CA2210688A1 - Tricyclic benzazepine vasopressin antagonists - Google Patents

Abstract

Tricyclic compound of general formula (I) as defined herein which exhibit antagonist activity at V1 and/or V2 receptors and exhibit in vivo vasopressin antagonist activity, methods for using such compounds in treating diseases characterized by excess renal reabsorption of water, and process for preparing such compounds.

Description

Wa! 96122282 PGT1US96101051 Title: "'RICYCLIr BENZAZEPINF VASOPRESSIN
ANTAGONISTS

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

2. Backoround of the ?nven ion 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 weil defined receptor subtypes: vascular V1 and renal epithelial V2 receptors. Vasopressin-induced antidiuresis, mediated 3`0 by renal epithelial V2 receptors, helps to maintain normal plasma osmolarity, blood volume and blood pressure.
Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is increased. V1 antagonists may decrease systemic vascular resistance, increase cardiac output and prevent SUBSTiTUTE SHEET (RULE 26) vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induce increases in total peripheral resistance and altered local blood flow, V1-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 c=-mediated incorporation of water pores into the luminal surface of these cells. V2 antagonists may correct the fluid retention in congestive heart failure, liver cirrhosis, nephritic syndrome, central nervous system injuries, lung disease and hyponatremia.
Elevated vasopressin levels occur in congestive heart failure which is more common in older patients with chronic heart failure. In patients with hyponatremic congestive heart failure and elevated vasopressin levels, a V2 antagonist may be beneficial in promoting free water excretion by antagonizing the action of antidiuretic hormone, On the basis of biochemical and pharmacological effects of the hormone, antagonists of vasopressin are expected to be therapeutically useful in the treatment and/or prevention of hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephritic syndrome, brain edema, cerebral ischemia, cerebral hemorrhage-stroke, thrombosis-bleeding and abnormal states of water retention.

SUBSTiTUTE SHEET (RULE 26) 'WO 96122282 PCT/US96101051 The following prior art references describe peptide vasopressin antagonists: M. Manning et al., 1. Med. Chem., 382 (1992) ; M. Manning et al., Med.
Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Patent 5,070,187 (1991); M. Manning and W.H. Sawyer, U.S. Patent 5,055,448(1991) F.E. Ali, U.S. Patent 4,766,108(1988); R.R. Ruffolo et al., Drucr News and Persnective, 4(4), 217, (May)(1991). P.D.
Williams et al., have reported on potent hexapeptide oxytocin antagonists [I. MP . Chem., 5, 3905(1992)]
which also er-hibit weak vasopressin antagonist activity in binding to V1 and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.
Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, 252, 579(1991); Y. Yamamura et al., Rr. 1. Pharmacol, 105, 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP 0514667-Al; EPO 382185-A2; W09105549 and U.S.5,258,510; WO 9404525 Yamanouchi Pharm.Co.,Ltd., WO 9420473; WO 9412476; WO 9414796; Fujisawa Co. Ltd., EP 620216-Al Ogawa et al, (Otsuka Pharm. Co.) EP 470514A
disclose carbostyril derivatives and pharmaceutical compositions containing the same. Non-peptide oxytocin and vasopressin antaaonist have been disclosed by Merck and Co.; M.G. Bock and P.D. Williams, EP 0533242A; M.G.
Bock et al., EP 0533244A; J.M. Erb, D.F. Verber, P.D.
Williams, EP 0533240A; K. Gilbert et al., EP 0533243A.
Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the prevention = 35 of preterm labor, B.E. Evans et al., .,~. MP . Chem. ~, 3919 (1992) ,~_T. Med. Chem., 36, 3993 (1993) and references SUBSTiTUTE SHEET (RULE 26) 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 Vl and/or V2 receptors and e:ihibit in vivo vasopressin antagonist activity. The compounds also exhibit antagonist activity at oxytocin receptors.
SUNLti!ARY OF THE INVENTT_ON
This invention relates to new compounds selected from those of the general formula I:

ZO

A-B R
Formula T
Wherein Y is (CH2)n, 0, S, NH, NCOCH3, N-lower alkyl (CI-C3), CH-lower alkyl (C1_-C3), CHNH-lower alkyl (C1-C3), CHNH2, CHN[lower alkyl (Cl-C3)]2, CHO-lower alkyl(Cl-C3), CHS-lower alkyl (Cl-C3), wherein n is an integer from 0-2:
A-B is - (CH2)m-N or N-(CH2)m ~ 1 .

SUBSTiTUTE SHEET (RULE 26) wherein m is an integer from 1-2, provided that when Y
is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when y is -(CH2)n and n is 2, m may not also be two.
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(Cl-C3), -SH, -SO lower alkyl(C1-C3), -S02-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3; lower alkyl(C1-C3); 0-lower alkyl(C1-C3), -N02, -NH2, -NHCO lower alkyl (C1-C3), -N-[lower alkyl(C1-C3)]2, -S02NH2; -SO2NH lower alkyl(Ci-C3) or -S02N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I. -OH, lower alkyl(Cl-C3), 0-lower alkyl(Ci-C3), or Ri and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:
O
II
-CAr wherein Ar is a moiety selected from the moiety .

SUBSTiTUTE SHEET (RULE 26) R ^

N
R, It7 X_R10 - '5 X Rjo S

RS

-~, l X ~o O

N--rX -'~o '11~S
R4 is hydrogen, lower alkyl(Cl-C3); -CO-lower ;
alkyl (Cl-C3) R5 and R-, are selected from hydrogen, (Cl-C3) lower alkyl, (C1-C3) lower alkoxy and halogen;
R6 is selected from (a) moieties of the formula:

SUBSTiTUTE SHEET (RULE 26) -NCOAr', - NCON-Ar-NCO(CH2 )n -cycloalkyl, R ( I R
a Ra Rb a -NCOCH2Ar' , :502 lo II R z O RQ -N-P O -N-P R L R

--1\5OZ-b~ve-alkti'1(C3-C8), -N5OZ-bvvealkelvl(C3-CS) R R
a a -NH-C-O-Io~ver alkyl(C3-C$)straight or branched -NH-C-lower alkyl(C3-C$)straight or branched, -NI-I-C-O-lower alkenyl(C3-C8)straight or branched, -NH-C-lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl =s defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is hydrogen, CH3, C2H=;, moieties of the formulae:

SUBSTITUTE SHEET (RULE 26) - (CF-~)q-N\ (CI-~)q- No R b - (CF~)q- \-1 -(CH2)20-lower alkyl(C1-C3) or -CH2CH20H; q is one, two or three; Rb is tiydroaen, CH3 or -C2H5;
(b) a moiety of the formula:
-X-R10; wherein Rio is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cyc1oalky1(C3-C6), R~ R5 -(CHZ)p / \ , / \

RS
{CHz)p N
R--tCHz)p S
R-3 0 -(CIH 2)p O
and p is zero to tliree :
X is 0, S, NH, NCH3, SUBSTITUTE SHEET (RULE 26) W 96122282 PGT/rTS96101051 \
C= 0 or a bond ~

and R; and R7 are as ere-viously defined = (c) a moiety of the formula:

Rb -N- COJ

wherein J is Ra, lower alkyl(C3-Cg) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-Cg) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiopliene, the moieties I ~ O 25 CH2 b R
or -CH2-y' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

-N11 D-Z~- E
G=F
= 35 SUBSTiTUTE SHEET (RULE 26) wherein D, E, F and G are selected from carbon or nitrogen and wherein the carbon atoms may be optionally substituted witli halcaen, (C1-C3)lower alkor.~=, -CO-lower alkyl ( Cl-C3 ) , C'r:^, (C1-C3 ) lower alko:-: , -C02-lower alkyl(Ci-C3), and Ra and Rb are as hereinbefore defined;
(d) a moiety selectecl from those of the formulae:

R
- N - COCI-Ll1r' I
R
c li -O-C-Ioiver alkvl (C 1-C3) , -S-locver alkv1(C1-C3) P R
\ ~ -NH(CF~) -CON b I~b Rb Rh Z ~
, - I\'H( Hz)q_ N\R - O- (CT~)2 -N~Rb n wherein r.c is selectec7 from halogen, (C1-C3)lower alkyl, -0-lower alkyl(Ci-Ci) and OH, Rb is as hereinbefore defined;
Ar' is a moiety selected frcm the arou_c ~
SUBSTITUTE SHEET (RULE 26) R$
R5 Rs R_ Rg R9 w' 8;)7R

Rg and Rg are indecendentll, hydrogen, lower alkyl (C1-C3); O-lowe'r alkyl(C1-C3); S-lower alkyl(C1-C3), -CF3, -CN, -OIi, -SCF3, -OCF3, halcgen, N02, amino cr NH
lower alkyl(Cl-C3), -N-[lower alkvl(C1-C3)]2--N(Rb)(CH2)q-N(Rb)2;
W' is 0, S NH, N-lower alkyl(Cl-C3), NCO-lower alkyl(C1-C3) or NSO-lower alkyl(C1-C3) or NSO2lower alkyl(C1-C3);
R25 is selected from the moieties I I
S
P~

~ /

R_ Ra SUBSTITUTE SHEET (RULE 26) and die moiety Z O
`
represents: (1) phenyl or substituted phenyl optionally substituted by one or two substituents selected from (Cl-C3) lower alkyl, halogen, amino, (Cl-C3) lower alkoxy, or (C1-C3) lower alkyl amino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring havina one heteroatom selected from 0, N or S; (3) a 6-membered aromatic (unsaturated) heterocyclic rina having one nitroaen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitroaen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrooen atom toaether with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3) lower alkyl, formyl, a moiety of the formula:
- (CH2) qN

Rb tialogen or (Cl-C3) lower alkoxy. For example, the fused heterocyclic ring may be represented by furan, pyrrole, pyrazole, thiophene, thiazole, oxazole, imidazole, pyrimidine or pyridine rina which may be substituted or unsubstituted.

.

SUBSTITUTE SHEET (RULE 26) DETAILED DESCRIPTION OF THE INVENTION
Within the group of the compounds defined by Formula I, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R3 is ainoiety :

CAr and Ar is selected from the moiety:
RS

N
R, wherein R5, R6 and R7 are as hereinbefore defined.
Especially preferred are compounds wherein R3 is the moiety:

- CAr and Ar is selected from the moiety:

NI-COR2.5 and 6 N

R6 is NHCOAr' and Ar' is SUBSTITUTE SHEET (RULE 26) \ ,R K
Rg wherein R8, Ro, R25 and W' are as hereinbefore defined.
Also especially broadly preferred are compounds wherein y in Formula I is -(CH2)n- and n is zero or one; A-B is I
(C L) I11 N or N-(CH2) m I~3 R

and R4, R5, R6, R7, R8, Rg and Rio are as hereinbefore defined; and m is an inteaer from 1-2.
The most broadly preferred of the compounds of Formula I are those wtierein Y is -(CII2 ) 11- and n is one;
A-B is -(CH 2) m-N or N-(CH2) m ; m is one or two R3 is the moiety:

- CAr -SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTlUS96/01052 Ar is RS R
NHCOR25 and 6 N
R; R7 lo R6 is -NCOAr', COAr', or -NCOCI~ Ar', -NCON -Ar' I I I I
Re IZb -NCO(CI-IZ ) I~ -cycloalkyl, X-R10 R

and Ar' is a moiety:

Rg Rg W, Cycloalkyl Ra, Rb and W' are as previously defined and Rg and Rg are preferably ortho CF3, Cl, OCH3, CH3, SCH3 or OCF3 substituents or Ar' is a disubstituted derivative wherein Rg and Rg are independently Cl, OCH3, CH3 and F.
The most highly broadly preferred of the compounds of Formula I are those wherein Y is -(CH2)n-, n is zero or one and SUBSTiTUTE SHEET (RULE 26) the inoiety Z Q

represents a phenyl, substituted phenyl, thiophene, furan, pyrrole or a pyridine ring;
A-B is - (CI-i2) n, - N or I - (CH2) in-It3 R

m is one when n is one and m is two when n is zero;
R3 is the moiety:

CAr wherein Ar is RS R_ ~

/ NFICOR~ and 6 N
R_ R-and R6 is selected from the group SUBSTITUTE SHEET (RULE 26) WO 96/22282 PGTlUS96/01051 r Ta ra -NCOAr', _ =HZAr' where Ar' is selected froin the moieties:
R5 RB Re R5 ~ ~ 2 W, N

and Ra, Rb, Rl, R2, R4, R5, R6, R7, Rg, Ro R25 and W' are as previously defined.
Most particularly preferred are compounds of the formulae:

R, R Ri Ri and / R2 R N ~ N-(CH2)m 2 ~ ~ R 1 R R
3 '' wherein m is an inteaer one or two; P.1 and P.2 are as previously defined;
R3 is the moiety:

CAr wherein Ar is selected froin moieties of the formulae:

SUBSTITUTE SHEET (RULE 26) RS RS
NI-EOR25 and 6 N

R6 is -NCOAr', NCO(CH2)n cycloalkyl, I I
R R, a -NCONAr', NCOCH2Ar', -X-RIo I I I
Ra Rb R
a wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:

Re F
R

F~ R
' '8 - W' N
R
s Ra is independently selected from hydroaen, CH3 or -C2H5; and R5 , R7, Rg, Rg, R1 o, R25, X and W' are as hereinbefore defined.
Also particularly preferred are compounds of the formulae:

SUBSTITUTE SHEET (RULE 26) _N Ri HN
R N N
N N. :;H2)m ( wherein m is an integer one or two; Ri and P.2 are as previously defined;
R3 is the moiety:
O
II
- CAr wherein Ar is selected from moieties of the formulae:
RS ~, NHCOR25 and 6 N

R6 is -NCOAr', NCO(CH2)n cycloalkyl, I I
R R
-NCONAr', NCOCH2Ar', -X-R10' = Ra RU R.

SUBSTITUTE SHEET (RULE 26) -NH-C-O-lower alkyl(C3 C8)straight or branched -NH-C-lower alkyl(C3 C$)straight or branched, -NH-C-O-lower alkenyl(C3-C$)straight or branched, -NH-C-lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl and wherein Ar' is selected from the moieties:

RRs R
s Rs W' N

Ra is independently selected from hydrogen, CH3 or -C2H5; and R5, R7, R8, Rg, R10, R25, X and W' are as hereinbefore defined.
Compounds of this invention may be prepared as shown in Scheme = by reaction of tricyclic derivatives of Formula 3a and 12 with a substituted or unsubstituted 6-nitropyridine-3-carbonyl chloride A to give the intermediates 5a and 5.t. Reduction of the nitro group in intermediates f-a and 5-t gives the 6-amino-3-pyridinylcarbonyl derivatives -rza and EL. The reduction of the nitro group in intermediates 5a and 5,11 may be carried out under catalytic reduction conditions (hydrogen-Pd/C; Pd/C-hydrazine-ethanol) or under SUBSTITUTE SHEET (RULE 26) chemical reduction conditions (SnC12-ethanol; Zn-acetic acid; TiC13) and related reduction conditions known in the art for converting a nitro group to an amino group.
The conditions for conversion of the nitro group to the amino group are chosen on the basis of compatibility with the preservation of other functional groups in the molecule.
Reaction of compounds of Formula -E& and L12 with aroyl chlorides, heteroaroyl chlorides, arylsulfonyl chlorides, diarylphosphinyl chlorides, diphenoxyphosphinyl chlorides, alkyl (C3-C8) carbonyl chlorides, alkenyl(C3-C8)carbonyl chlorides, alkoxy(C3-C8)carbonyl chlorides, alkenyloxy(C3-C8)car-bonyl chlorides, alkyl(C3-Cg)sulfonyl chlorides, alkenyl(C3-C8)sulfonyl chlorides cycloalkylcarbonyl chlorides, arylcarbamoyl chlorides or heteroaryl-carbamoyl chlorides as illustrated in Scheme 1, gives the novel compounds $; and 3' of this invention. The reactions may be carried out in solvents such as chloroform, dichloromethane, dioxane, tetrahydrofuran, toluene and the like in the presence of a tertiary base such as triethylamine, diisopropylethylamine or pyridine at O C to 50oC. lf more than one aroyl, heteroaroyl or arylsulfonyl group, etc. is introduced during the reaction, mild base treatment (NaOH, KOH etc.) in a lower alkanol removes the second such group to give the products 3a and 3t.

SUBSTITUTE SHEET (RULE 26) Scheme 1 RRi ~
Y

Y ZO R
RP R2 N-'(~2~m 2 m H
H
3a 3b CI O

-Ri R~
Y y \

(C 2 m N N- (C''H~
-o R5 ~ N R7 R5 ~ N R7 5a 5b =

SUBSTiTUTE SHEET (RULE 26) WO 96/22282 PCTlIIS96/02051 Scheme 1 (Cont'dj RR~
~ Y\ R
Y ROp R2 Z

_(~)m Q

F~ /N ~ N ~
NF~ NH~
6a 6b Ar'COCI
Ar'CH2COCI

7 cycloalkyi(CH2)nCOCI 7 Ar'NCOCI
I
F~
8a Bb R6 = -NHCOAr'; -NHCONAr'; -NHCO(CH2)n cycloaikyl;
'b -NHCOCH2Ar' SUBSTITUTE SHEET (RULE 26) Scheme 1 (Cont'd.) 6a 6b alkyi(C 3-C8)COCI
alkyl(C 3-C8)O-COCI
alkenyl(C3-Ce)-COCI
alkenyl(C3-C8)-OCOCI
aikyi(C 3-C8)SO2CI
aikenyl(C3-C8)S02CI
F~

- Sp2 Cl + 7a R 7 + 7a ~ LCI

P~

CH.t 902 c 1 P'7 F~
O

Ri 8b SUBSTITUTE SHEET (RULE 26) Scheme 1 (Cont'd.) R1 R~
~ Y
Y ~
zo ~ Zo ~

m N N-(Cf-12)m O

N F~
N R
' Pb q 8a 8b R6 = -NHCOalkenyl(C3-C8), -NHCOalkyl(C3-C8), - NHCO2a1kyl(C3-C8), -NHSO2alkyi(C3-C8), -NHCO2alkenyl(C3-C8) -NHSO2alkenyl(C3-C8) Rz _NHSO2 / P - NHSQzCHZ ~ ~
NH-Fp-~ F~ F~ 2 R
Z
O
I!
NHP
'7 SUBSTITUTE SHEET (RULE 26) Reaction of tricyclic derivatives of Formula _Ea and 6b with either a carbamoyl derivative I or a isocyanate derivative 14 gives compounds (Scheme 2) of Formula 1'a and I'b which are vasopressin antagonists and/or oxytocin antagonists of Formula I wherein R6 is -NHCONAr' I
Rb and Rb is H, CH3 or C2H5.

SUBSTITUTE SHEET (RULE 26) Scheme 2 6a 0 6b CI-C-NAr' I
or R b 0= C= NAr' 15 R Ri , Y Y
ZD ~ ZO
r 7 ~
(C m N ("' Ym O

R~ R ' Rs R7 N N
NHCONAr' NHCONAr' R b Rb 11a 11b Reaction of tricyclic derivatives of Formula 3a and 3b with a 6-chloro or a 6-fluoropyridinine-3-carbonyl chloride 12 gives intermediates 13a and 13b (Scheme 3).

SUBSTITUTE SHEET (RULE 26) Scheme 3 3a CI ~ 3b I j ~ I .
y .N

F' CI ( F ) Ri R, Y Y
ZO ~ ZO
(c R2 ,(CH) ~
2 m m RS ~ N R' R5 ~ NR
CI (F) CI (F) 13a 13b The intermediates 13a and 13b may be reacted with R10X- (14) wherein R10 is as previously defined and X is 0, S, NH or NCH3 to give derivatives of 15a and 15b as shown in Scheme 4.

SUBSTITUTE SHEET (RULE 26) Scheme 4 13a 13b Rt R~
Rz Y52m N ZO
KC( R7 (CH)m fl p 15a 15b The compounds of Formula I wherein Y, A-B, Z, R1, R2 and R3 are as defined and the R3 (-COAr) aryl group is N

SUBSTITUTE SHEET (RULE 26) wherein R6 is as previously defined may be prepared as shown in Scheme 5 by first synthesizing the pyridinyl moieties j-E which are to be attached to the tricyclic benzazepine units.
R-O

H- O ~ ZZ 6 N

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

SUBSTITUTE SHEET (RULE 26) WO 96122282 PC1'1US96/01051 Scheme 5 3a 3b CI O

R5 N F~
--r Ri RP
~
Z 0 Y 15 cry ~
~(CH2~m 14 _ O

F~ R
N

R6 '6 18a 18b The startina materials 3a and 3b in Scheme 1 can be made by literature methods. For example, intermediate 6,11-dihydro-5H-dibenz[b,e)azepines and substituted derivatives are prepared according to literature procedures: L.H. Werner, et al., ~T. Med.
Chem.,8,74-80 (1965); A.W.H. Wardrop et al., ~7. Chem.
oc. Perkins Trans I, 1279-1285 (1976).
Substituted 5,11-dihydrodibenz[b,e]azepin-6-one are prepared by literature procedures: J. Schmutz SUBSTITUTE SHEET (RULE 26) et al., Helv. him. Acta., 48, 336 (1965); and reduced to substituted 6,i1-dihydro-5H-dibenz[b,e]azepines with lithium aluminum hydride, borane, borane-dimethylsulfide and agents know to reduce an amide carbonyl to a methylene group. Intermediate 10,11-dihydrodibenz[b,f][1,4]thiazepines are prepared by literature procedures - for example, see K. Brewster et al., 1. Chem. Soc. Perkin I, 1286 (1976). Reduction of either dibenz[b,f][1,4]oxazepines [A.W.H. Wardrop et al., 7. Chem. Sec. Perkin Trans. 1, 1279 (1976)] and dibenz[b,f][1,4]oxazepin-11(lOH)-ones and dibenz[b,f][1,4]thiazepin-11(10H)-ones - J. Schmutz et al., HAlv. rhim. Acta.,48, 336 (1965); may be carried out with lithium aluminum hydride in inert solvents such as dioxane and the like. The tricyclic 6,7-dihydro-5H-dibenz[b,d]azepine intermediates of Formula la may be prepared by the literature procedures: T. Ohta et al., Te}rahedron Lyll., 21, 5811 (1985); Wiesner et al., 1.
Amer. Chem. aoc., 77, 675 (1955); or derivatives may be prepared by coupling procedures illustrated in Scheme 7.
The reduction of nitro compounds of structure type 131 followed by ring closure, affords lactams IZ which are reduced to give tricyclic azepines of Formula 12.
5,11-Dihydro-6H-pyrido[3,2-,][1]benzazepines are prepared by literature procedures - J. Firl et al., Liebins Ann. CheTM;. 469, (1989). 11H-Pyrido [2, 3-b][1,4]benzodiazepin-6(5H) ones have been reported by J.F.F. Liegeois et al., 1. M. hPm ,36, 2107 (1993) and these derivatives are reduced to 11u-pyrido[[2,3-b][1,4]benzodiazepines. The synthesis of tricyclic 1,4,5,10-tetrahydropyrazolo-[4,3-c][1]benzodiazepine and the 3-chloro derivative have been reported -G. Palazzinc, et al., J. Heterocyclic Chem., 26, 71 (1989). 4,10-Dihydro-SH-thieno[3,2-Lj[1]benzazepine 2.1a and 9,10-dihydro-4H-thieno[2,3-Y][1]benzazepine 21t may be prepared by coupling tributyltin derivatives la and SUBSTITUTE SHEET (RULE 26) 20 with 2-nitrobenzyl bromide in the presence of tetrakis(triphenylphosphine) palladium(O) as shown in Scheme 6.
Following coupling of intermediate 24 to give the tricyclic azepine 25, the nitro group is reduced to aive the 6-aminonicotinoyl derivative .26. The derivative 2-9 is then reacted with the appropriate acid chlorides as illustrated in Scheme 7 to give the products 27 and 27a.
Also depicted in Scheme 7 is the synthesis of intermediate tricyclic azepine 30 and 33. The tricyclic iactam derivatives 29 and 32 may be prepared by reduction of nitro intermediates Zg and 31, followed by ring closure of the corresponding amino derivatives.
These tricyclic lactam intermediates 29 and 2 may be reduced with lithium aluminum hydride (LAH) or borane to give the tricyclic azepines 30 and 33.

~

SUBSTITUTE SHEET (RULE 26) Scheme 6 O~ Sn Bu3 O O ~
J
S
S SnBu3 CH2Br N

y r S / \ \ /
S

N
H+ Zn: HOAc r ~ ~
cHO IIIIIIIIIII\ ~ ~
s N
S O H

LAH
Zn: HOAc \ / S ciiii::c> N N H H

21a 21b SUBSTITUTE SHEET (RULE 26) Scheme 7 Ri R 2 R, NH- (CH2)2 I ~
BH3S(CH3)2 23 ---- --t r Ri R
_ ~

Ri Cu/ 0 ~
N (CH2)2 R
O ~ -Np2 p N

Pd/C H 24 r -SUBSTITUTE SHEET (RULE 26) Scheme 7 (Continued) R
' P~ Ar'COCI or ~
Ar'CH2COC1 R2 or - Ar'COCI
O ~ ~ NH2 I
N ~
26 or cycloalkyl(CH2)nCOCi ~

R R' Rz Rb b 2 0 ( y R Ar', Ar'-CH2-, Ar'N - cycioalkyl(CH2)n- R2 N

O
- . II

SUBSTITUTE SHEET (RULE 26) Scheme 7 (Continued) P~
~
26 + 7a --- -s F~ Rz ~
, P~ N

O i NHR
R11a = alkyl(C3-C8)CO- N
iia 0 27a alkyl(C3-C8)O-C-alkenyl(C3-C8)CO-alkenyl(C3-C8)COCO-alkyl(C3-C8)S02 -alkenyl(C3-C$)S02-F~ Rz O

~

F~
- ~ o P-:)- ~2~2 ~

SUBSTiTUTE SHEET (RULE 26) Scheme 7 (Continued) Ri R' R~ R, R 2 R ~ / (1) H2,Pd/C ' .
~ r O (2) Ring close R2 N

I H
Np 0-alkyl O

or BH3 y Ri R

Ri Rt Rz NO2 0-alkyl R2 N

(1) Pd/C, H2 (2) ring closure r SUBSTITUTE SHEET (RULE 26) WO 96122282 PCTli1S96101052 F~ F~ F~ pt LAH Bt, O

or 5 N BH

P~ Ar'COCI
Rz zB~M

OAr' Tricyclic intermediates 42 for the synthesis of selected vasopressin antagonists of this invention wherein Y in Formula I is -CH2- and m is one, may be prepared as shown in Scheme B. Suitable 1-nitro-2-chloro or 1-nitro-2-bromo heterocycles 35 undergo halogen exchange when reacted with a alkyllithium reagent such as t-butyllithium, s-butyllithium or n-butyllithium to aive intermediates 3_7 which react with anhydrides of Formula 38. R12 is tert-butyl, secondary butyl, n-butyl, 2,6-dimethylpiperidine or a hindered non-nucleophilic dialkylamine. The nitro products 39 are reduced with hydroaen and a suitable catalyst or chemically reduced (Zn-acetic acid, TiC13 etc.) to the amino intermediates 40. Ring closure to the cyclic lactams _41 is conveniently carried out by heating in xylene or an inert solvent at 100 C to 200 C . The SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCTl1TS96/01051 cyclic lactams of structure type 41 are readily reduced by borane in tetrahydrofuran, borane-dimethylsulfide in tetrahydrofuran or lithium aluminum hydride in a suitable solvent such as dioxane to give the tricyclic compounds 42.
Alternatively phenyllithium derivatives 37b, which are prepared by lithiation of protected benzaldehyde derivatives or by lithiation of 2-chloro or 2-bromo protected benzaldehyde derivatives, are reacted with derivatives 38b wherein Z is as previously defined.
Derivatives 38b are prepared by standard procedures such as ring closure of 1-amino-2-carboxy heteroaromatic compounds or 1-amino-2-benzoic acid derivatives, with acetic anhydride (Scheme 8).

SUBSTiTUTE SHEET (RULE 26) WO 96122282 PC1'IUS96102051 Scheme 8 R
a R12Li Li -----> Z O

35, R= CI or Br NO2 36, R = H 37a O Ri O

O
38a O R
+ 1 Z O ~ L~ R
z CH3 O 0 Ri N 37b 38b / NOz C02 H

'- 3 9 SUBSTiTUTE SHEET (RULE 26) 0 R, z0 R 2 O Ri _ Ri ~ R2 z0 ~ ~ z~ p 15 N -~ N

20 Alternatively, as shown in Scheme 9, some of the tricyclic derivatives of structural type 42 may be prepared by "palladium" type coupling or "copper"
induced coupling of halogenated derivatives .43 to give tricylic lactams 44. Reduction of the lactam carbonyl 25 group aives the intermediates 42. Coupling of halogen derivatives 45 to effect ring closure with activated copper or "palladium' type reagents which induce aryl coupling gives lactams 46. Borane reduction of lactams 46 gives derivatives 47. Ullmann cross couplings of 30 halogenated hetterocycles and 2-bromonitrobenzenes and related cross couplings by low valent palladium species such as (Pd(PPh3)41 and PdCl2(PPh3)2 are known synethetic procedures; N. Shimizu et al., Tetrahedron Lett. 34, 3421 (1993) and references therein; N. M. Ali 35 et al., Tetrahedron, 37, 8117 (1992) and references SUBSTITUTE SHEET (RULE 26) wc- 96122292 PCT1I7S96101052 therein; J. Stavenuiter et al., Heterocycles, 26 2711 (1987) and references therein.

Scheme 9 , 5 CH2Br(or i) R

Z~ Rz ZO

N N

Br(or 1) ~ r Z~ 42 N
H O

R Rz R~ R2 Zo Z O N
o H
N

Tetrahydro-lH-l-benzazepin-5-ones 51 and the tetrahydro-lH-1-benzazepin-2,5-diones 52 are useful compounds for the synthesis of intermediate tricyclic heterocyclic structures 53 and 54 (Scheme 10). The tetrahydrobenzazepin-5-ones 51 and 52 may be formulated = 35 to give hydroxymethylene derivatives or reacted with SUBSTITUTE SHEET (RULE 26) either the Vilsmeier reagent or the N, N-dimethylformamide dimethyl acetal to give the dimethylaminomethylene derivatives. The construction of heterocyclic rings from a-hydroxymethyleneketones by reactions with hydrazine, N-methylhydrazine, hydroxylamine or formamidine to give pyrazoles, N-methylpyrazoles, oxazoles or pyrimidines respectively, is a standard literature procedure. See Vilsmeier formylation - Te*_rahedror., 49, 4015-4034 (1993) and references thereln and ring fcrmations -J.Heterocyclic Chem., 29, 1214 (1992) and references therein.
Substituted and unsubstituted tetrahydrobenzazepin-2-ones are known compounds which are prepared by reaction of a-tetralones with sodium azide under acidic conditions. [I. Chem. Soc. 456 (1937) ; Tetrahedron 42, 1807 (1993) ] (Schmidt reaction).
Reduction of tetrahydro-lH-benzazepin-2-ones gives the tetrahydro-1H-benzazepines 48 which acylation gives compounds 49. Oxidation of N-acyl tetrahydro-lH-be,nzapines of type 49 to give the 5-one derivatives is a known oxidative procedure; R. L. Augustine and W. G.
Pierson, 1. QrQ. Chem., 24, 1070 (19069).
The synthesis of 3,4-dihydro-l-H-l-benzazepine-2,5-diones ( 2.:R15=H) has been reported as well as the conversion cf 3,4-dihydro-1_-1-benzazepine-2,5-diones to 4-[(dimethylamino)methylene]-3,4-dihydro-lH-1-benzaze-pine-2,5-diones with N, r1-dimethylformamide, dimethylacetal: [W.-Y. Chen and N. W. Gilman, J.
Heterocyclic Chem., 2, 663 (1983)]. The preceding reference describes the synthesis of 2-methyl-5,7-dihydropY=ri mido [ 5, 4-~1] [?] benzazepin-6 ( 6H) -ones which may be reduced to remove the lactam carbonyl group to give tricyclic derivatives cf struct.:ral type ;4 wherein Z is a pyrimidine ring.

SUBSTiTUTE SHEET (RULE 26) Scheme 10 Ri Ri ~ \ .
R9 5 N -- - e ~/ ~

~ H N
F~ R ~ 49 48 (1) N B S s a; R15 = (CH3)3CCO
A" (2)(C6H5C-O)2O

R Br b; R15 = C6H5-CH2OC-i Rs 01 D N NCH32S=O /
c; R15=N02 Et3N N
R1s 50 a,b,c R 7 KMnO4 N

R1s (Continued) 51 a,b,c SUBSTITUTE SHEET (RULE 26) Scheme 10 (Cont'd.) R1 p p 5 R1 R,z p R2 N

52 (R15 = H) ~ 51 i -`

p CHN(CH3)2 R 1 ~

R N

r Z
z R1 0 O

a 2 z N
N I

SUBSTITUTE SHEET (RULE 26) Scheme 11 R R, ~
; 5 Y
/
~ Zo R
R2 N-(CH)m 2 m N~ H
gy H
3a 3b R$ R~

20 R Ri i Z O R

25 m N
=0 R5 N R' R5 N R7 56b 5Fa SUBSTITUTE SHEET (RULE 26) Scheme 11 (Cont'd.) Ri Ri = Y \
Y \ Z O

z -(CH~m \

R; N
N N

NHZ

57a C' CCF~57b RtF~ R~
Y Y ~

-("' 2~m ( m a o ~ ~ R7 R; N F~

59a 59b SUBSTITUTE SHEET (RULE 26) The compounds wherein the aryl group in the R3 moiety -COAr is are prepared as shown in Scheme 11. The tircyclic derivatives 2a and 3.1~ are reacted with a substituted or unsubstituted 4-nitrobenzoyl chloride F35 to give the derivatives 56a and 55b Reductions of the nitro group in derivatives 56a and 56b gives the 4-aminobenzoyl intermedites 57a and ~--7;2 which are then reacted with an acid chloride represented by formula ;$ to give the products 5Qa and f-22.1a.
The compounds wherein the aryl group in the R3 moiety -COAr is Rio ""7 are prepared by reactin of tricyclic azepines -La and -Lt with a substituted benzoyl chloride illustrated by structural formula GC, (Scheme 12) to give the products 61a and 61b. In a similar manner reaction of heteroaroyl chlorides 62, 63, or 64 with the tricyclic azepines 3a and 3b gives the products 65ti and 65b wherein the aryl groups are as illustrated in Scheme 13.
.

SUBSTITUTE SHEET (RULE 26) Scheme 12 3a 3b CI O .

R R

X' R 1 0 15 Ri Y Y ~
ZD ~ R z0 R 2 (C (CH) p ~ ~ ~ ~

25 X- R1o X-Rio 61a 61b SUBSTITUTE SHEET (RULE 26) Scheme 13 3a 0 3b ~X-Rio 62 a s O
'~4-~ X Rio 63 a 0 N X- Rio CI uS

Ri R15 Y ay"o ~ z0 ~

(Crl) N

N
I- O
Ar Ar 65a 65b ---' X-Rio Ar = X Rio ~ X-R1o , N
S O S
Reference Examnle 1 6.11-Dihydro-5H-dibenz(b.elazepine A mixture of 48.52 a(0.20 mol) of 2-aminobenzophenone-2'-carboxylic acid and 500 ml of xylene is refluxed for 67 hours, cooled to room temperature and filtered. The solid is washed with xylene to give 43.3 q (97,6t) of 6,11-dione as light tan crystals, m.p. 245-248 C. To SUBSTITUTE SHEET (RULE 26) 4.46 g (0.020 mol) of the preceding compound in 25 ml of tetrahydrofuran is added 12 ml (0.12 mol) of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran.
An additional 10 ml of tetrahydrofuran is added and the mixture is stirred overnight and then is refluxed (solids dissolve) for 4 hours. The solution is cooled and 15 ml of methanol added dropwise. The mixture is concentrated under vacuum, 50 ml of 2N sodium hydroxide is added and the mixture refluxed for 2 hours. The solid is filtered, washed with water, air dried and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 3.25 g (83%) of crystals, m.p. 117-122 C.
Reference EZ:amp1P 2 2-Chlorn-5u-^'ibPn2fb A1azezDine-6 '1-d;on Chlorine gas is bubbled into a mixture (partial suspension) of 1.0 g (450 mmol) of 5H-dibenz(b,e]-azepine-6,11-dione in 50 ml of glacial acetic acid. The temperature of the mixture rises to 38 C. On standing, as the temperature of the solutions decreases, a white solid precipitates. The mixture is filtered to give 0.40 g of solid (mixture of starting material and product in ratio of 1:8). The filtrate on standing gives 0.10 g of product as crystals, m.p. 289-293 C.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTlUS96101052 Reference Example 3 10,11-Dil:vdro-N,N-dimethyldibenzfb flfl 41oxazepine-2-sulfonam.ide To 5.88 g of 10,11-dihydro-N,N-dimethyl-11-oxodibenz[b,f][1,4]oxazepine-2-sulfonamide in 5 ml of tetrahydrofuran is added 20 ml of a molar solution of borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred overnight and then refluxed for 2 hours. The mixture is chilled, diluted with 10 ml of methanol and then concentrated, methanol added again and the mixture concentrated. To the mixture is added 20 ml cf 2N NaOH
and the mixture refluxed for 2 hours. The mixture is extracted with dichloromethane, the extract dried (MgSO4) and -f-4ltered. The filtrate is passed through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give 4.8 g of crystals. m.p. 99-102 C.
Recrystallization from diisopropylether-dichloromethane gives 3.96 g of crystals, m.p. 109-110 C.
Mass Spectrum (FAB) 305(M + H) .Anal . Calc' d. for C15H16N203S:C,59.2; H,5.3; N,9.2; S,10.6.
Found: C,57.6; H,5.2; N,8.9; S,10.1.
Reference Example 4 2-Crlcr^-5 6-dihydronneranthridinP
To a hot (70 C) solution of 2.62 g(17 mmol) of 6(5::)-phenanthridinone in 120 ml of acetic acid is added chlorine gas for 10 minutes. The solution is allowed to cool to room temperature and the mixture filtered. The crystals are filtered to give 1.35 g of crystals, m.p. 310-318 C.
To the preceding compound (1.57 g) in 25 ml of tetrahydrofuran is added 12 ml of a 10 molar solution of boron-dimethylsulfide in tetrahydrofuran. The mixture is refluxed for 18 hours, cooled and 15 ml of methanol is added. The mixture is concen~rated under vacuum and 50 ml of 2 N sodium hydroxide added. The mixture is SUBSTITUTE SHEET (RULE 26) refluxed for 2 hours and the solid filtered off and washed with water and air dried to give the product as a solid.

Reference Example 5 5 9-Chlorc-5H-dibenz(b,e?azepin-6,11-dione A mixture of 11.15 g of 5H-dibenz[b,e]azepin-6,11-dione and 600 ml of glacial acetic acid is heated on a steam bath until the solid dissolves. To the solution (70 C) is added chlorine gas. Chlorine is bubbled throughout the solution until a precipitate begins to form. The mixture is allowed to cool to room temperature and is filtered to give 7.3 g of product, m.p. 290 C to 295 C.
Reference E:-:amrle 6 4-Chloro-6,11-dihydre-5H-dibenzfb,elazepine To a mixture of 7.28 g 9-chloro-5c:-dibenz-[b,e]azepin-6,11-dione in 25 ml of tetrahydrofuran under argon is added 8.5 ml of 10 molar boron-dimethylsulfide in tetrahydrofuran. The mixture is stirred 18 hours at room temperature, 30 ml of tetrahydrofuran added and the mixture refluxed for 3 hours (solids ciissolved). The solution is cooled to room temperature and 25 ml of methanol added dropwise. The volatiles are removed under vacuum. To the residue is added 100 mi of 2 N
NaOH. The mixture is refluxed overnigh:. and filtered.
The solid is extracted with dichloromethane and the extract is washed with 2=N citric acid, water and dried (Na2SO4). The solvent is removed to give 4.2 g of solid which is triturated with ethyl acetate-hexane (1:2) to give crystals, m.p. 137 C to 141 C.
Reference Ez_a=nplA 7 , 0 1-r-'^y^rodibAnzfb, flr 4!}h; azepinA
To a mixture of 3.3 g of 10,11-ciihydro-ll-oxodibenz[b,f][1,4]t:iazepine in 25 ml of tetrahydrofuran is added 4.0 ml cf 10 molar borane-dimethylsulfide in tetrahydrofuran. The mixture is SUBSTITUTE SHEET (RULE 26) stirred at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional 30 ml of methanol is added and the solvent removed to give white crystals. A sample is purified by chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give white crystals, m.p. 145-148 C.
The following compounds are prepared as described in Reference Example 7.
Reference Example 8 4-Me*hyi-10 '1-dihydrod;berzfb flri 41*riazepine Reference Example 9 4-r'h' Qr^-10 ,'-^irydrodibAnzfb, = l r 1 4 1}hiaz pinP
Reference 10 2-Methyl-10 1'-dihvdrodibPr--fb fl ri z1*h;azepine Reference Examnle 11 2-^hlorc-10,11-dihydrodiber7fb,flrl,4lthiazenine Reference Ex.ample 12 2-MPl-hoxylO 11-dihydredibe^.zfb f1 ri al}hiazepine Reference Examnle 13 8-Chlor^-10,11-d-hvdrodibe.^.zfb,flr1.41thiaz pine Reference Examcle 14 4 8-Dichloro-1^,11-dihydrodibenzfb,flfl,41 hiazepine Reference Examnle 15 8-Chlcro-4-methyl-10,11-dihycirodibenzfb,_`1r1,41 -thiazepine Reference Examnle 16 8-Methoxv-10,11-dihydrodibenzfb,r'r1,41thiazepine Reference Examnle 17 7-rhl^rr'-4-me`hwI-10, 11-dihydr;,d ibenz fb, f l r-, 41 thiazApine The -following compounds are prepared as described in Reference Example 3.
Reference Examnle 18 2-C'^lorc-10, 11 -di hydredibe.^.z rb, f 1 r 1, 41 -o_=:azepinP

SUBSTiTUTE SHEET (RULE 26) Reference Example 19 2-Methyl-10 11-di hydY'orii hPnz fb f1 r 1 d1- x pi na Reference Ex.ample 20 4-ChloYo-10 11-dihydroc'ibenz fb fl rl 41-oxazepinP
Reference Examnle 21 3-MAthyl-10 i 1-di hydroc'irAnzrr flrl 41-oxazPpine Reference Example 22 7-Chloro-10 1i-dihydrodibenzfb flf1 d',-oxaz pine Reference Examnle 23 8-Chlorc-10.11-dihydrodibenzfb flfl 41-oxazepine Reference Exarr.nle 24 214-Dichloro-10.1?-dihydrodibPnzrb flri 41-oYaz pine Reference Example 25 4 8-~i^hlor^-10 i1-dihy^rodibenzrb flFI al-oxaz p;ne Reference Example 26 4-Chloro-8-me*hyl-10 11-dihydrodiberzrb f?fl 41-ox_azenine Reference Example 27 4-Methyl-7-chloro-10 11-dihydrodibenzrb flf1 Ql-oxaze-oine Reference Example 28 1-ChloYo-4-*netry'-101'-dihydYodibenzfb flfl 41-oxazepine RefPrencA Examale 29 2-Fluorc-10,11-dihvdrodibenzfb,flrl 41-oxazepinA
Reference Example 30 N-(2-Iodor)nPnyi)-2-icdonhenylacPtamide A solution of 13.32 g (0.05 mol) of 2-iociophenylacetic acid in 75 ml thionyl chloride is refluxed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2-iodophenylacetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture of 100 ml of toluene-dichloromethane (1:1) is added 11 g (0.05 mol) of 2-iodoaniline and (0.10 mol) of ciiisopropylethylamine.

SUBSTITUTE SHEET (RULE 26) The mixture is stirred at room temperature overnight and the solvent removed. The residue is dissolved in dichloromethane and the solution washed with 1N HC11 saturated sodium bicarbonate, brine and dried (Na2SO4).
The solvent is removed and the residue recrystallized from methanol-ether to give 16.0 g of light brown crystals, m.p. 160 -163 C.
Reference EYample 31 2-iodo-N-(2-i.odophenyl)benzeneethanamine To a suspension of 1.39 g (3 mmol) of 2-iodo-N-(2-iodophenyl)benzeneacetamide in 30 ml of tetrahydrofuran-ciichloromethane (1:1) is added 3.75 ml of 2.0 molar borane-dimethylsulfide in tetrahydrofuran.
The solution is stirred I hour at room temperature and then relfuxed for 16 hours. The mixture is cooled and water slowly added dropwise until gas evolution ceases.
The volatile are removed under vacuum and the aqueous residue made alkaline with 2N sodium hydroxide. The mixture is extracted with ether (50 ml) and the extract is washed with brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad is washed with ether and the f.iltrate evaporated. The residual solid is washed with isooctane to give 1.20 g of white solid.
Recrystallization -from diethylether/hexane gives white crystals.
Reference ExamblP 32 N- (4-r'~ trobenzoyl-N- (2-iodophenyl) -2-iodobenzeneethylamine To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-dichloromethane (5:1) and the solution washed with 1N

SUBSTITUTE SHEET (RULE 26) HC1, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethy_1 ether and hexane to give 1.10 g of product as a white solid.

Reference EXamvi~'3 3, 4-T); hvdr'^-!u-1- nza7Ap'' T1P- r1---ne To a solution of 225 ml of glacial acid and 8.5 ml of concentrated sulfuric acid is added 49.54 g (0.30 mol) of 2'-nitroacetophenone and 47.02 g (0.50 mol) of glyoxylic acid (hydrated). The mixture is heated at 100 C for 16 hours. The mixture is cooled and poured over crushed ice. After the ice melts, the mixture is filtered and the solid washed with cold water. The solid is dried and recrystallized from dichloromethane-hexane to give 20.1 g of 3-(2-nitrobenzoyl)acrylic acid as white crystals, m.p. 153-158 C. A solution of the proceeding compound (9.0 g) in 80 ml of ethanol and 1.6 g of palladium-on-carbon is hydrogenated in a Parr hydrogenator under 30 pounds per square inch cf hydrogen for 20 hours. The mixture is filtered through diatomaceous earth and the solvent is removed. The residue (7.0 g) is chromatoaraphed on silica gel with hexane-ethyl acetate (1:1) as solvent to give 4.0 g of 3-(2-aminobenzoyl)propionic acid as an orange solid, m.p. 103 -107 C. A 0.50 g sample of the preceding compound, 0.36 ml of triethylamine and 0.43 ml cf diethoxyphosphinyl cyanide in 20 ml of dichloromethane is stirred at room temoerature for 5 days. The solvent is removed, ethyl acetate is added and the mixture washed with water, 2 LT citric acid, 1M
NaHCO3, brine and dried (Na2SO4). The solvent is removed and the residue purified by chromatography over silica ael with ethyl acetate-hexane (1:1) as solvent to give 0.190 g of light brown crystals, m.p. 168 -170 C.

SUBSTITUTE SHEET (RULE 26) WU 96122282 PCI'IITS96/0l051 Reference Example 34 4-((Dimethylamino)methylenel-3,4-dihYdro-1H-1-benzazep;ne-2,5-dione A mixture of 0.250 g(1.43 ,mmol) of 3,4-5 dihydro-lN-l-benzazepine-2,5-dione and 5.5 ml (4.93 g, 41.5 mmol) of N,N-dimethylformamide, dimethylacetal is heated at 90 C for 1.5 hour. The mixture is cooled, diluted with diethyl ether and filtered. The solid is washed well with diethyl ether and dried to give 0.26 g of tan crystals, m.p. 203 -205 C.
Reference EYample 35 2-Methyl-6, 7-dihycirc-5?I-r)yrimido f 5. 4-dl f 11 benzazer)ine To a soluzion of 0.308 g (3.26 mmol) of acetamidine hydrochloride in 15 ml of methanol under argon is added 0.176 g of (3.26 mmol) of sodium methoxide and the mixture stirred for 5 minutes. To the mixture is added 0.50 g (2.17 mmo1) of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-5H-1-benzazepine-2,5-dione and the mixture stirred at room temperature overnight. The mixture (containing thick precipitate) is diluted with 3 ml of methanol, chilled and filtered. The filtrate is concentrated to dryness.
The residue and original solid are combined and chloroform added. The mixture is washed with water, the organic layer is treated with activated carbon and then filtered throuah a thin pad of hydrous magnesium silicate. The filtrate is evaporated to give 0.41 g of crystals, m.p. 257 -258 C.
The preceding compound is heated with 5 equivalents of lithium hydride in dioxane for 24 hours to give the product as a solid.
Reference Fxa.^.:nle 36 5.6-Dihydronyrido(2,3-b1f1,4 lbe^zcthiazepine To a suspension of 11.67 g of 2-thiobenzoic acid in a mixture of 32 ml of ethanol and 11 ml of water is added portion wise 12.72 g of solid sodium SUBSTTTUTE SHEET (RULE 26) bicarbonate. After the complete addition, the mixture is stirred for 15 minutes and 10.0 g of 2-chloro-3-nitropyridine added portionwise. The mixture is refluxed for 2 hours, cooled and then concentrated in vacuo. The residual aqueous solution is diluted with ml of water, acidified with 2N HC1 and extracted twice with 250 ml of ethyl acetate. The extract is concentrated under vacuum to give a yellow solid residue. The residue is dissolved in a minimum of ethyl 10 acetate by heating on a steam bath. The solution is cooled overnight and filtered to give 2.5 g of starting material. The filtrate is concentrated, chilled and ~iltered to give 12.5 g of 2-(3-nitro-2-pyridinylthio)ber.zoic acid as a yellow solid. The 15 preceding compound (5.0 g) and 0.75 g of Pd/C in 60 ml of ethanol is shaken in a Parr hydrogenator under 45 psi cf hydrogen for 18 hours. The mixture is filtered through diatomaceous earth and the filter cake washed with 200 ml of dichloromethane. The combined filtrate is evaporated in vacuo to give a solid. The solid is triturated with ethanol and filtered to give 3.6 g of yellow solid. This solid (3.0 g) is again hydrogenated with Pd/C (0.50 g) in 50 ml of ethanol and 30 ml of acetic acid under 45 psi of hvdrogen for 18 hours. The mixture is filtered throuah diatomaceous earth and the -filter cake washed with methanol. The combined filtrate is concentrated in vacuo to give 1.6 g of solid. This solid in 25 mi of N,N-dimethylformamide is again reduced with 0.80 g of Pd/C under 45 psi of hydrogen to give 0.57 g of solid. Recrystallization from ethyl acetate gives 0.28 g of 2-(3-amino-2-pyridinylthio)benzoic acid.
The preceding compound (0.20 g) is heated in 2-hydroxypyridine at 170 C to give 5,6-dihyciropyrido[2,3-'-~][1,4]benzothiazepine as a yellow solid. The preceding compound is reacted with borane-dimethylsulfide as SUBSTITUTE SHEET (RULE 26) described for Reference Example 3 to give the product as a solid.
Reference Example 37 2-Nitro-2'-carboxy-diphenylamine A stirred solid mixture of 13.7 g of anthranilic acid, 20.2 g of Q-bromoriitrobenzene, 13.8 g of anhydrous potassium carbonate and 0.1 g of copper metal is heated at 200 C in an oil bath. The reaction mixture is heated for 2 hours, cooled and the solid washed with ether (3 X l00 ml). The solid is dissolved in hot water and filtered. The filtrate is acidified with 40 ml of HCl and the resultincr solid is collected and dried to give 20.5 g cf the desired product as a solid, m.p. 262-265 C.
Reference EvamD1_e 38 2-A*r.ino-2' -carbor.y-diphenylamine A solution of 7.3 g of 2-nitro-2'-carboxy-diphenylamine in 50 ml of methanol containing 10%
palladium-on-carbon is hydrogenated under 42 pounds of pressure for 24 hours. The reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated to dryness in vac,,:o to give 6.6 g of the desired product as a solid, m.p. 72-75 C.
Reference Examn1P 39 5 '1-Dihydre-lOH-dibenzrb,eir1,41diazeoine-?1-one A mixture of 6.6 g of 2-amino-2'-carboxydiphenylamine in 300 ml of xylene is heated at reflux for 20 hours. The xylene is evaporated -n vacuo to a residue which is evaporar-ed from 210 ml of toluene in v u to a residue which is evaporated from 50 ml of chloroform to give a residue. The residue is dissolved in 10 ml of tetrahydrofuran and added to 400 ml of ice-cold hexane. The resulting solid is collected, to give 4.3 g of the desireci product as a solid, m.p. 121-123 C.

SUBSTITUTE SHEET (RULE 26) Reference Example 40 1i-Dihydro-lOH-dibenzfb lfl 41diazPpina To a stirred solution of 4.3 g of 5,11-dihydro-l01-1 -dibenz[b,e][1,4]diazepin-ll-one in 50 ml of 5 tetrahydrofuran, under nitrogen and cooled to 0 C is added 4.0 ml of a 10 molar solution of dimethyl sulfide-borane complex in tetrahydrofuran. The ice bath is removed after 30 minutes and the reaction mixture stirred at room for 18 hours. The reaction mixture is cooled in an ice bath and 30 ml of anhydrous methanol added dropwise and evaporated to dryness in vacuo.
Another 30 ml of methanol is added and evaporated to a residue. The residue is quenched with 30 ml of 40%
sodium hydroxide followed by heating at 110 C for 45 minutes and cooling to room temperature. The reaction mixture is diluted with 200 ml of water and extracted with methylene chloride (3 x 100m1). The combined extracts are washed with 1N HCl, water and 0.5 N NaOH.
The organic layer is dried and evaporated in vacuo to give 3.2 g of the desired product, m.p. 114-116 C.
Reference Examrle 41 5u-D'bPri7fb el z pire-6 11-ryion A mixture of 2.50 g of 2-aminobenzophenone-2'-carbox.ylic acid in 50 ml of xylene is stirred at reflux for 23 hours. The mixture is filtered to give 1.82 g of the desired product as a solid.
Reference FxamplP 42 2-Chlorc-5H-dibenzfb lazenine-ti '=i-dione A mixture of 1.0 g of 5:?-dibenz[b,e]azepine-6,11-dione in 50 ml of acetic acid is stirred while chlorine is bubbled into the reaction mixture until saturated. The temperature increases to 38 C. After standing, a precipitate forms and is filtered, washed with hexane and air dried to give 0.62 g of solid which is purified by chromatography to give the desired product as a solid, m.p. 289 -293 C.

SUBSTITUTE SHEET (RULE 26) Reference Ehample 43 2-Chloro-6,11-Dihydro-5L-dibenzfb.elazepine To a mixture of 7.28 g of 2-chloro-5,H-dibenz[b,e]azepine-6,11-dione in 25 ml of anhydrous tetrahydrofuran, under argon, is added dropwise 8.5 ml of (10 M) boron-dimethyl sulfide in tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is heated at reflux for 3 hours and cooled to room temperature. While stirring, 25 ml of methyl alcohol is carefully added, followed by 100 ml of 2 N NaOH. The reaction mixture is heated at reflux for 24 hours and the solid collected. The solid is dissolved in methylene chloride and washed with 2 N
citric acid, water and dried (Na2SO4). The volatiles are evaporated in vacuo to give 4.16 g of a residue which is crystallized from ethyl acetate-hexane to give 2.05 g of the des4 red product as a crystalline solid, m.p. 137-141 C.
Reference Eyample 44 2-r2-(Tributylstannyl)-3-thienyll-1,3-dioxolane To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml of anhydrous ether, n-butyl-lithium (1.48N, in hexane, 74.3 ml) is added dropwise under nitrogen at room temperature. After being refluxed for 15 minutes, the reaction mixture is cooled to -78 C and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue distilled at reduced pressure, given 34.16 g (77%) of the desired product.

SUBSTITUTE SHEET (RULE 26) Reference Ekam.ple 45 2-f2-f(2-Ni+-rop^Pnyl)mPthyll-3-thieny>>-1 L-dioxolane A mixture of 2-[2-(tributylstannyl)-3-thienyl]-1,3-dioxolane (8.8 gms, 20 mmols), 2-nitrobenzyl bromide (4.5 gms, 22 mmol) and tetrakis (triphenylphosphine)-palladium (0) (200 mg) is refluxed in degassed toluene for 16 hours under a nitrogen atmosphere. At the end, the reaction mixture is cooled to room temperature and filtered through diatomaceous earth. The toluene is removed by concentrating at reduced pressure and the product isolated by silica gel column chromatography by elution with 30% ethyl acetate:
hexane to give 4.5 gms of the desired product as viscous liquid. Mass Spectrum; M+292 Reference Example 46 4, 10-Di hycirc-5.T?-thieno f 3 2-c 1 r 11 bAnzaz T--ine A stirred solution of 4 gms of 2-[2-[(2-nitrophenyl)methyl]-3-thienyl]-1,3-dioxolane in acetone (50 ml) and acetic acid (90% 50 ml) is heated to 60 C.
Zinc dust (10 gms) is slowly added and after the addition, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water.
The organic layer is dried (Na2SO4) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate:
hexane to aive 2.0 g cf the desired product as a pale yellow crystalline solid, m.p. 86 C. Mass Spectrum;
M+202.
Reference Evamw!A A7 45-D; rydro-4 Q- T,Pt}" j'1-2- r<- r (2-^ tror)heny1)-re+'hyi 1-2-thienyl'oxaz^le To a solution of 4,5-dihydro-4,4-dimethyl-2-(2-thienyl) -oxazole (4.5 gms 25 mmol) in anhydrous ether at -70 C, n-butyl-lithium (2.5 molar solution in hexane, SUBSTITUTE SHEET (RULE 26) WO 96f22282 PGTIUS96/01051 11 ml) is added drop by drop under N2 atmosphere. The reaction mixture is stirred at -78 C for 45 minutes and tri-n-butyltin chloride (8.3 gms 25 mmol) in dry ether is added drop by drop. The reaction mixture is stirred at room temperature for 1 hour and quenched with water.
The reaction mixture is extracted with ether, washed well with water, dried and concentrated. The product obtained is pure enough for further transformation. The oil product, 4,5-dihydro-4,4-dimethyl-2-[3-(tributylstannyl)-2-thienyl)-oxazole is mixed with 2-nitrobenzyl bromide (5.5 g 25 mmol) in toluene and refluxed in the presence of tetrakis (triphenyiphoshine)-palladium (0) 200 mg) for 16 hours.
At the end reaction mixture is cooled to room temperature and filtered. Toluene is removed under reduced pressure and the product is isolated as brown oil by silica gel column chromatography by eluting it with 30% ethyl acetate:hexane to give 5.7 g of the desired product. Mass Spectrum; M+316.
Reference Er.ample 48 9,10-Dihyd*'n-4H-*'hiAno(3 ?_r`lf'lb ^za7pp1n-10-o*1e A solution of 4,5-dihydro-4,4-dimethyl-2-[3-[(2-nitrophenyl)methyl]-2-thienyl]oxazole 5 gms is refluxed in acetone/water (3:1 100 ml) contai.ning 1 N
HC1 (30 ml) for 24 hours. The reaction mixture is concentrated and the residue is dissolved in glacial acetic acid (i00 ml). The acetic acid is stirred at 70 C and zinc dust (10 gm) is slowly added. Stirring is continued at 70 C for 6 hours. At the end, the reaction mixture is cooled to room temperature and filtered.
Acetic acid is removed under reduced pressure and the residue is et:tracted wit:. c'l-lloroform. The chloroform layer is dried and concentrated to give 2.9 gms of the desired product as a brown solid.
Mass Spectrum: M1215.

SUBSTiTUTE SHEET (RULE 26) Reference Example 49 9,10-Dzhvdro-4u-thienof2,3-clfllbenzazepine A stirred solution of 2.0 g of 9,10-dihydro-4fi-thieno[2,3-cJ[i)benzazepin-10-one and lithium aluminum hydride (500 mg) in tetrahydrofuran is refluxed for 4 hours. At the end, reaction mixture is carefully quenched with ice cold water and extracted with chloroform. The organic layer is washed well with water and dried over anhydrous Na2SO4, filtered and concentrated. The product is purified by silica gel column chromatography by elutina it with 30% ethyl acetate:hexane to give 1.2 g of the desired product as a bright yellow solid. Mass Spectrum M+202.
Reference Example 50 2-Methylfurane-3-carbonyl chloride A mixture of 4.0 g of methyl-2-methylfurane-3-carboxylate, 30 ml of 2 N NaOH and 15 ml methanol is refluxed for 1.5 hours. The solvent is removed under vacuum te give a solid. The solid is extracted with dichloromethane (discarcied). 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-3-carboxylic acid. The preceding compound (0.95 g) and 3 ml of thionyl chioride is refluxed for 1 hour. The solvent is removed, toluene added (20 ml, three times) and the solvent removed to give the product as an oil.
Reference Example 51 2-'2-(^_'r=bu}ylstan^yi)-3-th;Pn.yll-i 3-dioxolane To a stirred solution of 15.6 g (0.10 mol) of 2-(3-thienyl)-1,3-dioxolane in 100 ml cf anhydrous ether, n-butyl-l=thium (1.48 N, in hexane, 74.3 ml) is added dropwise under n'trogen at room temperature.
After being refluxed f~r 15 minutes, the reaction mi::ture is cooled to -78 C and tri-n-butyltin chloride (34.18 g, 0.105 mol) in 100 ml of dry tetrahydrofuran is SUBSTITUTE SHEET (RULE 26) added dropwise. After the addition is complete, the mixture is warmed to room temperature and the solvent evaporated. To the oily residue 100 ml of hexane is added, and the resulting precipitate (LiCl) is filtered off. The filtrate is evaporated and the residue dis-tilled at reduced pressure, givina 34.16 g (77%) of the desired product.
Reference Exarr,ple 52 Methyl 6-aminonyridinA-3-carboxylate Dry methanol (400 ml) is cooled in an ice bath and HCl gas is bubbled into the mixture for 25 minutes.
To the MeOH-HC1 is added 30 g of 6-aminopyridine-3-carboxylic acid and then the mixture is stirred and heated a-- 90 C for 2 hours (all the solid dissolved).
The solvent is removed under vacuum and the residual solid dissolved in 100 ml of water. The acidic solution is neutralized with saturated sodium bicarbonate (solid separated) and the mixture chilled and filtered to give 30 g of white crystals, m.p. 150 -154 C.
Reference ExamnlP 53 6-f(5-fluorc-2-methylbenzoyl)aminoloyridine-3-carboxylic acid To a mixture of 4.5 g of methyl 6-amino-pyridine-3-carboxylate and 5.53 ml of triethylamine in 40 ml of dichloromethane (cooled in an ice bath) is added 6.38 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature under araon 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-2-methylbenzoyl)]amino]pyridine-3-carboxylate. The filtrate is concentrated to dryness and the residue triturated with hexane and ethyl acetate to give an additional 9.0 g of bis acylated compound.

SUBSTITUTE SHEET (RULE 26) A mixture of 12.0 g of methyl 6-[[bis(5-fluoro-2-methylbenzoyl)]amino]pyridine-3-carboxylate, 60 ml of inethanol-tetrahydrofuran (1:1) and 23 ml of 5 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-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 53, but substizuting the appropriate aroyl chloride, heteroaroyl chloride, cycloalkanoyl chlorides, phenylacetyl chlorides and related appropriate acid chlorides, the following 6-[(aroylamino]pyridine-3-carboxylic acids, 6-[(hetero-aroyl)amino]pyridine-3-carboxylic acids and related 6-[(acylated)amino]pyridine-3-carboxylic acids are prepared.
Reference Example 54 6-((3-Methyl-2-thienylcarbonyl)aminolr)yridinP-3-carboxy'_ic acid Reference Example 55 E-'(2-Methyl-3- '^ienylcarbonyl)amino?oyridinP-3-carboxylic acid Reference Examnle 56 E- T('2-Mat hyl -2-fUranylr'arbonyl ) ami no icyr r i na-3-carbox3,' ic acid Reference EXamplA 57 6-1(2-Metryl-3-furanyicarbony'_)aminolr)yridine-3-carbo=r.ylic acid Reference Example 58 6-1 (3-Fi uC'rn-2-TPtj'?y1~en7pvl ) ami no I Jy"'idine-3-^a;-boxylic acid Reference Exam-ole 59 F-( (2-Met'hy'_tJenzovl)aminolov'_"ZQi.n.e-3-carbovyllc acid Reference ExamplA 60 6-f(2-chlorobenzoyl)aminoinyridine-3-carboxylic acid %

SUBSTITUTE SHEET (RULE 26) Reference Example 61 6-f(2-F}ucrobPnzoy1)aminol,ovridine-3-carboxyl;c acid Reference Example 62 6-f(2-Chloro-4-fluorobenzoyl)aminolnyridine-3-carboxylic acid Reference Example 63 6-r(2,4-Dichlorobenzoyl)aminolnyridine-3-carboxylic acid Reference Efample 64 6-f(4-Chlore-2-fluorobenzoyl)aminoloyridine-3-carboxylic a i Reference Example 65 6-f(3,4,5-Trimefhoxybenzoyl)amincloyridine-3-carboxylic acid Reference Example 66 5-1(2,4-Dif2-uorobenzoyl)aminclnyridine-3-carboxYlic acid Reference Examole 67 6- f(2-??ro:nobenzoy'_ ) ami nol nyridine-3-carboxylic acid Reference Example 68 E-((2-Chlorc-4=n;}robenzoyl)aminc'oyridlne-3-carboxylic acid Reference Example 69 6-f(Te-!~rahydro_`l:Yanyl-2-carbonyl)aminolpyridine-3-carboxylic acid Reference Example 70 6- ((Tetrahydrethi eny' -2-carbonyl) aminol z)y--idine-3-carboxylic acid Reference E.xamnle 71 6-r(Cyclo^exylcar.-,onyl)aminolr)yridine-3-carboxylic acid Reference Examnle 72 F-f(cyclohet:-3-enecarbonyl)amine':nvridine-3-carboxylic acid Reference Exa:r:Dle 73 6-( (s-F''L'oro-2-mer}ylbenzeneacetyl)amiP.oloV'_"=^1ne-3-carboxyli c acid .

SUBSTITUTE SHEET (RULE 26) Reference Example 74 6_((2_rhlorobe_^.zeneacetyl)aminolr-yridine-3-carboxylic acid Reference Example 75 6-((cyclopertylcarbonyl)aminolp;7ridinA-3-c=rboxylic acid Reference Example 76 6- f (cyclohexylacetyl) aminoliDyridine-?-carboxylic acid Reference Examole 77 6-f(3-Methvl-2-t!:ienylacetyi)amir.olnyridine-3-carboxylic acid Reference Exam.ple 78 6- i(2-MP}hy? _3-th; e^.ylacetyl) aminol oyrid=nP- <-carboxyl; c acid Reference E xam'..7le 79 F-r(3-Methyl-2-furanylacetyl)aminolnyridinP-3-^arboxYiic -acid, m.p. 288-2900C
Examgle 80 6-f(2-Merhyl-3-f~-,ranylaceryl)amino'oyridine-3-carboxylic acid Reference EYample 81 r(3_Met'.:y1-2-'-etrahydrotri enylacetyl) aminolpyridi ne-3-carboxylic acid Reference Example 82 6- r (2-1~ethyl-?-rP*rahyd,- ~ ^ h;enyiacety' _)am=no, Dvr ^.inP-3-carboxylic acid Reference Example 83 r-r (2 5-Di chlorcbenzoyl)aminol-avridinP-3-car:,oxyl_ acid Reference Examole 84 6-1 (3. 5-Dichlorobenzoyl) ami nol p,,,ri dine-3-carboxy i i c acid Reference Exar,:nlP 85 6-f(2-Methyl-4-c::l2robenzoyl)amino! oyr=a=ne-i-carboxylic acid F.efor rlc EziamL`1P 86 6- f(2, 3-Dimethylbenzoyl) ami nol oyr_dine-?-carbo:jylic acid Reference Exa^^nle 87 6- f(2-Metho1:ybenzoyl ) aminol nvrid i ne- {-carbor.yl'_c acid SUBSTITUTE SHEET (RULE 26) Reference Example 88 E-r(2-Trifluoromethoxybenzoyl)aminolpyridine-3-carboxylic acid Reference Example 89 6-1 (4-Chloro-2-me*_hoxybenzoyl) ami nol pyridinP-3-carboxylic acid Reference Examnle 90 6- ~ ~2- (Trifluoror*.iethyl) benzoyil aminolpyridine-3-carboxylic acid Reference Example 91 F-f(2 E-n;chlorobPnzoyl)ami*1o1nyr;d;nP-3-carboYyli^ acid Reference Evample 92 6-1 (2 C`-ni ^1 rti y1 ~enzoj'l ) afi' `7^1'J:,7` PP-3-^aT'.,~OXylic acid Reference Example 93 6-1 (2-Methyl thiobenzoyl ) a*r,i nol nyridine-3-carboxyl ; c acid Reference Example 94 6- r(4-Fl::oro-2- (tr; fluoromethyl) benzoyl) aminol -oyridine-3-carbo}:ylic acid Reference Example 95 6-r(2 3-DichloYobP*1z,:Dy1)aminolDyridinP-3-carboxylic acid Reference Example 96 6-1 (Q-7!uoro-2-me}':r' be^zoyl ) aminol cyridine-3-carbc=rylic acid Reference Ffamn1 P 97 -1- r(2 3 _Tri c12icro:J T1^ov' ) aT[1ino inyr' d' nP-3-ca"'bov'y7l i c acia RefPrence EYamnle 98 6-f(5-=luoro-2-chlerobenzoyl)aminolDvridine-3-carboxylic acid Reference Examnle 99 E- r(2-= l uorc-~- (tr=fluorpmethyl ) benzoyl) arni.^.o 1 T)yrid; ne-3-^arboYvlic acid .
f SUBSTiTUTF SHEET (RULE 26) Reference Example 100 6-1 (5-Fluoro-2-mPt'^vlbenzoyl) amino1 pvridine-3-carbonyl chloride A mixture of 6.2 g of 6-[(5-fluoro-2-methyl-benzoyl)amino]pyridine-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 100, the following 6-(acy'_)amino)pyridine-3-carbonyl chlorides are prepared.
Reference Example 101 6- r( 3-Methyl-2-*-h i e.n.ylcarbonyl ) a*r,ino 1t)yridine-3-carbonyl chloride Reference EYamnle 102 ti- f(2-MAthyi -3-thienylcarbonyl) a minol Dvridine-3-carbonyl chloride Reference Examnle 103 6-1 (3-MPrhyi -2-==.:ranylcarbonyl ) amino? nyri dine-3-carbonyl chloride Reference Exar.lcle 104 6-((2-Me*hyl-?-furanylcarbonvl)aTi-:olnyridine-3-carbonyl chloride Reference Examnle 105 6-r(3-^luoro-2-mAt'_^ylbenzoyl)a*^inol-oyridine-3-carbonyl ^h,^r;cie Reference Eyam:le 106 6- f(2-M ti"=il 1:`enzcvl) aT^, rln i D~,"" C., nP-3-r'arb^TlyI chloT'ide Reference F'i;amriA 107 6-r(2-rr,lorobenzoyl)aminolnvridine-3-carbonyl chloride, white crystals SUBSTITUTE SHEET (RULE 26) Reference Example 108 6-f(2-Fluorobenzoyl)amino}T)vridine-3-carbonyl chloride Reference Example 109 E-r(2-Cnloro-4-fluorobenzoy')aminolpvridine-3-carbonyl chloride Reference Examnle 110 6-r(2 4-Dichlorobenzoyl)aminolnvridine-3-carbonvl chloride Reference Example 111 6-f(4-Ch'oro-2-fluor^benzo%,l)ami^olr)vridire-3-carbonvl chloride Reference EYample 112 ti- f (< 45 -T ,- imcthr., v n7 cy 1) ami n o l nv~r i din~ ~
~=be a- - ca rbo_n .y ~
chl^''ide Reference Examble 113 6- (('' 9-n_F1uorc=benzoyl ) a-ni no 1 oyridir.e-3-carbonvl chloY'ide Reference ExamwlP 114 F- r(2-Rromobenzoyl )aminol nyridine-3-ca*-bonyl chloride Reference EYamnle 115 6-r(2-rhloro-4-nitrobenzoyl)aminolpyrid_ne-3-carbonvl chloride Reference Eramnle 116 6-r('^A-rahydroruranyl-2-carbonyl)aminolr)vridine-3-carbon;,i c:^.'_cri de Reference Example 117 ti- r(TerrahvdrnthiPnyl-2-carbonyl) aminol ryridi ne-3-carbonyl chloride Reference Exam^le 118 6-F(''ycln^evy'carbonvl)aminolnyridine-3-carbonvl chloride Reference Fxam^le 119 6-f(^,,^loheV-3-PnP^=rbonyl)aminolnvrid_r.e-3-carbonvl chloride SUBSTITUTE SHEET (RULE 26) Reference Examole 120 6-f(2-naAthylbenzeneacetyl)aminolpyridinA-3-carbonyI
chloride Reference Examnle 121 5-f(2-C'^lorobenzenAacetyl)aminolpyridine-3-carbonvl chloride Reference Example 122 F-r(Cvclopentylcarbonyl)aminolpyridine-3-carbonyl chloride Reference Examnle 123 6-F(Cyclohevylacetyl)aminolnyr;dirP-3-car nyl chloride Reference EYample 124 C`-r(3-Me'-~%'1-2-}ti'ieT"y18.ce'- l)aTi"'j1D 'ine-3-ca r y y-i bonvl rhioriciA
Reference Examole 125 6-((2-NIe*hyl-3-thienylaceryl)ami^olpyridine-3-carbonyl ~hloride Reference Example 126 6-1 (3-Methvl-2-fura.^.ylacet yl ) amino 1 myridi rP-3-carbonyl chloride Reference Examvle 127 6-((2-Merhy'-3-f,-,ranylace*_vl)aminolnyrid4nP-3-carbonyl chloride Reference Example 128 6-1 (2-MArh;>1 -5-f1 õc~rCb nz Tl acAryl ) arPiT'o l pvT"=i C1nA-3-carbonyl chloride Reference Exam^le 129 E- f(3-Methyl-%-tetrahydro*hi enyi acA*yl) amino1 Dyr~ dlne-3-carbonyl c'^ioride RPfPYPnce FxamclP 130 F- f (2-r4Arhyl-3-rPtrahydrothiPnylacetyl ) aminolpyridine-3-carhonyl chloride Reference Examc1P 131 F- r(2 S-n; cr' orobenzoyl ) ami nol cyr- dinP-3-aarbonyl chloride SUBSTITUTE SHEET (RULE 26) Reference Example 132 6-f(3,5-Dichlorobenzoyl)arninolr)vridine-3-carbonyI
chloride Reference ExamolP 133 6-f(2-Methyl-4-chlorobenzoyl)aminclpvridine-3-carbonyl chloride Reference Example 134 E-r(2,3-Dimethylbenzoyl)aminolnvridine-3-carbonyl chloride Reference Example 135 6-((2-MethoXybenzoyl)aminol-cyridine-3-carbonyl chloride Reference EYam:le 136 6- r (2-'"ri fluoromethozybe_^.zoyl ) aminol nvridine-3-carbonyl cr:l'Jri de Reference Exam-cle 137 6-r(4-Chl(Drc-2-methovybenzoyl)aminolr)vridine-3-carbonyl chloride Reference Example 138 ti- r r2- ("'rifluoromethyl) benzoyl l ami nol vyridir.e-3-carbonyl chloride Reference Exam:~le 139 6-r(2,6-Dichlorobenzoyl)ami_^.cl,ovridine-3-carbonyl chloride Reference Exam^le 140 6-1 (2, 5-D'met'_:ylbenzoyl) a:r:i^olp,;,,ridine-3-carbony' chloride Reference Examnle 141 F- f (2-Matr:ylt'':iobenZoyl) amir.ol-ovridine-3-carbonyl chloride Reference E1_amcle 142 r- r(4-'~;'l,uo,-n-i- (r ri fl,icr^methy? ) benZOyl ) aminol pyriciine-3-c3rbonyl ^^l^ride Reference Examole 143 6-((2.3-D'_=chlorobenzoyl)aminolr)vridine-3-carbonyl chloride SUBSTITUTE SHEET (RULE 26) Reference Example 144 6-f(4-Fluorc-2-methylbenzoyl)aminolpyridine-3- arbonyI
chloride Reference Evample 145 E-f(2,3,5-Trichlorobenzoyl)ariinolayridine-3-carbonyl chloride Reference Example 146 6-1 ( ^-Fi uoro-2-chi^robenzoyl ) aminol r)Vridine-3- =rbnnyl chloride Reference Example 147 6-r(2-Fluorc-5- (t r; f' uoromethyI) benzoyl) ar^irol pyridine-3-^arbonyl chloride As described for Reference Example 53, the following bis acylated products (Table A) are prepared and purified by silica gel chromatography. These compounds are then hydrolysed to the acids (Table B) as described in Reference Example 53.
Table A
O

X O Ri C~"3 N N I
RC i ~3 R

-SUBSTITUTE SHEET (RULE 26) wa 96122282 PCTlUS96/01051 Ref. Ri R2 R3 R4 X M+
Ex No.

151 H 0Cu3 OCH3 OCH3 H 540 154 Br H H H H 520 155 Cl H ~ H H 412 156 Ph T: H H H 512 157 Cl H H Br H 474 158 CH3 H H F Br 159 CH3 H H H Br 468 M+ is molecular ion found from FAB mass spectrum Table B

p X O R

H
R

Ra ~

SUBSTITUTE SHEET (RULE 26) Ref. R1 R2 R3 R4 x M+
Ex No.

161 CH3 H H F H 2'7 4 166 Br F H H H 322 167 Cl ~ H H 294 168 Ph H H H H 318 169 C1 H H Br H 356 170 CH3 H H F Ci 17= CH3 H H H Br 336 M+ is molecular ion found from FAB mass spectrum.
RPfAr n Exam~2le 172 6-.krri no-5-bromopy idi n.-'~-ca boxyl ic acid To a stirred solution of 6-aminonicotinic acid (13.8 g, 0.1 mole) ir, 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 30%
NH40H. The separated solid is filtered and washed with water to give 18 a of solid; mass spectrum: 218 (M+).
RAfar n`-.P Fvamp.l e 173 Mcthyl Ei-amin^-^-brom Dyri ^+; nc-'3-.- rbnuyl at-a 6-Amino-5-bromopyridine-3-carboxylic acid (10 g, 50 mmol) is dissolved in saturated methanolic HCl (100 ml) and refluxed for 24 hours. The solvent, methanol, is re-moved under reduced pressure and the residue is dis-solved in ice cold water. The aqueous SUBSTITUTE SHEET (RULE 26) wo 96122282 PCTIUS96101051 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 (M+) .
Reference Examole 174 6-f(2-MAthyibenzAneacetyl)aminolpyridinP-3-carboxylic acid To a cooled (0 C) mixture of 5.0 g methyl 6-aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropyl-ethylamine in 40 ml of dichloromethane is added a solution of 12.2 g of 2-methylbenzeneacetvl chloride in 10 ml of dichloromethane. The mixture is stirred under argon at room temperature overnight. The mixture is diluted with 200 ml of dichloromethane and 50 ml of water and the organic layer separated. The organic layer is washed with 50 ml each of 1 M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate con-centrated to dryness. The residue (9.0 g) is chromato-graphed on a silica gel column with hexane-ethyl acetate (3:1) 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 (1:1) and 23 ml of 5 N NaOH
added to the solution. The mixture is stirred at room temperature overnight and the mixture concentrated under vacuum. Water (25 ml) is added and the mixture is stirred and acidified with cold 1 N HC1. The mixture is chilled and the solid filtered and washed with water to give 5.9 g of off-white solid.
Reference Examnle 175 6-1 (2-r=1ethylbenzeneacetv1 ) ami noinyr; d; *iP-3-carbonyl #= chloride A mixture of 4.5 g of 6-[(2-methylbenzene-acetyl)amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 1 hour and then con-SUBSTiTUTE SHEET (RULE 26) centrated to dryness under vacuum. To the residue is added 20 ml of toluene and the solvent removed under vacuum. The addition and removal of toluene is repeated and the residual solid dried at room temperature under vacuum to give 5.3 g of dark brown solid.
Reference Ex mple 176 t 1, 1' -Bipl-!enyl 1-2-Biphenylcarbonyl chloride A mixture of 5.6 g of [1,1'-biphenyl]-2-carboxylic acid and 29 ml of thionyl chloride is heated on a steam bath for 0.5 hour and the volatiles removed under vacuum. Toluene (40 ml) is added (twice) and the solvent removed under vacuum to give 6.8 g of a yellow oil.
Reference ExamglP 177 Methyl F-[rbisU1,1'-bipheny11-2-,,_carbonyl)laminolrDyridinP-3-carboyylate To a chilled (0 C) solution of 2.64 g of methyl 6-aminopyridine-3-carboxylate and 5.5 ml of diisopropylethylamine in 30 ml of dichloromethane under argon is added 6.8 g of [1,1'-biphenyl]-2-carbonyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature 2 days and then diluted with 120 ml of dichloromethane and 50 ml of water. The organic layer is separated, washed with 50 ml each of 1 M NaHC03 and brine and dried (Na2SO4). The solution is filtered through a thin pad cf hydrous`magnesium silicate and the filtrate concentrated under vacuum to give a solid. Crystallization from ethyl acetate gives 6.2 g of white crystals, m.p. 180-188 C.
Reference Evam::lP 178 r- r(rli ' -bipnenyl l -2-y}carbonyi)aminolpyridinP-~-^arbcxylic acid To a chilled (0 C) mixture of 6.0 g of methyl 6-[[bis[(1,1'-biphenyl]-2-ylcarbonyl)]amino]pyridine-3-carboxylate in 40 ml of inethanol and*30 ml of tetrahydrofuran is added slowly 18 ml of 2 N NaOH. The SUBSTITUTE SHEET (RULE 26) R/O 96122282 PC1'I1JS96/01051 mixture is stirred at room temperature overnight and brought to pH 5 with glacial acetic acid. The mixture is concentrated, acidified to pH 2-3 with 1 N HC1 and extracted with 250 ml of ethyl acetate. The extract is washed with 50 ml of brine, dried (Na2SO4) and the solvent removed under vacuum. The residual white solid is triturated with 15 ml of ethyl acetate to give 3.35 g of white crystals, m.p. 215-217 C.
Reference Examole 179 6-f1,'_'-biDhPnv,i-2-ylcarbony1)amino1pyridine-~-carbonvl chloride A mixture of 1.9 g of 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino)pyridine-3-carboxylic acid and 9 mi of thionyl chloride is refluxed for 1 hour and then con-centrated to dryness under vacuum. Toluene (15 ml) is added (twice) to the residue and the solvent removed under vacuum to give 2.1 g of a light brown oil.
Reference Examnle 180 6-r(Cyciohexylcarbonyl)aminoloyridine-3-c=rboXylic acid To a chilled (0 C) solution of 5.0 g of methyl 6-aminopyridine-3-carboxylate and 12.6 ml of diiso-propylethylamine in 50 ml of dichloromethane under argon is added a solution of 9.7 ml of cyclohexylcarbonyl chloride in 10 ml of dichloromethane. The mixture is stirred at room 'Lemperature overnight and diluted with 200 ml of dichloromethane and 60 ml of water. The organic layer is separated, washed with 60 ml of brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated under vacuum to give 12.8 g of a solid.
The above solid (12.0 g) in a mixture of 150 ml of tetrahydrofuran-methanol (1:1) is chilled (0 C) and 62 ml of 2 N sodium hydroxide added. The mixture is stirred at room temperature for 3 hours, neutralized with 10 ml of glacial acetic acid and concentrated under vacuum. The mixture (containina solid) is acidified to SUBSTITUTE SHEET (RULE 26) pH 1 with 1 N HC1 and extracted with 250 ml of ethyl acetate and twice with 100 ml of ethyl acetate. The combined extract is washed with 100 ml of brine, dried (Na2SO4) and concentrated to a white solid. Trituration with hexane gives 6.5 g of product as a white solid.
Reference Examnle 181 Methyl-2-7(4-ethoxy-oXob,:tyl)aminolbAnzoa P
A mixture of 19.2 g of methyl 2-aminobenzoate and 9.6 g of ethyl g-bromobutyrate is heated at 80-85 C
for 24 hours, cooled to room temperature and filtered.
The solid is washed with CH2C12 and the filtrate washed with 1NHC1, H20, 1NNaHCO3 and brine. The solvent is removed to give an oil. The oil is distilled and the fraction boiling at 45-75 C and 130-1-60 C were coliected and discarded. The residue is the product (55.4 g of oil) Reference FxamAle 182 Methyl 2- rN- (4-ethoxY-4-oAobutyl) -N- (2-me*hyinhAnyisulfonyl)amino)benzoate A miYture of 2.65 g of methyl 2-[(4-ethoxy-4-oxobutyl)amino)benzoate, 2.0 g of 2-methylphenylsulfonyl chloride and pyridine is heated on a steam bath for 16 .hours. The mixture is concentrated under a vacuum (remove pyridine) and 1N HC1 added. The mixture is extracted with dichioromethane and the extract washed with 1NHC1, H20, 1 M NaHCO3, brine and dried (Na2SO4).
The solution is filtered through a thin pad of hydrons magnesium silicate and the filtrate evaporated to give 3.8 g of solid which is crystallized from ethanol to give crystals, m.p. 100-1020C.
Reference FvamL`1P 183 Methyl and Ethyl i,2-Dihydr -5-hydrory-'-f(4-methv?nhAnyl)sulfonyll-3H-1-benzaz r ne-4-carboyylate To a mixture of 0.448 g of potassium tert-butoride in 2 ml of tetrahydrofuran; cooled to 0 C is added 0.838 g of methyl 2-[N-(4-ethoxy-4-oYobutyl)-N-(2-SUBSTITUTE SHEET (RULE 26) R'0 96122282 PCllIJS96/01052 methylphenylsulfonyl)aminolbenzoate in 12 ml of tetrahydrofuran. The mixture is stirred at O C for 4 hours (under argon), poured into water and neutralized =" with 2N citric acid. The mixture is extracted with dichloromethane and the extract washed with H20, brine and dried (Mg S04). The extract is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness to give 0.59 g of product (a mixture of methyl and ethyl esters).
Reference Examole 184 1,2,3,4-te*_rahydre-l-f(2-methylbhenyl)sulfonyll-5H-1-benzazepir.-5-one A 30 g sample of a mj.xzure of methyl and ethyl 1,2-dihydro-5-hydroxy-l-[(4-methylphenyl)sulfonyl]-3H-1-benzazepine-4-carboxylate in a mixture of 171 ml of concentrated hydrochloric acid and 171 ml of glacial acetic acid is refluxed 24 hours. An additional 170 ml of concentrated hydrochloric acid is added and the mixture refluxed for 24 hours. The mixture is concentrated under vacuum to near dryness, diluted with water and the solution brought to pH 8 with saturated NaHCO3. The mixture is extracted with dichloromethane and the extracted washed with H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give 12.0 g of a brown oil.
Reference Examnle 185 4-f(Dimethylamino)methyle_^_el-1,2,3,4-tetrahydro-l-F(2-Incthylpl_';,?nyl ) CL1 F=y11-5H-1-benzazepin-5-one A mixture of 1.89 g of 1,2,3,4-tetrahydro-l-[(2-methylphenyl)sulfonyl]-5H-1-benzazepin-5-one and 2.47 ml of ttert-butoxy-bis(dimethylamino)methane (Bredericks reagent) in 10 ml of dichloromethane is heated under argon on a steam bath for 16 hours. The mixture is concentrated to dryness under vacuum and the residue dissolved in CH2C12. The solution is filtered SUBSTITUTE SHEET (RULE 26) through a thin pad of hydrous magnesium silicate and the pad washed with 5% ethyl acetate in CH2C12. The filtrate is concentrated to dryness and the residue (1.96 g) crystallized from CH2C12-hexane to give 0.85 g of crystals, m.p. 180-185 C. A second crop of crystals (0.85 g) is recovered from the mother liquors and an additional 0.30 g is recovered from washing the pad of hydrous magnesium silicate with ethyl acetate.
Reference Example 186 ?.4.5.6-te}rahydro-ti-r(2-methylpheny')sulfonylloyrazolof4 3-dlrllb rzazepine A mixture of 1.55 g of 4-[(dimethylamino)-methylene]-1,2,3,4-tetrahydro-l-[(2-methylphenyl)-sulfonYl]-5H-1-benzazepin-5-one, 0.25 ml of hydrazine and 60 ml of ethanol is refluxed on a steam bath under argon for 2 hours. After standing overnight at room temperature, the solvent is removed under vacuum. The residue is dissolved in CH2C12 and the solution washed with water, brine and dried ((Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated to give 1.4 g of crystals, m.p. 76-79 C.
On a larger scale reaction with 18.29 g of 4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-l-[(2-methylphenyl)sulfonyl]-5H-1-benzazepin-5-one the product in CH2C12 is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate is concentrated to give 16.5 g of product (one spot by thin layer chromatography (silica ael) with hexane-ethyl acetate (1:2).
Reference EXamnle 187 1,4,5.6-Tetrahydror)yrazolo-[4,3-dlrl}benzazepinA
A mixture of 1.0 g of 1, 4, 5, 6-tetrahyciro-6-[(2-methylphenyl)sulfonyl]pyrazolo[4,3-g][1]benzazepine in 60 ml of 40% (V/v)H2SO4 in alacial acetic acid is heated at 60 C for 12 hours or until the tosyl group is SUBSTITUTE SHEET (RULE 26) removed. The mixture is poured into 100 ml ice and water with cooling. Solid NaOH is added portionwise (temperature kept below 300C) with efficient stirring and the pH brought to 8. The mixture is extracted with ethyl acetate and the extract dried (Na2SO4) and the solvent removed to give a solid.
Reference Eyamcle 188 10.11-Dihydrobenzfb,flfl,4loxazepir.e To a slurry of 7.35 g of lithium aluminum hydride 100 ml of tetrahydrofuran is added in portions 10.0 g of dibenz[b,f][1,4]oxazepin-10(11H)-one. An additional 100 ml of tetrahydrofuran is added and the mixture is refluxed for 6 hours and then stirred at room temperature overnight. To the chilled mixture is added dropwise 7.5 ml of H20, 7.5 ml of 15% NaOH and three 7.5 ml portions of H20. The mixture is filtered and the filter cake washed with tetrahydrofuran and dichloromethane. The filtrate is concentrated to dryness under vacuum to give 10.1 g of solid. The solid is dissolved in dichloromethane and the solution filtered through a thin pad of hydrous magnesium silicate. The filter cake is washed with dichloromethane and the filtrate concentrated to dryness to give 8.9 g of solid. Crystallization from dichloromethane-hexane gives 7.5 g crystals, m.p. 69-710C.
Reference Example 189 Pvridof2,3-bifl,4lbenzoxazepin-6(5H)-one A mixture of 21.4 g of phenyl salicylate, 25.71 g 3-amino-2-chloropyridine and 20 ml of 1,2,4-trichlorobenzene is refluxed for 1 hour under argon and the liberated phenol and HCl simultaneously distilled (from the refiuxing mixture) and collected in a solution of iN NaOH. The hot mixture is poured into 200 ml of ethanol and the precipitated solid collected by filtration. The solid is washed with ethanol and dried.

SUBSTITUTE SHEET (RULE 26) Recrystallization from methanol - DMF (6:1) gives 6.0 g of product, m.p. 268-2700C.
Reference Examn e 190 5,6-Dihydropvridof2,3-b1f1,41benzoxazepine A mixture of 2.8 g of pyrido[2,3-b][1,4]
benzoxazepin-6(51i)-one, 10 ml of tetrahydrofuran and 3 ml of 10M borane-dimethylsulfide in tetrahydrofuran is stirred at room temperature overnight and then refluxed for 3 hours. To the mixture is added dropwise under argon, 5 ml of methanol. The solvent is removed under vacuum and methanol added. The solvent is removed under vacuum and 12 ml of 2N NaOH added to the residue. The mixture is refluxed for 2 hours and extracted with ethyl acetate. The extract is washed with 2N citric acid, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue is chromatographed on a column (2" x 18") of silica gel (320 g) with hexane-ethyl acetate (1:1) as solvent to give 0.78 g of crystals, m.p. 172-1740C.
Reference Examole 191 N- (2-Hydro::yL,henyl ) - 2-chloro-3-cyri dinecarboxamide As described in J. Med. Chern., -37, 519 (1994), a solution of 1.09 g of 2-aminophencl in 15 ml of tetrahydrofuran is added dropwise to a mixture of 2.1 g of triethylamine and 2.33 g cf 2-chloropyridine-3-carbonyl chloride hydrochloride in 10 ml of tetrahydrofuran. The mixture is stirred at room temperature for one hour under argon and then refluxed for one hour. The solvent is removed under vacuum and the residue triturated with water: The solid is filtered off and washed with water to give 1.02 g of solid. Recrystallizaticn from 2-propanol gives crystals, m.p. 145-1460C.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTlI7S96101051 Reference Example 192 Pvridof2 3-blfi 51benzoxazepir-5(6H)one A mixture of 13.0 g of N-(2-hydroxyphenyl)-2-=y chloro-3-pyridinecarboxamide and 2.82,g of sodium methoxide in 100 ml of N, N-dimethylformamide is refluxed under argon for 3 hours. Sodium methoxide (0.50 g) is added and the mixture refluxed 2 hours and then stirred at room temperature for 2 days. The solvent is removed under high vacuum and the red-brown residue triturated with cold methanol. The mixture is filtered and the solid washed with chilled methanol to give 5.0 g of white solid, m.p. 250-253 C.
Reference E'xample 193 5, 6-nihydronvridof2 3-bl fl 1 Anzoxazepine To a stirred slurry of 0.886 g of lithium aluminum hydride in 20 ml of tetrahydrofuran is added 1.65 g of pyrido[2,3-b][1,5] benzoxazepin-5(6H)-one in portions. The mixture is diluted with 30 ml of tetrahydrofuran and refluxed under argon for 18 hours.
To the mixture is added 1 ml of water, 1 ml of 15% NaOH
and three one-ml portions of H20 and the mixture is filtered. The solid is extracted with dichloromethane and the solution passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness to give crystals, m.p. 125-129 C.
Reference Exam-cle 194 9.10-Dihydr^-4u-*niPno(2 3-c!F'lbAnzaz pine To a solution of 9.0 g at 4,5-dihydro-4,4-ciimethyl-2-(2-thienyl)oxazole in 200 ml of tetrahydrofuran, cooled to -78 C, is added 20 ml of a 2.5 molar solution of n-butyl lithium in hexane. The mixture is stirred -780C for 15 minutes and at O C for 30 minutes. To the stirred solution is added 6.0 g of 2-methylbenzoxazepine-4-one. The mixture is stirred at room temperature for 16 hours quenched with ice cold water and extracted with chloroform. The extract is SUBSTiTUTF SHEET (RULE 26) concentrated to dryness and 100 ml of 40% H2SO4 is added. The mixture is refluxed for 4 hours, cooled to room temperature and filtered to give 9,10-dihydro-4,10-dioxo-4g-thieno [2,3-_r_][1]benzazepine. The solid is washed with water to give 2.5 g of crystals. The solid is dissolved in 100 ml of dry tetrahydrofuran and 1.0 g of lithium aluminum hydride added. The mixture is refluxed for 16 hours, chilled and ice cold water is added dropwise. The mixture after dilution with water is extracted with chloroform-methanol (3:1) and the extract drieci (MgSO4). The solvent is removed and the residue chromatographed over silica gel with ethyl acetate-hexane (1:1) as solvent to give 1.8 g of solid;
Mass spectrum (C? ) 202 (M + H).
Refcranca Example 195 Methyl a- r( r 1 1l-giphenyl 1-2-carbonyl ) amino 1-3-methoxvbenzoate A mixture of 10.0 g of [1,1'-biphenyl]-2-carboxylic acid in 75 ml of methylene chloride and 12.52 g of oxalyl chloride is stirred at room temperature for 15 hours. The volatiles are evaporated ~m 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 25 methyl 4-amino-3-methoxybenzoate and 1.30 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 3.20 g of the desired product as a crystalline solid, m.p. 115-117 C.

SUBSTITUTE SHEET (RULE 26) pCTIUS96J01 051 `W o 96122282 Reference Examn].e 196 Methyl 4-((fl.l'-Biphenyil-2-carbonyl)aminol-2-chlorobenzoate A solution of 2.37 g of [1,11-biphenyl]-2-carbonyl 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,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 1.1 g of the desired product as a crystalline solid, m.p. 132-134 C.
M+H=365 Reference ExamQ!e 197 4-f(fl,l'-Biphenyll-2-carbonyl)aminol-2-chlorobenzoic Acid A mixture of 3.0 g of methyl 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoate in 75 ml of absolute ethanol and 2.0 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80 C to give 0.1 g of the desired product as a crystalline solid, m.p. 217-219 C
Reference Examnle 198 4-f([l,l'-Biphenyll-2-carbonyl)-aminol-3-methoxybenzovl Chloride ' A solution of 2.69 g of 4-[([1,1'-biphenyl]-2-carbonyl]amino]-3-methoxy benzoic acid in 5 ml of thionyl chloride is heated on a steam bath for 1 hour SUBSTITUTE SHEET (RULE 26) under Argon. The volatiles are removed in vacuo to give a residue which is stirred with hexane to give 2.58 g of crystalline solid, m.p. 121-123 C. M+=361.

Reference Example 199 Methyl 4-r(fi,i'-Ri-ohenyil-2-carbonyl)aminolbenzoatP
A mixture of 10.0 g of [1,1'-biphenyl]-2-carboxylic 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 cf an oil. A 7.5 g portion of the above oil in 25 ml of methylene chloride is added dropwise to a solution of 4.53 g of methyl-4-aminobenzoate and 4.3 g of N,N-diisopropylethylamine in 100 ml of methylene chloride at 0 C. The reaction mixture is stirred at room temperature for 18 hours and washed with water, and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and hexane added to the filtrate at the boil to give 8.38 g of the desired product as a crystalline solid, m.p. 163-165 C.
Reference Examnle 200 4-[(~1,1'-5ir)henyl?-2-carbonyl)aminolbenzcic Acid A 3.15 g sample of methyl 4-[([l,1'-biphenyl]-2-carbonyl)amino]benzoate is refluxed for 8 hours in 100 ml of ethyl alcohcl and 2.5 ml of lON sodium hydroxide.
The cooled reaction mixture is acidified with [[? acid]]
and the desired product collected and dried to give 2.9 g of the desired product as a solid m.p. 246-249 C.
M+H=318.

Reference Exam-ole 201 4-f(rl,l'-Ribhenyll-2-carbonyl)aminolbenzoyl Chloride A mixture of 1.39 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoic acid in 2.0 ml of thionyl SUBSTITUTE SHEET (RULE 26) 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 C.
Reference Examole 202 2- (Phenylmethyl) be.^.zoyl 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 E-.amnle 203 Methyl a- r[2- (Phenylmethyl ) benzoyl 1 amino l 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 for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate two times and hexane added to the filtrate at the boil to give 5.04 g of the desired product as a crystalline solid, m.p. 138-139 C.
Reference Example 204 Sodium 4-~F2-(Phenylmethy?)benzoyllaminolbenzoate 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 give 4.25 g of the desired product m.p. 340-346 C.

SUBSTITUTE SHEET (RULE 26) Reference Example 205 4- rf 2- (phenvimetryl ) benzoyi l a*nirol benzci^ Acid A mixture of 4.0 g sodium 4-[[2-(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 C in vacuo to give 3.75 g of the desired product, 246-247 C.
Mt=332.
Reference E::ample 206 4- f f 2- (Prenylmeth,,l ) benzQyl l amine l benzoyl Chloride 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 v u to give 1.53 g of the desired product as an oil. M+=346 as methyl ester.

Reference Example 207 Methyl 4-ff(2-Phenylmethyl)benzoyllaminol-2-chloro-benzoate 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 i-n vacuo to give 5.70 g of an oil. A 2.85 g portion of the above oil in 25 ml of methylene chloride is added to a solution of 50 ml of methylene chloride containing 1.85 g of methyl 4-amino-2-chlorobenzoate and 1.65 g of N,N-diisopropylethylamine by stirring at room temperature for 18 hours. The reaction mixture is washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate 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 C. M+=380.

SUBSTiTUTE SHEET (RULE 26) WO 96122282 PCTlUS96101051 Reference Example 208 Methyl 4-fF(2-Phenylmethyl)benzoyllaminol-3-methoxyber.zoate A solution of 2.85 g of 2-(phenylmethyl)benzoyl chloride in 25 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-3-methoxybenzoate and 1.61 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous 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 C. M+=376.

Reference Example 209 2-Chloro-4-(f(2-Phenylmethyl)benzoyllaminolbenzoic Acid A mixture of 2.8 g of methyl 2-chloro-4-[[(2-phenylmethyl)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 C. M+H=366.

Reference Fxamnle 210 3-MAthoXL-4-F~(2-r)henylmethvl)benzovllaminolbenzoic Acid A mixture of 2.05 g of methyl 4-[[(2-phenylmethyl)benzoyl]amino]-3-methoxybenzoate in 75 ml of absolute ethanol and 1.4 ml of 10 N sodium hydroxide is heated on a steam bath for 3 hours. Water is added to obtain a solution which is extracted with methylene SUBSTiTUTE SHEET (RULE 26) WO 96/22282 PGTlUS96/01051 chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80 C to give 1.87 g of the desired product as a crystalline solid, m.p. 176-178 C. M+H=362.
Reference Example 211 3-Methoxy-4-rf(2-r)henylmethyl)benzoyllaminolbenzoyl Chloride A mixture of 1.71 g of 3-methoxy-4-[[(2-phenylmethyl)benzoyl]amino]benzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 1.71 g of the desired product as a crystalline solid, m.p. 130-135 C. M+=376 as the methyl ester.

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

Reference Examnle 213 Methyl 4-f(ra'-(trifluoromethyl)f1,1'-bivhenyllcarbonyl)aminolbenzoate A solution of 3.13 g of [4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in 25 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-aminobenzoate and 1.43 g of N,N-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, SUBSTiTUTE SHEET (RULE 26) WO 96122282 PCl/7JS96/01051 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 C. M+=396.

ReTerence Eti:ample 214 3-Methoxy-4- r( r4'- (tri fluoromethyl ) fl, i'-biphenyi_?-2-carbonvl) a.mir.ol benzoyl .h ri d A mixture of 2.0 g of 3-methoxy-4-[([4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl)amino]benzoic acid in 20 ml of thionyl chloride is heated on a steam bath under Argon for 1 hour and hexane added. The resulting solid is collected and dried to give 1.92 g of the desired product as a crystalline solid, m.p. 136-138 C.

ReferencP EYample 215 3-Metnoxy-4-[((4'-tYi-'~luoromAthyl)[1.1'-biphenyll- -c~a bc~nyl)am?nolbenzoic Acid A mixture of 3.78 g of methyl 3-methoxy-4-[([4'-trifluoromethyl)[1,1'-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. W.ater 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 ja vacuo at 80 C to give 3.49 g of the desired product as a crystalline solid, m.p.
213-215 C.

Reference EVample 216 MP* yl ?-Merhozy-d-r ((d1 -rriflt]Orom-thyl) f l ~'-biphenyi_1-2-carbonyllaminolbenzoate A solution of 3.56 g of [4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in SUBSTITUTE SHEET (RULE 26) 25 ml of methylene 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 aaueous 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 C.
Reference Examr)lA 217 2-C'.:loro-4-r(r4'-(}riFiu^romP+-hyl) fi ,'-biT)henyil-2-sarbonyl)aminolbenzoy! !'hlnride A mixture of 1.39 g of 2-chloro-4-[([4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl)aminolbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The reaction mixture is concentrated to a residue in vacuo to a residue. Cold hexane is added to the residue and the solid collected and dried to give 1.39 g of the desired product.

Reference Example 218 2-Ch'oro-4-f(r4'-(triFluoromethyl)(1,1'-biphenyll-2-carbonyi)aminolbenzoic acid A mixture of 3.83 g of methyl 2-chloro-4-[([4'-(tri-7luoromethyl)[1,1'-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 C to give 3.42 g of the desired product as a crystalline solid, m.p.
187-189 C.

SUBSTITUTE SHEET (RULE 26) Wo 96122282 PCl/iJS96/01052 Reference Example 219 Methyl 2-Chloro-4-f(f4'-(trifluoromethyl)(1,1'-biphenyil-2-carbonyl)aminolbenzoate A solution of 3.56 g of [4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride in ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of methyl 2-chloro-4-aminobenzoate and 1.6 g of N,N-diisopropylethylamine in 10 50 ml of methylene chloride. The reaction mixture is stirred at room temr)erature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate(3X) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132 C.
Reference Example 220 4-r(f4'-(Trifluoromethyl)[1,1'-biphenyllcarbonyllaminolbenzoic Acid A mixture of 3.0 g of methyl 4-[([4'-(trifluoromethyl)[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 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 C. M+=385.

SUBSTiTUTE SHEET (RULE 26) Reference Example 221 Methyl 6-fF3-(2-Methylpyridinyl)carbonyllaminolpyridine-3-carboxylate 5 To a stirred solution of 3 g of methyl 6-aminopyridine-3-carboxylate and 4 ml of N,N-diisopropylethylamine 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 hours 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 222 6-fr3-(2-methylr)yridinyl)carbonyllaminolTDyridine-3-carboxylic Acid To a solution of 6.5 g of methyl 6-[[3-(2-methylpyridinyl)carbonyl]amino]pyridine-3-carboxylate in 100 ml of 1:1 tetrahydrofuran:methyl alcohol is added 20 ml of 5N NaOH. The reaction mixture is stirred overnight and evaporated i-n vacuo to a residue. The residue is dissolved in water and neutralized with acetic acid. The separated solid is filtered and air-dried to give 3.0 g of the desired product. M+=257.
Reference Example 223 Methyl F-r(f1,1'-Binheny11-2-carbonyl)aminol-nyridine-3-carboxylate 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 '[1,1'-biphenyl]-2-carbonyl chloride. The reaction mixture is stirred at SUBSTiTUTE SHEET (RULE 26) W 96122282 PC'TI7JS96/02052 room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo to a solid residue. The residue is stirred with ether, filtered and dried to give 3.0 g of the desired product:M+=332.
Reference Example 224 E-f(fl,l'-Bichenyll-2-^=rbonyl)aminolipyridine-3-carboxylic Acid To a stirred solution of 2.5 g of methyl 6-[([1,1'-Biphenyl]-2-carbonyl)amino]-pyridine-3-carboxylate in 50 ml of 1:1 tetrahydrofuran:methanol is added 10 ml of 5N sodium hydroxide and the mixture stirred at room temperature for 16 hours. The reaction mixture is concentrated in vacuo to a residue which is dissolved in water and neutralized with acetic acid.
The separated colorless solid is filtered and air dried to give 2.0 g of the desired product:M+=318.
Reference Example 225 Methyl 2-(2-Pyridinyl)benzoate A mixture of 12 g of methyl 2-(iodomethyl)benzoate, 20 g of n-butyl stannane and 2 g of tetrakis(triphenylphosphine)palladium (0) are refluxed in degassed toluene for 48 hours. The reaction mixture is concentrated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 5.5 g of the desired product as an oil. M+=213.

Reference Example 226 2-(2-Pyridiny1)benzoic Acid A mixture of 3.0 g of methyl 2-(2-pyridinyl)benzoate and 600 mg of sodium hydroxide in 50 ml of 9:1 methanol:water is refluxed for 4 hours. The reaction mixture is concentrated in vacuo and the residue dissolved in 50 ml of cold water. The solution SUBSTITUTE SHEET (RULE 26) is neutralized with glacial acetic acid and the resulting product filtered, washed with water, and dried to give 2.5 g of the desired product:M+1=200.

Example 1 N-[5-(Dibenz[b.fl(l,4loxazepin-10(11H)-ylcarbonyl)-2-nvridinyll-5-fluoro-2-methylbenzamide To a stirred solution of 0.39 g of 10,11-dihydrodibenz[b,f][1,4]-oxazepine, 1.1 ml of triethyl-amine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]-pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours, and diluted with 50 ml of dichloromethane and 20 ml cf water. The organic layer is separated, washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the f4 ltrate is concentrated to dryness under vacuum. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1) as solvent to aive a solid. Crystallization from ethyl acetate gives 0.335 g of off-white crystals, m.p.
180-186oC.
Examole 2 N-F=-r (9, 10-Dihydr(D-4H-thieno[2.3-clfilber:zazepi.n.-9-yl)c=rbonvi?-2-cvridinyll-5-fluo"o-2-metry'_bPnzamide As described for Example 1, 9,10-dihyciro-4-u-thieno[2,3-c][1]benzazepine in dichloromethane, in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a non-crystalline yellow solid.

SUBSTITUTE SHEET (RULE 26) Example 3 N-f5-r(4.10-Dihydro-5u-thienor3 2-cirilbenzazepine-5-ylcaYbon vi)-2-r)vridinyll-5-fluo*-o-2-m thylbenzam;de As described for Example 1, a mixture of 4,10-dihydro-5H-thieno[3,2-c][1]benzazepine and triethylamine in dichloromethane is reacted with 6-[(5-fluoro-2-methylbenzoyl)amincJpyridine-3-carbonyl chloride to give the product as a solid.
Example 4 N-fS-(Pyridor2,3-b1?,41benzoxaze--in-5(tiH)-yicarbonyi)-2-Tpvri dinyl l-5-f} uor^-2-methylbenza*nide As described for Example 1, 5,6-dihydro-pyrido[2,3-bJ[1,4]benzoxazepine is reacted in dichloromethane, in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)aminoJpyridine-3-carbonyl chloride to give the product as white crystals, m.p.
187-189 C.
Examni._e 5 N-rS-(Pvridof2,3-b1r1 5lberzoxazenin-6(5u)-ylrarbonyl)-2-,ovridinyll-5-fluoro-2-methylberzamide As described for Example 1, 5,6-dihydro[2,3-b][1,5Jbenzoxazepine reacted with 6-[(5-fluoro-2-methylbenzoyl)aminoJdichloromethane in the presence of triethylamine to qive the product as a non-crystalline solid.
Examr)lP 6 N-f5-r(6.?1-Dihvdre-5H-dibenzfb.elazenin-5-vl)carbonyil-2-pvrid nyl l-5-fluo*-^-2-*nPthylbenzamide As described for Example 1, 6,11-dihydro-5H-dibenz[b,e]azepine is reacted in dichloromethane in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)aminojpyridine-3-carbonyl chloride to qive the product as a solid.

SUBSTITUTE SHEET (RULE 26) Example 7 N-r5-r4,5-Dihydre-2-methylpyrazolof4,3-dlfllbenzazepin-6(2H)-yl)carbonyl-2-pyridinyll-5-fluoro-2-methyl-benzamide As described for Example 1, 2,4,5,6-tetra-hydro-2-methylpyrazolo[4,3-d][1]benzazepine is reacted in dicr.loromethane, in the presence of triethylamine, with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Example 8 N-r5-r(6 -,-Dihydrv-5?I-d-benz[b,dlazepin-5-yl)carbonyll-2-rvridinyll- -fluorc-2-methylbenzamide As describe for Example 1, 6,7-dihydro-SH-dibenz[b,dlazepine is reaction in dichloromethane in the presence of triethylamine, with 6-[(5-fluoro-2-methyl-benzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Example 9 LT-(5-f(4,5-Dihydro-6H-thienof3,2-dlfllbenzaze-oin-6-yl)carbonyll-2-r>yridiny11-5-fluoro-2-methylbenzamide As described for Example 1, 4,5-dihydro-6H-thieno[3,2-d][1]benzazepine is reacted in dichloromethane, in the presence of triethylamine, with 6-[(5-fluc=o-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride iLo give the product as a solid.
Example 10 N-[5-1(5 10-Dihydro-4u-}hienor3,2-clr2':benzazepin-4-yl)carbonvll-2-nvridinyl'-5-{luoro-2-methylbenzamide As described for Example 1, 5, 10-dihydro-4H-thieno[3,2--(;!][2]benzazepine in dichloromethane in the presence of triethylamine is reacr-ed with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbony' chloride to give the product as a solid.

SUBSTITUTE SHEET (RULE 26) 'WO 96/22282 PCTIUS96/01054 Example 11 N-(5f(4 s-DihvdrQpvrazolo(4 3-dlrllbenzazepin-6(1H)-yl)carbonyll-2-pyr;dinyll-5-fluorc-2-methylbenzamide To a solution of 0.20 mol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]ber.zazepine, 0.80 mol of triethylamine is added 0.42 mol of 6-[(5-fluoro-2-methylbenzoyl)amir.olpyridine-3-carbonyl chloride in ml of dichloromethane. The mixture is stirred under argon for 16 hours and diluted with dichloromethane 10 (25 ml). The mixture is washed with H20), 1MNaHC03, brine and dried (Na2SO4). The solvent is removed and the residue in methanol-tetrahydrofurane(1:1) stirred with 1NNaOH for 5 hours. The mixture is neutralized with acetic acid and the solvent removed. To the 15 residue is added H20 and the mixture extracted with ethyl acetate. The extract is washed with H20, 1NHC1, 1MNaHCO3 and dried (Na2SO4). The solvent removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Examnle 12 N (5-r(6 1i-Dihydre-sN-dibP^zfb elazepin-F-yl)carbonyli-2-DVr'dinv1lr1,'_'-biphenvll-2-carboxamide To a chilled (0 C) solution of 0.293 g of 6,11-dihydro-5p~-dibenz[b,e]azepine and 625 mL triethyl-amine '_n 3.5 ml of dichloromethane is added a solution of 0.657 a of 6-[([1,1'-biphenyl]-2-ylcarbonyl)aminol-3-pyridinecarbonyl chloride in 1.5 ml of dichloromethane.
The mixture is stirred under argon at room temperature fcr 16 hours and diluted with 40 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate con-centrated to dryness under vacuum. The residual solid is chromatographed on silica gel with ethyl acetate-SUBSTITUTE SHEET (RULE 26) hexane(1:1) as solvent to give the product as a glass.
Crystallization from ethyl acetate gives 0.395 g of white crystals, m.p. 134-1420C.
Example 13 N-f5-f(4 5 -nihyd~^-2 -mefihylnyrazo1 of4 3-dl(1lbenzazer) in-6 -yl ) carbony> > -2-nyr; dinyl 1 f 1, 1 ' -biphenyi 1 -2-carbo:=amide As described for Example 12,2,4,5,6-tetrahydro-2-methylpyrazolo[4,3-d][1]benzazepine is reacted with 6-[([1,ltbiphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Ex.amn? e 14 N-r5-r(6 7-n,ryd=^- -^;benz lb,dlazepin-5-yl.)carbony>>-2-TDyridinyl'rl,l'-binhenyll-2-carboxamide As described for Example 12, 6,7-dihydro-5H-dibenz[b,d]azepine is reacted with 6-[([1,11-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Example 15 N-fs-f(4,5-Dihydro-6':i-thienor3,2-dlrllbenzazepin-6-yl)carbonyl?-2-ovridinyll(1,1'-binhenyll-2-carboxamide As described for Example 12, 4,5-dihydro-6H-thieno[3,2-d][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Example 16 N-(5-f(5,10-Dihydro-4H-thienof3,2-c1(2lbenzazepin-4-yl)carbonyl'-2--oyridinyllfi,i'-biphenyll-2-carboxamide As described for Example 12, 5,10-dihydro-4H-thieno[3,2-c][2]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.

SUBSTITUTE SHEET (RULE 26) W a 95122282 PCTIUS96/02051 Example 17 N-fS-'(9,10-Dihydro-4H-thieno(2,3-clfllber.zazepin-9-yl ) carbo.^.yl' -2-pyridinyl 1 r1,' '-bi phenyl 1-2-carbox.amide As described for Example 12, 9,10-dihydro-4H-thieno[2,3-y][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
E'xample 18 N-(5-F(4,10-Dirydre-5)?-thieno(3,2-c1f11benzazepin-5-yr)carbony11-2-nyridinyll(1,'_'biUhenyll-2-carboxamide As described for Example 12, 4,10-dihydro-5F-thieno[3,2--(7][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride zo give the product as a solid.
Examole 19 N-fS-f(4,5-Dihydronyrazolor4,3-d?rilbe.n.zazer)in-6(1H)-v1)caYNonyl?-2-oyridinvll:l 1'-biphenyll-2-carboxamide As described for Example 11, 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine is reacted with 6-[([1,11-biphenyl]-2-ylcarbonyl)amino-3-pyridine-carbonyl chloride to give the product as a solid.
Examnle 20 N-F5-f(6,11-Dihvdre-5H-nyridof2,3-b1f1,51benzodiazepin-6-yl)carbonyl', -2-cvridinyl'-2-methy'_furane-3-carboYamide To a cooled (O C) solution of 0.296 g of 6,11-dihydr -5H-pyrido[2,3-b][1,5]benzodiazepine and 624 mL
of triethylamine in 3 ml of dichloromethane is added a solution of 6-[(2-methyl-3-furanylcarbonyl)amino]-3-pyridinecarbonyl chloride in 4 ml of dichloromethane.
The mixture is stirred at room temperature for 16 hours and the solvent removed under vacuum. To the residue is added 1M NaHCO3 and the mixture extracted with ethyl acetate. The extract is washed with H20, 1M NaHC03 brine and dried (Na2SO4). The solvent is removed under = 35 vacuum and the residue chromatoaraphed on silica gel SUBSTITUTE SHEET (RULE 26) with ethyl acetate-hexane as solvent to give the product as a solid.
Examnle 21 N-f5-[5(6H)-nhenanthridinyl)carbonyll-2-nyridinyll-2-methylfurane-3-carboxamide As described for Example 20, 5,6-dihydro-phenanthridine is reacted with 6-[(2-methyl-3-furanyl-carbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Ex_amnlP 22 N-fS-r(5 ?1-Dihydro-!ON-dibe^zfb elrl 41diazepin-10-yllcar^^^.yl'=-2-nyr;dinyl1-;-mAfihyifoYane-3-carboxamid As described for Example 20, 5, 11-dihyciro-10H-dibenz[:,,e][1,4]diazepine is reacted with 6-[(2-methyl-3-furanylcarbonyi)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
?/'xample 23 N-f5-r(5.1'_-Dihydro-lOH-dibenzfb.elrl 4id;az pin-10-yl)carbonyll-2-nvridinyllFl 1'-binhenyll-2-carboxamide As described for example 12, 5,11-dihydro-lOH-dibenz[b,e][1,4]diazepine is reacted with 6-[([1,1'-biphenyi]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Ei:arnale 24 5- (4- (4-?,:' y 1oxy)benzoyl-6, 1,-dihydry-5H-dibenzfb.elazepine To a solution of 6,11-dihydro-5H-dihydro-5H-dibenz[h,e]azepine (0.12 g, 0.6 mmol) in methylene chloride (2 ml) is added triethylamine (0.12 g, 1.2 mmol), followed by 4-butoxybenzoyl chloride ( (0.15 g, 0.72 mmol). The resulting mixture is stirred at room temperature for 2 hours, and then treated with 4 ml of iN NaO... The mixture is extracted with ethyl acetate (10 ml), and the extract is washed with 1N sodium hydroxide and brine (5 ml), dried over anhydrous sodium sulfate, and filtered through hydrous magnesium SUBSTiTUTE SHEET (RULE 26) VViJ 96/22282 PGT/1JS96/02052 silicate. The fitrate is evaporated, and the crude material is triturated with isoctane to give 0.24 g of white solid; Mass spectrum (CI), 372(MH+) Er.ample 25 10-((l,l'Biphenyl?-u-ylcarbonyl)-5,11-dihydro-10H-dibenzo-fb,el f1,41c:iazepine To a cooled (O C) solution of 0.5 g of 5,11-dihydro-l0,P-dibenzo[b,e][1,4]diazepine in 50 ml of CH2C12 and 12 ml of disopropylethylamine is added dropwise a solution of 0.67 g of [1,1'-biphenyl]-4-carbonyl chloride in 50 ml of CH2C12. The mixture is stirred at room temperature for 16 hours. An additional 0.3 g cf [l,1]-biphenyl]-4-carbonyl chloride in 30 ml of CH2C12 is added and the mixture stirred at room temperature 16 hours. The volatiles are removed under vacuum and the residue dissolved in 150 ml of CHC13.
The solution is washed with 50 ml of H20, dried (Na2SO4) and the solvent removed. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:5) and ethyl acetate-hexane (1:3) as solvent to give 0.86 g of solid, m.p. 152 -154 C; Mass spectrum (CI), 377 (MH+).
Example 26 10-(r1.1'-Birhenyll-4-ylcarbonyl)-10,11-dihydrodibenzfb.fl'1,41oxazepine To a cooled (0 C)solution of 1.0 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 7 ml of triethylamine in 30 ml of CH2C12 under argon is added dropwise 2.0 g of [1,1'-biphenyl]-4-carbonyl chloride.
The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of CHC13. The mixture is washed with 30 ml each of H20, 2NHC1, H20, saturated NaHCO3, H20, and dried (Na2SO4). Solvent is removed under vacuum to give 1.6 g of a yellow solid, m.p. 930-95 C;
Mass spectrum (CT), 378(MHT).

SUBSTITUTE SHEET (RULE 26) Example 27 9-(r1,1'-Biphenyll-4-ylcarbonyll-9,10-dihvdro-4H=
thieno(2,3-clfllbenzazepine As described for Example 26, 9,10-dihydro-4ji-thieno[2,3-c][1]benzazepine is reacted with [1,1'-biphenyl]-4-carbonyl chloride to give the product as a yellow solid; Mass spectrum (CI) 381 (MT).
E'Yample 28 5-(fl,l'-Biphenyll-4-y'_carbonyl)-6,7-dihydro-5H-di benz (b, dl azeiDine As described for Example 26, 6,7-dihydro-SH-dibenz[b,d]azepine is reacted with [1,l'-biphenyl]-4-carbonyl chloride to give the product as a solid.
Eramnle 29 6-(fl.'_'-Eiphenyll-4-yicarbonyl)5,11-dihydro-6H--oyrido [2, 3-el rl?benzazepine As described for Example 26, 5,111-dihydro-6H-pyrido[2,3-e][1)benzazepine is reacted with [1,1'-biphenyl]-4-carbonyl chloricie to give the product as a solid.
Example 30 5-(fi,l'-Biphenyll-4-ylcarbonyl)-5,6-dihydropyridor2.3-b1f1,41bP=^}hiazepine As described for Example 26, 5,6-dihydropyrido[2,3-b][1,41benzo-"hiazepine is reacted with [1,1'-biphenyl)-4-carbonyl chloride to give the product as a solid.
ExamnlP 31 10-(~!,1'-Birhenyll-4-ylcarbonyl)-10,11-dihydrofb,f 1r 1,4 lthiazepine As described for Example 26, 10,11-dihydro[b,f][1,41-thiazepine is reacted with [1,11-biphenyl]-4-carbonyl chloride to give the product as a solid.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTIUS9610]051 Example 32 10-(4-Benzoylbenzoyl)-10,11-dihydrodibenzfb,flrl,41oxazepine As described for Example 26, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as an off-white, m.p. 103 - 106 C; Mass spectrum (CI), 406 (MH{).
EYample 33 5- (4-Benzoylbe.^.zoyl) 5, 6, 11, 12-tetrahvdrodibenz[b.flazocine As described for Example 26, 5, 6, 11, 12-tetrahydrodibenz~b,f)azocine is reacted with 4-(benzoyl)benzoyl chloride to give the producz~ as a solid, m.p. 89 -92 C, Mass spectrum (CI), 418(MH+) EXample 34 10-r4-(Benzoylbenzoyl)-10.11-dihydrofb.flfl,Hlthiazepine As described for Example 26, 10,11-dihydro[b,f][1,4]thiazepine is reacted with 4-(benzoyl chloride to give the product as a solid.
Example 35 5- [4- (Benzoylbenzoyl) -5, 6-di hYdror)yrido [2, 3-b1i'l,4l.benzothiazenine As described for Example 26, 5,6-dihydropyrido[2,3-b][1,4]benzothiazepine is reacted with 4-(benzoyl)benzo;,l chloride to give the product as a solid.
Er_am-ci e 36 F-r(4-Eenzoylbenzcyl)15,11-dihydro-6H-ovridof2,3-elfllbenzazenine As described for Example 26, 5,11-dihydro-6N-pyrido[2,3-g][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.

SUBSTITUTE SHEET (RULE 26) Example 37 5-f(4-Benzqylbenzoyl)13-6,7-dihydro-SH-dibenzfb,diazepine As described for Example 26, 6, 7-dihydro-5,H-dibenz[b,d]azepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
Examnle 38 Q-f(4-Benzoylbenzoyl)1-9,10-dihydro-4H-thienof2,3-clflibenzazepine As described for Example 26, 9,10-dihydro-4Fi-thieno[2,3-c][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
EVamp1P 39 5-F(4-BenzoYlbenzovl)1-e,10-dihydro-5H-thieno~3,2-c1('lbenzazenine As described for Example 26, 4,10dihydro-5H-thieno[3,2-c][1]benzazepine is reacted with 4-(benzoyl)benzoyl chloride to give the product as a solid.
Examni A 40 5-(~' ''-R;r)r,Pnvll-4-ylcarbonly)-4,10-dihvdro-SH-*hienof3.2-c1(llbenzazepine As described fo Example 26, 4,10-ciihydro-5H-thieno[3,2-c][1]benzazepine is reacted with [1,1'biphenyl]-4-carbonyl chloride to give the product as a solid.
Examnie 41 o'- ( r1 !'-Binhenyl l-4-ylcarbonvl 1-1 , 4, 5, 6-fiPt'rahydr^c,vrazolc F4, 3-dl'? lbenzazepine As described for Example 26, 2 mmol of 1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine is reacted with 5 mmol of [1,1'-biphenyl]-4-carbonyl chloride. The product is stirred in methanol with 2N
NaOH for 16 hours and the mixture concentrated and extracted with ethyl acetate. The extract is washed SUBSTiTUTE SHEET (RULE 26) with 1 M citric acid, NaHCO3, H20, dried (Na2SO4) and the solvent removed to give the product of the example as a solid.
Examipl? 42 N-f4-1(5. ti-Dihyciropyrazolo-f4,'~-d) (i lb nzazAnin-r(!H)-yl ) carbonyl 1-3-chlerophPnyl 1 ri_i'-biphe*iyl 1-2-carbo_iami d.
As described for Example 11, 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[4,3-d][1]benzazepine is reacted with [l,1'-biphenyl]-4-carbonyl chloride to give the product as a solid.
'''Xample 43 j,?-rG-r{= f!1 cn-7a7Ppin-6(1u)-1 C... .~ ~r~^nrl -i-r}.l n.rn, r.
..hcny! i -9- (rli ma?-1-, i nO) TJ~
=ri ; nc_'7_ ~%~~IT~
car zamid As described for Example 11, 6-(2-chloro-4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo[4,3-d]benzazepine is reacted with 2-(dimethlamino)pyridine-3-carbonyl chloride to give the product of the example as a solid.
ExamplA 44 N-fa-r (5.6-r9jhyc!rop~~ -7n1nf4-3-''i ri1bAnzazPpin-y(1H)-yl)carbonylZphPnyl1-2-(dim thylaminn)pyridinA-3-=rboxamidA
As described for Example 11, 6-(4-aminobenzoyl)-1,4,5,6-tetrahydropyrazolo-[4,3-d]benzazepine is reacted with 2-(dimethylaminopyridine-3-carbonyl chloride to give the product as a solid.
Exam~le 45 12-tP'rahy'9"'nr3ihAnv (h flazn^in-^-y' ) r'?rti^nnyl ' -?-Dy'-"~---i; nyl ' - -fl`-inrn-2-mP*'hyl Pn"-aTMli!'3P
mo a ccoleci (0oC) and stirred solution of 0.246 g of 5,6,11-,12-tetrahydrodibenz[b,f]azocine 695 mL
of triethylamine in 5 ml of dichloromethane is added = 35 0.586 g of 6-[(5-fluoro-2-methylbenioyl)aminopyridine-3-carbonyl chloride. The mixture is stirred 16 hours - ill -SUBSTITUTE SHEET (RULE 26) under argon, diluted with 50 ml of dichloromethane and 20 ml of water, and the organic layer separated. The organic layer is washed with 20 ml each of NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residue (450 mg) is chromatographed on silica gel preparative plates to give a solid. Crystallization from ethyl acetate gives 0.20 g of white crystals, m.p. 198 - 200 C.
Example 46 N- f 4- (Dibenzrb fl f 1, 4'oxazepin-10 (11H) -ylcarbonyl)-phenyllfl,='-binhenyll-2-carboxamide To a mixture of 0.197 g of 10,11-dihydrodibenz[b,f][1,4]oxazepine and 0.402 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride in 5 ml of dichloromethane (cooled in ice bath) is added dropwise 0.154 g of N,N-diisopropylethylamine in 2 ml of dichloromethane. The mixture is stirred at room temperature under argon for 2 hours. The mixture is poured into water and the organic layer separated. The organic extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is concentrated to dryness to give 0.65 g of solid. The solid is purified by thick layer chromatography on silica gel with hexane-ethyl acetate (2:1) as solvent to give 0.110 g of a glass, m.p. 107 C-122 C. Anal.
Found: C, 80.8; H, 4.9; N,6Ø
E{amplA 47 N- rti- (Dibenz (b f' f i 41 oxazer)i.^.-10 (llu) -vlcarbonvll -3-chi or^^hPny' ' (1 1 ' bi z)henyl ) -2-carboxamide A mixture of 0.263 g of 10,11-dihydro-10(4-amino-2-chlorobenzoyl)dibenz[b,f][1,4]oxazepine, 0.195 g of [1,1'-bipheny]-2-carbonyl chloride and 0.116 g of .n,N-diisopropylethylamine in 7 ml of dichloromethane is SUBSTiTUTE SHEET (RULE 26) WO 96122282 PCl/US96/02052 stirred at room temperature.for 3 hours. The mixture is poured into water and extracted with dichloromethane.
The extract is washed with 2N Na2CO3, water, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate (pad washed with dichloromethane). The filtrate is concentrated to dryness to give a yellow solid. The solid is purified by chromatography on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give 0.12 g of SUBSTiTUTE SHEET (RULE 26) a yellow glass, m.p. 1450C-188 C: Anal.found: C, 73.6;
H, 4.6; N, 5. 0; Cl, 6.4.
EXample 48 N-f5-(Dibenzfb,flfl,4loxazepin-10(11H)ylcarbonyl)-2-pyYidinyll-c-~-fluoro-2-methylbenzamide ti As described for Example 46, 10,11-dihydrodibenz[b,f][1,4]oxazepine is reacted in dichloromethane with 2-[(2-methyl-5-fluorobenzoyl)amino]-5-pyridinylcarbonyl chloride in the presence of N,N-diisopropylethylamine to give the product as crystals. m.p. 180 C-186 C.

As described for Example 46 the following compounds can be prepared.
Example 49 N- f 4- (Diber.z fb, fl f 1. 4l oxazer)in-10 (11 H) -ylcarbonyl) -phenyl 1 -2- (2-w--i .i nyl) benzamide Ex.ample 50 N-f4-(Dibenzfb,f'f1,4loxazepin-10(11H)-ylcarbonyl)-phen%''_ 1-2- ( 3-nyri diny'_ ) benzamide Examr.le 51 N-f4-(Dibenzfb.flfl,4loxazepin-10(11H)-ylcarbonyl)-phenyl ~ -2- ( d-DV'-; d? nyl ) b-nza?TlidF' Example 52 N-f4-(Dibenzfb.flf1,41oxazepin-!0(11H)-ylcarbonyl)-3-chi_orophenyl?-2-(2-thienyl)benzamide Example 53 N- f Q-nibPnz fb. -F1 f i,. 4!oxazepi n-10(11u) -ylcarbonyl) -3-^hlcrophenyll-2-(3-thieny'_)benzamide As described for Example 48 the following compounds can be prepared.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTlUS96/0I051 Example 54 N-f5-(Dibenzffb.flf1,41oxazepin-10(11H)-ylcarbonyl)-2-gvridinyll-2-chloro-5-fluorobenzamide Example 55 N-f5-(Dibenzfb,flf1.41oxazepin-10(11H)-ylcarbonyl)-2-gvridinyl'-2-methyl-3-fluorobenzamide Example 56 N-f5-(Dibenzfb,flf1,41oxazepin-10(11H)-ylcarbonyl)-2-pyridinyll-2-methylbenzamide Example 57 N-fS-(Dibenzfb.fif1,41oxazepin-10(11H)-ylcarbonyl)-2-pvridinyll-2-chlorc-3-pyridinylcarboxamide Example 58 N- f5- (^ibenz fb, Fi r1 , 41 oYazepin-I 0(11H) -ylcarbonyl) -2-gvridinyll-2-hydroxybenzamide Example 59 N- r5- (r,iben, fb, f1 f l. 41 oxazepin-10 (11H) -ylcarbonyl) -2-pyridinyll-2-(dimethylamino)benzamide Example 60 N-fS-(Dibenzfb,flf'.41oxazepin-10(11H)-vicarbonyl)-2-pyridinyll-2-(dimethylamino)-3-,oyridinylcarboxamide Examnle 61 N-f5-(Dibenzfb.f1f1,41oxazepin-10(11H)-vlcarbonyll-2-w ridinyil-2-fluoro-5-crlorobenzamide ExamniP 62 N-fS-(Dibenzfb.flr1,41oxazepin-10(11H)-vicarbonyl)-2-py ridinyllfl,l-biphenyll-2-carboxamide ExamniP 63 N-r5-(Diber.zfb,flfl,41-oxazenin-10(11H)-ylcarbonyll-2-gvridinyll- -(3-oyridinyl)benzamide Example 64 N-f5-(Dibenzfb,flf1,41oxazeL,in-10(?1H)-ylcarbonyl)-2--ovridi nvl l -2- (2-nyridinyl) benza*.*.tide SUBSTITUTE SHEET (RULE 26) Example 65 N-f5-(Dibenzfb,flf1.41oxazepin-10(11H)-ylcarbonyl2-pyridinyll-2-(4-r)yridinyl)benzamide Example 66 N-f5-(Pyridof2,3-blf1.51benzoxazer)in-6(5H)-ylcarbonyl)-ti 2-nyridinyllfl.l'biphenyll-2-carboxamide A mixture of 0.198 g of 5,6-dihydropyrido[2,3-h][1,5]benzoxazepine, 0.155 g of N,N-diisopropylethylamine and 0.404 g of 6-[([1,11biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride in 12 ml of dichloromethane is stirred at room temperature for 3.5 hours. The mixture is poured into water and extracted with ciichloromethane. The extract is washed with 2N Na2CO3,H20, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The solid is dissolved hexane-ethyl acetate (1:2) and the solution filtered through a thin pad of hydrous magnesium silicate. The pad is washed with hexane-ethyl acetate (1:2) and the filtrate concentrated to dryness to give a glass, m.p.107 C-114 C Anal. Found:
C, 74.4; H, 5.7; N, 8.8 Example 67 N-f4-(Pyridof2,3-blf1,51benzoxazevin-6(5H)-ylcarbonyl)-3-chlorophenyllfl,l'-biphenyll-2-carboxamide A mixture of 0.198 g of 5,6-dihydropyrido[2,3-b][1,5]benzoxazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature for 2.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N
Na2CO3, H20, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate.
The filter pad is washed with 50 ml of hexane-ethyl acetate (1:2) and the filtrate concentrated to dryness.

SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCTlUS96/02054 The residue is triturated with ether to give a solid, m.p. 205-2170C. Anal. Found: C, 72.3; H, 4.2; N, 7.9;
Cl, 6.7.

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

Exampie 68 N-(5-(pvrid^f2 3-bl(l 51b nzoua:zep~--6(5N) ylcarbonyl) 3-nvridinvll(1 1'biDheryil-2-carboyamid Ex.amnie 69 N-f5-(Dyridor2 3-blf' 51b n^oxaz pin-6(5H)-ylcarbonyl) 2-Dvridinyli-2-chlo*-ob r=zamidA
Example 70 N-[5-(D%,ridor2,3-blrl,51benzcya!zenin-6(5H)-vlcarbonvl)-2-t)vridinyll-2-chioro-5-flucrobenzamicle Example 71 N-r5-(Pyridof2 3-blfl 5lbenzomaz pin-6(5H)-ylcarbonyl) 2-pyridinyll-2-hydroxybenzamide ExamolP 72 1`1-f5-(pvridof2 3-bl(1 5lb nzoxaz pin-6(5H)-ylcaYbonyl) 2-oyridinyll-2.5-d;fiuorcbA*izamid xampl3 N-f5-(?vrido(2,3-b'f1,51bPnzo'azyp~n-6(5u)-ylcarbonyl)-2-nyrid;^.y>>-2-mAtryibenzamid ExamnlA 74 I`T- f 5- (Dvrido r2, 3-bir1, 5jbAnzoxazApin-6 (5H) -yicarbonyl) -2-nvridinvll-2-(dimethylamino)b nzamid Examnle 75 N- r5- (P%=ri do f 2, 3-bl ~'_ ,51 benzouazAp~ n-6 (5u) -yicarbonyi )-2-r)yridinyll-2-(methylamino)benzamid Example 76 N- [5- (pyrido [2 3-bl ri 51 benzc)4 azer)in-6 (5F) -ylcarbonyi ) 2-T)vridinyll-2-(aminomethyl)benzamid SUBSTiTUTE SHEET (RULE 26) Example 77 N-f5-(Pyridof2,3-blf1,51benzoxazepin-6(5H) ylcarbonyl)-2--ovridinyll-2-methoxybenzamide Example 78 N-f5-(Pyridof2.3-blfl,5lbenzoxazeTDin-6(5H)-ylcarbonyl)-2-nvridiny11-2-chloro-5-fluorobenzamide Example 79 N-f5-(Pyridof2,3-blfl,51benzoxazepin-6(5H)-ylcarbonyl)-2-nyridinyll-2-methyl-3-fluorobenzamide ExamnlA 80 N- f5- (Pyrido f 2, 3-bl f 1, 51 benzoxazepin-6 ( 5H) -ylcarbonyl) -2-nvridinyll-2-fluorc-6-chlorobenzamide Example 81 N- f 5- (Pyri^c 12, 3-b' f, 51 benzoxazepin-6 (5H) -vicarbonyl) -2-r)vridinyll-2,6-dichlorobenzamide Example 82 N-fS-(Pyridof2,3-b1f1,51benzoxazepin-6(5H)-ylcarbonyl)-2-py ridinyll-2,5-dimethylbenzamide Example 83 N-f5-(Pyridof2,3-bl.fl,5lbenzoxazer)in-6(5H)-ylcarbonyl)-2-nyridinyll-2-chloro-3-DVridin vlcarboxamide Example 84 N- f 5- (Pvri do f 2, 3-bl f 1. 51 ber.zoxazepin-6 (5H) -ylcarbonyl) -2-r)vridinyl 1 -2- (methylami no)-3-,ovridi.nvlcarboyamide ExamplP 85 N-f5-( yridof2.3-b1f1.51benzoxazepin-6(5H)-ylcarbonyl)-2-T)vridinyli-2(dimethylamino)-?-T)yridinylcarboxamide Examnle 86 N-f5-(Pyridof2,3-blf1,51benzoXazetiin-6(5H)-ylcarbonyl)-2-t)vridiny11-2-(aminomethyl)4-nyridinylcarboxamide Example 87 N- r5- (Pyri do f 2, 3-bl f l, 51 benzoxazerir.-6 (5H) -ylcarbonyl )-2-lpvridinvll-2-(dimethylamino)-a-oyridinylcarboxamide As described for Example 67, the following compounds can be prepared.

SUBSTITUTE SHEET (RULE 26) Example 88 N-f4-(pvridof2 3-blrl 51b nzoxazepin 6(5H) ylcarbonyl) 3-chloro-F-methvlphe-n_yllrl õ -biphenv11-2- a*-boxamid Example 89 N-f4-(Pvridof2 3-blrl slb ^zoXazepin-6(5u)-yicarhonyl) ,_ -3,6-dimethvlphenvllfl õ -biphenyll-2- arboxamid _ Example 90 N-f4-(pvridof2-3-blfl 51hPnzoxaz p,~n-6(5H) yicarbonyl) 2-methvlphenvllfl 1'-biphenyll-2-carboxamid Example 91 N- fa- (Py,-ido f2, 3-bl f 1 s1b rzovazepin-ti (5H) -yl carbonyl) 2-^hlcrophPnyllfl i'-biphAnyil-2-c=rboxamide ExamnlA 92 TT-f4-(D`,.r;dof2,3-b1 FI S!bPnzoxaz pin-6(5N)-ylcarbonyl) 3-chloro-F-methylphenyll-2-(2-+-hiAnyl)benzamid Examole 93 N-f4-(Pvridof2 3-b1f1 51b nzoyaze-oin-6(5N)-ylcarbonyl) 3, 6-dimethvlr)henyll -2- (3-thienyl) benzamide ExamrDlP 94 N-r4-(Pvridof2,3-b1r1,51benzoxaz pir-6(5F)-yicarbonyl)-3-methylr)henyll-2-(2-thienyl)bPnzamide Example 95 N-f4-(pvridof2 3-blf! 5lbenzoxaz pin-6(5H)-ylcarbonyl) 3-chlorophenyll-2-(2-}hienyl)benza*nide Example 96 N-f4-(pyridof2 3-blfl 5lbenzoxaz pin-6(5H)-ylcarbonyl) 3-chloror)henvll-2-(3-*hienyl)benzamide Examn1P 9-7 N-f4-(Dyridof2 3-blri 51b nzoxazepin-6(5H)-yicarbonyl) 3-chlorobhenyll-2-(2-furanyl)bAnzamide ExamplA 98 N-r4-(Pvridof2 3-bf1,51benzoVaz ni^-ti(5u)-ylcarbonyl)-3-chlorophenyll-2-L2-pyridiry!)bArzamide SUBSTiTUTE SHEET (RULE 26) WO 96/22282 PCTliTS96/01051 Example 99 N- f4- (pvrido f 2 3-bl f 1 51 benzoxazepin-6 (5N) -vlcarbonyl) -3-chloroprenvll-2-(3-n%,ridinyi)benzamide ExamT)le 100 5 N-f4-(Pyridof2,3-b1f1,51benzoxazepin-6(5H)-vlcarbonyl)-3-chloror)henyli-2-(4-r)vridinyl)benzamide Examnie 101 N-ra-(pyridof2,3-b1f1,5lbenzoxazepin-a'(5H)-vlcarbonyl)-3-chlorophPnyll-2-(3-furanvl)b nzamid Exa=lP 102 N-F4-(Pyridof2,3-blf1,51benzoxazepin-6(5u)-ylcarbonyl)-3-me*hvlphenyl l~1,1'biphPnvil -2-carbor=amide Example 103 N- f 4- (Pyrido f 2,3-b1 f 1 51 benzo:,~azenin-r ( Su)-vlcarbonyll -3-methylr)henyll-2-(3-thienvl)benzamide ExamniA 104 N- Fa- (pyrido f 2 3-blf 1 51 benzoVazepin-6- (5N) -ylcarbonyl) -3-methylphenyl?-2-(2-pyridinyl)benzamide Example 105 N- f 4- (Pyrido f 2, 3-bl f l, 51 benzoxazepin-6- (5H) -ylcarbonyl )-3-methyphenyll-2-(3-nvridinyl)benzamide Example 106 N-f4-(Pyridof2,3-b1f1,51benzoxazenin-6(5H)-ylcarbonyl)-3-methvlr)henyl l -2- ( 4-r)yridinyl ) benzamide Example 107 N-f4-(Pyridof2,3-blfl,5lbenzoxazer)in-6(5H)-ylcarbonyl)-3-methylnhenyll-2-(2-furanyl)benzamide Example 108 N-f4-(Pyridof2,3-blfi,51benzoxaze-oin-6(5H)-ylcarbonyl)-3,6-dimethylnheny'_l-2-(2-thienyl)benzamide As described for Example 67, the following compounds can be prepared. - 120 -SUBSTITUTE SHEET (RULE 26) WO 96122282 PC.T/US96/01051 ExamDlP 109 N-f4-(pyridof2 2-bl(1 5lbenzoxazepin-6(5F)-ylcarbonyl)-3-fluoro-6-mAthylbhenyllfl 1-biphenyil-2-carboxamide "` Example 110 N- ( a- (Dyrido f 2 3-hl f i 51 benzoxazer)ine-6 (5H) -yl ^arbonyl )-3,6-dichloroohenyllfl 1'-bi-chAnyil-2-carboxami,de Example i11 N-fa-(pyridof2 3-blr 1, 51benzokaz gin-6(5u)-ylcarbonyl)-3-fluoronhenyl lr 1 il-biTphA*lvl l-2-carboxamide Examnle 112 N-f4-(Pyridof2 3-blf! Slbenzoxaz@pin-6(Su)-ylcarbonyl)-phenyllfl,?`-biphg*lyil-2-carboxamide Examole 113 ~,T- f a- (py*-id^ r2 3-bl [1. 5 1 hAnzoxam p=-6 (5H) -ylcarbonyl)-nhenyll-2-(2-*hienyl)benzamide Examole 114 N- (4- (pyrido r2 3-bl fI lbenzoY z pin-6 (5H) -ylcarbonyl)-nhenyll-2-(3-thienyl)benzamide Example 115 N-f4-(Pyridof2,3-bl(1 51bAnzoxaz nin-6( H)-vlcarbonyl)--chenyll-2-(2-thienyl)benzamide Example 116 N-f4-(pyridof2 3-blfl 51b nzoxazepir-6(5H)-vlcarbonvl)-3-fluorcohenyll-2-(2-thiAnyl)benzamide ExamplP 117 N-fa-(Pyridof2,3-bl[1,51benzoxazel~in-6( H)-ylcarbonyl l-,ohenyl 1-2- (3-th i enyl ) benzamide Examr)le 116 N- f 4- (Pyrido (2 , 3-bl f l, 51 benzoxazerDin-6 (5H) -yicarbonyl )-,ohenyi l-2- ( 2-furanyl ) benzamide Examole 119 N- (a- (P~,,,-; d^ r2 3-b1 f l.51bAnzoxazAoin-ti (5H) -ylcarbonyl ) -T)henyll -2- (2-r)vri dinyl ) benzamide Example 120 = 35 N-f4-(Pyridof2,3-blfl,5lbenzcxaz TDir.-6(5H)-ylcarbonyl)-bhenyll-2-(3-nvridinyl)benzamide SUBSTITUTE SHEET (RULE 26) Example 121 N-r4-(pyridof2.3-blf1.51benzoxazepin-6(5H)-kicarbonyl)-phenyll-2-(4-pyridinyl)benzamide xamplA 122 N-(4-(pyridof2 3-blfI 5lbenzoxazepiT-6(su)-ylcarbonyl)-3-flurorophenyl l -2- ( 3-furanyl ) benzamide Examnle 123 N-r4-(Pyridof2,3-b1f1,51be_^.zoxazenin-6(5H)-ylcarbonyl-3-methvl-ti-fiuorophenvllfi i'-biphenyll-2-carboxamide Example 124 N- f d- (Dyrido f 2 3-bl rl 51 benzot-aze-oi^-ti ( 5N) -yicarbonyl l-2-methylnhenyll-2-(2-furany'_)benzamide Exam-ole 125 ~,T-f4-(Dyridof2,3-b'r, 51bP^zovazPp;n-F(5u)-ylcarbonyl)-3-methylTDhe.^.y11 -2- (3-furany_1) benzamide Example 126 N- f 4- (Pyrido f 2, 3-bl f 1, 51 benzoxazeipir.-6 (5H) -ylcarbonyl) -3,6-dimethylphenyll-2-(3-r)yridinyl)benzamide Examnle 127 N-f4-(Pyridof2.3-b1f1,51benzoxazet)in-6(5H)-ylcarbonyl)-3. 6-dichloronhenyl l -2- (4-nyridir.yl) benzamide EXamnlA 128 N-r4-(pyridof2,3-blf' 5';benzoxazepin-6(5H)-ylcarb nyl )-tDhenyl l-2- ( 3-furanyl ) benzamide Example 129 N-f4-(Pyridof2,3-blrl,51benzoxazepin-6(5H)-ylcarbonyl)-3-flurcro~heny'1-2-(2-thienyl)benzamide Example 130 N- f 5- (Dyri do f 2, 3-bl r1, 41 benzoxaze,oin-5 ( 6H) -vlcarbonyl )-2-^vridinyll-5-fluore-2-methvlbenzamide As described for Example 46, the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (1 mmol) with 2-[(2-methyl-5-fluorobenzoyl)aminol-5-pyridinylcarbonyl chloride (1.0 mmol) in dichloromethane in the presence of ~T,N-diisopropylethylamine (3 mmol) gives the product as a glass.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PC1'/77S96/02051 ExamPle 131 N-f5-(Pyrido(2,3-bl(1.41benzoxazepin-5(6H)-ylcarbonyl)-2-pyridinyllr1,1'-bipheny11-2-carboxamide As described for Example 66. the reaction of 5,6-dihydropyrido[2,3-b][1,4]benzoxazepine (0.198 g) with 6-[([1,1'-biphenyl]-2-carbonyl)amino]pyridine-3-carbonyl chloride (0.404 g) in dichoromethane in the presence of N,N-ciiisopropylethylamine (0.155 g) gives the product as a solid.
Example 132 N- ( 4- (Pvri do (2 , 3-bl ! 1. 41 benzoxazepi n-5 ( 6H) -ylcarbonyl )-3-chloronhenyll~i,l'biiDhenyll-2-carboxamide As described for Example 66, reaction of 0.198 g of 5,6-dihyciropyrido[2,3-b][1,4]benzoxazepine with 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride in dichloromethane in the presence of N,N-diisopropylethylamine gives the product as a solid.
Example 133 N-f4-(6,11-Dihydronyridof2,3-blf1,51benzodiazerin-6(5H)-ylcarbonyl)-nhenyllfl.1'-bipheny11-2-carboxamide To a mixture of 10.55 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-5(6H)-one in 40 ml of tetrahydrofuran is added 15 ml of 10 molar borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred at room temperature 2 hours and then refluxed (under argon) for 4 hours. An additional 40 ml of tetrahydrofuran is added and the mixture refluxed overnight. To the cooled mixture is added 12 ml of methanol and the solvent removed. To the residue is added 30 ml of 2N NaOH and the solution refluxed 2 hours under araon. The mixture is extracted with ethyl acetate and the extract washed with 2N citric acid. The aqueous layer is made basic with 2N NaOH and extracted with ethyl acetate. The extract is washed with H20, brine and dried (Na2SO4). The solution is filtered SUBSTITUTE SHEET (RULE 26) through a thin layer of hydrous magnesium silicate and the filtrate concentrated to dryness to give 4.65 g of brown solid. The solid is purified by chromatography on silica gel to give the product as a solid. A 4.85 g 5 sample of crude product is triturated with ether to give 2.68 g of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine as a solid.
A mixture of 0.296 g of 6, 11-dihydropyrido[2,3-b][1,5]benzodiazepine, 0.604 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride and 0.232 g of N,N-diisopropylethylamine in 6 ml of dichloromethane is stirred at room temperature for 1.5 hours. The mixture is iDoured into water and extracted with dichloromethane. The extract is washed with H20, saturated NaHCO3, H20,brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous megnesium silicate and the filzrate concentrated to dryness. The residue is purified on thick layer silica gel plates with hexane-ethyl acetate (1:2) as solvent to give the product as a solid which is crystallized from ethyl acetate to give off-white crystals, m.p. 220oC-221oC.
ExamplA 134 N-f4-(6,1'-Dihydronyridof2,3-b1f1,51benzodiazeoin-E(5H)-vlcarbonyl)-3-chlorophenyllri,i'-binhenvll-2-carboxamide A mixture of 0.197 g of 6,11-dihydropyrido [2,3-b][1,5]benzodiazepine, 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of N,N-diisopropylethylamine in 8 ml of dichloromethane is stirred at room temperature for 1.5 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H20, saturated NaHCO3, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue is chromatographed on thick layer SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCl/US96101051 silica gel plates with hexane-ethyl acetate (1:2) to give 0.160 g of solid, m.p. 147 C-165 C.
Anal Found: C, 72.1; H, 5.1; N, 9.1; Cl, 6.3.
Example 135 N- f 4- ( 6 i 1-Dihydronvrido f 2 3-bl r i 51 hPnzodiazepin-6 (5H) ylcarbonyl)-r)henvll(1,1'-biphenyll-2-carboxamid hydrochloride Hydrogen chloride (gas) is bubbled into 50 ml of anhydrous chilled methanol for 15 minutes. A 25 ml sample of the methanolic hydrogen chloride is added to 0.30 g of N-[4-(6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-6(5H)-ylcarbonyl)phenyl][1,1'-biphenyl]-2-carboxam,ide. The mixture is stirred at 0 C
for 0.5 hours and allowed to warm to room temperature.
The solvent is removed and the solid dried under vacuum to give 0.31 g of solid, m.p. 195 C-210 C.
As described for Example 134, the following compounds can be prepared by reaction of 6,11-dihydropyrido[2,3-b][1,5]benzodiazepine with the appropriate substituted or unsubstituted [(arylcarbonyl)amino]benzoyl chloride or the appropriate substituted or unsubstituted[(arylcarbonyl)-amino]pyridinylcarbonyl chloride.
Example 136 N-r4-(- 11-Dihydror)yridor2 3-blrl 5lb nz diaz pir-6(5H)-vlcarbor,yl ) -?-chlorophenyl? -2- (2-thienyl) benzamide Examole 137 N-r4-(6 11-nihydroay*-idof2 3-b? rl,51bPnzodiazepin-6(5H)-ylcarbonyl)-3-chlcronhenyll-2-(3-thienyl)bQnzamide Examnle 138 N- f 4- ( 6, 11-Dihydror)vri do r2, 3-bl r? . 5i berzodiaz pin-6 (5H) -ylcarbony?)-3-c?:lorc-6-methvlohenyll-2-(2-thienyl)benzamide SUBSTITUTE SHEET (RULE 26) Example 139 N-f4-(6,11-Dihydrogvridof2,3-bif1,51benzodiazepin-6(5H)-ylcarbonyl)-phenyll-2-(2-thienyl)benzamide Example 140 5 N-f4-(6,11-Eihydropyridof2,3-bif1,51benzodiazepin-6(5H)-ylcarbonyl ) -Dhenyl 1 -2- ( 3-thienyl ) benzamide Example 141 N-f4-(6,11-DihydroDyridof2,3-bif1,51ber.zodiazepin-6(5H)-ylcarbonyl)-3-methylphenyll-2-(2-thienyl)benzamide Exampie 142 N-f4-(6,'_!-Dihydropyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-3,6-ciimethylphenyll-2-(2-thienyl)benzamide Example 143 N-r4-(E '1-DihydroDyrldof2,3-bi fl,5lbenzodiazeDin-6(5H)-ylcarbonyl)-3-methylpheny11f1,1'-biDhenYll-2-carboxamide ExamDlA 144 N-f4-(6,11-DihydroDyridof2,3-b1.f1,51benzodiazepin-6(5H)-ylcarbonyl)-3,6-dimethylphenyl1f1,1'-biphenyll-2-carboxamide Example 145 N-f4-(6,11-DihydrQpvridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-3,6-dichloroDhenyllf1,1'biphenyll-2-carboxamide Examnle 146 N- f 4- (E, '=-Di!-:ydroDyrido f 2, 3-b 1 f 1, 51 benzodiazepin-6 (5H) -ylcarbony'_)-3-methyl-6-chlorophenyllfl,l'-biphenyll-2-carboxmide Ex_ample 147 N-f4-(6,11-Dihydropyridof2,3-b1r'_,51benzodiazeDin-6(5H)-ylcarbonyl)-3-chloro-F-fluoroDhenyllfl,?'-biDhenyl)-2-carboxamide ExamDlP 148 N-r4-(6,11-DihydroDVridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-methylDhenylif1,1'-biT)henyll-2-carboxamide SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCI'/US96/01051 Example 149 N-[4-(6 i1-Dihydrobyridof2 3-blfi Slbenzodiaz pir-6(SH)-ylcarbonyl)-2-chlorophenyllfi,l'-bi-ohenyll-2-carboxamide Example 150 N-(4-(6 11-Dihydro~,ridof2 3-blf751bPnzodlazepin-6(5H)-yicarbonyl)-phenyli-2-(2-nyridinyl)benzamide Examnl,e 151 N-(d-(6 i1-nihydronyridof2 3-b1rl slb nzodiaz pin-6(5H)-ylcarbonyl)-nhenyl1-2-(3-nyridinyl)be*izamide Example 152 N-(Q-(6 11-Dihydropyridof2 3-blrl 5lbenzodiaz pir-6(SH)-ylcarbonyi)-nheny11-2-(4-pyridinyl)benzamide Examnle 153 N-f4-(5 11-nihydro^yridof2 3-bl(l.5'benzodiaz pin-E(5H)-ylcarbonyl)-3-chloroTDhenyll-2-(2-nvridinyl)benzamide Examnle 154 1`?- f 4- ( 6 11-Dihydropyr; do f 2 3-bl f 1 5l benzodiaz pin-6 (5H) -ylcarbonyl)-3-chloroz)henyll-2-(3-Dyridinyl)benzamide Examnle 155 N-f4-(6,11-Dihvdropvridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-3-chloronhenyll-2-(4-Dyridinyl)benzamide Example 156 N-f4-(6,11-Dihydropyridof2,3-b1f1,51benzodiaz pin-6(5H)-ylc=rbonyl)-3-mPthylt)henyll-2-(2-r)y*-idinyl)benzamidP
EXamole 157 N-f4-(6,11-Dihydror)yridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyi)-3-mArhy!phPnyll-2-(3-nyr;dinyl)benzanide Example 158 N-r4-(5,11-Dihydronvridof2,3-b1fl,5lbenzodiazepin-6(5H)-ylraYbonyl)-3-rnPthylnhPny>>-2-(4-nyridinyl)bAnzamide Example 159 N-f4-(6,11-Dihydronvridcf2,3-b1f'_ 5lbenzodiazepin-6(5H)-ylcarbonyl ) -:;-me*_hyl-6-fl uoroz)henyl l -2- (2-thiPnyl)benzamide SUBSTITUTE SHEET (RULE 26) Example 160 N- r 4- (6, 11-Dihyiropyrido f 2, 3-bl f 1, 51 benzodiazepin-6 (5H) -ylcarhonyi)-3 6-dimethylr)henyll-2-(2-r)yridinvl)benzamide Examnle 161 N-f4-(6 i1-Dihydro~vridof2 3-blfi 51benzodiazepin-6(5H)-ylcarbonyl)-3 6-dimethylr)henyll-2-(3-nvridinyl)benzamide Exampie 162 N-f4-(6,11-Dihydronyridof2,3-b1f1,51benzodiazepin-6(5H)-yicarbonyil-3 6-dimethylphenyll-2-(4-nvridinyl)benzamide Example 163 N-r4-(6,11-Dihydronyridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyi)-lohPnyll-2-methoxypvridine-3-carboxamide EVample 164 N-f4-(611-nihydror)vridof2 3-b'r! 51benzcdiazepir-6(5H)-ylcarbonyl)-3-chlorophPnyll-2-methylthior)yridine-3-carboxamide Example 165 N- f 4- ( 6 1 1-Dihvdror)yrido f 2, 3-b l f 1, 51 benzodiazepin-6 (5H) -ylcarbonyiN-3-mefihylnhenyll-2-methylr)yridine-3-carboxamide Example 166 N-r4-(6 1i-JihvdrQDVridof2 3-blrl 5lbenzodiazepin-6(5H)-ylcarbonyl)-3,6-dimethylphenyll-2-methylpvridine-3-carboxamide Ex.amDle 167 N- ra- (ti??-D;hvcironvridof2,3-b1 r1,51benzodiazepin-6(5H)-ylcarbonvi)-nrenyll-2-methyl,oyridine-3-carboxamide Ex.ample 168 N- f 4- ( 6 õ-Dihvdr^cvrido f 2, 3-bl r'_ , 51 benzodiazerpi n-6 (5H) -y'carboryl)-3-chlCrophenyl'-2-methvlr)vridine-3-carboxamide Examiole 169 N-r4-(6 'i-nirYdrenvridor2,3-birl,5!benzodiazepin-6(5H)- yicarbonvi)-~-cricro-6-mefihylphenyll-2-fluoropvridine-3-carboxarnicie SUBSTITUTE SHEET (RULE 26) Example 170 N-f4-(6 11-Dihydronvridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-3-chlorophenyll-2-fluoropyridine-3-carboxamide Example 171 N-f4-(6,11-Dihydronyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonYl)-3-methylphenyll-2-chlorovyridine-3-carboxamide Example 172 N-r4-(6 1i-DihydropvTidcf2 3-blrl 5lbenzodiazepin-6(5H)-vlcarbonyl)-3,6-dimethylphenyli-2-chloropyridine-3-carboxamide Example 173 N- fd- (-'' 1-Dihydronvri do f 2, 3-bl f 1, 51 benzodi azepin-6 (5H) -ylcarbonkil-Dhenyil-~-methylpvridine-2-carboxamide Example 174 N-fd-(5 11-Dihydr ~Dvridof2,3-blf1,51benzodiazepin-6(5H)-ylcarbonYl)-3-chlorophenyli-3-methylnv*-idine-2-carboxamide Example 175 N-rd-(5 11-Dihydrot)vridof2,3-b1f1,51benzodiazepin-6(5H)-yicarbonyl)-3-chlorophenyll-2-chloronyridine-3-carboxamide Example 176 N-f5-(6 11-DihydroD=v'ridof2,3-b1f1,5lbenzodiazepin-6(5H)-ylcaYb^nyl)-2--ovridinvi1f1,1'-bi,ohenyl?-2-carboxamide, m.p. 278oC-2810C
ExamplP 177 N-r5-(6 11-Dihvdronvridcf2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-r)vridinyll-2-(2-thienyl)benzamide Ex.ample 178 N-r5-(E 1!-Dihydronyridof2,3-b1r1,51benzodiazepin-6(5H)-wr y'carbonyl)-2-nvridinyll-2-(3-thienyl)benzamide Example 179 N- r5- ( 6 1i-Dihydronyri do f 2, 3-bl r'_ , 5lbenzodi azepi.r.-6 (5H) -ylcarbonyl)-2--Dvridinvll-2-5'luorobenzamide SUBSTITUTE SHEET (RULE 26) Example 180 N-f5-(6,11-Dihydropyridof2,3-b1f1,51benzodiazepin-6(5H)-Ylcarbonyi)-2-nvridinyll-2-(2-gvridinyl)benzamide Example 181 "=
N-fS-(6,11-Dihydrot)yridof2,3-blf1,51benzodiazepin-6(5H)-ylcarbonyl)-2-T)yridinyll-2(3-nyridinyl)benzamide Example 182 N-fS-(6,11-Dihydronyridof2,3-b1f1,51benzodiazenin-6(5H)-ylcarboryl)-2-nvridinyll-2-(d-pyridinyl)benzamide Example 183 N- f 5- ( 6, 11-DihydrozDyri do f 2, 3-bl f 1, 51 benzodiazepin-6 (5H) -ylcarbonyl ) -2-=cyridinyl l -2- (2-furanyl) benzamide Examole 184 N-r ;- (Fi -n hy^r~~vr~def2 3-b1F 1, 51rAnzodiazepin-6(5H)-ylcarbonyl)-2-nyridinyll-2-(3-furanyl)benzamide Example 185 N-f5-(6,11-Dihydropyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-nyridinyll-3-chloror)yridine-2-carboxamide Example 186 N-f5-(6,11-Dihydropyridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-nyridinyll-2-methylnyridine-3-carboxamide Example 187 N-f5-(6,11-DihydroDyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-TDyridiny11-5-fluor^-2-methylbenzamide ExamplA 188 N-fS-(6,?1-Dihydropyridof2,3-blfl,5lbenzodiazepin-6(5H)-vlcarbonyl)-2-r)yridinyll-2-chlorobenzamide ExamplA 189 N-f5-(6,11-Dihydror)yridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl ) -2-nvri di nyll -2-chloro-5-fluorobenzamide Example 190 N-f5-(5,11-Dihvdronvridof2,3-b1fl,51benzodiazepin-6(5H)-ylcarbonyl)-2-,oyridinyll-2-methylbenzamide ExamolP 191 N-f5-(6,11-Dihydror)yridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-nyridinyll-2,5-dimethylbenzamide SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCTJUS96J0] 051 ExamDle 192 N-fS-(6,i1-Dihvdror)vridof2.3-blf1,51benzodiazepin-6(5H)-ylcarbonyl)-2-pyridinyll-2-chloro-4-fluorobenzamide Example 193 N-f5-(6.1?-Dihydrogvridof2,3-b1f1.51benzodiazepin-6(5H)-ylcarbonyl)-2-t)vridinY11-2-chloro-6-fluorobenzamide Example 194 N-r5-(6.11-Dihydrot)yridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-,oyridinyll-2-methyl-3-fluorobenzamide Example 195 N- f 5- ( 6, ??-Dihvdror)yri do f 2, 3-bl f 1, 51 benzodiazenin-6 (5H) -ylcarbonyl)-2-cyridinyll-2-hydroxybenzamide Evample 196 N-FS-(6 '1-Dihydror)Y=ridof2.3-b1f' 5lbenzodiazenin-6(5H)-ylcarbonyl)-2-r)yridinyll-2-acetyloxybenzamide ExamiolP 197 N-fS-(6,'_1-Dihydronyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyi)-2-nyridinyll-2-aminobenzamide Example 198 N-f5-(6,11-Dihydrogvridof2,3-bifl,5lbenzodiazepin-6(5H)-vlcarbonyl) -2-cyri dinyl? -2- (methylami no) benzamide Example 199 N-f5-(6 1l-Dihydror)yridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyi)-2-,ovridinyll-2-(dimethylamino)benzamide Example 200 N- f 5- i-Dihydronyrido f 2, 3-bl f 1, 51 benzodiazepin-6 (5H) -yl^arbonyl)-2-,ovridinyll-2-aminomethylbenzamide Example 201 N-f5-(6 "-Dihydre-ovridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyi)-2-ny'-'idinyll-2-(diethylamino)benzamide Example 202 N-F5-(6 ii-Dihydrepyridor2,3-blrl 5lbenzodiazepin-6(5H)-ylcarbonyi)-2-t)vridinyl1-2-(dimethylaminomethyl)benzamide SUBSTITUTE SHEET (RULE 26) Example 203 N-f5-(6,11-Dihydropyridof2,3-blf1.51benzodiaz pin-6(5H)-ylcarbonyl) -2-t)vridinyll -2- (methylthio) benzami dP
Example 204 "=
N-f5-(6,11-Dihydronyridof2,3-b1f1,51benzodiaz pir-6(5H)-ylcarbonyl)-2-gvridinyll-2-chloror)yridinP-3-carboxamide Example 205 N-r5-(6,11-Dihydro-oyridof2,3-b1fl,51benzodiazepir.-6(5H)-ylcarbonyl)-2-t)vridinyll-2-fluoropyridine-3-carboxamid Examnle 206 N-f5-(6,11-Dihydro-oyridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-pvridinyll-2-mAthoxynyridine-3-carboxamide Example 207 N-f5- (6, 11-Dihydro-oyrido f2, 3-b1 f1, 5lbenzodiazepir.-6 (5H) -ylcarbonyl)-2-pyridinyll-2-methylthiopyridine-3-carboxamide Example 208 N-I5-(6,11-Dihydror)yridof2,3-blfl,5lbenzodiazepin-6(5H)-yicarbonyl)-2-t)yridinyll-2-aminonyridine-3-carboxamide Example 209 N-f5-(6,11-Dihydropyridof2,3-blfl.5lbenzodiazepin-6(5H)-ylcarbonyl)-2-c)yridinyll-2-methylamino-nyridine-3-carboxamide Example 210 N-f5-(6,1?-Dihydroayridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-nyridinyll-2-(dimethylamino)pyridine-3-carboxamide Example 211 N-f5-(6,1?-Dihydronyridof2,3-b1f1,51benzodiazepir.-6(5H)-ylcarbonyl)-2-nyridinyllthiophene-2-carboxamide Examole 212 N-f5-(6,'_1-Dihydroovridof2,3-b1fl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-r)yridinyllthiot)hene-3-carboxamide Examgle 213 N-rS-(6,11-Dihydronyridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbonyl)-2-t)yridinyllfurane-2-carboxamide SUBSTITUTE SHEET (RULE 26) Example 214 N-f5-(6,11-Dihydropvridof2,3-blfl,5lbenzodiazepin-6(5H)-ylcarbonyl)-2-gvridinyll-2 -mefihylthiophenP-3-carboxamidP
Examgie 215 N-f5-(6,11-Dihydropyridof2,3-b1f1,51benzodiazepin-6(5H)-ylcarbrnyi)-2-r)vY;dinyi'-3-metrylthiophene-2-carbouamide Example 216 N-r5-(6 i1-Dihydropvridof2 3-blfi 51benzodiaz pin-6(5F)-ylcarbonyl)-2-cvridinyll-2-rhlorothiophene-3-carboxamide Example 217 N-r5-(6,11-nihydroDyridof2,3-bl,1l,5!benzodiaz pin-6(5H)-ylcarbonYi-2-pyridinyil-2-methylthiophene-3-carboxamide Examnle 218 N-f4-r(5,11-D_hydre-l0u-dibenzfb,elf1,41diazepin-10-%,1)carbonyll-3-chlorophenyllfl,l'-biphenyll-2-carboxamide A mixture of 0.196 g of 5,11-dihyciro-10H-dibenzo[b,e][1,4]diazepine, 0.155 g of N,N-diisopropylethylamine and 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino)-2-chlorobenzoyl chloride in 12 ml of dichloromethane is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N K2C03,H20,brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated to dryness and the residue triturated with ether and the solvent removed. The residue is triturated with dichloromethane to give 0.31 g of solid, m.p. 158 C-184 C. Anal. Found for C33H24C1N302 1/2 H20; C,73.7; H, 4.6; N,7.5; C1,6.9.
As described for Example 218, the following compounds can be prepared by the reaction of 5,11-dihydro-lO~-I-dibenz[b,e][1,4]diazepine with the appropriate substituted or unsubstituted [(aryl-SUBSTITUTE SHEET (RULE 26) carbonyl)amino]benzoyl chloride or the appropriate substituted or unsubstituted [(aryl-carbonyl)amino]pyridinylcarbonyl chloride.

Example 219 5 N-f4-f(5,11-Dihydre-10H-dibenzfb,elfl,4ldiazepin-10-yl)carbonvll--ohenyllfl,l'-biphenyll-2-carboxamide Example 220 N-f4-r(5,11-Dihydro-lOH-dibenzfb,elf1,41diazepin-10-yl)carbonyll-3-methylphenyllfl,l'-biphenyll-2-carboxamide Example 221 N-f4-f(5,11-Dihydro-lOH-dibenzfb,elr1,41diazepin-10-yl)carbonyll-3,r-dimethylphenyllfi,l'-biphenyll-2-carboxamide Example 222 N-f4-r(5,11-Dihydr^-IOH-dibenzfb,elfl,4ldiazepin-10-yl)c=rbonyll-3-chlorophenyl?-2-(2-thienyl)benzamide Example 223 N-f4-f(5 11-Dihvdro-10H-dibenzfb,elfl,4ldiazepin-10-Y1)carbonyll-3-chlorophenyll-2-(3-thienyl)benzamide Example 224 N-fa-r(5 11-Dihys3.ro-lOH-dibenzfb,e1f1,41diazepin-10-yl) carbonyl l-3-^hi orophenyi1-2- (3-furanyl) benzamide Example 225 N-f4-r(5 11-D~.hydro-lOH-dibenzfb,elfl,4ldiazepin-10-yl)rarbonyll-?-c'.:lorophenyll-2-(2-furanyl)benzamide Example 226 N-fz-r(5 ii-Dihydro-lOH-dibenzfb,e'fl,4ldiazepin-10-yl)carbonyll-3-methylr)henyll-2-(2-thienyl)benzamide Example 227 N-fa-F(5 ll-Dihydre-lOH-diber.zfb,elf1,41diazepin-10-yl)carbony>>-j-methylr)henyll-2-(3-thienyl)benzamide Example 228 N-f4-f(5 11-Dihydro-lOH-dibenzfb,elf1,41diazepin-10-yl)carbonyll-3-me}hvl-chenyllfl,l'bi^henvll-2-carboxamide =_ SUBSTITUTE SHEET (RULE 26) Example 229 N-f4-r(s.1?-Dihydro-iOH-dibenzfb elfl 4ldiaz pin-10-v.l)^arbonyll-3 6-dimetrylphenyllri 1'-biphenyl-2-carboxamide Example 230 . =
N-ra-f(5 11-Dihydre-lOH-dibenzrb elfl 41diaz pir-10-yl)carbonyil-3-mAtnyl-6-chlorophenyilfl 1'-biphenyli-2-carboxamide Example 231 N-r4-r(5 11-Dihydro-10N-dibenzfb elfl 4ldiaz pir-10-yl)carbonyll-3-chloro-6-fluorophenyllfl i'-biphenyll-2-carboxamide Example 232 N-f4-r(5,11-Dihydre-lOH-dibenzfb.e1f1.41diaz pin-i0-yl)carbonyll-2-methylphenyllfl õ -biphenyll-2-carbovamide Example 233 N-r4-f(5,11-Dihydre-10H-dibenzfb,e1f1,4!diazepin-l0-y_l)carbonyil-3-chloro-ti-methylphenyllrl,l'-biphenyil-2-carboxamide Example 234 N-fa-f(5 1i-Dihydr^-10H-dibenzfb elf 4ldiazepin-10-yl)carbonyll-2-chlorophenyllfl,l'-biphenyll-2-carboxamide Example 235 N-t4r(5,11-Dihydr^-l0u-dibenzfb,elf1,41diazepin-l0-yllcarbonyll-Dhenyll-2-(2-,oyridinyl)benzamide Example 236 N- f 4- r(5, 11-Dihyciro-10??-diber.z fb, el f 1, 41 diazepin-l0-yl)carbonyll-phenyll-2-(3-r)yridinyllbAnzamide Example 237 N- f 4- f(5, 11-ni }-:ydro-l OH-dibenz fb, elr 1, 41 diazeipin-10-yl)carbonyll-phenyl1-2-(4-pyridinyl)benzamide Examnle 238 N-f4-r(5,11-Dihydro-l0u-dibenzfb,elfl,4ldiazepin-l0-yl)carbonyl1-3-chloro-ohenyl1-2-(2-pvridinyl)benzamide SUBSTITUTE SHEET (RULE 26) Example 239 N-f4-f(5.11-Dihydro-10H-dibenzfb,elf1.41diazepin-10-yl)carbonyll-3-^hlorophenyii-2-(3-r)vridinyl)benzamide Example 240 N-r4-f(5,?1-Dihydro-lOH-dibenzfb,elf1.41diazepin-l0-yl) carbonyl? -3-^hlorophenyl i-2- (4-pyri dinyl) benzamide Ex amn i A 241 N-f4-r(5,11-Dihydre-lOH-dibenzfb,elf1,41diazepin-l0-yl)carbonyl?-3-methylphenyll-2-(2-c)yridinyl)benzamidP
Example 242 hT-f4-f(5,11-Jihydr^-l0u-dibenzfb,e,lrl,4ldiazepin-10-yl)carbonyll-3-methyl-oheny'_1-2-(3-r)vridinyl)benzamide Examnle 243 j~,T- f 4- r(5, 1l-lli h=,C{ro-1 Ou-r~;bPnv x _ _fb.e1f1.41diazepin-l0-yl)carbony11-3-methvlr)henyll-2-(4-nvridinyl)benzamide Examole 244 N-ra-r(5,11-DihYdro-lOH-dibenzfb,elfl.41diazeTpin-10-yl)carbonyll-3,6-dimethylphenyll-2-(2-pyridinyl)benzami(Je Er.ample 245 N- r4- r(5, 1? -Dihydro-lOTi-dibPnzfb, el r1, 41 diazepir.-10-yl)carbonyll-3,6-dimethylphenyll-2-(3-pvridinyl)benzamide Example 246 N-f4-r(5 11-Dihydre-,OH-dibenzfb,e1f1,41diazepin-10-Yl ) carbonyl 1-3, 6-di **tethylr)henyl 1-2- (4-r)vridinyl)benzamide ExamolA 247 N-r4-r(5,11-Dihydr^-10H-dibenzfb,el.f1,41diazepin-l0-yl)carben%,llr)henyl1-2-^henylmethyl)benzamide Examole 248 N-r4-r(5,?1-Dihvdro-10H-d=benzfb,elf1,41diazenin-10-yl )ca _rbonvll phe*iyl 1-2- ( 3-chlorophenylmethyl ) benzamide Examr)lP 249 N-ra-r(5,11-r''ihydro-lOH-dibenzfb,e1f1,41diazepin-10-yl ) carbonvl 1-3-chlcro,oheny'_ 1-2- (phenylmethyl ) benzamide SUBSTiTUTE SHEET (RULE 26) Wfl 96122282 PCTIIIS96/01051 Example 250 N-f4-f(5 11-Dihydro-10H-dibenz(b elfl 41dia pin-10-yl)carbonyll-3-chlorophenyil-2-methoxynyYi_3_ carboxamide ExamTDle 251 N-f4-f(5 11-Dihyciro-10u=dibenzfb elfi 4ldiazepin-i0-yl ) carbonvl l-3-chlorophenyl l-2- (methyl} h io ) py*-i~ inP-3-carboxamide Example 252 N-f4-r(5 11-Dihydrc-l0u-dibenzfb elfl 41diazepin-10-11)c=-rbonvl i -3-methylr)henyl l -2-methylpyririne-3-carboxamide Exam-olP 253 N-r4-r(5 11-D.invdr^-10u-dibPrz(b el(1 41diaz r)ir-10-vl)carbonyll-3-methylnheny11-3-methyiryridine-2-carboxamide E::ample 254 N-r4-f(5 1?-Dihydro-10H-dibenzfb elfl 4ldiaz pin-10-yl)^arbonyll-3-mPthyiT)henyil-2-chloroDyridine-3-carbox.amide ExamnlA 255 N-f4-(5,11-Dihydro-lOH-diber.zfb.elr1,41diaz pin-10-yl)carbonyll-3 6-dimethylphenyil-2-fluoro-cyridin -3-carboxamide ExamnlA 256 N-f4-f(5,11-Dihydro-10H-dibenzfb.Plfl,4ldiaz pin-10-yl)carbony>>-3-mPthyi-ti-chlorochenyil-2-rhloYor)yridine-3-carboxamide ExamDlP 257 N-fS-r(5.11-Dihvdre-l0:-!-dibenzfb,elfl,4ldiazepin-l0-yl)carbonyll-2-nyridinyilrl i'-biDhenyll-2-carboxamide m.p.280 C-285 C
~ Example 258 N-fS-f(5.11-Dihvdro-lOH-dibenzfb.elfl,4ldiaz pin-10-yl ) carbonyl 1- -nyridinyl 1-2- (2-thienyl ) benzamidA

SUBSTITUTE SHEET (RULE 26) Examnle 259 N-f5-r(5 11-Dihydro-10H-dibenzfb,e1f1,41diazepin-10-yl)rarbonyil-2-wridinyll-2-(3-thienyl)benzamide Example 260 N_r5-r(5 11-Dihydro-10H-dibe^zrb,e1f1,41diazepin-10y!)^arbonYil-2-pyridinyll-2-(2-furanyl))benzamide Example 261 N-f5-r(5 i1-Dihydro-10?i-dibenzfb,e1f1,41diazepin-10-yl)carbonyil-2-nvridinyll-2-(2-pyridinyl)benzamide Example 262 N-f5-r(5 11-Dihvdro-lO.T-I-dibPnzib,e)r1,41diazepin-10-vl ) carbonyl 1-2-,ovri dinyl i-2- (3-pyridinyl) benzamide ExamplA 263 ~,T_ r 5_ r (5 , , _~ihvd.-o_, Ou-dibenzf b e l ' 1 4 !diazepin-10-yl)caYbony>>-2-w rldinyll-2-(4-r)yridinyl)benzamide ExampiA 264 N-f5-r(5 !!-n=.hvdre-lOH-dibenzfb,e1f1,41diazepin-10-y1)carbonvil-2-,oyridiny11-2-(2-furanvl)benzamide ExamPle 265 N-f~-r(5 11-Dihvdre-10H-dibenzfb,e,lf1,41diazepin-10-y')carbonyii-2-TDyridinyl?-2-(3-furanvl)benzamide Example 266 r1- ~_ r( S ,1-n; ryd,-n-1 0u-dibenz f b_ e1 f 1, 41 di azepin-I 0-yi ) ca-12on y,' -2-pv*-ic?; nyi 1-2-methoxypyridine-6-carboxamide EXample 267 rT- r=~- r(5 , 1-n; hydr--i Ou-^'=ib-nz rb, el r i, 41 diazepi n-i)-yl)carbonv" -?-Tpvr~dinyilpyr;dinA-3-carboxamide EXample 268 N- r=~- r(5 il-r`;hydr^-, 0u-d;benzr^ ei ri a1d; azepin-10-y' ) carbony' ' - -py*'~ -i -n.yl' - -r)y-i di necarboxamidA
Examnle 269 N- r^- r(5 11-n; hydT-o-' u-diber.z rb, Pl f 1, 4l di azetDin-I 0-xi)carbonyi1- -nvr'di*lyl i-2-methy1-5-fluorohenzamide SUBSTiTUTE SHEET (RULE 26) Example 270 N-f5-f(5,11-Dihvdro-10H-dibenzfb,elfl 4ldiazepin-10-vl)carbonv11-2-oyridinyll-2-chlorob nzamid Example 271 N-f~-f(5,:.1-Dihvdro-lOH-dibenzfb. 1f1,41di azepin-10-yi)carbonyll-2-nyridinyil-2-chloro- -fluorobenzamid Example 272 N-r5-r(5 11-DihYdro-10H-dibenzfb lfi 4ldiazepin-10-vl)carbonyll-2-pyridinyil-2-me+-hylbenzamid Example 273 N-f5-r(5,11-nihvdro-10H-dibenzrb,Plfi 41di azepin-10-vl)carbonyll-2-,oyridinyll-2 5-dim hylbenzamide FYamDlA 274 N-f:5-f(5,11-Dihvdr^-IOH-dibenzfb,eI rl 41 iazepin-10-vl)carbonvll-2-pvridinyll-2-chloro-4-fl orob nzamid Example 275 N-r5-r(5,11-Dihvdro-lOH-dibenzfb,elfl 41diazepin-10-vl)carbonvll-2-r)vridinyll-2-chloro-6-fl orob nzamid Example 276 N-f5-r(5,11-Dihvdro-10H-dibenzfb,_lfl 4'diazepin-10-y1)carbonyll-2-r)yridinyll-2-methyl-3-fiuorobAnzamid Examnle 277 N-f5-r(5 '1-Dihydro-10N-dibenzfb lfl 4ldiazepin-10-yl)carborvil-2-cyridiryl1-2-hydroYyberzamide Example 278 N-r~;-r(5 1?-Dihydr~-l0H-dibPnzfb lrl 41diazepin-10-,,,I)c=rbc)ny>>-2-r)yridinyll-2-acetyloXybenzamide Example 279 N- r;- r(s ,1-ni hydro-!OH-dibanzfk, elr 1 41 diazepin-1^-yl)carbonyl1-2-Dyridinyll-2-a*ninobenzamide Example 280 N- r:;- f( 5 l1-D; hydro-? 0H-d, bAnzf b e l rl 41diazepin-10 yl) rarbonyil-2-nvr; diny> > -2- (mPthyi artino) benzamide Example 281 N-f-c;-f(5,1?-Dihvdro-l0u-dibenzfb,-eI F1,41diazepin-10-yl)^a*-bonyll-2-nyridinyll-2-(aminom thyl)benzamide SUBSTITUTE SHEET (RULE 26) WO 96/22282 PCf/US96/01051 Example 282 N-f5-f(5,11-Dihydro-lOH-dibenzfb,elf1,41diazepin-10-yl)carbonyll-2-r)yridiny11-2-(dimethylamino)benzamide Example 283 5 N-f5-f(5.11-Dihydro-lOH-dibenzfb,elfi,41diazepin-10-y1) carbonyll-2-nyridinyll-2-chloror)yridine-3-carboxamide Example 284 N-f5-f(5,11-Dihydro-lOH-dibenzfb,elf1,41diazepin-l0-yl) carbonyll-2-nvridin vil-2-fluoronvridine-3-carboxamide Examnle 285 N- f 5- f(5, 1 1-Di hydre-1 0H-dibe.n.z fb, el f l, 41 diazenin-10-yl) carbonyli-2--oyridinyll-2-methoxynyridine-3-carboxamide Example 286 N-f~-r(5 11-nihs,dre-l0u-dibenzfb,elf1,41diazepin-10-yl)carbonyll-2-nvridinyll-2-(methylthio)r)yridine-3-carboxamide Exarrple 287 N-f5-r(5,11-Dihydr^-lOH-dibenzfb,elf1,41diazepin-l0-yl) carbonyll-2-,)vridinyll-2-aminobvridine-3-carboxamide Evample 288 N-r5-f(5,11-Dihydre-lOH-dibenz(b,el(l,4ldiazepin-10-yl) carbonyll-2-,,)yridinyll-2-(methylamino)pyridine-3-carboxamide Examnio 289 N- f5- f(5, 11-Di hydre-1C'H-dibenz fb, el r, , 41 ciiazer)i n-10-y1) carbonylI -2-pvrid=nyll-2-(dimethylamino)nyridine-3-carboxamide Examole 290 N-fS-f(5,11-Dihydre-l0E-dibenzfb,e1f1,41diazepin-l0-yl) c-arbony'l-2-nvridinv>>-2-me*ryltnior)henA-3-carboxamide Example 300 N- f5- r(5 11-Di hydr^-lOH-dibenz fb, e'rl, 41 diazepi _^.-10-y1) c-arbonyi l-2-Dvr; d; n;~i , _3_mAfih%,? thionhenP-2-carboxamide SUBSTITUTE SHEET (RULE 26) Example 301 N-r4-r(6,11-Dihydro-5H-dibenzrb.elazepin-5-yl) carbonyil-phenyl[i l'-biphenyll-2-carboxamide A mixture of 6,11-dihydro-5H-dibenz[b,e]
azepine (0.195g), 4-[([1,1'-biphenyl]-2-carbonyl)amino]
benzoyl chloride (0.41g) and 0.155 g of 11,N-diisopropylethylamine in 12 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane.
The extract is washed with H20, saturated NaHCO3, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with dichloromethane. The filtrate is concentrated to-dryness to give 0.66 g of a yellow solid. Chromatography on thick layer silica gel plates with hexane-ethyl acetate (1.5:1) gives crystals (0.165g) (from dichloromethane-ethyl acetate), m.p.

Examnle 302 N-(4-r(6,11-Dihydro-5?I-dibenzrb,elaze-oin-5-yl) carbony>>-3-crl^rophPnyilrl 1'-biphenyll-2-carboxamide A mixture of 0.195 g of 6,11-dihydro-SH-dibenz[b,e]azepine, 0.444 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.155 g of N,N-diisopropylethylamine is stirred at room temperature for 3 hours. The mixture is poured into water and extracted with dichloromethane. The extract is washed with H20, saturated NaHC03,H20, brine and dried (Na2SO4). The solvent is removed and the residue chromatographed on thick layer silica gel plates with solvent hexane-ethyl acetate (1.5:1) to give 0.32 g of crystals, m.p. 120 C-125 C.
As described for Example 302, the following compounds can be prepared by reaction of 6,11-dihydro-5u-dibenz[b,e]azepine with the appropriate substituted or unsubstituted 4-[(arycarbonyl)amino]benzoyl chloride SUBSTITUTE SHEET (RULE 26) or the appropriate substituted or unsubstituted 6-[(arycarbonyl)amino]pyridine-3-carbonyl chloride Examnle 303 N-f4-r(6,11-Dihydro-5H-dibPnzfb,elazepir.-5-yl) 5 carbonyl': iDhenyll -2- (2-*_hienyl ) benzamide Example 304 N-14-r(6,11-Dihydro-SH-dibenzfb,elazepin-5-yl) carbonyll-ohenyll-2-(3-thienyl)benzamide ExamplA 305 N-f4-f(6,11-rihydre-SF-dibenzfb,elazepin-5-yl) carbonyl 1 r)henyl l-3, 6-dic'_:lorophenyll -2- (2-thienyl)benzamide ExamplP 306 N-f4-r(6,11-nihydre-5H-dibenzfb,elazepir.-5-yl) carbonyll-3-chloror)henyli-2-(2-thienyl)benzamide Exarnmle 307 N- rc- r(6, ? 1-ni hydro-5F-?-di benz fb, el azepin-5-yl)carbonyll-3-chlorophenyll-2-(3-thienyl)benzamide Examole 308 N- r 4- f( 6, 11 -Dihydre-5H-di benz f b, el azepin-5-vl l carbonyl,-3-chlorc-6-methylphenyll-2-(2-thienyl)benzamide Example 309 N-(4-f(6,11-Jihydro-5E-dibenzfb,elazenin-5-yl) carbcnyl 1-3-rne*_hyloheny'_ l-2- (2- hienyl ) benzamide Example 310 N-r4-r(6,11-nihydre-5H-dibenzfb,elazepin-5-yl) carbonyll-3,6-dimethylTDhenyll-2-(2-}hienyl)benzamide Examnle 311 N-r4-r(6,11_^ihydre-5u-diber.zfb,e?azenin-5-yl) carbony'_1-3-methylphenyllrl,l'-biphenyll-2-carboxamide Exam-oiP 312 N-f4-f(6,11-Dihydre-5??-dibenzfb,elazepin-5-yl) carbonyll-3,6-dimethylnheny?lfl,l'-bir)henyll-2-carboxamide SUBSTITUTE SHEET (RULE 26) WCf 96122282 PCT/US96/02052 Examole 313 N-ra-r(6 11-Dihydro-5H-dibenzfb elazepir-5-yl) carbonyil-3-methyl-6-chlorQphenyllr' ''-biphenyll-2-carboxamide Ex_amr)le 314 N-f4-f(6,11-Dihydro-5H-dibenzrb,elazepin-5-yi) carbonvl?-3-chloro-r-mAthylr)henylll',i'-bipheny11-2-carboxamide Examr)le 315 N-r4-r(6.11-Dihydro-5H-dibenzfb,elazepin-5-yl) carbonyll-2-methyl,DhPnyll11l'-bipheny>>-2-carboxamide Example 316 N- r4- r (6, 11-Dihyd-=^-5H-dibenz fb, el azepin-5-vl) carbonv'?-2-cr'r~rcpheny'l " ''-biphenyi'-2-carboxamide Examole 317 N-r4-r(6,11-D=hvdro-5H-dibenzfb,elazenir.-5-y1) carbonyllphenyll-2-(2-r)yridinyl)benzamide Example 318 N-f4-f(6,11-Dihydro-5H-dibenzfb,elazepin- -yl) carbonyllphenyll-2-(3-r)yridinyl)benzamide Examole 319 N-f4-f(6,11-Dihydre-5H-dibenzfb,elazepin-5-yl) carbonyllphenyll-2-(4-gvridinyl)benzamide ExamnlA 320 N-r4-f(6,11-Dihyd--e-5u-dibenzfb,elazepin-:,-yl) carbonyll-3-chlcrophenyll-2-(2-oyridinyl)bAnzamide Example 321 N-r4-f(6,11-Dihydr^-5H-dibenzrb,elazenin-5-yl) carbonyil-3-ch'cro,ohenyll-2-(?-T)yridinyl)benzamide Example 322 N-f4-f(6,11-Dihydro-5:?-dibenzfb,elazepir.-5-y11 carbonyll-3-methylphenyll-2-(2-T)vridinvl)benzamide FVamnle 323 N-r4-r(6,11-Dihydro-5H-dibenzfb,elazer)in-5-yl) carbonyll-3-me}hylrhenyll-2-(3-ayridinyl)benzamide SUBSTiTUTE SHEET (RULE 26) Exam-olA 324 N-f4-f(6,11-Dihydro-5H-dibenzfb,elazepin-5-yl) c-arbony11 -3 6-dime*rYlnheny11 - 2 - (2-r)yri dinyl) benzamide Examole 325 `
N-f4-f(6,11-Dihydro-5H-dibenzfb,elazepin-5-yl) {
carbonvi '-3 , 6-dimethylr)henyl l-2- (3-nyridinyl) benzamide ExamplA 326 N- rc- r(6, 71-Dihydro-5H-diber.z fb, el azepir.-5-y1) carbonyil-3 6-d;mPthylphenyl1-2-(4-p,vridinyl)benzamide Example 327 N-f4-r(6,11-Dihydr^-5u-dibenzfb,elazet)in-5-yl) carbonYll-3-chloronhenvll-f3t-methylthio-1,1'-bi-ohenyll-2-carboxamide ExamplP 328 N-r4-f(6,11-nihydro-5H-dibenzfb,elazepin-5-yl) carbonyll-3-chlorophenyll-f?'-methoxy-l,l'-biphenyll-2-carboxamide Exam-cle 329 N-r4-r(6,11-Dihydro-5H-dibenzfb,elazeT)in-5-yl) carbon vllpheny11f4'-dimethylamino-l,1'-biphenyll-2-carbovamide Et_ample 330 N-f4-r(6,11-Dihydr,~-,-5H-dibenzfb,elazepin-5-yl) carbonyõ -3-mPthvlnhenyõ - r"-chloro-1 , 1' -bi phenyll -2-carboxamide Example 331 N-(4-r(6,11-Dihydro-5u-dibenzfb,elazenin-5-yl) c-arborvl1-'~-chloroTDhenyll-2-(3-furanyl)benzamide Example 332 N-r4-r(6,11-Dihydr^- -dibenzfb,elazepin-~-;-yl) carbonvllr)hAnY?l-2-(2-fsranyl)benzamide Exam-ole 333 N-r4-r(6,11-nihydr^_5H-c'ibA^zfb,Plazepin-5-yl) carbonyllphPnvil-r''-crloro-' !'-biphenyil-2-carboxamide SUBSTITUTE SHEET (RULE 26) WQ 96122282 PGTlUS96101051 Example 334 N-r4-r(6,11-Dihydro-5u-dibenzrb,elazepin-5 yl) carbonyll-3-chloroiDheny11r3'-chloro-l,l'-biphenyll-2-carboxamide Example 335 N- r4- r(6, 11-Dihydro-5?-i-dibenz rb, el azepin-5_yl) carbonyl'.-3-methylbhenyllf3'-chloro-1,1'-biphenyll-2-carboxamide Example 336 N-r5-f(6,11-nihydro-5u-dibenzrb.elazepin-5-yl) carbonyll-2-nyridinyllr3'-chloro-1,?'-biphenyll-2-carboxamide Example 337 N- r4- r( 6 " 1-ni hydro-5?'-dibe.n.z (b, e1 azepiT-S-yl ) carbonyll-3-chlcrophenyllr4'-fluoro-1,1'-biphenyll-2-carboxamide ExamplA 338 N- r5- r(6, 11-Dihydre-51~i-dibenz rb, e1 aze-oin-5-yl) carbonyll-2-nyridinyll-2-chlororDyridine-3-carboxamide 1 Examnle 339 1\T-r5-r(6,11-Dihydro-5u-dibenzrb,elazepin-5-yii-carbonyll-2-oyridinyll-2-fluoropyridine-3-carboxamide Examole 340 N-fS-r(6,11-Dihydre-5u-dibenzrb,elazepin-5-yl) carbonyl l-2-pyridi .^.y, ,-2-ami:^.or)vri di ne-3-carboxamide Examole 341 N-r5-r16,i1-D=.hydro-SH-dibenzrb,elazepin-5-yl) carbonyll-2--ovridinv'_1-2-(methylamino)nyri(Jine-3-carboxamide Example 342 N-r5-r(6,11-Dihydro-SH-dibenzfb,elazepir.-5-y1) carbonyl l-2-r)yri di nyl l-2- (di me`_rylamino) r)yridi ne-3-carboxamide Examole 343 N-r5-r(6,11-Dihydr,,:~-5H-dibenzfb,elazerin-5-yl) carbonyll-2-nvridinyl1-3-methylthiophene-2-carboxamide SUBSTITUTE SHEET (RULE 26) Example 344 N-fS-f(6,11-Dihydro-SH-dibenz(b,elazepin- -yl) carbonyll-2-nvYi^inyil-2-methyli-hiophere-3-carboxamide xample 345 N-f5-r(6 i1-Dirydro-5u-dibAnzfb elazepin-5-yl) carbonyll-2-nyridiny11-2-chlorobenzamide ExamnlP 346 N-f5-f(6,11-Dihvdro-5?I-dibenzfb elaz pin-5-yl) carbonyll-2-ovridinyil-2-cnloro-5-flu robenzamide Examnle 347 N-f5-f(6,11-Dihvdro-5u-dibenzfb,elazer)in-5-yl) carbonyll-2-nvridiny>>-2-cnloro-E-fluorob nzamide Examr-lA 348 N- 5-'(6,11-nihvdro-5H-dibenz~b elaz pin-5-yl) carbonyil-2-nvYid;nyil-2-mPthyl-'~-fluorobAnzamide EXamnle 349 N- f 5- f(6, 11-Di hydro-5H-dibenz (b, e l az pi n- -yl ) carbonyil-2-nvridinyil-2-(me*hylamino)benzamide Examole 350 N- f 5- f(6. 11-Di hyciro-5H-dibenz fb, el azer)i r.- -yl) carbonyll-2-nyridinyll-2-hydroxybenzamide Example 351 N-f5-f(6,11-Dihydro-5H-dibenzfb,elazepin-5-yll carbony11-2-nyridinyll-2-(aminomPthy?)benzamide Example 352 N-f5-r(6,11-Dihydr^-SH-nyridof2.3-b1f1,41benzodiazepin-5-vl)carbonyll-2-D~7ridinyll-5-fluoro-2-methylbenzamide As described for Example 1, 6,11-dihydro-5-~-i-pyrido[2,3-t][1,4]benzodiazepine (2 mmol) is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride (2.1 mmol) in the presence of triethylamine (4 mmol) in dichloromethane to give the product as a solid, m.p. 102 C-104 C.

SUBSTiTUTE SHEET (RULE 26) vVO 96/22282 PGTIUS961O1051 Example 353 N f4 f(6 11-DihydYo-FU-pyridor2 3-blfl 41benzod;azepin-5-v1) ca*-bonyl l-3-chloror)henyll r i, 1'-biiphenvl l-2-Jr carboxamide As described for Example 134, 6,11-dihydro-5-I-pyrido[2,3-b][1,4]benzodiazepine (0.197 g) is reacted with 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride (0.444 g) in the presence of H,V-diisopropylethylamine (0.155 g) in 12 ml of dichloromethane to give the product as a solid.

As described for Example 352, the following compounds can be prepared by reaction of 6,11-dihydro-5K-pyrido[2,3-h][1,4]benzodiazepine with the appropriate substituted or unsubstituted 4-[(arylcarbonyl)amino]
benzoyl chloride or the appropriate substituted or unsubstituted 6-[(arylcarbonyl)amino]pyridine-3-carbonyl chloride Examole 354 N-fd-((6 i1-Dihydro-5u-r)vridof2 3-b1r1,41benzodiazepin-S-,yl)carbonyl'iDhPn~,llfl i'-binhenyll-2-carbovamide Exam-ole 355 N f4 f(6 ii Dihydro-su-DVridof2 3-blfl 4lbenzodiazepin-5-vl)caYbonyll'ohAny11-2-(2-thienvl)benzamide xamplP 356 N-fa-r(6 ,!-DihvdYc-su-r)vridof2 3-b1f1,41benzodiazepin-S-yl)c=rbonyli-3-*nP}hylr)heny11r1 1'-binhenvll-2-carboxamide Examole 357 N- r4- r(6 õ-D1 hvdro-5~--ov-4do r2 3-bl f 1, 41 benzodiazepin-5-yl)carbonyll-'~-mefiryl-E-crloror>henyllrl,l'-binhenvll-2-^arboxamide ExamplP 358 NT f4 r(6 i' nihvdre-5H-nvrldof2 3-blf' 4lbenzodiazeAin-S yl ) carbonyl'-3 F-C71.*nPthylphanyl l rl l'-bipnenvl l-2-c-arboxamide SUBSTiTUTF SHEET (RULE 26) WO 96/22282 PCf/US96/01051 Example 359 N-f4-f(6,11-Dihvdre-5H-nyridof2 3-blfl 4lbenzodiazPpin-5-vl)carbonvli-3-methylbhenyll-2-(2-thienyl)b nz midP
Example 360 N-f4-f(6,11-Dihvdr^-5H-pyridof2 3-blf1 41benzodiaz pin-5-vl)carbonvll-3-chlorophAnyll-2-(2-thienyl)bAnzam;da xample 361 N-f4-f(6,11-nihvdre-5H-r)yridof2 3-blfl 41benzodia Ppin-5-vl) carbonyl lr)henyl l-2- (2-py,-idinyl) b nzamid Example 362 N-r4-f(6,11-Dihvdro-5H-,oyridof2 3-blfl 41 nzodiazepin-5-vl)carbonv'_lnhenyl1-2-(3-nvridinyl)benzamide Examnle 363 N-r4-f(6,11-Dihydr^-5u-nyr;dn[ 2.3 -bI rl alb nzodi az pin-S-vl)carbonyll-3-chloroL-henyll-2 (2 nvridinyl)' nzamid Example 364 N-f4-r(6,11-Dihydr^-5u-r)yridof2 3-blfl 41 nzodiazepin-5-vl)carbonyll-3-c!^loropheny11-2-(3-r)yridinyl)benzamide Example 365 N-f4-f16,11-Dihydro-5H-r)yridof2 3-blfl 4lbenzodiazepin-5-vl)carbonyil-3-methylr>henyll-2-(2-TDyridinyl)benzamide Example 366 N-f4-f(6 11-Dihydro-5u-r)Yridor2 3-blfl 41benzodiazepin-5-yl ) carbonyl 1 -3 , 6-dimA+-hylphenyl l-2- ( 3-pyr; diny_1) benzamide Examnle 367 N-f4-f(6,11-Dihydro-~--H-nyridof2 3-bifl 41benzodiazepin-5-yl ) carbonyl 1 nhenyl l-2- ( a-oy,-idinyl) benza*nide Examnle 368 N-f4-r(6,1?-Dihvdre-5H-Dvridof2 3-b1f1 4lbenzodiaz pin-5-yl)carbonyl'nhenyl'-2-chloror)yridine-3-carboxamide ExamnlA 369 N-r4-f(6 11-Dihydr^-5u-nyridor2 3-blri 41benzo iazepin- 5-yl)carbonyllpheny>>-2-fiuoronyridinP-3-carboxamide SUBSTITUTE SHEET (RULE 26) WO 96122282 PC'TIUS96JO1DS1 Example 370 N-f4-r(6,11-Dihydro-5u-nyridof2,3-b1f1,41benzodiazepin-5-yi)carbonyll-3-chlorophenyll-2-chloror)yridine-3-carboxamide Example 371 N-f4-r(6,1?-Dihydro-5u-,oyridof2,3-blf1,41ben odiazenin-5-vl)carboryllnhenyl1-2-methoxy,oyridine-3-carboxamide Example 372 N-r4-f(6 11-DihvdYc-Su-t)yridor2 3-blfl 4lbenzodiazepin-5-yl ) carbor.yl l-3-methy' nhenyl 1-2- (methylthio) nyridine-3-carboxamide Example 373 N- ra - r(r, 77-D; hyd,-c_^u-tDyrido r2, 3-b1 f 1, 4lbenzodiazepin-_y'_)^arbonyll-3-methylp'.:enyll-2-chloronyridine-3-carboxamide Example 374 N-f4-f(6,11-Dihydro-5H-pyridof2,3-b1f1,4lbenzodiazepin-5-yl)carbonyll,ohenyll-2-aminopyridine-3-carboxamide Examnle 375 N-f5-f(6,1?-Dihydro-5r-i-nyridof2,3-blfl,4lbenzodiazepin-S-yl ) carbonvl l-2-pyridinyl 1 f 1, 1'-bir)henyl l-2-carboxamide Examole 376 N-f5-r(6,11-Dihydr^-5H-nyridof2,3-blfl,4lbenzodiazenin-5-vl)carbonvll-2-r)yridinyll-2-(2-thienyl)ber.zamide Example 377 N-r5-r(6,11-Dihydro-5u-nyrldof2,3-b1f1,41benzodiazer) in-5-yl) carbonyl l-2-r)yridi nyll -2- (3-thienyl) benzamide Example 378 N-fS-r(6,11-Dihydro-5H-r)yridof2,3-blfl,41benz-odiazepin-5-y1)carbonyll-2-r)vridiny,l-2-(2-oyridinyl)benzamide E::ample 379 N-r5 -r(F,?1-Dihydro-5u-r)yridof2,3-b1f1,41benzodiazepin-5-vl)carbonyll-2-r)yridinyll-2-(3-,oyridinyl)benzamide Fxamn1P 380 N-f5-r(6,11-Dihydro-5u-nyridof2,3-b1r1,4lbenzodiazezD in-5-yl ) carbonyl l-2-nyri dinyi t-2- (4-ryri di nyl ) benzamide SUBSTITUTE SHEET (RULE 26) Example 381 N-r5-r(6,1?-Dihydro-5H-pvridor2,3-b1f1,41benzodiazepin-5-yl)carbonyll-2-nvridinyll-2-(2-furanyl)benzamide Example 382 N-r5-r(6,1i-Dihydro-5H-Pvridor2,3-b1f1,41benzodiazepin-5-yl)carbonyll-2-r)yridinyll-2-(3-furanvl)benzamide Example 383 N-r5-r(6,11-Dihydro-5H-T)vridof2,3-blfl,4lbenzodiazepin-';-yilcarboryil-2-nvridinyll-2-chlorobenzamide Example 384 N-f5-r(6,'1-DihYdre-5H-r)vridof2,3-blf1,41benzodiazepin-5-yllcarbonyli-2-nvrid;nyll-2-chloro-5-fluorobenzamide Examnle 385 N-f5-r(6 11-Dihyd-^-5H-t)vridor2,3-b1r1,41benzodiazepin-S-yl)carbony'l-2-nvridinyll-2 S-dimPthylbAnzamide Exa*noi e 386 N-f5-r(6 i1-Dihydr~-5H-nvridof2,3-blrl,4lbenzodiazepin-5-yl)carbonyll-2-nvridiny11-2-chloro-6-fluorobenzamide Examnle 387 N-r5-r(6 1i-Dihydre-5u-r)vridor2 3-b1f1 4lbenzodiazegin-5-yl)^=rbony>>-2-nvridinyll-2-mPthyl-3-fluorobenzamide Examole 388 N-r5-r(6 11-nihydr^-SN-p,vridor2 3-bI rl 41benzodiazepin-S-yl)carbonyii-2-nvridinyll-2-hydroxybenzamide Examnle 389 N-f5-1(6 'i-Dihydre-5H-r)vridof2,3-b1r1,41benzodiazenin-5-v1)carbonyll-2-nvridinyll-2-aminobPnzamide Examnle 390 N-r5-r(6 11-DihYdre-5u-,ovridof2,3-b1r1,41benzodiazeiDin-S-vl)carbonYil-2-nvr=dinyll-2-(methvlamino)benzamide Examnle 391 N- r5- r( 6 , 1_D; hyd'"n-5H--ay'-'ido r 2 3-bl f l, 41 benzodiazepin-5-yl)^arboryil-2-,ovridinvll-2-(dimethylamino)benzamide - 150 -SUBSTITUTE SHEET (RULE 26) Example 392 N-rS-r(6,11-Dihydro-5H-nyridof2,3-b1f1,4lbenzodiazepin-5-vl)carbonyll-2-pyridiny11-2-chloropvridine-3-carboxamide Example 393 N-f5-r(6,11-Dihvdro-5H-nyridof2,3-b1r1,41benzodiazepin-5-yl)carbonyll-2-nyridinyll-2-(dimethylamino)pyridine-3-carboxamide Example 394 N-f5-((6,11-Dihydro-SH-pyridor2,3-blr',4lbenzodiazenin-5-yl)carbonyll-2-oyridinyll-2-methylthionhnA-3-carboxamide F':amiDlA 395 N_ r 5_ (( 6, ,,_D; hyd,- 5- u_r) ti,rido f 2, 3 - b 1 ' 1, 41 benzodiazepin-5-vl)carbonyll-2-nyridinyil-3-methylthioDhene-2-carbo-amide ExamblP 396 N-r4-r(4,5-Dihydronyrazolor4,3-dlrllbenzazepin-6(1H)-yl)carbonyllphenyllrl,l'-binhenyll-2-carboxamide A mixture of 0.278 g of 4,5-dihydropyrazolo[4,3-d][1]benzazepine, 1.11 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride and 0.426 g of N,N-diisopropylethylamine in 12 ml of dichloromethane-tetrahydrofuran (1:1) is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N Na2CO3, H20, brine and dried (Na2SO4).
The solvent is removed under vacuum to give 1.45 g of solid. To the proceding solid in 25 ml methanol-tetrahydrofuran (1:1) is added 2.78 ml of 2N NaOH and the solution stirred at room temperature for 3.5 hours.
The solvent is removed under vacuum, water added to the residue and the mixture extracted with dichloromethane.
The extract is washed with H20, 0.5 N citric acid; H20, = 35 brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesuim silicate and the SUBSTITUTE SHEET (RULE 26) filtrate concentrated to dryness. The residue (0.95 g) is triturated with ether-dichloromethane to give 0.17 g of crystals, m.p. 255oC-260oC; Anal. found for C31H24N402-1/2H20: C, 75.9; H, 5.1; N, 10.8.
Examnle 397 N-f4-r(q 5-D;hydr^nyrazolor4 ?-dlrilbenzaz pin-6(IH)-yl)carbonyll-3-crloro-ohenvllfl 1'-biphenyll-2-carboxamide A mixture of 0.18S g of 4,5-dihydropyrazolo[4,3-d][1]benzazepine, 0.814 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]-2-chlorobenzoyl chloride and 0.284 g of N,N-diisopropylethylamine in 9 ml of dichloromethane-tetrahydrofuran (1:1) is stirred at room temperature overnight. The mixture is poured into water and extracted with dichloromethane. The extract is washed with 2N NaOH, H20, brine and dried (Na2SO4). The solvent is removed under vacuum to give 0.99 g of a solid. To the preceding solid in 15 ml of methanol-tetrahydrofuran (1:1) is added 1.75 ml of 2N1 NaOH and the solution stirred at room temperature for 2 hours. The volatiles are removed under vacuum and the mixture extracted with chloroform. The extract is washed with 1N citric acid, H20, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness. The residue (0.76 g) is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:2) as solvent to give 0.37 g of white solid, m.p. 172-2020C, Anal. found for 1/2 hydrate:
C, 70.1; H, 5.0; 9.8; Cl, 6.4.
Example 398 N- f 5- f( 4. 5-ni?-:': dr^oyrazolo r g, 3-;:1 r 11 benzazepi n-6 (1H) -yl l c=rbonvi l-2---vr; iiny1 1 r i.1'-hiphenyl l-2-carboxamide As described for Example 396, (0.1 mmol) of 4,5-dihydropyrazolo[4,3-d][1]benzazepine is reacted with =
(0.21 rr.mol) of 6- [ ( [1, 1'-biphenyl]-2-carbonyl) amino]

SUBSTITUTE SHEET (RULE 26) WO 96/22282 PGTl17S96/01051 pyridine-3-carbonyl chloride to give the product as a light tan solid. Recrystallized from ethyl acetate/hexane, m.p. 2280C-2340C as white crystals.
Example 399 N-f5-f(4,5-Dihydror)vrazolof4.3-dlfllbenzazepin-6(1H)-yl)carbonyl}-2-r)yridinyll-S-fluoro-2-methylbenzamide As described for Example 396, 0.10 mmol of 4,5-dehydropyrazolo[4,3-d][1]benzazepine is reacted with 0.21 mmol) of 6-[(5-fluoro-2-methylbenzoyl)amino]-2-pyridine-3-carbonyl chloride to give the product as a tan solid, (0.15 g) m.p. 126oC-176oC: Mass Spec (FAB)-found 442 (M++H) .
E'xample 400 N_ r5_ (du-Th; enp f 3, a-b' r l, 51 benzodiazer)in-9 (10H) -y1-2-pyridinyll-5-fluoro-2-methylbenzamide As described by J.B. Press et al in 1. Med.
Chem., 22. 725 (1979), 9,10-dihydro-4H-thieno[3,4-h][1,5]benzodiazepin-10(9H)-one is prepared. This intermediate (4.8 g) is dissolved in tetrahydrofuran under nitrogen and 4.2 g of lithium aluminum hydride (LAH) is added portionwise with stirring. The mixture is refluxed for 18 hours and quenched by the dropwise addition of water. The mixture is extracted with chloroform and the extract is filtered through diatomaceous earth. The organic layer is washed with water (200 ml), dried (Na2SO4) and the solvent removed.
The residual oil is chromatographed on thick layer silica gel plates with chloroform as eluent to give 1.2 g of 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine as a solid. The proceeding compound (0.5 g) is reacted with 1.06 g of 6-[(5-fluoro-2-methylbenzoyl)aminoJ
pyridine-3-carbonyl chloride, hydrochloride in dichloromethane which contains 7 ml of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 16 hours and then is washed with water, 1N HC1, saturated sodium bicarbonate solution, water and SUBSTITUTE SHEET (RULE 26) dried (Na2SO4). The solvent is removed and the residue purified by chromatography on silica gel with ethyl acetate-hexane (1:3) to give 1.1 g of a solid, m.p.
89 C-92 C.
Euample 401 N- r 4- ( 4u-T},; eno r 3, 4-bl f 1. 51 benzodi azepin-9 (10H) -yD -phenyl1 fl,l'-bi pheny11-2-carboxami de As described for Example 400, 9,10-dihydro-4H-thieno[3,4-,t][1,5]benzodiazepine is reacted with 4-(([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride to give the product as a solid.
Example 402 N-r4-(4u-Thienof3,4-b1 fl,5lbenzodiazepin-9(10H)-vl)-3-ch1 nrophenyl 1 r i, !'-bi phenyl l-2-carboxami de As described for Example 400, 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with 4-[([1,1'-biphenyl;-2-carbonyl)amino]-2-chlorobenzoyl chloride to give the product as a solid.
Example 403 r?- f 5- (4??-Thieno f 3, 4-bl f 1. 5l benzodiazepin-9 (1 0H) -yl) --p-~-; d; ny1 l r 1,,'-blphPnyl 1-2-ca_rboXami de As described for Example 400, 9,10-dihydro-4H-thieno[3,4-b][1,5]benzodiazepine is reacted with 6-[([1,1'-biphenyl]-2-carbonyl)amino]-pyridine-3-carbonyl chloride to give the product as a solid.
Example 404 5. 1i-Dih%:dr^-10- r4- (2-*_hi enyl) benzoyl 1-lOH-c?ib-1:z ~b,e 1 11,41d;azepine A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for 45 minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0 C) solution of 2.0 g of 5,1i-dihydro-10T.I-.-dibenz(b,e][i,4]diazepine and 7 ml =
of II,N-diisopropylethylamine in 30 ml of dichloromethane SUBSTITUTE SHEET (RULE 26) is added dropwise a solution of 3.15 g of 4-(2-thienyl)benzoyl chloride in 30 ml of dichloromethane.
The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HC1, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate (2:1) as eluent to give 1.8 g of solid, m.p.
1140C-1160C.
Examnle 405 5.il-Dihvdro-lr_r4-(3-thienyl)benzoyll-10u-d'_benzrb.e1 [ 1,41d, azenine To a mixture of 2.0 g cf 5,11-dihydro-l0H-dibenz[b,e][1,4]diazepine and 7 ml of N,N
diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(3-thienyl)benzoyl chloride in 30 ml of dichloromethane.
The mixture is stirred 16 hours at room temperature and diluted with dichloromethane (50 ml). The solution is washed with 30 ml each cf H20, 2N HC1, saturated NaHCO3, water and dried (Na2SO4). The solvent is removed under vacuum and the residue purified by chromatography on silica gel with hexane-ethyl acetate as eluent to give a solid.
R; ndinc Assay fi^ Rat Uepat; c VI RAr'Antors Rat liver plasma membranes expressing the vasopressin Vi receptcr subtvpes are isolated by sucrose densitv gradient according to the method described by Iesko et al., (1973). These membranes are quickly suspended in 50.0 mM '~'ris.HCl buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA) and 0. 1 mM
phenylmethylsulfonylflucride (PMSF) and kept frozen at -70 C until used in subseauent binding experiments. For binding experiments, the following is added to the wells of a ninety-six well format micrctiter plate: 100 ml of SUBSTITUTE SHEET (RULE 26) 100.0 mM Tris.HCl buffer containing 10.0 mM MgC12, 0.2%
heat inactivated BSA and a mixture of protease inhibitors: leupeptin, 1.0 mg%; aprotinin, 1.0 mg %;
1,10-phenanthroline, 2.0 mg %; trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF, 20.0 ml of [phenylalanyl-3,4,5,-3H] vasopressin (S.A. 45.1 Ci/mmole) 0.8 mM, and the reaction initiated by the addition of 80 ml of tissue membranes containing 20 mg of tissue protein. The plates are kept undisturbed on the bench top at room temperature for 120 min. to reach equilibrium. Non-specific samples are assayed in the presence of 0.1 mM
of the unlabeled antagonist phenylalanylvasopressin, added in 20.0 ml vOlume.
Fcr test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml. Upon completion of binding, the content of each well is filtered off, using a Brandel cell Harvester (Gaithersburg, MD). The raciioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquid scintillation counting in a Packard LS Counter, with an efficiency of 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON
SOFTWARE, OH) and displayed in Table I.
R'ndin^ Assay to Rat Kidney MPd"ilarv %7- RecPDtor's Medullary tissues from rat kidneys are dissected out, cut into small pieces and soaked in a 0.154 mM sodium chloride solution containing 1.0 mM EDTA
with many changes of the liquid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M sucrose solution containing 1.0 mM EDTA with many changes of the liauid phase, until the solution is clear of blood. The tissue is homogenized in a 0.25 M
sucrose solution containing 1.0 mM EDTA and 0.1 mM PMSF
using a Potter-Elvehjem homogenizer with a teflon =
pestle. The homoaenate is filtered through several SUBSTITUTE SHEET (RULE 26) WO 96122282 PGT/DS96IO] 051 layers (4 layers) of cheese cloth. The filtrate is rehomogenized using a dounce homogenizer, with a tight fitting pestle. The final homogenate is centrifuged at 1500 X g for 15 min. The nuclear pellet is discarded and the supernatant fluid recentrifuged at 40,000 x g for 30 min. The resulting pellet formed contains a dark inner part with the exterior, slightly pink. The pink outer part is suspended in a small amount of 50.0 mM
Tris.HC1 buffer, pH 7.4. The protein content is determined by the Lowry's method (Lowry et al., 1. Biol.
Chem., 1953). The membrane suspension is stored at -70 C, in 50.0 mt=STris. HCl, containing 0.2% inactivated BSA and 0.1 mM PMSF in aliquots of 1.0 ml containing 10.0 mg protein per ml o` suspension until sue in subsequent binding experiments.
For binding experiments, the following is added in ml volume to wells of a 96 well format of a microtiter plate: 100.0 ml of 100.0 mM Tris.HC1 buffer containing 0.2 % heat inactivated BSA, 10.0 mM MgCL2 and a mixture of protease inhibitors: leupeptin, 1.0 mg %;
aprotinin, 1.0 mg % 1,10-phenanthroline, 2.0 mg %;
trypsin inhibitor, and 0.1 mM PMSF, 20.0 ml of [3H]
Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM
and the reaction initiated by the addition of 80.0 ml of tissue membranes (200.0 mg tissue protein). The plates are left undisturbed on the bench top for 120 minutes to reach equilibrium. Non-specific binding is assessed in the presence of 1.0 mM of unlabeled ligand, added in 20 ml volume. For test compounds, these are solubilized in 50% dimethylsulf'o::icie (DMSO) and added in 20.0 ml volume to a fina'_ incubation volume of 200 ml. Upon completion of binding, the content of each we11 is filtered off, using a BrandelrJ cell Harvester (Gaithersburg, MD). The radioactivity trapped on the filter disk by the ligand-receptor complex is assessed by liquici scintillation counting in a Parkard LS Counter, with an efficiency of SUBSTITUTE SHEET (RULE 26) 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON
SOFTWARE, OH) and displayed in Table I.

Rad=oligand Bindinc Exper;ments wi h Humar. latPiPt-Membranes (a) p at 1 t Memhr?nP Pr parar i pn -Frozen platelet rich plasma (PRP), received from the Hudson Valley Blood Services, are thawed to room temperature. (Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY).
The tubes containing the PF.P are centrifuged at 16,000 x g for 10 minutes at 4 C and the supernatant fluid discarded. The platelets resuspended in an equal volume of 50.0 1*4 I'ris. HCL, pH 7.5 containing 120 mM
NaCl and 20.0 mM EDTA. The suspension is recentrifuged at 16,000 x g for 10 minutes. This washing step is repeated one more time. The wash discarded and the lysed pellets homogenized in low ionic strength buffer of Tris. HC1, 5.0 m, pH 7.5 containing 5.0 mM EDTA. The homogenate is centrifuged at 39,000 x g for 10 minutes.
The resulting pellet is resuspended in Tris.HC1 buffer, 70.0 mM, pH 7.5 and recentrifuged at 39,000 x g for 10 minutes. The final pellet is resuspended in 50.0 mM
Tris.HCl buffer pH 7.4 containing 120 mM NaCl and 5.0 mM
KC1 to give 1.0-2.0 mg protein per ml of suspension.
(b) Binding _o Vas^pressin Vi rece-otor subtype in Human Pl -tPiAt Memhr _n --In wells of a 96 well format microtiter plate, add 100 ml of 50.0 mM Tris. HC1 buffer containing 0.2%
BSA and a mixture of protease inhibitors (aprotinin, leupeptin etc.) 'I'hen add 20 ml of [3H)Ligand (Manning or Arg8Vasopressin), to give final concentrations ranging from 0.01 to 10.0 nM. Initiate the binding by adding 80.0 ml of platelet suspension (approx. 100 mg =
protein). Mix all reagents by pipetting the mixture up SUBSTiTUTE SHEET (RULE 26) and down a few times. Non specific binding is measured in the presence of 1.0 mM of unlabeled ligand (Manning or Arg8vasopressin). Let the mixture stand undisturbed at room temperature for ninety (90) minutes. Upon this time, rapidly filter off the incubate under vacuum suction over GF/B filters, using a Brandel Harvester.
The radioactivity caught on the filter disks is determined by the addition of liquid scintillant and counting in a liquid scintillator.

SUBSTITUTE SHEET (RULE 26) Bindincr to Membranes of Mouse Fibroblast Cell Line (LV-2) Transfected with the cDNA Exnressina the Human V2_ VasopresSin Receptor (a) Membrane Preparation 5 Flasks of 175 ml capacity, continuing attached cells grown to confluence, are cleared of culture medium by aspiration. The flasks containing the attached cells are rinsed with 2 x 5 m1 of phosphate buffered saline (PBS) and the liauid aspirated off each time. Finally, 5 ml of an enzyme free dissociation Hank's based solution (Specialty Media, Inc., Lafayette, NJ is added and the flasks are left undisturbed for 2 minutes. The content of all :lasks is poured into a centrifuge tube and the cells pelleted at 300 x g for 15 minutes. The Hank's based solution is aspirated off and the cells homogenized with a polytron at setting #6 for 10 sec in 10.0 mM Tris.HCl buffer, pH 7.4 containing 0.25 M
sucrose and 1.0 mM EDTA. The homogenate is centrifuged at 1500 x g for 10 minutes to remove ahost membranes.
The supernatant fluid is centrifuged at 100,000 x g for 60 minutes to pellet the receptor protein. Upon completion, the pellet is resuspended in a small volume of 50.0 mM Tris.HC1 buffer, pH 7.4. The protein content is determined by the Lowry method and the receptor membranes are suspended in 50.0 mM Tris.HC1 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.
(b) ReceT)Y-or Bindi na For binding experiments, the following is added in ml volume to wells of a 96 well format of a microtiter plate: 100.0 ml oF 100.0 mM Tris.HC1 buffer containing 0.2% heat inactivated BSA, 10.0 mM MaC12 and a mixture of protease inhibitors: leupeptin, 1.0 mg%;
aprotinin, 1.0 mg%; 1,10-phenanthroline, 2.0 mg %;
trypsin inhibitor, 10.0 mg % and 0.1 mM PMSF., 20.0 ml SUBSTITUTE SHEET (RULE 26) WO 96122282 PC'T/i1S96101051 of [3H] Arginine8, vasopressin (S.A. 75.0 Ci/mmole) at 0.8 nM and the reaction initiated by the addition of 80.0 ml of tissue membranes (200.0 mg tissue protein).
The plates are left undisturbed on the. bench top for 120 minutes to reach equilibrium. Non specific binding is = assessed iz the presence of 1.0 mM of unlabeled ligand, added in 20 ml voiume. For test compounds, these are solubilized in 50% dimethylsulfoxide (DMSO) and added in 20.0 ml volume to a final incubation volume of 200 ml.
Upon completion cf biding, the content of each well is filtered off, using a Brandel cell Harvester (Gaithersburg, MD).The radioactivity trapped on the filter disk by the ligand-receptcr complex is assessed by iiquid scintillation countina in a Packard LS
Counter, with an efficiency of 65% for tritium. The data are analyzed for IC50 values by the LUNDON-2 program for competition (LUNDON SOFTWARE, OH) and the data is displayed in Table I.
Vasopressin V- An aaonist Activity in Conscious Hydrated Rats:
Conscious hydrated rats are treated with compounds under study from 0.1 to 100 mg/kg orally or vehicle. Two to four rats are used for each compound.
One hour l-ater, arginine vasopressin (AVP, antidiuretic hormone, ADH) dissolved in peanut oil is administered at 0.4 mg/kg intraperitoneally. Two rats in each test would not receive arginine vasopressin but only the vehicle (peanut oil) to serve as water-loading control.
Twenty minutes later each rat is given 30 mL/kg of deionized water orally by gavage and is placed individually in a metabolic caae equipped with a funnel and a graduated glass cylinder to collect urine fdr four hours. Urine volume is measure and osmolality analyzed by use of a Fiske One-Ten osmometer (Fiske Assoc.., Norwood, MA, USA). Urinary sodium, potassium, and chloride are analyzed by use ef ion-specific electrodes SUBSTITUTE SHEET (RULE 26) in a Beckman E3 (Electrolye 3) Analyzer. In the following results, decreased urine volume and decreased osmolality relative to AVP-control indicates activity.
Vasopressi_*? V1 A_ntacronist Activity in .on io us Rats: 5 Conscious rats are restrained in a supine position with elastic tape. The area at the base of the tail is locally anesthetized by subcutaneous infiltration with 2% procaine (0.2 ml). Using aseptic technique to the ventral caudal tail artery is isolated and a cannula made of PE 10 and 20 (heat-fused) tubing is passed into the lower abdominal aorta. The cannula is secured, heparinized (1000 iu/cc), sealed and the wound closed with one or two stitches of Dexon 4-0. The caudal vein is also cannulated in the same manner for intravenous drug aciministration. The duration of the surgery is approximately 5 minutes. Additional local anesthesia (2% 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 (1.U.) (350 I.U.= 1 mg) injections are recorded prior r-o any drug (compound) administration, after which each rat is dosed orally with compounds under study 0.1-100 mg/kg (10 cc/kg) or intravenously 0.1-30 mg/kg (1 cc/kg). The vasopressin injections are repeated 30,60,90,120,180,240 and 300 minutes later. Percentage of antagonism by the compound is calculated using the pre-drug vascpressin vasopressor response as 100%.
Qxytoc' RP!'PDt^r Ri nyli nC
(a) Membrane pr parati on Female Sprague-Dawley rats weighing =
approximately 200-250 g are injected intramuscularly SUBSTITUTE SHEET (RULE 26) wo 96122282 PClfUS96102052 (i.m.) with 0.3 mg/kg of body weight of diethyistilbestrol (DES). The rats are sacrificed 18 hours later under pentobarbital anesthesia. The uteri are dissected out, cleaned of fat and connective tissues and rinsed in 50 ml of normal saline. The tissue pooled from six rats is homogenized in 50 ml of 0.01 mM Tris.
HC1, containing 0.5 mM dithiothreitol and 1.0 mM EDTA, adjusted to pH 7.4, using a polytron at setting 6 with three passes of 10 sec each. The homogenate is passed through two (2) layers of cheesecloth and the filtrate centrifuged at 1000 x g for 10 minutes. The clear supernatant is removed and recentrir"uged at 165,000 x g for 30 minutes. The resulting pellet containing the oxytocin receptcrs is resuspended in 50.0 mM Tris.HC1 containing 5.0 mM MgC12 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 [3H]oxytocin.
(b) Radicliaand Bindina Binding of 3,5-[3H]Oxytocin ([3H]OT) to its receptors is done in microtiter plates using [3H]OT, at various concentrations, in an assay buffer of 50.0 mM
Tris.HCl, pH 7.4 and containing 5.0 mM MgC12, and a mixture of protease inhibitors: BSA, 0.1 mg; aprotinin, 1.0 mg; 1,10-phenanthrcline, 2.0 mg; trypsin, 10.0 mg;
and PMSF, 0.3 mg per 100 ml cf buffer solution. Non-specific binding is determined in the presence of 1.0 uM
unlabeled OT. The binding reaction is terminated after 60 minuLes, at 22 C, by rapid filtration throuah alass fiber filters using a Branc'tel cell harvester (Biomedical Research and Development Laboratories, Inc., Gaithersburg, MD). Competition experiments are } conducted at equilibrium using 1.0 nM [3H]OT and varying the concentration of the displacing agents. The concentrations of aaent displacina 50% of [3H]OT at its SUBSTITUTE SHEET (RULE 26) sites (IC50) are calculated by a computer assisted LUNDON-2 program (LUNDON SOFTWARE INC., Ohio, USA).
BindinQ Assay to Rat Hepatic V Receptors and Rat Kidney Medullary V- Receptors or *Bindina to V- Receptor Subtype in Human ~1a 1 and ** ind;nq to m m ran G of Mouae7.ibroblast Cell r,in (LV-2) T ansf r-fiPd with the cDNA Exnressina the Human V- Recep or Tab1e I
ul V2 Ex. No. Structure C50( M ) IC50( M ) a :)C~ 1 0.24 0.054 N C"3 O NHCO
-N
F

2 Q ' 0.059 0.029 -N t NHCO

F
%

3 44% at l04M 20% at 10 M
\

O NHCO
-N
F

SUBSTITUTE SHEET (RULE 26) Cont'd.

Ex. No. Structure IC 50 ( M) IC 50 ( M) 12 100% at 1 M 90% at M
\ 1 1 , N

O / ~~
-N
24 =72% (uM) "=26% (1W) N

O

H
N
100% (1 M) 39% (1 M) O

SUBSTiTUTF SHEET (RULE 26) Cont'd.

Ex. No. Structure IC50( M) IC50 ( M) 26 46%'0 (14M) 29% (10 M) N

O

27 ` *0.014 **1.8 N DES

O

SUBSTITUTE SHEET (RULE 26) Cont'd.
. V I V2 Ex. No. Structure IC50( N1) IC50( N1) 32 53% (lO M) 33%(10 M;
\ f 1 /

N
O
` ~ CO

33 10% (10w) 16% (10~1IvI) N

CO

% (lO M) 62% (10 M) 45 ~

O ` -i NHCO

F
rt SUBSTITUTE SHEET (RULE 26) Table II
Vasopressin V2 Antagonist Activity in Conscious Hydrated Rats Ex. No. Dose N Urine Volume Osmolality (ma/ka) (mi/4 hrs) (MOsm/ka) * 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 26 i0 2 4.5 1058 45 10 2 6.6 979 4 10 2 6.8 878 2 10 2 16.5 591 32 '0 2 9.3 726 2 10 2 16.5 591 24 10 2 4.3 1492 27 10 2 3.3 1317 * Water-load control ** Water-load Contrcl +DMSO (10%) (20%) ~5 *** AVP-ccntrc!

SUBSTiTUTE SHEET (RULE 26) W O 96122282 PC'TI1JS96102052 Vasopressin Antidiuretic (V-) Response in Conscious Rats with Free Access to Water nr; nkina R fOra R z Not During the FXpGri tt1PP1 ~a 5 Male or female norrnotensive Sprague-Dawley rats (Charles River Laboratories, Inc., Kingston, NY) of 400-450 g of body weight were supplied with Laboratory Rodent Feed #5001 (PMI Feeds, Inc., Richmond, IN) and water ad libitum. On the day of test, rats were placed individually into metabolic cages equipped with stainless steel screens (to separate the feces from the urine) and funnels for collection of urine. Compounds, vehicle, or reference aaer.:. was given at various oral doses. During the test, rats were provided with no water or food. After dosing, urine was collected in graduated cylinders for four hours. Urine volume was measured. Urinary osmolality was determined using a Fiske One-Ten Osmometer (Fiske Associates, Norwood, MA
02062). An aliquot of each urine collection was analyzed for Na+,K+ and C1- using ion specific electrodes a in Beckman E3 (Electrolyte 3) analyzer.
The vehicle used for testing compounds was 20%
dimethylsulfoxide (DMSO) in 2.5% preboiled starch.

Table IV list results with compounds tested by this procedure.

SUBSTiTUTE SHEET (RULE 26) Table IV
Vasor)ressin V? Ant_agon;ct Activity 1_^. Conscious Rats Ex. No. Dose N Urine Volume Osmolality (mg/Kg) (ml/4 hrs) (MOsm/kg) 16 7-10+2 981+34 47 10 2 22.0 394 66 10 2 17.0 442 67 10 2 21.5 402 134 10 2 40.5 333 1 2 18.2 596 133 10 2 27.5 234 =35 10 2 39.5 284 3 2 26.8 391 2 19.5 526 176 10 12.8 567 257 10 2 22.5 317 301 10 2 41.5 363 352 10 2 9.3 779 396 10 2 21.8 238 397 10 2 29.8 288 398 10 2 20.5 316 399 10 2 17.0 404 400 10 2 24.8 270 *Control DMSO (20%)-2.5% corn starch Compounds were dissolved in DMSO and then diluted in 2.5% corn starch (final concer.-~.ration of DMSO was 20%).
All rats were orally dosed with this mixture at lOmV kg, by gavage.

SUBSTITUTE SHEET (RULE 26) WO 96122282 PCTIUS96Jo105]
Table III
Ox tocin Bindin Assa Ex. No. Dose ( M) % Inhibition IC50 (P-M) .~-2 10 86 1.1 12 10 76 0.61 24 10 97 1.8 25 10 94 0.113 26 10 73 2.5 32 10 88 1.8 The compounds of the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptabie acids or bases. These salts include, but are not 1-imited to, the following:
salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such craanic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts witi: alkali metals or alkaline earth metals, such as sodium,, potassiu*n, calcium or magnesium or with organic bases. mhe compounds can also be used in the form of esters, carbamates and other conventional "pro-cirug" forms, which, when administered in such form, convert to the active moi ety õ,.,.n *r; vo.
When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acce-,rable carriers, for example, sol-vents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible SUBSTITUTE SHEET (RULE 26) powders, granules, or suspensions containing, for exam-ple, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions contain-from about 0.05 to 5% suspending agent in an ing 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 denending on the particular compound employed, the mode cf administration and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 500 mg/kg of animal body weight, preferably given in divided doses two to four times a day, or in a sustained release form. For most large mammals the tota'_ daily dosage is from about 1 to 100 mg, preferably from about 2 to 80 mg. Dosage forms suitable for internal use comprise from about 0.5 to 500 mg cf the active compound in intimate admixture with a solid cr liquid pharmaceutically acceptable carrier.
This dosaae regimen may be adjusted to provide the optimal therapeutic, response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
These ac~ive compounds may be administered orally as well as by intravenous, intramuscular, or sub-cutaneous routes. Solid carriers =nclucie starch, lac-tose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaoli::, while '_iquid carriers include sterile water, polyethylene glycols, non-ionic surfac-SUBSTITUTE SHEET (RULE 26) WO 96122282 PGTlUS96J02052 tants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active in-gredient and the particular form of administration de-sired. Adjuvants customarily employed in the prepara-tion of pharmaceutical compositions may be advan-tageously 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 cf ease of preparation and administration are solid compositior.s, particuiarly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred.
These a~tive compouncis may also be adminis-tered parenterally or intraper`toneally. Solutions or suspensions ef these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydrox-ypropylcellulose. Dispersions can also be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the arowth of microorganisms.
The pharmaceutical forms suitable for in-jectable use ;.nc'_ude sterile aqueous solutions or dis-persions and sterile powders for the extemporaneous preparation cf sterile injectable solutions or disper-sions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exits.
It must be stable under condi-ions cf manufacture and storage and must be preserved aaainst the contaminating action of microorgariisms such as bacterial and fungi.
The carrier cbe _ a solvent ~ or nr r-7i .~_ r can spe_rsi o.~ medium con-taining, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable miYtures thereof, and vegetable oil.

SUBSTITUTE SHEET (RULE 26) The new tricyclic non-peptide vasopressin antagonists of this invention are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

1n particular, the vasopressin antagonists of this invention are therapeutically useful in the treatment and/or prevention cf hypertension, cardiac insufficiency, coronary vasospasm, cardiac ischemia, renal vasospasm, liver cirrhosis, congestive heart failure, nephrit;c syndrome, brain edema, cerebral ischemia, cerebra'_ hemorrhaae-stroke, thrombosis-bleeding and abnormal states of water retention.
In particular, the orytocin antagonists of this invention are useful in the prevention of preterm labor and premature birth which is a significant cause of infant health problems and infant mortality.

SUBSTITUTE SHEET (RULE 26)

Claims (142)

We claim:

1. A compound selected from those of Formula I:

wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N-lower alkyl (C1-C3), CH-lower alkyl (C1-C3), CHNH-lower alkyl(C1-C3), CHNH2, CHN[lower alkyl(C1-C3)]2,CHO-lower alkyl(C1-C3), CHS-lower alkyl(C1-C3), wherein n is an integer from 0-2;
A-B is wherein m is an integer from 1-2, provided that when Y
is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two;
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C1-C3), -SH, -SO lower alkyl(C1-C3), -SO2 lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2, -SO2NH lower alkyl (C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;

R3 is the moiety wherein Ar is a moiety selected from the group and X is O, S, -NCH3 or -NH
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;and (b) a moiety of the formula:
-X-R10, wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three;
X is O, S, NH, NCH3, or a bond and R5, and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
, -S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b) (CH2)q-N(R b)2;
W' is selected from O, S, NH, N-lower alkyl (C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3) R25 is selected from the moieties and the moiety represents: (1) phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy, and (C1-C3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N and S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alkyl, formyl, a moiety of the formula:

halogen or (C1-C3)lower alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

2. A compound according to Claim 1 wherein the moiety represents a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (C1-C3)lower alkyl amino and n, m, W', X, Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

3. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and n, m, W', X, Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

4. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

5. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

6. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

7. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

8. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

9. A compound according to Claim 1 wherein the moiety represents a fused 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

10. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom and Y, A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

11. A compound according to Claim 1 wherein the moiety represents a phenyl ring, optionally substituted by one or two substituents selected from (C1-C3) lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (C1-C3)lower alkyl amino, Y in selected from -CH2-, and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

12. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

13. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

14. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom wherein Y
is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 R25 are as previously defined in Claim 1.

15. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocylic ring having one oxygen heteroatom wherein Y
is selected from -CH2-, and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

16. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

17. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocylic ring having two nitrogen heteroatoms, Y is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

18. A compound according to Claim wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, Y is selected from -CH2-, and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

19. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is selected from -CH2-, and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

20. A compound according to Claim 1 wherein the moiety represents a phenyl ring, optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (C1-C3)lower alkyl amino, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

21. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

22. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is -(CH2)n, n is zero and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

23. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

24. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom, Y is -(CH2)n, n is zero and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

25. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is -(CH2)n, n is zero and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

26. A compound according to claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

27. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

28. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is -(CH2)n, n is zero and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

29. A compound according to Claim 1 wherein the moiety represents a phenyl or substituted phenyl ring, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and and A-B, R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

30. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

31. A compound according to Claim 1 wherein the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is selected from o, S, NH, NCOCH3, and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

32. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom, Y is selected from O, S, NH, NCOCH3, and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

33. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one oxygen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

34. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

35. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having two nitrogen heteroatoms, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

36. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one sulfur heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

37. A compound according to Claim 1 wherein the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen and one oxygen heteroatom, Y is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3) and A-B,R a, R b, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 1.

38. A compound according to Claim wherein Y
is selected from -(CH2)n-, wherein n is an integer zero or one;
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group W' is O or S; A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X, cycloalkyl and the moiety are as previously defined in Claim 1.

39. A compound according to Claim 1 wherein Y
is selected from -CH2-, R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group W' is O or S; A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl and the moiety are as previously defined in Claim 1.

40. a compound according to Claim 1 wherein Y
is selected from -CH2-, R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (C1-C3)lower alkyl amino and A-B, R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

41. A compound according to claim 1 wherein Y
is -(CH2)n-, wherein n is an integer zero;
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkyl amino and A-B, R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

42. A compound according to Claim 1 wherein Y
is selected from O, S, NH, NCOCH3 and N-lower alkyl (C1-C3);
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a phenyl ring optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy and (C1-C3)lower alkyl amino and A-B, R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

43. A compound according to Claim 1 wherein Y
is -(CH2)n-; n is an integer zero;

R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

44. A compound according to claim 1 wherein Y
is -CH2-;
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar'; is selected from the group and W' is O or S; and the moiety represents a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen heteroatom A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

45. h compound according to Claim 1 wherein Y
is -(CH2)n-; n is an integer zero;
R3 is the moiety wherein Ar is a moiety selected from the group and R5 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

46. A compound according to Claim 1 wherein Y
is -CH2-;
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-R,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

47. A compound according to Claim 1 wherein Y
is selected from O, S, NH, NCOCH3, N-lower alkyl (C1-C3);
R3 is the moiety wherein Ar is a moiety selected from the group and R6 is selected from the group wherein Ar' is selected from the group and W' is O or S; and the moiety represents a 5-membered aromatic (unsaturated) heterocyclic ring having one sulfur heteroatom A-B,R a, R b, R1, R2, R4, R5, R7, R8, R9, R10, R25, X and cycloalkyl are as previously defined in Claim 1.

48. A compound selected from those of the formulae:

wherein m is an integer one or two;

R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl (C1-C3), or -SO2N[lower alkyl(C1-C3)];
R2 is hydrogen, Cl, Bre, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:
R5 and R7 are selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen.
R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH-2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;and (b) a moiety of the formula:
-X-R10, wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three;
X is O, S, NH, NCH3, or a bond R5 and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
lower alkyl (C1-C3), -S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH, R b is as hereinbefore defined;
Ar' is a moiety selected from the group R B and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or NH-lower alkyl(C1-C3); N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is O, S, NH, N-lower alkyl(C1-C3), NCO-lower alkyl(C1-C3) or NSO2-lower alkyl(C1-C3) or NSO2 lower alkyl(C1-C3) and the pharmaceutically acceptable salts thereof.

49. A compound selected from those of the formula:

wherein Y is selected from O. S. NH, and N-lower alkyl(C1-C3);
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl (C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -NH lower alkyl(C1-C3) -SO2NH2; -SO2NH
lower alkyl(C1-C3),or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:
wherein Ar is selected from moieties of the formula:

R5 and R7 are selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;
R5 is selected from (a) moieties cf the formula:

lower alkyl(C3 C8)straight or branched -lower alkyl(C3-C8)straight or branched, -lower alkenyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three R b is hydrogen, -CH3 or -C2H5;and (b) a moiety of the formula:
-X-R10, wherein R10 is lower alkyl (C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl (C3-C6), and p is zero to three;
X is O, S, NH, NCH3 or a bond and R5 and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
-S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH, R b is as hereinbefore defined;
Ar' is a moiety selected from the group R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or NH-lower alkyl(C1-C3); N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is O, S, NH, N-lower alkyl(C1-C3), NCO-lower alkyl(C1-C3) or NSO2-lower alkyl(C1-C3) or NSO2 lower alkyl(C1-C3) and the pharmaceutically acceptable salts thereof.

50. The compound according to claim 1, N-[5-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-2-pyridinyl][1,1'biphenyl]-2-carboxamide.

51. The compound according to claim 1, N-[5-[(6,11-Dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-2-pyridinyl]-2-dimethylamino pyridine-3-carboxamide.

52. The compound according to claim 1, N-[5-[(9,10-Dihydro-4H-thieno[2,3-c][1]benzazepin-9-yl)carbonyl]-2-pyridinyl][1,1'-biphenyl]-2-carboxamide.

53. The compound according to claim 1, N-[5-[(9,10-Dihydro-4H-thieno[2,3-c][1]benzazepin-9-yl)carbonyl]-2-pyridinyl]-2-dimethylamino pyridine-3-carboxamide.

54. The compound according to claim 1, N-[5-[(4,10-Dihydro-5H-thieno[3,2-c][1]benzazepin-5-yl)carbonyl]-2-pyridinyl][1,1'-biphenyl]-2-carboxamide.

55. The compound according to claim 1, N-[ 5 [ (4 , 10-Dihydro-5H-thieno [3 , 2-c] [ 1 ] benzazepin-5-yl)carbonyl]-2-pyridinyl]-2-dimethylamino pyridine-3-carboxamide.

56. The compound according to claim 1, N-[5-[9,10-Dihydro-4F,-thieno[2,3-c[1]benzazepin-9-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide.

57. The compound according to claim 1, N-[5-[4, 10-Dihydro-5H-thieno [ 3, 2, -c] [1] benzazepin-5-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide.

58. The compound according to claim 1, N-[5-[(4,5-Dihydropyrazolo[4,3-d][1]benzazepin-6(1H)-yl)carbonyl]-2-pyridinyl]-2-dimethylamino pyridine-3-carboxamide.

59. The compound according to claim 1, N-[5-[(4,5-Dihydropyrazolo[4,3-d][1]benzazepin-6(1H-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide.

60. The compound according to claim 1, N-[5 (pyrido [2, 3-b] [1, 4] benzoxazepin-5- (6H) -ylcarbonyl ) -2-pyrdinyl]-5-fluoro-2-methyl benzamide.

61. A pharmaceutical composition useful for treating diseases characterized 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 a suitable pharmaceutical carrier and an effective amount of a compound of claim 1.

62. A method of treating diseases characterized 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 Claim 1 to said mammal in an amount effective to alleviate the disease.

63. A process for preparing a compound of the formula:

wherein Y is (CH2)n, O, S. NH, NCOCH3, N-lower alkyl (C1-C3), CH-lower alkyl(C1-C3), CHNH-lower alkyl (C1-C3), CHNH2, CHN[lower alkyl(C1-C3)]2, CHO-lower alkyl(C1-C3), CHS-lower(C1-C3), wherein n is an integer from 0-2;

A-B is wherein m is an integer from 1-2, provided that when Y
is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two;
R1 is selected from the group of hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C1-C3), -SH, -SO lower alkyl(C1-C3), -SO2 lower alkyl (C1-C3) , -CO-lower alkyl (C1-C3) , -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2, -SO2NH lower alkyl(C1-C3), -SO2N[lower alkyl(C1-C3)]2;
R2 is selected from the group of hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety wherein Ar is a moiety selected from the group R4 is hydrogen, lower alkyl(C1-C3); -CO-lower alkyl (C1-C3) ;
R5 and R7 are selected from the group, hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen R6 is selected from (a) moieties of the formulae:

lower alkyl(C3-C8)straight or branched lower alkyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p, -cycloalkyl(C3-C6), and p is zero to three;
X is O, S, NH, NCH3, and R5 and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8)branched or unbranched, -O-lower alkenyl(C3-C8)branched or unbranched, tetrahydrofuran, tetrahydrothiophene,the moieties or -CH2-K wherein K is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q -N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl (C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3);

the moiety represents: (1) phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy, and (C1-C3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N and S; (3) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom; (4) a 5 or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms; (5) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; wherein the 5 or 6-membered heterocyclic rings are optionally substituted by (C1-C3)lower alkyl, formyl, a moiety of the formula:

halogen or (C1-C3)lower alkoxy;
which comprises reacting a compound of the formulae:
with a compound of the formula:

wherein the moiety represented by the formula is an aroyl chloride or an aryl carboxylic acid which has been activated by conversion to a mixed anhydride or activated with a peptide coupling reagent to give compounds of the Formula I.

64. A compound selected from those of the formula:

wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formulae:

and X is O, S, -NCH3, or -NH:
R is independently selected from hydrogen, lower alkyl(C1-C3), -(CH2)q-OH, -(CH2)q-O-alkyl(C1-C3); q is one, two or three;
R4 is selected from hydrogen, lower alkyl(C1-C3),-CO-lower alkyl(C1-C3), P5 and R7 are selected from hydrogen, (C2-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formulae:
lower alkyl(C3-C8)straight or branched lower alkyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7, are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q -N(R b)2;
R25 is selected from the moieties.
W' is selected from O, S. NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and the pharmaceutically acceptable salts thereof.

65. A compound selected from those of the formula:

wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:
wherein Ar is selected from moieties of the formula:

R is independently selected from hydrogen, lower alkyl (C1-C3), -(CH2)q-OH, -(CH2)q-O-alkyl(C1-C3); q is one or two;
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

lower alkyl(C3-C8)straight or branched -lower alkyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, lower alkenyl(C3-C8)straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahyrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl(C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

66. A compound selected from those of the formula:

wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3),-CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:

R is independently selected from hydrogen, halogen lower alkyl(C1-C3), -(CH2)q-OH, -(CH2)q-O-alkyl(C1-C3); q is one or two; R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 is hydrogen, -CH3,-C2H5, Cl, Br, F, -O-CH3, or -O-C2H5;

R5 and R7 are selected from hydrogen, (C1-C3) lower alkyl,(C1-C3)lower alkoxy and halogen:
R6 is selected from (a) moieties of the formula:
wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S. NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8)branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar; is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3);-N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S. NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

67. A compound selected from those of the formula:

wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3),-NO2), -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:

R is independently selected from hydrogen, halogen, lower alkyl(C1-C3), -(CH2)q-OH, -(CH2)q-O-alkyl(C1-C3); q is one, two or three;
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen, (C1-C3)lower alkyl,(C1-C3)lower alkoxy and halogen.
R6 is selected from (a) moieties of the formula:

straight or branched straight or branched, straight or branched, straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one or two; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3;

or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moities or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
, -S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3) lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b) (CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S. NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

68. A compound selected from those of the formula:

wherein A-B is wherein R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-1ower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:

R is independently selected from hydrogen, halogen, lower alkyl(C1-C3), -(CH2)q-OH, -(CH2)q-O-alkyl(C1-C3); q is one, two or three;
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), R5 and R7 are selected from hydrogen(C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formula:
wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C1-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

69. A compound selected from those of the formulae:

wherein Y is -(CH2)n- and n is an integer zero or one;
A-B is wherein m is an integer one when n is one and m is an integer one or two when n is zero;
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl (C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:
wherein Ar is selected from moieties of the formula:

R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen(C1-C3)lower alkyl(C1-C3) lower alkoxy and halogen;
R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl(C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); - N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

70. A compound selected from those of the formula:

wherein Y is selected from O, S, NH, and N-lower alkyl(C1-C3);
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2,-SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethyleneedioxy;
R3 is the moiety:
wherein Ar is selected from moieties of the formula:

R4 is selected from hydrogen, lower alkyl(C1-3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen(C1-C3) lower alkyl(C1-C3) lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieites of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3);-N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

71. A compound selected from those of the formula:

wherein Y is O, S, NH and N-lower alkyl; and A-B is R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:

R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3) R5 and R7 are selected from hydrogen(C1-C3)lower alkyl(C1-C3) lower alkoxy and halogen;
R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, CH3 or -C2H5;
(b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, O-lower alkyl(C3-C8) branched or unbranched, O-lower alkenyl(C3-C8) branched or unbranched, tetrahydroguran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
, -S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

72. A compound selected from those of the formula:

wherein Y is selected from O, S, NH, and N-lower alkyl(C1-C3);

A-B is R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethyleneedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:

R4 is selected from hydrogen, lower alkyl(C1-3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen(C1-C3) lower alkyl(C1-C3) lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieites of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
, -S-lower alkyl(C 1-C 3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3);-N-[lower alkyl(C1-C3)2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

73. A compound according to claim 72 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
and Y, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72.

74. A compound according to claim 72 wherein A-B is Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72.

75. A compound according to claim 72 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72.

76. A compound according to claim 72 wherein A-B is Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72.

77. A compound according to claim 72 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:

and Y is NH; and, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 72.

78. A compound selected from those of Formula I:
wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N-lower alkyl (C1-C3), CH-lower alkyl(C1-C3), CHNH-lower alkyl(C1-C3), CHNH2, CHN[lower alkyl(C1-C3)12,CHO-lower alkyl(C1-C3), CHS-lower alkyl(C1-C3), wherein n is an integer from 0-2;
A-B is wherein m is an integer from 1-2, provided that when Y is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two;

R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl(C1-C3), -SH, -SO lower alkyl(C1-C3), -SO2 lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2, -SO2NH lower alkyl (C1-C3), or -SO2N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), 0-lower alkyl(Cl-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety wherein Ar is a moiety selected from the group and X is O, S, -NCH3 or -NH
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen, (C1-C3) lower alkyl, (C1-C3)lower alkoxy and halogen R6 is selected from (a) moieties of the formula:
straight or branched straight or branched, straight or branched, straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:
-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hvdrogen, -CH3 or -C2H5;and (b) a moiety of the formula:
-X-R10, wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three;

X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)12, -N(R b)(CH2)q-N(Rb)2;
W' is selected from O, S, NH, N-lower alkyl (C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3);
R25 is selected from the moieties and the moiety represents: a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom, wherein the 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom is optionally substituted by (C1-C3)lower alkyl, formyl, a moiety of the formula:

halogen or (C1-C3)lower alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

79. A compound selected from those of the formulae:
wherein Y is selected from -(CH2)-, O, S, NH, NCOCH3, N-lower alkyl (C1-C3), CH-lower alkyl(C1-C3), CHNH-lower alkyl(C1-C3), CHNH2, CHN[lower alkyl(C1-C3)12,CHO-lower alkyl(C1-C3), CHS-lower alkyl(C1-C3);

A-B is R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-1ower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -SO2NH2; -SO2NH lower alkyl (C1-C3), or -SO2N[lower alkyl(C1-C3)12;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety:

wherein Ar is selected from moieties of the formula:
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen(C1-C3)lower alkyl(C1-C3) lower alkoxy and halogen;
R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:
X is O, S, NH, NCH3, or a bond and R3 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3)lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
-S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl(C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); - N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from O, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

80. A compound according to claim 79 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
and Y, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

81. A compound according to claim 79 wherein A-B is Y is -(CH2)-; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

82. A compound according to claim 79 wherein A-B is Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

83. A compound according to claim 79 wherein A-B is Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

84. A compound according to claim 79 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:
Y is -(CH2)-; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

85. A compound according to claim 79 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:

Y is 0; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

86. A compound according to claim 79 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:
Y is NH; and R a, R b, R c, R1, R2, R3, R4, R3, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

87. A compound selected from those of Formula I:
wherein Y is selected from (CH2)n, O, S, NH, NCOCH3, N-lower alkyl (C1-C3), CH-lower alkyl(C1-C3), CHNH-lower alkyl(C1-C3), CHNH2, CHN[lower alkyl(C1-C3)]2,CHO-lower alkyl(C1-C3), CHS-lower alkyl(C1-C3), wherein n is an integer from 0-2;
A-B is wherein m is an integer from 1-2, provided that when Y
is -(CH2)n- and n=2, m may also be zero and when n is zero, m may also be three, provided also that when Y is -(CH2)n- and n is 2, m may not also be two;
R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, -S-lower alkyl (C1-C3) , -SH, -SO lower alkyl(C1-C3), -SO2 lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(Cl.-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -S02NH2, -SO2NH lower alkyl (C1-C3), or -S02N[lower alkyl(C1-C3)]2;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethylenedioxy;
R3 is the moiety wherein Ar is a moiety selected from the group and X is O, S, -NCH3 or -NH
R4 is selected from hydrogen, lower alkyl(C1-C3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen, (C1-C3) lower alkyl, (C1-C3)lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

straight or branched straight or branched, straight or branched, straight or branched, wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hydrogen, CH3, C2H5, moieties of the formulae:

-(CH2)2-O-lower alkyl(C1-C3) or -CH2CH2OH; q is one, two or three; R b is hydrogen, -CH3 or -C2H5;and (b) a moiety of the formula:
-X-R10, wherein R10 is lower alkyl(C3-C8), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three;
X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined.
(c) a moiety of the formula:

wherein J is R a, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -0-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahvdrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
-S-lower alkyl(C1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -O-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3); -N-[lower alkyl(C1-C3)]2, -N(Rb)(CH2)q-N(Rb)2;
W' is selected from O, S, NH, N-lower alkyl (C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3) R25 is selected from the moieties and the moiety represents: a 5-membered aromatic (unsaturated) heterocyclic ring having one S heteroatom wherein the 5 -membered aromatic (unsaturated) heterocyclic ring is optionally substituted by (C1-C3)lower alkyl, formyl, a moiety of the formula:

halogen or (C1-C3)lower alkoxy; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

88. A compound selected from those of the formula:
wherein Y is selected from -(CH2)-, O, S, NH, and N-lower alkyl(C1-C3);
A-B is R1 is hydrogen, halogen (chlorine, bromine, fluorine, iodine), OH, S-lower alkyl(C1-C3), -SH, -SO-lower alkyl(C1-C3), -SO2-lower alkyl(C1-C3), -CO-lower alkyl(C1-C3), -CF3, lower alkyl(C1-C3), O-lower alkyl(C1-C3), -NO2, -NH2, -NHCO lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2,-SO2NH2; -SO2NH lower alkyl(C1-C3), or -SO2N[lower alkyl(C1-C3)12;
R2 is hydrogen, Cl, Br, F, I, -OH, lower alkyl(C1-C3), O-lower alkyl(C1-C3), or R1 and R2 taken together are methylenedioxy or ethyleneedioxy;

R3 is the moiety:

wherein Ar is selected from moieties of the formula:
R4 is selected from hydrogen, lower alkyl(C1-3), -CO-lower alkyl(C1-C3);
R5 and R7 are selected from hydrogen(C1-C3) lower alkyl(C1-C3) lower alkoxy and halogen R6 is selected from (a) moieties of the formula:

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R a is hvdrogen, CH3, C2H5, moieites of the formulae:
-(CH2)2)-O-lower alkyl(C1-C3) or -CH?CH?OH; q is one, two or three; R b is hvdrogen, -CH3 or -C2H5;
and (b) a moiety of the formula:
-X-R10; wherein R10 is lower alkyl(C3-C8), lower alkenyl (C3-C8), -(CH2)p-cycloalkyl(C3-C6), and p is zero to three:

X is O, S, NH, NCH3, or a bond and R5 and R7 are as previously defined (c) a moiety of the formula:

wherein J is R a, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, -O-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties or -CH2-K' wherein K' is halogen, -OH, tetrahydrofuran, tetrahydrothiophene 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, (C1-C3) lower alkyl, hydroxy, -CO-lower alkyl(C1-C3), CHO, (C1-C3)lower alkoxy, -CO2-lower alkyl(C1-C3), and R a and R b are as hereinbefore defined;
(d) a moiety selected from those of the formulae:
-S-lower alkyl(C 1-C3) wherein R c is selected from halogen, (C1-C3)lower alkyl, -0-lower alkyl(C1-C3) and OH; R b is as hereinbefore defined;
wherein Ar' is selected from the group:

R8 and R9 are independently hydrogen, lower alkyl (C1-C3), O-lower alkyl(C1-C3), S-lower alkyl(C1-C3), -CF3, -CN, -OH, -SCF3, -OCF3, halogen, NO2, amino, or -NH-lower alkyl(C1-C3);-N-[lower alkyl(C1-C3)]2, -N(R b)(CH2)q-N(R b)2;
R25 is selected from the moieties W' is selected from 0, S, NH, N-lower alkyl(C1-C3), -NCO-lower alkyl(C1-C3), or NSO2-lower alkyl(C1-C3); and pharmaceutically acceptable salts thereof.

89. A compound according to claim 88 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
and Y, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

90. A compound according to claim 88 wherein A-B is Y is -(CH2)-; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

91. A compound according to claim 88 wherein A-B is Y is 0; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

92. A compound according to claim 88 wherein A-B is Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

93. A compound according to claim 88 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
Y is -(CH2)-; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

94. A compound according to claim 88 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
and Y is NH;
R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

95. A compound according to claim 88 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:

and Y is O;
R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

96. The compound according to claim 1, N-[4-(dibenz[b,f][1,4]oxazepin-10(11H)-ylcarbonyl)-phenyl]-[1,1'-biphenyl]-2-carboxamide.

97. The compound according to claim 1, N-[4-(dibenz[b,f][1,4]oxazepin-10(11H)-ylcarbonyl)-3-chloro-phenyl][1,1'biphenyl]-2-carboxamide.

98. The compound according to claim 1, N-[5-(dibenz [b, f][1, 4] oxazepin-10 (11H) ylcarbonyl)-2-pyridinyl]-5-fluoro-2-methylbenzamide.

99. The compound according to claim 1, N-[5-(dibenz[b,f][1,4]oxazepin-10(11H)-ylcarbonyl)-2-pyridinyl]-2-(4-pyridinyl)benzamide.

100. The compound according to claim 1, N-[5-(pyrido[2,3-b][1,5]benzoxazepin-6(5H)-ylcarbonyl)-2-pyridinyl][1,1'biphenyl]-2-carboxamide.

101. The compound according to claim 1, N-[5-(pyrido[2,3-b][1,4]benzoxazepin-5(6H)-ylcarbonyl)-2-pyridinyl][1,1'-biphenyl]-2-carboxamide.

102. The compound according to claim 1, N-[4-(pyrido [2,3-b][1,4]benzoxazepin-5(6H)-ylcarbonyl)-3-chlorophenyl][1,1'biphenyl]-2-carboxamide.

103. The compound according to claim 1, N-[4-(6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-6(5H)-ylcarbonyl)-phenyl][1.1'-biphenyl]-2-carboxamide.

104. The compound according to claim 1, N-[4-(6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-6(5H)-yl-carbonyl)-3-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

105. The compound according to claim 1, N-[4-(6,11-dihydropyrido[2,3-b][1,5]benzodiazepin-6(5H)-yl-carbonyl)phenyl][1,1'-biphenyl]-2-carboxamide, hydrochloride.

106. The compound according to claim 1, N-[4-[(5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-10-yl)-carbonyl]-3-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

107. The compound according to claim 1, N-[4-[(5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-10-yl)-carbonyl]-phenyl][1,1'-biphenyl]-2-carboxamide.

108. The compound according to claim 1, N-[4-[(5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-10-yl)-carbonyl]-3-methylphenyl][1,1'-biphenyl]-2-carboxamide.

109. The compound according to claim 1, N-[4-[(5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-10-yl)-carbonyl]-2-methylphenyl][1,1'-biphenyl]-2-carboxamide.

110. The compound according to claim 1, N-[4-[(5,11-dihydro-10H-dibenz[b,e][1,4]diazepin-10-yl)-carbonyl]-2-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

111. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-pheny][1,1'-biphenyl]-2-carboxamide.

112. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-3-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

113. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-3-methylphenyl][1,1'-biphenyl]-2-carboxamide.

114. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]-2-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

115. The compound according to claim 1, N-[5-[(6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepin-5-yl)carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide.

116. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepin-5-yl)-carbonyl]-3-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

117. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepin-5-yl)-carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide.

118. The compound according to claim 1, N-[4-[(6,11-dihydro-5H-pyrido[2,3-b][1,4]benzodiazepin-5-yl)-carbonyl]-3-methylphenyl][1,1'-biphenyl]-2-carboxamide.

119. The compound according to claim 1, N-[4-[(4,5-dihydropyrazolo[4,3-d][1]benzazepin-6(1H)-yl)-carbonyl]phenyl][1,1'-biphenyl]-2-carboxamide.

120. The compound according to claim 1, N-[4-[(4,5-dihydropyrazolo[4,3-d][1]benzazepin-6(1H)-yl)-carbonyl]-3-chlorophenyl][1,1'-biphenyl]-2-carboxamide.

121. The compound according to claim 1, N-[5-[(4,5-dihydropyrazolo[4,3-d][1]benzazepin-6(1H)-yl)-carbonyl]-2-pyridinyl][1,1'-biphenyl]-2-carboxamide.

122. The compound according to claim 1, N-[5-[(4,5-dihydropyrazolo[4,3-d][1]benzazepin-6(1H)-yl)-carbonyl]-2-pyridinyl]-5-fluoro-2-methylbenzamide.

123. The compound according to claim 1, N-[5-(4H-thieno[3,4-b][1,5]benzodiazepin-9(10H)-yl)-2-pyridinyl]-5-fluoro-2-methylbenzamide.

124. The compound according to claim 1, N-[4-(4H-thieno[3,4-b][1,5]benzodiazepin-9(10H)-yl)-phenyl]-[1,1'-biphenyl]-2-carboxamide.

125. The compound according to claim 1, N-[4-(4H-thieno[3,4-b][1,5]benzodiazepin-9(10H)-yl)-3-chloro-phenyl][1,1'-biphenyl]-2-carboxamide.

126. The compound according to claim 1, N-[5-(4H-thieno[3,4-b][1,5]benzodiazepin-9(10H)-yl)-2-pyridinyl][1,1'-biphenyl]-2-carboxamide.

127. The compound according to claim 1, 5,11-dihydro-10-[4-(2-thienyl)benzoyl]-10H-dibenz[b,e][1,4]-diazepine.

128. The compound according to claim 1, 5,11-dihydro-10-[4-(3-thienyl)benzoyl]-10H-dibenz[b,e][1,4]-diazepine.

129. A compound according to claim 79 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:
and Y, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

130. A compound according to claim 79 wherein A-B is Y is - (CH2) -; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

131. A compound according to claim 79 wherein A-B is Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

132. A compound according to claim 79 wherein A-B is Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

133. A compound according to claim 79 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:
Y is - (CH2) -; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

134. A compound according to claim 79 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:
Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

135. A compound according to claim 79 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:

Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 79.

136. A compound according to claim 88 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:

and Y, R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

137. A compound according to claim 88 wherein A-B is Y is - (CH2) -; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

138. A compound according to claim 88 wherein A-B is Y is O; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

139. A compound according to claim 88 wherein A-B is Y is NH; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

140. A compound according to claim 88 wherein A-B is R3 is the moiety:
wherein Ar is selected from moieties of the formula:

Y is - (CH2) -; and R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

141. A compound according to claim 88 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:
and Y is NH;
R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.

142. A compound according to claim 88 wherein A-B is R3 is the moiety:

wherein Ar is selected from moieties of the formula:

and Y is O;
R a, R b, R c, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R25 are as previously defined in Claim 88.