Dihvdro-5H-dibeflnzrb.e&pze~ifl-5-1'I 1 henyil-2- (4-pyridinvi) benzarnide N-r4-r (6.11-Dihydrc-SH-dibenzrb.elaze~i'-5-vl) carbbonl l heoroveny1-- (2-iivibn~ zamide 25N-r4-f (6,i1-Dihvdrc-5H-dibenri b. carboril 1-3-chicrorhenv1 1-2- (2-pvridinvfl benzamide 30 Examole 322 N-r4-r (6.11-Dihvdro-5H-dibeflzrb~elazepir-5-vlD carb'ony1 1-3-!TbethV1henl1-2- (2-ovridinvl) benzamidg .30 Example 323 N-r4-f 11-Dihvdro-5H-dibenzfb.elazepil-5-v1) 35 carbonvll-3-rnethyltheflyll-2- (3-pvridinvl)benzamide -143 N-r4-r 11-Dihvdro-5H-dibernz~b.-lazeipin-5;-v1) carbonvli 6-d4rymethvlTohenv 1 (2-pyridinvi) bgnzamide N-(4-r (6.12-Dihvdr-5-H-dibenzrib.elpzepih.---v1) carbonvl'1-3. 6-dinmethy1phenyl 1-2- (3-rovridinyvl) bpnzamide Example 326 N-r4-r 12-Dihvdro-SH-dibenzfb.elaZepin-5-vl) carbonyl 1-3. 6-direthlphenv 1 (4-1tvridinvl) benzpmide Exami~le 327 N- f4- r 11-D4 hvrc -SH-dibenz elazelpin-5-v1) carbonv11-3-chicrcnhenyPl-r3-ethvlthic-1. 2'-bip~henvll- 2-c arbo de Exampllp 32B N-[4-r 12-Dihvdrc-5-~ibenz carbonvl 1 -3-chlc roohenyll-r''-methoxv-1.l '-biphenvll-2car-bcmamride Exam~le 329 N-r4-r (6,i1-Dihvdro-H-dibe'z carbonvllohenvll r4 1 -dimethvlpminc-1. 2. -biohenvll-2cabxmide N-r4-r ll-Dihydrc-5H-dibenz rb.elaze~in-5-y1) garbonvl 1 -3-methylEphenv' r 2 1 -ch lcro-1. 1 '-biiphenyLL abxmd Exam~ie 331 N- r4- r ''-ihvdrc-5H-diibenz [b2. e~aer)4n-5-v1) carbonvil-3-chicorzhenll 1 (3-fulranvl)benzaMide Examr'le 332 carbonvlltohenll-2- (2-furanvl)benzamide *Emamole 133 N- r4- 11-Dihv.drc-SH-dlbe: z el azeipin-S-vl) caronvlphnl- r3t-,-ir 0 1 -biphenvl"-?-carboxa ide b nlih n l *ll 144- N-r4-f (6.1 -iy r -I4dbn r~ I z]i l crborwll-3-chiro~helvll r3'-rhloro-1. 1'-birherill-2- N-r4-r 1nhdc5-ie~f~lzyn5y_ carbonv1l-3-mflthVllhheyll r3'-chorcn-1. 1'-biphenyl1-2- Caror~11--tVr1~fll'r3'chor-12.-bihflll :0 £Examle 3367 ca-bonv1l3Ch1rOvidillril -hlor-1. 2-biphenvl-2carbr~v1 -2~yriifly 1 2oxaoopriileCabOam N-r4- f :j v H d e i l carbonyll I---oheifll fuor-vridifle3pnvxamid 1DhdcS -dbn7'ielzli i carbonv2.

1 -2-~vrdinvll -2chnio-vidinele3cprboxamide Examp~le 341 6 .11Dhvr5-dibeflrb.elazeapin-svl) cabonv1-2tr-)vrifnlli (rnth arniflO)Oarboxid 0 00 riivi'2-(meihainiflO~vridife 3 .0*cronl 2~viil1 c-aroxamide eleCpboamd :0 30-aml 14 00* aaroxmd 4 a 0: I (6.11-Dihvdro-5H-dibenzrb,,.ezp.in-s-vi carbonvi 1-2-pyridinil 2 methvlthiophene-3-cprhoxamide N-f5-r 11-Dihvdro-5H-dibenz carbonvil -2-ovridinvl -2-chlorobepnzpmide N- 11-Dihvdro-5H-diberizfb.elazepin-5-v1) carbonv. 1-2-ovridinvi 1- 2 Examole 347 N F 6. 12-D ihv d ro- IH- di benz fb, e 1azeoi n 5- I carbonvl'-2-ovyridinvPl-2-chloro--'-fluorgbenzamide Exam~1e 348 C- iD 4hvydr c- 5H- d ib e n z 1D. e Iz e p in -R 1I carbonvil-2-cvridinvll-?-methv1-~-fluorobenzamidie Exmle 349 (6.12-Dihvdro-SM-dibenzfb.elpzepin-5-vi) carborivll1-2-tovridinvl 1-2- (methvzlpmino) benzamide Examole 350 N-rs-r 11-Dihvdro-5H-dibenz rb.elazep~rn-5-v1'j carbonvyl -2-,oyridinyl -2-hvdroxvbenzprnide 11-Dihvd~rc-5H-dibenzflb.elpzep~in.-1-vl) carbony 1 -2-cr4 !inv 1-2- (aminornethv, l) benzamide Ey-aiole 352 N-rS-r (fS11-Dihvidrc'-§H-ovridof2. 3-b' 41benzodiazepincarbonv 1 -9-or~yidinyD -5--Fluoro-2-rnethvlbenzpmide As described for Example 1, 6,11-dihydro-511- *..*pyrido[2,3-bj [1,4)benzodiazepine (2 mznol) is reacted with 6- ((5-fluoro-2-methylbenzoyl*I')aminolpyridine-3carbonyl chloride (2.1 mmol) in the presence of 9:.triethylamine (4 mmol) in dichlorome'thane to give the product as a solid, rn.p. 1.02 0 C-104 0

C.

146 N- r4-f 12-DihydrO-SH-pvridl'2,3-b IrI T41benzocdia-zelin- 5-yl)caghonvl1-3-chloro~henv1? Ti. I -biphenyll-2carboxami de As described for Example 134, 6,11-dihydro-5jipyrido[2,3-b] [1,43benzodiazepine (0.197 g) is reacted with 4- 1'-biphenyl]-2-carbonyl)amino)-2chlorobenzoyl chloride (0.444 g) in the presence of VV diisopropylethylamine (0.155 g) in 12 ml of dichioromethane to give the product as a solid.

As described for Example 352, the following S compounds can be prepared by reaction of 6,11-dihydro- 5,P-pyri-do[2,3-1J 1, .4lbenzodiazepine with the appropriate substituted or unsubstituted 4-[(arylcarbonyl)amino] benzoyl chloride or the appropriate substituted or unsubstituted 6- [(arylcarbonyl) aminolpyridine-3-carbonyl chloride N-r4-r 11-pihydro-5H-2vridor2.3-b1 T1.41benzodiaze~in- 5-yl)carbnvlohen.\lf1,r. -biohenvl 1 -2-carboxamide EXAMo2le 355 N-r4-r 11-Dibvdrc-5H-Dyridor2.3-bl rl.41benzodiazepincarbcnyllohenvll-2- (2-thienvl)benzamide *25Exml35 N-r4-r(6,:2-Dihydrc-5Ri-oridcr2.A-blrE1.41benzodiazeyin- 5-y1)carl.bonyl'-3-mTethvl1Ohenvyl rl.l'-biohenvll-2carboxamideL Examole 357 N-f4.-r(6. 11-Dihvdrv'-5H-Rvridcr2. 3-bi rl.41benzodiazepincarbonvill-methyl-6-chloro~henvl' ri. 1-biphenvll- 2-carboxamide l-Dihvdrc-5H-rDvridnE2.3-b1 ri. 4lbenzodiazeopin- 5-v1)rarbcny1 1 E-dirnethv1phenv11 l.l '-biphenv'1-2- -147 N-r4-r(6.11-Dihvdrc-5H9-pvridor2.3-b 1 rl.41benzodiazepi- 5-vl)carboni1-3-mrethvl1phenv11-2- (2-thienvl)benzarnide N-r4-r(6.11-Dihvdr--5H-lpvridor2.3A-b1 T1.4lbenzodiaz.epincarbonvyl-3-chlgrcvhenv1 1-2- (2-thienvi) benzamicle N-r4-r (6.11-nihvdr--5H-12vridor2.3-b1 P. 41benzodiaze~pincarbonv11phenvil-2- (2-pvyridinvl)benzamide Examp1e 36 N-r4-f 1-Dihvd~rc-SH-Dvridor2. 3-bi fl14benzociiazepin- 5-v1)carbon%'29rphenv1'-2-(3-ovridinv1)beflzamide Examole 363 N-r4-r (6.11-Dihvdrc'-5M-t'vrido t 2. 3-b' '1.41benzodiazelpin- 5-yl)carbcnvll-3-chlorcr'henvll-2- (2-twvridinvl'ibenzamide N-r4-f (6.I1-Dihvdrc-5H-p~vridor2,3-bil .4lbenzodiazep-in- 5-vl)carbonvl'-3-chlorolhenv11-2- (3-twvridinvl)benzamide N-f4-( (6.1'-Dihvdcr-5H-r~yrido[2.3-bl r1.41benzodiaz.eiincarbonvyl-3-rn.ethvlohenvl1 (2-Dyvridinvl) berizamide N-r4-r(6.11-Dihvdro-5H-2vridor2.3-b1 tl.41benzodiazeipinarbcniv' 6-dimethv1Rheny1 (3pv'-i:dinvl) benzamidea N-r4-r 11-Di'hvr,-:H-r~'ridof2.3-b-% rl4lbenzodipzepincarbony1 ohenylI-- (4-ol'ridilvi) lenzaniLL Exanjp 368 N-r4-r(6,11-Dihvdrc-5MH-rvridor2.3-b1 f1.4lbenzodiazep2in7 5-yl)carbonvllhenl--chlroP2,rdile-3-Carb2oxamide ExarntlQ 369 N-f4-f e6,I1-Di-hvdrc-5M-L-yridof2,3-b1 ri.41benzodipz7e in- 5-vl)carbonv11p-henlV112?flurDr-,7dile-3-carboxanide 9.148 N-r4-[ 6.11-Dihydro-5M-Dvridor2.3-b1 i. 41benzodiaze]2in- Carbonvil -3-chioroohenvi 1-2-chloropvridine-lcarboxarnide N-f4-T (6.11-Dihvdro-5H-tvridof2.3-b1 rl.41benzodiazepinc.arbornvl 1 xhenv1' -2-rethovvridine-3-carboxamide Exzamle32 N-r4-f (6-.T1-Dihvdrc-5H-12yridor2.3-b l. 4ilbianzodiazelpin- 5-v1)carbonyll-3-rn~ethV1ipheflvll-2- (ehlthio)opvridine-3- EmamL~1e 373 S N1\-r4-r (.1Diviy5Mord23-lrL.41benzodiazecin- N-r'4-r(6. 12-Dihydro-SH,-O~vrid~r2--3-b fl. 41benzocdiazeTincarbonvllphenvll--2-amilopvridifle-3-carboxarnide Exam~1e 375 N-r5-[ 12-Dihvdro-5Mi-ovridor2.3-b1 Fl. 41benzodiazerin- 5-vl)carbonvVil2-12Vridilvill fi -bivhenvi-2-carboxamide Exmli2fi37 11-Dihvdrc-5H-iDvridor2.3-bl Fl. 41benzodiazer~incarb2onvll1-2-rovridinvl 1 (2-thienyl) benzarmide 25Exml37 (6.'-Dihvdr -5H-Povridof2.3-b 1 r.1ezdae-n carbonyl -2-pyridinyll1-2- (3-thienvi) benzarnice 11-Dihvdrc-5H-ryridof12.-b 1 l. lbenzodiazeyin- (6.1iiDih;drO,5H-.Ovridor2. 3-blrl,14benzcdiaze-oin- 5-vl)-a-bonll1-O-tri dilyl'- 2 (3-yridinvl)benzamide N-;y(.ADhdr 5H-Dyrido[2. 3-bI rl.41benzodiiazepin- 1abny -2-ovridinlvl'-2- (4-rvridiny3l)benzamide C C 149 I M I N-r5-r(6.11-Dihvdro--5H-rvridor2.3-b1 i1.41benzodipzet~incarbonvill-2-rvricdinv11 (2-furanvl)benzamide N-r5-r(6.11-Dihvcirc-5H-p~vridor2.3-b1 fh41benzodiazerincarbonvl' -2-ovyridinvl 1-2- furanvl) benzamide 1-Dihvdrc-5H-tvridor2. 3-bi Fl. 41benzodiazeTincarbonvl 1-2-Dvriciinvl 1-2-clocrobenzaMide Earl 8 N-f5-r(6.ll-Dihydrc -5M!-ovridcr2,3-bl rl.4lbenzodiazepin- 5-vl)carbonv11-2-Dvyridinv11-2-chloro-5-I'uorobenzamide S Emarrole 385 E1.41berizociazelpin- 5-vi) carbonv. 1-9-ovri-Iinvll-2. Ex~ample 386 1l--Dihvdrc-SH-ovridcF2. 3-b' [l.41benzodiazeoincarbonvi 1-2-,ovridinvil -2--hioro-6-fluorobenzamide ExamTole 387 N-r5-r(6.11-Dihvdrc-5H-pvyridor2.3-bl rl,41benzodiazepincarbonvi 1-2-tvridinv1 1-2-me,-hy1-3-flucrobenzamide ll-Dihvdro-5H,-2yvridor2.3 -b1 l.41benzodiazepin- S-lcrovl2 ),iiyl'2-hvdroxybenzamide Examn1e 389 N- r5- r(6.ll-Dihvdr, -5--ovridor2.3-b1 r1.41benzodiazeipincarbcny1'I-2ov)r 4 dirwyll2-amnfobenzamide Exarnole 390 (6.12-Dihvdro-5M-O%,ridcr2.3 -bl r'.4ibenzodiazeoin- 5-y' cabni12iv~iy -2(e-vaiobnai~ *00 N-r5-r (6 ih cr H r~or l i .41benz diaze nin.

carbonyl 1-vjcjv2l 2 (dimethvlamnino)beflzamide 150 N- r5-r(6. 11-Dihvdro-5H-t~yridof2.3-b ri. 41berzodiazepincarbonyl -2-Rvridinv1 1-2-chloroipvridine-3- (6.l1-Dihvdiro-l---Dridor2.3-bl rl. 4benzodiazelincarbonvill-2-,oyridinvil (dimethylarnino)Rvridine-3c~rbon1' 2-Drdiny' -2ethlhohe Examole 394 10N-r§5r(6. lI-Dihvdr',-,-o-1yrido 3-blir. 41benzodiazeo~in- 5-vl) carbonv11-2-ovr~dinvl 1-9-methylthiohene-2- Ezamn1e 395 N-r-r .5!Dihvdro--5vrzOra4.3-1 l'lbenzdaze6Hvl)carbonvllohenvllr'1. 1'-birhenyl'-2-carbomamide A mixture of 0.278 g of dihydropyrazolo[4, 3-a] [1]benzazepine, 1.11 g of 4- (([1,1l'-biphenyl-2-carbofYl)am~iflo~benzoyl chloride and 0.426 g of Ll,li-diisopropylethylamine in 12 ml of dichloromethane-tetrahydrofural is stirred at room temperature overnight. The mixture is poured into water and extracted with dichioromethane. The extract is washed with 2N_ Na2CO3, H20, brine and dried (Na2SO4).

The solvent is removed under vacuum to give 1.45 g of solid. To the proceding solid in 25 ml methanoltetrahydrofuran is added 2.78 ml of 2LU NaQH and the solution stirred at room temperature for 3.5 hours.

The solvent is removed under vacuum, water added to the residue and the mixture extracted with dichloromethane.

The extract is washed with H20, 0.5 11 citric acid; :35 brine and dried (Na2SO4) The solution is passed *through a thin pad of hydrous magnesuim silicate and the 151 filtrate concentrated to dryness. The residue (0.95 g) is triturated with ether-dichioromethane to give 0.17 g of crystals, rn.p. 255 0 C-260 0 C; Anal. found for C31H24N402-1/2H20: C, 75.9; H, 5.1; N, 10.8.

Examr~le 397 N-r4-r (4.5-Di'hvdroz~vrazolor4.3-d1 Illbenzazen-C1(H)vl)carbonvll-l--chioroohenv11 ri1i '-biThenv11-2carboxamide A mixture of 0.185 g of dihydropyrazolo[4,3-dW['jbenzazepine, 0.814 g of 4- 1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.284 g-of U-,U-diisopropylethylamine in 9 ml of dichloromethane-tetrahydrofuran is stirred, at room temperature overnight. The mixture is poured into water and ext:racted with dichioromethane. The extract is washed with 2.N NaOH, H20, brine and dried (Na2SO4). The solvent is removed under vacuum to give 0.99 g of a solid. To the preceding solid in 15 ml of methanol-tetrahydrofuran is added 1.75 ml of 2N NaOH and the solution stirred at room temperature for 2 hours. The volatiles are removed under vacuum and the mixture extracted with chloroform. The extract is washed with 1,N citric acid, H20, brine and dried (Na2SO4) The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (0.76 g) is chromatoaraphed on thick layer silica gel plates with hexane-ethyl acetate as solvent to give 0.37 g of white solid, m.p. '172-202 0 C, Anal. found for 1/2 hydrate: C, 702.-; H, 5.0; 9.8; C-1, 6.4.

Examiple 398 vl)carbonvl'1-2-n vr- iinvl i.2 '-biphenvDl-2-carboxamide As described for Exam-ple 396, (0.1 mmol) of 4,5-dihydropyrazolot4,3-dl [1]benzazepoine is reacted with (0.21 mmol) of 6-[([','-biphenyli1-2-carbonyl)amino] -152pyridine-3-carbonyl chloride to give the product as a light tan solid. Recrystallized from ethyl acetate/hexane, m.p. 228 0 C-234 0 C as white crystals.

Examele 399 N-f5-r(4.5-DihvdroDvrazolof4.3-dlrllbenzazein-6(1H)vl)carbonv 1 -2-rvridinvl -5-fluoro-2-methvlbenzamide As described for Example 396, 0.10 mmol of 4,5-dehydropyrazolo[4,3-d [l)benzazepine is reacted with 0.21 mmol) of 6-[(5-fluoro-2-methylbenzoyl)amino]-2pyridine-3-carbonyl chloride to give the product as a tan solid, (0.15 g) m.p. 126 0 C-176 0 C: Mass Spec (FAB)found 442(M++H).

E-xamiple 400 N-f5-(4H-Thienof3.4-blr1.51benzodiazecin-9(10H)-vl-2pvridinvll-5-fluorp-2-methvlbenzamide As described by J.B. Press et al in Z. &ed.

h1am., 22 725 (1979), 9,10-dihydro-4E-thieno[3,4hl[1,5lbenzodiazepin-10(9H)-one is prepared. This intermediate (4.8 g) is dissolved in tetrahydrofuran under nitrogen and 4.2 g of lithium aluminum hydride (LAH) is added portionwise with stirring. The mixture is refluxed for 18 hours and quenched by the dropwise addition of water. The mixture is extracted with chloroform and the extract is filtered through diatomaceous earth. The organic layer is washed with water (200 ml), dried (Na2SO4) and the solvent removed.

The residual oil is chromatographed on thick layer silica gel plates with chloroform as eluent to give 1.2 g of 9,10-dihydro-4E-thieno[3,4-b [1,5]benzodiazepine as 30 a solid. The proceeding compound (0.5 g) is reacted *with 1.06 g of 6-t(5-fluoro-2-methylbenzoyl)amino] pyridine-3-carbonyl chloride, hydrochloride in dichloromethane which contains 7 ml of L,Ndiisopropylethylamine. The mixture is stirred at room 35 temperature for 16 hours and then is washed with water, 1U HC1, saturated sodium bicarbonate solution, water and 1. -153dried (Na2SO4). The solvent is removed and the residue purified by chromatography on silica gel with ethyl acetate-hexane to give 1.1 g off a solid, m.p.

890C-~920C.

Examr1e 401 phenyl 1rli' heyl--aropmd As described for Example 400, 9,10-dihydro-4jithieno(3,4-1a] t,5]benzodiazepine is reacted with 4- [([1,1'-biphenyl)-2-carbonyl)aminolbenzoyl chloride to give the product as a solid.

0 Examnple 402 1,r-4H herf.-ll.';1bernzdiaein-9u0PH-')ril oh nn A If,'-biphernyl l-2-carboxamirie As described for Example 400, 9,10-dihydro-4jithieno 4-b] ti,Sbenzodiazepine is reacted with 4l'-biphenyll-2-carbonyl)amino] -2-chlorobenzoyl chloride to give the product as a solid.

Nl-r5-(4wz-~~'h~enor3. 4-hi f1.S'benzodiazepin-9(10H)-y1)-2pvridiny' 1rl.' '-b:-Dheny11-2-cap-bovamide As described for Example 400, 9,10-dihydro-411thieno[3,4-bl [l,5]benzodiazepine is reacted with 6- 1'-biphenyll-2-carbonyl)amino)--pyridine-3-carbonyl to 25 chloride to give the product as a solid.

-Eample 404 dL-nrv!rb.o1 fl .41dia~eipine A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for *minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0 0 C) solution of 2.0 g of 5,1ll-dihydro-10a-di-beflz~b,e][1,4]'diazepine and 7? ml of hl,hldiisopropylethylamfine in 30 ml of dichloromethane -154 *:too is added dropwise a solution of 3.15 g of 4-(2thienyl)benzoyl chloride in 30 ml of dichloromethane.

The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HC1, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate as eluent to give 1.8 g of solid, m.p.

1140C-116°C.

Example 405 5.11-Dihvdro-10-4-(3-thienvl)benzovl 1 dibenz'b.el r1.41diazenine To a mixture of 2.0 g cf 5,11-dihydro-10Hdibenz[b,e] [1,4]diazepine and 7 ml of 1,Hdiisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(3thienyl)benzoyl chloride in 30 ml of dichloromethane.

The mixture is stirred 16 hours at room temperature and diluted with dichloromethane (50 ml). The solution is washed with 30 ml each of H20, 2U HC1, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue purified by chromatography on silica gel with hexane-ethyl acetate as eluent to give a 25 solid.

Pindinc -asay R Rat HUpatic V1 Receptors Rat liver plasma membranes expressing the vasopressin Vi receptor subtypes are isolated by sucrose density gradient according to the method described by 30 Lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at 70°C until used in subsequent binding experiments. For binding experiments, the following is added to the wells of a ninety-six well format microtiter plate: 100 ml of 155- 100.0 mM Tris.HCI buffer containing 10.0 mM MgC12, 0.2% heat inactivated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg 1,10-phenanthroline, 2.0 mg trypsin inhibitor, 10.0 mg and 0.1 mM PMSF, 20.0 ml of [phenylalanyl-3,4,5,- 3 H] vasopressin 45.1 Ci/mmole) 0.8 mM, and the reaction initiated by the addition of 80 ml of tissue membranes containing 20 mg of tissue protein. The plates are kept undisturbed on the bench top at room temperature for 120 min. to reach equilibrium. Nonspecific samples are assayed in the presence of 0.1 mM of the unlabeled antagonist phenylalanylvasopressin, added in 20.0 ml volume.

For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligandreceptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and displayed in Table I.

Binding Assay t pRai KiPnev Medullary V? Recectors Medullary tissues from rat kidneys are dissected out, cut into small pieces and soaked in a S. 0.154 mM sodium chloride solution containing 1.0 mM EDTA with many changes of the liquid phase, until the 30 solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containina 1.0 mM EDTA with many changes of the liquid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and C.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate is filtered through several 156 r layers (4 layers) of cheese cloth. The filtrate is rehomogenized using a dounce homogenizer, with a tight fitting pestle. The final homogenate is centrifuged at 1500 X g for 15 min. The nuclear pellet is discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting pellet formed contains a dark inner part with the exterior, slightly pink. The pink outer part is suspended in a small amount of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry's method (Lowry et al., J. Biol.

Chem., 1953). The membrane suspension is stored at 0 C, in 50.0 mMTris.HCl, containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0 mg protein per ml of suspension until sue in subsequent binding experiments.

For binding experiments, the following is added in ml volume to wells of a 96 well format of a microtiter plate: 100.0 ml of 100.0 mM Tris.HCl buffer containing 0.2 heat inactivated BSA, 10.0 mM MgCL2 and a mixture of protease inhibitors: leupeptin, 1.0 mg aprotinin, 1.0 mg 1,10-phenanthroline, 2.0 mg trypsin inhibitor, and 0.1 mM PMSF, 20.0 ml of 3

H]

Arginine 8 vasopressin 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 ml of tissue membranes (200.0 mg tissue protein). The plates are left undisturbed on the bench top for 120 minutes to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 mM of unlabeled ligand, added in ml volume. For test compounds, these are solubilized in 30 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume *to a final incubation volume of 200 ml. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand- 35 receptor complex is assessed by liquid scintillation counting in a Parkard LS Counter, with an efficiency of 157 •t for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and displayed in Table I.

Radioligand Binding Experiments with Human Platelet MEmcranes Platelet M'embrane Preparation: Frozen platelet rich plasma (PRP), received from the Hudson Valley Blood Services, are thawed to room temperature. (Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY).

The tubes containing the PRP are centrifuged at 16,000 x g for 10 minutes at 4 0 C and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 mM Tris. HCL, pH 7.5 containing 120 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000 x g for 10 minutes. This washing step is repeated one more time. The wash discarded and the lysed pellets homogenized in low ionic strength buffer of Tris. HC1, 5.0 m, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000 x g for 10 minutes.

The resulting pellet is resuspended in Tris.HC1 buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g for minutes. The final pellet is resuspended in 50.0 mM Tris.HC1 buffer pH 7.4 containing 120 mM NaCl and 5.0 mM KC1 to give 1.0-2.0 mg protein per ml of suspension.

Bindinc t_ Vasoressin Vi recectcr subtype in Human i «plat t. Mrrb-anes In wells of a 96 well format microtiter plate, 30 add 100 ml of 50.0 mM Tris. HCI buffer containing 0.2% BSA and a mixture of prctease inhibitors (aprotinin, leupeptin etc.) Then add 20 ml of 3 H]Ligand (Manning or Arg 8 Vasopressin), to give final concentrations *2 ranging from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 ml of platelet suspension (approx. 100 mg protein). Mix all reagents by pipetting the mixture up 158 and down a few times. Non specific binding is measured in the presence of 1.0 mM of unlabeled ligand (Manning or Arg 8 Vasopressin). Let the mixture stand undisturbed at room temperature for ninety (90) minutes. Upon this time, rapidly filter off the incubate under vacuum suction over GF/B filters, using a Brandel Harvester.

The radioactivity caught on the filter disks is determined by the addition of liquid scintillant and counting in a liquid scintillator.

*1 e Binding to Membranes of Mouse Fibroblast Cell Line (TV- 2) Transfected with the cDNA Expressing the Human V_ Vasooressin ReceDtor Membrane Preparation Flasks of 175 ml capacity, continuing attached cells grown to confluence, are cleared of culture medium by aspiration. The flasks containing the attached cells are rinsed with 2 x 5 ml of phosphate buffered saline (PBS) and the liquid aspirated off each time. Finally, 5 ml of an enzyme free dissociation Hank's based solution (Specialty Media, Inc., Lafayette, NJ is added and the flasks are left undisturbed for 2 minutes. The content of all flasks is poured into a centrifuge tube and the cells pelleted at 300 x g for 15 minutes. The Hank's based solution is aspirated off and the cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500 x g for 10 minutes to remove ghost membranes.

The supernatant fluid is centrifuged at 100,000 x g for minutes to pellet the receptor protein. Upon completion, the pellet is resuspended in a small volume of 50.0 mM Tris.HCl buffer, pH 7.4. The protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HCl buffer containing 0.1 mM phenylmethylsulfonylfluoride (PMSF) and 0.2% bovine serum albumin (BSA) to give 2.5 mg receptor protein per ml of suspension.

Receptor Bindino 30 For binding experiments, the following is added in ml volume to wells of a 96 well format of a microtiter plate: 10C.0 ml of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgC12 and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg%; 1,10-phenanthrcline, 2.0 mg trypsin inhibitor, 10.0 mg and 0.1 mM PMSF., 20.0 ml 160 r Nt of 3 H] Arginine 8 vasopressin 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 ml of tissue membranes (200.0 mg tissue protein).

The plates are left undisturbed on the bench top for 120 minutes to reach equilibrium. Non specific binding is assessed in the presence of 1.0 mM of unlabeled ligand, added in 20 ml volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml.

Upon completion of biding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the 0 filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and the data is displayed in Table I.

Vasopressi- V 2 Antagonist Activity in Conscious Hydrated Rats Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound.

One hour later, arginine vasopressin (AVP, antidiuretic hormone, ADH) dissolved in peanut oil is administered at 0 0.4 mg/kg intraperitoneally. Two rats in each test would not receive arginine vasopressin but only the vehicle (peanut oil) to serve as water-loading control.

Twenty minutes later each rat is given 30 mL/kg of 30 deionized water orally by gavage and is placed individually in a metabolic cage equipped with a funnel and a graduated glass cylinder to collect urine fdr four hours. Urine volume is measure and osmolality analyzed by use of a Fiske One-Ten osmometer (Fiske Assoc.., Norwood, MA, USA). Urinary sodium, potassium, and chloride are analyzed by use of ion-specific electrodes 161 in a Beckman E3 (Electrolye 3) Analyzer. In the following results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity.

V1 Antagonist Activity in Conscious Rats: Conscious rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiltration with 2% procaine (0.2 ml). Using aseptic technique to the ventral caudal tail artery is isolated and a cannula made of FE 10 and 20 (heat-fused) tubing is passed into the lower abdominal aorta. The cannula is secured, heparinized (1000 iu/cc), sealed and the wound closed with one or two stitches of Dexon 4-0. The caudal vein is also cannulated in the same manner for intravenous drug administration. The duration of the surgery is approximately 5 minutes. Additional local anesthesia procaine or lidocaine) is provided as needed.

The animals are placed in plastic restraining cages in an upright position. The cannula is attached to a Statham P23Db pressure transducer and pulsatile blood pressure is recorded. Increase of systolic blood pressure responses to arginine vasopressin 0.01 and 0.2 international unit (350 1 mg) injections are recorded prior to any drug (compound) administration, after which each rat is dosed orally *with compounds under study 0.1-100 mg/kg (10 cc/kg) or i: intravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,180,240 and 300 30 minutes later. Percentage of antagonism by the compound is calculated using the pre-drug vasopressin vasopressor response as 100%.

Oxvtocin Receptor indinr Membrane Preparation Female Sprague-Dawley rats weighing approximately 200-250 g are injected intramuscularly 162 *oe 9ee with 0.3 mg/kg of body weight of diethylstilbestrol (DES). The rats are sacrificed 18 hours later under pentobarbital anesthesia. The uteri are dissected out, cleaned of fat and connective tissues and rinsed in 50 ml of normal saline. The tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.

HC1, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 with three passes of 10 sec each. The homogenate is passed through two layers of cheesecloth and the filtrate centrifuged at 1000 x g for 10 minutes. The clear supernatant is removed and recentrifuged at 165,000 x g O for 30 minutes. The resulting pellet containing the oxytocin receptors is resuspended in 50.0 mM Tris.HC1 containing 5.0 mM MgCl2 at pH 7.4, to give a protein concentration of 2.5 mg/ml of tissue suspension. This preparation is used in subsequent binding assays with 3 H]oxytocin.

Radicliand Bindino Binding of 3,5-[3H]Oxytocin 3 H]OT) to its receptors is done in microtiter plates using 3 H]OT, at various concentrations, in an assay buffer of 50.0 mM Tris.HCI, pH 7.4 and containing 5.0 mM MgC12, and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg; 1,10-phenanthroline, 2.0 mg; trypsin, 10.0 mg; and PMSF, 0.3 mg per 100 ml of buffer solution. Nonspecific binding is determined in the presence of 1.0 uM unlabeled OT. The binding reaction is terminated after 60 minutes, at 22°C, by rapid filtration through glass 30 fiber filters using a Brandel® cell harvester (Biomedical Research and Development Laboratories, Inc., Gaithersburg, MD). Competition experiments are conducted at equilibrium using 1.0 nM 3 H]OT and varying the concentration of the displacing agents. The concentrations of agent displacing 50% of 3 H)OT at its *1 163 sites (IC50) are calculated by a computer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

Bindina Assay to Rat Hepatic VI Receptors and Rat Kidney Medullary V2 Recetors or *Bindinp to VI Receptor Subtype in Human vlateet and **Binding to membranes of Mouse Fihrobas CeP1 Line (LV-2) Transfected with the CDNA Expressing the Human V2 Receto Table I

V

1 v2 Ex. No. Structure IC 5 0

IC

5 0 (4iM) 0-1 0.24 0.054

N

04'~N~

NHCO

2 0.039 0.029 Q N S

C,"

3 o NHCO

-N

F

\44% at IC.LM 20% at N S S NHCO -t N-N

F

164 see*S 0:.0* t~ Cont'd.

v

I

1C 50

(M

v 2 c,9 0

(A~M)

Ex. No.

Strture 12 100% at 1pM 12 I20%Ia 'p 0 NEW 9 0 at AM 0 *72% 4&M) (14iM) 39% (b±M) 100% Op~m) .004, 4...o 4 4.

.0 4 04.04 165 Cont'd.

VI1 1C 50 pM) V 2 10 50 (9.M) Ex. No. Structure 46% (14M) *0.014 29% (1ljiM) .8

G

N

*6

S

C.

C.

6O S

S

C

9OgS

C.

C S

S.C.

e.g.

C C

S.

C C CS S 14 C 6'S

S

SOS

C

SC.'

t

S

CSSS CS

C

166 Cont'd.

vi IC50 (jiM) v 2 10 50 (4~M) Ex. No.

Structure 53% (104±M) 33%(IOIIlvV Co -o (1011m) 16% (101±M Co -o 34% (10;iM) 62% (109±M) 0 167 Vaso~rassin V2 Antagonist Activity InCons s Hydrated Ratj Ex. No. Dose N4 Urine volume Osmolality ma/ka) (mi/A hrs) (MOsm/kc) 78 13.3 .1 0.3 229 6 **12.1 147+5 4 1-2.4 ±0.8 361 76 2 0.2 1226 58 26 1 2 4 .5 i058 10 2 6.6 979 4 1 0 2 6 878 2 1 2 C..5 591 32 10 2 9.3. 726 2 10 2 1G. 5 591 24 10 1 2 14 3 1492 27 10 2 3.3 131:7 Water-load corntroi Warter-load Control' +DMSO(l0%) AV con tro 1 168 Vasopressin Antidiuretic (V 2 Response in Conscious Rats with Free Access t- Water 1rinking Before But Not During the Experiment: Male or female normotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) of 400-450 g of body weight were supplied with Laboratory Rodent Feed #5001 (PMI Feeds, Inc., Richmond, IN) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with stainless steel screens (to separate the feces from the urine) and funnels for collection of urine. Compounds, vehicle, or reference agent was given at various oral doses. During the test, rats were provided with no water or food. After dosing, urine was collected in graduated cylinders for four hours. Urine volume was measured. Urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA 02062). An aliquot of each urine collection was analyzed for Na*,K+ and C1- using ion specific electrodes a in Beckman E3 (Electrolyte 3) analyzer.

The vehicle used for testing compounds was dimethylsulfoxide (DMSO) in 2.5% preboiled starch.

Table IV list results with compounds tested by this procedure.

169 *6 ft ft ot o *o* Table TV Vasopressin V 2 Arvtagonist Activity in Conscious Rats Ex. No. Dose N Urine Volume Osmolality (mg/Kg) (ml/4 hrs) (MOsm/kg) S16 7-10±2 981±34 47 10 2 22.0 394 66 10 2 17.0 442 67 10 2 21.5 402 134 10 2 40.5 333 3 2 28 396 1 2 18.2 596 133 10 2 27.5 234 135 10 2 39.5 284 3 2 26.8 391 1 2 19.5 526 176 10 2 12.8 567 218 10 2 34 222 257 10 2 22.5 317 301 10 2 41.5 363 302 10 2 40 356 352 10 2 9.3 779 396 10 2 21.8 238 397 10 2 29.8 288 398 10 2 20.5 316 399 10 2 17.0 404 400 10 2 24.8 270 404 10 2 6 909 *Control DMSO corn starch Compounds were dissolved in DMSO and then diluted in corn starch (final concentration of DMSO was All rats were orally dosed with this mixture at 10mV kg, by gavage.

170 0000 ft

D

Table III Oxytocin Binding Assay Ex. No. Dose (JM) Inhibition IC50 (pM) 1 1 12 2 10 86 1.1 4 10 20 12 10 76 0.61 24 10 97 1.8 10 94 0.113 26 10 73 27 1 83 32 10 88 1.8 33 1 37 1 54 The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases. These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such crganic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds can also be used in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible 171 powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode cf administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals the total daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier.

This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies 30 of the therapeutic situation.

These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, 35 sucrose and kaolin, while liquid carriers include sterile water, polyethylene glyccls, non-ionic surfac- 172 *too 9 0 tants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hardfilled or liquid-filled capsules. Oral administration of the compounds is preferred.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exits.

30

I

t must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi.

The carrier can be a solvent or dispersion medium conaining, for example, water, ethanol glycerol, 35 propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

S* 173 *~oo

I

The new tricyclic non-peptide vasopressin antagonists of this invention are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

In particular, the vascpressin antagonists of this invention are therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosisbleeding and abnormal states cf water retention.

In particular, the cxytocin antagonists of this invention are useful in the prevention of preterm labor and premature birth which is a significant cause of infant health problems and infant mortality.

1

O

9 *9 174

Claims (7)

1. A compound selected from those ofE Formula RI 0 A-B 2 Formula I wherein- Y is selected from (CH2)n, C, S, NH, NCOCH3, N- lower alkyl (C_1 CH-lower zlkyl(Cl-C3), CHNH-lower alkyl(CI-C3), CHNH2, CHNflower alkyl (Cl-C_3)',2,CHO-lower alkyl(Cl-C3), CHS-lower alkyl(Cl-C3), wherein n is an integer from 0-2; A-B is (CH)m or N(CH 2 wherein m is an integer from 1-2, provided that when Y is -(CH2)n- and n= 2, m may also be zero and when n is zero, m may also be three, provided also that when Y is 2 (CH2)n- and n is 2, m may not also be two; Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -SH, -SO lower aly(lC) -S2lwrakl.lC) C-oe alkyl(Cl-C3), -S02, lower alkyl(C!jC3), -O-lower 30alkyl(C1-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(C1-C3)2, -S02NH2, -SO2NH lower alkyl (Cl-C3), cr-SO 2 Nrlower alkyl(Cl-C3)]2; R2 is hydrogen, C-1, Br, F, I, -OH, lower alkyl(Cl-C3), be 0-lower alkyl(C2.-C3), or R, and R2 taken together are methylenedioxy or ethylenedioxy; S. 175 &roe 90660 R3 is the moiety 0 11 CAr wherein Ar is a moiety selected from. the group R7 NWGC 2 S 0 Ny-TX R 10 and X is 0, S, -NCH-3 or -NH- R4 is selected from hydrogen, l.ower alkyl(Cl-C3), -CO- lower alky'L(CI!-C3); R5 and R7 are selected from hydrogen, (Cl-C3) lower alkyl, (C1-C3)lower alkoxy and halogen R6 is selected from moieties of the formula:

176- -NCOAr', .1 NCON-Ar, I I RR b -NCO(CH2) -cycloalkyl, -NCOCH 2 Ar', -N-SO 2 R -N-SO 2 CH 2 I/ R R 7 R II R2 -NSO 2 -lower a lkyl(C 3 -c 8 R 0I 2 -N-P \I I R 1 -NSO 2 -oe alkenyl(C 3 -C 8 0 1I -NH-C-0-Iower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl (C 3 -C)straigh t or branched, 0 11 -NH-C-0-Iower alkenyl(C 3 -C 8 )s traight or branched, 0 1I -NH-C-lower alkenyl(C 3 -C 8 )straigh t or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: 177 -(CH)q-N ~R (CH-)q -No R b -0 -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three; Rb is hYdrogen, -CH3 Or -C2H;;and a moiety of the formula: -X-RlG, wherein Rio is lower alkyI(Ci-C8), lower alken-.I(i-C8) -(CH 2 )p-cycloalkv1(C1-C6), R- R -(CH9 2)/ R-R N R-. R and p is zero to three; X is C, S, NH, NCH3, 178 I C= 0 or a bond and R-z and R7 are as previously defined. a moiety of the formula: 'Rb N -COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbran--hed, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(03-C8) branched or unbranched, -0-lower alkenvl(C03-C8) branched or unbranched, tetrahydrofuran, c et rah,.drothiophene, the moieties R 8 S 0 N or -CH-2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: D -N E *G F wherein D, E, F and G are selected from carbon or :nitrogen and wherein the carbon atoms may be optionallyv -179- substituted with halogen, (C 1 -C3) lower alkyl, hydroy,, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -Con- lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R I a COCHAr' 0 11 -0-C-lower alkyl (C 1 -C 3 R b NHQCH)q qN R R b 3-lowver alkyl(C 1 -C 3 NH(CH 2 )q CON Rb Rb 0- (CH) 2 N\' 9 9* 9 9 wherein Rc is selected from haloaen, (Cl-C3)lower alkyl. -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -180- 8 R8R R 9 N RA an-: R? are independently hydrogen, lower alkyl (Cl-C3V, 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3) -N-[lower alkyl(Cl-C3) 12, N(Rb) (CH2)q-N(Rb)2; W' is selected from 0, S, NH, N-lower alkyl (Cl-C3), -NCO-lower alkyl(Cl-C3), or NSO2,-lower alkyl(Cl-C3) R25 is selected from the moieties S R 8 CH 2 -bR 181 of** and the moiety Z0 represents: phenyl or substituted phenyl optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, halogen, amino, (Cl-C3)lower alkoxy, and (CI-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from C, Uj and S; a 96-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; a 5 or 6-membered aromatic (unsaturated) heterocyclic -,ina having two ni!tr:)en atoms, a membered aromatic (unsaturated) heterocyclic rina having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-rnembered heterocyclic rings are optionally substituted by (Cl-C3)lower alkyl, formyl, a moiety of the formula: (CH2 qN R Rb halogen or (Ci-2--3)lower alkoxyI; and the pharmaceuticall-,- acceptable salts, esters and pro-drua- forms thereof. 2. A compound according to Claim 1 wherein the moiety z 0 *represents a phenyl ring optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, to '25 halogen, amino, (Cl-C3)lower alkoxy and (Cl-C3)lower alkyl amino and n, m, VP, X, Y, A-B, Ra, Rb, RI, R2, P3, R4, R5, R6, P.7, R8, Ra. R10, are as previously 0 .:defined in Claim 1. -182- 3. A compound according to Claim 1 wherein the moiety Z represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and n, m, X, Y, A-B, Ra, Rb, RI, R2, R3, R4, R5, R6,R7, R8, R9, RI0, R25 are as previously defined in Claim 1. 4. A compound according to Claim 1 wherein the moiety Z represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms and Y, A-B, Ra, Rb, Rl, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) O 20 heterocyclic ring having one sulfur heteroatom and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R25 are as previously defined in Claim 1. 6. A compound according to Claim i wherein the moiety Z0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom and Y,

183- *•g *o oooeo I I A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R 8 R9, are as previously defined in Claim 1. 7. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R 6 R7, R8, R9, are as previously defined in Claim 1. 8. A compound according to Claim 1 wherein the moiety ZL represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and Y, A-B, Ra, Rb, R 1 R2, R3, R4, R5, R6, R7, R8, R9, RI0, are as previously defined in Claim 1. 9. A compound according to Claim 1 wherein the moiety Z 0O represents a fused 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom and Y, A-B, Ra, R b RI, R2, R3, R4 R 5 R 6 S* R7, R8, R9, R10, R25 are as previously defined in Claim 10. A compound according to Claim 1 wherein the moiety Z 184 •O o o represents a 5-inembered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom and Y, A-B, Ra, Rb, Ri, R2, R3, R 4 RS, R6, R7, R8, R9, R10, P25 are as previously defined in Claim 1. 11. A compound according to Claim 1 wherein the moiety ZO represent s a phenyl ring, optionally substituted bv one cr two substituents selected from (Ci1-Ci) lower alkyl, halogen, amino, (Cj-C3)lower alkoxy, and (Cl-C3)lower -ilkyl aimaino, Y ir- seleCLed frow -CII,2-, -CH-lower alkyl(C 1 -C 3 -CHNH 2 -C-HN(CH 3)2 ICN-oe ly C 1 C) -CH H-lower alkyl (C 1-C 3 -CHN(C 2 H 5 2 -CHS-lower alkyl(C 1 -C 3 to. to I. *Vo*. and A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 12. A compound according to Claim 1 wherein the moiety ZO represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, is selected from -CH2-, -185- -CH-Iower alkyl(C 1 _C 3 -CHNH 2 4CHNH-Iower alkvI (C IC) -CHO-lower aikv'1 (C 1 -C 3 -CHN(CH 3 2 -CHN(C 2 H 5 2 -CFIS-Iower alkyl(C 1 -C 3 and A-B, Ra, Rb, Ri, R2, R3, R4, Pr,, R6, R7, R8, RQ, are as previously defined in Claim 1. 13. A compound accordina to Claim IL wherein the moiety ZO represents a 6-rnembered aromatic (unsaturated) heterocyclic ring ha-ving two nitrogen heteroatoms, is selected from -CH2-, -CH-lower alkvl(C 1 -C 3 -CHNH 2 -CHNH-lower alkyl (C -C 3 -CHO-lower alkyl (C 1 -C 3 -CHN(CH 3)2 -CHN(C 2 H 5 2 too: It 0 to. -CHS-Iovver alkNl(C -C) 15 and A3B,Ra, Pb. RI, R2, R3, R4, R, R6, R7, R8, FO, are as previously defined in Claim 1. 14. A compound according to Claim 1 wherein -186- the moiety zO0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom wherein Y is selected from -CH-iower alkyl(C 1 -C 3 -CHNH 2 -CHN(CH 3)2 CHIoeaky(C-C) -CH H-lower alkyl (C -3) -CHN(C 2 H 5 2 -CHS-lower alkyl(C -C) and A.B, Ra, Rb, Pl, R2, R3, R4, R5, R6, R7, R8, R9, Rio, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moietv zo V. S S 5 0 S S S. S 00005S represents a 5-membered aromatic (unsaturated) 15 heterocylic rina having one oxygen heteroatom wherein Y is selected from -CR2-, -187- -Cl--lower alkyl(C 1-C 3 -CF!NH 2 4CHN(CH 3 2 -CHNH-lower alkyl (C 1 -C 3 -HO-lower alkyl (C 1-C 3 -C-HN(C 2 H 5 2 -CHS-lower alkyl(C 1 -C 3 and A-B, Ra, Rb, R1 R 2 R3, R 4 F.5, R6, R.7, R8, P9, Rio, are as previously defined in- Claim 1. 16. A% compound acordina to Claim 1 wherein the moiety ZO represents a 5-meinbered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, 7 is selected from -CH-lower alkyl(C 1 -C 3 -CHNH 2 -CHNH-lower alkvl (C 1 -C 3 -HO-lower alkyl K- -CHN(CH 3)2 -CHN(C 2 H 5 2 0 000* -CH-S-lower alkyl(C 1 -C 3 and A-B, Ra, Rb, Ri. R-1, R3, R4, R6, R7, RS, Ra, R25 are as previously defined in Claim 1. 17. A compound according to Claim 1 wherein -188- C. C 0 *0000* the moiety ZO represents a 5-membered aromatic (unsaturated) heter,:cylic ring having two nitrogen heteroatoms, y is selected from -CH2-, -CH-Iower alkyl(C 1 -C 3 -CHNH 2 ICN-oe ly -CH H-lower akv I (CI-C 3 0 -CHN(CH 3 -CHN(CIH 5 2 -CHS-Iower alkyl(C 1 -C 3 and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R1i, are as previously defined in Claim 1. 18. A compound according to Claim wherein the moiety zO represents a 5-membered aromatic (unsaturated) heteroc-yclic ring having one nitrogen and one sulfur heteroatom, Yis selected from -CH2-, -189- -CHl-Iower alkyl(C 1 -C 3 -CHNH 2 -CHNH-Iower alkvl C- -CHO-lower alkyl (C -C 3 -CHIN(CH 3)2 -CHN(C2 2 H 5 2 -CHS-lower alkvl(C -C) and A-B,Ra, Rb, Ri, R2, R3, R4, R6, R7, R8, P9-, Rio, are as previously defined in Claim 1 19. Acompound according to Claim I wherein the moiety Z0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is selected from -CH2-, -CH-towver alkvl(C 1 -C 3)' -CHINH 2 ICN-oe lv C 1 C) -CHH-lower alkyl (C -C -CHN(CH 3)2 -CHN(C 2 H 5 2 S S. S S. 55 *5 -CHS-Iower alkvl(C 1 3 and A--B,Ra, Rb. F.i, R-2, R4, Fc., R6, R7, R8, R9, Plo, P5 25 are as previously defined in Claim 1. A compound according to Claim 1 wherein -190- the moiety represents a phenyl ring, optionally substituted by one or two substituents selected from (Ci-C3)lower alkyl, halogen, amino, (C 1 -C3)lower alkoxy and (C1-C3)lower alkyl amino, Y is -(CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, RIC, R25 are as previously defined in Claim 1. 21. A compound according to Claim 1 wherein the moiety Z represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is (CH2)n, n is zero and A-B,Ra, Rb, R1, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 22. A compound according to Claim 1 wherein the moiety ZL represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is -(CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 25 23. A compound according to Claim 1 wherein 1 191 1 1 *f I M- the moiety ZJ represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom, Y is (CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 24. A compound according to Claim 1 wherein 1 the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom, Y is (CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is (CH2)n, n is zero and A-B,Ra, Rb, Ri, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. A compound according to claim 1 wherein S* S*

192- S. S**o the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is -(CH2)n, n is zero and A-B,Ra, Rb, R1, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 27. A compound according to Claim 1 wherein r the moiety ZL represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, Y is -(CH2)n, n is zero and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 28. A compound according to Claim 1 wherein the moiety ZL represents a 5-membered aromatic (unsaturated) 20 heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is -(CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as *previously defined in Claim 1. 29. A compound according to Claim 1 wherein 1 S193 S *oI the moiety Z O represents a phenyl or substituted phenyl ring, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (Cl-C3) and and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, RI0, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moiety Z represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, RIO, are as previously defined in Claim 1. 31. A compound according to Claim 1 wherein the moiety ZL represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is a selected from O, S, NH, NCOCH3, and N-lower alkyl (C1-C3) and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, RT, R8, R9, R10, R25 are as previously defined in Claim 1. 32. A compound according to Claim 1 wherein the moiety Z *9 S194 a represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom, Y is selected from 0, S, NH, NCOCH3, and N-lower alkyl (C1-C3) and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 33. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom, Y is Sselected from 0, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, RI0, are as previously defined in Claim 1. 34. A compound according to Claim 1 wherein the moiety ZL represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, RI0, are as previously defined in Claim 1. 0 35. A compound according to Claim 1 wherein the moiety Z 25 represents a 5-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is selected from 0, S, NH, NCOCH3 and N-lower alkyl (Ci-C3) 195 and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, RI0 are as previously defined in Claim 1. 36. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, Y is selected from O, S, NH, NCOCH3 and N- lower alkyl (C1-C3) and A-B,Ra, Rb, R1, R2, R3, R4, R6, R7, Rg, R9, R10, R25 are as previously defined in Claim 1. 37. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is selected from 0, S, NH, NCOCH3 and N- lower alkyl (CI-C3) and A-B,Ra, Rb, R1, R2, R3, R4, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 38. A compound according to Claim wherein Y is selected from -(CH2)n-, 196 p *e o*o o eeo** -Cl--lower alkyl (C 1 -C 3 -CHMNH 2 ICN-oe ly C 1 C) -CH H-lower alkyl (C -C 3 -CHN(CH 3 2 -CHN(C2 H 5 2 -CHS-lower alkyl(C 1 -C 3 wherein n is an integer zero or one; R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the aroun x-R 0 /R7I-2 X-RI S and R6 is selected from the group a 197 a a. 0 .000 0 -NCOAr' Ra NCO(CH 2 )n -cycloalkyl, I -NCOCH 2 Ar' -NCONAr', I I RR b -X-R 1 0 wherein Ar' is selected from the croup R 5 R R 8 R 9 W W' is 0 or S; A-B,Ra, Rb, R1p R25, X, cycloalkyl and R R I N R R2, P4, R5, R7, RS, R9, the moieh, zO are as previously defined in Claim 1. 39. A compound according to Claim 1 wherein Y is selected from -CH2-, C C. C C *CCC C. C C .e*C 9*C* C C C C C CC C C 198 C C -CH-Iower alkyl(C 1 -c 3 -CHNH2,; -4HN(CH 3 2 -CHNH-Iower alkyl (C 1 -C 3 -CHO-lower alkyl (C 1 -C 3 -CHN(C 2 H,) 2 -CHS-Iower alkyl(C 1 -C 3 R3 is the moiety 0 11 -CAr 0. 00 00 0 t00 0 *0S# .S0* SICA 00 0 0 0400 *0* 0 4. 0 04*) *0 *0 0 9) 0 00 *0 0.0*00 0 199 0000 0 .000 0 *00600 0 wherein Ar is a moiety selected from the group X-R 1 0 R 7 X-RW S 0 N-r X -Ric and R6 is selected from the group -NCOAr' R1 -NC0(CH2)n -cycloalkyl, Ra -NCOCH 2 Ar' I -NCONAr', I I R a Rh wherein Ar' is selected from the group -200- W' is 0 or S; A-B,Ra, Rb, R1, R2, R4, R25, X and cycloalkyl and R5, R7, R8, R9, thie moiety zO 0 are as previously defined in Claim 1. a compound according to is selected from -CH2-, Claim I wherein Y -CH-lower alkyl(C 1 -C 3 -CHNH 2 ICN-oe lkl( 1 C) -CHH-lower alkyl (C -C -CHN(CH 3 2 -CHN(C 2 H 5 2 -CHS-Iower alkyl(C -C) R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group -201- R 5 R R 5 R7 5 0 R7 1 and R6 is selected from the group -NCOAr' -NC0(CH29r -cycloalkyl, a a 0-NCOCH Ar NCONAr', -X-R 1 K R R 202 wherein Ar' is selected from the group R 8 R 6 .O 9R R 9 WN and W is 0 or S; and *thle moiety Z 0 represents a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Cl-C3)lower alkoxy and (Cl-C3)lower alkyl amino and A-B,Ra, Rb, R1, R2, R4, R5, R7, R8, R9, R25, X and cycloalkyl are as previously defined in Claim 1. 41. A compound according to claim 1 wherein Y is wherein n is an integer zero; R3 is the moiety 0 CAr wherein Ar is a moiety selected from the group 203 f3X-RIO S X-I NHCO 2 X -Ri and R6 is selected from the group -NCOAr' -NCO(CH 2 )n -cycloalkyl, I I K K -NCOCH 2 Ar' -NCONAr', I I RA b S S. S wherein Ar' is selev:.ed from the group RI RRO R 3 R. N R andw, is 0or S; and -204- M -M the moiety Z0 represents a phenyl ring optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, haloaen, amino, (Cl-C3)lower alkyl amino and A-B,Ra, Rb, R1, P2-, R4, R5, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1. 42. A compound according to Claim 1 wherein Y is selected from 0, S, NH, NCOCHi and N-lower alkyl Ri iJS the moiety 0 11 -CAr wherein Ar is a moiety selected from the group 205 I X R 1 X-RI S -F0 ,-R 0 7- and R6 is selected from the group -NCOAr -NCO(CH-,) n -cycloalkyl, R aRa -NCOCH 2 Ar' -NCONAr', I I RIR b a wherein Ar' is selected from the group R8 R 5 81 yR R R 5 R arnd W' is 0 or S; and -2o6- the moiety represents a phenyl ring optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, halogen, amino, (Cl-C3)lower alkoxy and (Cl-C3)lower alkyl amino and A-BRa, Rb, Ri, R2, R4, R5, R8, R9, Pi0, P25, XK and cycloalkyl are as previously, defined in Claim 1. 43. A compound according to Claim 1 wherein Y is n is an integer zero; *607 R3 is the moiety -CAr wherein Ar is a moiety selected from the group R X-RI S 4 X-RIO 0 -Rio and Rr, is selected from the croup -NCOAr' -NCO(CH9 -cvcloalkyl, R R 4* V. *6 V 0 -NCOCH 2 Ar' -NCONAr', I I R Rb -X-R 1 0 wherein Ar' is selected from the group V* OV V VV. S V 208 and W is 0 or S; and the i-noiety zO represents a 6-inerbered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom A-B,Pa, Rb, RI, P2, R4, R5, R-1, R8, R9, RIO, R25, X and cycloalkyl are as previously defined in Claim 1. 44. A compound according to claim 1 wherein Y is -CH2-; R3 is the moiety -CAr wherein Ar is a moiety selected from the group S a. a a -209- X-RO F -I S R 7 R_ 0 RR 1 and R6 is selected from the group -NCOAr' Ra -NC0(CH 2 -cycloalkyl, IR) -NCOCH 1 Ar' Ri -NCONAr', I I wherein Ar'; is selected from he croup R, 8 R 8 R W' and W% is 0 or S; and 210 the moiety zO 0 represents a 6-rnembered aromatic (unsaturaced) heterocyclic ring having one nitrogen heteroatom A-B,Ra, Rb, R1, R2, R-4, R5, P.7, R8, R9, R10, R.25, X and cycloalkyl are as previously defined in Claim 1. A compound according to Claim 1 wherein Y is n is an integer zero; R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group R R6 R 5 R 7 X-RO -I I0S S* 0 X-R and P.6 is selected from the group 211 -NCOAr' RI -NCO(CH 2 )n -cvcloalkyl, -NCOCH 2 Ar' -NCON Ar', Ra Rb wherein Ar' is selecrted f rom the group, R 9 W and W' is 0 or S; and the moiety zO a represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-E,Ra, Rb, R4, F5, P7, R8 R9, P.10, P 2 5, and cycloalky. are as previously defined in Claim 1. 46. A compound according to Claim 1 wherein 15 is -CR2-; R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group -212- X-R 0 'NY S NfrCM 5 4X-Rl 0 0 -Rio and R6 is selected from the group -NCOAr' -NC0(CH 2) -cycloalkyl, a -NCOCH 2 Ar' -NCONAr', I I RR b -X-R 10 a. wherein Ar' is selected from the croup R R 8 R9 R 5 R and W' is 0 or S; and 213 the moiety zO represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-B,Pa, Rb, R1, R2, R4, P7, R8, Rq, R~io, R25, X and cycloalkyl are as prev.:iously defined in Claim 1. 47. A compound according to Claim 1 wherein Y is selected from C, S, NH, NCOCH?. f-lower alkvl (C-l-C3); R3 is the moiet-y. 0 CAr wherein Ar is a moiety selected from the group SX-RIO X-RI S 1 S S S Ni-CO G 2 5 0 -Rio and R,6 is selected from the group 214 -NCOAr' -NCO(CH 2 cycoalkyl, -NCOCH- 2 Ar' wherein Ar' is selected -NCONAr', I I R.1Rb from the group R R 8 N and W' is 0 or S; and the moiety zO0 represents a 5-inembered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-B,Ra, Rb, R1, R2, R4, R5, R-7, R8, R9, RIO, R25, X and cvcloalkvl are as previously defined in Claim 1. 48. A compound selected from those of the formulae: a a a. a. a a a a. a a. a a a a a a a and R/ 1- 1 N-(H 2 M wherein m is an integer one or two; -215- -v P.1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkyl(Cl-C_ 3 -SC-lower alkyl (Cl-C3), -CO-lower alkyl(ci-c3), -CF-z, lower alkyl(CI-C3), 0-lower alkyl(CI'-C3), -NH2, -NHCO lower alkyl(Cl-C 3 -N-[owe alyl(i-C3)12, -SO2NH2; -S02NH- lower alkyl (Cl-C3), or -S2111lower alkyl(Cl-C3)1; R-2 is hydrogen, Cl, Bre, F, I, -OH, lower alkyl(CI-C 3 0-lower alkyl(Cl-C3), or Pl and P2 taken together are methylenedioxv or ethylenedioxy; R.3 is the moiety: CAr wherein Ar is selected from moieties of the formula: R 5 R 7 X-R J'X- NFEORZ 010 S. an R7aeslce.rmhdoe,(lC)oe alkyl (C-3lwrakyadhlgn R6isseecedfom(aN mieiecf hefomua S.216 -NCOAr', I NCON-Ar, I I <a Rb -NCO(CH~) -cvcloalkyl, IR) -NCOCI- 2 Ar', -N-SO 2 RK RL N-SO C2 a 0 R2 I I] Ra R.. -NSO,-lower alkvl (C 3 -C 8 0 1I -N-P I 1 -NSO 2 -lower alkenyl(C -C 8 Ra 0 11 -NH-C-O-lowver alkyl(C -C 8 straight or branched 0 -NH-C-lower alkyl(C 3 -C 5 )straight or branched, 0 11 -NH-C-O-lowver alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C,)straight or branched, wherein cycloalky. is defined as C3 tO C6 cycloalkyl, cyclohexenyl or cycJlopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: 0* 0 0 000000 0 (CH 2 )q -N (CH 2 )q N Rlb (CF N-(CH)q -N 0 -(CH2()2-O-lower alkyl(C 1 -C 3 or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH31 or -r02H5;and a moiety of the formula: -X-Rlo, wherein Rio is lower alkyl(C3--C8)L lower alkenvl(C3-C8). -(0H2)p-cycloalkyl(C3-C6), R N R .{CIH2) p s 0 and p iszero to three; X is Q, S, NF-, NCH3, -218- C= 0 or a bond and R7 are as previously defined. a moiety of the formula: N -COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahy~drofuran, tetrahydrothiophene, the moieties R 8 S 0 N C or2H-~'w~r o -CH-K' her i Y is halogen, -OH, tetrahydrofuran, tetrahydrothiJophene or the heterocyclic ring moiety: -N zD E G==F -219- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3) lower alkyl, hydrox, -CO-lower alkYl(Cl-C3)L CHO, (C-C3)lower alkoxy, -C02- alkyl(Cl-C3), and Ra and R-b are as hereinbefore defined; a moiety selected from those cf the formulae: R I a N- CCHAr' R C -0-C-lower alkyl(CI-C 3 3-lower alkvl(C -C 3 NH(CH 2 q CON R 0 -y 2 -R R b NH(CH) q- N b R b a a a a. a a a a a a. a a a. a a. a wherein RC is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH, Rb is as hereinbefore defined; Ar' is a moiety selected from the group -220- S RS and PR9 are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(C1-C3) S-lower alkyl(Cl-C3), -CF3, -CNI, -OH, -SCF3, -OCF3, halogen, N02, amino, or NH-lower alkyl(Cl-C3); N-[lower alkyl(Cl-C3)]2, -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties X A N so9 moss *5#S S S S. S S S S S W' is 0, S, NHu-, N-lower alkyl(Cl-C3), NCO-lower alkyl(Cl-C3) or NSO2-lower alkyl(Cl-C3) or NS02 lower -221- alky'l(Ci1-C3) and the pharmaceutically acceptable salts thereof. 49. A compound selected from those of the fo'rmula: Y F N R 3 wherein is selected from 0, S. NH, and 11-lower alkvl(CI-C3); Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl (cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[lower alkyl(Cl-C3)]2, -NH lower alkyl(C.l-C3) -S02NH2; -SO2NH lower alkyl(CI-C3),or -SO2Nflower alkyl(Cl-C3)12; P2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Pl and taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: 0 11 CAr ,Dose*wherein Ar is selected from moieties of the formula: 1 1% 0 0-222- R RR NFCO2 -3-X-R 0 0 P; and R7 are selected from hydrogen, (Cl-C3)lower alkyl, (CI-C3)lower alkoxy and halogen; BR6 is selected from moieties cf the formula: *-223 -NCOAr', I NCOCH 2 Ar' I -NCON-Ar, I I R aR b -N-SO 2 a -NCO(CH )n Ra -cycloalkyl, -N-SO 2 CH 2 aR 0 R -N-P RI _NSO,-Iowver alkyl(C I-C 8 R 0 11 -N-P R 12 -NSO 2 -lower alkenyl(C 3 -C 8 0 -NH-C-O-lower alkyl(C -C 8 )straight or branched 0 1I -NH--C-lower alkyl(C -C )straight or branched, 0 11 -NH-C-O-lower alkenvl(C -C 8 )straight or branched, 03 300 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, wherein cycloalkyl is defined as Ci rto C6 cyc2.oalkyl, cyclohexenyl or cyclopentelyl; Ra is hydrogen, CH3, C25 moieties of the formulae: -224- -(CH)q -N R b ~~F1ND Noj (CH- N 0 -(CH2)2-O-lower alkyl(C1-C3) or -CH-2CH2OH; q is one, two or three Rb is h-ydrogen, -CH3 or a moiety of the formula: -X-lOwherein R10 is lower alkyl(03-C8), lower alkenv1 (C3-C8), -(CH2)p-cycloalkyl(C3-C6), N a a. a. a a. a R 0 and p is zero to three; X is 0, S, NH, NCH3 225 a M I C- 0 or a bond and and P-7 are as previously defined. a moietx' of the formula: Rb N N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-CB) branched or unbranched, -0-lower alkyl(CI-CS) branched or- unbranched, -0-lower alkenylI(C?-03-) branched or unbranched, te~rahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 N 00.. o*.zD *o *N F or-CH2E' werei K i ha-2e2.-O, ethyruan wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C 3 lower alkyl, hydroxy', -CO-lower alkyl(CI-'-C3), CHO, (Cl-C3)lower alkoxy,-02 lower alkyl(Cl-Ci), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- COCHAr' -0-C-lowver alkvl (C -C) Sf-~ NN R b NH(CH) q-N -S-lower alkyl(C 1 -C 3 NHCH 2 )q CON R Rb 0- (CI-y2 S S. S S *5 S *5 S S. S S. wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH, Rb is as hereinbef ore defined; Ar' is a moiet-Y selected from the group -227- S S 7, R 0 S R N 'R 8 1 N R8 and R9- are independently hydrogen, lower alk-yl (Cl-C3), 0-lower alkyl(C1-C 3 -lower aJlkyl(Cl-C 3 -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or NH-lower alkyl(Cl-C3); N-[lower alkYl(Cl-C 3 )1 2 N(Rb) (CH2)q-N(Rb)2; is selected from the moieties -b S R 0 -'28 W1 is 0, S, NH, N-lower alkyl(Cl-C3), NCO-lower alkyl(Cl-C3) or NSO2-lower alkyl(Cl-C3) or NS02 lower alkyl(Cl-C3) and the pharmaceutically acceptable salts thereof. 50. The compound according to claim 1, l1-Dihydro-5!i-dibenz~b,elazepin-5-yl)carbonylI-2- pyridinyl] [1,l1 biphenyl I-2-carboxamide. 51. The compound according to claim 1, 11-Dihydro-5ai-dibenztb,e~azepin-5-yl)carbonyl)-2- pyridinyll -2-dimethylamino pyridine-3-carboxamide. 52. The compound according to claim 1, 11-[5- l0-Dihydro-4li-thieno[2,3-r.3 [llbenzazepin-9- 0 yl)carbonyl]-2-pyridinyl] [1,1'-biphenyl)--2-carboxamide. 53. The comp~ound according to claim 1, l0-Dihydro-41-t,-hieno Il]benzazepin-9- yl) carbonyl] -2-pyridinyl] -2-dimethylamino pyridine-3- carboxamide. 54. The compound according to claim 1, l0-Dihydro-5li-thieno[3,2-r.] yl)carbonyll-2--pyridinyll l'-biphenyl]-2-carboxanide. The compound according to claim 1, L7- (4,l0-Dihydro-5w.-thieno[3,2-.-] yl) carbonyl] -2-pyridinyl] -2-dimethylamino pyridine-3- carboxamide. 56. The compound according to claim 1, 0 10-Dihydro-4.-thieno 3--.][llbenzazepin-9- yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide. 57. The compound according to claim I, l0-Dihydro-5!i-thieno[3,2,-.] yl) carbonyl]-2-pyr-idinyl]-5-fluoro-2-methylbenzamide. 58. The compound according to claim 1, (4,5-Dihydropyrazolo[4,,3-dj [l)benzazepin-6'(lH)- yl) carbonyl] -2-pyridinyl]-2-dimethylamino pyridine-3- carboxarnide. -229- 230 59. The compound according to claim 1, N-[5-[(4,5-Dihydropyrazolo[4,3- d] [l1]benzazepin-6(1II-yl)carbonyl] -2pyridinyll5 fluoro2meffiylbenide. The compound according to claim 1, N-[5(periodll2,3-b][1 (6I1)-ylcarbonyl)-2-pyrdiflyl-5-fluoro2methyl benzamide. 61. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective amount of a compound of any one of claims 1 to 62. A method of treating diseases characterised by excess renal reabsorption of water as well as congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia in a mammal comprising administering a compound of any one of claims 1 to 60 or of a composition of claim 61 to said mammal in an amount effective to alleviate the disease. 63. A process for preparing a compound of the formula: Formula I wherein Y is (CH 2 0, S. NH, NCOCH 3 N-lower alkyl (CI-C 3 CH-lower alkyl (C 1 C 3 CHNH-lower alkyl (Cl-C 3 CHNH 2 CHN~Lower alkyl (C 1 -C 3 2 CHIO-lower alkyl (Cl-C 3 CHS-lower (Cl-C 3 wherein n is an integer from 0-2; [n:\Iibc]02417:JCT A-B is (CH 2 )m-N or N -(CH 2 M R 3 wherein mn is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, mn may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, mn may not also be two; Rl is selected from the group of hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -So lower alkyl(Cl-C3), -S02 lower alkyl(Cl-C.3), -CO-lower alkyl(Cl-C3), -CF3, 'Lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), 0-lower alkyl(C1- C3), -N02, -NH2, -NHCO lower alkyl(C:'-C3), -N-[lower alkyl(Cl-C3fl2, -SO2NH2, -SO2NH lower alkyl(Cl-C3), S02N[lower alkyl(Cl-C3)]2; R2 is selected from the group of hydrogen, Cl, Br, F, I -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C-3), or R- and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety 0 11 CAr wherein Ar is a moiety selected from t he group 03 r R _x-R 1 0 R 7 R_ NCO 2 _X-Rlo S _F X-RIO 0 R4 is hydrogen, lower alky1(Cl-C3); -CO-lower alkyl (C1-C3); and R7 are selected from the group, hydrogen, (Cl-C3)lower- alkyl, (Cl-C3)lower alkoxy and halogen R6 is selected from moieties of" the formulae: S S S. 232 -NCOAr', NCON-Ar, I I RA R b -NCO(C- 2 -cvcloalkyl, IR -NCOCH 2 Ar, -N-SO 2 Ka R_ -N-SO2 CH 2 Ra 06 0R2 I I] -N-P I2 _NSO,-lower a lkvI(C -C 8 R 0I 2 -N-P 2 R -7 -NSO -oe alkenyl(C 3 -C 8 S a a 0 11 -NH-C-O-Iower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkvl(C -C 8 )straight or branched, 0 NH-C-0-lower alkenyl (C -C)straight or branched, 0 -NH-C-lower alkenyl(C -C,)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl: R& is hydrogen, CH3, C2H5, moieties of the formulae: 233 (CH )q -N No b p (CH )q-N 0 -iCH2)2-O-lower alkyl(Cl-C3) or -CH)CH2J-; q is one, two or three; Rb is hydrogen, -CH3 or and a moietv the formula: -X-Rlco is lower alk1v*(1C?-C8) lowier alkenyl (Ci-Cp, -(CH2) 0 -cycloalk2. (C1-C 6 R 5 R R 7 R_ -{H)N R. 300 and p is zero to three; X is 0, S, NH, NCH-3, -234- NK C=0 or a bond and R5 and R7 are as previously defined. a moiety of the formula: R b NCOJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched. -0-lower alkyl(C3-C3branched or unbranched, -0-lower alkenl (C 3 -C8)braflched or unbranched, tetrahydrofuran, tetrahydrothiophene. the moieties X N 0 or -CH2-K wherein Y is halogen, -OH, tetrahydrofuran, tetrahyvdrothiopDhene or the heterocyclic ring moiety: -N E G=F -235- wherein D, E, F and G are selected from carbon or nitrogen and whereini the carbon atoms may be optionally substituted with halogen, (Cl-C-0 lower alkyl, hydrox -CO-lower alkYl(Cl-C3), CHO, (CI-C_3)lower alkoxy, -C02- lower alkyl(Ci-Cj), and Ra and Fi- are as hereinbefore de f ined; a mc)iety selected from those :of the formulae: R N N- COCHMr R C -0-C-lower alkyl (C 1 -C 3 S- CHA -NRb R b NHQ Fq -N -S-lower alkyl(C 1 -C 3 '1'Rb N(CH 2 -CON Rb Rb 2 b 0 00 wherein Rc is selected from halogen, (Cl-C3)lower alkvl, -0-lower alkvl(Ci'-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group -23 6- R 4 N Re and Ro are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CNI, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); -N-[lower alkyl (Cl-C3) )2, N(Rb)(CH2)q -N(Rb)2; is selected from the moieties S 0 0 N 0 C H 2 a -237- the moiety ZO0 represents: phenyl1 or substituted phenyl optionally substituted by one or two substituents selected from (C-j-Ci)lower alkyl, halogen, amino, (CI-C3)lower alkoxy, and (Cl-C-3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from 0, N and S; a 6-membered aromatic (unsaturated) heterocy,.clic ring having one nitrogen atom; a 5 or 6-membered aromatic (unsaturated) heterocvclic ring havin two nitrogen atoms; a membered aromatic (unsaturated) heterocyclic ring having one nitr-ogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (Cl-C3)lower alkyl, formyl, a moiety of the formula: (CH 2 q N Rb halogen or (Cl-C3)lower alkoxy; which comprises reactina a compound of the formulae: 0 0 se. *-238- with a compound of the formula: 0 Ar-C-Q wnerein the moiety represented by the formula is an aroyl chloride or an aryl carboxylic acid which has been activated by conversion to a mixed anhydride or activated with a peptide coupling reagent to give compounds of the Formula 1. 64. A compound selected from those of the formula:R N N R and ON p N N wherein Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO- lower alkyl(Cl-C3), -S02-lower alkyl(Ci-C 3 -CO-lower alkyl(C1-Ci), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[lower alkyl(Cl-C3)]2, -SO2NH2; -SO2NH lower alkyl(CI-C3), or -SO2Ntlower alkyl(Cl-C3) 12; R2 is hydrogen, Cl, Br, F, 1, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: CAr wherein Ar is selected from moieties of the formulae: -239- 7* R ~NHCGR 23 R- 0 S 0 N-rX -Ri 'Ij- and X is 0, S, -N4CH3, or -NH: R is independently selected from hydrogen, lower alkyl(Cl-C3), -(CH N (C f )q N (C 1 )q ND (CH 2 )q -N 0 -(CHn)q-OH, -(CH2)q-0alkYl(CliC3); q is one, two or three; R4 is selected from hydrogen, lower- alkyl(Cl-C3)b-CO- lower alkyl (Cl-C3), P5 and R7 are selected from hydrogen, (Cl-03)lower alkyl, (Cl-C3)lower alkoxy and halogen; -240- I R6 is selected from moieties of the formulae: -NCOAr', a NCON-Ar, I I R. R b -NCO(CH) -cNvcloalkvl, IR) -NCOCH 2 Ar' R -N-SO 2 R 9 -2 R 7 N-SO 2 CH 2 R S 0 R2 -N-P a L R 7 2 -NSO 2 -lower alkyl(C 3 -C 8 0 11 -N-P R a 12 -NSO 2 -oe alkenyl(C 3 -CS) a ft* 0 11 -NH-C-O-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alky 1(C -C)straight or branched, 0 -NH-C-O-lower alkenyl(C 3 -C,)straight or branched, 0 11 -NH-C-lowver alkenyl(C -C 5 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl. or cyclopentenyl; Ra is hydrogen, CH3. C2H5, moieties of the formulae: -241- (CHAq- N R b ND (C)q N 0 -(CH2.)2-OD-iower alkyl(Cl-C3) or -CH2C'H2OH; q is one, two or three; Rb is hydrogen, -CH3 Or -02H5; and a moiety of .he formula: -X-RlC,; wherein'RIo is lower alkyl (C3-CB) lower alkenyl (C3-C8), -(CH2)p-CYCioalkyl(C3-C6), -(CH 2 )P R -(CI-yp -4) N a a a. a. a a a .a.a a a R. 0 a a *.aa a a a a. a a a a. a and p is zero to three: X is 0, S, NH, NCH3, -242- *a.a a a .aa a a C=0 or a bond and R5 and R7 are as previously defined. a moiety of the formula: COJ wherein J is Ra, lower alkyl(C3-Cg) branched or S unbranched, lower alkenyl(C3-Cg) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R8 S X b- 0 N or -CH2-yK wherein Y' is halogen, -OH, tetrahydrcfuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G=F -243- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3). CHO, (Cl-Ci)lower alkoxy, -C02- lower alk-yl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moietYv selected from those of the formulae: R N COCHAr' 0 11 -0-C-lower alkyl (C -C) R,: NHQ 2 I N R -S-lower alkyl(C 1 -C 3 ~Rb ~NH(H0- -CN2-N 9e a. a. a a a. a wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(CI-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -244- a R_ R RR 9 W\ R 9 R N R 1 N R8 and Ro are independently hydrogen, lower alkyl (CI-C3) 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -ON, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); N-[lower alkyl(Cl-C3)12, N(Rb)(CH2)q -N(Rb)2; is selected from the moieties. S 0 N 9R GCH 2 -bR W' is selected from 0, S. NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3), or NSO2-lower alkyl(Cl-C3); and the pharmaceutically acceptable salts thereof. .:-245- A compound selected from those of the formula: R R R Ri N 1 and N wherein Pl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkvl(Cl-C3), -SH, -So- lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -NO2, -NH-2, -1NHCO lower alkyl(Cl-C3), -N-[lower alkyl(Cl-Ci)12, -SO2NH2; -SO2NH- lower alkyl(Cl-CB), or -SO2N[lower alkyl(Cl-C3) 12; R2 is hydrogen, Cl, Br, F, I, -0OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and P2 taken together are methylenedioxy, or ethvlenedioxy; P3 is the moiety: 0 1i CAr wherein Ar is selected from moieties of the formula: *-246 X-R 10 7 3 X-RIO S 0 N--r7X -RIO R. is independently selected from hydrogen, lower alkyl (Cl-C3), (CH)q -N Rb (?H)1J-ND -(CH 2 -(CH2)q0O-alkYl(Cl-C3); q is one or two; R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (CI-C3); R; and R7 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen R6 is selected from moieties of the formula: C -247- -NCOAr', -NCOCH 2 Ar' 0 II R K -NCON-Ar, R R b /-N-SO 9 2 1 -NCO(CH: )n -cvcloalkyl, R 7 0 -N-P R N-SQ-CH.) R NSO 2 -loAwer alkvl(C 3 -C 8 R, -NSO 2 -lowver alkenyl(C 3 -CS) R C C C. C. 6 e.g C C C* C 6 C C C gIp 06 CC C PC 9 C C C. C 0 11 -NH-C-0-Iower aIkvI(C 3-C 8 straiglit or branched 0 11 -NH-C-lower alkyl(C -C 8 )straight or branched, 0 -NH-C-0-lower alkenyl(C 3 -C)tahtobaned 0 -NH-C-lower alkenyl(C 3 -C)tag obrnhd wherein cvc loalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopenteflyl; Ra is hydrogen, CH3, C2H;, moieties of the formulae: -248- C C -M I M /RIb H- No (CH )q -N 0 -(CH2)--O-lower alkyl(Cl-C3) or -CH2CH2I-; q is one, two or three; Rb is hvdroaen, -CH3 or a moiety of the formula: -X-RlC; wherein Ri1o is lower alkvl,(C3-C8). lower alkenyl (C3-C8) -(CH2)p-cycloalkyl(C3-C6), R 5 -(CH 2 )P *00. 00:* 0 *00* .0. R, 0 and p is zero to three: X is 0, S, NH, NCH3, -249- "I C=0 or a bond and R5 and P" are as previously defined a moiety of the formula: Tb 4- COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenvyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-CB) branched or unbranched, -C-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties N 00* 0..00: .00. 0 0:0. Or -CH2-1- wherein K' is halogen, -OH, tetrahyrofuran, tetrahydrothiophele or the heterocycl-ic ring moiety,: N E G=F -250- wherein D. E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydrox,, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy. -Ca 2 lower alkyl(Cl-C3), anid Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R COCHMr 0 -0-C-lower alkyl (C 1 -C 3 R b NH(C' 1 q- N~ -S-lower alkyl(C -C3 ~NH(CH 2 )q -CON R Rb Ab Rb ZRb, 0 (C H )2 N wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -251- R 8 R 9 WS R-. N R R 4R RS and Ra are independently hydrogen, lower alkyl(Ci- C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, 1,02, amino, or lower alkvl(Cl-C3); -N-[lower alkyl(Cl-C3)12, N(Rb) (CH2) qN (Rb) 2; is selected from the moieties 2 8 R8 -252- W' is selected from 0, S, NH-, N-lower alkyl (Cl-C3), -NqCO-1.ower alkyl(C1-C3). or NSO2-lower alkyl(Cl-C 3 and pharmaceutically acceptable salts thereof. 66. A compound selected from those of the formula: R RI S R R and R 2 N R2 N R R 3 R 3 wherein R.1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO- lower alkyl (C1-C3), -SO2-lower alkyl(Cl-C3) ,-CO-lower alkyl(Cj-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(Cl-C3))2, -SO2NH2; -SO2NH lower alkyl(ICl-C3), or -SO2N~lower alkyl(Cl-C3) 12; R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: 253 KF X- 0 0 N- X -Rio NS R is independently selected from hydrogen, halogen lower alkyl(Cl-C3), (CH N Rb ND -(CFH)q -N 0 -(CH2)q-OH, -(CH2})q0alkyl(Cl-C3); q is one or two; R4 is sele-Led from hydrogen, lower alkI%l(Cl-C3), -CO-lower alkyl Rq is hydrogen, -CH-3,-C-2H5, Cl, Er, F, -O-CH3, or -0- t* -254- and P7 are selected from hydrogen, (Cl-C3)lower alkyl, (C,'-03)lower alkoxy and halog-en: R6 is selected from moieties of the formula: -NCOAr', -NCOCH-,Ar' -NCON-Ar, I I R.1 Rb -N-SO 2 I -NCO(CH -cycloalky, -R -N-SO. 9 CH 2 RAR. 0 0 R II 0 11 -N-P R -NSO -lower alkyl(C -C 8 Xa -NSO 2 loe alkenyl(C 3 -C 8 I 0 IV. a CO-. *600 St. 0 11 -NH-C-O-lower alkyl(C 3 -C.)straight or branched 0 11 -NH-C-lower alky](Cf-C,)straight or branched, 0 11 -NH-C-O-Iower alkenyl(C -C 8 straight or branched, 0 -NH-C-lower alkenyl(C -C 5 )straight or branched, -255- wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopeltefyl; Ra is hydrogen, CH3, moieies of the formulae: (CH 2 N (CH 2 No (Cl- )q -N 0 09 N D -(CH 2 )2-O-lower alkyl(Ci--C3) or -CHCH2OH; q is one, two or three; Rb is hydrogen, -CH3 or and a moiety of the formula: -X-RlO; wherein RIO is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH 2 )p-cycloalkyl(C3-C6), -(CH 2 )P R.. {CH 2 )p 0 and p is zero to three: X is 0, NH, NCH3. -256- C=0 or abond and R; and R7 are as previously defined a moiety of the formula: Rb COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl,(C3-CS)branched or unbranched, 0-lower alky-l(Ci-C-) branched or unbranched, -0-lower alken%*I(C 3-CS) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S b- 0 N or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophele or the heterocyclic ring moiety: -N E G=F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally -257- substituted with halogen, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(Ci-C3)), CHO, (C1-C3)lower alkony, -C0 2 lower alkyl(Cl-C 3 and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R I COCHAr' 0 -0-C-lower alkyl (C -C) Rt, I -S-lower alkyl(C 1 -C 3 ~NH(CH)q -CON R Rb o- ICKH,) 2 N\ wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar; is selected from the croup: -258- RR NN R N R8 and R9 are independent~ly hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(CI-C3), -CF3. -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3) ;-N-tlower alkyl(Cl-C3) ]2, N(Rb) (CH2)q-N(Rb)2; is selected from the moieties S -X 0 N CH2 R 8 00 0: -259- a 0 M W, is selected from 0, S. NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3), or NSO2)-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof. 67. A compound selected from those of the formula: R /~Ra F N-N F 1/ R R and R N FN wherein Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -So- lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alk-yl(Cl-C3),-NO2, -NH2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(Cl-C3)12, -SO2NH2; -SO2NH lower alkyl(Cl- C3), or -SO2N~lower alkyl(Clt-C3)]2 R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and taken together are methylenedioxy1 or ethylenedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: -260- R.. X-RIO -R 6 X-RIO S X-RIO 0 N-TX -RI R is independently selected from hydrogen, halogen, lower alkyl(Cl-C3). -N (Cl- )q No a. (C Iq- ND (Cf-1)q -N 0 -(CH2)q-OH, -(CH2)q-0alkyl(C1-C3); q is one, two or three; R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl(Cl-C3); and R7 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy arid halogen. R6 is se2lected from moieties of the formula: -261- r- "I -NCOAr', Ra -NCOCH. 1 Ar' R -NCON-Ar, R R Ib -N-SO 1 XR -NCO(CH-)~ -ciycloalkyl, R- -N-SO 2CI XR 0 2 I I -r -N-P O\ -NSO,-lower alkvl(C -C 8 R 0 11 -N-P -NSO 2 -lowver alkeny(C 3 -CS) 0 11 -NH-C-O-Iower alkyl(C 3 -C.)straight or branched 0 11 -NH-C-lower alkvl(C 3 -C.)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 -NH-C-lower alkenyI(C.I-Cs)straight or branched, wnerein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Fa is hydrogen, CH3, moieties of the formulae: a -262- (CH )q N Rb R b -N (CH 2 )q -N 0 -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH2OH; q is one or two; Rb is hydrogen, -CH3 or and a moiety of the formula: -X-RiO; wherein Rio is lower alkyl(031-C8), lower alkenyi (C3-C8), (CH2)p-cycloalkYl (C3-C6), R 5 R -(CH 2 /A a 0 and p i's zero to three: X is C, S, NH, NCH3; -263- C=0 or a bond and FR5 and R7 are as previously defined a moiety of the formula: N-=Q wherein J is Ra, lower alkyl(C3-C3-) branched or unbranched, lower alkenyl(Ci-C8) branched or unbranched -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(Ci-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moities R 8 S 0N OH 2 or -CH2-1"' wherein K' is halogien, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G=F -264- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (C1-C3)lower alkyl, hydroxy, -CO-lower alkYl(CIL-C3), CHO, (Cl-C3)lower alkoxy, -C alk-yl(Cl-C-), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R I N- COCHAr' -0-C-lower alkyl(C 1 -C 3 S- zRb N' Rtb H(K)-A -S-lower alkyl(C 1 -C 3 NH(CH)q CON R ~Rb 0- (C 2 2 N 9 9 @9 9**9 9 9999 9* 9 9 9. *9 9 9* 999999 9 wherein Rc is selected from halogen, (Cl-C3) lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; Ar' is selected from the group: -265- s 8 IR 8 N 8 1 1 N R R4 R8 and RQ are independently hydrogen, lower alkyl (Cl-03), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halog~en, N02, amino, or -NH-lower alkyl(Cl-C3); -N-[lower alkyl(Cl-C3) 12, N(Rb) (CH2) q-N (Rb) 2; is selected from the moieties S R8 N R 2 6 6 W' is selected from 0, S. NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3), or NSO2-lower alkyl(Cl-C3); and pharmaceutically acceptable salts thereof. 68. A compound selected from those of the formula: /R and IR R 2 A-B R, A-B S wherein A-B is -CH 2 N or N-OH 2 wherein Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -So- lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl--C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -NO2, -NH2, -NHCO lower alkyl(Cl-C3), [lower alkyl(Cl-C3) 12. -S02NH2; -SO2NH lower alk-yl or -SO2N~lower alkyl (Cl-C3) 2; R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: 0 CAr wherein Ar is selected from moieties of the formula: -267- X-RIOX- 0 R NFLGO 25 01 R 7 X-Rio N. S R is independently selected from hydrogen, halogen, lower alkyl (Cl-C3), /Rb -(CH )q -ND (C1 q S 4(CH2)q-OH, -(CH2)q-O-alkyJ-(Cl-C3V; q is one, two or three; R4 is selected from hydrogen, lower: alkyl(Ci-C3), -CO- lower alkyl (Cl-C3), R5 and R7 are selected from hydrouen(Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; -268- R6 is selected from moieties of the formula: -NCOAr', NCON-Ar, I Rb -NCO(CH2 -cycloalkyl, I -NCOCH.,Ar' I KR -N-SO 2 Ra -0 R 2 R7 N-SO. 2 CH 2 R 0 11 -N-P I 0 ~R2 I I -N-P J 2 -NSO 2 l er alkenyl(C 3 -C 8 Ra -NSO 2 -lower alkyl(C 3 -C 8 @0 ~0 0 .0 S 0 000 S S 0050 S 0000 00 0 0 0000 @000 00 00 0*S0 0@ 0* 0 Oe 0* 00 0*SOOO S 0 I1 -NH-C-0-Iower a Ikyl(C 3 -C 8 straight or branched 0 11 -NH-C-lower alkyl(C 3 -C.)straight or branched, 0 11 -NH-C-0-lower alkenvl(C 3 -C 8 )straight or branched, 0 II -NH-C-lower alkenyl(C 3 -C 5 )straight or branched, wherein cycloalkyl. is defined as 03 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2HS, moieties of the formulae: -269- 02 N C/Rb -N R b -(CHF)q-N C -(CH2)2-O-lower alkyl(C1-C3) or -C-H2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 Or and a moiety of the formula: -X--R1O; wherein Ri0 is lower alkYP(C3-Cg),loealel (C3-C8V -(CH2)p-cycloalkyl(C 3 -C6), R 5 R H 2 )P R F- N R R, 0 and p is zero to three: K is 0, S, NqH, NCH3, *-270* C= 0 or a bond and Rc- and P.7 are as previously defined a moiety of the formula: N- COj wherein J is Ra, lower alkyl(C3-C8) branched or tillbra ndied, lower- aikenyl (C3-CFp braniched or uribrallcherd, -0-lower alkyl(Cl-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties N 0 0 or -CH-2-y' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G=F -271- wherein D, E, F and G are selected from carbon or nitroaen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3')lower alkoxy,, -Co 2 lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: N- COCHAr' 0 -0-C-lower alkyl (C i&3)I -S-lower alkyl(C 1 -C 3 ,,-Rb S_ OCI N NH~(CH 2 )q CON Rb Rb R b NHOZH 2 N R Rb ,R b 0.a 00 0 a. 0:0. wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; Ar' is selected from the group: -272- N8 N R4 R8 and R9 are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(Cl-C3)]2, -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties S Re 0 N R /C2- R8 W' is selected from 0, S, NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3), or NSO2-lower alkyl(Cl-C3); and 4 pharmaceutically acceptable salts thereof. -273- 69. A compound selected from those of Lhe formulae: R2 A- B fR wherein Y is -(CH2)n- and n is an integer zero or one; A-B is -(CH 2 M- N- or N (CH 2 m- wherein m is an integer one when n is one and m is an inteaer one or two when n is zero; RI is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkvl(Cl-C3), -S02)-lower alkyl CCl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Ci-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-flower alkyl(Cl-C3)]2, -SO2NH2; -SO2NH lower alkyl (Cl-C3), or -SO214[lower alkyl(Cl-C3)12; Ris hydrogen, Cl, Br, F, -OH, lower alkyl(Cl-C?), 0-lower alkyl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: CAr wherein Ar is selected from moieties of the formula: *-274- R 5 (7 R- R *HO 7 X-ft 25 0 R. -S R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (Cl-C3); and R7 are selected from hydrogen(Cl-C3)lower alkyl(Cl-C3) lower alkoxy and halogen; R6 is selected from moieties of the formula: *-275 m -NCOAr', Ra NCON-Ar, R a Rb -NCO(CH-)~ -cvcloalkyl, IR -NCOCH.,Ar', -N-SO 2 N-SO 2 CH 2 1 a 0 2 0 RR. RR aNO-ovraklC-d 0 RR -NSO,-lower a lkenyl(C 3 -C 8 R *:see 0 11 -NH-C-O-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C 3 -C,)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C,)stra ight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, wherein cvcloalkyl is defined as C3 C6 cycloalkyl, cyclohexenyl or cyclopenteflyl; Ra is hydrogen, CH-3, C2H5, Moieties of the formulae: (C 1- )q N /R b R b NC (CH 2 N -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH2OH1; q is one, two or three; Rb is hydrogen, -CH3 or and a moiety of the formula: wherein Rio is lower alkyl(C3-CB), lower alkeny! (C3-C8) (CH 2 )p-cycloalkYl (C3-C6), R 5 -(CHp /2)P -(CH2) -0 N .{CH 2 )p f 0 and p is zero to three: X is 0, S, NH-, NCH3, -277- C=0 or abond and RS and R7 are as previously defined a moiety of the formula: N- COJ wherein 3 is Ra, lower alkyl(C3-CS) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkylI(C3-CB) branched or unbranched, -0-lower alkenyl(C3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 0 N 0H N R 8 or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterociyclic ring moiety: E G=F -278- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy, -CO-lower alkyl(Ci-C3), CHO, (Cl-Ci)lower alkoxv,-C2 aikYl(Cl-C3), and Ra and Rb are as hereinbefore define-j; a moiety selected from those of the formulae: R Ia N- COCHAr' -0-C-lower alkyl (C 1 -C 3 S_ ~N'Rb R b NHWCH 2 qN -S-lower alkyl(C 1 -C 3 NH(C-z)q -CON R Rb 0 (CH-y 'CC. ~9 wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined" wherein Ar' is selected from the group: -279- 8 R R7, R 9 W, S NN NN N4 RB and R9 are independently hydrogen, lower alky1(Cl- C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-0 3 -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH- lower alkyl(Cl-C3); N-[lower alkyl(Cl-C3)]2, -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties R 8 R /CH R 8 -280- W, is selected from 0, S, NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-3), or NSO2-lower alkyl(Cl-C 3 and pharmaceutically acceptable salts thereof. A compound selected from those of the formula: RI R 1 Y I P R 3 wherein Y is selected from 0, S, NH, and N-lower alkyl (Cl-C3); Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkyl(C1-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(CI-C3), -N02, -NH2, -NHCO lower alkyl(Cj-C3), -N-(lower alkyl(C1-C3) ]2,-SO2NH2; -SO2NH lower alkyl (Cl- C3), Or -SO2N[lower alkyl(Cl-C3)]2; R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and R2 taken together are methylenedioxy or ethyleneedioxy; Ri is the moiety: 0 -CAr wherein Ar is selected from moieties of the formula: -281- N R 5 R 7 ~X-R 0 X-I R HO 25 0 R 7 -Ric R4 is selected from hydrogen, lower alkyl(C1-3). -CO- lower alkyl (Cl-C3); and R7 are selected from hydrogen(Cl-C3) lower alkyl(Cl-C3) lower alkoxy and halogen R6 is selected from moieties of the formula: a -282- -NCOAr', NCON-Ar, I I R, Rb -NCO(CH 2)n I -cycloalky], -NCOCH 2 Ar' -N-SO 2 R 2 R 7 N-SO 2 CH 2 R 0 RR 0 11 -N-P R ]2 -NSO 2 -oe al kenv(CI-C 8 0 11 -NH-C-O-lower alkvl(C 3 -C 8 )straight or branched 0 If -NH-C-lower a lkvl(C 3 -C 5 )straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )Straight or branched, 4 44 4*44 4*4444 4 Wherein cycloalkyl is defined as C3 t~o C6 cyc-loalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, moieites of the formulae: -283- R b (CI1)q N (C F)q- N C -(CH2)2-0-iower alkyl(C1-C3) or -CH2CH2OH; q is one, zwo or three; Rb is hydrogen, -CH3 Or a moiety of the formula: -X-RIO; wherein R10 is iower alkv\l(C3-C8), lower alkenyl! (C3-C8), (CH2)p-cycloalkyl (C-06), -(CH 2 )P (CH 2 )p 0:90 0 0* and p is zero to three: X is 0, S, NH-, NCH-3, C=0 or abond *SS*SS-284- and R5 and R7 are as previously defined a moi ety of the formula: 1- NCOJ wherein J is Ra, lower alkyrl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl (C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 N Rj& CH 2 or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G=F ~.wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3) lower alkyl, hydroxy, -CO-lower alkyl{Cl-C3), CHOC (Cl-C3)lower alkoxy, -285- -C02-lower alkyl(Ci1-C3), and Ra and Rb are as hereinbefore defined; a moietv selected from those cf the formulae: R N N- COCHAr' 0 11 -0-C-lower alkyl (C 1 -C 3 R b_ -S-lower alkvl(C 1 -C) 1R Rb NH(CH 2 )q9 -CON NH(CH) q- N R Rb z Tb (Cl-I) 2 N\ wherein is selected from halogen, (Cl-C3)lower aDlkvl, -0-lower alk-,l(Cl-r3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: U U U U U U U. U U U U. U -286- R 5 R8R R9\ R 9 W, S R N R N R4N R8 and R~9 are independently- hydrogen, lower alkyl (C1-C3), 0-lower alkyl(Cl-C3)L S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3) ;-N-[lower alkyl(Cl-C3)12, N(Rb) (CH2)q-N(Rb)2; is selected from the moieties 0 N CH 2 \bR N -287- W' is selected from 0, S, NH, f-lower alkyl(Cl-C 3 -NCO-lower alkyl(Cl-C3), or NSO2-iower alkyl(Cl-C 3 and pharmaceutically acceptable salts thereof. 71. A compound selected from those of11 the formula: N I A 2 F A-B wherein T is 0, NH and N-lowei alkyl; and A-B is CH,- N or N- CH,- KR 3 I Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SI-b -SO-lower alkyl(Cl-C3) -S02-lower alkyl(CV-C_3), -CO-lower alkyl(Cl-C3i, -CF3, lower alkyl(C-!-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N4-flower alkyl(Cl-C3)12-, -502NH2): -SO2NH lower alkyl(Cl-C3), cr -S02N[lower alkyl (Cl-C3))2-; R2 is hydrogen, Cl, Br, F, I, -OH. lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or R1 and P.2 taken together are methylenedioxy or ethylenedioxy; 9. R3 is the moiety: 0 CAr 99:6,wherein Ar is selected from moieties of the formula: A-288 R- N R6 R 5 R7 X-R X- NFEORXX-R 2510 R4 is selected from hydrogen, lower alkyl(Cl-C3). -CO-lower alkyl (Cl-C3) R5 and R7 are selected from hydrogen(Cl-C3)lower alkyl(Cl-C3) lower alkoxy and halogen; R6 i.s selected from moieties of the formula: *-289 -NCOAr', NCON-Ar, XR RA R b -NCO(CH2)n -cycloalkyl, If -NCOCH 2 ,Ar', -N-SO 2 I r2 N-SOICH 2 I 0 R, 11 -N-P 0 R a L R -NSO,-lower alkvJ(C.-Cd), a R, -N-P R 0 11 -NH-C-O-Jower alkvl(C 3 -C 8 )straight or branched 0 11 -NH-C-lowver a Ikvl(C -C,,)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 1I -NH-C-lower alkenyl(C -C 8 )straight or branched, wherein cycloalky1 is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyciopentenyl; Ra is hydrogen, CH3, C2H-I, moieties of the formulae: S* -290- M M N/ Rb N R b -ND (FqN C -(CH2)20-lower alkyl(Cl-C3) or -CH2CH-20H; q is one, two or three; Rb is hydrogen, CH3 or a moiety of the formula: -X-R1O; wherein R1o is lower alKvi-(C3-C8), lower alkenyl(C3-C8). -(CH2)p-cycloalkyl(C3-C6), R 5 R -(CH 2 )p 6 10R5 N 4-(CH 2 )p 0 and p is zero to three: X is 0, S, NH, NCH3, -291- C-0 or abond and R5 and R7 are as previously defined a moiety of the formula: N- COJ wherein J is Ra, lower alkyl(C3-C2) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0D-lower alkyl(C3)-C8) branched or unbranched, 0-lower alkenv-.l(C3-C81 branched or unbranched, tetrahydroauran, tetrahydrothiophene, the moieties N or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G=F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally -292- substituted with halogen, (Cl-C3) lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy,, -CO2-lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiet.? selected from those of the formulae: R N- COCHMr 0 11 -0-C-lowver alkyl(C 1 -C 3 R b NHYq- N~ RI -S-lower alkyl(C C) -NH(CH 2 )q CON R Rb b R 0 (CH) 2 9 9* 9 9* 9* wherein RC is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkqvl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -293- R 5 R 8 R N R I N R R4 RB and R9 are independently hydrogen, lower alkyl (Cl-03), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3. -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); -N-ihlower alkyl(Cl-C3))2, -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties R R 8 R8 'N. 1q, is selected from 0, S, NH, N4-lower alkyl(Cl-C3), -NCOlo~r akylC1-3),or NSO2-lower alkyl(Cl-C3); and pharmaceutically acceptable salts thereof. -294- 72. A compound selected from those of the formula: wherein Y is selected from 0, S, NH, and N-lower alkyl (Cl-C3); A-B is -CH- 2 N or N- CH 2 I I R3 3 Rl is h",ydrogen, halogren (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkyl (Cl-C3), -S02-lower alkyl (Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), N-[lower alkyl(Cl-C3)]2,-S02NH2; -SO2NH lower alkyl(Ci- C3), or -SO2N[lower alkyl(C1-C3)12; R2 is hydrogen, C-1, Br, F, 1, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and R2 taken together are methylenedioxy or ethyleneedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: to0 295 -1 -M S HC ~X-R 0 .4.250 R7. N rX -Ri R4 is selected from hydrogen, lower alkYl(C1-3), -CO-lower alkyl(C1-C3); and R7 are selected from hvdrogen(Cj-C3) lower alkyl(Cl-C3) lower alkoxy and halogen R6 is selected from moieties of the formula: 296 e- I -NCOAr', NCON-Ar, II I KR R a'Rk -NCOCH 2 Ar, -N-SO 1 1< a X -NCO(CH 2 )n I -cycloalkyl, -N-SO 2 CH 2 0R2 I -N-P 0 R 0 2 I I I- R. -N50 2 loe alkyl(C 3 -C 5 I -NSO -lower alkenv(C 2R 0 11 -NH-C-O-lower alkyl(C -C 8 stra ight or branched 0 -NH-C-lower alkyl(C -C,)straight or branched, 0 -NH-C-O-Iower alkenyl (C 3 -C 8 )tagtobrnhd 0 11 -NH-C-lower alkenyl(C 3 -C,)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieites of the formulae: -297 /R b (Cf )-N (C F4- No No C -(CH2)2-O-lower alkyl(CI-C3) or -CH2CH2OH; q is one, two or three; Rb is hy~drogen, -CH3 or and a moietyp of the formula: -X-R1O; wherein RIO is lower alkvl (C3-C8), lower alkenvi (C3-C8), -(CH2). cvcloalkvl(C3-C6), -(CH ,)9p R.. N R.. 0 0 and p is zero to three: X is 0, S, NH, NCH3, 298 C= 0 or a bond and R5 and R7 are as previously defined a moiety of the formula: R b wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophefle, the moieties R 8 S \XI 0 N R&CH 2 -b or -CH2-K' wherein K is halogen, -OH, tetrahydrofuran, tetrahvdrothiophene or the heterocyclic ring moiety: -N E G=F wherein D, E, F and G are selected from carbon or nitrogen and wherein carbon atomns may be optionally substituted with halogen, (CI-C3) -299 lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (C1-C3)Iower alkoxy, -C02-lower alkyl(CI-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N N- COCHAr' 0 0 11 -0-C-lower alkyl (C 1 -C) (CFH R R b NHC- qN. -S-lower alkyl(C 1 -C 3) ~NH(CH )q -CON R ~Rb 1-1Rb -0- wherein Rc is selected from halogen, (CI-C3)iower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: a a 300 a R R 8N N 1N R8 and R9 are independently hydrogen, lower alkyl (CI-C3), 0-lower 0 alkyl(CI-C-), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl lower alkyl(C1-C3Xi2, -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties \b R8 S N 255 R8B N R301 I W' is selected from 0, S, NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Ci- C3), or NSO2-lower alkyl(Cl-C3); and pharmaceutically acceptable salts thereof. 73. A compound according to claim 72 wherein A-B is N- CH 2 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: T R 6 NHCOR 2 R. 7 R 7 and Y, Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R-7, R8, R9, RIO, R25 are as previously defined in Claim 72. 74. A Compound according to claim 72 wherein A-B is N-CH- R Y is 0; and Ra, Rb, Rc, Ri, R2, R3, R4, R5, R6, R7, R8, R9, RiO, R25 are as previously defined in Claim 72. 75. A compound according to claim 72 wherein -302- A-B is N C2 R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formula: R R/ NHCOR 2 N Y is 0;and 1 a, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, RiO, R25 are as previoLIsly defined in Claim 72. 76. A compound according to claim 72 wherein 1 A-B is N-CH 2 13 Y is NH; and Rb, Rc, R1, R2, R3, R4, R5, R6, RT7 R8, R9, RIO, R25 are as previously defined in Claim 72. 77. A compound according to claim 72 wherein is N ci-i 2 R 3 0 1R3 is the moiety:

303- 0 0 11 -CAr wherein Ar is selected from moieties of the formula: R 5 R NHCOR2 N R 7 7 and Y is NH; and, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 72. 78. A compound selected from those of Formtila 1: DA-B F Formula 1 wherein Y is selected from (CH2)n 0, S, NH, NCOCH3, N-lower alkNvl (Cl* C3), CH-lower alkyl(Ci CHNH-lower alkvI(CI-C3), CHNH2, CHN[lower alkvl(CI-C3)12,CHO-lowver alkvl(CI CHS-lower alkyl(Cl- C3), wherein n is an integer from 0-2; 925 A-B is ~(CH 2 )m-N or N -(CH 2 m- 3R3 wherein m is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, m may also be zero and when n is zero, mn may also be three, provided also that when Y is -(CH2)n- and n is 2, mn mav not also be two; 49 304 R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S- lower alkyl(Cl-C3), -SH, -SO lower alkyl(CI-C3), -S02 lower alkyl(Cl-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), 0-lower alkyl(CI-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[Iower alkyl(C1-C3)1 2 -SO2NH2, -SO2NH lower alkyl (CJIC3), or -SO2N[lower alkyl(C-C3)1 2 R2 is hydrogen, Cl, Br, F, I, lower alkyl(CI-C3), 0-lower alkyl(CI-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxv; R3 is the moiety 0 1I CAr wherein Ar is a moiety selected from the group R 6 R 5 R7 I I R7I R 0 9 R7 NTX-Ri C. eee ~and X is 0, S, -NCH3 or -NH R4is seetdfrom hvroen lower alk 1/Cl C3) -CO-lower alIUy(Cl-C3) and R7 are selected from hydrogen, (CI-C3) lower alkyl, (CI-C3)lower alkoxy and halogen sets CC -305 R6 is selected from moieties of the formula: -NCOAr', Ra -NCOCH 2 Ar' I NCON-Ar, -N-SO 2 I -NCO(CH 2)n I -cycloalkyl, -N-SO 2 CH-1 2 Ra 0 R 2 -N-P a a 8 R 2 -NSO 2 -lower alkvl(C 3 -C 8 a 0 11 -N-P I -NSO -lower alkenvl(C 3 S. S 0 11 -NH-C-O-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alky](C 3 -C 8 )straight or branched, 0 11 -NH-C-0-lower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, 306 S. S S. S S wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenvi or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: R b c F o(CI%q-NO0 -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH,)OH; q is one, two or three; Rb is *hydrogen, -CH3 or CH;n a moiety of the formula: -X-RIO, wherein R10 is lower alkyl(C3-CB), lowver alkenvl(C3-CS), -(CH2)P- cxcloalkyl(C3-C6), Rb R RR R 4(G )p 0 N R-. S {IT) 0 and p is zero to three;

307- X is 0, S, NH, NCH3, C= 0 or a bond and R5 and R7 are as previously defined. a moiety of the formula: N N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahvdrofuran, tetrahvdrothiophene, the moieties R8 S 0 N or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahvdrothiophiene or the heterocyclic ring moiety: -N E 0% G=--F 308 wherein D, E, F and G are selected from carbon or nitrogen and whereji the carbon atoms may be optionally substituted with halogen, (CI-C3) lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy -C02-10wer alkyl(CI-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R I a N COCHAr' -0-C-lower alkyl (C 1 -C 3 S-Q -S-lower alkvl(C I-c 3) NH(CH-2 )q -CON R R b -Nl )qN R AC-2-N. wherein Rc is selected fromn halogen, (C1-C3)lower alkvl, -0-lower alkyl(CI-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: a a. a a. a a a a a a a a a. a 309 8 R.. R 9 S N N 8 R8 and R9 are independently hydrogen, lower alkyl (CI-C3), 0-lower alkyl(C1-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); -N-[lower alkyl(CI-C3)]2, -N(Rb)(CH2)q-N(Rb)2; W is selected from 0, S, NH, N-lower alkyl (Cl-C3), -NCO-lower alkvl(Cl- C3), or N502-lower alkYl(C1-C3); R25 is selected from the moieties 310 S 010 R 311 and the moiety ZO represents: a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, wherein the 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom is optionally substituted by (CI-CO3)lower alkyl, formyl, a moiety of the formula: (CH 2 qN "_R RI, halogen or (Cl-C3)lower alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 79. A Compound selected from those of the formulae: R N R R A-B wherein Y is selected from 0, S, NH, NCOCH 3 N-lower alkyl (Cj- C3), CH-lower alkyl(CI-C3), CHNH-lower alkvl(Cl-C3), CHNH2, CHNf lower a lkyl (C I-C3)12,CHO- lower alkvl(Cj CHS-lower alkvl(Cj C3); A-B is -(0-1 2 N- -r N C2 R 3 R 3 44*0 30 Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S- 00*0 lower alkyl (Ci -SH, -SO-lower alkvl(CI -S02-lower alkyl(CI1-C3), -CO-lower alkvl(CI-C3), -CF3, lower alkyl(CI-C3), O-lower alkyl(CI-C3), .0312 too* -N02, -NH2, -NHCO lower alkyl(CI-C3), -N-f lower alkyl(CI-C 3 )1 2 -SO2NH2; -SO2NH lower alkyl (CI-C3), or -SO2N~lower alkyl(CI-C3)12; R2 is hydrogen, Cl, Br, F, 1, -OH, lower alkvl(CI-C3), 0-lower alkvl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: *R 5 R7 L' X-RI LI-RI R-. R FC -FM-IICo 0 RX- R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(CI-C3); and R7 are selected from hydrogen(Cl -C3) lower alkyl(Cl-C3) lower alkoxy and halogen; R6 is selected from moieties of the formula: 0*S S.313 -NCOAr', a NCON-Ar, I I R aR b -NCOCH 2 Ar, I -N-SO 2 Ra -NCO(CH )n 0 11 -N-P Ra -cycloalkyl, -N-SO2 CH 2 Ra 91 0 -N-P Ra 0 -NSO 2 loe alkyl(C 3 -C 8 Ra -NSO,-lower al kenyl(C 3 -C 8 0 11 -NH-C-O-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C -C 8 )straight or branched, 0 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenvl(C -C 8 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenvl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: -314 Cl)qN C/Rb- R b -(CH2)2-O-lower alkyl(CI-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 or and a moiety of the formula: -X-R1O; wherein Rio is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p- R R -(CH 2 )P R N R 4-(C 2 0 and p is zero to three: X is 0, S, NH, NCH3, -315- C=0 or a bond and R5 and R7 are as previously defined a moiety of the formula: R~b wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahvdrothiophene, the moieties R 8 S 0 N 25 C H 2 R 2* or -CH2-K' wherein K' is halogen, -OH, tetra hyd rofu ran, tetrahydrothiophene or the heterocyclic ring moiety: 0% 0 -N E G=F -316- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Ci- C3)lower alkyl, hydroxy, -CO-lower alkyl(CI-C3), CHO, (CI-C3)lower alkoxy, -C02-lower alkyi(CI-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: N- COCHMr -0-C-lower alkvl (C 1 -C) R b NH(CH N -S-lower alkyl(C -C 3 ~NH(CH 2 )q -CON Z (C-y -2 N\, rb 0*0* a 0 wherein Rc is selected from halogen, (C1-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: 317 -8 8 R R9, 7, N R N R8 and R9 are independently hydrogen, lower alkyl(CI-C3), G-lower alkvl(C1-C3), S-lower alkvl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); N-[lower alkvl(CI-C3)12, -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties S" 03N CH H 2 -b R8 -318- Wis selected from 0, S, NH, N-lower alkyl(CI-C3), -NCO-lower alkvI(Ci- or NSO2-lower alkyl(CI-C3); and pharmaceutically acceptable salts thereof. 80. A compound according to claim 79 wherein A-B is N CH 2 R 3 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: RR R 6 ~NHCOR 2 R 7 and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R8, R9, RIO, R25 are as previously defined in Claim 79. 81. A compound according to claim 79 wherein A-B is N- CH.- 251 Y is and Ra, Rb, Rc, R1, R2, R(3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 79. 82. A compound according to claim 79 wherein 319 A-B isN RK 3 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are cis previously defined in Claim 79. 83. A compound according to claim 79 wherein A-B is N- CH- R 3 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, Rc5, R6, R8, R9, R10, R25 are as previously defined in Claim 79. 32 84. A compound according to claim 79 wherein A-B is N ICH 2 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: /R NHCOR 2 Y is and Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 79. A compound according to claim 79 wherein A-B is NtjC1 2 253 R3 is the moiety: CAr wherein Ar is selected from moieties of the formula: 321 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RiO, R25 are as previous defined in Claim 79. 86. A compound according to claim 79 wherein A-B is N- Cli,- R3 is the moiety: -CAr wherein Ar is selected fromn moieties of the formula: Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R2_9 are as previous] defined in Claim 79. 322 87. A compound selected from those of Formula I: Formula I wherein Y is selected from (CH2)n, 0, S, NH, NCOCH3, N- lower alkyl (Cl-C3), CH-lower alkyl(Cl-C3), CHNH-lower alkyl (C1-C3), CHNH2, CHNtlower aJlkyl (C1-C3) ]2,CHO-lower alkyl(Cl-C3), CHS-lower alkyl(Cl-C3), wherein n is an integer from 0-2; A-B is -(CH- 2 )m -N or 4-(CH 2 )m R 3 wherein m is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two; Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C1-C3), -SE, -SO lower alkyl(C-C3), -S02 lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cj'-C3), 0-lower alkyl(Cl-C3), -N02, -NH-2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(Cl-C3)]2, -S02NH2, -SO2NH lower alkyl or -S02N~lower alkyl(Cl-C3)12; R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lIower alkyl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety -323 0 11 CAr wherein Ar is a moiety selected from the group R_ d X-RIO R7 R_ NFE OR2.- EX-Rl,, x-Rj 0 r 3 X -Ri and X _Js 0, S, -NCH3 or -NH R4 is selected from hydrogen, lower alkyl(C-C3), -CO- lower alkyl(C;-C3); and R-7 are seleced from hydrocen, lower alkyl, (Cl-C3)lower alkoxy and halogen 10 Rro is selected from moieties of -Lhe formula: -324 r, -NCOAr', I -NCOCH 2 Ar' R -NCON-Ar, I I RR b -N-SO 2 Ra -NCO(CH:~)n, -cycloalkyl, R 2 R 7 N-SO 2 CH 2 a R 2 -N -P -o a R -NSO -lowe r alkyl(C -C 8 2R 0 11 -N-P Ra 12 -NSO -lower a lkerwl(C 0 11 -NI--C-0-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyI(C,-C)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C,)straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )s traight or branched, wherein cvcloalkvl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyc lopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: 0 top**: 325 (CH-)q -N /C-)q-N b -(CH 2 0 -(CH2)2-0-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 or a moiety of the formula: -X-RiO, wherein RIO is lower alkvl(C3-C8), lower alkenyl(C3-C8), -(CH2)F cvcloalkvl(C3-C6), R R -(CH 2 )p R.. (CH 2 )p 0 N R-. 0S R@ 0 and p is zero to three; X is 0, S, NH, NCH3, 00326 C= 0 or a bond and R5 and R7 are as previously defined. S a moiety of the formula: R b N -COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenYl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetra hyd ro thiophene, the moieties Re S 0 N or -CH2-K' wherein K is halogen -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (CI-C3)

327- lower alkyl, hydroxy, -CO-lower alkyl(CI-C3), CHO, (CI-C3)lower alkoxy, -C02-lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: N- COCHAr' R C 0 -0-C-lower alkyl (C -C) R b NH(CH )q qN- -S-lower alkvl(C 1 -C) t -NH(CH)q -CON Rb Rb ZR b (CI-2 wherein Rc is selected from halogen, (Cl-C3)lower alkvl, -0-lower alkyl(CI-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: S S 00 328 R 5 RRR R 9 s R N N R8 and R9 are independently hydrogen, lower alkyl (CI-C3), 0-lower alkyl(CI-C3), S-lower alkyl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, 1.N02, amino, or -NH-lower alkyl(CI-C3); -N-[lower alkyl(Cj-C3)12, -N(Rb)(CH2)q-N(Rb)2; Wis selected from 0, S, NH, N-lower alkyl (CI-C3), -NCO-lower alkyl(Ci- C3), or NSO2-lower alkyl(CI-C3) 20R25 is selected from the moieties 202 OE -SS sz* z HO01 N 0l and the moiety Z 0 represents: a 5-membered aromatic (unsaturated) heterocyclic ring having one S heteroatom wherein the 5 -membered aromatic (unsaturated) heterocvclic ring is optionally substituted by (Cl-C3)lower alkil, formyl, a moiety of the formula: -(CH 2 qN R Rb halogen or (CI-C3)lower alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof. 88. A compound selected from those of the formula: F A-B S wherein Y is selected from 0, S, NH, and N-lower alkyl(Cl-C3); A-B is CH,- N or N- CH 2 R1 is hyvdrogen, halogen (chlorine, bromine, fluorine, iodine), OH, loe Ily(1C) S,-OlwraklC1-3,-0-oe ly( -lower alkyl(C-C3), -F3, Olower alkyl(C-C), S0-lower alkyl(C-C3), 30 -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[lower alkyl(Cl-C3)12,- S02NH2; -SO2NH lower alkvl(CI-C3), or -SO2N[lower alkYI(Cl-C3)12; R2 is hydrogen, Cl, Br, F, 1, lower alkyl(C1-C3), 0-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethyleneedioxy; 331 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R. N R6 R 5 R- X-R -R S R- tX-R NCR25 0Q1 N--y-X-Rio "S R4 is selected from hydrogen, lower alkvl(C1-3), -CO-lower alkyl(CI-C3); and R7 are selected from Ilvdrogen(CI-C3) lower alkyI(CI-C3) lower alkoxy and halogen R6 is selected from moieties of the formula: 332 -NCOAr', I -NCOCH 2 Ar' R 0 11 -N-P 0 a NCON-Ar' R R b -N-SO 2 1 -NCO(CH 2 -cycloalkyl, 0 -N-P R -N-SO1H2 R R R 12 -NSO 2 -oe alkyl(C 3 -C 8 a -NSO 2 -oe allcenyl(C.-C.) I 0 11 -NH-C-O-lower alkvl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, 333 wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenvi; Ra is hydrogen, CHj, C2H5, moieites of the formulae: /R b (c F No -(CH2)2-O-lower alkvyl(CI-C3) or -CH2CH2'OH; q is one, two or three; Rb is hydrogen, -CH3 or and a mnoiety of the formiula: -X-R1o; wvherein R10 is lower alkyl(C3-C8), lower alkenyi (C3-C8), -(CH2)p- cvcloalkNvl(C3-C 6 -(CH 2 )P R- R. .{CH 2 K N R- 0 and p is zero to three: a a a a a 334 a *aa~aa a X is 0, S, NH, NCH3, C=0 or abond and R5 and R7 are as previously defined a moiety of the formula: COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkYl(C3-C8) branched or unbranched, -0-lower alkenyI(C3-C8) branched or unbranched, tetrahydrofuran. tetrahydrothiophene, the moieties Re S N or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahvdrothiophene or the heterocyclic ring moiety: -N ,D E G=/ .~.33F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3) lower alkyl, hydroxy, -CO-lower alkyl(CI-C3), CHO, (C1-C3)lower alkoxv., -C02-10wer alkyl(CI-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- COCHAr' 0 -0-C-lower alkyl (C 1 -C 3 -S-lower alkvl(C -C) NHCH)q -CON R AR Nl~l(Cj1)q 1 Rb 0- (CH 2 X N,, wherein RC is selected from halogen, (C)-C3)ower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: 5 S 6.. S.0. 0 **to *as* 336 ~R 9 W R R R 8 N I N R 4 R8 and R9 are independently hydrogen, lower alkv'l 0-lower alkyl(CI-C3), S-lower alkyl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(C [lower alkyl(C1-C3)]2, -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties R8 S x *0 N CH 2 -b 33 W is selected from 0, S, NH, N-lower alkvl(CI-C3), -NCO-lower alkyl(Cl- C3), or NSO2-lower alkyl(CI-C3); arnd pharmaceutically acceptable salts thereof. 89. A compound according to claim 88 wherein A-B isN H R 3 R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formula: R R 6 NHCORZ 2 N R 7 R 7 and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 88. A compound according to claim 88 wherein 25A-B3 is N CH,- Y is and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, Rg, RIO, R25 are as previously defined in Claim 88. 91. A compound according to claim 88 wherein 338 A-B is N- CH 2 R.1 3 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, defined in Claim 88. R7, R8, R9, RIO, R25 are as previously 92. A compound according to claim 88 wherein N CH 2 A-B is Y is NH; and Raj, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 88. 93. A compound according to claim 88 wherein A-B is r~-C" 2 0 CAr R3 is the moiety: wherein Ar is selected from moieties of the formula: a a. a. a a a. a a NH-COF Y is and 339 Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 88. 94. A compound according to claim 88 wherein 51 A-B is N- 2 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: 6 MIo~ N R- R 7 and Y is NH; Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 88. A compound according to claim 88 wherein A-B is CKI- R3 is the moiety: .0 CAr wherein Ar is selected from moieties of the formula: 340 and Y is 0; Rag Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 96. The compound according to claim 1, N-t4- (dibenz[b,f] [l,4)oxazepin-10(l1H)-ylcarbonyl)-phenyl)- 1'-biphenyl)-2-carboxamide. 97. The compound according to claim 1, N-[4- (dibenz Ib, f) [,4]oxazepin-10(llH)-ylcarbonyl)-3-chloro- phenyl] [1,llbiphenyl)-2-carboxamide. 98. The compound according to claim 1, (dibenz(b,f] [l,4loxazepin-l0(11H)ylcarbonyl)-2- pyridinyl] -5-fluoro-2-methylbenzamide. 99. The compound according to claim 1, (dibenz f) t1,4]oxazepin-l0(11H)-ylcarbonyl)-2- pyridinyl] (4-pyridinyl)benzamide. 100. The compound according to claim 1, (pyrido(2, 3-b) f1,Slbenzoxazepin-6(5H)-ylcarbonyl)-2- pyridinyl) l t biphenylll-2-carboxamide. 101. The compound according to claim 1, (pyrido(2, 3-b] f1,4lbenzoxazepin-5(6H)-ylcarbonyl)-2- pyridinyl) [1,1 '-biphenyl] -2-carboxamide. .*102. The compound according to claim 1, N-[4- (pyrido[2,3-b] [l,4]benzoxazepin-5(6H)-ylcarbonyl)-3- chlorophenyl] (1,1 'biphenyll -2-carboxamide. 103. The compound according to claim 1, N-[4-(6,11-dihydropyrido[2,3-b1 [,5]benzodiazepin-6(5H)- ylcarbonyl) -phenyl] (1.1 '-biphenyl] -2-carboxamide. 341 1-1 104. The compound according to claim 1, N-f 4- 11-dihydropyrido[2,3-b] f1,5]benzodiazepin-6(5H)-yl- carbonyl)-3-chlorophelyll [1,1'-biphenyl]-2-carboxamide. 105. The compound according to claim 1, N-[4- 11-dihydropyrido[2,3-bJ [1,5]benzodiazepin-6(5H)-yl- carbonyl)phenyl] [1,1 '-biphenyll -2-carboxamide, hydrochloride. 106. The compound according to claim 1, N-[4- [(5,11-dihydro-10H--dibenz[b,e] (1,4)diazepin-10-yl)- carbonyl]-3-chlorophenyl) (1,1 '-biphenyl]-2-carboxamide. 107. The compound according to claim 1, N-[4- 1i-dihydro-10H-dibenz~b,el 11,4]diazepin-10--yl)- carbonyl) -phenyl) -biphenyll -2-carboxamide. 108. The compound according to claim 1, N-[4- [(5,11-dihydro-1OH--dibenz[b,e] [1,4Idiazepin-10-yl)- carbonyl] -3-methylphenyl] (1,1 '-biphenyl)-2-carboxamide. 109. The compound according to claim 1, N-IA- 11-dihydro-IOH-dibenz(b,eI [1,4)diazepin-10-yl)- carbonyll-2-methylphenyl] [1,1 -biphenyl] -2-carboxamide. 110. The compound according to claim 1, N-14- 11-dihydro-1OH-dibenz [1,4)diazepin-10-yl)- carbonyl] -2-chlorophenyl) (1,1 '-biphenyl] -2-carboxamide. 111. The compound according to claim 1, N-[4- 11-dihydro-5H-dibenz[b,elazepin-5-y1)carbonyl]- pheny] [1,1 '-biphenyl]-2-carboxamide. 112. The compound according to claim 1, N-[4- [(6,11-dihydro-5H-dibenz~b,elazePin-5-yl)carbonyl-3- chlorophenyl] -biphenyl] -2-carboxamide. 113. The compound according to claim 1, N-[4- 11-dihydro-5H-dibenz~b,e)azepin5yl)carboflyl-3- methyiphenyl] 2. -biphenyll -2-carboxamide. 114. The compound according to claim 1, N-[4- 11-dihydro-5H-dibenz(b,e)azepn5yl)carboflyl- 2 :chlorophenyll '-biphenyl] -2-carboxamide. 342 115. The compound according to claim 1, 11-dihydro-5H-pyrido[2, 3-b] yl) carbonyl] -2-pyridinyl) -5-fluoro-2-methylbenzamide. 116. The compound according to claim 1, N-[4- 11-dihyciro-5H-pyrido[2,3-b] [1,4]benzodiazepin-5-yl)- carbonyl] -3-chiorophenyl] [1,1 '-biphenyl] -2-carboxamide. 117. The compound according to claim 1, N-[4- l1-dihydro-5H-pyrido[2,3-b] [1,4ibenzodiazepin-5-yl)- carbonyl~phenyl] [1,1 '-biphenyl] -2-carboxamide. 118. The compound according to claim 1, N-[4- 11-dihydro-5H-pyrido[2,3-bI [1,4]benzodiazepin-5-y1)- carbonyl) -3-methyiphenyl] 11,1 '-biphenyl] -2-carboxamide. 119. The compound according to claim 1, N-(4- W [(4,5-dihydropyrazolo[4,3-d] [llbenzazepin-6(1H)-yl)- carbonyllphenyl] l'-biphenyl]-2-carboxamide. 120. The compound according to claim 1, N-IA- [(4,5-dihydropyrazolo[4,3-d] [1]benzazepin-6(1H)-yl)- carbonyl] -3-chlorophenyl] [1,1 '-biphenyl)-2-carboxamide. 121. The compound according to claim 1, [(4,5-dihydropyrazolo(4,3-d] [1]benzazepin-6(1H)-yl)- carbonyl]-2-pyridinyl] 1'-biphenyl]-2-carboxamide. 122. The compound according to claim 1, (4,5-dihydropyrazolo[4,3-d] t1]benzazepin-6(1H)-yl)- carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide. 123. The compound according to claim 1, (4H-thieno[3,4-b] [1,5]benzodiazepin-9(1OH)-yl)-2- pyridinyl) -5-fluoro--2-methylbenzamide. 124. The compound according to claim 1, N-[4- (4H-thieno[3,4-b] [1,5]benzodiazepin-9(1OH)-yl)-phelyl]- [1,1 tbiphenyl] -2-carboxamide. 125. The compound according to claim 1,N-IA- (4H-thieno[3,4-b] [1,5]benzodiazepin-9(10H)-yl)-3-chloro- phenyl] [1,1'-biphenyl]-2-carboxamide. 126. The compound according to claim 1, :35 (4H-thieno[3, 4-b] [1,5]benzodiazepin-9(10H)-yl)-2- pyridinyl] 1'-biphenyl]-2-carboxamide. -343- 127. The compound according to claim 1, 5,11- dihydro-10-[4-(2-thienyl)benzoyll-10H-dibenz~b,e] [1,43- diazepine. 128. The compound according to claim 1, 5,11- dihydro-10-[4- (3-thienyl)benzoyl]-10H-dibenz~b,e] diazepine. 129. A compound according to claim 79 wherein A-B is -CH 2 -N R 3 R3 is the moiety: 0 -CAr wherein Ar is selected from moieties of the formula: R 6 -NHCOR 2 N and Y, Rat Rb, Rc, RI, R2, R3, R4, R5, R6, R-7, R8, R9, R25 are as previously defined in Claim 79. 130. A compound according to claim 79 wherein is N -CH2R R 3 Y is and Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, Rio, are as previously defined in Claim 79. 131. A compound according to claim 79 wherein -344- ~CH 2 ~I A-B is Y i s 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R:1O, R2 are as previously defined in Claim 79. 132. A compound according to claim 79 wherein A-B is -CH 2 -N Y is NH.; and Ra, Rb, Rc, Ri, R2, R3, R4, R5, R6, R7, R8, R9, Rio, are as previously defined in Claim 79. 133. A compound according to claim 79 wherein A-B is -CH 2 -N R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R6 NHCOR2. N R 7 R Y is and .6 S S. S S. S* S. *55S55 S S S S 345 Ra, Rb, RC, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 79. 134. A compound according to claim 79 wherein -1 A-B is -CH- 2 -N R 3 R3 is the moiety: 0 11 -CAT wherein Ar is selected from moieties of the formula: is R 5 R R NHC0R2_ R 7 R Y is 0; and Ra, Rb, Rc, Ri, R2, R3, R4, R5, REo, R7, RB, R9, Rio, are as previously defined in Claim 79. 135. A compound according to claim 79 wherein A-B is -CI{,-N R R3 R3 is the moiety: 0 CAr wherein Ar is selected from moieties of the formula: 346 N P..AJ' R 7 R 7 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R1O, are as previously defined in Claim 79. 136. A compound according to claim 88 wherein A-B is -CH 2 -N R R 3 R3 is the moiety: 0 11 -CAT wherein Ar is selected from moieties of the formula: _R 6 NHCOR2 N 10R7R and Y, Ra, Rb, R 0 Rl, R2, R3, R4, R5, R6, R7, R8, R9, R1o, R25 are as previously defined in Claim 88. 137. A compound according to claim 88 wherein A-B is -CHi 2 -N R 3 .15 Y is and a~a* 347- Rag Rb, R 0 R1, R2, R3, R4, R5, R6, R7, R8, R9, R 1 0, are as previously defined in Claim 88. 138. A compound according to claim 88 wherein A-B is -CKL-N R 3 Y isO0; and Ra, Rb, R 0 RI, R2, R3, R4, R5, R6, R7, R8, R9, R1O, are as previously defined in Claim 88. 139. A compound according to claim 88 wherein A-B is -CK- N Y is NH; and Ra, Rb, R 0 Ri, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 140. A compound accordi.ng to claim 88 wherein A-B is -CH.-N R3 is the moiety: 0 CAr wherein Ar is selected from moiet ies of the formula: 348 -R6 'NHCOR 2 N R7 R 7 Y is and Rap Rb, RC, RI, R2, R3, R 4 R5, R6, R-7, R8, R9, RiO, are as previously defined in Claim 88. 141. A compound accordi~ng to claim 88 wherein A-B is -CH 2 -N R 3 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R R 1 NHCOR2 N 10R7R and Y i4s NH; Ra, Rb, Rc, Ri, R3, R4, R5, R6, R7, R8, R9, RIO, are as previously defined in Claim 88. 142. A compound according to claim 88 wherein A-B isC-1 N *0 R3 is the moiety: *9349 _I 350 0 II -CAr wherein Ar is selected from moieties of the formula: R 6 NHCOR 2 N R 7 R 7 and Y is O; Ra, Rb, Rc, RI, R 2 R 3 R 4 R 5 R 6 R 7 R 8 R9, R 1 0 R 2 5 are as previously defined in Claim 88. 143. A tricyclic benzazepine vasopressin antagonist, substantially as hereinbefore described with reference to any one of the Examples. 144. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective amount of a compound of any one of claims 64 to 143. 145. A method of treating diseases characterised by excess renal reabsorption of water as well as congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia in a mammal comprising administering a compound of any one of claims 64 to 1 4 3 ,or of a composition of claim 144 to said mammal in an amount effective to alleviate the disease. 146. A process for the preparation of a tricyclic benzazepine vasopressin antagonist, substantially as hereinbefore described with reference to any one of the Examples. 147. Use of a compound of any one of claims 1 to 60 or 64 to 143 for the S 20 manufacture of a medicament for treating diseases characterised by excess renal reabsorption of water as well as congestive heart failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia. 148. A compound of any one of claims 1 to 60 or 64 to 143 when used for treating diseases characterised by excess renal reabsorption of water as well as congestive heart 2z failure, liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia in a mammal. Dated 10 December, 1999 American Cyanamid Company Patent Attorneys for the Applicant/Nominated Person 30 SPRUSON FERGUSON S* S .4.60 S