AU4442602A - Tricyclic benzazepine vasopressin antagonists - Google Patents

Description

S&FRef: 387830D2

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 Efren Guillermo Delos Santos Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) 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

N

Title: TRICYCLIC BENZAZEPINE VASOPRESSIN

ANTAGONISTS

1. Field cf the Invention This invention relates to new tricyclic nonpeptide vasopressin antagonists which 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.

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 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 Vl 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. V1 antagonists may decrease systemic vascular resistance, increase cardiac output and prevent 1 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 cAME-mediated incorporation of water pores into the luminal surface of these cells. V2 antagonists may correct the fluid 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 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 cf water retention.

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

Chem., 35, 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 Persective, 217, (May) (1991). P.D.

Williams et al., have reported on potent hexapeptide oxytocin antagonists Med. Chem., 35, 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., Er. 1. Pharmacol, 105, 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-Al Ogawa et al, (Otsuka Pharm. Co.) EP 470514A disclose carbostyril derivatives and pharmaceutical 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. Chm. 3919(1992), M. 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 in vivo vasopressin antagonist activity. The compounds also exhibit antagonist activity at oxytocin receptors.

SUMMARY OF THE INVENTION L0 This invention relates to new compounds selected from those of the general formula I: Formula I Wherein Y is (CH2)n, O, S, NH, NCOCH3, N-lower alkyl (Cl-C3), CH-lower alkyl (CI-C3), CHNH-lower alkyl (CI-C3), CHNH2, CHN[lower alkyl (C1-C3)]2, CHO-lower alkyl(C1-C3), CHS-lower alkyl (Cl-C3), wherein n is an integer from 0-2: A-B is N (CH 2 )m (CH 2 )M N 43 4

('I

wherein m 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.

Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -SM, -SO lower alkyl(Cl-C3), -SO2--ower 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-fIlower alkyl (CI--C3) -SO2NH2; -SO2NH lower alkyl(Cl-C-3) or -SO2N[lower alkyl(Cl-C3)]2; R2 is hydrogen, Cl, Br, F, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Ca.-C3), or- Ri and R2 taken together are iethylenedioxy or ethylenedioxy; R3 is the moiety: 0 11 CAr wherein Ar is a moiety selected from the moiety R 7 N~rX 0 R4 is hydrogen, lower alkyl(Ci-C3); -CO-lower alkyl (CI1-C3) and R7 are selected from hydrogen, (Cl-C3) lower alkyl, (01-03) lower alkoxy and halogen; R6 is selected from moieties of the formula: -6 -NCOAr', NCON-Ar I

I

F a Rb -NCO(CH 2)n

I

-cycloa Ik)1, -NCOCH 2 Ar, -N-SO 2

-R

2

R

7 N-SO 2 CH 2 0 1I

-N-P

0 11

-N-P

I

RA

R

2

R-.

_N 2 M Cg)

R

-t\SO-b",a-a keil C 1 2 3 8 0 11 -NH-C-O-Io%%er alkN7l(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C,-C 8 )straight or branched, 0 11 -NH--C-C-lowver alkenyl(C -C,)straight or branched, 0 11 -N K-C-lowver alkenyl(C.

1

-C

8 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cycloilexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H;., moieties of the formiulae: (ClH)q-N (f q R b -(CH2)2O-1ower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, CH-3 or -C2HSq; a moiety of the formula: -X-R1O; wherein Rio is lower alkyl(C3-C8), lower alkenyi (C3-C8).

-(CH

2 )p-cycloalkyl(C3-C6), -(CH 2 )P R

R

N

K;

S

0 and p is zero to three: x is 0. S, NH, NCH3, 8f-N or abonid and PR5 and R7 are as previously defined a moiety of'L the formula:

COJ

wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C 8 branched or unbranched, ,:--lower alkyl(Ci-CS) branched or unbranched, -O-lower alkenyl(CI-C8) branched or unbranched, tetrahydrofuran, Letrahydrothiophiene, the moieties Re S o

N

R& CH 2 _b/

A

8 or -CH2-y' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N Dz E

G=F

9wherein C, E, F and G are selected from carbon or nitroaer. and where3ii the carbon a--oms may be optionally substituted with halogen, (Cl-Ciicwer alkony. -CO-lower alkyl( Ci-C3) H' (Cl-02i)lower 0-lower alkyl(Ci-Ci), and and Rb are as hereinbefore defined:; a moiety seiected from those of the formulae: N- COCH-Ar' -0-C-lowver alkvl(C1C;

RI,

NHQCH)q

N

-S-lowver ailkv(C -C 3 NHCH,) q-CON

R

Rb wherein _S Selected from halogen, (Ci-Ci)lower alkyl, -0-lower alkyl(Ci-Ci) and OH, Rb i-s aS hereinbefore defined; Ar' is a moiet;' selected_ frcm the group

RS

S

RB and R9 are independently hydrogen, lower alkyl (Cl-C3) 0-lower alkyl (Cl-Ci) 3-lower alkyl (Cl-C3), -CF3, -011, -SCF3, -OCF3, halogen, N02, amino or NH lower alkyl(Cl-C3)L -N-[lower alkvl(Cl-C3)12, N(Rb) (CH2) qN (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 S x

-N

11 and t-e moiety Z represents: phenyl or substituted phenyl optionally substituted by one or two substituents selected from (Cl-C3) lower alkyl, halogen, amino, (Cl-C3) lower 1 alkoxy, or (C1-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 (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 (CI-C3) lower alkyl, formyl, a moiety of the formula:

(CH

2 qN

R,

halogen or (C 1 -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 #r- 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: 0

II

-CAr and Ar is selected from the moiety:

R

6 4N

R-

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: NHCOR and

R

Rg is NHCOAr' and Ar' is 13 wherein R8, Ro, R25 and W 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 (CH2or N4 N0 CH 2) 1 R 3 and R4, R5, R6, P-7, 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 (CI]2)11- and n is one; A-B is -(CH 2 )m-N or N (CH 2 ;mrnis one or two 3 R3 R3 is the moiety: 0 11 CAr 14 #e -N Ar is NIOR 2 and 6

N

R- R 7 R6 is -NCOAr', or -NCOJ-1 2 Ar', -NCON-r -NCO(C11I 2 -cycloalkyl,

-I

and Ar' is a moiety,: V W Cycloalkyl Ra, Rb and W' are as previously defined and RB and Rg are preferably ortho CF3, Cl, OCH3, CH3, SCH3 or OCF3 substituents or Ar' is a disubstituted derivative wherein RB 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 is zero or one and 15 th e mnoiety zO represents a phenyl, substituted phenyl, thiophene, furan, pyrrole or a pyridine ring; A-B is

-(CH-I

2 m is one when n is one and R3 is the moiety: N -(CH 2 in m is two when n is zero; 0 11 CAr wherein Ar is NF-r0R 2 and and R6 is selected from the group -16 p.

R

-NCOAr',

R

DXH 2 Ar' where Ar' is selected fromi the moieties: and Ra, Rb, RI, R2, R4, R5, R6, R7, R8, R9q, R25 and w, are as previously defined.

Most particularly preferred are compounds of the formulae: and R2 N

C

wherein m is an integer one or two; Pi and R2 are as previously defined; Ri is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formulae: 17 /NI-JCOR~ and 6

R-R

R6 is -NCOAr', NCO(CH 2 n cvcloalkyl, -NCONAr',

NCOCII

2 Ar', -X-R 10

II

wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties: R N Ra is independently selected from hydrogen, 01-3 or -C2HS; and R5, R7, R8, R9, R10, R25, X and WI' are as hereinbefore defined.

Also particularly preferred are compounds of the formulae: wherein m is an integer one or two; RI and R2 are as previously defined; R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formulae: NFJCOR 2 and R6 is -NCOAr',

R

-NCONAr', I I RA R b

NCO(CH

2 )n cycloalkyl,

NCOCH

2 Ar', -X-R 10 19 0 11 -NH-C-O-lower alkyl(C 3

-C

8 straight or branched 0 11 -NH-C-lower alkyl (C 3 -C 8 )s traight 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,)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexeny! or cyrCIOpentenyl and wherein Ar' is selected from the moieties:

R

5

R

8

N

N6W

R

9 Ra is independently selected from hydrogen, CH 3 or and R5, R-7, R6, R9, R10, R25, X and W' are as hereinbefore def"ined.

Compcunds of this invention may be prepared as shown in Scheme 7.by reaction of tricyclic derivatives of Formula and 22 with a substituted or unsubstituted 6-nitropyridine-3-carbonyl chloride to give the intermediates _5.a and L5z. Reduction of the nitro group in intermediates aA and c~ gives the 6-amino-3pyridirnylcarbony]l derivatives _r.a and Lt. The reduction of- the niraroup in intermediates -5 and L,1 may be carried out under catalytic reduction conditions (hydrogen-Pd/C; Pd/C-hydrazile-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 6b with aroyl chlorides, heteroaroyl chlorides, arylsulfonyl chlorides, diarylphosphinyl chlorides, diphenoxyphosphinyl chlorides, alkyl (C 3 -C8) carbonyl chlorides, alkenyl(C3-C8)carbonyl chlorides, alkoYy (C 3 -C8)carbonyl chlorides, alkenyloxy(C3-C8)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 Ba and 8b 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 00C to 500C. 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 ea and 8b.

21 Scheme 1 YlR zO zO R(C N H

H

3a 3b CI 0 155 NR7 NO2 4

R

1 Y Y zOR2 zO (C mN N (H -o

A

5 N A NO 2 NO2 22 Scheme 1 (Cont'd

R

1 2

A

2 2 -(CH)

NH

Ar'COCI ArCH 2 0CO cycloalkyl(CH 2 )nCOCI 7 Ar'NCOCI 7 A= -NHCOAr'; -NHCO NAr'; -NHCO(CH 2 )ncycloalkyI; R b -NHCOCH 2 Ar' 23 Scheme 1 (Cont'd.) alkyI(C 3 'c 8

COCI

alkyl(C 3

-C

8 )O-COCl alkenyl(C 3

-C

8

).COCI

alkenyl(C 3

*C

8

).OCDCI

alky4(C 3

.C

8

)SO

2

CI

alkenyl(C 3

-C

5

)SO

2

CI

A

2 2CI 7 0

C,

R 7 0 11 -P-0C 2

I

24 Scheme 1 (Cont'd.)

A

2 zO

A

2 O

F

N 0

-R

R6= *NHCOalkenyI(C 3 -c 8 -NHSO 2 akyI(C 3

'C

8 -NHCOalkyI(C 3 'c 8

-NHCO

2 alkyI(C 3

-C

8

-NHCO

2 alkenyI(C 3 -N HSO 2 alkenyI(C 3

C

8

-HO

.N1-6q 2

CF

0 11

,F

-6

F

2 25 Reaction of tricyclic derivatives of Formula a and 6b with either a carbamoyl derivative 2 or a isocyanate derivative I0 gives compounds (Scheme 2) of Formula lla and 11L which are vasopressin antagonists and/or oxytocin antagonists of Formula I wherein R 6 is -NHCONAr'

I

Rb and Rb is H, CH3 or 26 SchIem-e 2 J 1.

C1-C-NAr' o r R b OC NAr'

R

zO zO0 (C N CH 2 =0

N

5 N N NHCONAr NHCONAr' R11 Reaction of tricyclic derivatives of Formula Id and 2.b with a 6-chioro or a 6-fluoropyridinine-3carbonyl chloride J1j gives intermediates I-Id and ilkb (Scheme 3).

27- Sch-eme- 3 3 a C1 3 51 R 4N F CI (F) 12 RI Ri Y Y -7 zOX R zO

A

2 0 0 R5R7 R 5 N R 7 0(F) CI (F) 1a13b The intermediates 1_2_ and 1_3. may be reacteLwith RjOx- (14) wherein R10 is as previously defined and X is 0, S, NH or NCH3 to give derivatives of 1_5A and as shown in Scheme 4.

28- 14

R

zO 2 N OA 0

A

5 N X-R 1 0, N X-R 1 0 The compounds of Formula I wherein Y, A-B, Z, RI R2 and R3 are as defined and the R3 (-COAr) aryl group is 29 wherein R6 is as previously defined may be prepared as shown in Scheme 5 by first synthesizing the pyridinyl moieties 15 which are to be attached to the tricyclic benzazepine units.

R-

0 H-0 6

N

R

7 16 The preformed pyridinyl moieties 16 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.

30 cheme C N 7 R 6 17 R

I

Y'-O

F

The starting materials JA and lb in Scheme I can be made by literature methods. For example, intermediate 6. 1l-dihydro-5H-dibenz(b~e)azepines and substituted derivatives are prepared according to literature procedures: L.11. Werner, et al., J. Mpd £Jb.pm.,3, 74 80 (1965); A.W.H. Wardrop et al., aj. Chaem Perkins Trans 1, 1279-1285 (1976).

Substituted 5,1l-dihydrodibenz(b,elazepin-6one are prepared by literature procedures: J. Schmutz 31 et al., Hely. CJim. Act., 336 (1965) and reduced to substituted 6, 11-dihydro-5H-di-benz[b,elazepines with lithium aluminum hydride, borane, borane-dimethylsulfide and agents know to reduce an amide carbonyl to a methylene group. Intermediate 10,11dihydrodibenz 4thiazepines are prepared by literature procedures -for example, see K. Brewster et al., 12. Chm c= Perkin 1, 1286 (1976). Reduction of either dibenz~b,fJ [1,4]oxazepines Wardrop et al., 1. Cho 11= Perkin Trans. 1, 1279 (1976)] and dibenz[b,f] [1,4)oxazepin-11(1OH)-ones and dibenz f) 4]thiazepin-11. (10H) -ones Schmutz et al., Chirn. Aca,8 336 (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 2 may be prepared by the literature procedures: T. Ohta et al., Tet-rahedron 2-E, 5811 (1985); Wiesner et al., 1.

Amr Chm 77, 675 (1955); or derivatives may be prepared by coupling procedures illustrated in Scheme 7.

The reduction of nitro compounds of structure type 3U2 followed by ring closure, affords lactams .22 which are reduced to give tricyclic azepines of Formula -1-Dihydro-6.H-pyrido[3,2-z] [1]benz-azepines are prepared by literature procedures j. Firl et al., Lib~ Chem. 469, (1989). 112.-P-yrido[(2, 3b)[1,4jbenzcdiJazepi4n-6(5H) ones have been report:ed by V.F.F. Liegei et ale, c. Chem 3_E, 2107 (1993) and these derivatives are reduced to 1la-pyrido[[2,3bI [1,4]benzodiazepines. The synthesis of tricyclic 1, 4,5, 1 0-tetrahydropyrazol o- 3-c] [I Ibenzodiazepine and the 3-chloro derivative have been reocrted 0. Palazzinc, et al., Meterccyclic: Chpm., Zj 71 (1989) 4, 10O-Dihydr-o-5SH-thieno 2 aj 1]benzazepine 2ijA and 9, 10-dihydro-4H-thieno -b1 1)benzazepine 2_1.2 may be prepared by coupling tnibutyltin derivatives and 32 with 2-nitrobenzyl bromide in the presence of tetrakis(triphenylphosphine) palladium(O) as shown in Scheme 6.

Following coupling of intermediate 2A to give the tricyclic azepine 25, the nitro group is reduced to give the 6-aminonicotinoyl derivative 26. The derivative 2a is then reacted with the appropriate acid chlorides as illustrated in Scheme Z to give the products 27 and 27a.

Also depicted in Scheme 7 is the synthesis of intermediate tricyclic azepine 13 and 12. The tricyclic lactam derivatives 29 and 32 may be prepared by reduction of nitro intermediates 2a and 21, followed by ring closure of the corresponding amino derivatives.

These tricyclic lactam intermediates 29 and 22 may be reduced with lithium aluminum hydride (LAH) or borane to give the tricyclic azepines I2 and 3.

33 Scheme -6 0D 110 s SnBu 3 0- Fii A0) SnBu 3

H+

Zn: HOAc yNO2 $Zn: HOAc

LAH

7 S

N

H

21 a 21b 34 4~~ Scheme 7 R 1 -R 2

~N.I

'Ni C (NH-

(OH

2 2 a B H 3 S(C 3H) 2 -Cu

U/A

R

1

(OH

2 2 NO 2 Pd/C H 2 N0 2 35 Scheme 7 (Continued) Ar'COCI or ArCH 2 00CI or Ar' 1 I0COD Rb NH 2 o r cycloalkyl(CH 2 )nCODCI Rb

R

1 1 Arl, Ar'-CH 2 Ar'N cycloalkyl(CH 2 n- 0

NHC-R

1 1

I

36 Scheme 7 (Continued) Rl1a alkyl(C 3

C

8

)CO-

0 11 alkyl(C 3

'C

8

)O-C-

aIkenfl'(C 3 C 8 )CO alkenyl(C 3

C

8

)COCO-

alky((C 3

C

8 )S0 2 alkenyl(C 3

C

8 )S0 2

NHR

1 1 a P So-2 -a 0 11 CH SO2 F0- 37 Scheme 7 (Continued) H 2 'Pd/C Ring close No 2 O-alkyl H 0

LAH

o r 3 0-al kyl Pd/C,

H

2 ring closure 38

LAH

Sor N BH N H 0 3

H

a2 Ar'COCI 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 1 undergo halogen exchange when reacted with a alkyllithium reagent such as t-butyllithium, s-butyllithium or nbutyllithium to give intermediates 17 which react with anhydrides of Formula ai. R12 is tert-butyl, secondary butyl, n-butyl, 2,6-dimethylpiperidine or a hindered non-nucleophilic dialkylamine. The nitro products are reduced with hydrogen and a suitable catalyst or chemically reduced (Zn-acetic acid, TiC13 etc.) to the amino intermediates A4. Ring closure to the cyclic lactams A1 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 A4 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 42.

Alternatively phenyllithium derivatives 3b., 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 as ring closure of l-amino-2-carboxy heteroaromatic compounds or l-amino-2-benzoic acid derivatives, with acetic anhydride (Scheme 8).

40

R

N0 2

R=

R 12 L i 'Li NO 2 Cl or Br 36, R= H CH 3 W 2 41

NH

2 CO H O R 1

R,

zO 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 .4 to give tricylic lactams 44. Reduction of the lactam carbonyl group gives the intermediates 42. Coupling of halogen derivatives 45 to effect ring closure with activated copper or "palladium' type reagents which induce aryl coupling gives lactams 46. Borane reduction of lactams 46 gives derivatives 42. Ullmann cross couplings of halogenated hetterocycles and 2-bromonitrobenzenes and related cross couplings by low valent palladium species such as (Pd(PPh3)41 and PdC12(PPh3)2 are known synethetic procedures; N. Shimizu et al., Tetrahedron LetU. 34, 3421 (1993) and references therein; N. M. Ali et al., etrahron, 37, 8117 (1992) and references 42 therein; J. Stavenuiter et al., Heterocycles, 2& 2711 (1987) and references therein.

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

N

H 0 HO0 44 42 H 1

RI

.j VTetrahiydro-1H-1-benzazepin-5-ones a5j and the tetrahydro-lH-1-berlzazepin-2,5-diones Uj are useful compounds for the synthesis of intermediate tricyclic heterocyclic structures U1 and .5A (Scheme 10) The t et rahydrobenzazepin- 5-ones Ui and U2 may be formulated to give hydroxymethylene derivatives or reacted with 43 either the Vilsmeier reagent or the N, Ndimethylformamide dimethyl acetal to give the dimethylamiflomethylene derivatives. The construction of heterocyclic rings from a-hydroxymethyleneketones by reactions with hydrazine, N-methylhydrazine, hydroxylamine or formamidine to give pyrazoles, Nmethylpyrazoles, oxazoles or pyrimidines respectively, is a standard literature procedure. See Vilsmeier formylation 1T. ae±d.QL, A2, 1 4015-4034 (1993) and references there.-n and ring formations .Het erocyr Iic Chm. 2-9, 1214 (1992) and references therein.

Substituted and unsubstituted tet-rahydrobenzazepin- 2 -ofles are known compounds which are prepared by reaction of a-tetralones with sodium azide under acidic conditions. Chem. 456 (1937) Tetrae.dr.2 A2, 1807 (1993) (Schmidt reaction) ReductiLon of tetrahydrc-1H-benzazepifl-2-ones grives the tetrahydro-1H-benzazepines _4a which acylation gives comp~ounds 492. Oxidation of N-acyl tetrahydro-1Hbenzapines of type 492 to give the 5-one derivatives is a known ozidative procedure; R. L. Augustine and W. G Pierson, 1. r Chm. .2A, 1070 (1969) The synthesis of 3,4-dihydro-lF,-1-benzazepile- C.,Z:R15=H) has been reported as well as the conversion of 3,4-dihydiro2.*-'1-benzazepine-2,5-diones to 4- (dimet-hyFlamino) methylenel 4-di-hydro-1ii-1benzazevine-2, 5-di4ones with N-dimethylformamide, dimethylacetal: 'Chen and N. W. Gilman, Heterocyclic Chem., jQ 663 (1983)]. The preceding reference describes the synthesis of 2-methyl-5,7dihydropyrimido 4-.dl [11,benzazepin-n(61j) -ones which may be reduced to- remove the lactam carbonyl group to give tricyclic deri-vati*;ves cf structural type _4 wherein Z is a pyrimidine ring.

44 Scheme 0No

NBS

6 H 5 C0O) 2 0 4-9 a; R 15 =(CH 3 3 000 0 b; R 15

=C

6

H

5 -CH 2 01L

(CH

3 2

S=O

EtN c; =l R 1 a,b, c KMn0 4 (Continued) 5-1~ a, b, c 45 Scheme 10 (Cont'd.) Rl 52(R 1 5

=H)

RI H 0 46 Scheme 11 Rl Rl

HH

CI 0

R

5 N RA 7 NO2

F

R

1 Y Y zO zO

N

NO

NO2N2 56a 1i 47 Scheme 11 (Contd.

RlR 100 N N P NF- NH 202

NI-IN

a59 48H 2 The compounds wherein the aryl group in the R3 moiety -COAr is R7 NHCOR2 are prepared as shown in Scheme 11. The tircyclic derivatives 3a and 3b are reacted with a substituted or unsubstituted 4-nitrobenzoyl chloride fa to give the derivatives 56a and 5b. Reductions of the nitro group in derivatives 56a and 56b gives the 4-aminobenzoyl intermedites 512 and 57b which are then reacted with an acid chloride represented by formula 58 to give the products 59a and _J2b.

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

X-RIO

R7 are prepared by reactin of tricyclic azepines 3a and 3b with a substituted benzoyl chloride illustrated by structural formula 26 (Scheme 12) to give the products f1a and 61b. In a similar manner reaction of heteroaroyl chlorides 62, 63, or E4 with the tricyclic azepines 3a and 3b gives the products 65a and wherein the aryl groups are as illustrated in Scheme 13.

49 Scheme 12 cl 0 100 zO R 2 zO mN -0 X- R, to 50 Scheme J- X- Rio o N- X- Rio.6

R

2

Y\

O R Ar E XRi

S

R

10 0 X- Ri Reference Exampole 1 6. l1-Dihvdro-5H-dibenz[b.e Iazeile A mixture of 48.52 g (0.20 mol) of 2aminobenzophenofe-2'-carboxylic acid and 500 ml of xylene is refluxed for 67 hours, cooled to room temperature and filtered. The solid is washed with xylene to give 43.3 g of 6,11-dione as light tan crystals, m.p. 245-248 0 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. 117-122°C.

Reference Example 2 2-Chlcr-5H-dibernz b. eazeine-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- 2930C.

52 mm Reference Example 3 11-Dihvdrc-N. N-dimethvldibenz fb. f 1. 4 1 oxazepine-2sulfonamide To 5.88 g of 10,11-dihydro-N,N-dimethyl-lloxodibenz[b,f][1,4]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 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 2-Chlor_-5.6-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. 310-318 0

C.

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 is added. The mixture is concentrated under vacuum and ml of 2 N sodium hydroxide added. The mixture is 53 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-SH-dibenzfb.elazepin-6.1-dione A mixture of 11.15 g of 51-dibenz[b,e]azepin- 6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70°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°C to 295 0

C.

Reference E:-amel 6 0 -Chloro-6. 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 give crystals, m.p. 137 0 C to 1410C.

Reference Examole 7 1Q i h-ri rojbenz It7 f 1141thi azePine To a mixture of 3.3 g cf 10,11-dihydro-lloxodibenz[b,f] [l,4]thiazepine in 25 ml of tetrahydrofuran is added 4.0 ml cf 10 molar boranedimethylsulfide in tetrahydrofuran. The mixture is 54 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 Exarr,1le 8 4-Methv'-10.ul dihvdrodibenzrb.fl) 1.41rhiazepine Reference Examjle 9 4-Chlor, -10.72-iihvdrcdiben-rb~f' '1.41:thia-e~pinem Reference 2-M.4thvl 1 -0.1-dihvdrodibenzfb.fi rl,4 hiazepine Raferencp ExarnI21P 11 2-Chlorc-l0..11-dihvdrodiben.Eb.fl rl.lthiazeioine Referenca Example 12 2-Met hoxylg.11--dihvdrcdibenzrb.flr W4-hiazepine Reference Examole 13 8-Chior-2-0.l1-dihydrodibenzfb.fil t41thiazepine Reference Examyle 14 4.8-Dichloro-IC.,11-dihydrodibenzrb-f1 1.41thiazepine Refer-ence Examp 1S 8-hco4meh r011dhdoibnf~l 1 4 1- Reference Examv~re 16 8-Methoxv-20.u1-dihvdrcdibelzfb.f' t l.41thiazepine Reference Examnle 1? I-Ch~crc-4-mnehyl-10.11dihvdrcdibenzrb. fl-1. 41 thiazoorine The following compounds are prepared as described in Reference Example 3.

Ref~rence Examiple 18 2-Chlo--10 ''-dihvdrcdibenzrb. f'

T

.41-oxa.=zeoine 55 Reference Exarnp1e 19 2-Methv1-10. 1 -dihvcirodibenz rb. f 1 r1. 41 -oxaZ24jne Reference Example 4-Chloro-10,i1-dihvdrodibenzfb.fl rl.41-.oxpzepine.

Reference Example 21 3-Methvl-10,Jl-dihvdrodibenzfb~fl rl.41'-oxazepi-e Reference ExamT~le 22 7-Chloro-1 0. 11-dihydrodibenz Ib, f 1 f 1. 4--oxazenine Reference Examvp 23 8-Chlcrc-10,11-dihvdrodibenzrb.fI ',1.4!-ox-az,-tine Reference Emamrolp 24 2. 4-Dichicro-1O. 11-dihvdrodiben-7 [b f 1~ 4 1-oxazeci ne Reference ExamTpIe 4. e-Dichlcr,,'-10. 11-dihvdrodibenz fi r 1 *4 1 -oxazeDpne Reference Examvla 26 4-Chlorc-8-retl-hyl-1-0.11--dihvdro-dibenzrb~fI Reference ExamIple 27 4-ehl7chco1.1-iv[1bezbff.41oxzeline Reference Examiple 28 1-Chlorc-4-methvl.,-10. 1 -dihydroli ben- Fb, f rl.41- Reference Examnle 29 2-F-luoro-lO, .1-dihvd~rodibenzfb.f f1 1.41--xazeipineo Rpference Example N- (2-Iodorphenvl) -2-icdonheflvlacetami de A solution off 13.32 g (0.05 mol) of 2iodophenylacetic acid in 75 ml thiJonyl chloride is refluxed for 2 hours, and the volatiles removed under vacuum. Toluenie 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 inol) i4n a mixture cf 100 ml of toluenedichlor-omethane is added 11 g (0.05 mol) of 2iodoaniline and (0.10 mol) of dii-sor-ropylethylamine.

56 The mixture is stirred at room temperature overnight and the solvent removed. The residue is dissolved in dichloromethane and the solution washed with lN 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-iodoDhenyl)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 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 crystals.

Reference Example 32 N-(4-Nitrobenzovl-N-(2-iodophenvl)-2iodobenzeneethylamine 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 vacuum. The residue is dissolved in ethyl acetatedichloromethane and the solution washed with 1N 57 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 3.4-Dihydrc-lH-l-benzazDPine-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 1000C 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- 1580C. 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. 1030-1070C. 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 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2 N citric acid, 1M NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue purified by chromatography over silica gel with ethyl acetate-hexane as solvent to give 0.190 g of light brown crystals, m.p. 1680-1700C.

58 Reference Example 34 4- (Dimethylamino)methylenel-3.4-dihvdro-1H-1- A mixture of 0.250 g (1.43 mmol) of 3,4dihydro-li-l-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,-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. 203 0 -205 0

C.

Reference Example 2-Methyl-6. 7-dihvdrc-5H-pvrimidor5. 4-di lbenzazepine 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, and 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 equivalents of lithium hydride in dioxane for 24 hours to give the product as a solid.

Reference Exampleo 36 -Dihvdrovridor2.3-b 11. 4 1benzcthiazepine 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 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 HC1 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 material. The filtrate is concentrated, chilled and filtered to give 12.5 g of 2-(3-nitro-2pyridinylthio)ber.noic. 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 i 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 0.57 g of solid. Recrystallization from ethyl acetate gives 0.28 g of 2-(3-aminc-2-pyridinylthio)benzoic acid.

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

Reference Example 37 2-Nitro-2'-carboxy-diphenylamine 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 and dried to give 20.5 g of the desired product as a solid, m.p. 262-265C.

Reference Exampl 38 2-.A.ino-2'-carboxv-diDhenylamine 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 vacuo to give 6.6 g of the desired product as a solid, m.p. 72-75 0

C.

Reference Examoie 39 5,ll-Dihydro-!0H-dibenzfb.e1 f,41diazecine-11-one 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 Reference Example 5.11-Dihvdro-1OH-dibenzb.el 1.41diazeoine 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 11000 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 IN HC1, 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 Examcle 41 [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 azecine-6. 11-dione A mixture of 1.0 g of 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°-2930C..

62 Reference Example 43 2-Chloro-6.11-Dihvdro-5H-dibenz lb.el azeine To a mixture of 7.28 g of dibenz[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 is dissolved in methylene chloride and washed with 2 N citric acid, water and dried (Na2SO 4 The volatiles are evaporated in 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-(Tributvlstannvl)-3-thienvyl-1.3-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 -780C 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 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, given 34.16 g of the desired product.

63 Reference Example 2-r2-r (2-Nitrohenv)methl 1-3-thiienv 1-1.3-dioxolanp A mixture of 2-[2-(tributylstannyl)- 3 thienyl)-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 licuid. Mass Spectrum; M+292 Reference Examole 46 4,!0-Dihyr-H-thieno[3,2-c 1benzazerine A stirred solution of 4 gms of nitrophenyl)methyl]-3-thienyl]-1,3-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 (Na2SO4) 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°C. Mass Spectrum; M+202.

Reference Examp'le 47 4.-Dihvdrc-.4-d et-- 2 r (2i ro

D

henv )h ,Pthc1 2 thienv'oxazole To a solution of 4,5-dihydro-4,4-dimethyl-2- (2-thienyl)-oxazole (4.5 gms 25 mmol) in anhydrous ether at -700C, 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. 1-Dihvdro-4H-thioncf3.2-c1 r 1benzazepin-10-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 0 C and zinc dust (10 gm) is slowly added. Stirring is continued at 70°C for 6 hours. At the end, the reaction 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.

Mass Spectrum: M+215.

65 Reference Example 49 9.10-Dihydro-4H-thieno[2.3-c1 [Ibenzazepine A stirred solution of 2.0 g of 9,10-dihydro- 41-thieno[2,3-c][l]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-Methy'lfuran-3-carbonvl 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 2- 2- (Tributvlstann.,vl) -3-thienvl 11. 3-dioxolane 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, in hexane, 74.3 ml) is added dropwise under ni=rogen at room temperature.

After beina refluxed for 15 minutes, the reaction mixture is cooled to -780C and tri-n-butyltin chloride (34.18 g, S.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 (LiC1) 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-aminonvridine-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 Examole 53 6-f(5-fluorc-2-methylbenzov) aminolpvridine-3-carboxvlic 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 stirring at room temperature for 3 hours, the mixture is 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 additional 9.0 g of bis acylated compound.

67 A mixture of 1.2.0 g of methyl fIluoro-2-methylbelzoyl) )amino~pyridine-3-carboxylate, ml of methanol-tetrahydrofuran and 23 ml of 5 V 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 I 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-zuting the appropriate aroyl chloride, heteroaroyl chloride, cycloalkanoyl chlorides, phenylacetyl chlorides and related appropriate acid chlorides, the -ollowi-ng (aroylamino)pyridi44ne-3-carboxylic- acids, 6- (hetero--aroyl)ami-nolpyridi-ne-3-carb--oxyli- acids and related '6-[(acylateai)aminolpyri-dine-3-carboxylic acids are prepared.

Reference ExampIe 54 6-F (3-Methvl-2-thienvlcarbonyL) aminolovridine-3carboxylic acid Ref~rence Examole 6- (2-Methv1-3-thienvlcarbonv-) arino'ovridine-3carboxylic acid Reference Examnle 56 (3-Me-h'J,-2-furanlcarbny amin I nrdine-3carbox.,.'i1c acid Reference Example 57 (2-M-!-hy-3-f,,ranvl carbonv) )aminclnvridine-3> carboxylic acid Referenc,- Examp 58 Reference Exaro1z 59 (2-Methvlbe,-c-.' arinoloyri4 ne-3-carbcM.i c acid Referpnc- Examiple 6r(2-c)-.'c-obenzrov!) afinc~iOyrin- -carbocv 1 i! Pid 68 Reference Example 61 6-f (2-F"vorobenzovl)amprnilpyridine-3-carbpxylic arid Reference Fmamole 62 -r(2-Chloo4fuorobelZOV)amifl1Ovridifle-3-carboxylic

A

Refprence ExaMRno2 63 6-r A-Dichlorcbenzovl)aminl1Pyridife-3carboxvLic acid Reference Ezample 64 6-r 14-Chlorc-2-f'uorobenzovlaminlOOvridile-3-carbo>mvlIc Ll Reference Examolp 6- r(3~ 5-Tri'metho.-,vo,,enzcv1 amino 1 ovridine--3-carboxyl ic Referenc- Examvle 66 :r -(2.4-Difluorob-nzovl)aminclODvridfe3-arboxVlic acid Reference Fmarnole 67 6-f(2~-zmo-obenzovi)arinol1Pvridife-3-carboxylic aci-d Referencp Example= 68 ai .Referonce Examole 69 r--r (Te-rahvdrclu~rafyl-2-carbonli)a pinporvridir'e-3carboxylic- acid Reference Ez'amv 1 6-r(Te-ralivdrcthienflV--carhonfliamino!L%-idifle- 3 rarboxvl 4 c acid Referoncp Examole 71 6- r(Cvc1he-v nfl1)mifOO'iflcabXi cd Reference Example 72 g- (cvc~ohey-l-eflecarbOflV' a, rA otvrdine-3-carboxylic Rafprence- E:xavrole 7 6- r ~~ur2e~~e~naeV) pminorvr'djne-3carboxvlic acid 69 Reference Example 74 6- r (2-t)-1o-roben-zeneacetvl Iamino I rvridinz-3-carbo~xvl ic Reference Examolp r (v c 1one nt v1 c arbony 1) amjn o I i di n e- 3 -carbo 2vl iC: a ni d Reference Example's 76 6-f (c'hexv';!acetv 1) amino I pr 4!dine- '-carboxy 1 acid Reference Exampnle 77 zl.

Reference rxamiple 78 Rfere'-ncp Examrri! 79 r( 3 -M-thv 1-2- furanylacetv1) amino I rr'dine- 3-cartoxyl c acd m.p. 288-290 0

C

Exaincle (2-Methyl furanvlacetvl) ano~)p;Dvrjd-ne-' -carboxylic Reference Exarnole 81 r (3-M-eth\1-2-tmtrahvdrcth 4 envi-acetvI) arnincl rvridine-3carboxylic aZid Reference Example 82 carboxv'ic acid Reference Emamc'le 83 c D c l rb n oz~ r.4 nl-,7d n -at aci;d Ref-ence Emamnl1e 84 6-f (3 5-D- ch acid, vI rn o die -a bx Reference Exacnrie Referencp Eamnlp 86 6-f(2 acid Refoence Exa--n e 87 6-[r2Mtcv c)rioor ~bx2i acid 70 Reference ExamRlp R8 6- r(2-Triflloronmethoxybenzovfl aminolpvyridjne-3g-arboxylic acid Reference Exarn~1e 89 6-f (4-Chloro-2-methoxybenzovflainoloyridine- carboxylic acid Reference Example 6- r-T m th lbe zv lm-op rd n carboxyl in c Reference Example 91 rbno)ariclDrd e3c~hw' H Reference Examp1- 92 RPeferncp ExamRn! 91 6- f(2-Mohvli hichben-zov1) amnno pvridin-3-carboxyl ic acid Reference £E<amipie 94 6- r(4-F!1;r:c-2- f uorome-hv1) benzoyl) amino 1 vridine- 3-carboxv1~c acid Reference Exatnrila 6-r Dcirbnov~mni~rdip3croyi acid Reference Emamip1e 96 E-r (4-F-luorc-2-rnethylbenzovl) arinol ovridine-3-carb.:ylic Reference Fzarra1e 97 -(..-rch-rbnc amn~prd-e--abx~i Reference Emarn~le 98 6- f (5-F1uorc-2-chicroenzo.'1) amino 1 Dr idine- 3-carboxy i c Reference ExaMRnlp 99 E- r uorT-5- (tri f luromethv')benzo%'1) amino I tvri ri ne- 3-carbcvxvlic acid 71- SRef-rence Examp 100 r 5FIicr--e!ile-ol mn yiie I--rny chloride A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)aminojpyridife-3-carboxyli-c acid and 23 ml of thionyl chloride is refluxed for Ihour. An additional 12 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml of toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) 4s repeated to give 7.7 g of crude product as a solid.

As described for Reference Example 100, the following 6- (acyl)ami-no)pyri dine-3-carbonyl chlorides are prepared.

Reference Exarnle 101 6-f ethv1-2-thiensvlcarbonv1)aminol1ovridirie-3-carbcnvl ReferencP Exarmrol0 102 6-f (2-Methvl-3-thienvlcarbonvl)aminolipyridine-3-carbonfll chloride Pefer-nce Examcip 103 6(3-Mev1hy-2-f-rnvlcrbonvlmnolrovridin- 3 -carbonV1 chloride Ppfe~nce Exarnc-e 104 Reference Examnle 105 uor-.v-erZOhylbenac\'rl aino i-'-crdine-3cairiden Reference Examrcie 106 6- r 2-Ch' orobenlzovl) aminolov,,ridin--3-carbonvI -c .cride.

whiLte crystals 72 Reference Exampl1e 108 6-r(-loFa~olaioLyiie3rrov chicoride Reference Exampl1e 109 6- r (2-Chloro-4 fluorobenzov!) amino I vridine-3-c rbo,vl rh I i rite Refer-ence Examole 110 r--r 4 -Dichl orcbenzovl) amnino I pri dine~- -ca rbnnyi Reference ENArn~1e 111 6- f (4-Chlorc-2-f lun-robenzcyH aminol Tvridine-?-car onyl chloride Reference~ Exarnple 112 f (3 4.5-"r4 met-hoxvben-zov1!) amino Voridi ne-3-cprbo'v! chicrid- Reference Example 113 6- r *4-7)-fuorcbenzovl) amino I oridine-l-carbony chicride Reference Example 114 6- F (2-Promobenzov!) amrinol 1 vri dine- 3-carbonv1 chlorideLM Reference Examl~le 115 chloride Ref-rence Examlple 116 F Mmzetrahvdrofuranyl -2-carbonvli amino I vri di necarbonyl chicride Reference Example '11 6- r (Te,:ahvdroc hi env 1 -?-narbonyl) amino 1 I vrj dincarbonvl chloride Reference Example 118 6- r (Cwc1 ohemy !carbon,., amnino In\'r idino~- I-carbony 1 chicoride Reference Examn1e 119 6-1 F Cvhem-3-enecarbonv amino I ovyridi' n-3-carbonyl -73 Reference Example 120 6-f (2M-vbn~ectlIaio11yiin-3crov Reference Examole 121 6-1 (2-Clorobenze-neacetvl)aminl-oPrdie- 3 -carboflvi Reference Example 122 9- 1r (Cv-lonen-v Ia rbony) am i nopyridile-3-cabolv

I

Reference Examiple 123 6- r Cc hxlc-l mnl~:ii-'-abn, chloride Reference Exampole 124 chloride Raference Exampl=' 125 6-1 (2-Me*vl-3-thieflylaretyl amin. pvridine-3--carbonvl Reference Examl~lp 126 Reference Examr~1e 127 2-ethl 3-furanvlacorvl) amfi nolPvrid nle,;carbonfll chloride Reference Fza~Dle 128 6- f (2Mt-.'-fu~robenzeneacel'l arinovvridine-3rbronv 1 hloride P-eferenc- Eamip 129 6- r (3 -!eth i 12 -tetr Vahvcro hi env 1 c-tv 1 ar ino crdine- 3carbonvi chcride Re-Fe'nce Eamip 130 f 3t ,4-t 4n l c t la i ci,,i ie 3 r-arhonyl chcride Reference Examtnle 131 6-r(2 h -l zo l m o d n -3 ea-o chloridec 74 Reference ExamRle 132 6-f 5-Dichlorobenzovl) aminol1vriding-3-cprbonvI Reference Example 133 6-r (2-Methvl,-4-chiorobenzovl) arinolvRyidine-3-cp-rbonvI chicride Refe'-er-e Exarmp 134 3-Dimet-hvlhenzovl) aminolovyridine-3-carbonnv Reference Exarn~lo 135 6- r(2-Methoxvb-n~oy1 aminc!Rvridine-3-carbonvlI chloride Reference Examcle 1 36 6- r(2-Tr,' fluorcme,,hoxvbenznv1) a;mi no I nvr4 dine- 1-carbony 1 chloride Reference ExamL~le 117 6-r (4-Ch'orc--mTe-hom.vbenzf-v)arinolpridine-3--cprbonvl Reference ExamDle 138 6-r f2- (Trifluoroineth v1)benzovl11pminol1~vridine-3-carbonv1 cird Reference Examcn1e 139 6- r(2. 6-Dichiorc-benzovl)arminzlInvridine-3-carbonvl- Reference Ezam--le 140 6-1 6-Di-methylbenzoyl) a. c'idn--carbonv 6- (2Mehvlhioenovl ainc&oyridine-3-abov chloride Eamplp 142 r (4-Flucrc-2-(-''lii--ret hvl)benzo\'1)amTinol~vridine- 1-carhonyl c Ic~,de Reforence Exarnole 143 6-f 3-Dich2.orobenzovl) aminolr~yridihe---carbonvlclrd -75 Reference Exam]21e 144 6- r (.4-Flunrn-2-TflethVlbeflzOvl) amino I yri din e-3-carbonylI Reference Evxamtrde 145 6-f 5-richiirobenzovlI)amr1olrridifle-3carboflv R-ference 7xampl- 146 6- (-!ro2C-roez-lami-nol pridine-3-carbonvI chloride Reference Exam;Dle 147 r-r (2-loc5 tif1ooe-v~,noI)aiovr ie 3-carbonyl chlcride As described for Reference Example 53, the following bis dcy~ated products (Table A) are prepared and purified by silica gel chromatography. These compounds are then h,,ydro'lysed to the acids (Table B) as described in Reference Example 53.

0

CH

3 76 Ref R1 R2 R3 R4 x M Ex -148 CH3 H H H H 388 149 CH3 H -H F

PHL

-150 CH3 F H H H 426 -151 H OCH 3 OCH 3 OCH3 H 540 -152 Ci H H H H_430 -153 F H F H H 3496 -154 Br H H H H 520 155 Cl H F H H 412 156 Ph H H H H- 512 157 C1 Br H 474 158 CH3 H H F Br 159 -CH3 H H H Br 468 M+ is molecular ion found from FAB mass spectrum 200 77

J

Ref. R1 R2 R3 R4 X M Ex No.

160 CH3 H H H H 256 161 CH3 H H F H 274 162 CH3 F H H H 274 163 H OCH3 OCH3 OCH3 H 332 164 Cl H H H H 276 165 F H F H H 278 166 Br H H H H 322 167 C1 H F H H 294 168 Ph H H H H 318 169 Cl H H Br H 356 1 170 CH3 H H F C1 171 CH3 H H H Br 336 M is molecular ion found from FAB mass spectrum.

Reference Example 172 ;-Am.ino-5-bromopyridinei -carboxylic 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 R fere-ce Evample 173 Moth'- &-aminc-5-brraopyridir~ -3-~arboylate 6-Amino-5-bromopyridine-3-carboxylic acid g, 50 mmcl) is dissolved in saturated methanolic HC1 (100 ml) and refluxed for 24 hours. The solvent, methanol, is re-moved under reduced pressure and the residue is dis-solved in ice cols water. The aqueous 78 j 0.

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 Examcle 174 6-f (2-Methylbenzeneacetl) aminolpvridine-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 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 Example 175 6-1(2-Methylben eneacetyl)aminolDvridine-3-carbonyl chloride A mixture of 4.5 g of 6-[(2-methylbenzeneacetyl)amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 1 hour and then con- 79 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 rl. '-Biphenvll-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 6-[fbis(rl.l'-biphenvl-2- .:carbonvl)1aminolpyridine-3-carboxvlate 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,l'-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 NaHCC3 and brine and dried (Na2SO4). 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.

Reference Examle 178 -r ri. '-biphenyvl -2-vlcarbonyv)amino1pvridinecarbcxvyic acid To a chilled (00C) mixture of 6.0 g of methyl 6-[[bis[(1,1'-biphenyl)-2-ylcarbonyl)]amino]pyridine-3carboxylate in 40 ml of methanol and 30 ml of tetrahydrofuran is added slowly 18 ml of 2 N NaOH. The 80 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 HCI 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 -il.l" '-biphenvl1-2-vlcarbonyl am inolpOvridine-3-carbo n v y chloride A mixture of 1.9 g of 6-[([1,l'-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)aminol1vridine-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°C) and 62 ml of 2 N sodium hydroxide added. The mixture is stirred at room temperature for 3 hours, neutralized with 10 ml of glacial acetic acid and concentrated under vacuum. The mixture (containing solid) is acidified to 81 pH 1 with 1 N HCl 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 Exam]Rle 181 M~n9!:v1-2-r(4-ethoxv-oxobutv' )aminclbe'n'oatep A mixture of 19.2 g of methyl 2-aminobenzoate and 9.6 g of ethylj g-bromobutyrate is heated at 80-85 0

C

for 24 hours, cooled to room temperature and filtered.

The solid Is washed with CH2Cl2 and the filtrate washed with 1NHC1, H20, INNaHCO03 and brine. The solvent is removed to give an oil. The oil is distilled and the fraction boiling at 45-75 0 C and 13C-7 60 0 C were collected and discarded. T1he residue is the product (55.4 g of oil) Reference Example 182 Methyl 2- rN- (4-ethoxv-4--oxobutvl)-N- (2methyvLhenvisulfonvlami no benzoate A mixture of 2.65 g of methyl 2-[(4-ethoxy-4oxobutyl)aminolbenzoate, 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 HICl added. The mixture is extracted with dichloromethane and,- the extract washed with 1NHCI, H20, 1 M NaHCO3, 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 give crystals, m-p. 100-102 0

C.

Reference Example 183 m-it~'.v and rthyl 1.2-Dihydrc-5-!1vdroxy-"-r (4methv1hnnyl) sul 1fonyl 1-3H- !-ben, azeoine-4-carhnxylate To a mixture of 0.448 g of potassium te' butoride in 2 ml of tetrahydrofuran; cooled to OOC is added 0.838 g of methy'l 2-[N-(4-ethoxy-4-oobutyl)-N(2- 82 methylphenylsulfonyl)amino]benzoate in 12 ml of tetrahydrofuran. The mixture is stirred at OoC 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-tetrahvdrc-1-r(2-methylphenvl)sulfonvyi-5Hu1 A 30 g sample of a mixture of methyl and ethyl 1,2-dihydro-5-hydroxy-l-[(4-methylphenyl)sulfonyl-3H-1benzazepine-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 NaHC03. 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-f(Dimerhylamino)methylenel-1.2.3.4-tetrahvdro-l-r(2ehvyl1pheny! ulfcnyfv1 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 tert-butoxy-bis(dimethylamino)methane (Bredericks reagent) in 10 ml of dichloromethane is heated under argon on a steam bath for 16 hours. The mixture is concentrated to dryness under vacuum and the residue dissolved in CH2C12. The solution is filtered 83 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 CH2Cl2-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 1.4.5. 6-trahvd-rc-- methvlphenvl)sulfonvnlvpvrazolof4.3-d rllbenzazepine 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 ((Na2SO4). 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-l-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 gel) with hexane-ethyl acetate Reference Eamole 187 1.4,5,6-TetrahVdroovrazolo- 4 3-dl 1 benzazepine A mixture of 1.0 g of 1,4,5,6-tetrahydro-6- [(2-methylphenyl)sulfonyl]pyrazolo[4,3-][l]benzazepine in 60 ml of 40% (V/V)H2S04 in glacial acetic acid is heated at 600C 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 (Na2SO4) and the solvent removed to give a solid.

Reference Example 188 10.11-Dihvdrobenzb.fl l.41oxazepine 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(11H)-one. An additional 100 ml of tetrahydrofuran is added and the 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 dichlcromethane-hexane gives 7.5 g crystals, m.p. 69- 71oC.

Reference Example 189 Pyrido[2.3-bfl1.41benzoxazepin-6(5H)-one A mixture of 21.4 g of phenyl salicylate, 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 1N NaOH. The hot mixture is poured into 200 ml of ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried.

85 Recrystallization from methanol DMF gives 6.0 g of product, m.p. 268-270 0

C.

Reference Examole 190 5.6-Dihvdropyrido[2.3-bl f1.41benzoxazepine 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 2U NaOH added to the residue. The mixture is refluxed for 2 hours and extracted with ethyl acetate. The extract is washed with 21 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-Hydro::vyphenvl) -2-chlor--cvridinecarboxamide As described in J. Med. Chem., 37, 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 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. 145-146 0

C.

86 Reference Examole 192 Pvridof2.3-b1 r1.51benzoxazepin-5(6H) one A mixture of 13.0 g of N-(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 E-Dihvdropvridof2.3-b 1l. 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.

Reference Example 194 9.!0-Dihvdrc-4H-thieno\2. 3-cl Mibenzazeoine To a solution of 9.0 g at 4,5-dihydro-4,4dimethyl-2-(2-thienyl)oxazole in 200 ml of tetrahydrofuran, cooled to -78 0 C, is added 20 ml of a molar solution of n-butyl lithium in hexane. The mixture is stirred -78 0 C for 15 minutes and at OOC for minutes. To the stirred solution is added 6.0 g of 2-methylbenzoxazepine-4-one. The mixture is stirred at 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-4-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-methancl and the extract dried (MgSO4). The solvent is removed and the residue chromatographed over silica gel with ethyl acetate-hexane as solvent to give 1.8 g of solid; Mass spectrum (CI) 202 (M H).

Reference Examle 195 Myhv 4-_f '-Bipheny-2-'carb o n v amino-3methoyvben 7oate A mixture of 10.0 g of [l,1'-biphenyl]-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 vacuo 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 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 4-1 '-Bihenvl-2-ca-rbnyvl)aminl_ 2 chlorobenzoate A solution of 2.37 g of [l,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 NaHC0 3 and the organic layer dried(Na2S0 4 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-rFl. '-Riphenvl1-2-carbonv )aminol-- ohobn.

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 3vaca 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-l(fl.'-Biahenvll-2-r-arbonvl)-aminol-3-methoxvbenzovy Chloride A solution of 2.69 g of 4 -[([l,1'-biphenyl]-2carbonyllamino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour 89 under Argon. The volatiles are removed in Yacuo to give a residue which is stirred with hexane to give 2.58 g of crystalline solid, m.p. 121-123 0 C. M+=361.

Reference Example 199 Methyl 4-f (!.l'-Biohenvl!-2-carbenvl)aminolben7oate A mixture of 10.0 g of [l,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 ml of methylene chloride is added dropwise to a solution of 4.53 g of methyl-4-aminobenzoate and 4.3 g cf N,N-diisopropylethylamine in 100 ml of methylene chloride at 00C. The reaction mixture is stirred at room temperature for 18 hours and washed with water, and saturated aqueous NaHCO3 and the organic layer dried(Na2S04). 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 '-Biphenvyl-2-carbonvl)aminolbenzcic Acid A 3.15 g sample of methyl 4-[([l,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 g of the desired product as a solid m.p. 246-249 0

C.

M+H=318.

Reference Example 201 4-f (ril'- iphenv11-2-carbonvl)aminolbenzov1 Chloride A mixture of 1.39 g of ([1,1'-biphenyl]-2carbonyl)amino]benzoic acid in 2.0 ml of thionyl 90 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- (henylmethyl)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 vacu to give 5.74 g of the desired product as an oil. M+=227 as methyl ester.

Reference Example 203 Methyl 4r !2-(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-'f2-(Phenv methvl)benzovl1aminolbenzoate A mixture of 4.90 g of methyl (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 to give 4.25 g of the desired product m.p. 340-346 0

C.

91 Reference Example 205 4-rf2-(Phenvlmethyl)benzovllamirolbenzcic 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, 246-247 0

C.

M'=332.

Reference Example 206 4- f2-(Phenvlmeth 'l)benzoyvlamr.n-benzovy Chloride A mixture of 2.0 g of (phenylmethyl)benzoyl]amino]benzoiz 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 Examole 207 Methyl 4-f (2-Phenvlmethvl)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 for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHC03 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, 133-135°C. M+=380.

92 Reference Example 208 Methyl 4- f(2-Phenvlmethvllbenzovl1amino1-3methoxvbenzoate 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. 129-131 0 C. M+=376.

Reference Example 209 2-Chloro-4-r r(2-Phenvlmethl1)benzoylIaminobenzoic 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 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. 184-187C. M H=366.

Reference Example 210 3-Methoxv-4-r!r(2-henvmethvllben ovllaminolbenzeic 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 chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80C to give 1.87 g of the desired product as a crystalline solid, m.p. 176-178 0 C. M+H=362.

Reference Example 211 3-Methoxv-4-fr(2-henvlmethvl)benzovl1aminolbenzoyl Chloride A mixture of 1.71 g of 3-methoxy-4-[[(2phenylmethyl)benzoyl]amino]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 1.71 g of the desired product as a crystalline solid, m.p. 130-135 0 C. M+=376 as the methyl ester.

Reference ExamDle 212 4 '-(Trifluoromethvl)-1.1'-biphenvl 1 -2-carbonvl Chloride A mixture of 5.0 g of 4'- (trifluoromethyl) l,l'-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. M*=280 as methyl ester.

Reference Example 213 Methyl 4-r(r4'-(trifluormPethvl)fl. biDhenvll carbonvl) aminob enzoate A solution of 3.13 g of (trifluoromethyl) [1,1'-biphenyll-2-carbonyl chloride in ml cf 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 fcr 18 hours and washed with water, 94 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 3.36 g of the desired product as a crystalline solid, m.p. 164-165 0 C. M+=396.

Reference Example 214 -Mothoxy-4-r- 4' (t-rifluoroethyl 1. 1 -bipheny 1 -2carbonvy aminolbenzovl Chloride A mixture of 2.0 g of 3-methoxy-4-[([4'- (trifluoromethyl)[1,1'-biphenyl]-2carbonyl)aminolbenzoic 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-Methoy-4-r (4'-trifluoromthyl) rl.l'-biphenvI'-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.

213-215 0

C.

Referenc- Evample 216 Methyl 3-MethoYy-4- 4 rifluromethv!) I. 1 biphenyl1-2-carbonvl aminolbenzoate A solution of 3.56 g of (trifluoromethyl) [1,1'-biphenyl]-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 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 3.9 g of the desired product as a crystalline solid, m.p. 112-113 0

C.

Reference Example 217 2-Chlorc-4-f (trif1ucromethy) l. 1 -biphenyvl -2carbonvl)aminolbenzovy 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 2-Ch!ore-4- r(4'-(trifluoromethyl) l1'-biphenvl 1-2carbonyl)aminolbenzoic acid A mixture of 3.83 g of methyl 2-chloro-4- [([4'-(trifluoromethyl) [l,l'-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 3.42 g of the desired product as a crystalline solid, m.p.

187-189 0

C.

96 Reference Example 219 Methyl 2-Chloro-4- (14'-(trifluoromethvl) fl.l'biphenvl -2-carbonvl)aminolbenzoate A solution of 3.56 g of (trifluoromethyl)[1,l'-biphenyl]-2-carbonyl chloride in ml of methylene 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 220 4-r(r4'-(Trifluoromethyl biphenvllcarbonvl)aminolbenzoic Acid A mixture of 3.0 g of methyl (trifluoromethyl)[1,1'-biphenyl]-2carbonyl)amino]benzoate in 75 ml of absolute ethanol and 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°C to give 2.93 g of the desired product as a crystalline solid, m.p.

243-245 0 C. M+=385.

97 Reference Exam]2le 221 Methv3. E-rr3-(2-Methvlpvr~dinvlAcarbonvll1aMinlrpvriin..

3-carboxylate 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 drorpwise 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 .jZ 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 Ey-arnp 222 6- Fr 3- (2-ipehvlvr dinl) carbony! Iamino I nridine-3carboxylic Acid To a solution of 6.5 g of methyl methylpyridinyl) carbonyllamino~pyridine-3-carboxylate in 100 ml of 1:1 tetrahydrofuran:methyl alcohol is added ml of 5N NaOH-. The reaction mixture is stirred overnight and evaporated Lia vau to a residue. The 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 Examole 223 Met-hy! r--r (fl.1-Biphe:,nvll-2-carbonl)amino'-o~vridine-3abxlt To a solution of 1.5 g of methyl1 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 [I,1'-biphenyl)-2carbonyl chloride. The reaction mixture is stirred at 98 r 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 -r(rl. 1'-Biphenvl 1-2-c-rbonvl)aminolpvridine-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 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-Pyridinvl)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 vacuo 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.

Reference Example 226 2-(2-Pvridinvllbenzoic 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 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- r5- (Diben- rb. f! f1 4Aoxa 4-1)4n-10 1.1i)-%vlcarbon1 Dvridinyl I -5-f 1uor-2-r-eth,!benzamide 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 dichlcromethane is added 1.17 g of 6- [(5-flucro-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 IM 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.

Examnle 2 N-r5-r(9 10-Dihvdr--4H-thienof2, 3 -c irlbenzazep i n-9v_)carbonvI erridinv1 -5-flucr -2-methyibenzamide As described for Example 1, 9,i0-dihydro-4-Pthieno[2,3-c] ll)benzazepine in dichloromethane, in the presence of triethylamine is reacted with 2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a non-crystalline yellow solid.

100 N-rS-r 10-!Jihvdro-5!!-thienor3. 2-cl vlcarbonvl) -?-ovridinv11-5-fluoro-2-methylbenanide As described for Example 1, a mixture of 4, dihydro-5.H-thielo[3,2-c] t1)benzazepine and triethylamine in dichioromethane is reacted with 6- [(5-fluoro-2methylbenzoyl) amincjpyridine-3-carbonyl chloride to give the product as a solid.

N-r5-(PVridor2.3-hll.41benzoma2eT2:n-5(6H)-v'carZonv')-2pvridinvil -5-flucrc-2-methv..,benzanide As described for Example 1, 5,6-dihydropyrido[2,3-b ["L,4]benzoxazetie is reacted in dichioromethane, in the presence of triethylamine, with 6- [(5-fluoro-2-methylbenzoyl)amfinolpyridifle-3-carbonyI chloride to give the product as white crystals, rn.p.

187-189 0

C.

Examole N-t5-(Pwddo[2.1-bl 1 5 !benzoxazetin-6(SH)-vlcarbonyl)- 2-iDyridinvi -5-fluoro-2-methvlbenzamide As described for Example 1, 5,6-dihydro[2,3b] tl,.r)benzoxazepine reacted with 6- [(5-fluoro-2methylbenzoyl)amfifo~dichloromethane in the presence of triethylamine to give the product as a non-crystalline solid.

1-Dihvr--5H-dibenzfb.elaze~oi-5-v1)carbonfl- 2-vyridi nyl' -5-fluorc-2-rethylbenzamide As described for Example 1, dibenz(b,elazepine is reacted In dichloromethane in the presence of triethylamine, with 6-t(5-fluoro-2methylbenzoyl) ami-nolpyridine-3-carbonyl chloride to grive the product as a solid.

101 N- f- f4. 5-Dihvdrc-2-methvlpvrazclo 3-d I rl Iben zzp;)in..

6 (2H) carbony!' yri dinvil oro-2-methl benz-aid As described for Example 1, 2,4,5,6-tetrahydro-2-methylpyrazolo 3-d) [l1j]benzazepine is reacted in dichloromethane, in the presence of triethylamine, with 6-f( (:-f'luoro-2-methylbenzoyl) amino) pyridine-3carbonyl chloride to give the product as a solid.

10Exml8 Nr (677-Dhvdr,- 5H-di.ben-, fb, dIazeif-5-vl) carbonvl1Iz-,ovrinvlP--fluor-2-nethvl!benzamide As describe for Example 1, 6,7-dihydro-5MdibenzFb,:d)azecine is reaction d--chloromethane in the presence off triethylamine, with 6- (5-fluoro-2-methylbenzoyl)ami-no~pyri'di-ne-3-carbonvl chloride to give the product as a solid.

(4,5-Dihvdro-6H-1thiencr3.2-dl !1ibenzazenin-6vl)carbcnv1,1-2-ovr,:idinylP-5-fluoro-2-methvIbenzamide As described for Example 1, 4,5-di4hydro-6qthieno[3,2-d] [I]benzazepine is reacted in dichioromethane, in the presence cf triethylamine, with 6-f (5-flucro-2-methylbefzoyl)aminolpyridie3-carboflyl chloride to give the product as a solid.

ExamRnle IQ 10-rD'ihvdrc-4M-thieno t 3.2-c! 1 F1benzazerinvl) carbonyv1-2ovri,7-dinvlvV5flucro-2methbelzamide As described for Example 1, 5, lO-di4hydro-4ithienof13,2-L) [2jbenzazepine in dichloromethane in the presence off triethylamine is reacted with 9-f 2-methvllbenzoyl) amin-olpyridine-3-carbony'; chloride to give t-he product as a solid.

-102 Examiele 11 N-1rr(4.5-Dihvdrnovrazolo14.3-d1 rllbenzazepin-6(1JH)vl)ca-bonv11-2-ovridinv1l-5-fluorc-2-mrethylbenzmide To a solution of 0.20 mol of 1,4,5,6tetrahydropyrazolo(4,3-d] [1benzazepine, 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(: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, IMNaHCC3 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.

Example 12 N-lr-(r 6.1-Dihvdrc-5H-dihenzb.elaze in-5-v1)carbonvl1l- 2-oyridinvl rl.l1'-binhenyl'-2-carboxamide To a chilled (OOC) solution of 0.293 g of 6,1J-dihydro-5fl-dibenz[b,e]azepine and 625 mL triethylamine in 3.5 ml of dichloromethane is added a solution of 0.657 g of 6-[(ll,l'-biphenyl)-2-ylcarbonyl)amino]-3pyridinecarbonyl 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 lM NaHCO3, 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 residual solid is chromatographed on silica gel with ethyl acetate- 103 hexane(1:l) as solvent to give the product as a glass.

Crystallizatio n from ethyl acetate gives 0.395 g of white crystals, m.p. 134-142 0

C.

N-f f 5-Dihvdrc ,-2-methvloyrazpo or4. 3-d l F1bhenz azepin- As described for Example 12,2,4,5,6tetrahydro-2-methylpyrazolo[4, 3-di [1]benzazepine is reacted with i, Ibiphenyl)-2-ylcarbonyl) amino] -3pyridinecar-bonyl chloride to give the product as a solid.

Exarncl 14 2-c\vr4dinv! 1.1 '-binhenyl 1-2-carboxamide As described for Example 12, 6,7-dihydro-5Hdibenz~b,dj'azepine is reacted with ([1,1'-biphenyll- 2-ylcarbonyl) amino) -3-pyridinecarbony. chloride to give the product as a solid.

Exarle N-fE-r (4,5-')ihvdrc-H--!thienor3.2-d1 rllbenzazeipin-6vl carbcn, 1 1 -2-ovr~ dinvi 1 "i11 -bio.henvi 1-2-carboxamide As described for Example 12, 4,5-dihydro-6Hthienoi3,2-dI (1]benzazepiJne is reacted with biphenyl]I -2-ylcarbonyl') amino]-3-pyridi44necarbonyI chloride to give the product as a solid.

Emarnole 14 (5 ODbdc-H-heo22c 21benzpzenin-4vl)crbon 1 -2-\'ridinv l r1'-biihenvi -2-carboxamide As described f. Example 12, 3, 10-dihydro-4Hthienc[r3,2-c] benzaz-epi-ne is reacted with b-iphenyl] -2-yl!carbc.y. amino) -3-pyr:idi necarbonyl chloride to- give the product as a solid.

104 -pihvciro-4H-thienor2. 3-clrlmbenzazepin-9y I) carbony! 1-'>-2yrjdinyl 1 1i I-b~henyll -2-carboxaride As described for Example 12, 9,lO-dihydro-4Hthieno(2,3-~.][Ilbenzazepine is reacted with biphenyl] -2-ylcarbonyl) amino I-3-pyridinecarbony.

chloride to give the product as a solid.

Exmi 18 N-r5n-r(4,10-Dihvdrr'-5-thieflor3.2-c'rllbenzazeoin-5vi)carbcnvll-2-ovrdilll r. I'birhenv,11-2-carboxamide As described for Example 12, 4,l0-dihydro-5thieno[3,2-a)I [ibenzazepine is reacted with 6-f bip~henyl) -2-ylcarbonyl) amino) -3-pyr-idinecarbonyl chloride to give the product as a solid.

Examole- 19 vlcarb--nvl'-2-pvrdilvll 1'-ihenvP 1-2-caRrboxamide As described for Example 11, 1,4,5,6tetrahydropyrazolo[4, 3 [ijbenzazepine is reacted with 6-Il([l, i'-biphenylJ-2-ylcarbofyl) amino-3-pyridinecarbonyl chloride to give the product as a solid.

6. 1-Dihydrc-5-H-xDvridor2.3-bI !I 51benzodiazeipin- 6 v)carbonvil-9-c~yrdiflv12,-et\'1-furafe-3-arboxamide To a cooled (0 0 C) solution of 0.296 g of 6,11dihydro-5.P-pyrido[2, 3 -b][1,5]berizodiazepine and 624 mL of triethylamine in 3 ml of dichloromethane i4s added a solution of 6-Il(2-methyl-3-furanylcarbonYl)amil-3pyridinecarbolyl chloride in 4 ml of dichloromethaie.

The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaH-C03 and the mixture extracted with ethyl acetate. The extract is washed with H20, IM NaHCO3 brine and dried (Na2SO4) The solvent is removed under vacuum and the residue chromatographed on silica gel 105 with ethyl acetate-hexane as solvent to give the product as a solid.

methy1furane-1-carboxamidl As described for Example 20, 5,6-dihydrophenant-hridine is reacted with 6- 1( 2 -methyl-3-furanylcarbonyl) amino] -3-py-''-tinecarbonyl chloride to give the product as a solid.

Examcip 22 SI cart=.,!-ovrdi nil-2-epthv -ran-3-carbnxamide As described for Example 20, 5,"1l-dihydro-l0L:dibenz,,e 1 1, 4 1diazeoine is reacted wit-h (2-methyl- 3-furanvlcarbon2-) ami' no) -3-pyri-dinecarbonyl chloride to give the product as a solid.

Ezamolp 23 N-Sf51-Dhdo H-iezberl.4ldiaze]2in-10.

yi) carbonvi 1 -2-oyri'dinyl 1 f 1. 1 '-biphenyl 1 -2-carboxamidep As described for example 12, 5,11-dihydro-10jidibenz[b,e][1,41diazenine is reacted with biphenyl-2---yi-carbonyl) amino)-3-pyri.dinecarbonyIl chloride to give the product as a Solid.

Ex amole 24 d4 oenz rb. el azer jne To a solution of 6,l1i-d4hydro-5h-dihydro-51idibenz[b ,e]azeoine (0.12 g, 0.6 mmol) in methylene chloride (2 ml1) i4s added triethylamine (0.12 g, 1.2 mxol), followed by 4-butoxybenzoy. chloride (0.15 g, 0.72 mmol)-. The resultin-g mixture is stirred at room temperature for 2 hours, and then treated with 4 ml of IN NaOi-. The mixture is exzracted with ethyl acetate ml), and the ext.ract-- is washed with IN sodium hydroxide and brine (5 ml), dried over anhydrous sodium sulfate, and filtered through hydrous magnesium 106 silicate. The fitrate is evaporated, and the crude material is triturated with isoctane to give 0.24 g of white solid; Mass spectrum TOI, 372(MH 4 10-(t1.'Biphenv11-y1vcarbofll)-5.11-dihvdrO-lQHdibenZo-fb~e1 fl.41diazeyine_ To a cooled TOMC solution of 0.5 g of 5,11dihydro-10a-dibenzo~b,e)M1,4]diazepile in 50 ml of CH2Cl2 and 12 ml of disopropylethylamile is added dropwise a solution of 0.67 g of [1,1'-biphenyl)-4carbonyl chloride in 50 ml of CH2Cl2. The mixture is stirred at room temperature for 16 hours. An additional 0.3 g cf 1:,11-biphenyll-4-carbonyl chloride in 30 ml of CH2Cl2 is added and the mix:ture 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) and the solvent removed. The residue is chromatographed on silica gel with ethyl acetate-hexane and ethyl acetate-hexane as solvent to give 0.86 g of solid, m.p. l520-154OC; Mass spectrum 377 Example 26 (rl.l1'-iphenvll-4-vlarhoflvl) -1 0.11dihvdrcdibenz-fb.fl1 l. loxaze2,ine To a cooled (OOC0solution of 1.0 g of 10,11dihydrodiberlz~b,fj[1,4)oxazepile and 7 ml of triethylamine in 30 ml of CH2C12 under argon is added dropwise 2.0 g of [l,1'-bipheryl)-4-carbonYl chloride.

The mixture is stirred at room temperature for 16 hours and diluted with 50 ml Of CHCl3. The mixture is washed with 30 m! each Of H20, 2NHCl, 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 378(MH+).

107- 9- (rl, '-Biohenv11I-4-y Icarbonyl-9 1 -dihvr-~4Hthi eno f2. 3-c1 r 11 benzazepjnep As described for Example 26, 9,1O-dihydro-4i thieno[2,3-c] [llberizazepine is reacted with biphenyl]-4-carbonyl chloride to give the product as a yellow solid; Mass spectrum (CI) 381 (MT).

5-(f2.1'-Biphenvil-4-ylcarbcnv1)-6.7-diVdr-5pdibenz it l azenine As described for Examole 26, 6,7-dihydro-5Hdibenz[b,d~azepine is reacted with [l,1'-biphenyl]-Acarbonyl chloride to give the product. as a solid.

Exarle 29 6- '"ih n i -i a b n l 5 1 -i v ,o 6 Pv.idof2.3-et r!!benzazePine As described for Example 26, 5,111-dihydro-6Hpyridot2,3-e] [1)benzazepine is reacted with biphenyll-4-carboiyl chloride to give the product as a solid.

[1 '-Biphenyl I-4-vlcarbonyl) 6-dihydrOpyri do 3bi rI.41benzothiiazerpine As described for Example 26, 5,6dihydropyri-do[2,3-b] [1,41'benzczhiazepine is reacted with [1,1'1-biphenyl]-4-carbonyl chloride to give the product as a solid.

Examiole 31 d4 hvdr: Fb, f1 4 lt4azepine As described for Example 26, 10,11dihydrc f 4' -hazetoine is reacted with 1, 1biphenyl]-4-carbonvwl chloride t-o give the product as a solid.

-108- Example 32 10-(4-BenzQovhfenZoVH-10.11dihvrodibenzrb.firl.41oxazepine As described for Example 26, 10,11dihydrodibenz[b,f] [1,4]oxazepine is reacted with 4- (benzoyl)benzoyl chloride to give the product as an offwhite, m.p. 1030 10600; Mass spectrum 406 Example 33 (4-Benz ovbenzov1) 5.6.11.12tetrahvdrodibenzflzb. fazine As described for Example 26, 5,6,11,12tetrahydrodibenzib,flazocife is reacted with 4- (benzoyl)benzoyl chloride to give the product as a solid, m.p. 890-920C, Mass spectrum 418(MH) Example 34 r4 (Benzcovhben :ov1 -10. 11 -dj hvdro rb. f f 1 H I thi azePj ne As described fcr Example 26, 10,11dihydro[b,fl[1,4]thiazepine is reacted with 4-(benzoyl chloride to give the product as a solid.

Examole 5-r4- (Benzov1benlz0vl 6-dihvdripvridor2._3r1.41 benzo-,iazeoine As described for Example 26, 5,6dihydropyrido[2,3-bl[1,4]benzothiazepie is reacted with 4-(benzoyl)benzo-yl chloride to give the product as a solid.

Examnle 36 E- r (4-Benzovlbenlzc1'l 15. 11-dihydrc- 6H-pvridr2. 3-I f11benzazevine As described for Example 26, 5,11-dihydro61pyrido[2, 3 ?I [lbenzazepife is reacted with 4- (benzoyl)benzoyl chloride to give the product as a solid.

109 -r(4-Be-nzovlbenzovl) 13-6. dibenz fb.dl aze~ina As described for Example 26, 6,7-dihydro--51dibenz~b,dlazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.

O-f (4-Benzovlbenzov1 1O--dihvdro-4Hr-hienor2. 3-c' f~Ibenzazpinea As described for Example 26, 09,10-dihydro-41thieno[t2, 3-c] ~1)benzazepine is reacted with 4- (benzoyl)benzoyl chloride to give the product as a solid.

Example 39 5- (4-BernzovbenzovD 0dhd,-Hrheo32 ci rllben7azenine As described for Example 26, thieno[3, 2-c] [1)benzazepine is reacted with 4- (benzoy.')benzoyl chloride to give the product as a solid.

Exarnole thieno13. 2-cl !11benzazeipin-- As described fo Example 26, 4,10-di4hydr-o-5H- :zhieno,"3 [1]lbenzazepine is reacted with [1,11'ihenyll-4-carbonyl chloride to give the product as a solid.

Examole 41 1, [11 '-Biihenvl 1 -4-ylcarbponv' 4.5. 6tetrahvdrcovyrazo:lcr4. 3-d' Klbenzazeoine As described for Example 26, 2 mznol of 1,4,5, 6-tetrahydropyrazolo[4,3-d) [2lbenzazepine is reacted with 5 mmol of [.3,1i-biphenyl-4-carbonyl chloride. The product is stirred in methanol with 2N NaOH -For 16 hours and th*e mixture concentrated and extracted with ethylI acetate. The extract is washed 110with 1 M citric acid, NaHCO3, H20, dried (Na2SO4) and the solvent removed to give the product of the example as a solid.

N-r-rf; TiyioyanIo(.1dI 1 rlbhnz azppin-j-6(1H)~ vI~aboly'-l-chlorohenlr '-bip henv1l-2ca rboxrie As described for Example 11, 6-(2-chloro-4aminobenzoyl)-1, 4,5, E-tetrahydropyrazolo[4,3d](l)benzazepine is reacted with [l,1'-biphenyl]-4carbonyl chloride to give the product as a solid.

Examrp1- 43 b mid As described for Example 11, 6-(2-chloro-4aminobenzoyl) 6-tetrahydropyrazolo[4, 3dlbenzazepine is reacted with 2-(dimethlamino)pyridine- 3-carbonyl chloride to give the product of the example as a solid.

Example-44 As described for Exampole 11, 6-(4aminobenzoylhl1, 4 6-tetrahydrop~yrazolo-[4,3djbenzazepine is reacted with 2-(dimethylaminopyridine- 3-carbonyl chloride to give the product as a solid.

To a ccoled (0 0 C) and stirred solu~tion of 0.246 g of 5,6,11,12>terahYdrodibenz~b,f"Jazocine 695 mL of triethylamile in 5 ml of dichloromethane is added 0.586 g cf 6-I (5--fluoro-2-methylbenzoyl)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.

Exampl- 46 N-[r4- (riberiz fbfir ['loxazepin-1 0(11H) -v.lcarbonv1 p~henfl rl.'-biohenw1)-2-carboxamide To a mixture of 0.197 g off 10,11dihydrodibenz[b,f]t2.,4)oxazepine and 0.402 g of 4- 1'-biphenyl)-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 cf 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. 107 0 C-122 0 C. Anal.

Found: C, 80.8; H, 4.9; Examry'e 47 N-r4-(Dib-nzrb.f' [.41oxaze~ln-10(11H'-vlc-arbonyl)- 3 chi or oihenv' if1. 4heny I 1 -2--carboxamide A mixture of 0.263 g of l0,11-dihydro-l0(4amino-2-chlorobenzoyl)dibenz~b, 4]oxazepine, 0.195 g of [1,J.'-bipheny)-2-carbonyl chloride and 0.116 g of hl,bldiisoprpylethylamine in 7 ml of dichloromethane is 11,L2 stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane.

The extract is washed with 2N 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 a yellow glass, rn.p. 145 0 C-188OC: Ana..foundc: C, 73.6; H, 4.6; N,5.0; Cl, 6.4.

Examnple 48 As described for Example 46, 10,11dihydrodibenz~b,fJ [1,4]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.

phpnyll-2- (2-py'icd 4 ny' )benzamide Examvl e phenv' 1-2-(3-oy'v rd fy') h-zamide ph-ny' I Ii nv' -hamid- 'x a M121 -12

P

4 'l nr~~ofly (2-thienvI) benza.Tid Fxamp~l---3 As described for Examr-ie- 48 the following compounds can be prepared.

11.4- N- T5- (Diben r rb.flI rI. 41oxazepin-1o0(11H)-vlcarbgnv 1) -2pyridinvi 1-2-chloro-5-fluorobenzamide N- F5- (Dibenz Ib. f If!.41oxaze~in~-10 (118) -vlcarbon 1 pyridinyl' -2-rethv1-3-fluorobenzamide N-r5-(Diben.zfb.f1 f2.41pxpzep~ir-1O(11H)-vlcarbonvl)-2pyridinv1 1-2-rethvlbenzamide f 41pxazerpin-10 (11H) -%'1carbonvH- -2pvridinv11 -2-chlcrc-3-pvridin\'lcarboxamide Ryri dinvi 1-2-hvdroxvb~enzamide fl,41oxaze~in-10(11H)-vicarbon1'i-2p~yridinyll-2- (dirnthlamino)benzamide N-F5-(Dibenzrb.f 1 F.1Alxazepin-10(11H)-vlcarbonvl)-2p~vridinvll-2- (direthvlainro)-3-Dvridiflvlcarbxamfide l.41oxazepin-10(11H)-vlcarbofl)H-2- Ryridinvl 1-2-fluorc'-5-chlorobenzamide xmpe6 rl,41pxaepin-i0(11H)-vlcprbonv1)-2ipvridinvll I -bi~henvi' -2-ca;rboxAmideg N-r5-(Dibeflzfb.f1 f141-oxazeplin-10(11H)-vlcarbonvll-2p~vridinvl 1-2- (3-vv.-idinv1 benzarnide N-f -(.Dibenzf.b~f' l.4loxpzepr-10(11H)-ylcarbonvl)-2t~vrdinvl 1 (2-ridj'invl benzarnide 115 Example b.f 1 [l.41oxazepin-10 (1H)-vlcarbonvl2vpridinvll-2-(4-ovridinvl)benzamide Example 66 N- 5- (Pvrido 2. 3-bl 51 benzoxazepin-6 (5H) -vlcarbonyl) 2-ovridinvll l. 1 'biphenv1-2-carboxamide A mixture of 0.198 g of 5,6-dihydropyrido[2,3- 0.155 g of diisopropylethylamine and 0.404 g of 6-[([l,1'biphenyl]- 2-carbonyl)amino]pyridine-3-carbonyl chloride in 12 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 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 Example 67 N-\4-(Pvridof2.3-bl 1.51benzoxazepin-6(5H)-vlcarbonyl)- 3-chlcrophenvl'r1. 1'-biphenvll-2-carboxamide A mixture of 0.198 g of 5,6-dihydropyrido[2,3- 0.155 g of N,Ndiisopropylethylamine and 0.444 g of 4-[([1,1-biphenyl]- 2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 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 2V 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, rn.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 canbe prepared.

Example 68 N-f5-(Pyridcf2,3-b1 rfL51benzoxaeir4-6(5H)--vlcarbonvl)- 3-Dvriciinvl I ri 'bimhenvi 1-2-carboxp-lide N-r5-(Pvridof2.3-bl fI.51benzoxazelin-6(5H)-vlcarbonvl)- 2-nyr iinyl 1-2-chlorobenzamide Examole N-r5-(Pvridof2,3-bl [I 2-ovridinvl 1-2-chlorc-5-fluorobenzanide N-r5-(Pvridor2,3-b 1 rl.51benzoxaZeoin-6(5H)-vlcarbonvH)- 2-o,-idinv' 1-2-hvdroxybenzamide EaRe7 N-r5-(Pyridor2.3-bl F1.51ben'zoxaze~in-6(5H)-vlarbonv1)- 2-RyridinvP Exampl!e 73 N-r5-(pvrdcor2A fl.51benzo-:azeo~in-6(5H)-vlcrbonvn)- 2-rwyrid~hv 1 1-2-rethvlbenzamide Examile 74 N-r5-(Pvridor2.3-bl ri51ben-zcxazepin-~6(5H)-ylcarbonvl)..

2-ovriciinvil-2- (dimethylamino)benzamide Examp1le N-t5-(PDvrciof2.3-1 ri~c1benope~n-6(5H)..vi-carbonvl)- 2-ipvrirdinvil-2- (methylamino~benzamidle (pvricg2. 3-bi rl. 51benz'xazein-6(5H)-vlc-arbonvl)- 2-nvridinv1l--2- (aminomethvl)benzamide 117 r CPvr, -jo2, 3-bl r 1,51 benzomazepin-C-(5H) -vlcarbonv 1)- 2-Dyvridinvi 1-2-mrehoxvbenzarnide N-!5-(?vricdbr2.3-b1 F1.Slbenzoxazeo~in-6(5H)-vlcarbonvl)- 2-ovridinv. 1-2-chlorc-5-flucrobenzanide N- (P\rir-o 12,3-b 1 r i. 5lbenzoxpzepin- 6(5H) -vicprbonv1) 2-ovridinwl 1-2-rethvl-3-flucrobenzamide N-l- vro[.-lfl51benzom:a-eii-6(5H)-vlcarbonv1)- 2-o~vridiny!1 -2-fluorc-6-chicrobenzamide N- r ziP..r r 2. "-bl f 1,5 1ben-o>:azet'i nr- (5H) -vcarbonvl) 2-o~vridinvl-2. 6-dichicrcbenzamide N\1r5-(Pvri4do[2.3-bl1 r151benzoxazetnin-6(5H-)-vlcarbonv1)- 2-ipvridinv1 1 N-r5-(Pvridor2.3-bl rl.51benzpymazepin,-6(5H)-vlcarbcnvl)- 2-Dvridinvl 1-2-chloro- 3-]2vridinvlcarboxanide N- r5-(Pvridof2,I-bl [r1.51bernzoxazeDP 6(5H)-vlcarbonv1)- 2-nvrid,'nvl 1 (ethylarnino) -3-tovriciinvlcarboxamide EanP8 N-(5-(Pvridcf2.3-b 1 r1.51benzcxaze-in-6(5;H)-vicarbonv1)- 2-c'yridirw' 1-2 (di ne+-hvlamnno)- -toyridinv1lcarboxamide Examol0 86 N!-r5--(Pv.rido[2.3-b 1 F.51benzoazeti-6(5M)-vlcarbonvl)- 2-ov,,ridinyl 1 (aminomet-hvl)4-o~vridi'nvlcarboxanide Exam]2le 87 N-r5-(?vridcr2.3-bl fL51benzc>:azeri2-6(5H)-vlcarbolvl)- 2-Tpvrid nvl1- 2- (dimethyl amrino' -4 -rDriiinlcarboxamlide As described for Example 67, the fcllowing compounds can be prepared.

118 N- f4- py-i ro2.3-bl r1. 51 benzoxazepin-6 (5H) -ylcarbonvl" 3-chlorn-6-Tnethyl1phenl I f 1 1-bilohenvl I-2-carboxarnide N-r4--(Pv'idof2.3-bl fl.51be-zoxa-,epifl-6(5H)-v!carbonll- 3. 9-djynethv!]phenlv r. 1 -bipheriv1-2-carboxamidie N-r4-(Pv'-idof2.3-b1 rl.51be-nzoxazepin-6(5H.)-vlcarbonvl)- 2-rnethyllhenyl I rlI. I '-biphenvl I-2-carbxamfide- Exa2l 91 N-[4-(?W,-idor2,3-hlrl.51beflzoYazepi-(5H)-vicarbonv1)- -2-ch1irorhenvil rI. 'bi2h 1-2-carboxprnide rA-(Pvippr2.3-bl r.51benzoxazeT i4-6(5H)-vlcarboflv1)- 3-rhioro-g-rnethvl1Phefll- 2 -(2-1±ienvl)belzamride N-f4-(Py-idof2.3-bl r.51benzoazein-6(SH)-vlcarbonfl)l 3. 6-dimrehylphenvi (3-thienvi) benzamide Example 94 N-r4-(PvridoF2,3-b1 l.51enzoxpzepin-6(5H)-ylcarbonvl)- 3-rnethvlthefyll (2-thienvl)b2ef7amide L-xamRIe Nl-[4-(Pvridpf2.3-bl rl.51enzoxazerin-6(5H)-ylcarbonyl)- -3-chiororhenl1-2- (2-thienvl)beflzamide Examnple q6 N- (?%vidr f2.3-b 1. 51enzoxazepin-6 v1carboflyl) 3-chloro~henfl12-(3-hienv1)beflzamide Examle 9 N\-r4-(?v-idpr2.3A-b fl.51beflzoxazer)if6(5H)-virarbolvl)- 3-chlcrohenlV (2-firanvl )beflzpride N-r 4 -(PDvrdr2.3-hb.51benzoxpzeri6(5)-vlca-bonvl)-3 nhlcroiphel 1-2- (9nriin- bnzamide 119 Example 99 N-F4-(pvridor2.3-bI F1.51benzoxaze~in-65H'-vlcarhpyl)-.

3-chlorophenvi 1-2- (3-pvridinvL ~benzamide N-f4-(Pvridor2,3-bI fl.51lbenzoxazetin-6(5H-vlcronl)- 3-chloroo~henvll-2- (4-o~vri-dinvl'Jbenzpmide N-r4-(?\'r:idor2.3 -bi rl.5lbenzoxazer~in-6(5H)-vlcprbnvl).

3-chlcrcophenyl1-2- (3-furanvl')benzamide Exaroe 102 N-r4-(?\tridor2.3-bt fl.

5 1benzovapepnr-6(5H)-vlcprbonvl)- 3-methyiphenvil 1T 1. 1 1 biohpnvl 1-2-carboxamide Emarrple 103 ri4'\rio23b I e- zzcn S v abnl 2-rethvlohenvll-2- (3-thienr,v~benzpmide Examrole 104 N-r4-(Pvrido[2.3-bl f1i.51benzoxazepi.---(5H)-vicarhcnv1)- 3-methvlo~henvyl 2-.(2-o2vridinvl) benzamiie Example~ 105 N-rA-(Pvr-idof2.3-blr 5bnzxze~n6(H-vcroy) 3-methyp~henyll-2- (3-p~vridinvl)benzpmide Example 106 N-r4-(Pvridor2,3-b 1 ri51benzoazt,in6(5H)-vicarbon.11..

3-methvinhenvi 1-2- (4-oDvridin%,I~benzpmide Example 107 N-r4-(Dvridor2.3-b1 r1.51benzoxazep-in-6(5H)-vlcprbonv1)- 3-rethvlohenvil (2-furanvi lbenzamide Examole 108 N-iA-(Pvridor2.3-bl f1,51benzoxazeoin-6(5H)-vlcarb)onv1)- 3. 6-dimethvlcihenvil-2- (2-thienvl)benzamide As described for Example 67, the following compounds can be prepared.

120 N- r4- (Pvrido f2. 3-bl r 1. 51benzoxaze~in6 (5H) -v~carbonyl) 3-fluor-6--methv1-henl tI 1-binhenv'I 1-2-carbox aridp N-(4-CPvridpf2.3-b1 fl.5lbenzoxazecine-6(5H)-v'carbon-vl)- 3. 6-dichioroo~henvll rl. 1 -biohenvll-2-carboxarnide N-r4-(Pvridlor2.3-b1 ri Slbenzoxazeoin-6(5H)-vlcarbonv1)- 3-fluorcohenvl' El. 1-biphenv1l-2-carboxamide Eail 1 N-r4-(PvridoF2.3-bl f..5'benzoxazep~n-6(5HI-vlcarbonV1)iphenv1 1l! .'-biRhenv 1 -2-carboxamide N-f4-(Pridor2.3-b1 f1.5'h,-nzoxa7e2n-6(5H)vicarbonvi) -ohenvll-2- (2-t-hienvl~benzamide N-[4-(PyridoE2.3-bl f1.51benzoxazepif-6(5H)_vlcarbonvi) -ohenvl 1 C3-thienvi) benzamidie N-r4-(Pvridor2.3-bl rl.51lbenzoxazeipifl-6(5H)vicarbonvi) -ohenvll-2- (2-thienvl)belarnide N-r4-(Py-vrf2.3-hl l.51benzoxpz.epin-6(5H)-vlcarbonvl)- 3i-fluorcphenvll-2- (2-h~i~ovl)beflzamfide Examno1e 117 N-r4-(Pvrid or2.3-b1 r.5Sbenzoypzeoin-6(SH)vicarbonvl) -vhenvll-2- (3-t-hienyl) benzarnide N-f4-(Pv-idof2.'I-bl f.51benzoxazep2jn-6(5Hvicarbonvyl) her vD-2- 2-fnanv~benzanide N-r4-(Pyridc 2.3-bl r1.Sbenzoxpzeoin-6(5H)v'-ra-ronvl)-1ohenylv12-(2-OvridinlV)beflzamide N-r4-(Pyridcr2.3-b1 l.5benzcxazepin-6(5H.)vicrarbonvi) -vhenyl I (3-pvridi nvi benzamide 121 N- q- (pyricio[2. 3-bi ri. 51benzoxazerpin-6 vlcarbonvl) -phenvll (4-R'vr~dinvl) benzarnide N- (Pvridor2. 3-hbI ri ,S Ihen? oxazej~i-6(5I-9l-vlcarbcpnvI) 3-f'urorophenvll1-2- (3-furanv',)benzarnide N- f4- (Pvrido12, 3Thl r 1.51 benzoxaze~in-6 (5H) -vlcarbpn1-3rethv!,'-6-"lucrnTPhenI I f 1 -bihenv-2-carboxamiie Example 124 N-r4-(Pvridor2.3-b 1 1.51benzoxazepin'-E(5)-v1carbonv1)- 2-m-,+-hvlphenv1-1-2-(2-furanfl)beflzamide Examip1o 125' >1 ben-,oma-ze;:r;-6(5H) crbonyl) 3-,re:'1othenvP1--(UafLrav1)bezamide N-r4-ePvridor2.3-b' f.51benzoxazepin-6(5H)-v1carbonfl)- 3. 6-direthvlipherwi 1-2- (3-ovridinvl) benzarnide Exaile127 N-f4-(P-vrido!12.3-b 1 3. E-d; oro~henv1 (4-ovri.dfr benzamide Examiple 2 8 N-fA-(pvridor2.3-b1 vlabnl-~eyl2(-uay~ezmd Fmarnp1e 129 N-r4-(pvr,,ido[2.3-bl !151beflZomazePJ~in-6(5)-vlcarbofl1)- 3-flurcr-pnT'X21-2- (2-thi-envl,) benzarnide Examiplp 130 N-f§-(PvridoF2.3-b 1 r,1enzoaeD42.n-5(6H)-v1carbonflY 2-nvridinvll-'luor2-,t hVbelzamide As described for Example 46, the reaction of 6-dihydropyrido[ 2 4]benzox:azepine (1 mmnd) with 2-i 2 -methyl-5-fluorobeflzoyl)aminc-5-pyridinylcarbony1 chloride (1.0 minol) in dichloromehale in the presence of 11,V_-diisopropylethylamile (3 minol) gives the product as a glass.

1.22 N-fS-(Pyridor2. 3-WI rl.41benzoxazenin-5(6H'I-vlcarbonvl)- 2-Rvridinv1 t 1. 1 -b-4 henv1 -2-carboxamide As described for Example 66., the reaction of 5,6-dihydropyrido[2,3-b] t1,4]benzoxazepine (0.198 gj) with 1 1-biphenyl) -2-carbonyl) aminlo)pyridine-3carbonyl chloride (0.404 g) in dichoromethane in the presence of U,N-diisopropylethylamine (0.155 g) gives the product as a solid.

xml13 N-r4-(Pv-idor2.3-b' r1.41benzoxazer~1n-5(6H'i-vlcarbonv1)- I-chlorophenyll 1. 1'binhenyll-2-carboxamide As described for Example 66, reaction of 0.198 g of 5,6-dihbydropyridol2,3-bl [2,4]benzoxazepine with 0.444 g of 4-[([1,1'-biphenylV-2-carboflyl)amilo)-2chlorobenzoyl chloride in dichioromethane in the presence of ILVI-diisopropylethylamine gives the product as a solid.

N-r4-(6.11-DihvdroD~Vridor2.3-b1 r1.51benzodipzepin-6(5H)ivlcarbonvl) -ohel I 1 A -ihenvP 1-2-carboxamide To a mixture of 10.55 g of 6,11dihydropyrido 3-b] 51benzodiazepin-5 (6H) -one in ml of tetrahydrofuran is added 15 ml of 10 molar boranedimethylsulffide 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 added 30 ml of 2N NaOH and the solution refluxed 2 hours under argon. The mixture is extracted with ethyl acetate and the ex~tract 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 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 N,V-diisopropylethylamine in 6 ml of dichloromethane is stirred at room temperature for hours. The mixture is poured into water and extracted with dichloromethane. The e:tract is washed with saturated NaHC03, 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-

221 0

C.

Example 134 N-f4-(6.1-Eihvdroovridof2.3-b1 51benzodiazein-6(5H)vlcarbonvy)-3-chlorophenvyl' 1' -biheny- 2 -carbomamide A mixture of 0.197 g of 6,11-dihydropyrido [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 dichloromethane is stirred at room temperature for hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with saturated NaHC03, 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 is chromatographed on thick layer 124 silica gel plates with hexane-ethyl acetate to give 0.160 g of solid, m.p. 147 0 C-165 0

C.

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

Examiple 135 N- fr4- (E.11Dihydroovri do[f 2 3 -bl r1. 51benzodiazepin-6 vlcarhonvl)-henvllrl.l'-biphenl'-2-carboxamide.

hydrochlcride 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 -f4-(6,'>l-dihydropyrido[2,3bi l,5]benzodiazepin-6l(5)ylcarbonyl)phenyl)[1,1'biphenyl]-2-carboxamide. The mixture is stirred at 0 0

C

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. 195 0 C-210 0

C.

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

Exam]21p 136 N-!4-(.11-Dihvdroovridof2.3-bl f.5benzodia-e7if-6(5H)vlcarbov)?-c-hirolhenl-2-> (2-thienvl)benzamide F-xamDle 137 N- rl5lbenzodiazepin-6(5H)ylcarbonvl) 13hl ronhenvi 2 1-2- -thienflbenzamide xmmle 138 N-!4-(E1-0lD ihvdroOrido 2 3 1bl !I.5 benzo.4azepin-6 vlcarbofvly -ohloro -6-methy-henv 1 (2thienvl)benzamide 125 Examr~1- 139 N-M4-(6.11-DihvdroppvricdpF2.3-bI !1.51benzodiazein..6(5H)vicarbonvl)-iphenvli-2- (2-thienv1lbenzamide N-F4-(6,11-Dihvdrppvyridor2.3-bI fl.51benzodiazerpin-6(5H)vlca'-bonlvl -ozhenyll-2- (3-thienvl)benzamide N1-f4-(6,li-Dihvprpovridor2.3-bI [1.51benzodipzenin-6(5H)vlcarbonyl)-3--methvlphenv11-2- (2-thienvl)benzpmidie Examole 112 N-r4-(E.l1-Dihvct-rpvridor2,3-bI f>l5benzodiazepin-6(5H)vicarbonvl)-3. 6-dimethy1Thenv! 1 (2-thienvl)benzpmide Exampl 143 vlcarbonv1)-l-methvlphenvlrL.1'-biohenvll-2-rarbpxpmide Examplep 144 N-M4-(E.l1-Dihvdroov, ridor2.3-bl fl.5lbenzodiazepin-6(5H)vlcarbonvl)-3. E-dimethylpheivll 11,2'-bipheiv1-2carboxarnide ExamyplJ 14 N-r4-(E..11-Dihvdropvridor2.3-bl 11,51benzodiazepin-6(5H)vlcarbonv1)-3.6-dichlcro~henv11 fl..2'biphenvll-2- Exarnp1p 14E N-r4-(E.K"-Dihvdropyvridor2.3-bl fl.51benzodiazepin-E(5H)vlcarbonvDl-3-merhvl-E-chlorcophenvll rl.l'-bi~henv11-2carboxmide N-r4-(6.11-Dlihvdirppyridor2.3-bi vlcarbonv1)--chlor-g-fuorohenyI1 fi. '-biphenvl',-2-' Examnle 148 N-f4-U3.21-Yihydro\*,:-i'dp2.3-b','. enci vlcarbonvl)-2-rnethylp~henvll fl1-ben11-2-carboxamide -126 N- 11-Dihvdropvrido r2.3-bl f 1. Slbenzpdiazevi -6 vlcarbonyl) -2-chlorophenyl11, i '-bilhenvl 1-2-cpr~boxpmide N- r4- 11-Dihvdrovrilo r2. 3-bl rl. Slben-ndipzeL-i n-6 (5H) vicarbonvl) -thenv1 1-2- (2-L~vridinv1 bernzamide N- r4-(6~,11-r!Mhvcdrovvrido r2.3-bl ri 51benzodi Aaepi n--6 vlcarbcnyl) -Phenvl 1 -?-(3-nvridinv1)benzamidef Examr~le 152 N-r4-(6.11-Dihydropvyridor2.3-b \lcarbonv -p2henvl1-2-(4-1pvridinvl)benzprnide Exarilp 153 (6 1 1-Di hydro;',yridc f2. 3-bl f 1 51bernzodiaze~in-6 (5H) vlcarbponvl) -'-chlorophenv11 (2-ovridinvl)benzprnide N-r4-(6.11-Dihvdrcopvridof2.3-bl rl.51benzodipzepin-6(5H)vlcarbonv1)-3--chlororheny11-2- (3-ovridinvl)benzamide Exarle 155 N-r4-6$..11-Dihvdropyridor2,3-b1 rl,5lbenZodiazeipin-6(5H)vlcarbonvl)-3-chicroohenvll-2- (4-ovriciinvl)benzarnide N-r4-(6.11-Dihvpirppvridor2.3-bl vlcabon1)-4-nethiohen1'l-2- (2-ovridinvl)benzamid- Examole 1157 N-r4 11-Dihydroo~vridor2.3-blflr1Sbenzodiazepip.-6(5H)ylcarbonvl!)-3-methyiohelvll-2- (3-ovridinyl)benzanide N-r4-(6.11-pDihvpropvridoF2.A-blrl.Slbenzodiazepin-6-(5H)vlcarbonv1)-3-rn~ethy1PhenvlV-2- (4-ovridinyl)benzanide N-r4-6.1-D-ihvdroovridcr2.3-b 1 rI.51benzopiazepin-E(5Hl)vicarbonvi) -3-rethvi--6--fluoroohenvl-2- (2thionv ben7amide 127 N- r 11-DihVdirniprido r2.I-b 1 f1. S 1benzodiazeTin-6 (5H) v 1carboflvl) 6-dimel-hThvPefv 11-2 (2 -ovridinvl) benzamide N- r 4-(6 11 -!ihvdrpp~vr ido f2,3-b 1 r 1 ~lbenzodi azelpin-6 (5H) vlIcarbonyl) 6-dimethylphenvP 1-2- fl -pvridinvl) benzamide Examnle 162 N-(4-(6.11I-Dihvdrco~vrjdor2.3-bl 1 r5ibenzodiazepin-6(5H)vlcarbonvl1-3. 6-dimethvl~phanll1-2-(4-Pridinl1)beflzamide Eal 6 N-(4-(6."-I-Dihvdronvrdor2A'4bI I.51benzodiazep~in-6(5H)yicarbonyl -heny 1 1-2-ne-hcxvovr idine- I-carboxamfide N-[4-(1-'-"--ihvdrcr~vrid'fr2.,4-b rj.51ben-ciazepin-6(5H)vicarbonvi) -3-chlorop~henvl' -2-rethvlthioo~vridifle-3- Examnp 165 N-,Ir4-(6,11-'ihv&-oovridor2.3-bI rl.5'benzodiazerpin-r6(SH)abxmd N-~r4-(611-DihydrOPRvridof2.3-bl rl9bemnzodiipzeTin-6(5H)vlcarbonvl)-3. -rdjmtvlrhenv1-2-methv1P~vridifle- 3 Exarnolp 167 N-r4-(6.':-1)ihydrotvrdor2.3-bI r.5benzodiazp]ifl-6(5HYylCarbonvl) -Phen\',11-2-mehvl1Dridirne--arboxamide Fxamotle 168 N-f4-(6.l1-D)ihvdrctovridof2.3-bl r.5lbenzodiazep:ifl-6(5H)vicarbonvl) chlc-roohenv2)-2-methvlpvridine-3- Examile 269 N-f4 611-~ihdoyil 2 3 l ,5 1benzodipazepi E(5H) vlcrbfll)-I-"b' cro-'-methvlphfl\'l 1 1 uropri dine- 3carboxamid:e 128 N- f 1 DihydroD~vrido r 23 Ir1. 51berlzodi az2n- vi carbonvil) 3 -nhl ro]phenvi 1 2- fluoroEpvrid4 ne- Icarboxamide Examle 171~2J N-r4-(E.11-DihvdnROvridor2.3-bl 1.1benzodiazep-6C5H)vlcarbonv -3-rethyvrhhenv3A -2-chloroovyriiine-3narbxamide N-r4-(6,11-Dihvdrotvridcr2.3bhl rl.51enzcdiaze~in-6(5H)vlcarbonvi) 9-dimethvl-o)henv1' -2-chloropvridine-3- Nl r -r Dhdn),- or2 -lf1. 5benzodi azevin-6 (5H) vicarbnnflV1DhenflV-i-methvltpyridine- 2 -arhoxamide N-f4-(6,11-Dihvdroovridor2.34bI vicnarbonvi -3 .lrpev -1-methvlpvridine-2- N-FA 6 D yrord .Ib r 1benzodiazeroin- r(5H) yl mg onvl 1-chloroghefl 1-2-;horovr-idjne- 3 1.-r5 6 11-,hdrtyiof* r131benzodi azepi.- 6 vcr -hnv1) 2-pridinvi 1 r 1. 1 -hheflv!'-2-Cprboxpamide, m.p. 278OC-281 0

C

N-r- 1-ivroig--3b !',51benzodize~in-6(5H)yl rarbofvl I 2-gyiidfl 1 2 (2-thienvl) beflzamie N-f5 61i-ihdoyio 2 hI!.51 benzdiazei n-6 vicrarbonyl -2-vridci nlI fluorobenzamide -129- 11-Dihvdroovrio r2. 3-b1 [f1. 51 ben zodiizelpin-6 (5H) vlcarbonvl) -2-ovridinvll-2- 2 -pvridinvl)benzamide Exampl1e 181 N-r5--(6.11-Dihvdroovripor2.3-bI rl.

5 vicarbonvi) -?-rDvidinyil -2 (3-ovridinvl) benzamide- N-rs-(6.:1-Dihvdroo\',ridor2.3-bI rl.51benzodiazeipin-6(5H)vlcarbcnvl) -2-Rvridinv11 (4-,ovridinvl)benzprnide xml18 E Dhcrrr or.3b 1. 51benzodipzeyin-6 (5H) Examole 184 N- r 7- dh~r~vrco r2. 1-bl1.5 benzcdi azeipin-6 vicarbonvl)-2-ovridinvl-2-(3-furanvl)benzanide Examrole 185 N-f 1- 11-Dihvdro'~'rido Q. 3-bl1. 51 Sbenzodiazeipin-6 (5H) vlcarbonvl)-2-pvridinvl 1 -3-chloroovridine-2-carboxrnide N-f5-(6.11-Dihvdrc2pvridor2.3-b1 rl,51benzodiazepin-6(5H)vlcarbcnvl) -?-Dvridinvl 1-2-rethvlovridine-3-carboxpmide N-r5-(6A11-Dihvdror)vridor2.3-blrF2.5benzodiazepin-6(5H)vlcarbonv' -2-o~vridinv11-5-fluor--2-rpthvlbenzamide 25Exml18 N-T5-(-..R--ihvdr-ot)vridor2.3-b r>.5lbenzodiazein-6(5)vicarbonv1)-2-r~Vridinvl-12-chlorobenzamide Exarnole 189 N-r5-(E.11-Dihvdroov, ridof2.3-bI r1,51benzodipzerpin-6(5H)- ,icrbvlro)-2-vridifl--~lv' 1-2-m'l:hvobenzpmid Exam]ole 191 35N-r5-(E,11-DIhvdroo'Yridor2.3-bl r.1lbenzodiazeo2in-CE(5H)vlcarbonl) oridinvl-2 -cinethvbenzaride 130 N- r 1 1-Dihvdrpoorido r 2 bl 1. 5 1benzociiazeyin- 6(5H) vicar-bonvi) -2-pyridinvill-2-chloro-4-fluorobenzamijde N- r5- (6.:-Dihvdropyriio r 2. 3-hb1 r 1 1bonzodi azein- 6 vi1carbonnvi) 2-pvridinvl I -2-chloro-r-f lucrobenzami de N-f5-(E.''-DihvdrOD~vridor2.3b1 vlcarbonv -2-o~vridinl-2-rethl-3-fluorobenzamidie Eall 9 yroy of2 r 1, 1benzodi azevin- 6 5H) vlIcarbonvi) -2-L-yridinyll1-2-hvdroxvbenzamide 6 Dhdoy or2 1 ,5 1b-nzodi azepin- 6(5H) vlr-arbonyl)-2-rOvridinvl-2-actvlombenlzamide Examule 197 NIf-61-~hdrordf. b r>.51benzodipzeoin-6(5H)vicarbonvl) -2-ovridinvl 1-2-aminobenzainide N-r5-(6.11-nihydr02yridor2.3-b1 ylcarbonv1)-2 -O~vrdinlV-2- (rnthylaminfl) benzam~ide N- F5- 1 1 Dihvdiropvrido r2. 3-bl r 1 51 benzodiazavin-6 (5H) \'lcarbonvl) -2-ovridinyll (imet-hvlmnfo)belzamfide Txm~ 0 N-f5-(.-D-"!ihvd-Ry~ridor2.3I-bl rl.51benzodiazeoin-6(5H)vlcarbonvl)2-ovridiflvil-2aminomethvlb2enzamide f vdc5r~lr.3b[.lbenzodiazepifl-6(5HYvlcarbonv)-2-DV, idifll- 2 (iethylamfinolp-eflamfide Examole 202 N- r 5- 1 -[ihvdrco\?rj do r 2.1-11 r ,5 1benzod;azepi n- 6 -f 5 H) vlcarbonvi) -2-2yridinvil -2- (dimethvlarninornet-hvl)benzamide 131 N-f5--(6.1'-pihvdropvridor2.3-bl F1.51be-nzodiazelin-6(5H)vlcarbonv1) -2-o~vridinvl 1-2- (met-hvlthio) benzamide E~xam2ZU20 N-r5-(6.11-Dihvdrocvvridof2.3-b1 r1.51bernzodia-ze~in-6(5H)vicarbonyl) -2-1?vridinvl 1-2-chlorot)vridina-3-carboxanide ExaMple 205 vlcarbonvi) -2-ovridinvll-2-fluoroipvridine-3-carboxanide 10Exml20 11-DihydroovriLdor2.3-bl vlcarbonvl)-2-pvriinll-2-mthoxvridife3-Carboxamide 2J-Dihvdrror-idof2.3I-bl ri. r 1 benzodi azevin.-6(5F) vlcarb-onv.) -2 -oyridinvll -2-methvlthiopvridine-3- N-r5-(6.11-Dihvdrorvridor2.3-blr1.51benz~diazeifl-6(5H)vicarbonv1)-2-ovridinfl-12-amifloOvr~din-3-carboxamide N- 11-Dihvdroipvridof2. 3-b I rl.51ben zcdi azeipin-E (5H) vcarbnl) -2-D-vridinvl- 2 -(methlanino)vridie3 ~~carbony)x~viil11hOh~COamide \1r5-(6,I1-Dihvdroovyridor2.3-bl r.5benzodipzepin-6(5H)vlcabonv)2-r-ovrinv1-2-(imethflam-3-CprbOide-3 N-r;5(611-Dihvdrno2yridor2.3-bl r.5benzociazein-6(5H)- ~vlcarbov)2ovridiylthipfep2carboxmide 132 4 Eamp1e 214 (6 11-DihvdrovridO r23- Irl.51banzodiazeoin-6 y I arbonyl) -2-pyrj jinl1-2 -met hV'thionhefl- 3 -carknxanidp N- r5- il-Dihvd'-poyrido f2.3-b I rl,51benzodi azeipin-6 cH) vicarbonvi) -2-pvyridinvl 1 I -3-methvlthiophene-2-carhoyprnjde N- r5- (6,112-Dihydroopvrido r2.3-bl 1. 51benzodiazeroir-6 (5H) vicarbonvi) -2-nyri diny! I -2-chlorothiophene-3-carboxamiie Examn1e 217 N- r5- '-iihdroyv'do f 2.A-bI 1.51benzodiazei~in-6 (5H) vlcarbonvl-2-vr'dil1-2-methvlthiophene-3-carboxamide N- 14- r(5, 11hydr -M-di-nz rb. e I f1,41 diazepi -)abnl--clr hnlfl,1'-biphenvll-2carboxamide A mixture of 0.196 g of 5,11-dihydro-10Hdibenzo~b,e] [1,4]diazepile, 0.155 g of Nj,tldiisopropylethYlamile 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 dichioromethane. 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 dichioromethale to give 0.31 g of solid, m.p. 158 0

C-

1840C. Anal. F'ound 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 5,11l, 4]diazepine with the appropriate substituted or unsubstituted t (aryl- 133 carbonyl)amilo]beflzoyl chloride or the appropriate substituted or unsubstituted [(arylcarbonyl) amino)pyridinylcarboflyl chloride.

N- f f(5. 11Dihdr-1OH-dibenz rb, el riL41 vl )ca-honylVP-thlvll 1 '-biphenv'11-2-carboxarnide N- f 4- 1DihdrO1Qwdibelz [belf 1,41 v1)carbon11-3-fletrhvli-henl1 rl. '-biiphenvll -2abxmd v1)ca-rbonfl-3.;zdimethv1Dhbernvi rY.!t-b-henvJA-2xml22 !-Dihvdr--1 QH-diihelz Fb. ei rl41 vl)carbonv1-l-chlorOiphenvl-l2-(2-thienlbenzamide hrdcIHdiezl~l1.41diaze]2ifl10vl)carbonfll-3-h1Oroihenvil- 2 t -furnv)benzamide Example 224 ,-ir-10-dibez'lb ll4diazepin-10vl) car~onvl-3-ch1oro~henfl-l 2 (-furanvl)benzainide v1)carb2onfl-3Tflehlhefll-2(2-urnvl)benzamide f2.Eivi--O-ihe-,bpr.4diaeri-10vI) bonv11-3-mrT-het~henfli'/ (-thienvi')benzamflde FEmample 227 N-gr511[ [dc-O-i~e~r~li.4dazep~if- 1 0v1) carbonv I 3tflethVl-henvll K I r t''bihenyl I -?-carbOpTlide 134 N-r4-r(5A'1-Dihvdrp--10H-dihenzrb.e21 rL41diazenin-l10- V1)carbonl-3.6-dimethV1Dhenll rl'l-biphenvl-2caroxmide N-r4-f 11 -!ihvdjr -10H-diben7Zfb~e I r 4ldiaZepin-10vl)carbonv11-3rnethV1-6-hlorohelvll fi. -biphenvll-- Exmple 231 N,1r[4r(5,11-pihvdrc'-10H-dibenzrb.e' r1.41diazeoin-10vl)carbonfl-13-chlcr, 6fluroiphelvll il. I'-biphenvll-2l~crbovf-2-ethlpeflcl l..'-iphnvl-2 N-!4-r(5.l1Dihydrc10Hibelzfbe1 t,1diazeo2in-10- -i~ev v1croy)2mtylhnlf~lblhnl--2 c!0-ihn~ber,1diazein-10v v1)arbonrlv--hc--h1OrO lthenll l bi~henll-2arbfla1Ohnv x2(2mrdnibfzmd Dhf1-1Hdbezher.41diazepiri-10vl) crbonv11-2-hlorl 2 (3-yvrid1-blzpenlide vl~cprb~lV11chrf-ll 2 (4dvre n1bf~md -~i.1Divi- 1HF1.nzhell41diazenin-10crbonvI h1orhefl 12(2yri dinvi) bnzamide 135 N- 1-Dihvdro-10H-dibenz rb. e I l. 41dipze]in-1 0vi) carbon I I -3--ch Iorop~henyl 1 (3-Tpvridinvi) hen zamide Exampip 240 v! )carbcnvl '-chi orophenvl 1-2- 4 -rDvridinvl)benzamide Example 241 N- [4-r ii-:Di~.drc-10H-dibenz fb, e I r1. 41di azenin-iv I)carbonylI '3--met hviiphenyl 2 -pvridinvli ben zpmiie Examrole 242 N- 14- f(5, l-Dihvdrc-10Hdibenfb. e. if1. 41dia yl)carbonyl 1-3-methylohenv' (3-ovridinvl)benzamide Examnp 243 vi) carbonyl I-'--methvichenv1 1-2- (4-tovridinvl) benzamiie Examrole 244 N-r4-1 (5 1 1-D'hvdrc-10H-dibenz rb.e' rl.41di azepjI-Q-.

vi) carbonvi 1-3.6-dimethyiphenvi 1-2- (2- Ypvr4dinvl) benzamide~ Exmle245 N-r4-r(5'-!Di.vdr-0H-dibenzrb.-e fh.41diazepin-l10vl) carbcnvl 6-dimethyiphenvi 1-2- (3nyridinvi) benzamidep -4h d T IH--e z b e f,4 d a,]i -0 v 1 c-arbonyl1 6-dimethvlohenvl 1-2- (4px'r4diny!) benzamide Examole 247 N-4 (S -id--O -ib n r~ li4d ae~n lQ v! )carbcnv.I 1 ohen,! 1-2-chenyrnethvl) benzanide Examole 248 vi)carbonv1oheV '1 1 (3-chlorcophenvimethvl)benzamide Examontle 249 N-4 r5 1 -lh -iLe z l~l14 d a e~n l vl)carbonvl 1 -3-chlcrohen'l-2- (chenvlmet-hvl)henzamide i36 N-r4-rt5.;11Dihvirp-10H-diibenzrel fl.41diazepin-lovlcroyl--hor1hni-2-methoxvpvr,-dine-3- N-r4-r(5.11-Dihvdirc-IOH-dJienzrb.el rl.4ldiazeipin-10vi) cabnvll-3-cllroDhenfli 1 2 -(mnehvlhiO)Dvricline-3- Examyle 252 N- f 4 r 1Dihvcdr-i014-rJbpnz[b, el 1, 4 1di Examnle 253 f 1i v -IO -ih- 7f iA iaz T) 0 vi ahnl-'-ehl~eni etlrviie2 N-4r5,1phv oIH-rinzbef.4diazep2in-10yl) -p rbonlI mpthvlhfv I I loovidfe N-4- iinhd n1!-io-r. vi) carbnl 1 3 .6-dimethyiphenl fluoropvridife-3 raroxmide F-a pl 3-carboxarnida N-r5-r 1-Dihvdrc-1 H-dibenz fbel-l' .4dizep-1OQ yl) carbnnvl1 2-vridinl 1 1 1 -ihenl -2-carboxamidfe..

m.p.280 0 C-285 0

C

Fxmvi258 S 1Dh r-O-ien b l1 4 izTi-=vi )carbonyl 1 -2,vridjinl 1 7- 2C hienyvi beflzamida 137 Examol~e 259 N-r5-r(5,11-Dihvdrp-10H-dibenflzb~el Fh41dipzepin-1pvl)carbpnvll-2-pvridinvll-2- (3-1hienv1)benazprnide 10vlarbonv'-2-vridin1 1 (-franv))benzamnidce N-r5--'(5,1--Dihvdro)-10H-ibeflzrb.el1.41dipzepin-A0yl) c arbonyv11-2-rovr':'Invi 1 (2-ipridinvl)belz am id- Exam2l 262 vi) carbonv I 1 -2-cyridinyl (3-o-vri dinv ben zam ide vl)c arbonyl 1-7-ovr~ifl -(4-cyridiny1)ibenz amid £xamrn1e 264 .2-Di'hvcrc-10H-dibenZ Fb.el ri.41diazeipin- 10-v1)carbonv1 1 -2-oyridinl-2- (2-l'uranvl)benzamidea N-r:r(5.1Dhvdro1 Hdibe,zrbe.1r141diazeP1n- 10-vl,)carbonl-2-~ridi\'1-2-(3-furalvl)belzamide Rza 121, 266 N-rr 1-flihvy~ r'-10M-di-b-nrv'el l. 41i azepincarboxamicie E-vanmiplp 267 )car-bonl l-2-pyv di nyl rvam21e 298 d lO -Ib n t lr1 l -P2 138 Exam~ile270 N- f -r(.1-ivr[ Hriezfel. 4 1dipazepRinlO-vi) carbon yl -2-pyridinyll -2-chloroben am ire, N-5 5 lDhr-O-ie7fe [I 14ldApzeRincarbonvll- 2 -cvridinvll- 2 N-r-r(,1 Dhvr-0-iezf2 el ,4ldipazelpincarbonyllI-2-pvridinyl I-2-methvlbenzpmideip Example 273 N~f- ll-rihydro-lOH-diherz fb.e If! Aldi azeyincarbonyl 1- 2 -ovridinvl 1-2. Emamo'p 274 N-r-r(,11Qhdc-O-ie7 If. 41dipaze~in- 10-v!) crbony 1-2-12%'ridinyl I-2-chlorc-4-f IuorobenzaMide N-r5-r(5.11-Dihydro-1OH-dibenzfb .el F1.4'diazepin- 10-v1)carbornv11-2-ovyridinv1 1 -2-cehor-6-fluorobenzanide Examnle226 20N-r5-r 11-Dihydro-10H-dibenzlb.el fl.4ldiazepin- 1 rbonyl1 -vii 1-e f I uorobamezmd 1'-Dihydro-1OH-dibenz rb.el fl.41diazelincarbon' 1 -2-ovridinl-2-hcetvoxvbenzamicie N-r -r (5.11-Dihvdro-10H-dibenlyrb.el rl-.41diazepin- 30i-1)carbnv' -2-vridinvl-2-aceninolenzaie N- r 1 1-Di hydr-1OH-dbenl.Zfb. el r 1. 4 1diazejin- 0- larbon,11-2-vriinv-2- ne-vlino bezare N-f r (5 1 1 -pihvdro-I 1Mdibenz rb. el r 1.4 1dip.epin- 1-0-yl)carbonylv1?-Ovridifll- 2 -(aminomethvl)benzamide 139 Example 282 N-F5-r(5.l1-Dihvd ro-lOH-iibenzrb).el rl.41diazevincarbonvi' -2-oyVridinyl 1-2- (dimethylamino) benzamide N-r5-r(s.11-pihvdrc-1OH-dibenzrb.el fl41diazeyin-10-vl) carbonyl 1-2-tovridinhv11-2-chlorotvridifle-3-carbox-amide N- 5- r-(S.11-Dihvdr&,-10M-dibenz fb. e IF I,41diazep~in-10-vl) carbonvl V-2--Pvridinvil-2- fluoroovNridine-3-carboxamide mml28 N-r.5-r(5.11-DihvdC^-10!H-dibenz~b.e1 Ti.41diazepin-10-vl) carbonvl1-2-oyvridinvl1-2-methoxvovridie-3-carbovamide 1 0-vl) carbony I -2-tovridinvll-2- rnthvithi o~iriifle3carboxamide N-r5-r(5,''-Dihvdro-10H-dibenzrb~e1 f1.41diazei~in-10-vl) carbon\vll-2-ovyrid-invl'-2-aminoovridie3-carboxamide mmpe28 N-r5-[(5.11-Di.hvdr--IH-dibelzfb.e1 fl.41diazerin-10-vl) ca rbonv,1'-2-c~vrid:iv1'-2- (meths'lamino)pv'ddifle-3- Exarno1e 2B9 carbonvl'-2--ovr2A:"w-1 1 -2-(dime1r'vlamino)Pvridifle-3- Examole 290 'E~hd O1dbnzbari.41dipzeoin-0-v') carbonv '-2-o~vridin.1 1 -2-methylthin;ophene--3-carboxamide Exml 0 140 N- r4- r(6.1 11-Dihvdro-SH-dibenz b. el carbony I-Tphenvi rl.' 1 -biphenvlIlI-2-cprboxpm-ici A mixture of 6, ll-dihydro-SH-dibenz~b,el azepine (0.195g), 4- 1 -biphenyl)-2-carbonyl) amino] benzoyl chloride (0.41g) and 0.155 g of UU diisopropylethylamine in 12 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichioromethane.

The extract is washed with H20, 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 (0.165g) (from dichioromethane-ethyl acetate), m.p.

224 0 C-225 0

C

Exaol 32 N-f4-r (6,11-Dihvdro-5Hi-dibe2nzfb.elazeoin-5-vl) carbonvil-3-chioro~henvll tl -biohenvl'-2-carboxamide A mixture of 0.195 g of 6,11-dihydro-5iidibenz~b,elazepine, 0.444 g of 4-[Ul1,1'-biphenyl]-2carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of li,p-diisopropylethylamine is stirred at room temperature for 3 hours. the mixture is poured into water and extracted with dichioromethane. The extract is washed with H20, saturated NaHCO3,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- 514-dibenz(b,e)azepine with the appropriate substituted or unsubstituted 4- [(arycarbonyl)aminolbenzoyl chloride 141 or the appropriate substituted or unsubstituted 6- [(arycarbonyl) arinolpyridine '-3-carboflYl chloride Examo1'- 303 carbonv1'nhefll-2- (2-t-hienvl)beflzamidea N-r4-f(61-ivr-Hdbn~f~lzri--i carbonv1 I helvi 1- 2 (3-thienl) belzamride carbonv11nhen1l-3.-dich1crorhenvl-l?( 2 thienvI )b-nzarmide Fmampl0e 306 -D hyr Hdh- b e carbonv1,-3-chicroohenflV12-(2thienl)benzamide Examle 30~7 carbcnvl1-l-chloro~henvl? (3-thienvlbeizamfide Examole 308 N-r4-f carbonv11-3-chlo-rm1h,,Iinvi'>( 2 thoflyl)kenzamide E-xam.%le 309 car bv11-3:?eV1OihenlV112)(?-hen,I)benzam~di Examnle-310 N- f 4-f(,1 7jh d c 5 e zJ .e z p l cabn!13 -tmthihn! (-ini ezmd E 311r 1e- 4 6 dc-5H-dib:.- .eze carbcnv--rnet bvlphenll i '-tbhenfll1-2-carboxamfide Examnle 2 1d, t r4- 6 h 7rj l carbonvl 1 -3.r-dimethvlrohefiv2 2 [1.1-biohenll-2 abxmd 142 N- f -r f 1 1-Dihvdro-5H-d'ihenz fb. el narborivll-3-methv'-6-chlorohelll T. '-bi~henvilcarboxamide Exa~mle 314 N-r4-f 1'-Dihvdro-5H-dibenzrb.elaze~in-r--v1) carbonvPl--hloro-'-methyl1Phenll r) '-bi~henvll-2- N\-M4-f(611-Dihvdrc-5H-dibenzrb.elazepi'-5-vl) carbonvll-2-methvlohenvl 1 rl.l -biphenvP'-2-carboxarnide N-r4-r 11-Dihvdro-5H-dibenzrb.elazein-5'-vl) carbonvI'1-9-c'",IrchenlV1ri.1 '-biphenv1 1 -2-carboxamide Exm Il 1 N-r4-T 11-Dihvdrc'-5H-dibenzfb. carbonvlloheonvll (2-oyridinvl)belzarnide N-r4-r 11-Dihvdro-5H-dib2enzrb.elazeil-5-vl) carbonv-iphenvll-2-(3-oridilvl)belzamide Exair.]2e 31 9 N-(4-f (6.11-Dihvdr,:-5H-dibenfl~b.elazepinfl51) carbonvllp~helll 2 -(4-2yridinvl)belzarnide N- r4-1 1 1 -r~hvdr-5H-dib-nzrb. el carbonvi -3--1hirohenv1-2-P2-p~ridinl)benzarnide Exarn~ie-322 carbofll1-3-chlcthenvl-9l 2 (2-Dvyridirlvl)benzamfidep N-r4-F 11-Dihvdro)-5H-dibenlfb.elazeoil-5-vlI carbonvPl-Tflethv!L-hehvil-2-(3-rvridiriv1)benzamfide 143 N- r4- f 1 -Dihvdro-5H-dibenz rb. elazepin---vl) carbonyl 1-3, 6-di methvlohenv' 1 (2-ovyridinv1) hen~amide Examlple 325 N-f4- F 1 1-Dihvdro-5H--dibelz fb, elazepi-5 -v1) carbonyl 1-3, 6-dimethv1obenvl1 (3-tPvridinvl) benzpmide Examvle 326 N- r4-f 6 D h d o S -i en .e zii carbonyl -3-dimethihen1'- -2-ethvRvrhic-Ll) bhenv11ic ~Emarrp!e 328 1~4- f -rihvdr-SH-,ibenzb. el azeir-r-vl) carbonvi I -1-chl crrobenyl 1 -r3 -mrethyi-1. -biphen 1 2carbcxamid- Examop 329 ~N-M~r4-6 1 -ihdr carbnvl hnvll eny I 2-imth-mthox-1. -biphenl -2carbcmamide Examole 330 N-r4-r 11-Dihvdro-5M9-dibenz fb.elazep)in-59-yl) Examl~±e 331 N-Mr-(6.11-Dihvdr:-5H-dibenfl~b.elazer, carbonv 1 hvlcrhe vl h3-ranvlbienrie2 Examvie 332 Ni-r4-r l2-Dihvdrc carbbnvl lhenvl'-2- 2-uranvlrbnzamie~m~p xamie 333 Nr4-(6. 11-DZihvc,,rc-5H -dibenz Ibh.el carbonv,11phenvPl-f3'-Ch10rc-1.' '-bip2henvil-9-carboxamide 144 N-r4-r ll-Dihv ro5FHdibenf h elbepin-Svl) carbonv 11-3 -hc ro~hen 1 1 r I I-chlonro-1. 1'1-biThhenvl 1-2- Exml 3 N-[r4- f 1 -Dihvdr S-rH-dibeflZ rb, el rarbonvy -3-methvl~henyl-I f3'-chiorn-1. 11-biphenvli--2- (611-ihvdrc5H-dibeflrb~elazein-5vl) narbcnvll-2-Ovlinfll 1 r3i-chloro-l.1'-bithenll-2carorii 2 O ridnvi~1pppvidiecaboimid N-t!-F (6-11-DTihd hp 7be carbsnvl 2 -tw-Liifl 1-2-fhorp-idine- 3 -carboxamid Examta1e 341.

6.ll 2 Divrc5Hdibeflrb. carbnvl12O-crdifyll--i2~ne0tviain-)-crdine3id 1 1Dhvrc-F5Mdibenl! Fb. laze- ~~rr-nxa(rnidjfe ~id~e NPvrml~r 26 1~i~r 5-4eZ~bepe~f5 1 N, 1 D h -c 5 -ih n h e z ri 145 (6.11-Dihvdro-5H-dibenz [b~elazeo~in-5-1') carbonyll1-2-p2yridinvil-2-rnethvlih' ophene-3-carboxamide N-f5-r (6.l1-Dihvdrc-5H-dlibenzrb~elazeyin-5--vl) carbonvi 1-2-ovridinvl 1-2-chlorobenzyamide rExample 346 (6.11-Dihvdrc-5H-iibeflz!b.elazepifl-5-v1) carbonv11-2-tPyridinvil-2-chor-5flurobelzamide ExamtnPN 348 carbonvl1-2-rcvridinv11-2-cehv1r-3'-fluorobeflzamide Exampole 349 N-rs-r 11-Dihvdr-o-SH-dibenzib,elazepin-5-vl) carbonvl 1-2-oyvridill1-2- (methvlIamino) benzamide Examnle 350 N-r5-f 11-Dihydro-5H-dibenz carbonvil -2-ovridinvl 1-2-hvcfroxvbenzarnide N\-fS-F ll-Dihvdro-5H-dibenzfb.eazeipin--v1') cabn,---c,~iyl2(mnm~v~ezmd Examvie 352 (6.i"-Dihvdirc'-5H-0vridof2. 3-b' 1 r41benzodiaze~fl- 5-vl)carbonvP1-2-~riliny' '-5-fluoro-2-methvlbenzamide As described for Example 1, 6,12-dihydro-5jipyrido[2,3-bj [1,4)benzodiazepile (2 mrnol) is reacted with 6- (5-fluoro-2-methylbelzoy4)amfino)pyridifle-3carbonyl chloride (2.1 mxnol) in the presence of triethylamine (4 minol) in dichiorornet:hane to give the product as a solid, mr-. 102 0 C-104 0

C.

146 Exam2e353 N- f(6. j1-hvdrc-5H-yv-itdr2. 3-bl rl, 41 ben Zodi azepin- 5-vl)ca'-bonv11-3-chloro~helV11 Efl. '-bilhenv11-2>- As described for Example 134, 6,l1-dihydro-5iipyrido[2,3-1i [1,43benzodiazepine (0.197 g) is reacted with 4- 1'-biphenyl]-2-carbonyl) amino) -2chlorobenzoyl chloride (0.444 g) in the presence of Vj,V'diisopropylethylamine (0.155 g) in 12 ml of dichioromethane to give the product as a solid.

As described for Example 352, the following compounds can be prepared by reaction of 6,11-dihydro- 5P.-pyri-do(2,3-]2) [1,4]benzodiazepile with the appropriate substituted or unsubstituted (arylcarbonyl)amino] benzoyl chloride or the appropriate substituted or unsubstituted (arylcarbonyl)aminolpyridine-3carboflyl chloride N-E4-E (6.11-Dihydrc-EH-Pvridinf2.3-b1 rl.41benzodiazeninatoy hn, f1.' 1 1-biohenvl I-2-carboxamidea Ex.amv e- 35 N-r4-r (61-Dihvdrc-SH-Rvridtor2.3-b1 l.41benzodiazeopincarbon'v!1hefvl-l2 ('-'ienvl)benzamide N- r -D4 hydrc-5H-oDvridO f2-1-bl r 1 4 1benzodiaze]2in- 1-3-r'methl1henv1 1 rl. '-hiiphenvll-2- Example. 35~7 N-E4-r (6.l-Dihvdr -5M-~rid-oI2.3-bl (141benzodiazepin- 5-vl)carbonv11-3-methV!6--chloro~hellrl. l'-bi]Rhenvl1ca-rb oam ide Exmampoe 358 N-I4-1(6,1- hdr-H vrI2..-br.4benzodiazeyif- 5-vl)carbonvil-3. 6-dirne+-hvl]2hefllli r1 -iph-nyI-7- 147 N-r4-r (6.11-Dihvdcr-5H4-t~ridor2.3-b1 rl.41benzodipzepin- 5-vl)carbonv11-3-TrerhvlhenlP-2-(2thienlV)belzamide Examo1e 360 f4- r 6, j-pihvdr-'-5H-pvri dor2, I-b I! K41 ben-,odiazep)in carbonv 1 '--hlorcr~henv11-2- (2-thienvl'Jbenzamidep N-rA-[ (6.11-nihvdr-5H-Pvyridor2,3-b1rl.41benzodiazepincarbonv11~henvP1-2- (2-2vridinyl)benzamidep xm~le 32i N-f4-r (6.12-Dihvdrc -SH-Ovridor2,.3-bl r1.41benzodiaze~pin- )carbon\'I iphenv11-2-(3-vrddinV1)belzam!ide Ema ole 3E3 N\-r4-f -ihdT5Hor o23-b' r141benzcdiaze~in.

5-v1)carbonv11-3-ch1orothenfl-2-(2-hrdinli)belzamide N-[4-r (6,11-Dihvdr'-M-ov1ridor2.3-bi r1.41benzodiazep-in- 5-vl)carbonv1 1 -3-ch1oronhelvil-2 (-ri:dinvl)benzamide N-[4-f(6.1'.-Dihvdro-5,H-zvrido[2.3-bl l.41benzodiazepin- 1-3-rmethvIhenvMl-2- (2-ovridinvl)benzamide N- r-r 11-~Dihvciro5H-1Pvrido!2. 3-N fl,4lbenzociiazepin- )c~arbonQ' 1-3, 6-dimethyliphenv1 (3n% r i: inVI) benzam!ide Examrple 368 r 11-r-ihvdc=--H-nyrido f2. 3-1-0l1 l4 lbenzcdipzeypin- Exam]21e 369 N-r4-r(T -ivrc5-, ro2.-ll.4ben~ndipzepin- 5-v1' carbonlp-henyl I ~~ucrcpyri di-3-cprboxamfide 148 N- r4- r 1-Dihvdirc.-SH-pvri dof2. 3-b! 41benzodi azepincarbonvl 1 -3-chlornohenv1 1-2-nhlnropvridine-i- N- r4- r '-!ihvdro-5H-ovridor2.3-b I rl.41benncpip azeipincarbornv1 1phenv! -2-mpethoxvpvyridine-3-carboxamide N-r4- f 12-DihvdrncSH-pvrido[2. 3-bh i fl41benzodi azepin- 5-y 1 I) rbonyl 1 -3-retv'Qhevl 1 (me-hv,1thio)ovridine-3- Exampl1e 373 !1.411benz,-jiazevincarboxamide Exam~Xe 374 N-I'4-!(6.11-Dihydro-5H-O~vrido[2.3-bl [l.41benzodiazerincrbrlonvllphelv11-2-amiloP~vridile-3-carboxamfide Examu1e 375 N-I5-[ 11-Dihvdro-5H-Ovridor2. 3-h ri. 41benzodiaze~pin- 5-vl)carbonl-2-~vr-dinflV1. -biphenv1'-2-carboxanide N- r5-r611-Dihvdirc-SH-O~vridof2. 3-b rl. 41benzodiazeTin- 5-%v!)-arbonv1-2-tvridil 2-(2thel belzamidCe Examle 37 -r 61-ivcr-HRrio23brl.41benzodipzepinca-rbcnvl' -2-pvridinv! 1-2- ('-thieny1l benzarnide .1-Dihvdro-5H-rvr1do[r2.3-b 1 [.41benzodiazeR'in- ;n'12 (?-vri di nvi)benzarnide (6 -phdri.-tvidor2 3Al 1,41benzodiazepin- ;-v1)carbofnnlvi2Oryridill 1 2 -(3-pvridinli)befl7am2~de Examole-380 N-r5;-r (.11-ihvdr -5H-O~yridof2.3b 1 r.41benzodIiazepinr-V1)_Carb~lV' -2-ovyridinvl'-9- (4-~vridinvl)berizamide 149 Exarnole 38~1 N-r5-r((6.1'-Dihvdro-5H-Dvridor2.3-blrlL41benzodiazepincarbonvill-2-,VridinVll (2-furanvl)benzamidle N-[5-r (6,.-ihyr 5H-Ipvrido r2. 3-bl ri .,1bernzodi Azei~incarbonvi -2-tov'ddinvlII-- (-fu ran v I)bJezamid- I'-Dihvdr.-5H-12vridor2. 3-b fi. 41benzodiazer~incarbonvl 1-2-o~vridinvl -2-chlorobenzarnide xme38 N-f5-f(6.1-Dihdrc-SH-vridic.-bl r>4lbenzodipzepjncarbonyl -2-ovriciinvil- Emarrm'e 385 r 1-ivr5Ho df 3-b! 1 1. 4 1benzodiazelpin- 5-vi)carbonv' 1-2-ovridinvl' Exarnole 386 (6.11.-Dihvdrz'-5H-ovridcr2.3-b rl,4lbenzodiazeoincarbonvill-2-ovridinv' 1-2-chloro-6-fluorobenzamide Examole 387 N-f5-r(6.11-Dihvdrc-5H-ovridor2.3-b1 rl.41benzodiazepincarbonvi 1-2-ovridinvl 1-2-rmethl-?-flucrobenzamide Exmole 386 (6.1X-Dihvdirc-SH-opvridor2.3 -bl fl.41benzodiazeoin- -),iivl'-hd~vezmd xme38 (6,2i-Dihvdrc-5H-Ovridor2.3-b 1 rl.4lbenzodiazeolinvi) carbcnyl I -2-ovridj nv2 1-2-arninobenZarni de Exanla' 390 N-f5-r(6.1:-Dihvdrc-5H-ov,%ridor2.3-bl f1.4lbenzodiazeoin- 5-v.)carbonv1-2-ordlv1 -(hithai)belzarnide Exarnp1l e N- r !-ivr-Hrv-'d 2 -bl11,l 4 1benzodiazeloin- 5-lcrovl2r,,-ivl2(!m--%Imn~ezmd 150 N-r5-r(6.11-Dihvdro-5H-v-rior 2 3 -bl rl.41benzodiazevincarbonvi 1-2-ipyridinvi 1-2-chlcropvridip'g-3cabxamide N-r5,-r(6. 11-Dihvdr-5'H-t~vridoE2. 3-bi rl.4lbenzodiazepjincarbonvll-2-1ovridinvl~l- 2 (dimethylafilio)Driciine-3caronvl-2-orbdnyo 1--yetmibopne3 £:<amipe 394.

N-r5-r (6.1-Dihvdr-H-ovri' or2.3-b1 r.41benzodiazep~in- 5-vl) carbonyl I -9-pyr, diny! I -3)-methylthiophene-3- Ex<amnle 395 dO~r~1O43-b I'!.41enzei a-6(lpivl)ca-rb-nfllt~hell r. '-b~rohenyl'-2-carb~oxpride A mixture of 0.278 g of dihydropyrazolo[ 4 3 J [I]benzazepine, 1.11 g of 4lI..biphenyl)-2-carboflyl)amilbeflzoyl chloride and 0.426 g of VLE-diJisopropylethylamile in 12 ml of dichioromethane-tetraflYdrofuran is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2V Na2CO3, H20, brine and dried (Na2SD4).

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 NaCH 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 dichioromethane.

The extract is washed with H20, 0.5 N citric acid; 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 C3 1 H24N402-1/2H20: C, 75.9; H, 5.1; N, 10.8.

Examrole 397 N-Ld-r(4.5-Di'hv;d-royrpolor4.3-d1[llbenZazeoin-6,(lH)vl)carbonvl1--~clorohenvil rl.1'-biohenvll-2carbo'xaride A mixture of 0.185 g of dihydropyrazolo[4,3-l[2jbenzazepine, 0.814 g of 4- 1'-biphenyl)-2-carbonyl)arnino]-2-chlorobenzoyl chloride and 0.284 g off .N,N-diisopropylethylamine in 9 ml off dichloromethane-tetrahydrofuran is stirred, at room temperature overnight. The mixture is poured into water and ex,: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 2Ni 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 1N 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 chromatographed on thick layer silica gel plates with hexane-ethyl acetate as solvent to give 0.37 g of white solid, m.o. 172-~2020C, Anal. found for 1/2 hydrate: C, 70.; 5.0; 9.8; C.1, 6.4.

Examnle 198 N-fE5-1 3-d' r' 'benzazeioin-6(lH)vl)carbonvP1-2-O--,r4:inV 1 1 !,2-biphenvl 1 -9-carboxamide As described for Example 396, (0.1 mmcl) of 4,5-dihydropyrazolof 4 ,3-d][1]benzazepine is reacted with (0.21 mmol) of 6-(['-.'-Ibiphenli--2-carbony)amilo) 152 pyridine-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.

Example 399 N-f5-r(4.5-DihydroDvrazolor4.3-d1 r11benzazepin-6(1H) vl)carbonvll-2-vpridinvll-5-fluoro-2-methylbenzamide 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 Example 400 N-f5-(4H-Thienof3.4-b 1 l.51benzodiazepin-9(10H)-vl-2pvridinvll-5-fluoro-2-methylbenzamide As described by J.B. Press et al in Med.

Chem., 22. 725 (1979), 9,10-dihydro-4h-thieno[3,4- [l,5]benzodiazepin-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-4h-thieno[3,4-b] [1,5]benzodiazepine as a solid. The proceeding compound (0.5 g) is reacted with 1.06 g of 6-[(5-fluoro-2-methylbenzoyl)amino] pyridine-3-carbonyl chloride, hydrochloride in dichloromethane which contains 7 ml of I,Vdiisopropylethylamine. The mixture is stirred at room temperature for 16 hours and then is washed with water, I1 HC1, saturated sodium bicarbonate solution, water and 153 dried (Na2SO4). The solvent is removed and the residue purified by chromatography on silica gel with ethyl acetate-hexane to give 1.1 g of a solid, rn.p.

89 0 C-92 0

C.

Exarn!l- 401 N- r4- (4U'w-hi-nr' 4 I ri 51berzodi a-,epin-9 (10H) -y I) phenyllrT19'-biphernvll-2--arbcvmxmide As described for Example 400, 9,10-dihydro-4jithieno[3,4-a] [1,Slbenzodiazepine is reacted with 4- 1'-biphenyl]-2-carbonyl)anolbenzoyl chloride to give the product as a solid.

7xam2op 402 cv- Iorph-% 11 I, -'-ihiprvl -)-carboxamnide As described for Example 400, 9,10-dihydro-4jithieno[3, 4-b] [1,5]benzodiazepine is reacted with 4l'-biphenyl>12-ca--bonyl)amilo]-2-chlorobenzoyl chloride to give the product as a solid.

pyricli ny I I' "I-hj p 1 'enyvI -pbovamj de As described for Example 400, 9,10-dihydro-4jithieno[3, 4-b] [1,5]benzodiazepine is reacted with 6- 2i-biphenyl)-2-carbonyl)am2-no)-pyridie3-carbonyl chloride to give the product as a solid.

E'cample 404 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 5,1-,-dihydro-10L.-di-benz~b,e)[1,4diazepile and -7 ml of tl,U-diisopropylethylamine in 30 ml of dichloromethane 154 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 NaHC03, 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-116oC.

ExamDle 405 5.11-Dihvdr-10-f4-(3-thienvl)benzovyl-10Hdibenzrb.ell r .41iazeoine To a mixture of 2.0 g cf 5,11-dihydro-O1idibenz[b,e](1,4]diazepine and 7 ml of I,Udiisopropylethylamine 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 cf H20, 21 HC1, saturated NaHC03, 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 solid.

Pinding gsay r P= pDati V1 0fePtOrs Rat liver plasma membranes expressing the vasopressin Vl receptor subtypes are isolated by sucrose density gradient according to the method described by Lesko et al., (1973). These membranes are quickly suspended in 50.0 mM Tris.HC1 buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at until used in subsequent binding experiments. For binding experiments, the following is added to the wells of a ninety-six well format micrctiter plate: 100 ml of 155 100.0 mM Tris.HC1 buffer containing 10.0 mM MgCI2, 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 3indinc Assav to Rat Kidney Medullarv _cctors Medullary tissues from rat kidneys are dissected out, cut into small pieces and soaked in a 0.154 mM sodium chloride solution containing 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 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 rmM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate is filtered through several 156 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.HCI 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.HC1, 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 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 Parkard LS Counter, with an efficiency of 157 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 Bindingc Exeriments with Human Platelet Mer-ihranes Platelet Mer-brane 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 PP? 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 mrM 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.HCl 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.HCl 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 Vasonressin Vi recertor subtype in Human Platelot Mrmtsranes: In wells of a 96 well format microtiter plate, 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 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.

159 Bindina to Membranes of Mouse Fibroblast Cell Line (LV- 2) Transfected with the cDNA Expressina the Human VY Vasopressin Receptor 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 Binding 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.HC1 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-phenanthrcline, 2.0 mg trypsin inhibitor, 10.0 mg and 0.1 mM PMSF., 20.0 ml 160 t of [3H] 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 cf biding, 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-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.

Vasopressin v Antaaonist Activity in Conscious Hydrated Ras: 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 0.4 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 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.

Vasopressin V1 Antagonist Activirv 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 intravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,180,240 and 300 minutes later. Percentage of antagonism by the compound is calculated using the pre-drug vascpressin vasopressor response as 100%.

Oxvtocin Receptor indinrc Membrane Prenaration Female Sprague-Dawley rats weighing approximately 200-250 g are injected intramuscularly 162 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 for 30 minutes. The resulting pellet containing the oxytocin receptors is resuspended in 50.0 mM Tris.HCl 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]oxytccin.

Radicliaand Bindino Binding of 3,5-[3H]Oxytocin 3 H]OT) to its receptors is done in micrciter plates using 3 H]OT, at various concentrations, in an assay buffer of 50.0 mM Tris.HC1, pH 7.4 and containing 5.0 mM MgCl2, 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 minutes, at 22°C, by rapid filtration through glass 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 163 sites (IC50) are calculated by a computer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

Bindina Assav to Rat Hepatic V 1 RecePtors and Rat Kidney Medullar, 2 RecePtors or *Bindina to VI Receptor Subtype i- Human Platelet and **R1inding 'o merbranes of Mouse Fih-obhasf Cell Line (LV-2) Transfected with the cDNA Expressina the Human V2 Receptor

V

1

V

2 Ex. No. Structure 1C 5 0 0±M) IC 5 0 (9M) o0.24 0.054 N

CR

3 a V/ N-CO

F

2 0.039 0.029 Q N S

C"-

3 o NHCO

-N

F

34 44% at 10C±M 20% at Nn

HCO-

F

164 Cont'd.

v

I

IC 5 0

.LM)

v 2

IC

50 Ex. No. Structure 100% at Illm .72% (s±M) 9 0% at giM GaNK 100% Og~M) 39% (1pLM) 165 Cont'd.

v 1 1C0(iLM) V 2

IC

5 0 (9iM) Ex. No. Structure 46% (hI M) O0.014 29% "1.8 166 Cont' d.

v 1 I C 50 (p.M) V 2 1C 50 (4.M) Ex. No.

Structure 323

N

0 /Co-J 1% (10 1 ±M) 33%(1O%±M: (1011m) 16% OP.M) Co -o 34% (1oliM) 62% (104M) 167 Vasopssin V2 Antagonist Activity Cons____ ~jis Hydrated ]&at 1 c Ex. No. Dose 14 Urine Volume OSnolality (malka) (ml/4 hrs) (MOsm/kc) 78 13.3 0.3 229 6 22.1 i 497 +53 4 Z0.8 361 -_76 2 0.2 1226 58 26 20 2 4 .5 i058 10 2 6.6 9 7 9- 4 10 2 r 878 2 10 2 ig-.5 591 32 10 2 q.3 726 2 10 2 16.5 591 24 1 0 2 4319 27 10 2 3.3 1317 Water- load control Wal-er-load Contrcol AVP-n.tr c2 168 Vasopressin Antidiuretic (Vj) Response in Conscious Rats with Fre APccees te Water Drinking Before But Not During th Expri-ment: 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 Cl" 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 VoDqn-esc~in V2 An1.aaonic, Atc'ivity in scioug Ras Ex. No. Dose N Urine Volume Osmolality (mg/Kg) (m114 hrs) (MOsm/kg) 6 -0±2981±34 47 10 2 22.0 394 66 10 2 i7.0 442 6*7 10 2 21.5 402 134 10 2 40.5 333 3 2 28 396 2 18.2 596 133 10 2 2-7. 5 234 10 2 39.5 284 3 2 26.8 391 2 19.5 526 17 6 1 C -1 12.8 56-7 218 10 2 34 222 257 10 2 22.5 317 301 102 41.5 363 302 10 240 356 352 1.0 2 9.3 779 396 10 2 21.8 238 39-7 10 2 29.8 288 398 10 2 20.5 316 399 10 2 17.0 404 400 10 2 24 .8 27 0 404 10 2C909 *Control DMSO corn starch Compoundis were dissolved in DMSO and then diluted in corn starch (final concent:rati4on of DMSO was All rats were orally dosed with this mixture at lOmV kg, by gavage.

170 Table III Oxytocin Binding Assay Ex. No. Dose (iLM) Inhibition IC50 (M) 12

I

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 3 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 organic 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 4- .zi.

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% cf 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. Fcr example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies 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, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glyccls, non-ionic surfac- 172 <r v 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.

It must be stable under conditions cf 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 containing, for example, water, ethanol glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

173 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 cf 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.

174

Claims (4)

1. A compound selected from those of Formula R A-B2 Formula I wherein- Y is selected from (CH2)n, C, S, NH, INCOCH3, N- lower alky]l 23), CH-lower =lkyl(C27C3), CHNH-lower alkyl(Cl-C3), CHNH2, CHNtlower alkyl(Cl-C3) ,2,CHO-Iower alkyl(C1-C3), CHS-lower a=lkyl(Cl-C3), wherein n is an integer from 0-2; A-B is orH 2N _N .1(CH 2 m wherein in 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, mn may also be three, provided also that: when Y is -(CH2)n- and n is 2, mn may not also be two; R1 is hydrogen, nalogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -SH, -SO lower alkyl(Cl-C3), -SO2 lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(CP-C3), 0-lower 30alkylc,'l-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(CI-C3)]2, -S02NH2, -SO2NH lower alkyl (Cl-C3) cr -S0 2 N~lower alkyl(Cl-C3) ]2; R2 is hydrogen, C1, Br, I, -OH, lower alkyl(C1-C3), 0-lower alkyl(C27-C3), or and R2 taken together are methylenedioxy Or ethylenedioxy; 175 R3 is the moiety 0 -CAr wherein Ar is a moiety selected fromr the group X-RIO R7 R_ -_F3-X-R 0 0 N-T i and X is 0, S, -NCH3 or -NH R4 is selected from hydrogen, lower alkyl (Cl-C3), -CO- lower alky'l(Cl.-C3); R5 and R7 are selected from hydrogen, (Cl-C3) lower alkyl, (Cl-C3)lower alko>xy and halogen R6 is selected from moieties of' the formula: 176 -NCOAr', I -NCOCH 2 Ar' I -NCON-Ar, I I -N-SO 2 R -NCO(CH2)n -cycloalkyl, R R2 N-S0 2 CH 2 o -N-P 0 -NSO 2 -lower alkyl(C 3 -C 8 Ia -N-PI R 12 -NSO 2 -oe alkenyl(C 3 -C 8 0 11 -NH-C-C-lower alkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C 3 -C 8 )straight or branched, 0 -NH-C-C-lower alkenyl(C 3 -C 8 )S Igto rnhd 0 11 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH 3 moieties of the formulae: 177 -(CH )q-N R b (CH. 2 )q -N 0 (CH2)2--lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, -CH3 Or -C2Hc;;afld a moiety of the formula: -X-Rlc, wherein Plo is lower alkyl(Ci-C8), lower alkev.'2(Ci-C8) -(CH-)p-cycloalkyvl(C1-C6), -(CH 2 )p R 5 -0 N R. R 0 and p is zero to three; X is C, S, NH, NCH3, 178 C=0 or a bond and R= and R7 are as previously defined. a moiety of the formula: I b N -CC) wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkYl(C3-CS) branched or unbranched, -0-lower alken\'l(C3-C8) branched or unbranched, tetrahydrofuran, tecrahvdro thiophene, the moieties N or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothioPhene or the heterocyclic ring moiety: G-=F wherein D, E, F and G are selected f-rom carbon or nitrogen and wherein the carbon atoms may be optionallyv 179 substituted with halogen, (Cl-Ci) lower alkyl, hydroy,, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -c02l- lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- GOCHAr' 0 11 -0-C-lower alkyl(C 1 -C 3 Rb iCl)q- N -S-lowver alkylI(C 1 -C 3 Rb HCH) (CO_2N, 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:

180- I, ~N R 8 Rg W, S R~ anRo are JndePendently hydrogen, lower alkyl (C1-C3), 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 alkvl(Cl-C3)]2, 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) P25 is selected from the moieties S N- 181 and the moiety Z0 represents: phenyl or substi!tuted phenyl optionally substituted by one or two substituents selected from Cl-C3)lower alkyl, halogen, amino, (Cl-C3)lower alkox-y, and (CI-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from C, 11 and S; a -'-membered aromatic (unsaturated) heterocYclic ring having one nitrogen atom; a 5 or 6-membered aromatic (unsaturated) heterocyclic -,ino_ having two nitrYoaen atoms; a s- mem.bered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-mernbered heterocyclic rings cAre optionally substituted by (Cl-C3)lower alkyl, formyl, a moiety of the formula: (CH2 qN R Rb halogen or lower alkoxy,; and the pharmaceut icall-. acceptable salts, esters and pro-drug 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 aJDkyl, halogen, amino, (Cl-C3)lower alkoxy and (Cl.C3)lower alkyl amino and n, m, Y, Y, A-B, Ra, Rb, R1, P2, R3, R4, R5, R6 R7, R8, PO-, Rio, are as previously defined in Claim 1. -182- 3. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and n, m, X, Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6,R7, R8, R9, R10, R25 are as previously defined in Claim 1. 4. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms and Y, A-B, Ra, Rb, RI, 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) heterocyclic ring having one sulfur heteroatom and Y, A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, RI0, are as previously defined in Claim 1. 6. A compound according to Claim 1 wherein the moiety Z represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom and Y, 183 A-B, Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R 9 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, R 1 R2, R3, R4, R5, R6, R7, R8, R9, R 1 0 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, Ri, R2, R3, R4, R5, R6, R7, R8, R9, are as previously defined in Claim 1. 9. A compound according to Claim 1 wherein the moiety Z represents a fused 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom and Y, A-B, Ra, Rb, Ri, R2, R3, R4, R5, R 6 R7, R8, R9, R10, R25 are as previously defined in Claim 1. 10. A compound according to Claim 1 wherein the moiety Z 184 if represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroaton and Y, A-B, Ra, Rb, R1, R21, R3, R4, R5, R6, R7, R8, Rq, Rio, P25 are as previously defined in Claim 1. 11. A compound according to Claim 1 wherein the moiety zO rec'resent.s a phenyl ring, optionally substituted by one cr two substicuents selected from (Ci-Ci) lower alk-yl, halogen, amino, (Cl-C3)lower alkoxv-, and (Cl-C3)lower aikyi aminIo, Y ir- elected fromi -C112-, -CH-lower alkyl(C 1 'C 3 -CHNH 2 I-N-oeaky(C-C) -CHH-lower alkyl (C -C 3 -CI-N(CH 3)2 -CHN(C2 2 H 5 2 -CHS-Iower'alkyl(C 1 -C 3 and A-B, Ra, Rb, R1 R2, R3, R4, R5, R6, R7, R8, R9, Ri0, 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 alkvl(C 1 -C 3 -CHNH 2 -CHN(CH 3)2 -CHNH-Iower alkyl (C -C 3 -CHO-lower alkyl'CI -CHN(C 2 H 5 2 -CFIS-iower alkyl(C 1 -C 3 and A-B, Ra, Rb, Ri, R2, R3, R4, R6, R7, R8, RQ, RiO, are as previously defined in Claim 1. 13. A compound according to Claim I wherein the moiety zO represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, is selected from -CH2-, -CH-Iower alkyl(C -C 3 -CHNH 2 -CHNH-lower alky I (C -C 3 -CHO-lower alkyl (C 1 -C 3 -CHN(CH 3)2 -CHN(C 2 H 5)2 -CHS-Iovver alkvl(C 1 -C 3 and AB,RFa, Rh:, RI, P 3, R4, P6, R7, RB, Ro, are as previously defined in Claim 1. 14. A compound according to Claim 1 whersin -186- the moiety ZO0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom wherein is selected from -CH-Jower alkyl(C 1 -C 3 -Cl-NH 2 -CHN(CH 3 )2 -CHNH-iowe- alkyl (C -3) -CHO-lower alkyl (C -3) -CHN(C 2 H 5 2 -CHS-lower alkvl(C -C) and A-B,Ra, Rb, PI, R2, R3, R4, Rr5, R6, R,7, R8, P 9 Rio, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moiety zo represents a 5-membered aromatic (unsaturated) heterocylic ring having one oxygen heteroatom wherein Y is selected from -CH2-, -187- -CH-Iower alkyl(C 1 -C 3 -CHN H 2 -CHFN(CH 3)2 ICN -oe lkl( 1 C) -CH -ower alkyl (C C 3 -CHN(C 2 H 5 2 -CHS-Iower alkyl(C 1 -C 3 and A-B,Ra, Rb. R1, P2, Pi, R,4, F.5, R6, R7, R8, R9, are as previously defined ir. Claim 1. 16. A compound accz rd:ina to Claim 1 wherein the moiety ZO represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from -CH-Iower alkyl(C 1 -C 3 -CHNH 2 -CHNH-Iower alkvl (C 1 -C 3 -CHO-lower alkN7 C C -CHN(CI- 3)2 -CHN(C2 2 H 5 2 -CHS-]ower alkyl(C 1 -C 3 and A-B, Ra, Rb, Rj. Rn, R.3, R.4, Rc,, R.6, R-7, RS, P9, Rio), P.25 are as previously defined in. Claim 1. 17. A compound according to Claim 1 wherein -188- the moiety ZO represents a 5-membered aromatic (unsaturated) heter-c'cylic ring having two nitrogen heteroatoms, y is selected from -CH2-, -CH-Jow,%ei alkvi(C 1 -C 3 -CHNH 2 -CHN(CH 3 )2, -CHNH-Iower alkyl (C -C 3 -C HO-Jower alkvl C1- -CHN(C.2115)2 -CHS-lower alkyl(C 1 -C 3 and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, are as previously defined in Claim 1. 18. A compound according to Claim wherein the moiety zO represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, ~sselected from -CH2-, -189- 4CH-Iover alkyl(C 1 -C 3 -CHNH 2 -CNH-Iower alkNvl (C 1 -C 3 -CHO-lower alkyl (C -C 3 -CHN(CH 3)2 -CHN(.C 2 H 5 2 -CHS-Iower alkv!(C 1 -C 3 and A-B,PRa, Rb, RI, R2, R3, R4, R6, R7, R8, RqG, R1io are as pre..iously defined in Claim I. 19. A" compound accord-"ing to Claim I wherein the mnoiety ZO represents a 5-rnembered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is selected from -CH2-, -CH-Iovver alkvl(C 3)' -CHNH 2 ICN-oe lkl( 1 C) -CHH-lower alkl (C -C -CHN(CH 3 2 -CHN(C 2 H 5 2 -CHS-Iower alkyl(C -C) and ABRa, Rb. P2, P3, P.4, Rr., R6, P7, R8, RQ, are as previcusl'- 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 (Cl-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (CI-C3)lower alkyl amino, Y is -(CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, RS, R9, RIC, R25 are as oreviously 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, Rg, R9, R10, R25 are as previously defined in Claim 1. 22. A compound according to Claim 1 wherein the moiety 0 represents a 6-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, RS, R9, R10, R25 are as previously defined in Claim 1. 23. A compound according to Claim 1 wherein 191 the moiety 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 the moiety Z 0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen 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. A compound according to Claim 1 wherein the moiety ZL 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, RS, R9, R10, R25 are as previously defined in Claim 1. 26. A compound according to claim 1 wherein 192 the moiety represents a 5-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. 27. 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 -(CH2)n, n is zero and A-B,Ra, Rb, RI, R2, R3, R4, R5, R, R7, R8, R9, R10, R25 are as previously defined in Claim 1. 28. 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 -(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 193 the moiety Z O represents a phenyl or substituted phenyl ring, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, R25 are as previously defined in Claim 1. A compound according to Claim 1 wherein the moiety LO represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from 0, S, NH, NCOCH3 and N-lower alkyl (CI-C3) and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, 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 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, R10, R25 are as previously defined in Claim 1. 32. A compound according to Claim 1 wherein the moiety ZO 194 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 selected from 0, S, NH, NCOCH3 and N-lower alkyl (CI-C3) and A-B,Ra, Rb, RI, R2, R3, R4, R5, R6, R7, R8, R9, are as previously defined in Claim 1. 34. A compound according to Claim 1 wherein the moiety z 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, R1, R2, R3, R4, R5, R6, R7, R8, R9, 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 two nitrogen heteroatoms, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (Cl-C3) 195 and A-B,Ra, Rb, R1, R2, R3, R4, R5, R6, R7, R8, R9, are as previously defined in Claim 1. 36. A compound according to Claim 1 wherein the moiety ZL 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 (Ci-C3) and A-B,Ra, Rb, R1, R2, R3, R4, R6, R7, R8, 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 (C 1 -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 ICl--lower alkyI(C 1 -C 3 *CN 2 -CH"N(CHr 3 2 ICN-oe lkl( 1 C) -CH H-lower alkyl (C 1 -C 3 -CHN(C2 2 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 group x-R X-R 1 R S R7 0 R.. N-rX -Ri and R6 is selected from the group 197 -NCOAr' R -NCO(CH 2 )n -cycloalkyl, XR -NCOCH 2 Ar' I -NCONAr', I I I R aR b wherein Ar' is selected from the croup R 5 R 8 I 8 A\I 1 RO W' is 0 or S; A-B,Ra, Rb, R1, Rio, P25, X, cycloalkyl and the moiehI R2, R4, R5, R-7, RS, R9, zO0 are as previously defined in Claim 1. 39. A compound according t~o Claim 1 wherein Y is selected from -CH2-, 198 -CH-ower alkyl(C 1 -C 3 -CHNH 2 -CHMN(CH 3 2 -C-HNH-lower alkyl (C -C 3 -C-HO-lower alkyl (C -CHN(C 2 H 5 2 -CHS-Iower alkyl(C 1 -C 3 R3 is the moiety -CAr 199 wherein Ar is a moiety selected from the group R R7 /"NI-EO 2 5 4 X-' 0 N~X -Rio NS R6 is selected from the group -NCOAr' -NCO(CHI) ~,-cycloalkyl, R -NCOCIl 2 Ar' -NCONAr', R; Rh wherein Ar' is selected from the group -200- 8 R RQ W, Tel is 0 or S; A-B,Ra, Rb, R2, R4, R5, R7, R8, p.9, R2r,, and cy.cloalkyl and the moiety zO are as previously defined in Claim 1. a compound according to Claim 1 wherein Y is selected from -CH2-, -CH-lower alkyl(C 1 -C 3 -CHNH 2 ICN-oe lkl( 1 C) -C0H-lower alkyl (C -C -CHN(CH 3)2 -CHN(C2 2 H 5 2 -CHS-lower alkyl(C -C) R3 is the moiety 0 -CAr wherein Ar is a moiety selected from the group -201- S 4 X-RIO 0 NI-EOR 5 -Ri and R6 is selected from the group -NCOAr' NC0(CH 2 )n -cycloalkyl, a -NCOC1 2 Ar' 51 -NCONAr', I I RA R b -202- wherein Ar' is selected from the group and W' is O or S; and the moiety Z represents a phenyl ring optionally substituted by one or two substituents selected from (Ci-C3)lower alkyl, halogen, amino, (Ci-C3)lower alkoxy and (C1-C3)lower alkyl amino and A-B,Ra, Rb, Ri, 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 II CAr wherein Ar is a moiety selected from the group -203- S- I R, F X -R N- -X -Rio and R6 is selected from the group -NCOAr' -NCO(CH 2 )n -cycloalkyl, -NCOCH 2 Ar' -NCONAr', I I Ra Rb -X-Rio wherein Ar' is selected from the croup and W' is 0 or S; and -204- the moiety z0 represents a phenyl ring optionally substituted b-y one or two substituents selected from (Cl-C3)lower alkyl, halogeni, amino, (Cl-C3)lower alkyl amino and A-B.Ra, Rb, R1. R2 R 4 R5, R7 R8, R9, R10, R25, IX and cycloalkyl are as previously defined in Claim 1. 42. A compound according to Claim 1 wherein Y is se-lected from 0, S, NH, NCOCHI and H-lower alky.1 Ri is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group -205- NC X-RI S R( 0 NHCcx- 5 X-Rio and R6 is selected from the aroup -NCOAr -NCO(CHI) n -cycloalkyl, I I IZI Ra -NCOCH 2 Ar' R -NCONAr', I I R. R b -X-R 1 0 wherein Ar' is selected from the group and W' is 0 or S; and -206- the moiety ZO 0 represents a phenyl ring optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, halogen, amino, (Ci-C3)loWer alko-y, and (Cl-C3)lower alkyl amino and A-B,Ra, Rb, R1, R2, R4, R5, R-1, R8, R9, P25, 1X and cycloalkyl are as previously defined in Claim 1. 43. A compound according to Claim 1 wherein Yx is n is an integer zero; -207- R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group /L X-RI .R 6 R250 N-rX -Rio 'S and Rr is selected from the croup -NCOAr' -NC0(CH 2 -cycioalkyl, R -NCOCH 2 Ar' I -NCONAr', R Rb wherein Ar' is selected from the group 208 R R 5 R Rq WR and VP is 0 or S; and the moiety 0 reoresents a 6-ienibered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom A-B,Ra, Rb, R1, R2, P4, RS, P.1, R8, R9, Ri1o, R25, X and cycloalkyl are as previously defined in Claim 1. 44. A compound according to claim 1 wherein Y is -CH2-; P3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group -209- _F4 X-RI S /"N-EOIZ:- 0 X R i o and R6 is selected from the group -NCOAr' -NC0(CH9 -cycloalkyl, Ra -NCONAr', -X-R 1 0 R aR b -NC0CH,Ar' wherein Ar'; is selected from he group, R8 R9 W, NB and is 0 or S; and 210 the moiety Z,0 represents a 6-rnemberei aromatic (unsaturaced) heterocyclic ring having one nitrogen heteroatom A-B,Ra, Rb, F1, R2, P.4, R5, P.7, R8, R9q, RiO, 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; R.3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group R R 5 .R X-R I O R. R 0 X-Ri NS and P.6 is selected from the group 211 -NCOAr' -NCO(CH 2) -cycloalkyl, R -NCOCH 2 Ar' -NCONAr', I I RR R wherein Ar' is selected from the aroup RR R 9 W, and W' is 0 or S; and the moiety zO0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom AEB,Ra, Rb, R2, R4, P.7, R8, R9, P-1, R25, and cycloalkyl are as previously defined in Claim 1. 46. A compound according to Claim 1 wherein is -CH2-; R3 is the moiety 0 11 CAr wherein Ar is a moiety selected from the group -212- X-R 0 X S 0 N<--rX R 10 and R6 is selected from the group -NCOAr' -NC0(CH 2) -cycloalkyl, A a -NCOCH 2 Ar' -NCONAr', I I Ra R b -X-R 10 wherein Ar' is selected from the croup R 5 R8 and W' is 0 or S; and 213 the moiety zO represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-2,Ra, Rb, R1, R2, P4, P7, R8, RQ, R~io, R25, X and cycloalkyl are as previously defined in Claim 1. 47. A compound according to Claim 1 wherein Y is selected3 from 0, S, NH, NCOCH-.. fl-lower alkyl (CI-Cl); R3 is the moiety. 0 CAr wherein Ar is a moiety selected from the -croup /R_ X-RI _X -Rl 0 S NIEO 25 KF X-R 1 0 0 N--X -Ri 'NS and R6 is selected from the group 214 -NCOAr' -NCO(CH 2 -cycioalkyl, R -NCOCH 2 Ar' -NCONAr', I I R11 R b -X-R 10 wherein Ar' is selected from the group and W' is 0 or S; and the moiety zO0 represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-B,Ra, Rb, P1, R2, R4, R5, R-7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1. 48. A compound selected from those of the formulae: and N-(CH2)mr wherein m is an integer one or two; -215- Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C,), -SH, -SO-lower alkyl(Cl-C-3), -S02-iower alkyl(Cl-C3), -CO-lower alkcyl(Ci-C3), -CF-z, lower alkyl(Ci-C3), 0-lower alkyl(C:'-C3), -14H2, -14HCO lower alkyl(Cl-C 3 -14-[lower alkYl(Cl-C__)]2, -S02NH,2; -SO2NH lower alkyl (Cl-C3) or -S021111ovier alkyl (Cl-C3); P, is hydrogen, Cl, Bre, F, I, -OH, lower alkyl(C 1 -C 3 0-lower alkvl(C1-C3.), or P1 and P2 taken together are methylenedioxy or ethylenedioxy; P3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formula: 9 R 5 R 7 X-R XR1 R 7 XF and R7 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl.C3)lower alkoxy and halogen. R6 is selected from moieties of the formula: -216- -NCOAr', a NCON-Ar, I I R a R b -NCO(CH -cvcloalkyl, -NCOCH 2 Ar, -N-S02-O 2 KA R- N-SO 2 CH 2 I I I -N-P- Ra. RR 0 11 -N-P R -NSO 2 ,-lover alkenvl(C -C 8 R 0 11 -NH-C-O-lower alkvl(C -C )straight or branched 0 -NH-C-lower alkyl(C -C.)straight or branched, 0 11 -NH-C-O-lovwer alkenyi(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 8 )stra ight or branched, wherein cycloalky! is defined as Ci tO C6 cycloalkyl, cyclohexenyl cr cyclopentenyl; Ra is hydrogen, CH-3, moieties of the formulae: N RI Rb (CH-)q-No (CI%)q -N 0 -(CH-)2-O-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three: Rb is hydrogen, -CH3i or a moiety of the formula: -7-PlC, wherein R1O is lower alkyl (C3-C8) lower alkenvlI(C3-C8), -(CH2)p-cyclcalkyl(C3-C6), R 5 H 2/ R- R N S 4CC) and p s zero o three; X is 0, S3, 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, tetrahlydrofuran, tetrahydrothiophene, the moieties I I -b R 8 S 0H N or -CH2-K' wherein I" is halogen, -OH, tetrahydrofuran, tetrahydrothiJophene or the heterocyclic ring moiety: -N E G F -219- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms mayv be optionally substituted with halogen, (Cl-C3) lower a lkyl, hydroxy, -CO-lower alkyl(Cl-C3). CHO, (C-C3)lower alkoxy, -c02- allkyl(Cl-C3), and Ra and R-b are as hereinbefore defined: a moiety., selected from those cf the formulae: R N- COCH-Ar' R C -0-C-lower alkyl (C 1 -C 3 -S-lower alkvl(C -C) 1 -1 R bN H C H q C O N I R Rb N W H 2 q- N1 0 (CI-y2 N wherein Rc is selected from halogen, (Cl-Ci)lower alkyl, -0-lower alkyl(Cl-C3) and OH, Rb is as hereinbefore defined; Ar' is a moiety selected from the group -220- oW, S R~ 8 N R8 and P.9 are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(C1-C3), -CF3, -CU, -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 N Q CH 2 \R/ w, is 0, S, NH, N-lower alkyl(Cl-C3), NCO-lower al kyl(Cl-C3) or NSO2-lower alkyl(Cl-C3) or NS02 lower -221- alkyl (C-1-C3) and the pharmaceutically acceptable. salts thereof-;. 49. A compound selected from those of the formula: Y F N I R 2 wherein is selected from 0, S. NH, and fl-lower alkyl (CI-C3); P.1 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(Cj-C3), -N-[lower alkyl(Cl-C3)]2, -NH lower alkyl(Cl-C3) -S02NH2; -SO 2 NHq lower alkyl(Cl-C3),or -SO2NI~lower alkyl(Cl-C3)12; P.2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Ri and taken together are methyle-edioxy or ethylenedioxy; P.3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formula: -222- X-RI0 -F3- -I S -X -R 0 NFIH2,, "S F; anci R7 are selected from hydrogen, (Cl-C3)lower alkyi. (Cl-C3)lower alkon, and halogen; R6 is selected from moieties cf the formula: -223- -NCOAr', -NQCOCH 2 Ar' I -NCON-Ar, I I Ra R b -N-SO 2 a -NCO(CH: )n -cvcloalkyl, R N-SO2 CH 2 R 0 -N-P -o Ra -NSO,-low-,er al kyl(C 3-C 8 R 0 11 -N-P R -NSO 2 loe alkenyl(C 3 -C 8 0 -NH-C-Glower alkvl(C -C 8 )straight or branched 0 11 -NH-C-lowver alkvl(C -C )straight or branched, 0 11 -NH-C-O-lower alkenvl(C -C.)straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 5 )straight or branched, wherein cycloalkyl is de 4 ned as C3 CO C6 cycloalkyl, cyclohexenyl or cyclopentelyl; Ra is hydrogen, CH3, C25 moieties of the formulae: -224- /Rb R b ~(CH -Noj (CH- )q-N 0 -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three Rb is h-ydrog-en, -CH3 or a. moiety of the formula: RiC,, wherein Ri0 is lower alkyl(C3-C8), lower alkenvl.-(C3-C8), -(CH2)p-cycloalkyl(C3-C6), R 5 R R- N R 0 and p is zero to three; X is 0, S, NH, NCH3

225- C= 0 or a bond and and are as previously a moiety of thie formula: Rb d~e f ined N -COJ wherein J is Ra, lower alkyl (C3-03) branched or unbranched, lower alkenyl(C3-CS) branched or unbranched, -0D-lower alkyl(CI-CS) branched or- unbranched, -0D-lower alkenyliO3-C3) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties N(.T or -CH2-K' wherein Y' is halogen, -OH, tetrahydrofuran, etrahvdrothiophene or the heterocyclic ring moiety: -N DE G F -226- 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, hydron~,, -CO-lower alkyl(CI'-C 3 CHO, (Cl-C3)lower alkoxy, -cc2-_ lower alkyl(C-l-Ci), and Ra and Rb are as hereinbefore defined; (di) a moiety selected from those of the formulae: R I'a COCHAr' -0-C-lower alk'l (C -C) S_ CK-N R R b HC N -S-lower alkyl(C 1 -C 3 NH(CH 2 )q -CON R Rb AR (C-y N\_ 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 moiet-.. selected from the group -227- RR R. W, R N RR I 4 N R8 and Ra are independently hydrogien, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C 3 -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or NH-lower alkyl(Cl-C3); N-[lower alkyl(Cl-C3)] 2 N1(Rb) (CH2)q-N(Rb)2-; is selected from the moieties C H 2 R 8 N 8 28- W' is 0, S, NH, N-lower alkyl(Cl-C 3 NCO-lower alkyl(CI-C3) or NSO2-lower alkyl(C 1 -C3) or NS0 2 lower alkyl(Cl-C3) and the pharmaceutically acceptable salts thereof. 50. The compound according to claim 1, 11-Dihydro-5!-dibenz[b,e~azepin-5-y)carbyl).. 2 pyridinyl] 1'biphenyl] -2-carboxamide. 51. The compound according to claim 1, 11-Dihydro-5,H-dibenz[b,e~azepin-5-ylcarbonyl.2. pyridinyl) -2-dimethylamino pyridine*-3-carboxamide. 52. The compound according to claim 1, 10-Dihydro-4u.-thieno[2, [1)benzazepin-9- yl) carbonyl] -2-pyridinyl] -biphenyl]-2-carboxamide. 53. The compound according to claim 1, 10-Dihydro-41-_t*hieno[2,3-- [llbenzazepin-9- yl)carbonyl]-2-pyridinyl]-2-dimethylamino pyridine-3- carboxamide. 54. The compound according to claim 1, 10-Dihydro-5P,-thieno[3,2-.) yl)carbonyl]-2-pyridinyl] [1,1 '-biphenyl]-2-carboxamide. The compound according to claim 1, h7- 10-Dihydro-5wa-thieno3,2-.,-] yl)carbonyl]-2-py-ridinyl]-2-dimethylamino pyridine-3- carboxamide. 56. The compound according to claim I, 10-Dihydro-4p.-thieno[2, 3--.][ljbenzazepin-9- yl) carbonyl) -2-pyridinyl ]-5-fluoro-2-methylbenzamide. 57. The compound according to claim 1, 10-Dihydro-5!i-thieno[3,2,-.bj yl) carbonyl]-2-pyr-idinyl]-5-fluoro-2-methylbenzamide. 58. The compound according to claim 1, [(4,5-Dihydropyrazolot4,3-.I [1]benzazepin-6(lH)- yl) carbonyl] -2-pyridinyl] -2-dimethylamino pyridine-3- Carboxamide. 229 230 59. The compound according to claim 1, N-[5-[(4,5-Dihydro'pyrazolo[4,3- d][1]benzazepin-6(1H-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide The compound according to claim 1, N-[5(period[2,3-b][1,4]benzoxazepin-5- (6H)-ylcarbonyl)-2-pyrdinyl]-5-fluoro-2-methyl 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: R, A- B Formula I wherein Y is (CH 2 O, S. NH, NCOCH3, N-lower alkyl (C 1 -C 3 CH-lower alkyl (C 1 C3), CHNH-lower alkyl (C 1 -C 3 CHNH 2 CHN[lower alkyl (C 1 -C 3 2 CHO-lower alkyl (C 1 -C 3 CHS-lower (C 1 -C 3 wherein n is an integer from 0-2; [n:\libc]02417:JCT A-B is ~(CH- 2 )m-N or N "C 2 )m~ k~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, mn may also be three, provided also that when Y is (CH2)n- and n is 2, m may not also be two; Rl is selected from the group of hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -SH, -SO lower alkyl(Cl-C3), -S02 lower alkyl(Cl-C.3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(C1-C3), 0-lower alkyl(Cl-C3), 0-lower alkyl(Cl- C3), -N02, -NH2, -NHCO lower alkyl(C:-C3), -N-flower alkyl(Cl-C3H12, -SO2NH2, -SO2NH lower alkyl(Cl-C3), SO2N [lower alkyl (Cl-C3) ]2; R2 is selected from the group of hydrogen, Cl, Br, F, I -OH, lower alkyl(CI-C3), 0-lower alkyl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety 0 11 -CAr wherein Ar is a moiety selected from the group 231 N R7 R_- 2510 R4 is hydrogen, lower alkyl(Cl-C3); -CO-lower alkyl (C1-C3); and R7 are selected from the group, hydrogen, (Cl.-C3) lower alkyl, (Cl-C3)lower alko:xy and halogen R6 is selected from moieties of the formulae: -232- -NCOAr', -NCOCH 2 Ar' I NCON-Ar' I I RA R b -NCO(CH2)n -cvcloal kyl, R2 -N-SO 2 CH 2 02 -N-P L R_ -NSO,-1ower alkyl(C -C 8 1R -N-P -NSO 2 loe alkenyl(C 3 -CS) 0 11 -NH-C-O-lower alkyl(C -C 8 )straight or branched 0 -NH-C-lower alkvI(C 3 -C,)straight or branched, 0 11 -NH-C-O-lower alkenyl(C -C 5 straight or branched, 0 11 -NH-C-lower alkenvl(C 3 -C 5 )straight or branched, wherein cycloalkylj is defined as C3 to C6 cycloalky., cyclohexeiyl or cycloperitenyl, Ra is hydrogen, CH3, moieties of the formulae: 233 /Rb -(~No (CF-1)q -No (CHi2q- N 0 -(CH2)2-O-lower alkyl(Cl-03) or -CH2)CH2O)H; q is one, two cr three; Rb is hydrogen, -CHi or 22H5; and a moiety- the formula: -X-P-1r) is l ower a Ikvl, IC-) lower a! kenyl (CH2)p -cycloalkxQ (C3-C6) -(CHj) -p/ R N R 4CF p S 300 and p is zero to three; X is 0, S, NH, NCH3, 234 C=0 or a bond and R5 and R7 are as previously defined. a moiety of the formula: RTb -1 4-COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl (C3-Cg)branched or unbranched, -0-lower alkenl (C 3 -C8)branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 N R 8 or -CH2-K wherein K. is halogen, -OH, tetrahydrofuran, LetrahiwdrothiOphele or the heterocyclic ring moiety: -N E G=F -235- wherein D, E, F and G are selected from carbon or nitroaen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C-0 lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-,C-)lower. alkoxy, -Co 2 lower alkyl(Ci-Ci), and Ra and PI- are as hereinbefore def ined; a mz:iety- seilect-ed from those cf he formulae: R N COCHAr' -0-C-lower alkyl (C -C) -S-lower alkyl(C 1 -C 3 S- (C N ,R b Rb NH(CFI-) -N R ZR b 0- (CH- 2 2 wherein Rc is selected3 from halogen, (Cl-C3)lower alkyl, -0-lower alkvl(Ci'-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group -23 6- SN R 4 N RB_ and Ro are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(Cl-C3); -N-flower alkyl(Cl-C3)] 2 -N(Rb)(CH2)q -N(Rb)2; is selected from the moieties F S WI' is selected from 0, S, NH, 14-lower alkyl (Cl-C3), -NCO-lower alkyl (Ci-C3), or NSO2-lower alkyl(Cl-C3); -237- the moiety zO represents: phenyl cr substituted phenyl optionally substituted by one or two substituents selected from (C 1 -C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy, and (Ci-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroacom selected from 0, 1 and S; a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; a 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 (C 1 -C3)lower alkyl, formyl, a moiety of the formula: (CH 2 qN Rb halogen or (C 1 -C3)lower alkoxy; which comprises reacting a compound of the formulae: Y Y zO or zo 2N N (C2)m H I H -238- with a compound of the formula: 0 Ar-C-Q wherein~ the moiety represented by the formula is an arc'yl 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 I. 64. A compound selected from those of the formula: 0 N and N N wherein Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SO- lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-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(Cl-C3), or -SO2N[lower alkyl(Cl-C3))2; P2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and P2 taken together are methylenedioxy or ethylenedioxy; R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formulae: -239- R- R- -F-X-R 0 S X-R 4- 0 X-RIO and X is 0, S, -14CH3, or -NH: R is independently selected from hydrogen, lower alkyl(Cl-C3). -(CH 2 )q -N R RI, (CH 2 )q -N 0 (CH2) q-OH, (CH2) q0alkYl (C1-C3) q is one, two or three; P4 is selected from hydrogen, lower alkyl(Cl-C3),-CO- lower alkyl (01-03), and R7 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; -240- R6 is selected from moieties of the formulae: -NCOAr', a NCON-Ar, I I R aRb -NCO(CH -cvcloalkvl, R -NCOCH 2 Ar, I R 2 -N-SO 2 1Ra- -N-SO 2 CH? Ra 0 ~R2 -N-P 0 1 X aR 7 2 -NSO 2 -lower alkyl(C 3 -CB), 0 11 -N-P I -NSO 2 -oe alkenyl(C 3 -C 8 1 0 11 -NH-C-O-lower alkyl(C 3 -C 5 )stra ight or branched 0 11 -NH-C-lower alkvl(C -C 8 )straight or branched, 0 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lowver alkenyl(C -C 8 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra. is hydrogen, CR3, moieties of the formulae: -241- (CH)q -N -(CH)q -No R b (C I ND(CE )N 0 -(CH2.'2-O-lower alkyl(Cl-C3) or -CH2)CH2OH; q is one, two or three; Rb is hydrogen, -CH3 Or :and (bi a moiety of the formula: -X-RIC.; wnere2.n P1 0 is lower alkyl(Ci-Ca), lower alkenyl (C3-C8), (CH2)p-cycioalkYl (C3-C6), H 2 )P 1 N R R.. 0 and p is zero to three: X is 0, S, NH, NCH3, -242- C=0 or abond and R5 and FR7 are as previously defined. a moiety of the formula: R b N- COJ wherein 3 is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-CB) 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 0H N or -CR2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N E -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 alk-yl, hydroy,, -CO-lower alkyl(Ci.-C3), CHO, (Cl-Ci)lower alkoxy, -C02- alk-yl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moietv selected from those of the formulae: R N -COC-LM R C 0 11 -0-C-lower alkyl(C 1 -C 3 R b Rh NHt(CH)q- N S-lower alkyl(C 1 -C 3 NH(C q CON ~-Rb ~Rb R. wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alk-yl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the croup: -244- R_ 8 R 8 R R 9 9 W/ R N R N RB and Ro are independently' hydrogen, lower alkyl (Cl-C3I), O-lower alkyl(Cl-C3), S-lower alkyl(Cl-C 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. ob -b 0 Q&H 2 R. W' is selected from 0, S. NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3)L or NSO2-lower alkyl(Cl-C3); and the pharmaceutically acceptable salts thereof. -245- A compound selected from those of the formula: N~N I I R 3 R 3 wherein Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkvl(Cl-C3), -SH, -So- lower alkyl(Cl-C3) -S02-lower alkvl(C!-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NqHCO lower alkyl(C1-C3), -N-[lower alkyl(Cl-CI))2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N~lower alkvl(C-l-C3)]2; R2 is hydrogen, Cl, Br, F, I, -OH. lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and P.2 taken together are methylenedioxy,. cr e-hylenedioxy; P3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: -246- 1 0 S NFEM. -F-X-RX- 0 N--X -Rio R is independently selected from hydrogen, lower alkyl (C1-C3)' (CH)q -N R- (CF ND (C-I N 0 -(CH2)q0alkYl(C1-C3); q is one or two; R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alk'l (CI-C3); Rr, and are selected from hydrogen, (Cl-C3)lower alky.L, (Cl-C3)lower alkoxy and halogen R6 is selected from moieties of the formula: -24'7- -NCOAr', -NCOCH 2 Ar' 0 11 -N-P R K -NCON-Ar, R aR b -N-SO1, I R -NCO(CH,), -cvcloalkyl, R 7 0 -N-P R N-SO 2 )CH 2 I -NSO 2 -lowver alkv'I(C 3 -C 5 )8 -NSO 2 -Iowver alkenyl(C 3 -CS) a 0 11 -NH-C-O-Iower alkvl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl(C -CQstraight or branched, 0 -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, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, 'cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, moieties of the formulae: -248- -(CH)q-N Rb -~1ND (CF N 0 -(CH2)2-O-lower alkyliCl-C3) or -CH2CH2OH; or three; Rb is hvdrogaen, -CH3- or and a moiety of the formula: wherein R10 is lower alkvlAIC3-C8), (C3-C8), -(CH2)p-cycloalkYl(C3-C6). R -(CH 2 )P q is one, two lower alkenyl Ri 4{CH 2 )p-4 N R and p is zero to three: X is 0, S, NH, NCH3, -249- C= 0 or a bond and R5 and P.7 are as previously defined a moiety of the formula: COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenvl(C3-CB) branched or unbranched, -0-lower alkyl(C3-CB) branched or unbranched, -0-lower alkenyl (C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties N or -CH2-K' wherein K' is halogen, -OH, tetrahyrofuran, tetrahydrothiophene or the heterocyclic ring moiety,: -N ,DE 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, hydroxy, -CO- lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -C02- alkyl(CI-C3), and Ra and Rb are as hereinbefore defined; a moi.ety selected from those of the formulae: R COCHMr lower ailkyl (C 1 -C 3 R b ~NH(Hq- N -S-lower alkyl(C -C3 1 1 3) NH(CH 2 )q CON ~Rb o- (C-1, 2 -N R, Rvb 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 4 N Rg and Ra are independently hydroaen, lower alkyl (Ci- 03), 0-lower alkyl(C1-C3), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, Vx02, amino, or lower alkvl(Cl-C3) -Nq-[lower alkyl(Cl-C3)]2, N(Rb) (CH2)q-N(Rb)2; is selected~ from the moieties S -b- 0 N R. H H 2 R8/ -252- W' is selected from 0, S, NH, N-lower alkyl (Cl-C 3 -NCO- lower 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 F N F N R 3 R 3 wherein P.1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH. S-lower alkyl(Cl-C3), -SH, -SO- lower alkyl(Cl-C3), -S02-lower alkyl (Cl-C3) i-CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N- flower alkyl(Cl-C3)]2, -S02NH2; -SO2NH lower alkyl(C"l-C3), or -SO2N~lower alkyl(Cl-C3)]2; R2 is hydrogen, Cl, Br, F, I, -OH, lower alk')l(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- I X-Rl Nx- 2 r 0Ri R 1 R is independently selected from alkyl (Cl-C3), hydrogen, halogen lower Rb N N (CF ND (CH q N 0 -(CH2)q-OH, -(CH-,)qC)alkyl(Cl-C3V q is one or twc; R4 4s selezted from hydrogen, lower alkx'1(C1-C3), -CO-lower alkyl(1-C3); R; is hydrogen, -CH3,-2H-5, Cl, 2r, F, -O-CH3, or -0- -254- Rc and P7 are selected from hydrogen, (Cl-C3)lower alkyl, (C,:-C3)lower alkoxy and halo'gen: R6 is selected from moieties of the formula: -NCOAr', NCON-Ar, R Rb -NCO(CH2 )n -cycloalkyl, -NCOCH-,Ar, R -N-SO 2 Ra 1 -N-SO. 2 CH 2 I R R 0 II -N-P 0 11 -N-P Ra 12 -NSO -lower alkvl(C 2 -NSO 2 -lower alkenyl(C 3 -CS) 1 0 11 -NI--C-O-lower alkyl(C 3 -C.)straight or branched 0 11 -NH-C-lower alkyI(C 3 -C,)straight or branched, 0 11 -NH-C-O-Iower alkenyl(C -C 5 )straight or branched, 0 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, -255- wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cycaIopentenyl; Ra is hydrogen, CR3, moieties of the formulae: -(CH 2 N Rb (CH 2 )q -N 0 -(CH 2 )2-O-lower alkyl(Cjl-C3) or -CHCH20H; q is one, two or three; Rb is hiydrogen. -CH3 or and a moiety of the formula: -X-RlO; wherein Rio is lower alkyl(C3-C8), lower alkenyl (C3-CB), -(CH 2 )p-cycloalkyl(C3-C6), -(CH 2 )P R.. {CH 2 )p N R.. 0 and p is zero to three: X is 0, IS. NH, NCH3, -256- C=0 or abond and R5 and R7 are as previously defined a moiety of the formula: COJ wherein Q3 is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenv..i (C3-CS)branched or unbranched, -0-lower aly(~C)branched or unbranched, -0-lower alkenvl(C-3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties X N or -CH2,-K' wherein K' is halogen, -OH, tetrahydrofuran, cetrahydrothiophene 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, (Cl-C3) lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkox-y, -C02- lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- COCHAr' -0-C-lower alkyl (C NHCK)NR R -S~~Fq Rb S-lower alkyl(C 1 -C 3 *NH(CH)q -CON ~Rb R b 0 N'\ wherein F.c 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: -258- N I 4 N R8 and R9 are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(C1-C3), S-lower alkyl(Cl-C 3 -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 S X R CH 2R8 -259- 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. 67. A compound selected from those of the formula: RA N- R a I/A- F N-N R. A I and F N A 2 N wherein R1 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 dlk-yl(Cl-C3),-NO21, -NH2, -NHCO lower alkyl(Cl-C3), -N- (lower alkyl(Cl-C3Y12, -SO2NH2; -SO2NH lower alkyl(Cl- C3), or -S02N[lower alkly1(Cl-C3)I,-.; R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), 0-lower alkyl(Cl-C3), or Rl and P.n taken together are methylenedioxry or ethylenedioxy; R3 is the moiety: 0 11 CAr wherein Ar is selected from moieties of the formula: -260- R- RI -F X-RIO S 4 X-RIO 0 N--X -Ri R is independently selected from hydrogen, halogen, lower alkyl.(Cl-C3). N Rb R b (CF N 0 -(CH2)q-OH, -(CH2)q0alkyl(Cl-C3); q is one, two cr three; R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl(Cl-C3); and P7 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen. R6 is selected from moieties of the formula: -261- -NCOAr', NCON-Ar, R aR aR b -NCO(CH 2)n -cycloal kyl, a -NCOCH 2 Ar, R -N-SO 2 R aR- N-SO 2 CHI) R 02 -N-P o -NSO,-lower alkvl(C 3-C 8 KR 0 11 -N-P R -NSO 2-lo~~er alkeny(C 3 -CS) 0 11 -NH-C-O-Iower alkyl(C 3 -C,)straight or branched 0 11 -NH-C-lowver alkvI(C 3 -C 8 )straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 8 )straight or branched, 0 -NH-C-lower alkenN l(C.-Cs)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra ics hydrogen, CH3, moieties cf the formulae: -262- -(CH )q -N R b (CH2)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-RlO; wherein R10 is lower alkyl(Ci-CB), lower alken'1 (C3-CB), -(CH2)p-cycloalkyl(C3-C6), R 5 R -(CH-1 2 )P R 4 C H 2) pN 0 and p i;s zero to three: X is.C, S, NH, NCH3; -263- C= 0 or a bond and R5- and P7 are as previously defined a moiety of the formula: -N-CWj wherein J is Ra, lower alkyl(C3-103) branched or unbranched, lower alkenyl(C3i-Cs) branched or unbranched -0-liower alkyl(C3-C8) branched or- unbranched, -0-lower alkenyl(Ci-Cg) branched or unbranched, tetrahydrofuran, tetrahydrothiophene. the rnoities R 8 S 0 Nl or -CH2-lK wherein K' is halogen, -OH, tetrahydroturan, 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(C1-C3), CHO, (Cl-C3)lower alkoxy, -cop alk-yl(Cl-C-), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- COCHAr' -0-C-lower alkyl(C 1 -C 3 Rb NH(CH)q- N -S-lower alkyl(C 1 -C 3 -NH(CH-)q -CON R (CH 2 2 N\_ 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- R 5 R8RZ R N R 8 N RB and Ro are independently hydrogeni, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(C1-C3), -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 S R B X R CH O 2 R RB -266- W' is selected from 0, S. NH, N-lower alkyl(Cl-C3), -NCO-lower alkyl(Cl-C3), or NqSO2-lower alkYl(Cl-C3); and pharmaceutically acceptable salts thereof. 68. A compound selected from those of the formula: R I 5 R R and R R 2 A-B R2 A-B wherein A-B is CH 2 -N or N-OH 2 wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3),-S, SO lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl (Cl1-C3), -CF3, lower alkyl(CI-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[lower alkyl(Cl-C3)]2, -SO2NH2; -SO2NH lower alkyl(Cl-C3), or -SO2N(lower alkyl(Cl-C3)12; PR2 is hydrogen, C1, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or R.1 and R2 taken together are methyienedioxy or ethyienedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: -267- 7N R 7 S R NHCO~n 010 R 7 X -Ri R is independently selected from hydrogen, halogen, lower alk-yl(Cl-C3), (CF -N RI,(C F ~No Rb (CH )q -No N 0 (CH2)q-OH, -(CH2)q0alkyl(C1-C3'; q is one, two or three; R4 is selected from hydrogen, lower alkyl(C,1-C 3 -C0- lower alk-yl (01-03), and R7 are selected from hydrogen(Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; -268- R6 is selected from moieties of the formula: -NCOAr', NCON-Ar, II I XR 1 R Rb -NCO(CH, -cycloalkyl, -NCOCH,,Ar, a -N-SO 2 1 -0 R 2 N-SQ.C 2 2 R L R- 2 -NSO0 2 -low er alkyl(C 3 -C 8 )1 R 0 ~R2 I I -N-P I I R] -NSO 2 -oe alkenyl(C 3 -C 8 R 0 -NH-C-O-lower alkyl(C 3 -C 8 )straight or branched 0 -NH-C-lower alkyl(C 3 -C.)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C 5 )straight or branched, 0 11 -NH-C-lower alkenyl(C 3 -C 5 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, moieties of the formulae: -269- R b Rb (Cf No (CH,)q N NC -(CH2)2-O-lower alkyl(Cl-C3) or -C-H2CH2OH; or three; Rb is hydrogen, -CH3 or'-C2HS; and a moiety of the formula: wherein R10 is lower alicyi(03-S), (C3-C8), -(CH2)pCycloalkyl(C3-C6), q is one, two lower alkenyl -(CH 2 )P R N R. 0 and p is zero to three: X is 0, S, NH, NCH3, -270- C=0 or abond and Rr, and R7 are as previously defined a moiety of the formula: wherein J is Ra, lower alkyl(C3-C8) branched or unbrcuiched, Liower iilkeny] brainched or unbranched, -0-lower alkyl(Cl-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties Re S 0 N R& H 2 or -CH2-yK wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: 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, (C1-C3)lower alkoxy-, -C02- lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R Ija N N- COCHAr' C -0-C-lower alkyl (C 1 -C 3 S_ XRb N -S-lower alkyl(C 1 -_C3) NH(CH2 )q -CON R ~Rb (C7y 2 N\ Rb wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower aJlkyl(Cl-C3) and OH; Rb is as hereinbefore defined; Ar' is selected from the group: -272- R9 R N "NZ N8 1 N R8 and R9 are independently hydrogen, lower alkyl (Cl-C3), 0-lower alkyl(Cl-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N'02, amino, or -NH-lower alkyl(Cl-C3); -N-flower alkyl(Cl-C3)) 2 N(Rb) (CH2)q-N(Rb)2; is selected from the moieties 0b N R CH 2_b R 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. -273- 69. A compound selected fromI those Of Lhe formulae: R2 wherein Y is -(CH2)n- and n is an integer zero or one; A-B is -(CH 2 N- or N- (CH 2 wherein m is an integer one when n is one and mn is an intecer one or two when n is zero; Ri is hydrogent, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SO-lower alkyl (Cl-C3), -SO,-lower alkyl (Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(Cl-C_3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NI-CO lower alkyl(CI-C3), -N-flower alkyl(Cl-C3)]2, -SO2NH2; -SO2NH lower alkyl (Cl-C3) or -SO21q[lower alkyl (Cl-C3)1]2; Rn is hydrogen, Cl, Br, F, -OH, lower alkyl(Cl-C3i), 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: -274- S R- R.. NHCO 4X-R k R-S R4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (Cl-C3); arnd R7 are selected from hydrogen(Cl-C3)lower alkyl(Cl-C3) lower alkoxy and halogen; R6 is selected from moieties of the formula: -275- -NCOAr',- Ra NCON-Ar, R R b -NCO(CH2) n-cNvcloalkyl, -N-SO 2 -N-SO 2 CH 2 o0 R2 -N-P P 0 R1 L -NSO,lIoxer alky](C 3 -C 8 R -N-P R J- -NSO,)loe alkenyl(C 3 -C 8 R 0 11 -NH-QO--lower alkvl(C 3 -C 5 )straight or branched 0 11 -NH-C-lower alkyl(C 3 -C 5 )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 )straight or branched, wherein cvcloalkyl is defined as 03 tO C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, moieties of the formulae: 2'U- /Rb RI, 02 F )q No (CH 2 )q -NOD N C -(CH2)2-O-iower aikyi(Ci-C3) or -CH2CH2OHf; q is one, two or three; Rb is hydrogen, -CH3 or and a moiety of the formula: -X-Rio; wherein Rio is lower alkyi(C3-C8), lower alkeny! (C3-C8) -(CH 2 )p-cycloaikyl(C3-C6), -(CH 2 )P R -0 N 0 and p is zero to three: X is 0, S, NH, NCH3, -277- 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-CS) branched or unbranched, lower alkenyl(C3-CB) branched or unbranched, -0-lower alkyl(C3-C 8 branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R8 S or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -N ,D E G=F -278- wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionall,, substituted with halogen, (Cl-C3)lower alkyl, hydroy,, -CO-lower alkyl(Ci-C3), CHO, (Cl-C3A)lower alkoxv, -C0-- lower alk-yl(Cl-C3}, and Ra and Rb are as hereinbefore define-j; a moiety selected from those of the formulae: R COICHMr -0-C-lower alkyl (C 1 -C 3 ,Rb NHCl )q-NR R R S-lowerialkyl(C 1 -C 3 1-1'Rb NH(CH 2 )q CON R /Rb 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- R 8 R N R 8 I "N R 4 RB and R9 are independently hydrogen, lower alkyl (cl- C3), 0-lower alkyl (Cl-C3) S-lower alkyl (C1-C 3 -CF3, -CN, -OH, -SCF3. -OCF3, halogen, N02, amino, or -NH- lower alkyl(Cl-C3); N-Clower alkyl(Cl-C 3 2 -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties S N R R -280- W, is selected from 0, S, NH, N-lower alkyl(Cl-C3), -NCO-'±ower alkyl(Cl-3), or NSO2-lower alkyl(Cl-C 3 and pharmaceutically acceptable salts thereof. A compound selected from those of the formula: RIR F N 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 (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.-SO2NH2; -SO2NH lower alkyl (C 1 C3), cr -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- X-R R 0 R7R 1 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: -282- -NCOAr', NCON-Ar, II I XR RA R b -NCO(CH -cvcloalkyl, -NCOCH 2 Ar, -N-SO, -R 2 R 7 -N-SO0 2 CH 2 a 0 -N-P 0 a R7 2 -NSO 2 -Iower alkyl(C 3 -C 8 R 0 11 -N-P I NS-lower alkenv(C O2- I 0 11 -NH-C-O-lower alkvl(C -C,)straight or branched 0 -NH-C-lower alkvl(C 3 -C 8 )straight or branched, 0 11 -NH-C-O-Iower alkenyl(C 3 -C 8 )straight or branched, 0 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, wherein cycloalkyl is defined as 03 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2HS, moieites of the formulae: -283- R b (C )q -ND (C F )q No N -(CH2)2-0-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, zwo or three; Rb is hydrogen, -CH3 or a moiety of the formula: X-R1O; wherein Rio is lower alkvl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-CYClOalkYl(C3i-C6L, R -(CHp /2)P 0 R R 0 and p is zero to three: X is 0, S, NI, NCH3, t=0 or abond -284- and R 5 and R7 are as previously defined a moiety of the formula: Rb N-COJ wherein J is Ra, lower alkyl(C3-CS) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties Re S 8 1- 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, (C 1 -C3) lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (C1-C3)lower alkoxy, -285- -C01-lower alkyl(Cji-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those cf the formulae: R Ia N COCHAr', -0-C-lower alkvl (C 1 -C 3 -R R b Rb NH(CH) q- N~ R b S-Iower alkvl(C 1 -C) NH(CH)q -CON Rb ZAR (CH 2 N\ wherein Rc is selected from halogen, (Cl-Ci)lower aDlkyl, -0-lower alkyl(Cl-C73) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -286- R 5 R R R N R I N R8 and R9 are independently hydrogen, lower alkyl (Cl-C3). 0-lower alkyl(C1-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)J2, N(Rb) (CH2)q-14(Rb) 2; is selected from the moieties RS 0 N R &CH 2 \b N -28'7- W' is selected from 0, S, NH, fl-lower alkyl(Cl-C 3 -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C 1 -0 3 and pharmaceutically acceptable salts thereof. 71. A compound selected from those of the formula: F A-B wherein Y is 0, 1*H and N-lowei- alkyl; and A-B is CH,- N or N- CH, 33 Rl is hydrogen, halogen (chlorine, bromine, fluorine, iodine OH, S-lower alkyl(Cl-C3), -SH, -SO-lower alkyl(Cl-C3), -S02-lower alkyl(Cl-'03), -CO-lower alkyl(Cl-C3j, -CF3, lower alkyl(CI-C3), 0-lower alkyl(Cl-C 3 -N02, -NH2, -NHCO lower alkyl(Cl-C3), -Nq-[lower alkyl(Cl-Cl)12, -SO02NH2:, -SO2NH lower alkyl(: 1 or -S02N[lower alkyl(Cl-C3)1 2 R2 is hydrogen, Cl, Br, F, I, -OH. lower alkyl(Cl-C3), 0-lower alkyl(Cl-C3), or Rl and P.2 taken together are methylenedioxcy or ethylenedioxy; R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: -288- X-RioXX-R -SS -CO-lower alky (C-C3 SR4 anis selected from hydrogen(Crj-klClower, alkyl(CI-C3) lower alkoxy and halogen; R6 i;s selected from moieties of the formula: -289- -NCOAr', NCON-Ar, R aRaRb -NC0(CH, -c'c loalkyl, a -NCOCH.,Ar' R a -N-SO 2 R a Dr'- N-SOIC C R IR, R i L -NSO,-lower alkyI(C.-Cd, R 0 R -N-P R 0 -NH-C-O-lovver alkvl(C 3 -C 5 )straight or branched 0 -NH-C-lowver a Ikvl(C -C,)straight or branched, 0 11 -NH-C-O-Iower alkenyl(C 3 -C 8 )straight or branched, 0 11 -NH-C-lower alkenyl(C -C,)stra ight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyc2.ohexenyl or cyciopentenyl; Ra is hydrogen, CH3, moieties of the formnulae: -290- Rb R b 02 1 )q No 2 ND7 'r-N (CF)q N c -(CH-2)20-lower alkyl(Cl-C3) or -CH2CH2OH; q is one, two or three; Rb is hydrogen, CH3 or a moiety of the formula: -X-RlO; wherein R.10 is lower alky.l(C3-C8), lower alkenyJAC3-CB), -(CH2)p-cycloalkyl(C3-C6), -(CH 2 )P -(CH2)p N 0 and i' is zero to three: X is 0, S, NH, NCH3, -291- C=0 or abond and P5 and R7 are as previously defined a moiety of the formula: R b N- COJ wherein J is Ra, lower alkyl(C3-C2) branched or unbranched, lower alkenyl(C3-Cg) branched or unbranched, 0l-lower alkyl(Cl-C8) branched or unbranched, 0-lower alken'.l (03-08) branched or unbranched, tetrahydrociuran, tetrahydrothiophene, the moieties 0 N CH 2 cr -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: 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, -C02-lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiet.' selected from those of the formulae: R COCHAr' -0-C-lowver alkyl(C 1 -C 3 R b NHl) q- N~ R -S-lower alkyl(C 1 -C) ~NHCH)q -CON R ~Rb 0- (CHy 2 )N\ wherein Rc is selected from halogen, (Cl-C3)lower alkyl, -0-lower alkyl(C1-C3) and OH-; Rb is as hereinbefore defined; wherein Ar' is selected from the group: -293- N R N j R8 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-[lower alkyl(Cl-C3)12, -N(Rb) (CH2)q-N(Rb)2; is selected from the moieties R 8 0 R N W' is selected from 0, S, NH, N4-lower alkyl(Cl-C3), -NCO-lower alkyl(C1-C3), 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 -H 2 N or N- CH- 2 I I R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(Cl-C3), -SN, -SO-lower alkyl(Cl-C3), -S02-lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(C',-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(CI-C3), N-flower alkyl (Cl-C3) ]2,-S02NH2; -SO2NH lower alkyl (Cl- C3), Or -SO2N[lower alkyl(C1-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 ethyleneedioxy; R3 is the moiety: 0 CAr wherein Ar is selected from moieties of the formula: 295 R 5 R7 X-R R 0 R-X-Ri R4 is selected from hydrogen, lower alkyl(CI-3), -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: 296 -NCOAr', -NCON-Ar, I I I RA R R b -NCOCH 2 Ar, -N-SO 1 0 R2 1 -N-P \2/ R 2 -NSO2-lower alkyl(C 3 -CS)i a -NCO(CH 2 -cycloalkyl, R2 R7 N-SO2 CH 2 112 -NSO 2 -lower alkenvl(C 3 -CB) 0 1I -NH-C-O-Iower alky](C -C 8 straight or brancl~ed -NH-C-lower alkyl(C 3 -C 5 )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.)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenvi or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieites of the formulae: 297 R -(CHt)q -ND -clEH-N 0 -(CH2)2-O-lower alkyl(CI-C3) or -CH2CH2OH; q is one, two or three; Rb is hvdrogen, -CH3 or -C2Hc;; and a moietyr of the formula: -X-RIO; wherein RIO is lower alkNvl(C3-C8), lower alkenyi (C3-C8), -(CH2)j cycloalkvl(C3-C6), R 5 R 1 N R. .(CH 2 )p 0 and p is zero to three: X is 0, S, NH, NCH3, 298 C= O or a bond and R5 and R7 are as previously defined a moiety of the formula: Rb N-COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahvdrofuran, tetrahydrothiophene, the moieties N or -CH2-K' wherein K' is halogen, -OH, tetrahydrothiophene or the heterocyclic -N E /I tetrahydrofuran, ring moiety: 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) 299 lower alkyl, hydroxy, -CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -C02-lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R COCH.Ar' 0 11 -0-C-lower alkyl (C 1 R b NH(CH)q- N R S-lower alkyl(C 1 -C 3 NH(CH q -CON ~Rb ~Rb -(C 2 2 N-_ wherein Rc is selected from halogen, (Cj-C3)lo%%er alkyl, -0-lowver alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: 300 RS 8 R N R R N R8 and R9 are independently hydrogen, lower alkyl (CI-C3), 0-lower alkvl(C1-C-), S-lower alkyl(Cl-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkvl(Cj-C3);-N-L low.er alkvl(C 1-C3)12), -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties /b R8 S N 255 R8N 301 W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1- C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof. 73. A compound according to claim 72 wherein A-B is N- CH- 3 R3 is the moiety: O II CAr wherein Ar is selected from moieties of the formula: R_ S R, NHCOR 2 N and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as 2 previously defined in Claim 72. 74. A compound according to claim 72 wherein A-B is N- CH- 3 Y is 0; and Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72. 75. A compound according to claim 72 wherein 302 A-B is N R3 is the moiety: 0 -CAr wherein Ar is selected from moieties of the formula: R 5 6" NH-C0R 2 N R- R 7 Y is0; and Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, RiO, R25 are as previously defined in Claim 72. 76. A compound according to claim 72 wherein 1 A-B is N CH 2 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 72. 77. A compound according to claim 72 wherein A-B is N C1--- 1 R 3 R3 is the moiety., 303 0 11 CAr wherein Ar is selected from moieties of the formula: R 5 R -R -NHCOR 2 N R 7 R 7 and Y is NH; and, Ra, Rb, Rc, R1, R2, R3, R,4, R5, R6, R7, R8, R9, RIO, are as previously defined in Claim 72. 78. A compound selected from those of Formutla 1: zO 0 DA-B F Formula 1 wherein Y is selected from (CH2)n, 0, S, NH, NCOCH3, N-lower alkvl (Cli C3), CH-lower alkyl(CI CHNH-lower alkv J(CI-C3), CHNH2, CHN[lower alkyl(Cl-C3)12,CHO-lowver alkvl(C 1-C3), CHS-lower alkyl(Ci C3), wherein n is an integer from 0-2; A-B is (C )m -N or N(CH 2 )M- 3 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 mav, not also be two; 304 Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S- lower alkyl(C1-C3), -SH, -SO lower alkyl(Cl-C3), -S02 lower alkyl(Cl-C3), -CO-lower alkyl(CI-C3), -CF3, lower alkyI(CI-C3), 0-lower alkyl(CI-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N-[lower alkyl(C1-C3)12, -SO2NH2, -SO2NH lower alkyl (CI-C3), or -SO2N[lower alkyl(CI-C 3 R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(Cl-C3), 0-lower alkvl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxv; R3 is the moiety 0 11 CAr wherein Ar is a moiety selected from the group R 6~ R 5 R 7 X-RI 1 0 -I R 7 R -F X-R o RX-R and X is 0, S, -NCH3 or -NH R4 is selected from hvdrogen, lower alkYI(CI-C3), -CO-lower alkyl(Cl-C3); and R7 are selected from hydrogen, (C1-C3) lower alkyl, (C1-C3)lower alkoxy and halogen 305 R6 is selected from moieties of the formula: -NCOAr', Ra -NCOCH 2 Ar' R -NCON-Ar, I I -N-SO 2 R RNOC, -cy cloalkyl, R, -N-SO 2 CH 2 a t -N-P o Ra 2 -NSO 2 -lowe r alkvl(C 3 -C 8 1 a 0 11 -N-P R 1 -NSO -lower alkenvl(C -C 8 1R 0 11 -NH-C-O-lower alky](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 )stra ight or branched, 0 -NH-C-lower alkenyl(C 3 -C 8 )straight or branched, 306 wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenvi or cyclopentenyl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: /R b N (CFY No I) oI -(CH 2 J -(CH2)2-O-lower alkyl(Cl-C3) or -CH2CH2)OH; q Ihydrogen, -CH3 or a moiety of the formula: -X-R1O, wherein R10 is lower alkyl(C3-CS), lowNer cvcioalkyl(C3-C6), q-N 0 is one, two or three; Rb is al kenv -(CH2)P- -(CH 2 )p R 407 N R- 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: R b N N-CO) wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C 8 branched or unbranched, -0-lower alkeny](C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 N /CH- or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahvdrothiophene or the heterocyclic ring moiety: -N E 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(CI-C3), CHO, (CI-C3)lo~wer alkoxy -C02-lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R N- COC1-Ar' -0)-C-lower alkyl (C 1 -C 3 R b -S-lower alkvl(C 1 -C 3 NH(:H) q -CON R Rb H(C)qN R (CH- 2 N, wherein Rc is selected fromn halogen, (Cl-C3)lower alkyl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: 309 'R 9 L R 9 WS R-. N) 1 N R8 and R9 are independently hydrogen, lower alkvl (CI-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-[lower alkyl(CI -C3)12, N(Rb)(CH2)q-N(Rb)2; Wis selected from 0, S, NH, N-lower alkyl (CI-C3), -NCO-lover alkvl(Ci- C3), or NSO2-lower alkyl(Cl-C3); R25 is selected from the moieties 310 S -b X 03 N R C 2 R8 F 311 and the moiety Z0 represents: a 6-mernbered 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-C3)lower alkyl, formyl, a mnoiety of the formula: (CH 2 qN R halogen or (CI-C3)lower alkoxy; and the pharmaceutically acceptable salts, 1. esters and pro-drug forms thereof. 79. A compound selected from those of the formulae: R, A-B R wherein Y is selected from 0, S, NH, NCOCH 3 N-lower alkyl (Ci- C3), CH-lower alkyl(CI-C3), CHNH-lower alkvl(CI-C 3 CHNH2, CHN~lower a lkyl(CI -C3)]2,CHO- lower alkvl(C 1 -C 3 CHS-lower alkvl(Cl- C3); A-B is (CH- 2 N or N- (CH- 2 RI is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S- lower alkvl(CI-C3), -SH, -SO-lower alkvl(CI-C3), -SO2-lower alkyl(Cl-C3), -CO-lower alkvl(CI-C3), -CF3, lower alkyl(C I-C3), O-lower alky](CI-C3), 312 -N02, -NH2, -NHCO lower alkyl(CI-C3), -N-flower alkvl(Cl-C 3 )1 2 -SO2NH2; -SO2NH lower alkyl (CI-C3), or -SO2N[lower alkvl(C 1 -C 3 2 R2 is hydrogen, Cl, Br, F, 1, -OH, lower alkx'l(CI-C3), 0-lower alkyl(CI-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 /L R.. 0 N~X -Rio R4 is selected from hydrogen, lower alkyl(CI-C3), -CO-lower alkYl(CI-C3); and R7 are selected from hydrogen(C I-C3) lower alkyl(Cl-C3) lower alkoxy and halogen; R6 is selected from moieties of the formula: 313 -NCOAr', I -NCOCH 2 Ar' -NCON-Ar, I I R aR b -N-SO 2 R -NCO(CH2 )n Ra RR -cycloalkyl, -N-SO2 CH 2 I/ RKR 02 Ii R K 1 R -NSO 2 -lower alkyl(C 3 -C 8 R 0 11 -N-P R 12 -NSO,-Iower alkenyl(C -C 8 0 11 -NH-C-O-lower a lkyl(C 3 -C 8 )straight or branched 0 11 -NH-C-lower alkyl (C -C)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3-C.)straight or branched, 0 -NI-I-C-lower alkenvl(C -C 8 )straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenvi; Ra is hydrogen, CH3, C2H5, moieties of the formulae: 314 /Rb 01)q-N C -(CH2)2-O-Iower alkyl(Cl-C3) or -CH2CH2OH; q is one., two or three; Rb is hydrogen, -CH3 or and a moiety of the formula: -X-RiO; wherein R1O is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p* cvcloalkyl(C3-C6), -(CH2)P R (CH 2 )p -0 N R -(Cayp) S 0 and p is zero to three: X is 0, S, NH, NCH3, 315 N- C=0 or a bond and R5 and R7 are as previously defined a moiety of the formula: Rb NCOJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-CS) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R 8 S 0 N CH 2 -0 or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: -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, (Cl- C3)lower alkyl, hydroxy, -CO-lower alkyl(CI-C3), CHO, (Cl-C3)iower alkoxy, -C02-lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R I a N- COCH.Ar' -0-C-lower alkyl (C -C) S- (Cf NRb R b NH(CH N 7 R R b -S-lower alkyl(C 1 -C 3 Rb Rb 0 I- 2 ,\k 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: 317 R 5 R 8 R RR 9 N R8 and R9 are independently hydrogen, lower alkyl(CI-C3), 0-lower alkvl(CI-C3), S-lower alkvl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(C1-C3); N-[lower alkvl(CI-C3)]2, -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties S R.. CH 2\/E OH 318 W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1- or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof. A compound according to claim 79 wherein A-B is N- C 2 I R 3 R3 is the moiety: O II CAr wherein Ar is selected from moieties of the formula: R 5 R RR 'V R 6 NHCOR 2 N RI and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79. 81. A compound according to claim 79 wherein A-B is N- CH- R 3 Y is and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79. 82. A compound according to claim 79 wherein 319 A-B is N CH- 2 53 Y is 0; and Raj, Rb, Rc, RI, R2, R3, R.4, R5, R6, R7, R8, Rcq, RIO, R25 are as previouIsly defined in Claim 79. 83. A compouind according to claim 79 wherein 101 A-B is N- Cit- R 3 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previously defined in Claim 79. 320 84. A compound according to claim 79 wherein A-B is N- C- 2 3 R3 is the moiety: O II -CAr wherein Ar is selected from moieties of the formula: R 5 R R% R, N 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 N- CH2- R 3 R3 is the moiety: 0 II -CAr wherein Ar is selected from moieties of the formula: 321 6 'NHCOR 2 N 6 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R.4, 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- CKi- 153 R3 is the moiety: 0 11 CAr wherein Ar is selected fromn moieties of the formula: R R N Y is NH; and Ra, Rb, Rc, RI, R2, R3, R4, R5, R6, R7, R8, R9, RIO, R25 are as previous) defined in Claim 79. 322 87. A compound selected from those of Formula I: ZO A-B 2 Formula -1 wherein Y is selected from (CH2)n, 0, S, NH, NCOCH 3 N- lower alkyl (Cl-C3), CH-lower alkyl(Cl-C3), CHNH-lower alkyl(Cl-C3), CHNH2, CHN~lower alkyl(Cl-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 1NJ(CH 2 )M- 103 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 and n is 2, m may not also be two; Ri is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(CI-C3), -SH, -SO lower alkyl(Cl-C3), -S02 lower alkyl(Cl-C3), -CO-lower alkyl(Cl-C3), -CF3, lower alkyl(C'-C3), 0-lower alkyl(Cl-C3), -N02, -NH2, -NHCO lower alkyl(Cl-C3), -N- [lower alkyl(CI-C3))2, -SO2NH2, -SO2NH lower alkyl (Cl-C3), Or -S0 2 N(lower alkyl(Cl-C3)]2; R2 is hydrogen, Cl, Br, F, -OH, lower alkyl(CI-C3), 0-lower alkYl(Cl-C3), or Rl and R2 taken together are methylenedioxy or ethylenedioxy; R3 is tLhe moiety 323 0 11 CAr wherein Ar is a moiety selected from the group R 6 N N.S ad Xis0, -CH or-7 and is seece fro oieie o-teNomua 324 -NCOAr', a NCON-Ar, I I -NCO(CH~ -cvcloalkyl, IR) -NCOCH 2 Ar' -N-SO 2 I T2 N-SO 2 CH 2 -R 2 -N-P 0/ R aR_' 0 11 -N-P R -NSO -lower alkv](C 3 -C 8 a -NSO 2 -lower alkerwl(C 3 -C 8 0 11 -NH--C-O-lower alkyl(C -C )traight or branched 0 -NH-C-lower alkyl(C,,-C)straight or branched, 0 11 -NH-C-O-lower alkenyl(C 3 -C.)straight or branched, 0 II -NH-C-lower alkenyl(C 3 -C 8 )Straight or branched, wherein cvcloalkvl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyci opentenvl; Ra is hydrogen, CH3, C2H5, moieties of the formulae: 325 b -2 d-N-(CH 2 )q-N 0 -(CH2)2-0-lower alky](CI-C3) or -CH2-CH2)OH; q is one, two or three; Rb is hv drogen, -CH3 or a moiety of the formula: -X-RiO, wherein R1O is lower alkv](C3-C8), lower alkenyl(C3-C8), -(CH2)F cvcioalkvl(C3-C6), R 5 R- (CH 2 p -(CH- 2 -0 N R- (Cl-i 2 S R 0 and p is zero to three; X is 0, S, NH, NCH3, 326 C= O or a bond and R5 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, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-CS) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties R S e 0 N CH 8 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(Cl-C3), CHO, (CI-C3)lower alkoxy, -C02-lower alkyl(CI-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: N- COCHAr' -0-C-lower alkvl (C -C) 1 3 -S-lower alkyl(C 1 -C) Rb bR 0 2 N wherein Rc is selected from halogen, (Cl-C3)lower alkvl, -0-lower alkyl(Cl-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group: 328 R 9 9 R 8 N 8 N R8 and R9 are independently hydrogen, lower alkyl 0-lower alkyl(CI-C3), S-lower alkyl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, 15N02, amino, or -NH-lower alkyl(Cl-C3); -N-[lower alkvl(Cj-C3)12, -N(Rb)(CH2)q-N(Rb)2; W is selected from 0, S, NH, N-lower alkyl (CI-C3), -NCO-lower alky](Cl- C3), or NSO2-lower alkvl(Cl-C3) is selected from the moieties 329 S9 R8 0 N CH O 2 4 RS 330 and the moiety Z0 represents: a 5-membered aroma tic (unsaturated) heterocyclic ring havring one S heteroatom wherein the 5 -rmembered aromatic (unsaturated) heterocyclic ring is optionally substituted by (Cl-C3)Iower alkyl, formyl, a moiety of the formula: -(CH 2 qN R b 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: Y F A-B wherein Yi is selected from 0, S, NH, and N-lower alkyl(CI-C3); A-B is CH,- N or N- CH- 2 R1 is hyvdrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S- lower alkvl(Cl-C3), -SH, -SO-lower alkyl(C1-C3), -S02-lower alkyl(CI-C3), -CO-lower alkyl(CI-C3), -CF3, lower alkyl(C-C3), 0-lower alkvl(Cl-3) -N02, -NH2, -NHCO lower alkyl(C1-C3), -N-flower alkyl(CI-C3)]2,- SO2NH2; -SO2NH lower alkvl(Cl-C3), or -SO2N~lower alkyl(C1-C3)12; R2 is hydrogen, Cl, Br, F, 1, -0OH, lower alkyl(CI-C3), 0-lower alkv](CI-C3), or R1 and R2 taken together are methylenedioxy or ethvleneedioxv; 331 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R-. 1' R R- X-RIX- S R- 0 R-. N-7X -i 'S R4 is selected from hydrogen, lower alkvl(CI-3), -CO-lower alkyl(Cl-C 3 and R7 are selected from livdrogen(CI-C3) lower alkyl(CI-C3) lower alkoxy and halogen R6 is selected from moieties of the formula: 332 .4. -NCOAr', a -NCOCH 2 Ar' I -NCON-Ar, I I R R b -N-SO 2 a -NCO(CH 2 -cycloalkyl, 2R) R 2 -N-SO C H 2 Ra R, 0 R2 I I -N-P 0 a 1 -NSO 2 -oe alk yl(C 3 -CS), I Ii 7 -N-PI -NSO 2 -Iower alkenyl(C,-C 8 I 0 11 -NH-C-O-lowver alkvl(C 3 -CS )stra ight or branched 0 11 -NH-C-lower alkyl(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 5 )straight or branched, 333 wherein cycloalkyl. is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyi; Ra is hyvdrogen, CH3, C2H5, moieites of the formulae: N,/Rb o R b D(CF -N C -(CH2)2-O-IowAer alkvlI(CI-C3) or -CH2)CH2)OHq is one, tw,,o or three; Rb i~ hy drogen, -CH3 or and a moietv of thle formula: -X-RiO; wherein R1O is lowver alkyl(C3-C8), lowver alkenyi (C3-C8), -(CH2)p- cyc loalkNvl(C3-C6), R-. -(CH~p R- R.. R.. KC 2- N R 4CFY P S R.. 0 and p is zero to three: 334 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, low-,er alkenyl(C3-C8) branched or unbranched, -0-lower al1kY](C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbrariched, tetrahydrofuran, tetrahydrothiophene, the moieties \b R8 S 0 N Q C 2 or -CH2-IK' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophefle or the heterocyclic ring moiety: -N E G=F 335 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, (C1-C3)lower alkoxv, -C02-lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety selected from those of the formulae: R Ia N- COCH1Ar' 0 11 -0-C-lower alkyl (C 1 -C 3 R b Rb R b S-lower alkvl(C 1 -C) N(CH 2 q CON Rb ~Rb ,1A NCH N wherein Rc Is selected from hialogen, (Cl-C3)ower alkyl, -0-lowver alkyl(Ci-C3) and OH; Rb is as hereinbefore defined; wherein Ar' is selected from the group:

336- S N R- R 8 N R8 and R9 are independently hydrogen, lower alkvl 0-lower alkyl(Cl-C3), S-lower alkvl(CI-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, N02, amino, or -NH-lower alkyl(C1I-C3);-N- [lower alkyl(C1-C3))2, -N(Rb)(CH2)q-N(Rb)2; is selected from the moieties N N 337 W' is selected from 0, S, NH, N-lower alkyl(Ci-C3), -NCO-lower alkyl(C1- C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof. 89. A compound according to claim 88 wherein A-B is N- C- RI R3 R3 is the moiety: O II -CAr wherein Ar is selected from moieties of the formula: R R R, NHCORS N R_ R7 and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, RS, R9, R10, R25 are as previously defined in Claim 88. A compound according to claim 88 wherein A-B is N- CH- R 3 Y is and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously S defined in Claim 88. 91. A compound according to claim 88 wherein 338 rZ- 1 r A-B is N- CH 2 R Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, RS, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88. 92. A compound according to claim 88 wherein A-B is N- CH 2 I R 3 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88. 93. A compound according to claim 88 wherein A-B is N- CH 2 R3 R3 is the moiety: O II -CAr wherein Ar is selected from moieties of the formula: R R R NHCOR N Y is and 339 Ra, Rb, Rc, Ri, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88. 94. A compound according to claim 88 wherein A-B is N- CH- R3 R3 is the moiety: O II -CAr wherein Ar is selected from moieties of the formula: R- RI NHCOR 2 N and Y is NH; Ra, Rb, Rc, RI, R2, R3, R4, RS, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88. A compound according to claim 88 wherein A-B is CR- R 3 R3 is the moiety: 0 O -CAr wherein Ar is selected from moieties of the formula: 340 R 5 R R NHCOR 2 N and Y is 0; Ra, Rb, Rc, RI, R2, R3, R4, R_5, R6, R7, R8, R9, R 1 0 R2 are as previously defined in Claim 88. 96. The compound according to claim 1, N-[4- (dibenz[b,f] [l,4loxazepin-l0(1lI-)-ylcarbonyl)-phenyl)- 1, 1 -biphenyl) -2-carboxamide. 97. The compound according to claim 1, N-[4- (dibenz[b, f) 11,4]oxazepin-10(llH)-ylcarbonyl)-3-chloro- phenyl)[1, l'biphenylJ-2-carboxamide. 98. The compound according to claim 1, (dibenz[b, fi [,4]oxazepin-lQ(l1H)ylcarbonyl)-2- pyridinyl] -5-fluoro-2-methylbenzamide. 99. The compound according to claim 1, (dibenz~b, f) [l,4)oxazepin-l0 (llH)-ylcarbonyl)-2- pyridinyl] (4-pyridinyl) benzamide. 100. The compound according to claim 1, (pyrido(2,3-b] tl,5]benzoxazepin-6(5H)-ylcarbonyl) -2- pyridinyl l'biphenyl]-2-carboxamide. 101. The compound according to claim 1, (pyrido[2,3-b] [l,4jbenzoxazepin-5(6H)-ylcarbonyl) -2- pyridinyl] 1'-biphenyl]-2-carboxanide. 102. The compound according to claim 1, N-(4- (pyrido[2, 3-b] [l,4]benzoxazepin-5 (6H)-ylcarbonyl)-3- chiorophenyl] [1,l1 biphenyl) -2-carboxamide. 103. The compound according to claim 1, N-[4-(6,ll-dihydropyrido[2,3-b) [1,5)benzodiazepin-6(5H)- ylcarbonyl)-phenyl) [1.1 '-biphenyl)-2-carboxamide. 341 104. The compound according to claim 1, N-[4- 11-dihydropyrido[2,3-b] [1,5lbenzodiazepin-6(5H)-yl- carbonyl) -3-chlorophelylJ 1, 1 1-biphenyl) -2-carboxamide. 105. The compound according to claim 1, N-[4- 11-dihydropyrido[2,3-b] [1,5]benzodiazepin-6(SH)-yl- carbonyl)phenyl] [1,1 '-biphenyl]-2-carboxamide, hydrochloride. 106. The compound according to claim 1, N-[4- l1-dihydro-10H-dibelz [1,4]diazepin-10-yl)- carbonyl)-3--chlorophenyl] (1,1 '-biphenyl)-2-carboxanide. 107. The compound according to claim 1, N-[4- 11-dihydro-10H-dibenz [1,4]diazepin-10-yl)- carbonyl)-phenyl) 1'-biphenyl]-2-carboxamide. 108. The compound according to claim 1, N-[4- 11-dihydro-1OH-dibenz [1,4ldiazepin-10-yl)- carbonyl]-3-methylphenyl] [1,1 '-biphenyl]-2-carboxamide. 109. The compound according to claim 1, N-[4- 11-dihydro--10H-dibenz(b,e] (1,4)diazepin-10-yl)- carbonyl)-2-methylphenyl] [1,1 '-biphenyll-2-carboxamide. 110. The compound according to claim 1, N-[4- (5,11-dihydro-1OH-dibenz~b,e] [1,4]diazepin-10-yl)- carbonyl]-2-chlorophenYl) .'-biphenyl]-2-carboxanide. 111. The compound according to claim 1, N-[4- 11-dihydro-5-dibenz~b,eazepin5-y)carbonylV- pheny] 1'-biphenyl] -2-carboxamide. 112. The compound according to claim 1, 11-dihydro-5H-dibenz~b,eazepin5-y)carbonyl)V3 chiorophenyl '-biphenyl]-2-carboxamide. 113. The compound according to claim 1, N-[4- ll--dihydro-5H-dibenz~b,e~azepin5yl)carbonyl- 3 methyiphenyl] 1'-biphenyl]-2-carboxamide. 114. The compound according to claim 1, N-[4- 11-dihydro--5H-dibenz e]azepi-n-5-y1i)carbonyl] -2- chloroohenyl] [1,1 '-biphenyl]-2-carboxamide. 342 115. The compound according to claim 1, 11-dihydro-5H-pyrido[2, 3-b) yl) carbonyl]I -2-pyridinyl] -5-fluoro-2-methylbenzamide. 116. The compound according to claim 1, N-[4- ll-dihydro-5H-pyrido[2, 3-b] carbonyl) -3-chlorophel) 1, 1 -biphenyl)]-2--carboxamide. 117. The compound according to claim 1, N-[14- 11-dihydro-5H-pyrido 3-b) 1, 4 benzodiazepin-5-y1) carbonyllphenyl) 1'-biphenylll-2-carboxamide. 118. The compound according to claim 1, N-[4- 11-dihydro-5H-pyrido 3b) 4 1benzodiazepin-5-yl) carbonyl]-3-methylphenYll 11,1 '-biphenyl]-2-carboxamide. 119. The compound according to claim 1, N-[4- ((4,5-dihydropyrazolo[4,3-d] (lbenzazepin-6(1H)-yl) carbonyllphenyll [1,1 '-biphenyl]-2-carboxamide. 120. The compound according to claim 1, N-14- I (4,5-dihydropyrazolo[4,3-d][llbenzazepin-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(lH)-yl)- carbonyll-2-pyridil)(1,l'-biphenyl]-2-carboxamide. 122. The compound according to claim 1, (4,5-dihydropyrazolo[4,3-d][1]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]benzodiazepif9(1H)Yl)-phenYlV- 1 -biphenyl 3-2-carboxamide. 125. The compound according to claim I, N-[4- (4H-thieno[3, 4-b] [1,5benzodiazepin9(OH)yl)-3chloro- phenyl] [1,1 '-biphenyl]-2-carboxamide. 126. The compound according to claim 1, (4H-thieno[3, 4-b] [1,5]benzodiazepif-9(1H)-Ylh 2 pyridinyl] 1'-biphenyl]-2-carboxamide. 343 127. The compound according to claim 1, 5,11- dihydro-10-[4-(2-thienyl)benzoylj-1OH-dibenz[b,e] diazepine. 128. The compound according to claim 1, 5,11- dihydro-lO-[4-(3-thienyl)benzoyl]-10H-dibenz[b,eI diazepine. 129. A compound according to claim 79 wherein A-B is -CH- -N R 3 R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R "NHCOR 2 N R7 R 7 and Y, Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, Rio, R25 are as previously defined in Claim 79. 130. A compound according to claim 79 wherein A-B is -C 2 N Y is and Rat Rb, Rc, Ri, R2, R3, R41 R5, R61 R71 R8, R9, RiO, are as previously defined in Claim 79. 131. A compound according to claim 79 wherein 344 A-B is H 2 N R, 3 Y is 0; and Rat Rb, Rc, Ri, R2, R3, R4, R5, R6, R7, RB, R9, RiO, 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 -CHi 2 -N R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R- R -R6 /\NHCOR 2 N K7 R 7 Y is and 345 Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, RB, R9, R10, are as previously defined in Claim 79. 134. A compound according to claim 79 wherein A-B is -CH- N IR R3 is the moiety: 0 II -CAr wherein Ar is selected from moieties of the formula: Rs R R, -NHCOR 2 N R 7 R 7 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, RI0, are as previously defined in Claim 79. 135. A compound according to claim 79 wherein I A-B is -CH -N I R 3 is the moiety: CAr wherein Ar is selected from moieties of the formula: 346 R N\ R6NHCOR. R 7 R 7 Y is NH; and Ra, Rb, R 0 R1, R2, R3, R4, R5, R6, R-7, R8, R9, R1O, are as previously defined in Claim 79. 136. A compound according to claim 88 wherein A-B is -CH 2 -N R3 is the moiety: 0 11 -CAr wherein Ar is selected from moieties of the formula: R\ 6 NHCOI 2 10R77 and Y, Ra, Rb, Rc, R1, 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 -CI-i2-N Y is and 347 Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 138. A compound according to claim 88 wherein A-B is N I R 3 Y is 0; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 139. A compound according to claim 88 wherein I A-B is C N R3 Y is NH; and Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 140. A compound according to claim 88 wherein I A-B is -CHL--N R3 R3 is the moiety: 0 II -CAr wherein Ar is selected from moiez-ies of the formula: 348 Rs Rs R, NHCOR 2 N R 7 R 7 Y is and Ra, Rb, Rc, R 1 R2, R3, R4, R5, R6, RT, R8, R9, R 10 are as previously defined in Claim 88. 141. A compound according to claim 88 wherein I A-B is CH2 N R3 R3 is the moiety: 0 II -CAr wherein Ar is selected from moieties of the formula: R Rs R\ -NHCOR 2 N R7 R7 and Y is NH; Ra, Rb, Rc, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, are as previously defined in Claim 88. 142. A compound according to claim 88 wherein I A-B is CH- N R3 is the moiety: 349 350 O II -CAr wherein Ar is selected from moieties of the formula: RS RS R6 -NHCOR 2 N R7 R 7 and Y is O; Ra, Rb Re, R 1 R2, R 3 R 4 R5, R6, R7, R 8 R9, R10, R 25 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 o1 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 143,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 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 faIiluire liver cirrhosis, nephrotic syndrome, central nervous system injuries, lung disease and hyponatremia in a mammal. Dated 24 May, 2002 American Cyanamid Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON