AU1941300A - Tricyclic benzazepine vasopressin antagonists - Google Patents

Description

S&F Ref: 384290D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

S

S

S

S

Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: The following statement is a full performing it known to me/us:- American Cyanamid Company Five Giralda Farms Madison New Jersey 07940 0874 United States of America Jay Donald Albright, Efren Guillermo Delos Santos, Xuemei Du, Marvin Fred Reich and Aranapakam Venkatesan Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Tricyclic Benzazepine Vasopressin Antagonists description of this invention, including the best method of 5845c -1- Title: TRICYCLIC BENZAZEPINE VASOPRESSIN

ANTAGONISTS

1. Field of the Invention This invention relates to new tricyclic nonpeptide vasopressin antagonists which are useful in Streating conditions where decreased vasopressin levels 15 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.

20 2. Backoround 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 V 1 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. V 1 antagonists may decrease systemic vascular resistance, increase cardiac output and prevent 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. Vi 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 cAMP-mediated incorporation of water pores into the luminal surface of 15 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 20 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 of water retention.

The following prior art references describe peptide vasopressin antagonists: M. Manning et al., -3- J. Mad. Chem., 35, 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 -DrUg News and Perspective, 217, (May) (1991). P.D.

Williams et al., have reported on potent hexapeptide oxytocin antagonists Med. Chem., 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to V 1 and V 2 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., Br. 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-A1 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 25 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., I. Med. Chem. 3919(1992), J. Med. Chem., 6, 3993(1993) and references 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 V, and/or V 2 receptors and exhibit in vivo pressin antagonist activity. The compounds also exhibit antagonists activity of oxytocin receptors.

Summary of the Invention This invention relates to new compounds selected from those of the general Formula 1: '700

A-B

wherein Y is a bond or a moiety selected from -CIIOH, -CI-I-lower alkyl(Cj-C 6 -CH-S-lower alkyl(CI-C 6

-CHNH

2 -CHNH-lower alkyl(CI-C 6 -CH[N-lower alkyl(C 1

-C

6 2 CH- IHN CH-N CH-N -CHOCO-lower alkyl(Cl-C 6

-CHNH(CH

2 )mNH 2

-CHNH(CH

2 )m -NH-lower alkyl(CI-C 6

-CHNH(CH

2 )m-N [lower alkyl(C I-C 6 2

-CHNH(CH

2 )m-S-lower alkyl(CI-C 6

CHNH(CH

2 )m -0-lower alkyl(CI-C 6

~OH

low r Iyi(C 1

-C

6 S, 0, -NH, -N-lower alkyl(CI-C 6 -NCO-lower alkyl(C 1

-C

6 m is an integer of 2 to 6; A-B is a moiety selected from

(CH

2 and N- (CH2)- 13 13 R R3 wherein n is an integer 1 or 2 provided that when Y: is a bond, n is 2; and the moiety: represents: an unsaturated 6-membered heterocyclic aromatic ring containing one nitrogen atom, optionally substituted by one or two substitutents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy S" 10 or (C1-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, or S; and the moiety: C 0

E

represents: an unsaturated 6-membered heterocyclic 15 aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Cl- C3)lower alkoxy or (C1-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent 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 -6optionally substituted by (Cl-C3) lower alkyl, halogen, or (Cl-C3)lower alkoxy;

R

3 is -COAr, wherein Ar is a moiety selected from the group consisting of:

R

R R6 R N and 6 S R -N a a wherein X is selected from 0, S, -NH, -NCH3 and -NCOCH3;

R

4 is selected from hydrogen, lower alkyl(Cl-C3),

-CO-

lower alkyl (C1-C3), Rl and R 2 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3) lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -7- R R RR Fb 1a 21a Ia I a I -NCOAr', -CONAr', -NCOCH 2 Ar, -NCONAr',

R

-CH 2COAr' -NCO-(CH 2 CYCloal kyl Ra R R a 1

I

-N-SO

2 7 N- SO 2 CH 2

RR

a -N -P o e /l y 3 C. s r h or br nc ed S -N--lower alkyl(C -C 8 )straight or branched, a i *-N-C-O-lower alkyl(C 3 C)straight or branched, aS -owerI o e alkl 3

-C

8 s(rC3ght orranhed, rachd *1 -N-C-lower alkenylC-C)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or (CH)q N~R ~(CH 2 )q-ND C2)q -N2

CH

2 )qN 0 S

S

S

SS

alkyl(C1-C 3 -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: Rb wherein J is Ra, lower alky1(C3-C8) branched or unbranched, lower alkenyl(C 3

-C

8 branched or unbranched, 0-lower alkyl(C3-c 8 branched or unbranched, -0-lower alkenyl(C 3

-C

8 branched or unbranched, tetrahydrofuran, tetrahydrothionhene, and the moieties: R

C)

R 8 I 0 or -CH2-K' wherein K' is (Cl-C3) -lower alkoxy, halogen, tetrahycirofuran, tetrahydro-thiophene 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, (C1-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -C02lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula:

R

COCHAr' wherei n R i s select ed fromn halogen, C3) lower alkyl, -0-lower alkyl(C 1 -C 3 0-I, -0-C-lower alkyl(CI- C 3 S-lIow er al kyl (Cl-0C 3 R RRb 2)O(RH 2 2 Rb wherein Ra and Rb are as hereinbefore defined; (di) a moiety of the formula: -M-Rd wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C 8 (CH2)p-cycloalkyl(C 3 when M is 0, S, NH, NCH 3 and the moiety -M-Rd wherein Rd is selected from the moieties: 2)p (CH 2 )p- (CH 2)p wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: R 5 R8 a. a a and -11wherein W' is selected from O, S, NH, N-lower alkyl(C1- C3) NHCO-lower alkyl(Cl-C3), and NSO2lower alkyl(C1-C 3

R

7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(Ci-C3)12, -OCF3, -OH, -CN, -S-CF 3 -NO2, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C3), -0-CO-lower alkyl (Cl-C3) and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(Cl- C3), -NH-lower alkyl (C1-C3), -N-[lower alkyl(C1-C 3 2 -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION 15 Within the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R 3 is the moiety: 0 -C-Ar 20 and Ar is selected from the moiety:

R

R

6

R

7

R

wherein Ra, Rb, R 1

R

2

R

5

R

6 and R 7 are as hereinbefore defined.

Especially preferred are compounds wherein R 3 is the moiety: -12- -C-Ar and Ar is selected from the moiety: R

R

6 is

S.

9 9

S

*SS*

*5

S

59 R Ra I a Ia -NCOAr', -CONAr',

R

I a

-NCOCH

2 Ar', R R -NCONAr', CH 2 CMAC, -NCO-(CH 2 cyci oai kyl; wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Rat Rb, Rl, R 2

R

5

R

6

R

7 as hereinbefore defined; and Ar' is selected from the moieties: R'1 0 wherein R 8

R

9 R1 0 and W' are as hereinbefore defined.

Also especially preferred are compounds wherein Y is CH2, -CHOH, -CHNH2, -CHNH-lower alkyl (Cl- -13- C3), -CHN~lower alkyl(Cl-C3)]2 and -CR0-lower alkyl(cl- C3); and Ra, Rb, Rl, R 2

R

4

R

5

R

6

R

7

R

8 and R 9 are as hereinbefore defined.

The most preferred of the compounds of Formula I are those wherein Y is CR2, -CHOR, -CHNR2, -CHNII-lower alkyl (Cl-C 3 -CRN~lower alkyl (Cl-C3)]2 and -CR0lower alkyl (Cl-C3);

R

3 is the moiety 0 11 -C-Ar Ar is selected from the moieties: *5 :R

R

7

N

R

6 is R R R R a ia b -NCOAr', -NCOCH Ar', -NCONAr', Ra 2 cyci oal kyl (CR2)n-cycloalkyl wherein cycloalkyl is defined as (C3- C6) cycloalkyl, cyclohexenyl or cyclopentenyl; Ra, Rb, Rl, R 2

R

5

R

7 are as hereinbefore defined; and Ar' is a moiety: -14-

SN"

wherein R 8

R

9 and R 10 are as previously defined.

The most highly broadly preferred of the compounds of Formula I are those wherein Y is a bond or CH2, -CHOH, -CHNH2, -CHNH-lower alkyl(C1-C3), -CHN(lower alkyl(C1-C3)]2 and -CHO lower alkyl(C1-C3), wherein the moiety: 4 :is an unsubstituted or substituted thiophene, furan, 4 on *membered aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms.

Ra, Rb, R

I

R

2

R

4

R

5

R

7

R

8

R

9 and R1 0 are as previously defined;

R

3 is the moiety:

QE

is an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms; a 5membered aromatic (unsaturated) heterocyclic ring having 15 one heteroatom selected from 0, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms.

Rag Rb, R 1

R

2

R

4

R

5

R

7

R

8

R

9 and R 1 0 are as previously defined;

R

3 is the moiety: 0 1I -C-Ar wherein Ar is: R 6 and R 6 is selected from the group 0e C.

I S 0 0

S

5 *000 e.g.

6* 0@ C See...

C

R R ,a b -NCONAr', -NCOAr', -CONAr', -NCOCH 2 r,

H

2 CAr', -NCO-(CH )n-cycloalkyI -%VR; where Ar' is selected from the group S. I

S.

0ee0

S

e.g.

0e S.

0e 0

S

S. 0 5* and W' and cycloalkyl are as previously described.

More particularly preferred are compounds of the formula: -16- R 2

R

3 wherein D is -CH or N;.

R

3 is the moiety: 0 11 -C-Ar 5 wherein Ar is selected from the moieties:

R

-R6 R

R

6 is

R

I a -NCOAr',

CF

2 CQ~r', R R I ra CONAr',

-NCOCH

2

RPR

ia b -NCONAr',

-NCO-(CH

2 -cycloalkyI and Ar' is selected from the moieties: -17wherein Ra, Rb, Rl, R 2

R

5

R

7

R

8

R

9

R

1 0 cycloalkyl and W' are as hereinbefore described.

Also particularly preferred are compounds of the formula:

S

wherein D is -CH or N;

R

3 is the moiety: R 3 0 11 -C-Ar wherein Ar is selected from the moieties:

R

R 6 R 6

N

R

6 is -18- R R ia b -NCONAr', -NCOAr', -CONAr', -NCOCH 2 r,

H

2 CAr', -NCO-(CH 2 cycl oaikyI M- Ar' is selected from the moieties:

R

N

wherein Ra, Rb, Rl, R 2

R

5 1 R 6

R

8

R

9 RIO, cycloalkyl M, Rdj, and W' are as hereinbefore described.

More particularly preferred are compounds of the formulae: 27N and 1R

R

3 wherein Y is selected from -CH2, -CHOH, -CHNH2, -CHNHlower alkyl(Cl-C3), -CHN[lower alkyl(Cl-C3)]2 and -CHO lower alkyl(Cl-C3); and the moiety: Q

E

-19represents: an unsaturated 6-membered heterocyclic aromatic ring containing one nitrogen atom, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one hetero.tom selected from O, N or S; a 5-membered aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alkyl, halogen, or (C1-C3)lower alkoxy;

R

3 is the moiety:

O

O

*II

-C-Ar wherein Ar is the moiety: 5

RR

6 or R

R

R

6 is S. R R R Ia a -NCOAr', -NCOCH 2 Ar'. NCQ CH 2 n cycl oal kyl wherein Ra is independently selected from hydrogen or CH3; Ar' is selected from the moieties:

R

8 aR

R

9

R

R W N wherein R 1

R

2

R

5

R

7

R

8

R

9 R1 0 and W' are as hereinbefore described.

Also particularly preferred are compounds of the formulae: R E R E RN and R 3 R 3 wherein Y is selected from -CH2, -CHOH, -CHNH2, -CHNHlower alkyl(C1-C3), -CHN[lower alkyl(C1-C3)12 and -CHO lower alkyl(C1-C3); and the moiety: 0E :represents: an unsaturated 6-membered heterocyclic aromatic ring containing one nitrogen atom, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from N or S;

R

3 is the moiety: -21- 0 1I -C-/Ar wherein Ar is selected from the moieties: R 5 I and

R

6 is R R RRtl I aIaI a a I -NCOAr', -CONAr', -NCOCH 2 Ar', -NOONAr', Rb CH 2 00Ar', -NC0-(CH 2 cycoalkyl Ra is independently selected from hydrogen, -CH3 or- C2H5 and Ar' is selected from the moieties: R N wherein Rl, R 2

R

5

R

7

R

8

R

9 and R 1 0 are as hereinbefore defined.

Compounds of this invention may be prepared as shown in Scheme I by reaction of azepine derivatives of Formula I. with a substituted or unsubstituted 4-nitrobenzoyl chloride Aa or a substituted or unsubstituted 6aminopyridine-3-carbonyl chloride -412 to give the inter- -22mediate 5a and 5b. Reduction of the nitro group in intermediate 5 gives the 4-aminobenzoyl derivative 6a and the 6-aminonicotinoyl derivative 6b. The reduction of the nitro group in intermediate 5 may be carried out under catalytic reduction conditions (hydrogen-Pd-/C; Pd/C-hydrazine-ethanol) or under 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 compatability with the preservation of other func-tional groups in the 9; molecule.

Reaction of compounds of Formula J with aroyl 15 chloride or related activated aryl carboxylic acids in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine and diisopropylethylamine or pyridine and the like, affords the com- 20 pounds 8 which are vasopressin antagonists.

9.

o oo* -23- Schee 1 4 a) A=CH 4 b) A=N

A=CH

A=N

NO2 2 -24- Scheme 1 (cont'd)

(C

3 C,)aIkyl CCCI

(C

3 al k ylI- 0- CCUI

C

3 C,)aI kenyl CCCI (0C3- C,)aI kenyl C) CCA (0 3- al k yI- SO 2

CI

(03- 08) al k enylI SO 2

CA

6a) A=CH 6b) A=N

S

S.

S

S

S

S.

R

-fCH 2 S0 2

CI

R

2 Ar'COCI Ar'CH 2

CCCI

cyci oal kyl (CH 2 )nCCCI Ar'NCOCI R

R

8a) A=C

T

6 8b) A=N R Reaction of tricyclic derivatives of Formula with either a carbamoyl derivative .2 or a isocyanate derivative 12j gives compounds (Scheme 2) of Formula 11 which are vasopressin antagonists of Formula I wherein

R

6 is -NHCO NAr'

RO

o r R b O=C=NAr a..

0 9*q* *000 a a 0* a a.

4* a *0 a.

zo

YQE

2 'nN:) NHCQ'4Ar' 1i1a) A=CH 1 1 b) A=N 1 1 R b Reaction of tricyclic derivatives of Formula with arylacetic acids, activated as the acid chlorides IJ2, anhydrides, mixed anhydrides or activated with known activating reagents, gives compounds j1. (Scheme 3).

0 -26- 0

I--H

2 Ar' 12a et 0s 0 @00#00 a 0*0* p 0@ 0@ 0 4 0 4 1 3 a) A=CH 1 3 b) A=N NHCOCH 2 Ar' 6. a The compounds of Formula I wherein Y, Rl, R 2 Rand R 4 are as defined and the moiety: Q

E

is as previously defined and the Ar' moiety is: -27and R 1 0 is -NH lower alkyl(C1-C3) and -N-[lower alkyl(C1-C3) ]2 may be prepared, as shown in Scheme 4, by reacting the tricyclic derivatives _a and 6b with a pyridinecarbonyl chloride 14 to give the derivatives The derivatives 15 are reacted with the appropriate mono alkylamines or dialkylamines to give vasopressin antagonists of formulae 1.

S -28- 0 cl G N CI (F) 14

R

2 R2" 5a) A=CH 1 5 b) A=N -C1(F) 16a) A=CH 16b) A=N -29- The compounds of Formula I wherein E, Y, R 1

R

2

R

3

R

5 and R 7 are as defined and the R 3 (-COAr) aryl group is

R

R

N

R

7 wherein R 6 is -M-Rd wherein M is O, S, NH, N-CH3 and Rd is as previously defined may be prepared as shown in Scheme 5 by first converting the azepine derivatives 1 into the intermediate 17 and then reacting these nicotinolyl intermediates with derivatives of the formulae: 10 HM-Rd in the presence of a non-nucleophilic base such as N,N-diisopropylethylamine to give products 18. The best results are obtained in the displacement of the halogen in the pyridine intermediates 17, when the halogen atom is a fluoro group. With nucleophilic amines (M=NH, NCH3) the reaction can be carried out with the 6-chloro, bromo or fluoro derivatives 17 in the absence of a a.

non-nucloephilic base; in a non-nucleophilic solvent; or with excess amine and no solvent. With derivatives HORd the 6-fluoro derivative 17 is required 20 for satisfactory conversion of 17 to 18.

Scheme hal ogen- hal ogen halogen C, Br, F

S

S S hal ogen R d -31- Alternatively, the products 18 may be prepared by first forming derivatives of the Formula 1j and then coupling these derivatives with the azepine compounds 3 (Scheme The carboxylic acid intermediates are activated for coupling to the azepine compounds 3 by reaction with peptide coupling reagents, or preferably by conversion to the acid chlorides, anhydrides or mixed anhydrides.

Scheme 6 HD 0

R

R

*I

V M-R, 101 As an alternative method for synthesis of compounds of this invention as depicted in Formula I wherein Ra, Rb, R 1

R

2

R

5

R

7 A, and Y are as previously defined and R 3 is 0

SII

-C-Ar is the coupling of aryl carboxylic acids 20 with the azepine derivative (Scheme 7) The aryl carboxylic acids are activated for coupling by conversion to an acid chloride, bromide or anhydride or by first reacting with an activating reagent such as N,N-dicyclocarbodiimide, diethyl cyanophosphonate and related "peptide type" activating reagents. The method of activating the acids 20 for coupling to the azepine derivative 3 is chosen on the -32basis of compatibility with other substituent groups in the molecule. The method of choice is the conversion of the aryl carboxylic acid 20 to the corresponding aroyl chloride. The aryl acid chlorides 21 may be prepared by standard procedures known in the art, such as reaction with thionyl chloride, oxalyl chloride and the like.

The coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydrofuran, dioxane in the presence of pyridine or tertiary bases such as triethylamine and the like (Scheme 7) Alternatively, the aroyl chlorides, prepared from the aryl carboxylic acids 20 may be reacted with derivatives 3 in pyridine with or without 4- (dimethylamino)pyridine to give derivatives 22.

15 In general, when the aryl carboxylic acids are activated with N,N-carbonyldiimidazole and other "peptide type" activating reagents, higher temperatures are required than when the aroyl chlorides are used.

The reaction may be carried out in a higher boiling 20 solvent xylene or without a solvent (100 0 C to 150 0

C)

The activation of aryl carboxylic by conversion to the acid chlorides with thionyl chloride or e oxalyl chloride is preferred since the more reactive aroyl chlorides give better yields of product. The synthesis of selected examples is illustrated in Scheme 7.

o *e -33- Scheme 7 ArC-OH -kArC-Cl 21 wherein Ar is as previously defined activating" reagent 4* a a a a. a.

a Yr R2z

N

Ar 2 Ar'CH 2 CN I

A:

Ra R7 Ar ArCON cycloalkyl(CH) c Ra R7 Ar'C(DH~- Ar'-NCON H A RRb7 Rd M

A

A:

7 r'-N CO

R

a -34- The synthesis of compounds of Formula I wherein R 3 is 0

II

-C-Ar the Ar group is

R

s 5 R

R

6 is -CO. -Ar' and where Ar' is as previously defined is carried out according to Scheme 8. The azepine compounds are 10 reacted with mono-methyl terephythalyl chloride 23 (prepared from mono-methyl terephthalate and thionyl chloride) in the presence of a tertiary base such as triethylamine in solvents such as dichloromethane, tetrahydrofuran, dioxane, toluene and the like to give 15 derivatives ZA. These ester intermediates 24 are hydrolyzed with two to ten equivalents of an alkaline hydroxide such as potassium or sodium hydroxide in aqueous methanol or ethanol to give the corresponding acids after acidification and workup. The free acids are converted to the acid chlorides with thionyl chloride and these acid chloride intermediates reacted with aminoaryl derivatives of formula: Ar'- NHR 8 wherein Ar' and Ra are as previously defined to give compounds 2.2.

S. OS F; 4;

S

S

5555 .555 Sn.

S S OS S

S

55*555

S

.55.

.55.

S*SS

*S S S S "5

S

5555

SS

S S 0 55 @5 5 -36cI 0 UI-1t

RY

2 3 u 0

N

R

5

R

R _R Z(O 2)SOCI 2

RR

R

5 7 0E

N

R

7 Ar. S I-R57 II-R N-Ar' -37- Certain of the tricyclic azepines as exemplified by compounds 33-35 are prepared through an initial ring closure of inter-mediate acyclic derivatives 30 followed by formation of the third ring through the use of literature procedures (Scheme 9) Ring closure of acyclic derivatives of structural type 30 wherein the nitrogen atom is pro-tected with a p-toluensulfonyl group may be ring closed to give the 0-keto esters 31 which exist in the enol form as shown (structure 31) Decarboxylation gives intermediates 32 which by literature procedures are converted to the tosyl protected tricyclic azepines 31-35. The tosyl protecting group in the derivatives, as exemplified by tricyclic azepines 33-35, can be removed as described in the literature Carpenter and M. Lennon, J. Chem.

Soc. Chem. Comm; 665, 1979) for sulfonamide cleavage of benzazepine derivatives.

oo*oo ooo *oooo Sol THONHO 0 oI- JO

N

loso

I

VHOOO/ 1 a2 OOTHO) JO

-HN

~cOz

HOC

6 GWOPS *-39- Scheme 9 (cont'd) 1)Br 2 S

NH

2 CH NH NH

II

2) NH 2 NH 2 CH3 Tos Tos Tos 3: U Certain intermediate azepines with a fused heterocyclic ring, as exemplified by structure AA, which are useful in preparing the intermediate tricyclic azepines necessary for the synthesis of the vasopressinoxytocin antagonists of this invention may be prepared ee as illustrated in Scheme 10. Standard chemical reactions and conditions are used to convert the azepinones of structural type AA into the tricyclic 10 azepines of formulae 47-50 (via intermediates and As shown in Scheme 10, expansion of a sixmembered ring into a seven-membered lactam is carried out by reaction of the ketone derivative 3j with hydroxyl amine to give the oxime derivative which in most cases exists as a mixture of syn and anti forms (structures gi and The mixture of oximes on reaction with 4-methylbenzenesulfonyl chloride gives either a mixture of oxime Q-tosylates or in some cases a single Q-tosylate 39. Heating the oxime Q-tosylates with potassium acetate in a alcohol-water mixture (such as ethanol-water or n-butanol-water) gives the 7membered lactam derivatives l1. Reduction of the-lactam with borane, or lithium aluminium hydride (LAH) affords the fused heterocyclic azepines 42. The azepines AZ may be converted to intermediates 43 and 44, which are useful in the preparation of the novel compound of this invention. As hereinbefore stated, the heterocyclic azepines of structural types illustrated by formulae may be prepared by the methods exempli-fied in Scheme or literature methods for ring closures to azepines.

e -41- Scheme

RR

zO

NI-{

2 zO.

0 Fe 11 C t-O-SOP KOAc R R8 ~t 0 1

-H*

2

R

ZO

2 R Nvrs Ri1 zO FTsON LAH BH H ~cool

R

7

-A

A OH; N KW 04A IN)2 -42- Scheme 10 (cont'd) R 0 Ri11 L- 44 N2 as..

a S S aa a a

S

20 R

CN(H

2 1 R Iower alkyl 2 R Cl,Br, CN, C0 2 0H 3 CH 2CHO -N2 R 23=H, Iow eral kyl, C, -NH 2 -43- Scheme 10 (cont'd) R24

J,

'9 9* 49 B CH, N G=O, S

R

2 4 lower alkyl G O, S, N R lower alkyl, CO 2

CH

Certain of the compounds of this invention wherein Ra is as previously defined are prepared by introduction of the Ra group either in a final step or in the penultimate step as shown in Scheme 11. In the derivatives 51 introduction of the Ra substituent (Ra not H) may be carried out in the final step by first forming the anion of the amide function of derivative l5 followed by the appropriate alkylation of the nitrogen atom to give 10 products 52. In derivatives where protection-deprotection is needed the derivatives 51 are converted to the protected intermediates 52a and 52h which on deprotection afford compounds 52. The R 27 group may be a tertiary butoxy carbonyl group, an acetyl group or other known amine protecting moieties. The R 2 8 group may be a tertiary butylcarbonyl group, an acetyl group or other known hydroxy protecting moieties.

-44- Scheme 11

N

NHR 26

QE

1 NaH 2) R aCA(Br or 1) Ra(fot H) 26 R- N-R a a. R b R 26 CC)Ar;-OC~fH 2 A; Ar;

-CXXCH

2 ),,cyc oalkyI ;-CXXHAr';

R

-SQ

2 1 2

R

SqCH2 R2 -I I)

R

II j -C0 2 1ow er al kyl(- C 8 R 2 COowe r a]lky I( 3

C

8

-SO

2 1Iower a]lkyl (C 3

C

8 -0-Iower alkenyl(C 3 -CXlower aikenyl(Cd 8 Sq 2 Iow er a]ikenyl (C 3 C8) 1) NaH R7-N- (CH2)q -CI (Br or 1) R 27=t-Boc Ac 5.2a 27b R a=R -N-(WH Ra= RbN"iQH 2 q 51 1)NaH 28 R? -OGjCH 2 1 2 -CH 2 CI (Br or 1) 28 Ra=R -0C (OH 2 1 2

H

2 Compounds of this invention represented by the formula 59. may be prepared from the compounds repre- -46sented by those of formula 58 as shown in Scheme 12.

The 6-chloro, bromo or fluoro intermediate 17 is reacted with an amino derivative of the formula RaNH2 wherein Ra is as hereinbefore defined to give compounds of the formula 58. Reaction of the 6-aminonicotinoyl derivative 51 with an R 26 -chloride wherein R 2 6 is defined as shown in Scheme 12 affords compounds of this invention as exemplified by formula 59.

*a e oo* *o -47-

S

Scheme 12 y

O

N=

R RNH 2 hal ogen(CI ,Br, F)

N

N'

NH

R

a

S.

Rb

R

2 =COAr' -COH Ar'; -CCNAr'.

CO(CH )ccoalkyI -COCHAr' y -N ZO

QE

1R 26 0 11 -C0 2 -l1ow er al kyl (C 3

C

8 -CO Ilow er al kyl (C 3 08) -so0 2 low er al kyl (C 3 C8) c0 2 -l1ow er al kenyl (C 3

C

8 -C MlIow er al kenyl (C 3

C

8 -so0 2 lower alkenyl(C 3 Ca) -48- Reference Example 1 6.7-Dihvdrobenzo[blthiophen-4 (5H)-one, Oxime To a solution of 4-keto-4,5,6,7-tetrahydrothionaphthene in 260 ml of ethanol is added 27.4 g of hydroxylamine hydrochloride. To the mixture is added 16.5 g of sodium acetate and 66 ml of water and then the mixture is refluxed for 3.5 hours; chilled in an ice bath and filtered. The solid is washed with water and ethanol to give 13 g of solid which is dried at 65 0

C

under vacuum to give 11.7 g of crystals, m.p. 124-126 0

C

(mainly one isomer syn or anti). The filtrate is concentrated under vacuum and extracted with 250 ml of dichloromethane. The extract is washed with 100 ml each of water, brine and then dried (Na2SO4). The solvent is 15 removed and the solid dried at 65 0 C under vacuum to give 32 g of crystals, m.p. 106-109 0 C (mainly one isomer syn or anti).

Reference Examole 2 6.7-Dihvdrobenzol[bthiophen-4 (5H)-one, Oxime-O-tosvlate 20 To a stirred solution of 12.2 g of 6,7-dihydrobenzo[b]thiophen-4 (5H)-one, oxime (mixture of isomers) in 26 ml of dry pyridine is cooled to 0 0 C is added 15.3 g of p-toluenesulfonyl chloride (all at once). After 5 minutes, a solid separates and the mixture is stirred at 0°C for 1 hour. To the cold mixture is added 195 ml or 2N HC1 and the mixture filtered to give a solid which is washed with water and dried (under vacuum) to give 21.5 g of product as crystals, m.p. 117 0 -120 0

C.

Reference Example 3 5.6,.7.8-Tetrahvdro-4H-thienof 3 A mixture of 21.45 g of 6,7-dihydrobenzooxime-Q-tosylate, 136.1 g of potassium acetate, 528 ml of ethanol and 904 ml of water is refluxed for 22 hours. The mixture is concentrated under vacuum (to remove ethanol), chilled and filtered S-49to give a solid. The solid is washed with water, dried (in air) and recrystallized by dissolving in hot ethyl acetate and diluting the solution with hexane. Chilling and filtering gives 7.1 g of crystals, m.p. 128 0 -132 0

C.

Reference Example 4 5.6,7. 8-Tetrahvdro-4H-thienof3.2-blazepine To a mixture of 4.54 g of lithium aluminum hydride in 400 ml of dry tetrahydrofuran under argon is added dropwise a solution of 10.0 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one in 200 ml of tetrahydrofuran. After the addition, the mixture is heated at 45 0 -50 0 C (exothermic reaction), and cooled to room temperature. The mixture is chilled in an ice bath and 4.5 ml of water added dropwise over 1 hour, 15 followed by the dropwise addition of 4.5 ml of 2N sodium hydroxide and the dropwise addition of 14 ml of water.

The mixture is filtered through diatomaceous earth and the filter cake washed with tetrahydrofuran. The filtrate is concentrated to.give a solid. The solid is crystallized from hexane to give 5.5 g of off-white crystals, m.p. 66-68 0

C.

To a mixture of 21.2 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b)azepin-5-one in 100 ml of tetrahydrofuran under argon, chilled to 0°C is added 25.2 ml of a 10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The solution is stirred at room temperature for 16 hours and is refluxed for 5 hours.

S. The mixture is cooled to room temperature and 85 ml of methanol added dropwise (exotherm). The solvent is removed and 100 ml of methanol is added (2 times) and after each addition the solvent is removed. To the residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted with dichloromethane.

The extract is dried (Na2SO4) and the solvent removed to give 15.4 g of brown solid, m.p. 55 0 -57 0 C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p. 64 0 -65 0

C.

Reference Example 4-(4-Nitrobenzovl)-5.6.7.8-tetrahvdro-4H-thienof3.2-blazepine To a solution of 10.71 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic).

The mixture is stirred for 3 hours at 25 0 C and then washed with water, sodium bicarbonate solution, brine and dried (Na2S04). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling 15 overnight and filtering gives 16 g of light brown crystals, m.p. 141 0 -142 0

C.

Reference Example 6 S4- (4-Nitrobenzovl)-4.5. 6.7-tetrahvdro-8H-thieno 3.2-blazepin-8-one To a solution of 9.0 g of 4-(4-nitrobenzoyl)- 5,6,7,8-tetrahydro-4H-thieno[3,2-b)azepine in 713 ml of acetone is added 6.74 g of MgS04 and 351 ml of water followed by 8.2 g of KMnO4 and heating at 70 0 C for 18 hours. Another 6.24 g of MgS04 and 8.2 g of KMn04 is 25 added and heating continued at 70 0 C for 8 hours. An additional 6.24 g of MgSO4 and 8.2 g of KMn04 is added and heating continued at 70 0 C for 18 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with acetone and 500 ml of methylene chloride. The combined filtrates are evaporated in vacuo to a residue which is washed with water and air dried to give 5.7 g of a solid. The solid is crystallized from ethyl acetate to give 5.1 g of off white solid, m.p. 184-186 0

C.

-51- Reference Example 7 4-(4-Aminobenzovl)-4,5.6.7-tetrahydro-8H-thieno 3 .2-b1azepin-8-one To a mixture of 2.0 g of 4-(4-nitrobenzoyl)- 4,5,6,7-tetrahydro-8H-thieno[3,2-b]azepin- 8 -one in 40 ml of glacial acetic acid is added 20 ml of 6N-hydrochloric acid. The mixture is cooled and 3.53 g of iron powder added in portions. The mixture is allowed to warm to room temperature and is heated at 70-80 0 C for 1 hour and then cooled to 0°C. To mixture is basified with NaOH (pH 14) and extracted with 200 ml of ethyl acetate.

The aqueous layer is again extracted with 200 ml of ethyl acetate and the extracts combined. The combined extract is washed with 100 ml each of H20 and brine and 15 dried (Na2SO4). The extract is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to give a solid which is crystallized from ethyl acetate-hexane to give 1.24 g of crystals, m.p.

216-218 0

C.

Reference Example 8 2-Chloro-4-(4-nitrobenzovl) 6. 7. 8-tetrahvdro-4Hthienof3.2-blazepine A solution of 6.04 g of 4-(4-nitrobenzoyl)- "5,6,7,8-tetrahydro-4H-thieno(3, 2 -b]azepine in 40 ml of tetrahydrofuran is cooled to 0 C and 5.34 g of N- Schlorosuccinimide added in portions. After the addition, the mixture is heated at 70 0 C overnight. The mixture is concentrated, diluted with 300 ml of dichloromethane and the mixture washed with 100 ml each of saturated K2C03 solution, H20, IN HCI and brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the residue chromatographed by HPLC on silica gel (2-columns) with a Waters-Prep-500 instrument and the solvent system ethyl acetate-dichloromethane containing 2% diethylether. The middle cuts are -52combined and concentrated to give 0.135 g of 2,3-dichloro-4- (4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno- [3,2-b]azepine, m.p. 140 0 -142 0 C. The latter cuts are combined, concentrated and the residue crystallized from ethyl acetate-hexane to give 2.8 g of crystals, 1190- 120 0

C.

Reference Example 9 2-Chloro-4-(4-nitrobenzovl)-4.5.6.7-tetrahvdro-8Hthieno[3.2-blazepin-8-one To a stirred solution of 0.336 g of 2-chloro- 4-(4-nitrobenzoyl)-4,5, 6,7-tetrahydro-4H-thieno[3,2b]azepine in 36 ml of acetone-water is added 0.21 g of anhydrous magnesium sulfate and 0.275 g of potassium permanganate. The mixture is heated at 70 0

C

15 overnight. An additional 0.275 g of potassium permanganate and 0.21 g of magnesium sulfate is added and the mixture heated at 70 0 C for 6 hours. An additional 0.275 g of potassium permanganate and 0.21 g of magnesium sulfate is added and the mixture stirred 20 and heated at 70 0 C for 24 hours. The hot mixture is filtered and the filtrate evaporated. The residue is s'ee heated in a few ml of ethyl acetate, cooled and filtered to give 0.20 g of product as a solid. The reaction is repeated on 10 times the scale to give 1.3 g of off- °go 25 white crystals, m.p. 165 0 -168 0

C.

Reference Example Methyl 4- 2-(2-chlorophenvl)-2-cvano-2-(4moroholinvl)ethyl benzoate A 0.876 g sample of 60% sodium hydride in oil is washed with hexane followed by the addition of 60 ml of dry N,N-dimethylformamide. The reaction mixture is stirred for 1 hour under argon at room temperature after the addition of 4.73 g of a-(2-chlorophenyl)-4-morpholineacetonitrile. To the reaction mixture is added 4.58 g of methyl 4-(bromomethyl)benzoate and stirring continued for 3 hours. Several drops of acetic acid is -53added to ice water and the reaction quenched. The pH is 3-4 and saturated NaHCO3 added to adjust the pH to 6-7.

Upon cooling a solid forms which is filtered, washed with water and dried to give 5.92 g of yellow solid.

Crystallization from methylene chloride-hexane gives 2.10 g of the desired product as a crystalline solid, m.p. 116-118 0

C.

Reference Example 11 Methyl 4-f2-(2-chloroThenyl)-2-oxoethvllbenzoate A mixture of 1.0 g of methyl [4-(2-chlorophenyl)-2-cyano-2-(4-morpholinyl)ethyl]benzoate and 14 ml of acetic acid and 6 ml of water is heated at reflux for 20 minutes then poured over crushed ice. After stirring for 15 minutes, the resulting solid is collect- 15 ed, washed with water and air dried to give 0.63 g of tan solid, m.p. 40-42 0

C.

Reference Example 12 4-f2-(2-Chlorophenvl)-2-oxoethvllbenzoic acid A mixture of 18.78 g of methyl 20 chlorophenyl)-2-oxoethyl]benzoate in 288.8 ml of 72.2 ml of water and 5.2 g of NaOH is refluxed for 3 hours then acidified with 2 N citric acid. The reaction ~mixture is evaporated in vacuo to remove the CH30H. The aqueous phase is extracted with CH2C12 and acidified with 1 N HC1. The resulting solid is collected and dried under vacuum to give 17.27 g of the desired product, m.p. 168-172 0

C.

Reference Example 13 Methyl 4.5.6,7-tetrahvdro-4-oxo-3-benzofurancarboxvlate To a solution of 2.11 g of 4-oxo-4,5,6,7tetrahydrobenzo(b]furan-3-carboxylic acid in 100 ml of methanol is added 202 mg of p-toluenesulfonic acid hydrate and the mixture heated at reflux for 24 hours.

The reaction mixture is cooled to room temperature and the methanol concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and -54washed with 30 ml of saturated sodium bicarbonate and ml of brine. The organic layer is dried with Na2SO 4 filtered and the filtrate concentrated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 1.75 g of the desired product as a white crystalline solid, m.p. 100-102 0

C.

Reference Example 14 Methyl 5.6.7.8-tetrahvdro-5-oxo-4H-furo[3.2-blazepine-3carboxvlate To a mixture of 1.0 g of methyl 4,5,6,7tetrahydro-4-oxo-3-benzofurancarboxylate and 502 mg of sodium azide in 5 ml of chloroform is added dropwise at 32-36 0 C under argon 1.4 ml of sulfuric acid. The reaction mixture is stirred at room temperature for 24 15 hours. The reaction mixture is diluted with 14 ml of water and rendered alkaline with NH40H and extracted with chloroform. The separated organic layer is washed with water, brine and dried with Na2SO4 and concentrated in vacuo to give 1.0 g of the desired product as a white 20 solid.

Reference Example 4,5.6.7-Tetrahvdro-4-f f(4-methylphenl)sulfonylloxyliminol-3-benzofurancarboxylic acid To a partial solution of 2.8 g of 4,5,6,7-tetrahydro-4-(hydroxyimino)-3-benzofurancar- S* boxylic acid in 7 ml of pyridine is added portionwise at 0°C, 3.01 g of p-toluene sulfonyl chloride under argon.

The mixture is stirred for 1 hour then diluted with ml of cold 1 N HC1, filtered, washed with water and dried with Na2SO4. The filtrate is concentrated in vacuo to give 4.78 g of the desired product as an offwhite solid, m.p. 155-165 0

C.

Reference Example 16 5.6.7.8-Tetrahydro-5-oxo-4H-furo[3.

2 -blazeDine-3carboxvlic acid A mixture of 1.0 g of (E)-4,5,6,7-tetrahydro- 4-[[[(4-methylphenyl)sulfonyl]oxy]imino]-3-benzofurancarboxylic acid, 5.9 g of potassium acetate, 23 ml of ethanol and 39 ml of water is heated at reflux for 48 hours. The reaction mixture is concentrated in vacuo, ml of methylene chloride added and the separated organic layer washed with water, brine and dried with Na2SO4. The organic layer is concentrated in vacuo to a solid which is purified by chromatography on a preparative silica gel plate by elution with 0.5% acetic acid in ethyl acetate. The eluted band is washed with 15 1% acetic acid in ethyl acetate. The organic layer is :dried with Na2SO4 and concentrated in vacuo to give 200 mg of off-white solid which is crystallized from ethyl acetate-hexane to give 165 mg of the desired product as a white solid.

Reference Examle 17 and 5 6. 7-Tetrahvdro-- (hydroxyvimino)-3benzofurancarboxvlic acid To a solution of 30.0 g of 4,5,6,7-tetrahydro- 4-oxo-3-benzofurancarboxylic acid in 225 ml of ethanol S" 25 is added 22.97 g of hydroxylamine hydrochloride, followed by 18.10 g of sodium acetate and 55 ml of water. The reaction mixture is heated at reflux for hours and concentrated in vacuo to a residue which is diluted with 600 ml of ethyl acetate, washed with 2 x 200 ml of water, brine and dried over Na2SO4. The organic layer is concentrated in vacuo to a residue which is dried under vacuum to give 31.0 g of the desired product as a solid.

-56- Reference Example 18 and (Z)-6.7-Dihvdro-4-(5H)benzofuranone. 0-F(4methvlohenvl) sulfonyl oxime To a partial solution of 28.0 g of and (Z)-4,5,6,7-tetrahydro-4-(hydroxyimino)benzofuran in 54 ml of pyridine is added portionwise at 0°C, 38.8 g of ptoluene sulfonyl chloride under argon. The mixture is stirred for 1 hour then diluted with 600 ml of ethyl acetate and 400 ml of cold 2 N HC1. The organic layer is washed with 200 ml of water and 200 ml of brine, and dried with Na2SO4. The filtrate is concentrated in vacuo to give 50 g of the desired product as a solid.

Crystallization from ethyl alcohol by allowing to stand at room temperature gives 19.9 g of off-white needles, 15 m.p. 123-125 0 C. The filtrate is allowed to stand and the crystals collected and dried to give 10.0 g of the desired product as an off-white solid, 83-85 0

C.

Reference Example 19 4-(2-Chloro-4-nitrobenzovl)-5.6.7. 8-tetrahvdro-4Hthienof3. 2-blazepine To a solution of 15.0 g of 5,6,7,8-tetrahydro- S" 4H-thieno[3,2-b]azepine in 150 ml of dichloromethane oeo cooled to 0°C is added 27.2 ml of triethylamine. After stirring 5 minutes, a solution of 28.0 g of 2-chloro-4nitrobenzoyl chloride in 140 ml of dichloromethane is added slowly. The solution is stirred at room temperature overnight, diluted with 450 ml of dichloromethane and the solution washed with 200 ml each of water, 2N citric acid, 1 M sodium bicarbonate and brine. The organic layer is dried over Na2SO4, filtered through a thin pad of hydrated magnesium silicate and the filtrate concentrated under vacuum. The residue is crystallized from ethyl acetate to give 24.3 g of off-white crystals, m.p. 131-134oC.

0 -57- Reference Example 4-(2-Chloro-4-nitrobenzovl)-4.5. 6.7-tetrahvdro-8Hthienof3.2-blazeoine-8-one To a solution of 2.02 g of 4-(2-chloro-4nitrobenzoyl)-4,5, 6,7,8-tetrahydro-4ii-thieno 3,2-b] azepine in 144 ml of acetone is added 1.56 g of magnesium sulfate, 72 ml of water and 1.89 g of potassium permanganate. The mixture is stirred and heated at 70-75 0 C for 4 hours. An additional amount of magnesium sulfate (1.56 g) and potassium permanganate (1.89 g) is added and the mixture stirred and heated at 75 0 C for 16 hours. Magnesium sulfate (1.56 g) and potassium permanganate (1.89 g) are added and the mixture stirred and heated at 75 0 C for 5 hours. The 15 mixture is filtered through diatomaceous earth and the filter cake washed with acetone and dichloromethane The filtrate is concentrated and the residue (1.4 g) is heated with ethyl acetate, the mixture (with insoluble solid) cooled and filtered to give 1.0 g of product as a solid. The solid is washed with water and dried to give crystals, m.p. 180 0 -185 0

C.

S"" Reference Example 21 I5-Fluoro-2-methvlbenzovl chloride A mixture of 8.0 g of 5-fluoro-2-methylbenzoic 25 acid and 52 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are removed under vacuum and two times 50 ml of toluene is added and the solvent removed under vacuum to give 8.5 g of product as a gum.

Reference Example 22 2-Chloro-5-(methvlthio)benzovl chloride A mixture of 2.03 g of thio)benzoic acid and 10 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are removed under vacuum and 20 ml of toluene added and removed under vacuum (2 times) to give 2.2 g of brown needles.

-58- Reference Example 23 2-Chloro-4-nitrobenzovl chloride As described for Reference Example 21, 25 g of 2-chloro-4-nitrobenzoic acid is reacted with thionyl chloride (124 ml) to give the product (27.0 g) as a brown oil.

Reference Example 24 chloride As described for Reference Example 21, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an offwhite solid.

Reference Example 2.3-Dimethylbenzovl chloride 15 As described for Reference Example 21, 3.0 g of 2,3-dimethylbenzoic acid is reacted with 40 ml of thionyl chloride to give 3.2 g of the product as a colorless oil.

Reference ExamPle 26 20 2-Chlorobenzoyl chloride As described for Reference Example 21, 3.13 g of 2-chlorobenzoic acid is reacted with 40 ml of thionyl oo chloride to give 3.32 of product as an off-white semi solid.

25 Reference Example 27 4-f(2-Methvlbenzovl)aminolbenzoic acid A mixture of 43.42 g (0.26 mol) of ethyl 4aminobenzoate and 40.8 g (0.26 mol) of 2-methylbenzoyl chloride in 150 ml of dichloromethane is cooled in an ice bath and 26.56 g (0.26 mol) of triethylamine is added dropwise. After the addition, the solution is stirred at room temperature overnight. The mixture is poured into water and the organic layer separated. The organic layer is washed with water, 1 N HC1, 1 M NaHCO3 and dried (Na2SO4). The solvent is removed and the solid slurried with ethyl acetate and filtered to give S-59- 57 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate as crystals, m.p. 110-115 0

C.

A mixture of 50.7 g (0.20 mol) of the preceding compound, 280 ml of ethanol and 55 ml of 10 N NaOH is refluxed for 5 minutes. The mixture is cooled to room temperature, diluted with 200 ml of water and acidified with concentrated hydrochloric acid (pH 1-2).

The mixture is filtered and the solid washed with water and dried to give 51 g of product as white crystals, m.p. 270-275 0

C.

Reference Example 28 4-f (2-Methvlbenzovl) aminolbenzovl chloride A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino]benzoic acid and 32 ml of thionyl chloride is 15 refluxed for 1.5 hours. The solution is concentrated under vacuum. Toluene is added and the solvent removed under vacuum. Toluene is added and the mixture chilled and filtered to give a yellow solid, m.p. 135-141 0

C.

Reference Examrle 29 20 4-[(2,6-Dimethoxvbenzovl)aminolbenzoic acid A mixture of 2 g (10 mmol) of 2,6-dimethoxybenzoyl chloride, 1.65 g (10 mmol) of ethyl 4-aminobenzoo oate, 1.11 g of triethylamine and 61 mg of 4-dimethylaminopyridine in 10 ml of dichloromethane is refluxed for 20 hours. The mixture is diluted with water and the organic layer separated. The organic layer is washed with water, 1 N HC1, 1 N Na2CO3, brine and dried (Na2SO4). The solvent is removed to give a solid which is crystallized from ethyl acetate to give 1.22 g of ethyl 4-[(2,6-dimethoxybenzoyl)amino]benzoate as crystals, m.p. 183-185 0

C.

A mixture of 3.88 g (11.79 mmol) of the preceding compound, 17.3 ml of 2 N NaOH and 20 ml of methanol is stirred at room temperature overnight.

Methanol (30 ml) and water (10 ml) are added and the solution refluxed for 1/2 hour. The solvents are O removed under vacuum and the residual solid triturated with ether and the ether decanted. The solid is dissolved in 30 ml of water and acidified with 2 N HC1 (pH The mixture is filtered, the solid washed with water and dried at 60 0 C under vacuum to give 3.0 g of solid, m.p. 236-240 0

C.

Reference Example Ethyl 4- (4-Dvridinvlcarbonvl)aminolbenzoic acid To a cooled mixture of 1.78 g (0.01 mol) of isoniconinoyl chloride hydrochloride in 5 ml of dichloromethane is added 2.52 g (0.025 mol) of triethylamine. To the solution is added a solution of 1.65 g of ethyl 4-aminobenzoate in 5 ml of dichloromethane. After stirring at room temperature overnight, 50 mg of 4-di- 15 methylaminopyridine is added and the mixture is refluxed for 24 hours. The mixture is poured into water and filtered to give 3.4 g of brown solid. A 0.50 g sample is triturated with ethyl acetate to give 0.37 g of ethyl 4-[(4-pyridinylcarbonyl)amino]benzoate as yellow o"o 20 crystals, m.p. 143-145 0

C.

Reference Example 31 2-Methvlfurane-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.

S-61- Reference Example 32 4-fN-Methvl-N-(2-methvlbenzovl)aminolbenzoic acid A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexane under argon to remove the oil. To the washed sodium hydride is added 5 ml of N,Ndimethylformamide. To this mixture is added dropwise a solution of 8.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 ml of dimethylformamide. The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours. The mixture is diluted with water and extracted with dichloromethane. The extract is dried (Na2S04), concentrated to reduce the volume and the solution filtered through a thin pad of 15 hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 11 g of an oil (1:1 mixture of product and N,N-dimethylformamide). The preceding product, ethyl 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30 ml of methanol and 25 ml of 2 N NaOH added. The mixture is refluxed for 2 hours and the solvent removed. The residue is extracted with ether (discard) and the remaining residue dissolved gig• in 50 ml of water. The basic solution is acidified with 2 N citric acid and the solid filtered off and washed with water. The product is air dried to give 6.72 g of crystals, m.p. 187-190 0

C.

Reference Example 33 4-fN-Methvl-N-f(2-methvlbenzovl)aminolbenzoyl chloride A solution of 6.72 g of 4-[N-methyl-N-(2methylbenzoyl)amino]benzoic acid in 20 ml of thionyl chloride is refluxed for one hour. The volatiles are removed in vacuo. Toluene is added to the residue and then the toluene removed in vacuo (repeated several times) to give the 7.3 g of product as a brown oil.

-62- As described for Reference Example 32, but substituting the appropriate ethyl 4-t(N-aroyl)amino]benzoate, the following compounds are prepared.

Reference Examnle 34 4- [N-Methyl-N- (2-chlorobenzovl'Jaminolbenzoic acid Reference Example N-[N-Methvl-N-(2. 5-dichlorobenzovl')aminolbenzoic arid Reference Example 36 N-[N-Methvl-N-(2. 4-dichlorobenzovl)aminolbenzoic acid Reference Examrple 37 4- [N-Methyl-N- (2-chloro-4-methvlbenzovl)amino lbenzoic .:.:Reference Examp'le 38 4- [N-methyl-N- (2-methvl-4-chlorobenzovl) amino lbenzoic ad Reference Examiple 39 4-fN-Methvl-N-(2. 4-dimethvlbenzovl)aminolbenzoic acid Reference Example 4-fN-Methvl-N- 3-dimethylbenzovl)aminolberizoic acid Reference Example 41 4- [N-Methyl-N- (2-methoxvbenzoyl) pminolbenzoic acid S Reference Example 42 4-[N-Methvl-N- (2-trifluoromethoxvbenzovl)aminlbeflzoicr 25Reference Example 43 4-fN-Methvl-N- -methoxyclbenzovl)ami olb zc cd Reference Example 44 4-[N-Methyl N-(2-methoxvlthobenzovl)aminolbeni aid Reference Examiole 4- [N-Methyl-N- (2-methylthiop2hen-3vicarbonvl) aminolbenzoic acid -63- Reference Examrple 47 4- [N-Methyl-N- (3-methvlthioiphefle-2vlcarbonvl)aminolbenzoic acid Reference Examole 48 4-rN-Methyl-N- (2-methvlfuran-3-vlcarboflvl) aminolbenzoic acid Reference Examiple 49 1- [N-Methyl-N- (3-methvlfuran-2-vlcarbonyllamilolbeflzoiC Reference Examiple 4- [N-Methyl-N- (phenylacetyl) amino lbenzoic acisd Reference Example 51 4- [N-Methyl-N- (2-chlor Phenvlacetvl)apminolbenzoic acid Reference Examiple 52 4- N-Methyl-N- (2-methoxynhenyacety-l) aminolbenzoic acid Reference Example 53 4- N-Methyl-N- (2-methvlphenylacetvl) aminol benzoic acid *9.Reference Example 54 4-rN-Methyl-N- (cyclohexylcarbonyl) ainol benzoic acid 20 Reference Examole 4- [N-Methyl-N- (3-cclohexenecarbonvl)aminolbenzoic acid Reference Example 56 g* 4- N-Methyl-N- (cyclohexvlacetvl) aminolbenzoic acid Reference Examiple 57 7. 8-Dihvdro-5 (6H) quinolinonie o A mixture of 57.93 g of 3-amino-2-cyclohexele- 1-one, 76.8 g of 3-(dimethylamilo)acroteil, 62.5 ml of glacial acetic acid and 270 ml of toluene is refluxed under argon for 16 hours and concentrated under vacuum to dryness. Toluene (200 ml) is added and the solvent removed under vacuum. To the residue is added one liter of dichloromethane and then 200 ml of saturated NaHCO3 slowly added and solid NaHCO3 added to bring the pH to 8. The mixture is filtered and the CH2Cl2 layer separated. The CH2Cl2 layer is passed through a thin pad of hydrous magnesium silicate and the filtrate -64concentrated to dryness. The residual black oil is extracted with hot hexane and the hexane decanted. This process is repeated until no more product extracted into the hexane. The hexane extracts are combined and the solvent removed to give 17.3 g of product as an oil.

Reference Example 64 7.8-Dihvdro-5(6H)quinolinone. oxime To a solution of 3.78 g of 7,8-dihydro- 5(6H)quinolone in 20 ml of ethanol is added 2.68 g of hydroxylamine, hydrochloride, 3.23 g of sodium acetate and 5 ml of water. The mixture is refluxed under argon for 4.5 hours, cooled and filtered. The solid is washed with 30 ml of ethanol-water and dried under vacuum to give 3.58 g of solid, m.p. 232-236C. Recrystallization from ethanol gives crystals, m.p. 234-236 0

C.

Reference Example 7.8-Dihvdro-5(6H)cuinolinone. 0- (4-methvlphenyl) sulfonylloxime *To a mixture of 2.30 g of 7,8-dihydro-5(6H)- 20 quinolinone, oxime, 3.59 g of 4-methylphenylsulfonyl chloride in 32 ml of acetone is added a solution of 0.84 g of potassium hydroxide in 10 ml of water. The mixture is refluxed for 0.5 hour under argon and the volatiles removed under vacuum. Water is added to the 25 residue and the mixture is filtered and the solid washed with water and 1 N NaHC03. The solid is dissolved in dichloromethane, dried and the solvent removed to give 3.83 g of solid. Recrystallization from diethyl ether gives crystals, m.p. 102-104 0

C.

Reference Example 66 5.7.8.9-Tetrahydro-6H-pyrido3.2-blazepin-6-one A mixture of 8.26 g of 7,8-dihydro-5(6H)quinolinone, Q-[(4-methylphenyl)sulfonyl]oxime, 54.63 g of potassium acetate, 193 ml of ethanol and 354 ml of water is refluxed for 20 hours. The mixture is concentrated under vacuum to remove volatiles and the aqueous residue (contains solid) is added chloroform.

The mixture is filtered through diatomaceous earth, the filter pad washed with chloroform and the filtrate concentrated to dryness. The residual solid is recrystallized from acetone to give 2.81 g of crystals, m.p. 156-159 0

C.

Reference Example 67 6.7.8.9-Tetrahvdro-5H-ovrido[3,2-blazepine A mixture of 1.56 g of 5,7,8,9-tetrahydro-6Hpyrido[3,2-b]azepine-6-one, 3.31 g of lithium aluminum hydride in 40 ml of tetrahydrofuran is refluxed for 4 hours. The mixture is cooled and 25 ml of methanol is added dropwise. The mixture is filtered through diatomaceous earth, the filter cake washed with tetrahydrofuran and the filtrate concentrated to dryness under vacuum. Water (50 ml) is added to the residue and the mixture extracted with diethyl ether. The extract is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with) diethyl 20 ether. The filtrate is concentrated under vacuum to give 1.01 g of crystals, m.p. 70-71 0

C.

Reference ExamPle 68 6.78. 9-Tetrahvdro-5-(2-chloro-4-nitrobenzovl) pvrido[3.2-blazepine 25 To a mixture of 2.90 g of 6,7,8,9-tetrahydro- 5ti-pyrido[3,2-h]azepine, 2.37 g of triethylamine in ml of dichloromethane is added 5.16 g of 2-chloro-4nitrobenzoyl chloride in 50 ml of dichloromethane. The mixture is stirred at room temperature under argon for 3 hours and then poured into water. The organic layer is separated and washed with 1 N NaHCO3, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the pad washed with CH2C12 and ethyl acetate and the filtrate concentrated to dryness. The residual solid (7.13 g) is triturated -66with ethyl acetate to give 4.41 g of off-white crystals, m.p. 143-145 0

C.

Reference Example 69 6.7.8.9-Tetrahvdro-5-(4-amino-2-chlorobenzovl)-5Hpyridof3.2-blazepine A mixture of 3.31 g of 6,7,8,9-tetrahydro-5- (2-chloro-4-nitrobenzoyl)-5H-pyrido[ 3 ,2-h]azepine and 6.78 g of stannus chloride dihydrate (SnCl2.2H20) in 200 ml of methanol is refluxed for 2 hours under argon. The solvent is removed under vacuum and 5 ml of saturated NaHCO3 solution and solid NaHC03 added to bring the pH to 7. The mixture is extracted with ethyl acetate, the extract filtered through diatomaceous earth and the filtrate washed with saturated NaHCO3, H20, brine and dried (Na2SO4). The filtrate is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness to give 2.58 g of an amorphous solid. Anal. Calc'd for C16H16ClN30; C,59.9; H,5.7; N,13.1; Cl, 11.1 Found: 20 C,60.5; H,5.0; N,12.9; C1,11.6.

Reference ExamPle *Methyl 6-aminovridine-3-carboxvlate Dry methanol (400 ml) is cooled in an ice bath 25 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).

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

C.

Reference Example 71 6-f(5-fluoro-2-methvlbenzovl)amino1pvridine-3-carboxvlic -67- To a mixture of 4.5 g of methyl 6-aminopyridine-3-carboxylate and 5.53 ml of triethylamine in 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 acette to give an additional 9.0 g of bis acylated compound.

A mixture of 12.0 g of methyl fluoro-2-methylbenzoyl)]amino]pyridine-3-carboxylate, ml of methanol-tetrahydrofuran and 23 ml of 5 N NaOH is stirred at room temperature for 16 hours. The mixture is concentrated under vacuum, diluted with 25 ml of water, cooled and acidified with 1 N HC1. The mix- 20 ture 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 71, but substituting the appropriate aroyl chloride, heteroaroyl chloride, cycloalkanoyl chlorides, phenylacetylchlorides 25 and related appropriate acid chlorides, the following 6- [(aroylamino]pyridine-3-carboxylic acids, 6-[(heteroaroyl)amino]pyridine-3-carboxylic acids and related 6- [(acylated)amino]pyridine-3-carboxylic acids are prepared.

Reference Example 72 6-[(3-Methvl-2-thienvlcarbonyl)aminolpvridine-3carboxylic acid Reference Example 73 6- r (2-Methyl-3-thienvlcarbonyl)aminopvridine-3carboxylic acid -68- Reference Example 74 6-f (3-Methvl-2-furanvlcarpflvl)amiflplridifle-3carboxylic acid Reference Example 6-f (2-methvl-3-furanvlcarbonvl')aminolpyridine-3carboxylic acid Reference Example 76 6-f (3-fluoro-2-methvlbenzovflaminolpvridifle-3-carboxylic Reference Example 77 6-f (2-Methlbenzovl)aminolovridife3carboxyllc acid Reference Emamole 78 6-f (2-chlorobenzovl)aminolpridine3-crboxylic acid Reference Example 79 6-f (2-Fluorobenzovl)aminolpvridife3carboxylic acid Reference Examnle 6-f (2-Choro4fluorobenzov)aminO1Ipvridine-4carboxylic Reference Examn-le 8' 6-f(2.4-Dichlorobenzovlaninofpv-rdc!fle carboxylic acid Reference Exarnpl- 82 Reference Examiple 83 6-f 5-Trimethoxvbenzov)aminol1Pyridine 3 carboxylic Reference Examnle 84 6-f (2.4-Difluorobenzovl)aminilPvridife3carboxylic acid Reference Example 6-f (2Bromobenzovl)amino1pyridine3carboxlI c acid Reference Examole 86 6- (2Choo4-nitrobenzov)amiolO1Pridine 3 carboxylic Reference Examo~le 87 6-f (Tetrahvdrofuranv1-2-carbonl)aminflO1Pridine- 3 carboxylic acid -69- Reference, Example 881 6-f (Ttrahvdrthienvl-?-cabn) amnlviine-3carboxvlic acid ReferenceP Example-89 6-f (Cvcoevcabnlain~l viiecroxylic acid Reference Exavle 6- f (cclohex3-efecarbonv) aminIPri di ne 3 carboxylic Reference xample 91 6-f (-Floro2-methyLbenzefactvl)aminol~ridine- 3 c arb oxlc acidL Reference Example 92 6- f 2 Chlorobenefeacetvl) ami)I pri di ne 3 carboxylic Aci- Reference Example 3 6-f (cvloentvlcarboflvl)afInDplp-ridine3carbOKVlic acid Reference Examp)le 94 6-f (cclohexlcetvl)aminlpridi

IP

3 -arbOxvlic acid Reference xample 925 6-f 3 Methl2thiefllacetvl)amnpypri ine 3 carboX-lC ****Reference Example 96 2 Methvi>Thieflvlacet l) inl vriine3carboxYvl-cQ Reference Eample 9-7 6-f 3 Methl2ffuranlaetvl~aminppri iecrovic Reference Example 98 (2Methvl-3-furanyla-cet.-,l') amnD idne3carboxvlic Re-ference xample-99 6-f 3 Methl2tetrahvdrothienlacevlamino1pvridine- 3 carboxvlic aid Reference Example 100M 6-f 2 Methl 3 tetrahvrothienlaetvl)aminol~vridine-3 carbonxvlic acid Reference Exampile 101 6- f 5-Dichlorobenzovl) ami nol Vri dine3-carboxylic acid Reference Examnle 102 6- f 5-Dichlorobenzovl) aminolpvridie3-carboxylic aci-d Reference Examrile 103 6-f (2-Methl-4-chlorobenzovl) amino 1 P2ridife carboxylic Reference ExamT~le 104 6-fr 3-Direthlbenzovl) aminolvridife3carboxylic acid Reference Example 105 6-f (2-Methoxivbenzovl)aminolpvridife-carboxylic acid Reference Example 106 6- f (2-Trif luoromethoxvbelzovl) amino I ovridine-3carboxylic acid Reference Examole 107 6-f (4-Chloro-2-methoxvbenzovl)aminolpvridine-3carboxylic acid Reference Example 108 6-f f2-(Trifluoromethvl)benzovllaminol1pyridifle- 3 :25 a. 30 carboxylic acid Reference Example 109 6-f 6-Dichlorobenzov)aminolpyridine3-carboxVlic acid Reference Examole 110 6- f 6-Dimet hvlbenzo) amino pyridine 3carbnxvl ic acidl Reference Example 111 6fI(2-Methvlthiobefzovl)aminolvridine-3carboxylic acid Reference Example 112 6-f(4Fur--tilurmtv~ezvlaioiyiie 3-carboxylic acid R~eference Example 113 6-F 3Dichorobenzov)aminol1pyridine3carboxylic acid Reference Examvle 11-4 6-f (4Fuoro2methvlbenzov)minolOvridine 3 -carboxylic -71- Reference Examle 115a 6-i 3 ,5-Trichlorobeflzovl)amfiflO1Pridine 3 carboxylic Ref erence Example 116 6-f (5-Fluoro-2-chlorobenzolZO 'amio1 pridine 3 -carboxylic Reference Exampl e 117 6- f (2-Fluoro-5- (tri fluoromethvLhbeflZO l aminolIPyridine- 3-carboxylic-aaid Reference Examp-le 118 6-1 (5-Fluoro2mehVlbenzov) amino 1 vridine 3 carbonvl A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)aminolpyridine-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. 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) is repeated to give 7.7 g of crude product as a solid.

As described for Reference Example 118, the following 6- (acyl) amino) pyridine-3-carbonyl chlorides are prepared.

Reference Examvle 1192 6-F (3methvl-2-thienv~carbon l'-aminolpyridine3carbonyl Reference Example 120Q 6-f (2Methv-3-thienvlcarbonvl) aminol pvridine-3-carbonyI r~rd Reference Example 121 6-i 3 Methl2furanvlcarbonvl)amin Pridin- 3 -carbonvl Reference Example -122 6-f 2 Methl3furanvlcarbonvl)amino)vridine 3 carbonvl -72- Reference Example 123 6- f (3-Fluoro-2-methvlbenzOvl) aminol pvridine-3-carUbonvl Reference Example 124 6-f (2-Methvlbenzovl)aminolPvridine-3-carbonvl chloride Reference Example 125 6-f (2-Chlorobenzovl) aminolpvridine-3-carbonvl chloride.

white crystals Reference Example 126 fr-f {2-Fluorobenzovl~aminol]pvridife-3-crboflV1 chloride 9 9 0 Reference ExamPle 127 6-f (2-Chloro-4-fluorobenzovl) pminolovridine-3-carbonvl chloride Reference Example 128 6-f (2,4-Dichlorobenzovl)aminolpvridine-3-carbol Reference Example 129 6-f (4-Chloro-2-fluorobenzovl) aminolpvridine-3-carbonvl Reference Example 130 6-f (3,4,5-Trimethoxvbenzov1)aminlpyridie3-carboflyl Reference ExamPle 131 6-f 24-Difluorobenzov)aminolpyridine3carbonV1 clrd Reference Example 132 6-f (2-Bromobenzovl)aminolpridine3carbonyl chloride Reference Example 133 6-r (2-Choro4-nitrobenzov)mnolpyridine3carbony1 hoip Reference Example 134 6-f (Tetrahvdrofuranl-2-carbonvl)aminoloyridine- 3 carbonvi chloride Reference Examole 135 6-f (Tetrahvdrothienl-2-carbonvl)aminolpyridine- 3 carbonvl chloride 0 -73- Reference Exampl136LI 6- f (Cvclohxlpbnl amio lvridinez-abov Reference Example 137 6- Ccohx3eearbnnl) amiovrdn 3crnl Reference Example 138 6- f 2 -Methvlbenzeneacetvl) amino I pyrid ine-3-c-anv Reference Example 139 6-F 2 etCl)oaobeDOeIePcetvldumino4-cribineyl Reference Examolp 140 6- f (CYClo)Qentvcarbonl) mino pvr-iii~ clrd Reference Example 141 6-r (Gvclohexvlacetv1.)aminolpridine-3-carbonvl chloride Reference Example 142 Reference Exampl- 14' *nlcev am-LKLPn- cronyl Reference Example 144 25 6-F 3 -Methvl-2-furanlcetvl)amn pri ne l Reference Example 145 6- f 2 -Me hvl-3-furanvlpcetvl) mnolpvridine-3-carbonvl 30 Reference Example 146 6-F 2 -Meh1-5-fluiorobenzeneacetvl)aminolpvridine- 3 carbonyl chloride Reference ExamRP 147 6-F 3 -Methl -2-tet rahvdrt-hienv IacetvjL) mno lpvridine-3carbonyl chloride 0 -74- Reference Example 148 6-f (2-Methvl-3-tetrahvdrothienvlacetvl) amino 1lpvridine--3carbonvi chloride Reference Examrle 149 6-f (2.5-Dichlorobenzovl) aminolpvridine-3-carbonvI Reference Example 150 6-F (3.5-Dichlorobenzovl)pminolovyridine-3-cprbonvl 6-F 2-Mthv-4-clo chlnorl ie prdie3-cabn Reference ExamT~le 152 6- 3hl-Dichvlobenzovl) aminolvridine-3-carbnn Reference Examr~1e 153 6-F (2Methoxyenzolanlolpvrdie-icrne-l chloride Reference Examnle 154 6-F (2-Trfooethoxvbenzovl)aminolp~vridine-3-carbonvlor Reference Example 155 6-F (2-Triforo2methoxvbenzovl)aminolpvridine-3-carbonvI Reference Examrole 156 6-F F2-C(iloromethovbenzovllaminolpvridine-3I-carbonvl Reference Example 156 6-F2(2.6iclorohbenzovlaminol ridine--carbvl Reference Exampole 158 6-F 6-Dimehlbenzovl) aminoliovridine-3-carbonvl Reference Example 159 6- F(2-Methvlthiobenzovl) amino 1 ovridine-3-carbonvl chord Reference Example 160 6- f (4-7'uoro-2- (trifluoromethvl)benzoyl) amin~o Tvridine- 3-carbonvi chlori-de Reference ExamPle12161 6-f (2,3-Dichlorobeflzovl)aminfloPyridine- 3 -carbonyl Reference Examp~le 162 6-f (4-Fluoro-2-methvlbelzovl) pminolpvridine-3-carbonvl Reference ExamPle-3163 6- 5-Trichlorobenzovl)amfinlopvridine- 3 -carbonvl Reference Example 164i 6-f (5-Fluoro-2-chlorobenzovl) arinlpvridine-3-carbonvl clrd Reference ExamPle 165l~ 6-f 3-carbonvi chloride :As described for Reference Example 71, the following bis acylated products (Table A) are prepared and purified by silica gel chromatography. These compounds are then hydrolysed to the acids as described in Example 71 (Table B).

-76a.

a a a a a a a a a. a a a CH 3 3RR 167 C388HFH 2 168 CH3 H H H H 426 169 H OCH3 OCH3 OCH3 H 540 170 C1 H H H H 430 171 F H F H H 396 172 Br H H H H 520 173 Cl H F H H 412 174 Ph H H H H 512 175 C1 H H Br H 474 176 CR3 H H F Br 177 CR3 H H H Br 468 5 M+ is molecular ion found from FAB mass spectrum -77-

*SS*

S

S

No. 178 CH3 H H H H 256 179 CH3 H H F H 274 180 CH3 F H H H 274 181 H OCH3 OCH3 OCH3 H 332 182 Cl H H H H 276 183 F H F H H 278 184 Br H H H H 322 185 Cl H F H H 294 186 Ph H H H H 318 187 Cl H H Br H 356 188 CH3 H H F Cl 189 CH3 H H H Br 336 M+ is molecular ion found from FAB mass Reference Example 190 spectrum.

6-Amino-5-bromopyridine-3-carboxvlic 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 -78- NH4OH. The separated solid is filtered and washed with water to give 18 g of solid; mass spectrum: 218 Reference Example 191 Methyl 6-amino-5-bromoovridine-3-carboxvlate 6-Amino-5-bromopyridine-3-carboxylic acid g, 50 mmol) 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 dissolved in ice cold water. The aqueous solution is neutralized with 0.1 N NaOH and the solid which separates is filtered; washed well with water and air dried to yield 10 g of product as a solid: mass spectrum 231 Reference Example 192 6-[(2-Methylbenzeneacetvl)aminoloyridine-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 20 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 dichioromethane 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 con- Scentrated to dryness. The residue (9.0 g) is chromatographed on a silica gel column with hexane-ethyl 30 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 S-79stirred 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 193 6-r(2-Methvlbenzeneacetyl)aminolpvridine-3-carbonvl 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 concentrated 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 194 2-(2-Pvridinvl)benzoic acid *A mixture of methyl 2-iodobenzoate (12 g, 47 mmol), 2-pyridinyl-tri-n-butyl stannane (20 g, 55 mmol) and tetrakis (triphenyl phosphine) palladium (2 g), 20 is refluxed in toluene (degassed) for 48 hours. The reaction mixture is concentrated under vacuum and the residue is chromatographed on a column of silica gel with 50% ethylacetate:hexane as eluent. The initial fractions (2 lits) are discarded and finally the product 25 methyl 2-(2-pyridinyl)benzoate, is eluted and isolated as an oil. (Yield: 5.5 mass spectrum, 213 A mixture of the preceding compound (3.0 g, 14 mmol) and NaOH (600 mg, 15 mmol) is refluxed in MeOH:water (50 ml) for 4 hours. When the reaction is complete, it is concentrated under vacuum and the residue dissolved in 50 ml of cold water. Neutralization with glacial acetic acid affords a solid which is filtered off and washed with water to give 2.5 g of brown solid; slightly soluble in water; mass spectrum (CI) 200 (M1).

Reference Example 195 Ethyl 3-fN-(3-ethoxycarbonyl-2-pvridinvl)-N-(4methvlphenvlsulfonyl) aminobutane-1-carboxylate A mixture of 13.4 g of ethyl 2-[(4-methylphenylsulfonyl)amino]pyridine-3-carboxylate, 23.1 g of anhydrous potassium carbonate and 20.4 g of ethyl 3bromobutane-1-carboxylate in 300 ml of N,N-dimethylformamide is heated at 110 0 C under argon for 6 hours.

The mixture is concentrated to dryness under high vacuum and to the residue is added CH2C12 and H20. The organic layer is separated and washed with water (3 times), treated with activated carbon and dried (MgSO4). The solvent is removed and the residue chromatographed on a short column of silica gel. The column is eluted with 1900 ml of CH2C1 2 then 1300 ml of CH2C12 and finally with 4 L of 5% ethyl acetate in CH2C12. The 5% ethyl acetate in CH2C12 fractions are combined and the combined fraction dried (MgSO4) and the solvent removed to give 16.9 g of white crystals. A 0.5 g sample is 20 recrystallized from toluene to give white crystals (washed with hexane) (0.39 g) m.p. 129.5-130 0

C.

Reference Example 196 Ethyl 8 9-dihvdro-5-hvdroxv-9- (4methylphenvllsulfonyll-7H-pyridof2.3-blazepine-6- 25 carboxylic acid To a solution of 7.85 g (70.0 mmol) of potassium tert-butoxide in 150 ml of tetrahydrofuran, chilled in an ice bath, is added 15.2 g (35.0 mmol) of ethyl 3-[N-(3-carbethoxy-2-pyridinyl)-- (4-methylphenylsulfonyl)]aminobutane-l-carboxylate in 150 ml of dry tetrahydrofuran dropwise over 50 min. The mixture is stirred in an ice bath for 5 hours and poured in 500 ml of ice water. The mixture is brought to pH 5 with HC1 and extracted with ethyl acetate (4 times). The extract is dried (MgSO4) and the solvent removed under vacuum. The residue is chromatographed on silica gel -81with 10% ethyl acetate in CH2C12 as eluent. Fractions containing product are combined and the solvent removed to give 12.8 g of a pale yellow gum; Mass Spectrum (FAB) 389 411 (M+Na).

Reference Example 197 6.7.8.9-Tetrahydro-Q-f(4-methylphenyl)sulfonvl1-5Hpyridof2.3-b1azepin-5-one A mixture of 13.2 g of ethyl 8,9-dihydro-5hydroxy-9-[(4-methylphenylsulfonyl]-7f-pyrido[2,3-h]azepine-6-carboxylate, 265 ml of dimethylsulfoxide and 1.52 ml of water under argon is heated at 150 0 C 16.5 hours. The mixture is poured into 2700 ml of ice water and the mixture chilled 16 hours. The mixture is filtered and the solid washed with water and dried. The 15 tan solid is dissolved in ethyl acetate and the solution washed with 50 ml (4 times) of water. Activated carbon is added to the solution and the mixture filtered through magnesium sulfate. The filtrate is concentrated e to dryness under vacuum to give 10.4 g of solid. The solid (9.24 g) is filtered through silica gel with ethyl acetate in dichloromethane as solvent. The filtrate is concentrated under vacuum to give 6.7 g of off-white solid; Mass Spectrum (CI) 317.

Reference Example 198 25 6.7.8. 9-Tpt-rahydro-5- (2-chloro-4-nitrobenzovl) pyridof3.2-bhazepine. 1-oxide To a solution of 0.497 g of 6,7,8,9-tetrahydro-5-(2-chloro-4-nitrobenzoyl)-5-pyrido[3,2-h]azepine in 7 ml of chloroform is added 1.04 g of 3-chloroperbenzoic acid. The mixture is refluxed overnight and the solvent removed under vacuum. To the residue is added 100 ml of water and the mixture extracted with dichloromethane. The extract is washed with H20, 1 N NaHC03, H20 and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with 10% methanol in -82ethyl acetate to give 0.49 g of product as a glass (foam), m.p. 110-125 0

C.

Reference Example 199 6.7.8,9-Tetrahvdro-5H-ovridor2,3-blazeoin-5-one A solution of 5.00 g of 6, 7 ,8,9-tetrahydro-9- [(4-methylphenyl)sulfonyl]-5H-pyrido[2,3-b]azepin-5-one in 60 ml of 40% sulfuric acid in acetic acid is heated at 60 0 C for 11 hours. The mixture is chilled and poured into 350 ml of ice water (cooled in an ice bath) with thorough stirring. To the cold mixture is added solid NaOH until the pH is 8 while keeping the temperature below 30 0 C. The mixture is filtered and the solid washed with ethyl acetate. The organic layer of the filtrate is separated and the aqueous layer extracted 15 with ethyl acetate. The organic layer and extracts are combined and treated with activated carbon. The mixture is filtered through MgSO4 and the solvent removed under vacuum to give 2.0 g of yellow crystals.

Reference Example 200 6. 7,8. 9-Tetrahvdro-9- (2-chloro-4-nitrobenzovl)-5Hpyridof2.3-blazepin-5-one To a solution of 6,7,8,9-tetrahydro-5ipyrido[2,3-b]azepin-5-one and 0.234 g of triethylamine in 6 ml of dichloromethane is added 0.506 g of 2-chloro- 25 4-nitrobenzoyl chloride in 2 ml of dichloromethane. The mixture is stirred at room temperature overnight under argon. The solution is washed with H20, 10% NaHCO3 and dried (MgS04). The solvent is removed to give a brown oil which crystallizes. The mixture is chromatographed on silica with a waters Prep-500 instrument with ethyl acetate-hexane as solvent to give 2.4 g of offwhite crystals, m.p. 162-164 0 C (identified as Q-2chloro-4-nitrobenzoyl derivative (2-chloro-4-nitrobenzoyl enolate of product) and 0.80 g of product as crystals, m.p. slowly decomposes 160-220 0

C.

0 -83- Reference Example 201 6-(4-Aminobenzovl)-l.4.5.6--tetrahvdroovrazolo[3.-d- lthieno 13. 2-bl azeoine A mixture of 2.0 g of 6-(4-nitrobenzoyl)- 1,4,5, 6-tetrahydropyrazolo(3,41- ithieno(3,2-t]azepine in ml of absolute ethanol is stirred under argon while 1.6 ml of hydrazine is added. The reaction mixture is heated at 60 0 C for 1.5 hours. The reaction mixture is cooled to room temperature and 400 mg of 10% Pd/C added and the reaction mixture heated at 100 0 C for 1.5 hours.

The reaction mixture is filtered through diatomaceous earth and the cake washed with met~hylene chloride. The *filtrate is concentrated jin va-i to a residue which is crystallized from ethyl acetate:hexane to give 1.4 g of the desired product as yellow crystals, 242-260'C.

Reference Examole 202 7-F (Dimethylamino)methvlenel-4,5. 6,7-tietrahvdro-4-(2chloro-4 -nit robenz ovl) -8H-t-!ieno f 3. 2-bl azeoin-8-one A mixture of 3.0 g of 4,5,6,- 7 -t-errahydro-4-(2chloro-4-nitrobenzoyl)-8H-thienofj, 2-_blazeoin-8-one and ml of tert-butoxy-bis(dimet-hylaminomethane is heated a steam bath 2 hours followed by th ,e addit-ion of ml of methylene chloride. The reaction mixture is refluxed for 1 hour. The reaction mixture is evaporated j vau to a residue which is diluted with 100 ml of *.:methylene chloride and filtered through a pad of hydrous magnesium silicate. The filtrate is filtered through a short column of silica gel to give 2.4~5 g of the desired product as a yellow foam.

Reference Examle 203 6- (2-Chloro-4-nitrobhenzovl)-1., 5.6tetrahvdropyrazolof3. 4-dlthieno[3.2-blazepine To a mixture of 2.2 g of 7-[(dimethylamino) methylene] 7-tetrahydro-4- (2-chloro-4nitrobenzoyl)-811-thieno(3,2-12]azepine in 40 ml of ethanol is added 341 il of hydrazine followed by heating -84at 60 0 C for 1.5 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in 100 ml of ethyl acetate and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give 1.85 g of the desired product as a yellow-orange solid.

Reference Example 204 6-(2-Chloro-4-aminobenzovl)-1.4.5.6tetrahvdropyrazolof3.4-dlthienof3.2-blazepine A mixture of 1.8 g of 6-(2-chloro-4-nitrobenzoyl)-l,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-h]azepine in 35 ml of absolute ethanol is added 5.42 g of tin (II) chloride followed by hearing at reflux for 1 hour at 80 0 C. The volatiles are evaporated in vacuo to a residue which is partitioned between 150 ml of ethyl 15 acetate and saturated aqueous NaHCO3 the reactants are stirred at room temperature for 1 hour and filtered.

The organic layer is separated and washed with 30 ml of brine, dried (Na2SO4) and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated 20 in vacuo to give 1.55 g of a yellow-orange foam.

Reference Examole 205 7-f(Dimethylamino)methvlenel-4. 56.7-tetrahydro-4-(4nitrobenzovl-8H-thieno 3,2-b azepin-8-one A mixture of 3.2 g of 4,5,6,7-tetrahydro-4-(4- 25 nitrobenzoyl)-8H-thieno[3,2-h]azepin-8-one and 32 ml of tert-butoxybis(dimethylamino)methane is heated on a steam bath for 3.5 hours. The reaction mixture is allowed to stand for 48 hours. The reaction mixture is evaporated in vacuo and the concentrate is dissolved in 150 ml of methylene chloride and filtered through hydrous magnesium silicate two times. The volatiles are evaporated in vacuo to a residue which is dissolved in ml of ethyl acetate and filtered. The filtrate is cooled to give 3.2 g of the desired product as a light orange solid, m.p. 214-216 0

C.

Reference Examiple 206 N-14-[ 7- (Dimethvlpminomethvlene) 1-5. 6,7. 8-tet rphvdro-8oxo-4H-thien)f 3. 2-b I azepin-4-vI) carbonyl Iphenyll -2methvlbenzamide A mixture of 100 mg of N-[ 4 -((5,6,7,8-tetrahydro-8-oxo-4H-thieno[3, 2-12]a zepin-4-y1) carbonyl] phenyl]-2-methylbenzamide and 1 ml of tert-butoxybis- (dimethyl amino) methane is heated at 50'C for 1 hour. To the reaction mixture is added 3 ml of methylene chloride and heating continued for an additional 2 hours at 0 C. The volatiles are evap~orated to a residue which is dissolved in 25 ml of methylene chloride and filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated jfl yv*cn to a residue which is purified by chromatography on preparative thick layer silica gel plates by elution with ethyl acetate to afford 20 mg of the desired product as a light yellow solid.

Reference Example 207 2-Chloro-7-f (dimethylaminomethylenel-4.5. 6.7te-trahvdro-4-(4-nitrobenzovl-8H-thieno[3.2-blazepin-8- .one A mixture of 1.1 g of 2-chloro-4,5,6,7tetrahydro-4- (4-nitrobenzoyl) -811-thieno 2-u] azepin-8one and 11 ml of tertbutoxy-bis(dimethylamino)methane is heated at reflux for 3.5 hours. The reaction mixture is allowed to stand for 24 hours. The reaction mixture is evaporated in vau and the concentrate is purified by column chromatography on silica gel to give 520 mg of the desired product as a non-crystalline solid.

Reference Example 208 8-Chloro-2. 4.5. 6-tetrahvdro-2-methvl-6- (4nitrobenzovl)Rjvrazolof3.4-dlrhieno[3.2-blazepine A mixture of 500 mg of 2-chloro-7-[(dimethylamino)methylene-4,5,6,-7-tetrahydro-4-(4-nitrobenzoyl)- 811-thieno[3,2-12]azepin-8-one in 15 ml of absolute -86methanol is stirred under argon while 131 p4l of Nmethylhydrazine is added. The reaction mixture is heated at 80*C for 18 hours. The reaction mixture is cooled to room temperature and concentrated in vaun~ to give 420 mg of the desired product as a solid.

Reference Example 209 6- (2-Chloro-4-aminobenzovl) 4,5. 6tetrahvdropvrazolo f3. 4-dI Pvridof 3. 2-bI azeipine As described for Reference Example 204, 6-(2chloro-4-nitrobenzoyl) 4, 5, 6-tetrahydropyrazolo- 4-dlpyrido[3,2-b]azepine is reduced with stannus chloride (SnC12) in ethanol to give the product as a solid.

Reference Exampile 210 5- (2-Chloro--4-aminobenzovl) 1 0-dihvdro-5H-tovrido f 3. 2bi thieno f2. 3-el azepine As described for Reference Example 204 5-(2chIo ro 4-n it robe n z oy1) 10-d ih yd rc,- 5 "-py r ido 2 thieno(2,3-a.Jazepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.

Reference Exampl- 21' (2-Chloro-4-arninobenzovl)-6. 3.2 bi thieno r3. 2-elazepine As described for Reference Example 204 5-(2chlo ro -4 -n it robe n zoyl1) 10 -dihydr o 5j-pyr ido[(3, 2 -12- :thieno[3,2-ajazepine is reduced with stannus chloride (SnCl2) in ethanol to give the product as a solid.

Reference Example 212 (4-Nitrobenzovl) 7. 8. f3. 2-blazepine A solution of 2. 96 g of 6, 7,8, pyrido[(3,2-D)]azepine, 3.03 g of triethylamine and 4 .45 g of 4-nitrobenzoyl chloride in 30 ml of dichloromethane is stirred under argon at room temperature for 4 hours.

The mixture is poured into water and the organic layer separated and washed with saturated NaHCO3, H20 and -87brine. The organic layer is dried (Na2SO4) and filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness to give 6.35 g of solid. Trituration with 25 ml of dichloromethane gives 5.50 g of light yellow solid. A sample from a prior run in trituration gives white crystals, m.p. 231-233 0

C.

Reference Example 213 (4-Nitrohen7oyl)-6.7.8. 9-tetrahydro-5H-Ovrido 3 2-h azepine. 1-oxide A mixture of 1.18 g of 5-(4-nitrobenzoyl)- 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine and 1.37 g of 3-chloroperoxybenzoic acid in 10 ml of dichloromethane is stirred at room temperature overnight under argon.

The mixture is diluted with 15 ml of dichloromethane and 15 the solution washed with 1 N NaHCO3, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filter pad is washed with 50 ml of ethyl acetate. Then the filter pad ~is washed with ethyl acetate-methanol and the 20 ethyl acetate-methanol wash collected and the solvent removed to give 0.86 g of crystals, m.p. 231-233 0

C.

Referenc Example 214 5-(2-Chloro-4-nitrobenzovl)-. 7. 8. pyridof3.2-blazepine, 1-oxide 25 A mixture of 0.497 g of 5-(2-chloro-4-nitrobenzoyl) -6,7,8,9-tetrahydro-5H-pyrido[ 3 ,2-b]azepine and 0.38 g of 3-chloroperoxybenzoic acid in 7 ml of dichloromethane is refluxed under argon for 16 hours. The solvent is removed under argon and to the residue is added water. The mixture is extracted with dichloromethane and the extract washed with 1 N NaHCO3, H20 and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The pad is washed with ethyl acetate and then with ethyl acetate-methanol The ethyl acetate-methanol wash is collected -88separately and the solvent removed under vacuum to give the product as a glass, m.p. 110-125 0

C.

Reference Examiple 215 (2-Chlo-ro- 4-nit robenzov1) 9-hvdroxv-6, 7.8. 9tertrahydro-5H-Prirdo f3. 2-bI azepine. 0-acetrate A mixture of 0.49 g of 5-(2-chloro-4nitrobenzoyl) 7,8, 9-tetrahydro-511-pyrido[3, 2- ~]aepie,1-oxide in 5 ml of acetic anhydride is heated in an oil bath at 900 for 36 hours. Toluene (25 ml) is added and the mixture concentrated under high vacuum.

The process is repeated and the residue chromatographed on silica gel preparative plates with ethyl acetate as solvent to give 0.24 g of crystals, m.p. 162-165 0

C.

Anal. Calc'd for Cl8Hl5ClN3OS. C,55.5; H,4.1; N,10.8.

Found: C,55.5; H,4.0; N,10.6.

Reference Examiple 216 (4-Nitrobenzovl) -9-hvdroxv-6. 7.8. Tpyrido[3. 2-blazeipine. 0-acetate A mixture of 0.58 g of 5-(4-nitrobenzoyl)- 6,7,8, 9-tetrahydro-5H-pyrido[3, 2-tIazepine, 1-oxide and ml of acetic anhydride in 10 ml of dichloromethane is :refluxed for 2 days. An additional 2 ml of acetic anhydride is added and the mixture refluxed 2 days. T o the mixture is added toluene (30 mi-twice) and the solvent removed under high vacuum. The residue is chromatographed on silica gel preparative plates with ethyl acetate as solvent to give 0.37 g of crystals, m.p. 135-137 0

C.

Reference Example 217 5-(4-Nitrobenzovl)-9-hvdroxv-6. 7.8.9-tetrahvdro-5H- Pyrido 3. 2-b I azeipne To a mixture of 0.5 g of 5-(4-nitrobenzoyl)-9hydroxy-6,7, 8, 9-tetrahydro-5fi-pyrido(3,2-tjazepine,

Q-

acetate in 10 ml of methanol-water is added KHCO3 and the mixture stirred at room temperature overnight.

The mixture is concentrated under vacuum, diluted with W -89ml of water and extracted with ethyl acetate. The extract is dried (Na2SO4) and the solvent removed to give the product as a solid. Chromatography on silica gel with ethyl acetate as solvent gives crystals, m.p.

182-185 0

C.

Reference Example 218 6. 7. 8-Tetrahvdro-5- (4 -nit robenzoyl) -9H -pvrido f 3. 2-bl azeroin-9-one A mixture of 0.5 g of 5-(4-nitrobenzoyl)-9hydroxy-6, 7,8, 9 -tetrahydro-5li-pyrido[3,2--t]azepine in ml of dimethyl sulfoxide and 1 ml of acetic anhydride is stirred ac room temperature 16 hours. To the mixture is 9 9added 10 ml of water and 1 N NaHCO3. The mixture is extracted with ethyl acetate and the extract washed with water, 1 N NaHCO3, brine and dried. The solvent is **removed to give a solid, chromatography on silica gel 999999with ethyl acetate as solvent gives the product as a solid, m.p. 188-190*C.

Reference Eape219 5,6.

7 ,8-Tetrahvdro-5-c2-chloro-4-nitrobenzovl)-9Hpvrido[3. 2-blazepin-9-one .:As described for Reference Example 218, 5-(2chloro- 4-nitrobenzoyl) -9-hydroxy-6, 7, 8, 9-tetrahydro-511pyrido[3,2-Djazepine is reacted with dimethylsuif oxideacetic anhydride to give the product as a solid.

Reference Example 220 6, 7,8, 9-Tetrahvdro-9- (4-nitrobenzovl) -5H-pvrido f2. 3boI To a solution of 2.11 g of 6,7,8,9-tetrahydro- 5Sh-pyrido(2,3-_djazepin-5-one in 40 ml of dichloromethane is added 3.28 g of solid NaHCO3. To the stirred mixture under argon is added dropwise 3.14 g of 4-nitrobenzoyl chloride in 30 ml of dichloromethane containing 2 ml of tetrahydrofuran and the mixture is stirred overnight.

To the mixture is added tetrahydrofuran and water and the mixture filtered. The solid is washed with 9 chloroform (solid dissolved) and the organic layer of the filtrate separated. The organic layer is filtered through MgSO4 and the filtrate concentrated to dryness to give a white solid. The solid from two runs is dissolved in ethyl acetate-CH2Cl2 and filtered through short silica gel column and the product fraction collected. The solvent is removed and the solid dissolved in hot chloroform-methanol and the solution treated with activated carbon. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness under vacuum to give 7.73 g of white crystals; Mass Spectrum (CI) (CH 4 312 (MH Reference Example 221 S6- (Dimethvlamino)methvlenel-6.7.8.9-tetrahvdro-9-(4- 15 nitrobenzoyl)-5H-pyridof2.3-blazepin-5-one To a slurry of 0.50 g of 6,7,8,9-tetrahydro-9- (4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 10 ml of tetrahydrofuran under argon is added 0.70 g of tertbutoxy-bis(dimethylamino)methane and the mixture is stirred at room temperature overnight. The volatiles are removed under vacuum and the residue in ethyl acetate-CH2Cl2 filtered through a short column of silica gel. The silica gel is washed with ethyl acetate (discard) and then with chloroform containing 3% 25 methanol to give 0.51 g of the product as a yellow solid.

Reference Example 222 6- (Dimethvlamino)methvlene -6.7.8.9-tetrahvdro-9-(2chloro-4-nitrobenzovl)-5H-pvrido[2.3-blazepin-5-one To a solution of 0.20 g of 6,7,8,9-tetrahydro- 9-(2-chloro-4-nitrobenzoyl)-5fi-pyrido[2,3-h]azepin-5-one in 2 ml of dioxane is added 0.504 g of tert-butoxybis- (dimethylamino)methane and the mixture is stirred at room temperature. The volatiles are removed under high vacuum. The residue is dissolved in ethyl acetate CH2C12 and the solution passed through a short -91column of silica gel (ethyl acetate -CH2Cl2) eluate is discarded) Elution with ethyl acetate -CH2Cl 2 (8:2) gives the product as a yellow glass (0.19 Mass Spectrum (CI) (CHO); 401 (M-fft.

Reference Example 223 1,4.5. 6-Tetrahvdro-6- (4-nitrohenzovlioyrazplor3. 4dIpvrijo[2. 3-bI azepine To a slurry of 0.51 g of 6-[(dimethylamino)methylene] 7, 8, 9-tetrahydro-9- (4-nitrobenzoyl) -51jpyrido(2,3-12]azepin-s-one in 17 ml of methanol under argon i s added 0.14 g of hydrazine hydrate.Thmitr is stirred overnight and the solvent removed under vacuum. The residue is dissolved in hot chloroformmethanol (95:5) and filtered through silica gel and washed filter pad with chloroform-methanol C(95:5) .The filtrate is concentrated to dryness to give 0.48 g of yellow solid.

Reference Example 224 1. 4.5. 6 Tetr rahyd r o- 6- (4 -am i nobhe nzo v 1) yr a zo Io f 3. 4 -di1 rovrido[2. 3-blazepine To a slurry of 0.170 g of 1,4,5,6-tetrahydro- 6 4 -nitrobenzoyl)pyrazolo[3,4-djpyrido(2,3-Lj]azepine in 8 ml of ethanol under argon is added 0.573 g of stannous S Schloride dihydrate (SnCl2*2H20) The mixture is reflux- .25 ed for 1 hour, diluted with ice-water and made basic with 10% NaHCO3 solution. The mixture is stirred hours and extracted with chloroform (3 times) The extract is dried (MgSO4) and the solvent removed under vacuum. Chromatography on silica gel with ethyl acetate as eluent gives 0.10 g of off-white crystals.

Reference Example 225 8-f rnimethylaminomethylenel-5.6.7.8-tetrphvdro-5-(4nitrobpnzoyl)-9H-ovyridor3.2-hlazepin-9-one As described for Reference Example 221, 5, 6 7 ,8-tetrahydro-5-(4-nitrobenzoyl)-9ii-pyrido[3,2-la]- -92azepin-9-one is reacted with tert-butoxybis(dimethylamino) methane to give the product as a solid.

Reference Example 226 1, 4,5. 6-Tetrahvdro-6- (4-nitrobenzovl) Pvrazolo f3, 4-d Ipyrido f 3. 2-bi azeipine As described for Reference Example 223, 8- [(dimethylamino) methylene]j 6, 7, 8-tetrahydro-5- (4nitrobenzoyl)-9i-pyridoj3, 2-u]azepin-9-oe is reacted with hydrazine hydrate to give the product as a solid, m.p. 255-256 0

C.

Reference Examrle 227 a 5. 6-Dihvdro-6- (4-aminobenzovl) -4H-isoxazolo F5. 4-di t th ien o f 3. 2 -b 1 a zen ine A mixture of 0. 50 g of 7- [(dimethylamino) :15 methylenel 5, 6, 7-tetrahydro-4- (4-nitrobenzoyl) -8Hjthieno[3,2-Diazepin-8-one, 0.234 g of hydroxylamine, hydrochloride and 16 ml of methanol is refluxed for 4 *..hours. The mixture is chilled and filtered and the solid washed with a small amount of cold methanol and cold ethyl acetate to give 0.41 g of tan crystals, m.p.

218-222'C. The preceding compound in ethanol is refluxed with SnCl2-H20 for one hour, cooled and diluted with ice-water. The mixture is made basic with NaHCO 3 and is stirred for 3.5 hours at room temperature.

*:25 The mixture is extracted with ethyl acetate and the extract washed with brine. The extract is dried (Na2SO 4 and the solvent removed. The residue is chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.

Reference Examlple 228 6. 7. 8-Tetrahydro-5- (4-nitrobenzovl) -9H-ovrido 3. 2-bi aze~in- 9-one A mixture of 0.313 g of 5-(4-nitrobenzoyl)-9hydroxy-6,7,8, 9-tetrahydro-5ai-pyrido[3,2-LLIazepile, 4 ml of CH2Cl2 and 0.75 ml of dimethylsulfoxide is chilled to and 0.405 g of cyanuric chloride is added. The -93mixture is allowed to stand at -25 0 C for 6.5 hours and 0.41 g of triethylamine is added. The mixture is stirred 10 minutes and poured into water. The mixture is extracted with dichloromethane and the extract washed with water, brine and dried (Na2SO4). The solvent is removed to give 0.39 g of solid. Chromatography on silica gel with ethyl acetate as solvent gives 0.17 g of crystals, m.p. 188-190 0

C.

Reference Example 229 Methyl 4-f(fl.l'-Biohenvll-2-carbonvl)aminol-3methoxvbenzoate A mixture of 10.0 g of [l,l'-biphenyl]-2carboxylic acid in 75 ml of methylene chloride and 12.52 of oxalyl chloride is stirred at room temperature for 15 15 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 NaHC03 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 3.20 g of the desired 25 product as a crystalline solid, m.p. 115-117 0

C.

Reference Example 230 Methyl 4- (fl.1'-Biphenvll-2-carbonvl)aminol-2chlorobenzoate A solution of 2.37 g of (1,1'-biphenyl]-2carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-2-chlorobenzoate and 1.49 g of N,Ndiisopropylethylamine in 50 ml of methylene chloride.

The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer -94is 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 231 4-f (11. 1'-Biphenyll-2-carbonvl)aminol-2-chlorobenzoic Acid 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 S. 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 15 vacuo 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 232 .1 '-Biphenvll-2-carbonvl)-aminol-3-methoxybenzovl Chloride A solution of 2.69 g of 4-[([l,l'-biphenyl]-2carbonyl]amino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour under Argon. The volatiles are removed in vacuo to give a residue which is stirred with hexane to give 2.58 g of 25 crystalline solid, m.p. 121-123 0 C. M+=361.

Reference Example 233 Methyl 4-f (fl.1'-Biphenyll-2-carbonyl)aminobenzoate 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 of N,N-diisopropylethylamine in 100 ml of methylene chloride at 0°C. The reaction mixture is stirred at V room temperature for 18 hours and washed with water, and saturated aqueous NaHC03 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 8.38 g of the desired product as a crystalline solid, m.p. 163-165 0

C.

Reference Example 234 4-f([l.l'-Biphenyll-2-carbonvl)aminolbenzoic Acid A 3.15 g sample of methyl 4-[([1,1'-biphenyl]- 2-carbonyl)amino]benzoate is refluxed for 8 hours in 100 ml of ethyl alcohol and 2.5 ml of 10N sodium hydroxide.

The cooled reaction mixture is acidified with acid]] S* 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.

15 M+H=318.

Reference Example 235 4-f (fl.'-Biohenvll-2-carbonvl)aminolbenzoyl Chloride A mixture of 1.39 g of 4-[([1,l'-biphenyl]-2carbonyl)amino]benzoic acid in 2.0 ml of thionyl 20 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 236 25 2-(Phenvlmethvl)benzovl Chloride A mixture of 5.0 g of 2-(phenylmethyl)benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.74 g of the desired product as an oil. M+=227 as methyl ester.

Reference Example 237 Methyl 4-ff2-(Phenvlmethvl)benzovllamino]benzoate 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 -96for 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 238 Sodium 4-f f2- (Phenvlmethvl) benzovl aminolben7oate A mixture of 4.90 g of methyl 4 -[[2-(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 S" give 4.25 g of the desired product m.p. 340-346 0

C.

15 Reference Examole 239 4 -f 2 -(Phenvlmethvl)benzovllaminolbenzoic 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 acu to give 3.75 g of the desired product, 246-247 0

C.

M+=332.

Reference Examole 240 4-f f2-(Phenvlmethvl)benzovllaminolbenzovl Chloride 25 A mixture of 2.0 g of 4-[2-(phenylmethyl)benzoyl]amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 1.53 g of the desired product as an oil. M+=346 as methyl ester.

Reference Examole 241 Methyl 4-f f(2-Phenvlmethvl)benzovllaminol-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 -97oil 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 NaHCO3 and the organic layer dried(Na2SO 4 The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 2.96 g of the desired product as a crystalline solid, m.p. 133-135 0 C. M+=380.

Reference Example 242 Methyl (2-Phenvlmethvl)benzovllamino1-3methoxvbenzoate A solution of 2.85 g of 2-(phenylmethyl)- 15 benzoyl chloride in 25 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4amino-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 NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 2.2 g of the desired .product as a crystalline solid, m.p. 129-131 0 C. M+=376.

25 Reference Example 243 2-Chloro-4-rf(2-Phenylmethyl)benzovllaminolbenzoic 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. 184-187 0 C. M+H=366.

98 Reference Example 244 3-Methoxv-4-[[(2-phenylmethyl)benzovllaminolbenzoic acid A mixture of 2.05g of methyl 4 2 -phenylmethyl)benzoyl]amino] U -3-methoxybenzoate in 75mL of absolute ethanol and 1.4mL of 10N 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 1.87g of the desired product as a crystalline solid, m.p. 176-178°C. M+H=362.

Reference Example 245 3-Methoxv-4-r[(2-phenylmethyl)benzoyl]aminolbenzoyl Chloride A mixture of 1.71g of 3-methoxy-4-[[(2-phenylmethyl)benzoyl]amino]benzoic acid in 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 1.71g of the desired product as a crystalline solid, m.p. 130-135°C. M+ =376 as the methyl ester.

Reference Example 246 [4'-(Trifluoromethyl)- 1 '-biphenyll-2-carbonyl Chloride A mixture of 5.0g of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid in 5.0mL 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 5.36g of the desired product as a colorless oil.

M+ =280 as methyl ester.

Reference Example 247 Methyl-4-[([4'-(trifluoromethyl) 1' -biphenyllcarbonyl)aminolbenzoate A solution of 3.13g of [4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl chloride in 25mL of methylene chloride is added dropwise to an ice cold solution of 1.84g of methyl 25 4-aminobenzoate and 1.43g -99of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 3.36 g of the desired product as a crystalline solid, m.p. 164-165 0 C. M+=396.

Reference Example 248 3-Methoxv-4-f (4'-(trifluoromethvl) l.1'-biohenvl1-2carbonvl)aminolbenzovl Chloride A mixture of 2.0 g of 3-methoxy-4-[([4'- (trifluoromethyl) [1,1'-biphenyl]-2carbonyl)amino]benzoic acid in 20 ml of thionyl chloride 15 is heated on a steam bath under Argon for 1 hour and S' 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 249 3-Methoxy-4-f (4'-trifluoromethvl) [.1'-biphenyll-2carbonvl)aminolbenzoic Acid Po* A mixture of 3.78 g of methyl 3-methoxy-4t rifluoromethyl) '-biphenyl]-2-carbonyl)amino]benzoate in 75 ml of absolute ethanol and 2.20 ml of 25 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 3.49 g of the desired product as a crystalline solid, m.p. 213- 215 0

C.

Reference Example 250 Methyl 3-Methoxv-4-f (4'-trifluoromethvl) 11.1'biohenvl -2-carbonvl) amino 1 benzoate A solution of 3.56 g of [4'-(trifluoromethyl) [1,l'-biphenyl]-2-carbonyl chloride in 25 ml of 0 -100methylene chloride is added dropwise to an ice cold solution of 1.81 g of methyl 4-amino-3-methoxybenzoate and 1.62 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate and hexane added at the boil to give 3.9 g of the desired product as a crystalline solid, m.p. 112-113 0

C.

Reference Example 251 2-Chloro-4-(([4'-(trifluoromethvl) [l.1'-biphenvll-2- Scarbonvl)aminolbenzovl Chloride A mixture of 1.39 g of 2-chloro-4-[([4'- 15 (trifluoromethyl) [1,1'-biphenyl]-2-carbonyl)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 252 2-Chloro-4- ([4'-(trifluoromethvl) 1,'-biphenvll-2carbonvl)aminolbenzoic acid S: A mixture of 3.83 g of methyl 2-chloro-4- 25 ([4'-(trifluoromethyl) 1 '-biphenyl]-2-carbonyl) 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.

0 -101- Reference Example 253 Methyl 2-chloro-4-f(14'-(trifluoromethl) biphenyll-2-carbonyl)aminolbenzoate A solution of 3.56 g of [4'-(trifluoromethyl)- [l,l'-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of methyl 2-chloro-4-aminobenzoate 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(Na2SO 4 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 15 product as a crystalline solid, m.p. 130-132 0

C.

Reference Example 254 4-1 (Trifluoromehvl) ll. 1biphenvl carbonvl)amino1benzoic Acid A mixture of 3.0 a of methyl fluoromethyl) [1,1 '-biphenyl]-2-carbonyl)amino]benzoate 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 25 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.

Reference Example 255 Methyl 6- f3-(2-Methylpyridinyl)carbonvlaminolpyridine- 3-carboxylate To a stirred solution of 3 g of methyl 6aminopyridine-3-carboxylate and 4 ml of N,N-diisopropylethylamine in 100 ml of methylene chloride is added dropwise 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 -102hours and quenched with water. The organic layer is washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue which is stirred with ether and the resulting solid collected and air dried to give 6.8 g of the desired product. M+=390.

Reference Example 256 6-F f3-(2-methylovridinvl) carbonvl1aminolpyridine-3carboxylic Acid To a solution of 6.5 g of methyl methylpyridinyl)carbonyl]amino]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 in vacuo to a residue. The residue is dissolved in water and neutralized with 15 acetic acid. The separated solid is filtered and airdried to give 3.0 g of the desired product. M+=257.

Reference Example 257 Methyl 6- 1 '-Biphenvl1-2-carbonvl)aminol-oyridine-3carboxvlate To a solution of 1.5 g of methyl 6-aminopyridine-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 [1,l'-biphenyl]-2-carbonyl 25 chloride. The reaction mixture is stirred at 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 258 6-f ([l.'1-Biphenyll-2-carbonvl)aminlopridine-3carboxylic Acid To a stirred solution of 2.5 g of methyl 6- [([1,1'-Biphenyl]-2-carbonyl)amino]-pyridine-3- 0 -103carboxylate 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.

Example 1 N-4-f 4 .5-Dihydroovrazolo[3.4-dlthieno[3,2-blaze.pin- 6 (lH)-vl)carbonvllphenyll-2-chloro-4-fluorobenzamidp To an ice bath cooled mixture of 296 mg of 6- (4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-h]azepine in 3.5 ml of methylene chloride is added 417 tl of triethylamine followed by a solution of 15 483 mg of 2-chloro-4-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An addi- ~tional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give a residue which is crystallized from ethyl acetate:hexane to give 520 mg of a white solid.

25 To a suspension of 340 mg of the preceding compound in ml methanol is added 1.2 ml of 1N NaOH. The reactants are stirred at room temperature for 1 hour. The reaction mixture is evaporated in vacuo to a residue which is diluted with 100 ml of ethyl acetate and filtered. The filtrate is washed with 30 ml each of water, brine and dried (NaSO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to a residue which is stirred with ethyl acetate:hexane to give 255 mg of white crystalline solid, m.p. 258-266 0

C.

0 -104- Example 2 N-f4- (4.5-Dihvdropvrazolof3.4-dlthieno f3.2-bl azepin- 6(1H)-vl)carbonvl phenvl -5-fluoro-2-methvlbenzamide To an ice bath cooled mixture of 297 mg of 6- (4-aminobenzoyl) 4,5, 6-tetrahydropyrazolo[3, 4-d]thieno[3,2-h]azepine in 3.5 ml of methylene chloride is added 417 p1 of triethylamine followed by a solution of 432 mg of 2-methyl-5-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 50 ml of methylene chloride is added followed by ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through 15 hydrous magnesium silicate and the filtrate evaporated in vacuo to give 570 mg of a foam residue. To a suspension of 564 mg of the preceding compound in 4 ml of *methanol and 4 ml of tetrahydrofuran is added 2.0 ml of e• 1N NaOH. The reactants are stirred at room temperature for 2 hours. The reaction mixture is diluted with 2 ml of IN HC1 and evaporated in vacuo to a residue which is partitioned between 50 ml of ethyl acetate and 20 ml of water. The resulting solid is collected, washed with ethyl acetate and dried to give 305 mg of the desired 25 product as white crystals, m.p. 310-312 0

C.

Example 3 N-f4-[(4,5-Dihvdroovrazolo[3.4-dthieno[3.2-blazepin- 6(1H)-yl)carbonyll-3-chlorophenvl1-5-fluoro-2methvlbenzamide To an ice bath cooled mixture of 345 mg of 6- (2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo- [3,4-d]thieno[3,2-h]azepine in 3.5 ml of methylene chloride is added 417 41 of triethylamine is added a solution of 432 mg of 2-methyl-5-fluorobenzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon.

0 -105- An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine.

The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give a foam residue. To a solution of 800 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 2.7 ml of IN NaOH. The reactants are stirred at room temperature for 1.5 hours.

The reaction mixture is neutralized with 1N HC1 and evaporated in vacuo to a residue which is diluted with ml of methylene chloride and water and then filtered.

SThe collected solid is dried at 60 0 C to give 275 mg of o, the desired product as an off-white solid, m.p. 310- 15 312C Example 4 N-f4-f(4.5-Dihvdropvrazolor3,4-dthienof3,2-blazepin- S6(1H)-vl)carbonvl 1-3-chlorophenvl -5-chloro-2fluorobenzamide To an ice bath cooled mixture of 345 mg of 6- (2-chloro-4-aminobenzoyl)-1, 4,5, 6-tetrahydropyrazolo- [3,4-d]thieno[3,2-b]azepine in 3.5 ml of methylene chloride under argon is added 417 ji1 of triethylamine followed by a solution of 482 mg of 25 benzoyl chloride in 1.5 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. An additional 40 ml of methylene chloride is added followed by 20 ml of water. The organic layer is washed with 20 ml each of 2N citric acid, 1M NaHCO3 and brine. The organic layer is dried (Na2SO4), filtered through hydrous magnesium silicate and the filtrate evaporated in vacuo to give 650 mg of the desired product as a solid residue. To a solution of 500 mg of the preceding compound in 4 ml methanol and 4 ml of tetrahydrofuran is added 1.51 ml of IN NaOH.

The reactants are stirred at room temperature for 18 -106hours. The reaction mixture is neutralized with IN HC1 and evaporated in vacuo to a residue which is diluted with 50 ml of chloroform and washed with water, brine and dried (Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate. The filtrte is evaporated in vacuo to a residue which is crystallized from ethyl acetate containing ethyl alcohol. The collected solid is dried to give 215 mg of the desired product as an off white solid, m.p. 282-288 0

C.

Example N-[4-f 4,5-Dihvdro-2-methyvlvrazolof3,4-d1thienof3.2-bl- S"azepin-6(2H)-vllcarbonvlIphenvyl2,4-dichlorobenzamide To an ice bath cooled mixture of 290 mg of 2,4,5,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo- 15 [3,4-d]thieno(3,2-h]azepine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon is added 186 g1 of triethylamine followed by 156 l of 2,4-dichlorobenzoyl chloride. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is S* dissolved in 50 ml of methylene chloride and washed with 20 ml each of water, IN NaHCO3, 2N citric acid and brine. The organic layer is dried (Na2SO4) and Sfiltered. The filtrate is concentrated in vacuo to give 25 a foam residue which is crystallized from ethyl acetate to give 330 mg of the desired product as a white crystalline solid, m.p. 265-267 0

C.

Example 6 N-14-f 4.5-Dihvdro-2-methylDyrazolof3.4-d1thienof3.2-blazeDin-6(2H)-vllcarbonylophenyllcyclohexane carboxamide To an ice bath cooled mixture of 260 mg of 2,4,6-tetrahydro-2-methyl-6-(4-aminobenzoyl)pyrazolo- [3,4-d]thieno[3,2-h]azepine in 4.0 ml of methylene chloride and 2.0 ml of dioxane under argon is added 168 Il of triethylamine followed by 134 il of cyclohexanecarbonyl chloride. The reaction mixture is stirred at -107room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 60 ml of methylene chloride and washed with ml each of water, IN NaHC03, 2N citric acid and brine. The organic layer is dried (Na2SO4) and filtered. The filtrate is passed through a pad of hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is crystallized from ethyl acetate to give 185 mg of the desired product as a white crystalline solid, m.p. 240-242 0

C.

Example 7 N-[4-[f4,5-Dihvdropvrazolo[3.4-dlthieno[3.2-blazepin- 6(2H)-vllcarbonvl1phenvl1-2-methvlbenzamide To a solution of 400 mg of 6-(4-aminobenzoyl)- 15 1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-blazepine in 12.0 ml of dioxane under argon is added 65 mg of sodium hydride (60% in mineral oil). After stirring for minutes, 176 u1 of o-toluoyl chloride is added. The reaction mixture is stirred at room temperature for 18 hours under argon. The reaction mixture is evaporated in vacuo to a residue which is dissolved in 40 ml of methylene chloride and washed with 20 ml each of water and brine. The organic layer is dried (Na2SO4) and filtered. The filtrate is concentrated in vacuo to give 25 a residue which is purified by chromatography on silica gel plates by elution with 1:1 ethyl acetate:hexane 100 mg of N-[4-[[4,5-dihydro-2-(2-methylbenzoyl)pyrazolo- [4,3-d]thieno[3,2-]jazepin-6(2) -yl]carbonyl]phenyl-2methylbenzamide as a white foam and 200 mg of the product as a white foam.

Example 8 N-[4-f(4.5-Dihydropvrazolof3.4-dlpyridof3.2-blazepin- 6(1H)-vl)carbonvl1 henvl -5-fluoro-2-methvlbenzamide As described for Example 2, 2 mmol of 6-(4aminobenzoyl)-1,4,5, 6-tetrahydropyrazolo[3,4-d]pyrido- -108- [3,2-bJazepine is reacted with 2.2 mmol of 5-fluoro-2methylbenzoyl chloride to give the product as a solid.

As described for Example 8, the following compounds are prepared.

Example 9 N- 14- (4-5-Dpihvdropvrazolo f3. 4-d I pvrido f3. 2-bI azepin- 6 N- 14- F(4.5-Dihvdropyrazolo f3. 4-d rwvridn f 3.2-bl a7PDin- 6(1H)-vl)carbonvll-3-chlorophenvll-5-fluoro-2methvlbenzamide Example 11 N-[4-f(4,5-Dihvdropvrazolo[3.4-dlpvridoV%.2-blazepin- 6 (lH) -vi)carbonvillohenvil -2-chloror'vridine-3-carboxamide Example 12 N-F5-[(4.5-Dihvdropyrazolor3.4-dlpvrido[3.2-blazerin- 6 (1H) -vi)carbonv 1 -2-Pyridinvl 1-5- fluoro-2methvibenzamide To a solution of 2 mmol 1,4,5,6-tetrahydropyrazolo[3,4-d~pyrido[3,2-blazepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mmol of 6- (5-f luoro-2-methylbenzoyl) amino) pyridine-3carbonyl chloride. After stirring over the mixture is worked-up as described for Example 1 and the initial solid treated with 1N NaOH in methanol as described for Example 1 to give the product as a solid.

Example 13 N-F5-r(4.5-Dihvdropyrazolof3.4-dlthienof3.2-blazepin- 6(lH) -vl)carbonvll-2-o)vridinvll-5-fluoro-2methvlbenzamide To a solution of 2 mmol of 1,4,5,6-tetrahydropyrazolo[3,4-d]thieno[3,2-h]azepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 4.2 mznol of (5-fluoro-2-methylbenzoyl)aminolpyridine-3carbonyl chloride. After stirring overnight, the mixture is worked-up as described for Example 1, and the -109initial solid treated with 1N NaOH as described for Example 1 to give the product as a solid.

Example 14 N-f4-f 10-Dihvdro-5H-pvrido[3. 2-blthienof2. 3-elazepin- 5-vl)carbonvll-3-chlororhenll-5-fluoro-2methvlbenzamide To a solution of 2 mrol of 5-(2-chloro-4aminobenzoyl)-4,10-dihydro-5li-pyrido[3,2-a]thieno- [2,3-ajazepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methyl- :9 .9 benzoyl chloride. After stirring at room temperature overnight, the mixture is washed with H20, 1M NaHCO3 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.

Example 999999 N-r4-r (6.1 ihvdro-5H-PV rido3.2-blt hienoIJ.2-elazepin- 5-vl)carbonvll-3-chloroohenyll-5-fluoro-2methvlbenzamide 9.9.

0-406 To a solution of 2 mmol of 5-(2-chloro-4aminobenzoyl)-6, 10-dihydro-5l-pyrido[3,2-Ljthieno- [3,2-aeazepine and 10 mmol of triethylamine in 25 ml of dichloromethane is added 2.1 mmol of 5-fluoro-2-methylbenzoyl chloride. After stirring at room temperature for 16 hours, the solution is washed with H20, 1M NaHC03 and brine. The solution is dried (Na2SO4) and the solvent removed to give the product as a solid.

Examle 16 N-f4-[(4.5-Dihvdropvrazolof3,4-dlpvridor2.3-blazepin- 6(1H)-vl)carbonvll phenvll-5-fluoro-2-methvlbenzamide As described for Example 1, a solution of 2 mmol of 4-(4-aminobenzoyl)-4,5-dihydropyrazolo [3,4-dIpyrido[2,3-bjazpeine and 10 mnol of triethylamine is stirred with 4.2 mmol of 5-fluoro-2-methylbenzoyl chloride in dichloromethane to give a solid. The solid is stirred with 1N NaOH in methanol and the mixture 0 -110worked-up as for Example 1 to give the product as a solid.

Example 17 f(4,5-Dihydropyrazolof 3.4-d I prido[2 3-b Ia zepin- 6 (1 H) -yvI) carbon I I -2-ovridinyll -5-fluoro-2rnethvlbenzamide As described for Example 13, pyrazolo[3,4-djpyrido[2,3-klazepine is reacted with 6- (5-fluoro-2-methylbenzoyl) amino] pyridine-3-carbonyl chloride to give the product as a solid.

Examole 18 N-F4-f(4,5-Dihydropyvrazolo[3.4-dlrovrido[2,3-blazepin- 6(lH)-vl)carbonvllohenvll rl.l'-biohenvll-2-carboxamide As described for Example 1, a solution of 2 9..:15 mrnol of 4-(4-aminobenzoyl)-4,5-dihydropyrazolo[3,4pyrido[2,3-t]azepine and 10 rnmol of triethylamine is stirred with [1,1'-biphenyl]-2-carbonyl chloride in 9....dichloromethane for 16 hours at room temperature. The initial solid is stirred with 1N NaOH in methanol as described in Example 1 to give the product as a solid.

r 4,5 D ihydr opyr az o1-o f3. 4- d IPyr jd o[12.3-bIa z eT)in 6 (1H) 1) c ar bo n yI I- 2 yr id in I I f1 1bi Phe n yI I-2 carbox-amide .:25 As described for Example 13, a solution of mmol of 4,5-dihydropyrazolo[3,4-djpyridot2,3-1]azepine and 10 mmol of triethylamine is stirred with 4.2 mmol of (5-f luoro-2-methylbenzoyl) amino] pyridine-3carboflyl chloride in dichloromethane at room temperature for 16 hours to give the product as a solid.

Exmple N-r4-[ (4.5-Dihvdroipvrazolof3,4-d1pvrido[2.3-blazetin- 6 (1H)-vi) carbonvill-3-o2henvi 1-5-fluoro-2-methvlbenzamide As described for Example 2, a solution of 2 mmol of 4- (2-chloro-4-aminobenzoyl)-4,5-dihydropyrazolo- 4-djpyrido[2, 3-t.]azepine and 10 mmol of triethylamine 111is stirred with 4.2 mmol of 5-fluoro-2-methylbenzoyl chloride in dichioromethane at room temperature to give a solid. The solid is stirred with 1N NaOH in methanol as described for Example 2 to give the product as a solid.

The following compounds are prepared as described for Example 1 (Table A).

HN\

S. N 9 R2

NHCC-,R

x R -112- 0* 000 sea:* 9 Se a 600000 600 :04r0, T .No 4i R3. R4 21 Cl H H H H H 22 Cl H H H H Cl 23 Cl H Cl H H H 24 Cl H Cl H H Cl Cl H H Cl H H 26 Cl H H Cl H Cl 27 F H H Cl H H 28 F H H Cl H Cl 29 CH3 H H H H H 30 CH3 H H IH H Cl 31 CH3 CH3 H H H H 32 CH3 CH3 H H H Cl 33 OCH3 H H H H H 34 OCH3 H H H H Cl 35 OCF 3 H H H H H 36 OCF3 H H H H Cl1 37 Cl1 H H H Cl1 H 38 Cl H H H Cl Cl 39 CH3 H H H CH3 H CH3 H H H CH3 cl 41 S-CH3 H H H H H 42 S-CH3 H H H H Cl 43 CF3 H H H H H 44 CF3 H H H H Cl CF3 H F H H H 46 CF3 H F H H Cl 47 Cl H H F H H 48 Cl H H F H Cl 49 N02 H H H H H N02 H H H H Cl 51 NH2 H H H H H 52 NH2 H H H H Cl -113- Ex. No. Rl R2 R3 R 4 R5 x 53 N (CH3) 2 H H H H H 54 N (CH3) 2 H H H H cl OCH3 H H Cl H H 56 OCH3 H H H H Cl 57 Cl Cl H H H H 58 Cl Cl H H H Cl 59 CF3 H H H F H cl cl H Cl H H 61 NHCH 3 H H H H H 62 NHCH 3 H H H H Cl1 63 H CF3 H H H H 64 H CF3 H H H Cl a a a. a.

-114- As described for Example 1, the following compounds are prepared (Table B).

Table B

HN

N

X

N NH R R 2 -115- R R R CH3 H H H H H 66 CH3 H H F H H 67 CH3 F H H H H 68 H OCH 3 OCH3 OCH3 H H 69 c 1 H H H H H F H F H H H 71 Br H H H H H 72 Cl H F H H H 73 Ph H H H H H 74 Cl H H Br H H CH3 H H H H B r 76 CH3 H H F H Cl 77 Cl H H Cl H H 78 CH3 CH3 H H H H 79 Cl H H F H H Cl H H CF3 H H 81 Cl H H H F H 82 Cl H H H Cl H 83 C 1 H H F H H 84 H H H H H

'N

H H H H H 86 CH3 H H H CH3 H 87 Cl H H F H Cl 88 cl H F H H Cl 89 Cl Cl H H H H Cl H H Cl H H 91 -OCH3 H H H H H 92 rOCF3 H HH H H -116- Table B (cont.'d) 93 -CF3 H H H H H 94 c 1 c 1 H Cl1 H H -SCH3 H H H H H 96 Cl H NO2 H H H 97 CH3 H H CH3 H H 98 F H H Cl H H 99 cl H H NH? H H 100 CF-i H H H H 101 -OCH3 H H Cl H H 102 Cl H H 5SCH3 H H 103 F H H H CF3 H 104 F H CF3 H H H 105 CF3 H F H H H 106 NO2 H H H H H 107 F H H H HH 108 Cl H NH2 H E H H w -117- The ffollowing compounds are prepared as described in Example 2 (Table C).

Table C

HN-N

N

N

R

1 0

NH

R R S. S4 -118- 109 Cl H H H H H 110 Cl H H H H Cl ill Cl H Cl H H H 112 Cl H Cl H H Cl 113 Cl H H cl H H 114 Cl H H Cl H Cl 115 F H H Cl H H 116 F H H Cl H Cl 117 CH3 H H H9 H H 118 CH3 H H iH H Cl 119 CH3 CH3 H H H H 120 CH3 CR3 H H H Cl 121 OCH 3 H H H H H 122 OCH 3 H H H H Cl1 123 OCF 3 HH H H H 124 OCF 3 H H H H Cl1 125 C 1 H H H Cl1 H 126 Cl H L H H C I C1 127 CH3 Hj H H CR3 H 128 CR3 H H H CR3 Cl 129 S-CH3 H H H H H 130 S-CH3 H H H H Cl 131 CF3 H H H H H 132 CF3 H H H H Cl 133 CF3 H F H H H 134 CF3 H F H H Cl 135 Cl H H F H H 136 Cl H H F H Cl 137 N02 H H H H H 138 N02 H H H H Cl 139 NH2 H H H H H 140 NH2 H H H H cl -119- Table B (cont'cl) 141 N (CH 3 2 H H H H H 142 N (CH3) 2 H H H H Cl 143 OCH 3 H H cl1 H H 144 OCH3 H H H H Cl1 145 cl c1 H H H H 146 cl C1 H H H cl1 147 CF3 H H H F H 148 cl C1 H Cl H H 149 NHCH3 HH H H H 150 NHCH3 H H H H Cl1 151 H CF3 H H H H 152 H CF3 H H H Cl

S..

S

S*

S. 55

S

S -120- As described for Example 2, the following compounds are prepared.

Table D

NH

CH2

S*

R

A C or N -121- .too*:

S.S.

000.

-O

.00.

e iii. 153 CH3 H H H H -C 154 CH3 H H HH H N 156 cl H HF H H c 157 cl H H H cl c 158 cl H H H H N 159 cl H cl H H c 160 cl H cl H H N 161 cl H H F H c 162 -OCH3 HH H H c 163 -OCH3 H H H H N 164 -OCH3 H H cl H c 165 -OCH3 H H -OCH3 H c 166 -OCH3 H H -OCH3 H N 167 -OCH3 H H cl H N 168 CH3 F H H H c 169 H F H H H N 170 CH3 -CH3 H H H 171 cl i H H c 172 CI 1 H H H N 173 F cl H H H c 174 F H! cl H H N 175 -SCH3 H H H H c 176 -SCH3 H H H H N 177 F H H cl H c 178 F H H cl H N 179 F H H H cl c 180 H -CF 3 H H H c 181 H -CFm) H H H N 182 CF3 H H H H c 183 -OCF3 H F H H c 184 CH3 H ,qF H c -122- As described for Example 5, the following compounds are prepared (Table E).

Table E ~.No R.4 R 185 CH3 H H H H H 186 CH3 H H F H H 187 CR3 H H H H 188 CH2Ph H H H H Cl 0 189 Cl H H H H H 190 F H F H H H 191 Br H H H H H 192 Cl H F H H H 193 Ph H H H H H 194 Cl H H Br H H 195 CH3 H H H H Br 196 CR3 H H F H Cl 197 Cl H H Cl H H 198 CR3 CH3 H H H H 0 199 Cl H -H F HH -123-

S

5* 5*

S

*5 Ex. No R 1 R2 R3 R4 R5 x 200 cl H H CF3 H H 201 CI H H H F H 202 Cl H H H Cl H 203 Cl H H F H H 204 -I H H H H H

'N)

205 H H H H H 206 CH3 H H H CH3 H 207 Cl H H F H Cl 208 CI H F H H Cl 209 Cl Cl H H H H 210 Cl H H Cl H H 211 -OCH3 H H H H H 212 OCF 3 H H H H H 213 -CF3 H H H H H 214 Cl Cl1 H cl1 H H 215 -SCH3 H9 H H H H 216 Cl H N02 H H H 217 CH3 H H CH3 H H 218 F H H ClI H H 219 Cl H H NH2 H H 220 F CF3 H H H H 221 -OCH3 H H Cl1 H H 222 Cl1 H H -SCH3 H H 223 F H H H CF3 H 224 F H CF3 H H H 225 CF3 H F H H H 226 N02 H H H H H 227 1 F H H H H H 228 1 Cl1 H NH2 H H H -124- As described for Example 5, the following compounds are prepared (Table F).

Table F *o RI R2 R3 R4 229 CH3 H HHH 230 CH3 H H F H H 231 CH3 H H H H 232 CH2Ph HH H H Cl1 233 C 1 H H H H H 234 F H F H H H 235 Br H, H H H H 236 C 1 H F H H H 237 Ph H H H H H 238 Cl1 H H Br H H 239 CH3 H H H H B r 240 CH3 H H F H Cl1 241 C 1 H H I Cl1 H H 242 CH3 CH3 H H H H 243 Cl H H F H H -125- Exlo Rl R2 3 244 Cl H H CF3 H H 245 Cl H H H F H 246 Cl H H H Cl H 247 Cl H H F H H 248 H H H H H

N

249 H H H H H 250 CH3 H H H CR3 H 251 Cl H H F H Cl 252 Cl H F H H Cl 253 Cl Cl H H H H 254 Cl H H Cl H H 255 -OCH3, H H H H H 256 OCF3 H H H H H 257 -CF3 H H H H H 258 Cl Cl H Cl H H 259 -SCH3 H H H H H 260 NO? H H H 261 CH3 H H CH3 H H 262 F H H C 1 H H 263 Cl H H NH2 H H 264 F CF3 H H H H 265 -OCH3 H H Cl H H 266 Cl H H -SCH3 H H 267 F H H H CF3 H 268 F H CF3 H H H 269 CF3 H F H H H 270 N02 H H H H H 271 F H H H H H 272 Cl H NH2 H H H -12 6- As described for Example 2, the following compounds are prepared (Table G).

Table G

HN'\

N N x 0

I

NH

o .3 R4. 273 CR3 H H H H H 274 CR3 H H F H H 275 CR3 F H H H H 276 CH2Ph H H H H Cl1 277 C 1 H H H H H 278 F H F H H H 279 Br H H H H H 280 Cl1 H F H H H 281 Ph H H H H H 282 Cl1 H H B r H H 283 CR3 H H H H Br 284 CR3 H H F H Cl1 285 Cl H H Cl1 H H 286 CR3 CR3 H H HH 287 Cl H H F H H -127- Ex. No Rl R2 R3 R4 S. S S SS* S 288 Cl H H CF3 H H 289 Cl H H H F H 290 Cl H H H Cl H 291 Cl H H F H H 292 H H H H H 293 H H H H H 294 CH3 HH CH3 H 296 ClHH H HHC 297 Cl Hl H H H Hl 298 Cl H H Hl H Hl 299 CH3 Hl H H H H 300 OCF H H Hl H H 301 -OCF3 H H H H H 302 OCl Hl H Hl H H 303 -SCH3 H H H H H 304 Cl Hl H0 H H H 305 -CH3 H H CH3 H H 306 F H H Cl H H 307 Cl H H NH2 H H 308 F CF3 H H H H 309 -OCH3 H H Cl H H 310 Cl H H -SCH3 H H 311 F H H H CF3 H 312 F H CF3 H H H 313 CF3 H F H H H 314 N02 H H H H H 315d F H H H H I H 1 316 Cl H NH2 H H H -128- As described for Example 2, the following compounds are prepared (Table H).

.Table

H

:M RxN .i .R5x 317 CR3 H H H H H 318 CH3 H HF H H 319 CR3 E H H H 320 CH2Ph H H H H Cl 321 Cl H H H H H 322 F H F H H H 323 Br H H H H H 324 Cl H F H H H 325 Ph H H H H H 326 C1 H H Br H H 327 CH3 H H H H Br 328 CR3 H H F H Cl 329 Cl H H Cl H H 330 CR3 CH3 H H HH 331 Cl H H F HH -129- C C

C.

C

Ex. No Ri R2 R3 R4 R5 x 332 cl H H CF3 H H 333 Ci H H H F H 334 Cl H H H Cl H 335 ci H H F H H 336 H H H H H 33-7 ~4H H H H H 338 CH3 H H H CH3 H 339 Ci H H F H Cl 340 Ci H F H H Cl 341 Cl Cl H H H H 342 Cl H H Cl H H 343 -QCH3 H H H H H 344 OCF3 H H H H H 345 -CF3 H H H H H 346 Cl Cl H C i H H 347 -SCH3' H H H H H 348 Cl H N02 HH H 349 CH3 H H CH3 H H 350 F H H Cl H H 351 Cl H H NH2 H H 352 F CF3 H H H H 353 -OCH3 H H Cl H H 354 Cl H H -SCH3 H H 355 F H H H CF3 H 356 F H CF3 H H H 357 CF3 H F H H H 358 N02 H H H H H 359 F H H H H H 360 Cl H NH2 H -r H H -130- N-[14-r 5-Dihydro-2-methvyliorazolor3 4-d Ithielor3. 2blazepin-6(2H)-vl) cprbonvl-lphenivll-2-mfethylbenzamide As described for Example 5, 2,4,5,6tetrahydro-2-methyl-6- (4-aminobenzoyl) pyrazolo 4-.j thieno(3,2-bjazepine is reacted with 2-methylbenzoyl chloride to give the product as crystals (from ethyl acetate) m.p. 257-260 0

C.

Example 362 N-f4-rc4,5-Dihvdropyrzolo[3,4-dlthielo3.2-blazepi- 6(1H)-v1)carbony11Phenvl l.1'-biphenvll-2-carboxamide As described for Example 2, 6-(4-aminobenzoyl) 6-tetrahydropyrazolol3, 4-djthieno[3, 2-bjazepine (297 mg) is reacted with 0.542 g of biphenyl]-2-carbonyl chloride to give 0.70 g of bis acylated product. A mixture of this product in 13 ml of tetrahydrofuran-methanol and 2.3 ml of 1 N NaOH is stirred for 18 hours at room temperature. To the mixture is added 2.3 ml of 1 N HCl and the solvent removed. The mixture is triturated with 50 ml of CH2Cl2, filtered and the solid washed with CH2CI2 and water to give 0.27 g of off-white crystals, m.p. 280- 284 0

C.

N-r4-f (4,5-Dihvdiro-6H-isoxazolo[5.4-dlthieflo[3. -bl azepin-6-vl) carbonvllphenvl1-5-fluoro-2methlbelzamide As described for Example 1, a solution of 2 mrnol of 5, 6-dihydro-6-(4-aminobenzoyl)-4Hisoxazolo [5,4-_djthienoI13,2-b.Iazepine and 5 mrnol of triethylamine is reacted with 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane under argon for 16 hours to give the product as a solid.

The subject compounds of the present invention are tested for biological activity.

Binding Assay to Rat Hepatic VI cptors S-131- Rat liver plasma membranes expressing the vasopressin V1 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-HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0.1 mM phenylmethylsulfonylfluoride (PMSF) and kept frozen at -70 0

C

until used in subsequent binding experiments. For binding experiments, the following is added to the wells of a ninety-six well format microtiter plate: 100 il of 100.0 mM Tris*HCl buffer containing 10.0 mM MgCl2, 0.2% heat inactivated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg aprotinin, 1.0 mg 1,10- 1 phenanthroline, 2.0 mg trypsin inhibitor, 10.0 mg 15 and 0.1 mM PMSF, 20.0 p.1 of [phenylalanyl-3,4,5- 3

H]

vasopressin 45.1 Ci/mmole) at 0.8 nM, and the reaction initiated by the addition of 80 Cl. of tissue membranes containing 20 p.g of tissue protein. The plates are kept undisturbed on the bench top at room 20 temperature for 120 min. to reach equilibrium. Nonspecific samples are assayed in the presence of 0.1 JIM of the unlabeled antagonist phenylalanylvasopressin, •o added in 20.0 p.1 volume to a final incubation volume of 200 p 1. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the S"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).

Binding Assay to Rat Kidney Medullary V2 Recetors Medullary tissues from rat kidneys are dissected out, cut into small pieces and let soak in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA with many changes of the liquid phase, until the -132o solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF using a Potter-Elvehjem homogenizer with a teflon pestle. The homogenate is filtered through several layers (4 layers) of cheese cloth. The filtrate is rehomogenized using a dounce homogenizer, with a tight fitting pestle. The final homogenate is contrifuged 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 15 al, J. Biol. Chem., 1953). The membrane suspension is stored at -70 0 C, in 50.0 mM Tris-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 use in subsequent binding experiments.

For binding experiments, the following is added in L1 volume to wells of a 96 well format of a microtiter plate: 100.0 p.1 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, 10.0 mg and 0.1 mM PMSF, 20.0 .1 of 3 H] Arginine 8 vasopressin 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 .1 of tissue membranes (200.0 p.g tissue protein). The plates are left undisturbed on the bench top for 120 min. to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 pM of unlabeled ligand, added in 20 .1 volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 p volume to a final incubation volume of 200 .t1.

Upon completion of binding, the content of each well is -133filtered 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).

Radioliaand Binding Experiments with Human Platelet Membranes Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY.

Platelet Membrane Preparation: Frozen platelet rich plasma (PRP), received 15 from the Hudson Valley Blood Services are thawed to room temperature. The tubes containing the PRP are centrifuged at 16,000 x g for 10 min. at 4 0 C and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 mM Tris-HC1, pH 7.5 containing 120 20 mM NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000 x g for 10 min. This washing step is S. repeated one more time. The wash is discarded and the lysed pellets homogenized in low ionic strength buffer of Tris*HCl, 5.0 mM, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000 x g for 10 min. The resulting pellet is resuspended in Tris*HCl buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g for 10 min.

The final pellet is resuspended in 50.0 mM Tris-HCl buffer pH 7.4 containing 120 mM NaCl and 5.0 mM HC1 to give 1.0-2.0 mg protein per ml of suspension.

Bindino to Vasopressin V1 Receptor Subtype in Human Platelet Membranes: In wells of a 96 well format microtiter plate, add 100 il of 50.0 mM Tris*HCl buffer containing 0.2% BSA and a mixture of protease inhibitors (aprotinin, -134- 0 leupeptin etc.). Then add 20 p1 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 p1 of platelet suspension (approx. 100 p.g protein). Mix all reagents by pipetting the mixture up and down a few times. Non-specific binding is measured in the presence of 1.0 [LM of unlabeled ligand (Manning or Arg 8 Vasopressin). Let the mixture stand undisturbed at room temperature for ninety (90) min. Upon this time, rapidly filter off the incubate under vacuum suction over GF/B filters, using a Brandel® Harvester.

Determine the radioactivity caught on the filter disks by the addition of liquid scintillant and counting in a liquid scintillator Binding to Membranes of Mouse Fibroblast Cell Line (LV- 2) Transfected with the cDNA expressing the Human V 2 Vasopressin Receptor 20 Membrane Preparation Flasks of 175 ml capacity, containing 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 min. The content of all flasks is poured into a centrifuge tube and the cells pelleted at 300 x g for 15 min. 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 min to remove ghost membranes. The supernatant fluid is centrifuged at 100,000 x g for -135qw min 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 Bindina For binding experiments, the following is added in Ll volume to wells of a 96 well format of a microtiter plate: 100.0 p1 of 100.0 mM Tris.HCl buffer containing 0.2% heat inactivated BSA, 10.0 mM MgCl2 and 4 a mixture of protease inhibitors: leupeptin, 1.0 mg 15 aprotinin, 1.0 mg 1,10-phenanthroline, 2.0 mg trypsin inhibitor, 10.0 mg and 0.1 mM PMSF, 20.0 Ll of 3 H] Arginine 8 vasopressin 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 p1 of tissue membranes (200.0 gg tissue protein). The plates are left undisturbed on the bench top for 120 min to reach equilbrium. Non-specific binding is assessed in the presence of 1.0 pM of unlabeled ligand, added in 20 p1 volume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 p1 volume to a final incubation volume of 200 .11. Upon completion of binding, the content of each well is filtered off, using a Brandel® cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand-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).

-136- Vasopressin V- Antaconist Activity in Conscious Hvrdated Rats Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound.

One hour later, arginine vasopressin (AVP, antidiuretic hormone, ADH) dissolved in peanut oil is administered at 0.4 pIg/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 for four 15 hours. Urine volume is measured 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 060 in a Beckman E3 (Electrolyte 3) Analyzer.

In the following results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity. The results cf this test on representative compounds of this invention are shown in Table 2.

Vasopressin VI Antagonist Activity in Conscious Rats Conscious rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiltration with 2% procaine (0.2 ml). Using aseptic technique the ventral caudal tail artery is isolated and a cannula made of PE 10 and 20 (heat-fused) tubing is passed into the lower abdominal aorta. The cannula is secured, heparinized (1000 sealed and the would closed with one or two stitches of Dexon 4-0. The caudal vein is also cannulated in the same manner for intravenous -137drug 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 (I.U.)(350 I.U.=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 min. later.

Percentage of antagonism by the compound is calculated using the pre-drug vasopressin vasopressor response as 100%.

-138- TalS Binding Assay to Rat Hepa.tic VI Receptors and Rat Kidney Medullary V2 Receptors or *Bindingp to Vl Recetor Subtvne in Human Platelet and **Binciinct to Membranes of Mouse Fibroblast Cell Line Transfected with the cDNA Expressinct the Human V-2p2L--

N-N

o NHCOAr 0 AA

R

-139- ViINyjI4 N o 361 CH3 H CRH 2.01 0.024 *1 .74 *0 .22 CR3 H cI C H 2.1 0.038 1~ *4.1 *0 6 CR3 H CRH 4.7 0.23 7 H H C \HC 2.1 0.12 *0.24 *0 .13 1 H H cICRH 2.0 0.34 2 H H CH 3 CRH 1.7 0.069 t F0 .0 71 3 H Cl OH 3 C H 24% at 0.0061 4 H Cl F CR 8% ar 0.036 1 .Lm -140- 0al 1 f± A~ Tn (rcn-,ri r-i vasopressin~~hin VoiIQ1.dIQ.I Wo. ~~Lt a -i t I r~ ~m m *78 13.3±0.3 229±6 6 12.1+1 497+53 4 12.4±0.8 361±30 76 2+0.2 1226+58 110 2 15.3 535 2 10 2 117.8 429 7 10 2 120.8 322 Water-load control Water-load Control4-DMSO AVP-control Omvtocin Pecepto- Rinding Mpmbrane P-paration Female Spracrue-Dawley rats weighing approximately 200-250 g are injected intramuscularly 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.RCl, containing 0.5 mMv dithiothreitol and 1.0 mv 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 contrifuged at 1000 x g for 10 min. The clear -141supernatant is removed and recentrifuged at 165,000 x g for 30 min. 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]Oxytocin.

Radioligand Binding Binding of 3,5-[ 3 H]Oxytocin 3 H]OT) to its receptors is done in microtiter plates using 3 H]OT, at various concentrations, in an assay buffer of 50.0 mM Tris.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 min., at 22 0 C, by rapid filtration through glass fiber filters using a Brandel® cell harvester 20 (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 sites (IC50) are calculated by a computer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).

The results of this assay on representative examples are shown in Table 3.

SUBSTITUTE SHEET (RULE 26) -142- STable 3 Oxvtocin Binding Assay UMose Inhibition 361 10 57 6.4 10 47 6 10 94 1.7 7 10 1 10 93 2 10 91 1.3 3 1 21 4 1 0_ The compounds of the present invention can be 5 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 10 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 in viva.

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 powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, -143and elixirs containing, for example, from about 20 to 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 of 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 20 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 000 optimal therapeutic response. For 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 glycols, non-ionic surfactants 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 de- -144sired. 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 20 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 of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi.

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

The new tricyclic non-peptide vasopressin antagonists of this invention are useful in treating conditions where decreased vasopressin levels are -145desired, 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 vasopressin antagonists of this invention are therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosisbleeding and abnormal states of water retention.

In particular, the oxytocin antagonists of this invention are useful in the prevention of preterm 15 labor and premature birth which is a significant cause of infant health problems and infant mortality.

e oo o*

Claims (38)

1. A compound selected from those of the formula: 0E 0 0 A-B wherein Y is a bond or a moiety selected from -(CH 2 -CHOI-, -CI-O-lower alkyl(C 1 -C 6 -CH-S-lower alkyl(C 1 -C 6 -CHNH 2 -CHNH-Iower alkyl(CI-C 6 -CHIIN-Iower alkyl(C 1 -C 6 2 CH-No 0 1 C H- N CH-N,_ -CHOCO-lower alkyl(C 1 -C 6 -CI-NI-(CH 2 2 -CI-NH(CH 2 -NH-Iowver alkyl(C 1 -C 6 -CHN H(CH_ 2 )m,-N[lowver alkyl(C 1 -C 6 2 -CHNH(CH 2 )n. 1 -S-Ioxver alkyl(C 1 -C 6 ~;o-CHNH(CH 2 )m,-0-ower alkyl(C I-C 6 I OH 1 w r l y C C 6 S, 0, -NH, -N-lower alkyl( CI-C 6 -NCO-lower alkyl(CI-C 6 mn is an integer of 2 to 6; A-13 is a mnoiety selected from -(CH)nN- and C2n R 3 wherein n is an integer 1 or 2 provided that when Y is a bond, n is 2; and the moiety: -147- represents: an unsaturated 6-membered heterocyclic aromatic ring containing one nitrogen atom, optionally substituted by one or two substitutents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, or S; and the moiety: 0E O E 10 represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Ci- C3)lower alkoxy or (Cl-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom S. 20 together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (Cl-C3)lower alkyl, halogen, or (Cl-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: -148- 6 R X RandR6 S R N wherein X is selected from 0, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower aikyl (Cl-C3) -CO- lower alkyl (Cl-C3), R1 and R2are selected from hydrogen, (Cl-C3) lower alkyl, (Cl-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)iower alkyl, (Cl-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -14 9- R Ia -NCOAr', R R -NCONAr', -CONAr', -NCOCH 2 Ar', CH 2 00Ar', R a -N-S O2 R I a -NC O-(CH 2 cyclI oal kyl N- SOCH 02 2 RaO ,a -N-P- 2 4 S S Ra a0 -N-C-0-lower alkyl (C 3 C.)straight or branched, I NSO 2 lower al k l (3 8 .S agtrah branched, ed N-C-o-e alower 3,al yl(3-)t r ahedrbrahd RO R 0l a N-C-lower al kenyl (03- 0 8 )st rai ght or branched, -NSO 2 -lIow er al kenyl (C 3 C 8 )straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -150- (CH)q N~R (CH 2 No C 2 )qNj (H 2 )q N 0 9 9 .9 9 9 9**9 .99 9*99 9 9* *99* 9*99 .9 9. 9 9 V

9. 9 9* .9 alkyl(C1--C3), -CR2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b -N11 -CM 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 10 alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: R8- R 8- -151- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N E F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -C0 2 lower alky'l(Cl-C 3 and Ra and Rb are as hereinbefore VOGO10 defined; 0 a moiety of the formula: 0OOvO R sa R S...e 696 0 lowerowe aikyl, C- -0 -lower alkyl(C 1 -C 3 3FI wheei -0C-lowe r a sC 1 C) -S-lneoe dekfined; 3 wheei Ra andet Rb ae aso eeibeurldfied -152- -M-Rd wherein Rd is lower alkyl (C 3 lower alkenyl(C3-C 8 -(CH 2 )p-cycloalkyl(C3-C6), when M is O, S, NH, NCH3 and the moiety -M-Rd wherein Rd is selected from the moieties: (CH2)p I (CH 2 )p wherein p is zero to four and M is a bond or M is selected from O, S, NH, NCH3; wherein R 1 R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: 5 8 R R and -153- wherein W' is selected from 0, S, NH, N-lower alkyl(Cl- C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C 1 -C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C1- C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1- C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C3), -0-CO-lower alkyl (C1-C3) and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower aikyl (C1-C3), -N-[lower alkyl(Cl-C3)12, -O-lower alkyl(Ci-C3), -N(Rb)(CH2)q-N(Rb)2, and the pharmaceutically acceptable salts thereof. 2. A compound according to Claim 1 wherein Y 15 is -CH2-; A-B is a moiety: (CH 2 )nN- and N- (CH 2 1 3 13 R R wherein n is an inteaer 1 or 2 and R 3 is as defined in Claim 1. 20 3. A compound according to Claim i wherein Y is a bond, A-B is a moiety: and N- (CH 2 3 3 R R wherein n is an integer 2 and R 3 is as defined in Claim 1. 4. A compound according to Claim 1 wherein Y is O, S, NH, N-lower alkyl(C1-C 6 -NCO-lower alkyl(C1- C6), A-B is a moiety: -154- (CH and N- (CH)- R 3 13 R R wherein n is an integer 1 or 2 and R 3 is as defined in Claim 1. A compound according to Claim 1 wherein Y is -CH2-; A-B is a moiety: -(CH 2 and N- (CH 2 )n R3 3 R R wherein n is an integer 1 and R 3 is as defined in Claim 1. 6. A compound according to Claim 1 wherein Y 10 is 0, S, NH, N-lower alkyl -NCO lower alkyl(C1- C6) and A-B is a moiety: (CH 2 and N- (CH 2 R3 3 R R wherein n is an integer 1 and R- is as defined in Claim 7. A compound selected from those of the formula: S Y O E A-B wherein Y is a bond or -CH2-, A-B is -155- (CH2 and N- (CH 2 3 3 R R wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered hererocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Ci- C3)lower alkoxy or (Ci-C3)lower alkylamino; a 10 membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom S: 15 together with either one o::ygen or one sulfur atom; wherein the 5 or 6-membered heterocyciic rings are optionally substituted by (C1-C3)lower alky:l, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: 6- 6 R6 R R M~d and/ SdR R 7 N wherein X is selected from 0, 5, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower aikyl (Cl-C3), Rl and R 2 are selected from hydrogen, (Cl-C3) lower alkyl, (Cl-C3) lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (CI-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -157- R R R R R -NCOAr', -GONAr', -NCOCH 2 A, -NCONAr', R I a -OH 2COAr', -N CO-(CH 2 cycl oal kyl R R R -N-SO 2 -N-SO 2 CH 2 b N P N j P *R 2 2 R aO ~-N-C-0-lower alkyl (C 3 C)st r aight or branched, -NNSO 2 we alkyl(C 3 -C 8 )straight or branched, -NC-C- lower alk eyl C)st raight or branched, RO a a- N-C-lower alkenyl (C3- C) straight or branched, -NSO 2 lower alkenyl(C 3 C,)straight or branched, wherein cycloalkyl is defined as CC 3 -C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -158- (CH Nb C2)q- No (CFY)q N 0 (CH 2 N\ 10 a a a. aikyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b -caj wherein J is Ra, lower alkyl(C3-CB) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: 8 CH 2 8 I R 0 -R 8" 9- or -CH2-K' wherein K' is (Cl-C 3 )-iLower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic 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, (C1-C3)lower alkyl, hydroxy,- CO-lower alkyl CH-O, (Cl-C3) lower alkoxy, -C02- lower alkyI(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: N- COCHAr' Rc CC *.:lower alkyl, -0-lower alkyl(C I- C 3 Q-I, a15 -0-C-lower alkyl(C 1 -C 3 -S-lower alkyl(C,-C 3 -S-CH )2 b NH(CH 2 b NH(CH)q NC$b R b 2q R b 0- (CH 2 2 N Rb wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -160- 0 M- Rd wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6) 1 when M is 0, S, NH, NHCH3 and the moiety -M-Rd wherein Rd is selected from the moieties: (CH 2 )(CH 2 12N R R R'R (CH 2 )p (CH 2 S 0 wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are I 4 0 09 V@ a 999999 9 .9.9 9 9 9. 9 @9 99 9 *9 .4 ~9 9 9. 9 *4 9. as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -161- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(Cl-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, 0-lower alkyl(C 1 -C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C 3 -S-lower alkyl(Ci-C 3 halogen, -NH-lower alkyl(C 1 C 3 -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(CI-C3), NHCO lower alkyl(C 1 C 3 -0-CO-lower alkyl (C1-C3) and CF3 and; R 1 0 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (C1-C3), -N-[lower alkyl(C1-C 3 2, -0-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof. 8. A compound selected from those of the 15 formula: S Y o "wherein Y is a bond, or -CH2-, A-B is (CH2)nN- and -N-(CH2)n wherein n is an integer I or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents -162- selected from (Cl-C3)lower alkyl, halogen, amino, (Cl- C3)lower alkoxy or (Cl-C3)lower alkylamino; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R 6R R and Sd N *wherein X is selected from 0, 5, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl (Cl-C3), -CO- lower alkyl (Cl-C 3 Rl and R 2 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R6 is selected from moieties of the Lormulae: -163- R R R RRb ija a Ia b -NCOAr', -CONAr', -NCOCH 2 Ar', -NOONAr', R I a -CH 2 00Ar, -NCO-(CH 2 cycloalkyl, R R R a a 2 -N-SO 2 CH 2 R ~RR -N-P 0-r-P 1 2]-222 RR 2R -N-C-O-lower alkyl(C -C)straight or branched, R a 0l Ra 1 NO lower al kyl (C 3 C,)st raight or branched, *S 2- lower al kyl (C 3 C 8 )st raight or branched, 2 ,afj lower alkenyl (C 3 C.)st raight or branched, R 0 R aI a -N-C-lower alkenyl(C 3 C 8 )straight or branched, NSO 2 -Ilower alkenyl(C 3 C.)straight or branched, wherein cycloalkyl iJs defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -164- (CH N ~(CH 2 No C 2 No (H 2 )q-N 0 *e S alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of he formula: R b cQJ wherein J is Ra, lower alkyl(C3-Cg-) branched or unbranched, lower alkenyl(C3-CB) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenvl(C3-C8) branched or unbranched, terrahydrofuran, tetrahydrothiophene, and the mole:_';es: R "'O-CH 2 R8 /3- 0 -165- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahycirofuran, tetrahydro-thiophene 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 halogren, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(C1--C3). CHO, (Cl-C3)lower alkoxy, -C02- lower alkyl (C1-C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: R* a -N-CGGHAr' R. wherein R is selected from halogen, (C 1 -C3) lowe alyl,-0-lower alkyl(C CHI, lower alkyl (C 1 -C 3 -S-lower alkyl(Cl-C 3 (CH R b ~NH(CH 2 )q C\ <b NH(CH 2 )q N(Rb 0 C wherein Ra and Rb are as hereinbefore defined; (di) a moiety of the formula: -M-Rd. -16 6- wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C8), (CH2)p-cycloalky1(C3-C6), when M is 0, S, NH, NCH 3 and the moiety -M-Rd wherein Rdj is selected from the moieties: (CH 2 )p (CH 2 p- (CH 2 )p- wherein p is zero to four and M is a bond selected from 0, S, NH, NCH3; wherein Rl, or M is R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: RgR ,and -167- wherein W' is selected from O, S, NH, N-lower alkyl(Cl- C 3 NHCO-lower alkyl(C1-C 3 and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(Cl-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C3), -S-lower alkyl(Cl-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(Cl-C3) 2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(Cl-C3), NHCO lower alkyl(C 1 C3), -O-CO-lower alkyl (Cl-C3) and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(C 1 C3), -NH-lower alkyl (C1-C3), -N-(lower alkyl(Cl-C3) ]2, -O-lower alkyl(Cl-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof. 9. A compound selected from those of the *15 formula: S Y O YE S A-B wherein Y is a bond or -CH2-, A-B is -(CH 2 )nN- and -N-(CH 2 .3 3 R R wherein n is an integer I or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: OE represents: a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; wherein the 5-membered heterocyclic ring is -168- optionally substituted by (C 1 -C3)lower alkyl, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R 6 R X I N MRd and S R7 N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy :and halogen; R 6 is selected from moieties of the formulae: -169- R R R R R a iaa b -NCOAr', -CONAr', -NCOCH 2 Ar', -NCONAr', -CH 2COAr', -NCO-(CH 2 ),-cycl oai kyI R R R -N-SO 2 SO 2 CH 2 *2 2 R R RaO 1 -N-P N- P- R R 2 2 R2 -N-C-O-Iower alkyl(C 3 C 8 )St raight or branched, R jai lower al kyl (C 3 Cd)st raight or branched, NSO- Iow0 loe a key (CI C(Cs -C)sr igtor aight rbrachd RO R rI a-N-C--lower alkenyl(C 8 -straight or branched, -NSO 2 -oe alkenyl (C 3 C.)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -170- (CH)q N~R ~(CH 2 No C 2 )q N j q )N \0 alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or 5 a moiety of the formula: f~ 0 0 0 0..0* 0*0* 0* 0.9.0. 9 too* :00 to0 N-CQ= 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 unbranchei, -0-lower alkenyl(C3)-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: 8 CH-b 8 -1 R R N S I/ 0 -171- or -CH2-K' wherein K' is (Cl-C3) -lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N Dz E G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl--C3), CHO, (Cl-C3)lower alkoxy, -C02- lower alkyl (C1-C3) and Ra and Rb are as hereinbefore 10 defined; a moiety of the formula: Ra N- COCHAr' @6 00 t S S S S 444* @5 4 S ~*54 4. 44 5 S *00 w her ei n R. issel ect edf r om hal ogen, C3) lower alkyl, -0-lower alkyl(C 1 -C 3 CH' -0-C-lower alkyl (C 1 NH(CH 2 -S-lower alkyl(Cl-C 3 -NH (CH 2 CCN<Rb R b 0-(CH 2 2 N Rb wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -172- -M-R wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C 8 -(CH2)p-cycloalkyl(C3-C6), when M is 0, S, NH, NCH 3 and the moiety -M-Rd wherein Rdj is selected from the moieties: (CH 2 a a a. (CH 2 )p- a a a. wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: R8 8 9 R w S and ,1 -173- wherein W' is selected from 0, S, NH, N-lower alkyl(C 1 C 3 NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C3), -S-lower alkyl(CI-C3), halogen, -NH-lower alkyl(C 1 C 3 -N-[lower alkyl(C1-C3)12, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C1- C3), -O-CO-lower alkyl (C 1 -C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (C1-C3), -N-[lower alkyl(C1-C3) 2, -O-lower alkyl(C 1 -N(Rb)(CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

10. A compound selected from those of the 15 formula: e Y A B wherein Y is a bond or -CH2-, A-B is (CH 2 and N- (CH 2 S* R R wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: QE represents: a 5-membered aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; wherein the 5-membered heterocyclic ring is optionally -174- substituted by (C1-C3)lower alkyl, halogen, or (C 1 C3) lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R 7 x R N M and R 6 S s Md R 7 N wherein X is selected from 0, S, -NH, -NCH-I and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (Cl-C3), Rl and R2are selected from hydrogen, (Cl-C3)lower alkyl, (C1-C3)lower alkoyy and haiogen; R 5 i4s selected fromhydogen (C-C3)lower alkyl', (C-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -175- R R R R R ia a a a b -NCOAr', -CONAr', -NCOCH 2 Ar', -NCONAr', R -CH 2 COAr', -NCO-(CH 2 cyci oal kyl, R R R a ja -N-SO 2 -N-SO 2 CH 2 2. O2 R 2 R. R 0 a a.1 /P R 2 R -N-C-O-Iower alkyl(C 3 C)straight or branched, R a a 1 -N-C*-2ower al kyl (C 3 C .)st r a lght or branched, Nlowe al kenyr (C 3 C 8 )srg t r ai rbranched, RO N-C- l-ow er al kenyl (C 3 8) st rai ght or branched, -N 2 -lower alkenyl (C 3 C)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -176- (CH N ~(CH 2 No (C 2)q- NQo i)q N 4 alkyl(Cl-C3), -CH2CH20H, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or 5 a moiety of the formula: Rb wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothioihene, and the moieties: R8D R 8 J N S 0 -177- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N 1- \-E G=F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -002- lower alkyl (C1-C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: R RC w herei nR. i ssel ect ed fr om hal ogen, (C 1 -C3) ~lower alkyl, -0-lower alkyl(C .15 -0-C-lower alkyl(C 1 -C 3 -S-lower alkyl(Cl-C 3 S- (H RbNH(CH RqCU b -NHCH b0-(H N Rb R b (O 2 )2 R wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -178- wherein Rdj is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6) 1 when M is 0, S, NH, NCH 3 and the moiety -M-Rdj wherein RdJ is selected from the moieties: (CH 2 )p- S S (CH 2) p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; 10 wherein Ar' is selected from moieties of the formula: S. S S S S S ,and -179- wherein w' is selected from O, S, NH, N-lower alkyl(C1- C3) NHCO-lower alkyl(Cl-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C 1 -C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C1- C3), -S-lower alkyl(Cl-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C 1 NHCO lower alkyl(C1- C3), -0-CO-lower alkyl (CI-C 3 and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(C 1 C 3 -NH-lower alkyl (Cl-C 3 -N-[lower alkyl(Cl-C3)]2, -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the S" pharmaceutically acceptable salts thereof.

11. A compound selected from those of the 15 formula: O E A-B wherein Y is a bond or -CH2-, A-B is (CH 2 and 3 3 R R wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: OE represents: a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the -180- membered heterocyclic ring is optionally substituted by (Cl-C3) lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R x N MR\ and heren x MR N R wherin Xis selected from 0, S, -NH, -NCH3 and -NCOCH3; 0:::oR 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (Cl-C3), Rl and R2are selected from hydrogen, (Cl-C3)lower 10 alkyl, (Cl-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -181- R R R R Fb Ia I a Ia I a I -NCOAr', -CONAr', -NCOCH 2 Ar', -NCONAr', R CH 2COAr', -NCO-(CH 2 cyci oal kyl R R R a a1 -N-SO 2 N- SO S 2 CH 2 .2 *a -N-P P-] R 2 2 R2 2 a 0I -N-C-O-lower alkyl(C 3 C,)straight or branched, R a Ia I -N-C-lower alkyl(C 3 -C,)straight or branched, NS 2- lower al kyl (C 3 C,)str aight or branched, Raf -N-C-C-I ower a! kenyl (C 3 C 8 )st raight or br anched, R 0 R a ,a ia- N- C-lIow er al kenyl (C 3 C,)st rai ght or branched, 2 -lower alkenyl(C 3 C,)straight or branched, wherein cycloalkyl is defined as (C 3 -C6) cycloalkyl, cyclohexenyl or cyciopentenyl; and Ra is independently selected from hydrogen, -CR3 or -182- (CH N ~(CH 2 No C2)q -N3iI (CH 2 N 0 alkyl(C1-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CR3 or 5 a moiety of the formula: 0 0 000000 0000 0000 0**0 0* *0 0 .00000 0 0*00 0000 00 0 0* 0* 00 0 N-CQOJ 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 10 alkenyl(C3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothioohene, and the moieties: 0 -183- or -CR2-K' wherein K' is (C1-C3)-lower aikoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N Dz E G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(C1--C3), CR0, (Cl-C3)lower alkoxy, -C02- lower alkyl (C1-C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: COCHAr' R C w her ei n RC issel ect ed f r o hal ogen, (C 1 -C) I* :low er al kyl, 0-l1ow er al kyl (C 1 -C 3 W, S-0-C-lower alkyl(C 1 -C 3 -S-lower alkyl(Cl-0 3 S- CHRbNH(CH )~c\Rb NH (CH 0q <R b C wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -M-Rdj -184- wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C 8 -(CH 2 )p-cycloalkyl(C3-C6) 1 when M is 0, S, NH, NCH 3 and the moiety -M-Rd wherein Rd is selected from the moieties: (CH 2)p to..:0 4* 9055 (CH 2 )p- (CH 2 wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moiet-ies of the formula: ,and -185- wherein W' is selected from 0, S, NH, N-lower alkyl(C1- C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C 3 -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C 3 -0-CO-lower alkyl (C 1 -C 3 and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (Cl-C3), -N-[lower alkyl(C1-C 3 )1 2 -O-lower alkyl(C1-C3), -N(Rb)(CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

12. A compound selected from those of the 15 formula: S Y *o A B A-B wherein Y is a bond, A-B is (CH 2 )nN- and N (CH 2 2 3 3 R R wherein n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (Cl-C3)lower alkyl, halogen, amino, (C 1 -186- W C3)lower alkoxy or (C1-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (Cl-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R 6 X *R R and MR R S d N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; 15 R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (C1-C3)lower Salkyl, (Ci-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -187- R R R R R a a aa b -NCOAr', -CONAr', -NCOCH 2 Ar', -NOONAr', R -CH 2 CAr', -NCO-(CH 2 cycl oal kyI R RR -N-SO 2 -N-SO 2 CH 2 2 R2 R R R -N-PN-P Riy~cjt g or R] lower alkyl(C 3 C,)strai ght or branched, -SO 2 -loe ky l C agtrah branched ed -S NC- loe alower al kenyl t r ainchedrbra, hd RO a-N-C-&lower alkenyl (C 3 C)str aight or branched, NSO 2 w al kenyl (C 3 C)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -188- C H 2) q N b C H2)q -N jD ~(CH 2 N 10H 2 )q-N 0 (CH2)q01ower alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 Or a moiety of the formula: Rb 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 (C 3 -C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: N S -18 9- or -CH2-K' wherein K' is (Cl-C3)-Iower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N 1-D 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, (C1-C3)lower alkyl, hydroxy,- CO-lower alkyl(CI-C3), CHO, (C1-C3)lower alkoxy, -C02- lower alkyl (Cl1C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: XX1CHAr' R C w her ei n RC is sel ect edf r om hal ogen, (C 1 -0 3 lower alkyl, -0-lower alkyl(C 1 -C 3 CH, lower alkyl (C 1 -C 3 -S-lower alkyl(Cl-C 3 S- CH RbNH(CH 2 CI\ -NH(CH )-N(Rb,-R wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -190- 0 wherein Rdj is lower alkyl(C3-C8), lower alkenyl(C 3 -C 8 -(CH2)p-cycloalkyl(C3-C6), when M is 0, S, NH, NCR 3 and the moiety -M-Rd wherein Rd is selected from the moieties: R RR1 -(CH1~) (CH 2 )p- (CH 2 p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; 10 wherein Ar' is selected from moieties of the formula: ,and S-191- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C 3 NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C1-C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl (C1- C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(CI-C3), NHCO lower alkyl(C 1 C3), -O-CO-lower alkyl (Cl-C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C 1 C3), -NH-lower alkyl (Cl-C3), -N-[lower alkyl(C1-C3)]2, -O-lower alkyl(C 1 -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

13. A compound selected from those of the 15 formula: N 0 E0 E 2n Y -2 •go• A B wherein Y is a bond or -CH2-, A-B is -(CH2)nN- and -N-(CH2) n R R 3 wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, -192- FW optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Ci- C3)lower alkoxy or (Ci-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alkyl, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: 5 R R R 6 R :N R and MRdR S R7 N wherein X is selected from 0, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(CI-C3), -CO- •lower alkyl(Cl-C3), R 1 and R 2 are selected from hydrogen, (Cl-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -193- R R RR Fb -NCOAr', -CONAr', -NCOCH 2 Ar', -NCONAr', R -CH 2 00Ar', -NCO-(CH cycl oal kyl, R R R a a -N-SO 2 4 -N-SO 2 CH 2 s R2 R2 R 0 R R a a P- R 2 2 R 22 lower alkyl (C 3 C,)st raight or branched, aa I -N-C-lower alkyl (C 3 C 8 straight or branched, NSO 2- lower al kyl (C 3 C.)st raight or branched, N- 0-0-lower al kenyl( straight or br anched, R 0I R a 1 Ia-N-C-lower al kenyl (03- C 8 )st raight or branched, NSO 2 lower al kenyl (C 3 C 8 )st rai ght or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -194- 0 (CH N C2)q- No~ (CH 2 r (CH 2 )q N a a a a a a. a. a a. alkyl(Cl-C3), -CH2CH20H, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b -N11 -CM 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 10 alkenyl(C3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: 0 -195- go or -CR2-K' wherein K' is (Cl-C3) -lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N DI1_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, CCl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CR0, (Cl-C3)lower alkoxy, -C02- lower alkyl(Cl1C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: 6 R a. N- COCHAr' pR CC lower alkyl, -0-lower alkyl(G 1 -C 3 CHI, .a 0 -0Cao e al y o l y CI C -S(C a.HC 2)2R.2q. NHC, b 12qif CH22N F whri aan baeashribfoedfnd -0-C-ltyow ter forul(C-a:-Slwraky( -196- wherein Rdj is lower alkyl(C3-C8), lower alkenyl(C3-C 8 (CH2)p-cycloalkyl(C3-C6), when M is 0, S, NH, NCH 3 and the moiety -M-Rdj wherein Rdj is selected from the moieties: S S 55*. S 5* S S S (CH 2 p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: R8 ,and -197- wherein W' is selected from O, S, NH, N-lower alkyl(C1- C 3 NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(Ci-C 3 and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower.alkyl(C1- C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF 3 -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C1- C3), -O-CO-lower alkyl (C1-C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(Cl- C3), -NH-lower alkyl (C1-C3), -N-[lower alkyl(C1-C 3 )1 2 -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

14. A compound selected from those of the 15 formula: O E A--B A-B wherein Y is a bond or -CH2-, A-B is (CH2) N- and (CH 2 S. 3 R3 R R wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, -198- optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Cl- C3)lower alkoxy or (Cl-C3)lower alkylamino; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: 6 RAR 6 R X N and 6 S MRd N N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (C1-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -199- R -NCOCH 2 Ar', R R ia b -NOONAr', -NCOAr', -CONAr', CH 2 COAr', -NCO-(CH 2 cyci oal kyl, a N- SOi R -N-SO 2 CH 2 -N-C-O-lower alkyl(C 3 C 8 straight or branched, R al -N-C-lower alkyl(C 3 C)straight or branched, NSO 2 -oe alkyl(C 3 C 8 )straight or branched, ~af -N-C-O-lower alkenyl(C 3 C.)straight or branched, RO0 R a I1, I'-N-C-lower al kenyl( C.)st rai ght or branched, -NSO2-lower al kenyl (C3- 08)st r aightd or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -200- ~(CH N ~(CH 2 )q NO C2)q- No 2 q N 4 alkyl(Cl-C3), -GH2CR2OH, q is one, two, or three, Rb is independently selected from hydrogen, CR3 or 5 a moiety of the formula: R b -1 CJ wherein J is Ra, lower alkyl(C3-CB) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: R R N S I/ 0 1- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahycirofuran, tetrahyciro-thiophene or the heterocyclic 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, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (Cl-G3)lower alkoxy, -C02- lower alkyl(Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: COCHAr' w her ein RCis sel ect edf r om hal ogen, (0 1-03) lower alkyl, -0-lower alkyl (Ci-C 3 CH', lower alkyl (C 1 -C 3 -S-lower alkyl(C0 1 -C 3 S- CH bNH(CH )Rb2N NH(CH 2 )q b ~R b wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -202- wherein Rd is lower alkyl(C3-G8), lower alkenyl(C3-C 8 -(C112)p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rd wherein Rd is selected from the moieties: R R1 C- 2 )p I 2 )p 2 12 R R (CH 2 )p (CH 2 )p S 0 wherein p is zero to four and M is a bond or M is selected" from 0, S, NH, NCH3; wherein R 1 R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moie:-es of the formula: R8 *0* ,and -203- wherein W' is selected from 0, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(Cl-C3), and NSO2lower alkyl(Cl-C 3 R 7 is selected from hydrogen, lower alkyl(Cl-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 .C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(Cl- C3), -N-(lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF 3 -N02, -NH2, O-lower alkyl(Cl-C3), NHCO lower alkyl(C 1 C3), -O-CO-lower alkyl (Cl-C3) and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (C1-C3), -N-[lower alkyl(CI-C3)] 2 -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

15. A compound selected from those of the 15 formula: N O E A--B wherein Y is a bond, n is an integer 2; and the moiety:-CH2- A-B is *C E (CH N- and (CH 3 R3 wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: represents: A 5-membered aromtic (unsaturated) heterocyclic ring having one heteroatom selected from O, 0 -204- N or S; wherein the 5-meinbered heterocyclic ring is optionally substituted by (Cl-C3)lower alkyl, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R R x MR d S and a. *aaa.. a a wherein X is selected from 0, 5, -NH, -NCH3 and -NCOC{3; R 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- lower alkyl (Cl-C3), Rl and R 2 are selected from hydrogen, (Cl-C3) lower alkyl, (C1-C3) lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -205- *R R R R Fb IaIa I a Ia I -NCOAr', -CONAr', -NCOCH 2 Ar, -NOONAr', R Ia CH 2COAr', -NCO-(CH 2 cyci oal kyl, R R R SO2CH 2-- 22 R. R a a R R R o7 Ra -N-P-oe alylCJ...pihto bachd RaOO 2- 2 we lkl(3 8 tagto rnhd R a lower aky(C-C 8 straight or branched, RO0 a lall N- C- Ilow er al keyl C)str aight or branched, -S02lower alkyl C 8 )st raight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or 6- ~(CH 2 No C2)q- CH 2 )q-N 0 0* a a a. a a a. alkyl(C1-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: Rb 1 CM wherein J 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(C3-08) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: R 8O H b 'R8 0 -207- 4P or -CH2-K' wherein K' is (C1-C3)-lower aikoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: 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- lower alkyl (Cl-C3) and Ra and Rb are as hereinbef ore defined; a moiety of the formula: R C w her ei n R i s sel ect ed fr om hal ogen, (0 1-03) lower alkyl, -0-lower alkyl(0 1 -0 3 CH', -0-C-lower alkyl(0 1 -0 3 -S-lower alkyl(Cl-C 3 -S-CH bNH(CH 2 )qC -Nb NH(CH R b ,N(R 2)q- Rb (CH 2 )2 -,R wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: MR -208- wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is 0, 3, NH, NCH3, and the moiety -M-Rd wherein Rd is selected from the moieties: (CH 2 )p too..: 0 9 too* to 0.* (CH 2 p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein R 1 R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from R 5 R 8 moieties of the formula: R8 ,and -209- 49 wherein WI is selected from 0, S, NH, N-lower alkyl (Cl- C 3 NHCO-lower alkyl(Cl-C3), and NSO2lower alkyliCl-C 3 R 7 is selected from hydrogen, lower alkyl(Cl-C3), halogen, 0-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(Cl- C3), -S-lower alkyl(Cl-C3), halogen, -NH-lower alkyl (C 1 C3), -N-[lower alkyl(Cl-C3)]2, -OCF3, -OH, -CN, -S-CF 3 -N02, -NH2, 0-lower alkyl(Cl-C3), NHCO lower alkyl(Cl- C 3 -0-CO-lower alkyl (Cl-C3) and CF3 and; 'R 10 is selected from hydrogen, halogen, lower alkyl (Cl- C3), -NH-lower alkyl (Cl-C3), -N-[lower alkyl(Cl-C3)]2, -0-lower alkyl(Cl-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

16. A compound selected from those of the formula: N 0 E4 A-B wherein Y is a bond or -CH2-, A-B is -C and N- (CH 2 133 RR wherein n is an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the moiety: 0QE represents: A 5-membered aromtic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; -2 1W wherein the 5-membered heterocyclic ring is optionally substituted by (Cl-C3)lower alkyl, halogen, or (Cl- C3) lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R6 R R N \and R 6 Se MR7 d R N 0*~ewherein X is selected from 0, S, -NH, -NCH3 and -NCOCH3; 4 is selected from hydrogen, lower alkyl(Cl-C3), -CO- *Vso:lower alkyl (Cl-C3), RI and R2are selected from hydrogen, (Cl-C3) lower alkyl, (Cl-C3) lower alkoxy and halogen; R 5 is selected seesfrom hydrogen, (Cl-C3) lower alkyl, (Cl-C3) lower alkoxy and halogen; R 6 is selected from moieties of the formulae: egos e606. -211- Rb I a -NCONAr', -NCOAr', -GONAr', -NCOCH 2 r, -H 2 COAr', -NCO-(CH 2 cyci oat kyl, R -N-SO 2 a -N-S 2 CH 2 RaO I -N-C-C-lower alkyl(C 3 C,)straight or branched, R lal I lower aikyl(C 3 C,)straight or branched, NSO 2 lower alkyl(C 3 C,)straight or branched, RO a-N-C--lower alkenyl(C 3 C)straght or branched, NSO 2 -oe alkenyl(C 3 -C,)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyciopentenyl; and Ra is independently selected from hydrogen, -CR3 or -212- (CH N -(CH 2 No W2)q- Ncj -(CH 2 )qN 0 -(CH2)q-O-lower alkyl(C1-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b COJ wherein J is Ra, Lower alkyl(C3-CB) branched or unbranched, lower alkenyl (C 3 -C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl (C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophele, and the moieties: -213- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene 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, (C1-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (C1-C3)lower alkoxy, -C02- lower alkyl (C1-C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: R COCXHAr' C o ~wherein RC is select edfromn halogen, (01-0 3) lower alkyl, -0-lower alkyl(C CJ), 0-i, lower alkyl(C 1 -C 3 -S-lower alkyl(C,-0 3 -AH(H b 0-(C N Rb NHC 2 )qN~ R 2 F wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: M-Rd -214- wherein Rdj is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rdj wherein Rd is selected from the moieties: (CH 2 )p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -215- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C1-C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C3), -0-CO-lower alkyl (C 1 -C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C 1 C3), -NH-lower alkyl (C 1 -C 3 -N-[lower alkyl(C1-C3)12, -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

17. A compound selected from those of the S* 15 formula: Y 0 E *I* wherein Y is a bond or -CH2-, A-B is (CH2)nN- and -N-(CH 2 R R wherein n is an integer 1 or 2 with the proviso that 20 when Y is a bond, n is an integer 2; and the moiety: OE represents: A 5-membered aromtic (unsaturated) heterocyclic ring having one nitrogen atom together with -216- either one oxygen or one sulfur atom; wherein the membered heterocyclic ring is optionally substituted by (C1-C3)lower alkyl, halogen, or (C 1 -C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R 5 Rs 6 R /R 7 X MR and R 6 S MRd -=N N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C 1 -C3), 10 R 1 and R 2 are selected from hydrogen, (C1-C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Ci-C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: 9 -2 17- 1W R R R R R aiaa ia b -NCOAr', -CONAr', -NCOCH 2 A, -NCONAr', R I a CH 2 00CrW, -NCO-(CH 2 cyci oal kyl, R R R aa -NS 2 s N- S 2 CH 2 s R2 R2 R R a a -N-P-aN-P R R 2 -J22 2 *a 1 lower alkyl(C 3 C,)straight or branched, 0 jal a -N-C-lower alkyl(C 3 -C,)straight or branched, 1 3* -S 2- low er al kyl (03- C,)st raight or branched, R a N- C-0-1ow er al kenyl (C 3 -Csrih or br anched, RO0 R Il, I'-N-C-lower al kenyl (03- C,)st rai ght or branched, NSO 2 l ower al kenyl (C 3 -0 8 ,)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -GH3 or -218- (CH 2 N~R ~(CH 2 ND (CH 2 No1 i~q N alkyl(Cl-C3), -CH2CH2OH, q is one, twio, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b -N-CQ wherein J is Ra, lower alkyl (C3-CB) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: N S I/ 0 -219- 4D or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N I, z-E G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl--C3), CHO, (Cl-C3)lower alkoxy, -C0 2 lower alkyl (Cl-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: Ra COCHAr' wherein R is selectedf rom halogen, (C -C) lower alkyl, -0-l1ow er al kyl (C C 3 CHI, -0-C-lower alkyl(C I-C 3 -S-lower alkyl(Cl-C 3 Rb (CHNH(CH)q R ~NH(CH b)-qCH< F wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -220- wherein Rd is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is O, S, NH, NCH3, and the moiety -M-Rd wherein Rd is selected from the moieties: (CH 2 (CH 2 )p- (CH 2 wherein p is zero to four and M is a bond or M is selected from O, S, NH, NCH3; wherein R 1 R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: R 8 R R and -221- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(Cl-C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C1- C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(Cl-C3), NHCO lower alkyl(C 1 C3), -O-CO-lower alkyl (C1-C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (Cl-C3), -N-[lower alkyl(Cl-C3)]2, -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

18. A compound selected from those of the 15 formula: N E A-B wherein Y is a bond, A-B is -(CH and -N-(CH 2 3 13 R R wherein n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents -222- selected from (Cl-C3)lower alkyl, halogen, amino, (C l C3)lower alkoxy or (C 1 -C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (C 1 -C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: f, V 6 R 6 R X R and R 6 MR 7 S R N wherein X is selected from 0, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(C 1 -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (C 1 -C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 5 is selected 20 from hydrogen, (C 1 -C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -223- WR RRR R aa ajb -NCOAr', -CONAr', -NCOCH 2 Ar', -NOONAr', -CH 2 00Ar', -NCO-(CH 2 cycloalkyl R aR Ra SO 2 -N-SO 2 CH 2 R2 R2 R RR *a I N-P- R R 2 -22 2 a ii lower alkyl(C 3 C.)straight or branched, R lal lower alkyl(0 3 -C.)straight or branched, -NSO 2 -oe alkyl(C 3 -C,)straight or branched, I a C-0- l ow er al kenyl (C C 8 straight or branched, RO0 R aI ,a -N-C-lower al kenyl (03- C, 8 )st raight or branched, NSO 2 lower alkenyl(C 3 -C,)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -224- (CH 2 )q -N (C2)q -N \-j (CH 2 r\ ID alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: R 8z -C bR8 N S -225- 01 or -CR2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic 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, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (Cl-C3)lower alkoxy, -C02- lower alkyl (Cl1C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: R N- COCHAr' a. wherei n R is selected fromn halogen, (CI- C3) lower alkyl, -0-lower alkyl(C 1 C 3 CHI, -0-C-lower alkyl(C 1 -C 3 -S-lower alkyl(Cl-C 3 S- (CH 2 2 NH(CH 2 )q-N Rb R b NH(CH CCt<R b H 2 2 N R b wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -226- -M-Rd. wherein Rdj is lower alkyl(C3-C8), lower alkenyi(C3-C8), -(CH2)p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rdj wherein Rd is selected from the moieties: (CH 2)p S S S. S S. SS S. (CH 2 )p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -227- wherein W' is selected from O, S, NH, N-lower alkyl(C1- C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(Ci-C3); R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(Cl- C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C1- C3), -O-CO-lower alkyl (C 1 -C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (C 1 -N-(lower alkyl(C1-C3)]2, -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

19. A compound selected from those of the 15 formula: O E I N A-B wherein Y is a bond or -CH2-, A-B is (CH 2 )nN- and N- (CH 2 3 13 R R wherein n is an integer 1 or 2 with the proviso that 20 when Y is a bond, n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C 1 -C3)lower alkyl, halogen, amino, (Ci- -228- C3)lower alkoxy or (C 1 -C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: S 5 /R 6 R 6 R 6 R N R N /MR and 6 S R N .MRd R wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C 1 -C3), R 1 and R2 are selected from hydrogen, (C 1 -C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (C1-C3)lower alkyl, (Ci-C3)lower alkoxy 20 and halogen; R 6 is selected from moieties of the formulae: -22 9- wR R R R Rb a ia a ia b -NCOAr', -CONAr', -NCOCH 2 A, -NCONAr', R CH 2 CAr', -NCO-(CH 2 cycloalkyI R R R N S O 2 -1 O 2 C R R2 R 0 RaOa D-N-P- R o 2 2 R 2- 5 lower alkyl(C 3 -0 8 .)straight or branched, RR a I -N-C-lower alkyl(C 3 C 8 straight or branched, *goo~ NSO 2 lower alkyl(C 3 C.)straight or branched, R a lower al kenyl( 0)st rai ght or branc-hed, R II a lower al kenyl (0 3 -C,)st raight or branched, -NSO 2 -lower alkenyl (C 3 Cd)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -230- ~(CH 2 No C2)q -Ncj CH 2 )q-N 0 alkyl(Cl-C3), -GH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: Rb -N11 -CM wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieLt;es: /Ib S -2 31- or -CR2-K' wherein K' is (Cl-C 3 )-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene 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, (CC-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cli-C3), CR0, (Cl-C3)lower alkoxy, -C02- lower alkyl (Cl-C3) and Ra and Rb are as hereinbefore defined; a moiety of the formula: R a COCHAr' ~wher einR c i s sel ect ed f rom hal ogen, (01-0C3) 0lower alkyl, lower al kyl (C J~ 15 -0-C-lower alkyl(C 1 -0 3 -S-lower alkyl(Cl-C 3 S C R H H 2)R NH(C RbRb wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -232- wherein RdA is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rdj wherein Rdj is selected from the moieties: (CH 2 )p (CH 2 )p- (CH 2 )p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -233- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(C1-C 3 and NSO2lower alkyl(C1-C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C 1 C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(C1-C3)12, -OCF3, -OH, -CN, -S-CF 3 -NO2, -NH2, O-lower alkyl(Ci-C3), NHCO lower alkyl(C1- C3), -O-CO-lower alkyl (C1-C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C 3 -NH-lower alkyl (C 1 -C 3 -N-[lower alkyl(C1-C3)1 2 -O-lower alkyl(C 1 -C 3 -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof. A compound selected from those of the 15 formula: N A-B wherein Y is O, S, NH, N-lower alkyl(C1-C6), -NCO-lower 0 alkyl(C1-C6); A-B is -(CH 2 N- and N-(CH 2 3 13 SR 3 R 20 wherein n is an integer 1; and the moiety: QE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Cl- -234- C3)lower alkoxy or (C 1 -C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (C 1 -C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: RS s R R and R 6 S MRd 7 S d R N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; 15 R 4 is selected from hydrogen, lower alkyl(Ci-C3), -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (CI-C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 5 is selected S" from hydrogen, (C 1 -C3)lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -235- *R R RR Fb IaIaIa Ia I -NCOAr', -CONAr', -NCOCH 2 Ar', -NCONAr', R I a -CH 2 00Ar', -NCO-(CH CYC'oal kyI R R R SO 2 SO 2 CH 2 a R -N-P P- R 2 R 2 aI lower alkyl(C 3 -0 8 .)straight or branched, R R 1ai1 lower alkyl( 3 -C 8 )straight or branched, 00 NSOI -ower al kyl( C )St raight or branched, lower alkenyl(C 3 -C)straight or branched, R 0I a- N-C-lower al kenyl( C 8 )st r alght or branched, -NSO 2 -oe alkenyl(C. 3 -C,)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CR3 or -236- S (CH N (CH 2 No C2)q-N (CH 2 qN 0 C. C a C C CC C C CC -(CH2)q-O-lower alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: R b -1 CaJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophele, and the moieties: N S 0 -237- of or -CH2-K' wherein K' is (Cl-C3) -lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N 1.1D 'E G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl (Cl-C3), CHO, (Cl-C3) lower alkoxy, -C02- lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: COCHAr' w her ei n RC i s sel ect edf r om hal ogen, (0 1-0C3) lower al kyl, lower alkyl (C -C 3 H -0-C-lower alkyl(C 1 -C 3 ),'Sloe ak(C- 3 R R b NH(CH 2 qCN( 2) b 2) R b N(H, R b R b IN(C qN( R b (CH 2)2 N R wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -238- -M-Rd wherein Rd is lower alkyl(C3-C8), lower alkeflyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rd wherein Rdj is selected from the moieties: (CH 2 )p 0 04 so** *0 S 0. (CH 2 )p- (CH 2) p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH-A; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -239- wherein W' is selected from O, S, NH, N-lower alkyl(C 1 C 3 NHCO-lower alkyl(Ci-C 3 and NSO2lower alkyl(C 1 -C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(Ci-C 3 and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C1- C 3 -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1- C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF 3 -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C 3 -O-CO-lower alkyl (Cl-C3) and CF3 and; R10 is selected from hydrogen, halogen, lower alkyl(C1- C3), -NH-lower alkyl (Cl-C3), -N-[lower alkyl(C1-C3)12, -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

21. A compound selected from those of the formula: N A-B wherein Y is a bond, -CH2-, O, S, NH, N-lower alkyl(C1- C6), -NCO-lower alkyl(Cl-C) A-B is (CH 2 )nN- and (CH 2 )n R R 3 20 wherein n is an integer 1 or 2 with the proviso that when Y is a-bond, n is an integer 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents -240- selected from (Cl-C3)lower alkyl, halogen, amino, (C l C3)lower alkoxy or (Ci-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (CI-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: 5 R R R R X .S d R 7 N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C1-C3), SR 1 and R 2 are selected from hydrogen, (C 1 -C3)lower alkyl, (Cl-C 3 )lower alkoxy and halogen; R 5 is selected from hydrogen, (C 1 -C 3 )lower alkyl, (C 1 -C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -241- R R R R R a a a aib -NCOAr', -CONAr', -NCOCH 2 Ar, -NOONAr', I a -CH 2 00Ar', -NCO-(CH 2 CYCloalkyl, R R R SO 2 N S0 2 CH 2 RH 0 R ,I a -N-P j RR2 2 R 2 2 N-C-O- lower al kyl (03- C,)st raight or branched, RHO NI -N--oe aly(3alltaih rbrnhd -C-lower al yl C 3 -C 8 str aib r banched, ower alkylr (03- y( C3)s raight rachd, rachd a N-C-I ower al kenyl (C 3 CB st rai ght or branched, -NSO 2 -lower alkenyl(C 3 -C 8 straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -242- (CH)q N~R (CH 2 No (C2)q- No (Cf- q N I alkyl(C1-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: Rb wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-CB) branched or unbranched, -0-lower alkenyl(C3-CB) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: 80 CH; b 0 -243- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: -N D~-E G=F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C 3 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 moiety of the formula: -N-CGOCHAr' w her ein R i s sel ect edf r om hal ogen, (0 1-03) lower alkyl, -0-lower alkyl(C 1 -C 3 CH', -0-C-lower alkyl(0 1 C 3 -S-lower alkyl (C I C 3 -S-(CH 2 2 N RbNH(CH 2 )q -CCN b ~NH(CH 2 )qN~ R wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -244- -M-Rd wherein Rdj is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH 2 )p-cycloalkyl(C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-Rd wherein Rdj is selected from the moieties: (CH 2 )p a. a a (CH 2 )p- (CH 2 p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein Rl, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: ,and -245- Swherein W' is selected from O, S, NH, N-lower alkyl(C 1 C3) NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C1-C 3 R 7 is selected from hydrogen, lower alkyl(C1-C3), halogen, O-lower alkyl(C1-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl(C1- C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C 1 C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, O-lower alkyl(C1-C3), NHCO lower alkyl(C 1 C 3 -O-CO-lower alkyl (C1-C3) and CF3 and; R 10 is selected from hydrogen, halogen, lower alkyl(C1- C 3 -NH-lower alkyl (Cl-C3), -N-[lower alkyl(C1-C3)1 2 -O-lower alkyl(C1-C3), -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

22. A compound selected from those of the formula: S T--B A- B wherein Y is a bond, or -CH2-; A-B is -(CH 2 )nN- and N- (CH 2 1 "3 3 R R wherein n is an integer 1 or 2 with the proviso that 20 when Y is a bond, n is 2; and the moiety: OE represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (Ci- -246- C 3 )lower alkoxy or (C 1 -C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from 0, N, or S; a membered aromatic (unsaturated) heterocyclic ring having two adjacent 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 (C 1 -C3)lower alkyl, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: R R R R X R \and MRd R S R N wherein X is selected from O, S, -NH, -NCH3 and -NCOCH3; "15 R 4 is selected from hydrogen, lower alkyl(C1-C3), -CO- lower alkyl(C1-C3), R 1 and R 2 are selected from hydrogen, (C 1 -C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 5 is selected Sfrom hydrogen, (C 1 -C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -247- WR R RR Fb -NCOAr', -CONAr', -NCOCH 2 Ar, -NOONAr', R I a CH 2COAr', -NCO-(CH 2 cycl oal kyl, R R R1 N S 02-N-SO 2CH2 I II Iia N-P- RRoR2 RaO1 lower alkyl(C 3 C.)st r aght or branched, R 0 .Ra all -N-C-lower alkyl(C -C )straight or branched, -NSO 2 lower al kyl (03- C 8 st raight or branched, R a ower alkenyl(C 3 -C.)str aight or branched, RO0 Ra a1, I'-N-C-lower al kenyl( C.)st rai ght or branched, NSO 2 lower alkenyl(C,-C,3)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or -24 8- -(CH 2 q N b ~(CH 2 No (M 2)q ND CH 2 NI S* *5 A a alkyl(Cl-C3), -CH2CH2OH, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: Rb -N-CQM wherein J is Ra, lower alkyl(C-3-C8) branched or unbranched, lower alkenyl(C3-CB) branched or unbranched, 0-lower alkyl(C3-C8) branched or uribranched, -0-lower 10 alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moiet.ies: R~ R N S -24 9- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophene or the heterocyclic ring moiety: F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3)lower alkyl, hydroxy,- CO-lower alkyl(Cl,-C3), CHO, (Cl-C3)lower alkoxy, -C02- lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined; a moiety of the formula: N- COCHAr' C lower alkyl, -0-lower alkyl(C 1 -C 3 CH-, -0-C-lower alkyl(C 1 -C 3 -S-lower alkyl(C-C 3 (CH 2 2 RbNH(CH 2 C< R Rb Rb' N H (C H 2 N b0 CH2 N wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -250- -M-Rd wherein RdJ is lower alkyl (C3-C8) lower alkenyl (C3-C8), -(CH 2 )p-cycloalkYl(C3-C6o) when M is 0, S, NH, NCH3, and the moiety -M-Rd wherein Rd is selected from the moieties: (CH 2 )p *9 99 9 9 0 0e 9 909* a.. *9*9 9* 9 9. 99 9 9* -(CH 2 )p- (CH 2 p- wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein R1, R 2 and Ra are as hereinbefore defined; 10 wherein Ar' is selected from moieties of the f ormula: and 1- wherein W' is selected from 0, S, NH, N-lower alkyl (Cl- C 3 NHCO-lower alkyl(Cl-C 3 and NSO2lower alkyl(Cl-C 3 R 7 is selected from hydrogen, lower alkyl(Cl-C 3 halogen, 0-lower alkyl(Cl-C3) and CF3; R 8 and R 9 are independently selected from hydrogen, lower alkyl (C 1 C 3 -S-lower alkyl(Cl-C3), halogen, -NH-lower alkyl(Cl- C 3 -N-[lower alkyl(Cl-C3)]2, 0OCF3, -OH, -CN, -S-CF3, -NO 2 -NH2, 0-lower alkyl(Cl-C3), NHCO lower alkyl(Cl- C 3 -0-CO-lower alkyl (C1-C3) and CF3 and; R1 0 is selected from hydrogen, halogen, lower alkyl (C 1 C3), -NH-lower alkyl (Cl-C 3 -N-[lower alkyl(Cl-C 3 )1 2 -0-lower alkyl(cl-C 3 -N(Rb) (CH2)q-N(Rb)2; and the pharmaceutically acceptable salts thereof.

23. The compound according to Claim 1 hN-[4- 4 ,5-Dihydropyrazolo(3.4-Li]thieno[3, 2-laIazepin-6(lH)- S yl) carbonyl]phenyl] -2-cnloro-4i-fluorobenzamide.

24. The compound according to Claim 1 hl-[4- so 5-Dihydropyrazolo 4-a]thieno 2-u] azepin-6 (1H) yl) carbonyliphenyl] -5-fluoro-2-methylbenzamide. 20

25. The compound according to Claim 1 11-[4- se* 5-Dihydropyrazolo[3, 4--c]thieno 2-b2)azepin-6 (MH) yl)carbonyl]-3-chlorophenyl]-s-fluoro-2-methylbenzamide.

26. The compound according to Claim 1 N-[4- 4 ,5-Dihydropyrazolo[3,4- ijthieno[3,2-b]azepin-6(lH) yl)carbonylj-3-chlorophenyl]-5-chloro-2-fluorobenzamide.

27. A compound according to Claim 1 kN-[4- 4 ,5-Dihydro-2-methylpyrazolo(3, 4-djthieno[3,2-12I- azepin-6 (2H) -yl] carbonyl] phenyl] 4-dichlorobenzamide.

28. A compound according to Claim 1 kN-[4- 4 ,5-Dihydro-2-methylpyrazolo[3, 4-d.thieno[3,2-12]- azepin- 6(2H) carbonyl ]phenyl] cyclohexane.

29. A compound according to Claim 1 Nj-[4- 4 ,5-Dihydropyrazolo[3,4-dilthieno[3,2-la]azepin-6(2H)- yl] carbonyliphenyl] -2-methylbenzamide. -252- A compound according to Claim 1 [(4,5-Dihydropyrazoolo[3, 4I.thieflo[3, 2 -b]a zepin- 6 (lH) yl) carbonyl]I -2-pyridinyl]I -2-chloro-4-f luorobelzamide.

31. A compound according to Claim 1 [(4,5-Dihydropyrazolo[3,4-_djthieflo(3, 2-1)azepin- 6 (lH) yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbelzamide.

32. A compound according to Claim 1 f(4,5-Dihydropyrazolo[3, 4-d]thieno[3, 2-1]azepin- 6 (lH) yl)carbonyl]-2pyridinyl-5-chloro-2fluorobenzamide.

33. A compound according to Claim 1 5-Dihydropyrazolo 4]thieno[3, 2-bIazepin- 6 (MH) yl)carbony11-2-pyridifyl-3f1uoro-2methylbenzamide.

34. A compound according to Claim 1 N-115- 5-Dihydropyrazolol3, 4-_d]thieno[3, 2-1]azepin-6(H) yl) carbonyl] -3-chloro-2-pyridilyl] -5-fluoro-2-methyl- benzamide.

35. A compound according to Claim 1 N-I[S- 1(4, 5-Dihydropyrazolo 13, 4-a]thieflo13, 2- azepin-6(lH) yl) carbonyl] -2-pyridinyl] -2-chloro-6-fluorobenzamide.

36. A compound according to Claim 1 11-14- [(4,5-DihydropyrazoloI3,4-dithieno(3,2-b]azepin- 6 (lR) yl)carbonyl]-3-phenYlV- 2 (dimethylamino)pyridine- 3 carboxamide.

37. A compound according to Claim 1 1-15- 1 (4,5-DihydropyrazoloI3,4-d]thienoI3,2-b]azepin- 6 (lH) yl) carbonyl) -2-pyridinyl] (methylamino)pyridine- 3 carboxamide.

38. A compound according to Claim 1 5-Dihydropyrazolo[3, 4dpyrido[3, 2-)2azepin- 6 (1) yl) carb onyl] phenyl] -5-fluoro-2-methylbenzamide.

39. A compound according to Claim 1 N1-[4- 5-Dihydropyrazolo[ 3 4-d]pyrido[3, 2-2)azepin-6(1H) yl) carbonyl] -3-chlorophenyl] -5-f luoro-2-methylbenzamide. A compound according to Claim 1 N-[4 I(4, 5-Dihydropyrazolo3, 4C]pyridoI3, 2-b)azepin- 6 (MH) 3- yl) carbonyl] -3-chiorophenyl] -2-methylpyridine-3-carbox- amide.

41. A compound according to Claim 1 [(4,5-Dihydropyrazolo[3, 4-djpyrido[3,2-h]azepin-6(1H) yl) carbonyl) -2-pyridinyl] -5-fluoro-2-methylbenzamide.

42. A compound according to Claim 1 5-Dihydropyrazolo[3, 4-_d]pyri do[ 3,2-12Iazepin-6(lH) yl) carbonyl) -2--pyridinyl]I -5-chloro-2-f luorobenzamide.

43. A compound according to Claim 1 Nj-(4- 4 ,5-Dihydropyrazolo[3,4--dIpyrido3,2-12Iazepin6(H)- yI) carbonyl) -3-chlorophenyl]1 1 '-biphenyl]-2-carbox- amide.

44. A compound according to Claim 1 4 ,5-Dihydropyrazolo[3,4-_dpyrido[3,2-b]azepin6(lH)- yl) carbonyl )-2-pyridinyl 1, l'-biphenyl]I-2-carboxamide.

45. A compound according to Claim 1 4 5-dihydropyrazolo 4 -d]pyrido[(3, 2-121azepin- 6(1H) yl) carbonyl]) -2-pyridinyl]1 (dimethylamino) pyridine-3- carboxamide.

46. A compound according to Claim 1 N-[4- 4 5- D ihydropy ra z o 1o[3, 4 -d]py r ido[(2, 3- bI a zep in -6(1H) yl) carbonyl] -phenyl] -5-fluoro-2-methylbenzamide. ,47. A compound according to Claim 1 N-(4- 5- D ihydropy ra zol1o[(3, 4- py r ido 3 zep in- 6 (1 H) yl)carbonyll-3-chlorophenyl]-5-tluoro-2-methylbenzamide.

48. A compound according to Claim 1 4 ,5-Dihydropyrazolo(3,4-_d3pyrido[2,3-b]azepin-6(lH)- :oo..yl) carbonyl] -2-pyridinyl] -5-fluoro-2-methylbenzamide.

3049. A compound according to Claim 1 4 5-Dihydropyrazolo[3, 4- flpyrido[2, 3-b]azepin-6 yl) carbonyl I-2-pyridinyl] (dimethylamino) pyridine-3- carboxamide. A compound according to Claim 1 N-[4- 5-Dihydropyrazolo(3, 4-_dlyrido 3-12]azepin-6(1H) yl) carbonyl] -3-chlorophenyl] -2-chloropyridine-3-car- boxamide. 254 51. A compound according to claim 1 N-[4-[(4,10-Dihydro-5H-pyrido[3,2- b]thieno[2,3-e]azepin.-5-yl)carbonyl]-3-chlorophenyl)] -5-fluoro-2-methyl-benzamide. 52. A compound according to claim 1 N-[4-[(4,10-Dihydro-5H-pyrido[3,2- b]thieno[2,3-e]azepin-5-yl)carbonyl]phenyl]-2-(dimethylamino)pyridine-3-carboxamide. 53. A compound according to claim 1 N-[5-[(4,10-Dihydro-5H-pyrido[3,2- b]thieno[2,3-e]azepin-5-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide. 54. A compound according to claim 1 N-[4-[(6,10-Dihydro-5H-pyrido[3,2- b]thieno[3,2-e]azepin-5-yl)carbonyl]-3-chlorophenyl]-5-fluoro-2-methylbenzamide. A compound according to claim 1 N-[4-[(6,10-Dihydro-5H-pyrido[3,2- lo b]thieno[3,2-e]azepin-5-yl)carbonylphenyl]-2-(dimethylamino)pyridine-3-carboxamide. 56. A compound according to claim 1 N-[5-[(6,10-Dihydro-5H-pyrido[3,2- b]thieno[3,2-e] azepin-5-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide. 57. A compound according to claim 1 N-[4-[(6,7-Dihydro-5H-pylrido[3,2- b]thieno[2,3-d]azepin-5-yl)carbonyl]phenyl]-5-fluoro-2-methylbenzamide. 58. A tricyclic benzazepine vasopressin antagonist, substantially as hereinbefore described with reference to any one of the Examples. 59. A pharmaceutical composition useful 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 in a 20 mammal comprising a suitable pharmaceutical carrier and an effective amount of a compound of any one of claims 1 to 58. O A method of treating diseases characterised by excess renal reabsorpotion of water as 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 58 or a composition of claim 59 to said mammal in an amount effective to alleviate the disease. 61. A process for preparing a compound of the formula: YE SYOE A-B wherein Y is a bond or a moiety selected from -(Cl-I 2 -CHOH, -CHO-loweri alkyl (C 1 -C 6 -CH-S-lower alkyl (C 1 -C 6 -CHNH 2 -CHN-lower alkyl (C 1 -C 6 -C[N-lower C CH-N I CH--NCH--N~1 CH- alkyl (C-C6)]2CH-N J -CHOCO-lower alkyl alkyl (C 1 -C)2, (CI-C 6 -CHNH (CH 2 2 -CHNH(CH 2 -NH-lower alkyl (C 1 -C 6 -CIINH(CH 2 )m-N [lower alkyl(C 1 -C 6 2 -CHNH(CH 2 )m-S-lower alkyl (C I-C 6 255 OH /1_I II f f 0 -CHNH(CH 2 )m0-ower alkyl (CI-C 6 IuVVII Ylkl S, 0, -N] alkyl (C1-C6), -NCO-lower alkyl (C1-C6), mn is an integer of 2 to 6; -(CH 2 )nN-N (C2n A- i~c -a mr;- or-1pnt" rini R nnr R 3 HI, -N-lower 11111A I A J 1 i fltlL t1.,tt IJfl l. Yfl.ILII II 1 an integer 1 or 2 with the proviso that when Y is a bond, n is an integer 2; and the Moiety: -256- represents: an unsaturated 6-membered heterocyclic aromatic ring containing one nitrogen atom, optionally substituted by one or two substitutents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino; a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, or S; and the moiety: OE 10 represents: an unsaturated 6-membered heterocyclic aromatic ring containing one or two nitrogen atoms, optionally substituted by one or two substituents selected from (C 1 -C3)lower alkyl, halogen, amino, (Cl- C3)lower alkoxy or (C1-C3)lower alkylamino; a membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from 0, N or S; a aromatic (unsaturated) heterocyclic ring having two adjacent nitrogen atoms; a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom 20 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, halogen, or (C1-C3)lower alkoxy; R 3 is -COAr, wherein Ar is a moiety selected from the group consisting of: -257- R x R N \and 6 wherein X is selected from 0, S, -NH, -NCH3 and -NCOCH 3 R 4 is selected from hydrogen, lower alkyl(Ci-C 3 -CO- lower alkyl (Cl-C 3 Rl and R 2 are selected from hydrogen, (Cl-C3)lower alkyl, (Cl-C3)lower alkoxy and halogen; R 5 is selected from hydrogen, (Cl-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R 6 is selected from moieties of the formulae: -258- RjRa R R -NCOAr', -CONAr', -NCOCIl 2 Ar', -NCONAr', R C 2 C0Ar', -NCO-(CH 2 )11- cycl oal kyl, Ra R Ra -N-SO 2 N- SO 2 CH 2 2 2 R R R 0 R NTalY 2 2 2 aO lower alkyl(C3 -C 8 st raight or branched, Ra 0al I -N-C-lower alkyl(C 3 -C.)straight or branched, -NSO 2 -lower alkyl(C 3 -C 8 )straight or branched, RO N-C-lower al kenyl (03-C08):straight or branched, -NSO 2 -lower alkenyl(C 3 -C)straight or branched, wherein cycloalkyl is defined as (C3-C6) cycloalkyl, cyclohexenyl or cyclopentenyl; and Ra is independently selected from hydrogen, -CH3 or 9- 2 q *N.Rb 2 N j (CH 2)q- jo alkyl(Cl-C3), -CH2CH20H, q is one, two, or three, Rb is independently selected from hydrogen, CH3 or a moiety of the formula: 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(C 3 -C 8 branched or unbranched, tetrahydrofuran, tetrahydrothiophene, and the moieties: R~ CH- R 8 Z N S 0 -260- or -CH2-K' wherein K' is (Cl-C3)-lower alkoxy, halogen, tetrahydrofuran, tetrahydro-thiophele or the heterocyclic ring moiety: -N zDE G= F wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted with halogen, (Cl-C3) lower alkyl, hydroxy,- CO-lower alkyl(Cl-C3), CHO, (CC-C3)lower alkoxy, -C02- lower alkyl (Cl-C3), and Ra. and Rb are as hereinbefore defined; a moiety of the formula: R a COCHAr' w her ein RC i ssel ect ed f r o hal ogen, (C1- C 3) lower alkyl, -0-lower alkyl(C 1 CH -0-C-lower alkyl(C I-0C 3 -S-lower alkyl(C 1 -C 3 -S-(CH)~KbR HC 2 l< Rb -HC2) CNRb wherein Ra and Rb are as hereinbefore defined; a moiety of the formula: -261- wherein RdJ is lower alkyl (C3-C8) lower alkenyl.(C 3-C 8 (CH2) p-cycloalkyl (C3-C6) when M is 0, S, NH, NCH3, and the moiety -M-RJ wherein Rdj is selected from the moieties: 4 a S S S*SS S S *SSS S S S 55 S S S S. (CH 2 )p- (CH 2)p wherein p is zero to four and M is a bond or M is selected from 0, S, NH, NCH3; wherein R1, R 2 and Ra are as hereinbefore defined; wherein Ar' is selected from moieties of the formula: and 262 wherein W' is selected from O, S, NH, N-lower alkyl (C 1 -C 3 NHCO-lower alkyl (C 1 -C 3 and NSO 2 lower alkyl (C 1 -C 3 R 7 is selected from hydrogen, lower alkyl (C 1 -C 3 halogen, O-lower alkyl (C 1 -C 3 and CF 3 R 8 and R 9 are independently selected Sfrom hydrogen, lower alkyl (CI-C 3 -S-lower alkyl (C 1 -C 3 halogen, -NH-lower alkyl (C 1 -C 3 -N-[lower alkyl (C 1 -C 3 )12, -OCF 3 -OH, -CN, -S-CF 3 -NO 2 -NH 2 O-lower alkyl (Ci-C 3 NHCO lower alkyl (C 1 -C 3 -O-CO-lower alkyl (C 1 -C 3 and CF 3 and; R 10 is selected from hydrogen, halogen, lower alkyl (CI-C 3 -NH-lower alkyl (C 1 -C 3 -N-[lower alkyl (C 1 -C 3 2 -O-lower alkyl (C 1 -C 3 -N(Rb) (CH 2 )-N(Rb) 2 which comprises reacting a compound of the formula: Y Z YOE A-B -N-(CH2)n wherein A-B is H and H 0 II with a compound of the formula: Ar-C-C wherein Q is a halogen or an activating group, which results from conversion of an aryl carboxylic acid to a mixed anhydride or from activation with a peptide coupling reagent, S 15 to give compound of the Formula I. 62. A process for preparing a tricyclic benzazepine vasopressin antagonist, substaitially as hereinbefore described with reference to any one of the Examples. *000 0@ Dated 22 February, 2000 20 American Cyanamid Company Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0 0 04