AU731925B2

Tricyclic benzazepine vasopressin antagonists

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.

AU731925B2, drawing sheet 1 — Sheet 1 of 754

Term

Term ended

Expired 20 June 2017, 9.3 years ago.

22 claims: 10 independent, 12 dependent

1
What is claimed is:1. A compound selected from those of the formula: wherein Y is CH2;A-B is a moiety selected from and -N-(CH2)- represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;the moiety: is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C1-C3)lower alkyl, hydroxy, -COCCI3, -COCF3, WO 97/49707 PCT/US97/10736 -3160 -CH=CH-NO2,-(CH2)qNO2 , II /A -C-O-lower alkyl(CC3), -(CH2)qN\^ Rb ’ -(CH2)q-NQ , ^CH2)q-lO , -<CH2)q-N^3° , -(CH2)q -O-lower alkyl (C,-C3), -(CH2)qOH, || F=1 F= -C-1ower alkyl (0,-63), -CH2-N^>N , -CH2-N-^a -CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower 5 alkylamino, CONH-lower alkyl(C1-C3), and -CONflower alkyl(C1-C3)]2;Q is one or two;317 Rb is independently selected from hydrogen, -CH3 or-C2Hs;Re is H, lower alkyl(C|-C3), hydroxyethyl, -CH2CO2R40, -CH2C(CH2OH)3;R?o is H or lower alkyl (C1-C4);R·’ is a moiety of the formula: O —C—Ar wherein Ar is a moiety selected from the group consisting of 10 R4 is selected from hydrogen, lower alkyl(C|-C3);-CO-lower alkyl (C1-C3);R20 is hydroxy;R2 is selected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy, hydroxy and halogen;R6 is selected from (a) moieties of the formula: |R:\LEBZ)05389.doc:!am WO 97/49707 PCT/US97/10736 -318-NCOAr’, -NCOCH2Ar’, -NCO-(CH2)n-cycloalkyl , -NCONAr', R -NH-C-O-lower alkyl(C3-C8) straight or branched, 0 -NH-C-1ower alkyl(C3-C8) straight or branched, -NHS02-lower alkyl(C3-C8) straight or branched, -NH-C-O-lower alkenyl(C3-C8) straight or branched, 0 II -NH-C-1ower alkenyl(C3-C8) straight or branched, -NHSO2-lower alkenyl(C3-C8) straight or branched, 319 wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl;R;l is independently selected from hydrogen, -CH3, -C2H5, —(CH2) — -(CI-l2)(|-O-lower alkyl(C,-C3) and -CH2CH2OH: q is one or two;R1 is selected from hydrogen, (CrC3) lower alkyl, (C,-C3) lower alkoxy, hydroxy and halogen: R“ and Rb are as hereinbefore defined;(b) moieties of the formula: —X— R7, wherein R7 is lower alkyl(C3-Cg), lower alkenyl(C3-C8), -(CH2)p-cycloalkyl(C3-C6), R1 —(CH2)p-^'l |R:\LIBZ]053X9.doc:lam WO 97/49707 PCT/US97/10736 -320wherein p is one to five and X is selected from O, S, NH, NCH3;wherein R1 and r2 are as hereinbefore defined;(c) a moiety of the formula: -N-COJ 5 wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties: R or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety: WO 97/49707 PCT/US97/10736 -321wherein 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, (Ci-C3)lower alkoxy, -CO2~ 5 lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;(d) a moiety of the formula: -N-COCH Ar' wherein Rc is selectedfrom halogen, (C^Cp lower alkyl, -0-lower alkyl(Cη-C3), OH, II -0-C-lower alkyl(Cn-C3), -S-lower alkyl(C^cp, R and Ra and Rb are as hereinbefore defined wherein Ar' is 10 selected from moieties of the formula: WO 97/49707 PCT/US97/10736 -322- wherein W' is selected from O, S, NH, N-lower alkyl(ΟχC3), NHCO-lower alkyl(C1-C3), and NS021ower alkyl(ΟχC3) ;5 R-θ and R9 are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl (C1-C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, 0-lower alkyl(C1-C3), -o-c-cc^y , 10 -N(Rfo)(CH2)vN(Rb)2/ and CF3 wherein v is one to three and;r!0 is selected from hydrogen, halogen and lower alkyl (C1-C3);WO 97/49707 PCT/US97/10736 -323r!4 is -0-1 ower alkyl(C3-Cg) branched or unbranched , Rh I -o-ch2-c-o r' , - 0- ch2- (CH2)„- 0 > Rb WO 97/49707 PCT/US97/10736 -324- q is 1 or 2;wherein n is 0 or 1;-325 Ra is hydrogen, -CH3 or -C2H5;R' is hydrogen, (C[-C3)lower alkyl, (C]-C3)lower alkoxy and halogen;is hydrogen, (C[-C3)lower alkyl, (C]-C3)Iower alkoxy and halogen;R20 is hydrogen, halogen, (C 1-C3)lower alkyl, (C]-C3)lower alkoxy, NH2. -NH(C] C3)lower alkyl, -N-[(Ci-C3)lower alky 1]2, Ul -N N-1 ower dkyl(Ct-C3) - NH- (CH2) - NHI ower d kyl (C]- C3) , - NH- (CH2)p- N(l ower d kyl <0,- C3))2 , N-1 ower d kyl (C.- C.) , I 0 and the pharmaceutically acceptable salts thereof.
2
A pharmaceutical composition useful for treating disease in a mammal
3
3d characterized by excess renal reabsorption of water, the pharmaceutical composition comprising an effective amount of a compound of Claiml, or a pharmaceutically acceptable salt, ester or prodrug form thereof, and a suitable pharmaceutical carrier. -326 3. The compound according to Claiml which is [4-(3-Dimethylaminomethyl-3 hydroxy-5H,l ΙΗ-pyrrolo [2, l-c][l,4]bcnzodiazepine-10-carbonyl)-phenyl]-bipheny 1-2carboxylic acid amide.
4
Λ compound selected from those of the formula:•D''r E ZO >=f O'a-b wherein Y is CH2;A-B is a moiety selected from -(CHJnR and the moiety: end -N-(CH2)- represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C)-C3)lower alkyl, halogen, amino, (Cj-C3)lower alkoxy or (Ci-C3)lower alkylamino;the moiety: is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms rn^ybe optionally substituted by a substituent selected from: -Ύ1Ί /Λ zRb -RVX -/-<r -(CH R4 is selected from hydrogen, lower alkyl(Ci-C3);-CO-lower alkyl(Ci-C3);R.1 and R2 are independently selected from hydrogen, (C[-C3)lower alkyl, (C[C3)lower alkoxy, hydroxy and halogen;R^ is selected from (a) moieties of the formula: -328 NC0(CH2)n cycloalkyl Ra o II — NH- C—O— lower alkyl (C3-Cg) straight or branched — NH~ C — lower alkyl (C3-C8) straight or branched ^SO2 lower alkyl (C,-C8) , — NSO2— lower alkenyl (CrC8) , O II ~ NH— C — O ~ lower alkenyl (Cj-C^ straight or branched 5 O II or — NH- C ~ lower alkenyl (C3-Cg) straight or branched wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl;Ra is independently selected from hydrogen, -CH3, -C2H5, -329 -(CH2)q - (cnpq rQ -(CH2)q-O-lowcr alkyl(C]-C3) and -CH2CH2OH;q is one or two;R1, R2 and R^ arc as hereinbefore defined;or (b) moieties of the formula;wherein R? is selected from lower alkyl(C3-C8), lower alkenyl(C3-Cs), -(CI-i2)pcycloalkyl(C3-C6), wherein p is one to five;X is selected from O, S, NH, NCH3;R1 and r2 are as hereinbefore defined;or -330 (c) a moiety of the formula: % I -N-COJ wherein J is Ra, lower alkyRC3-C8) branched or unbranchcd, lower alkcnyl(C3-Cs) branched or unbranched, O-lowcr alkyl(C3-Cg) branched or unbranchcd, -O-lowcr alkcnyl(C3-Cs) branched or unbranchcd, tetrahydrofuran, tctrahydrothiophcnc, the moictics or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, 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, (C[-C3)Iower alkyl, hydroxy, -CO-lower alkyl(Ci-C3), CHO, (Ci-C3)lower alkoxy, -CO2-lower alkyl(Ci-C3), and Ra and Rb are as hereinbefore defined;or -331 (d) a moiety of the formula: R Γ -N-COOHAr' R c wher ei n Rc is sei ect edf r om hd ogen (Ct-C ) lower dkyl, -O-low er dkyl(C(-C3), CH, O II -O-C-lowe dkylCC^Cp, -S-lower dkyl (C(-C3), -S-(CH2)2-N - NH(CH2)q- CCN -NH(CH2)Qf<Rb .0(0<)N<Rb Rb ' ^Rb and Ra and Rb are as hereinbefore defined wherein Ar' is selected from moieties of the formula: -332 wherein W' is selected from O, S, NH, N-lower alkyl(C 1-C3), NHCO-lower alkyl(C]-C3), and NSO21ower alkyl(C 1-C3);and are independently selected from hydrogen, lower alkyl(C 1-C3), -S-lowcr alkyl(Cj-C3), halogen, -ΝΉ-lower alkyl(C 1-C3), -N-[lower alkyl(C 1 -C3)]2, -OCF3, -OH, CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C 1-C3), O II -oc-cq-cp , -N(Rb)(CH2)vN(Rb)2, and CF3 wherein v is one to three and;RIO is selected from hydrogen, halogen and lower alkyl(Ci-C3);R14is -333 - Ο I ower d kyl (C3- Cg) br cnched or unbr cnched, - NH I ower d kyl (C3- Cg) be cnched or unbr cnched , -334 q is 1 or 2;n is 0 or 1;-335 Ra is hydrogen, -CH3 or -C2H5;R' is hydrogen, (Ci-C3)lower alkyl, (Ci-C3)loWer alkoxy and halogen;R4^ is hydrogen, (Ci-C3)lower alkyl, (Ci-C3)lower alkoxy and halogen;R2^ is hydrogen, halogen, (Cj-C3)lower alkyl, (C1 -C3)lower alkoxy, ΝΉ2, -NH(C[C3)lower alkyl, -N-[(Cj-C3)lower alkyl]2, λ N-1 ower d kyl (C - C ) / * -NH-(CH2)-NHIower dkyl(CrC3), - NH- (CH2)p- NO ower d kyl (C,- C3))2 , / \ - NH-(CH ) -N N-l 2 p \____/ / \ - NH- (CH ) - N O 2 p \____/ and the pharmaceutically acceptable salts forms thereof.
10
10-carbonyl]-phcnyl )-biphenyl-2carboxylic acid amide. and the moiety :represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (Ci-C3)lower alkyl, halogen, amino, (Ci-C3)lower alkoxy or (Ci-C3)lower alkylamino;the moiety: -337 is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F arc selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (Cl-C3)lowcr alkyl, hydroxy, -COCCI3, COCF3, -CH=CH-NO2 -(CH2)qNO2 -C-O-lower alkyl (C,-C3) -(CH2)q-N -(CH2)q-O-lower alkyl (C, -C3) · -338 Rb Rc ’ - (CH -CHO, amino, (C]-C3)lowcr alkoxy, (Ci-C3)lowcr alkylamino, CONH-lowcr alkyl(C]-C3), and -CON[lowcr alkyl(C 1 -C3))2;q is one or two;Rb is independently selected from hydrogen, -CH3 or -C2H5;Re is selected from H, lower alkyl (C1-C4), hydroxyethyl, -CI-UCC^R^O or CH2C(CH2OH)3;R^O is H or lower alkyl(C]-C4);R3 is a moiety of the formula: II wherein Ar is the moiety: R4 is selected from hydrogen, lower alkyl(Ci-C3);-CO-lower alkyl(Ci-C3);RJand R3 are independently selected from hydrogen, (C]-C3)lower alkyl, (C1C3)Iower alkoxy, hydroxy and halogen;-339
11
11' R.14 is selected from:O or q is 1 or 2;n is 0 or 1;Ra is hydrogen, -CH3 or-C2H5;R' is hydrogen, (Ci-C3)lower alkyl, (C[-C3)lower alkoxy and halogen;is hydrogen, (Ci-C3)lower alkyl, (C}-C3)Iower alkoxy and halogen;R^O is hydrogen, halogen, (Ci-C3)lower alkyl, (Ci-C3)lower alkoxy, NH2, -NH(CjC3)lower alkyl, -N-[(C1-C3)lower alkyl]2. -340 / \ - NH- (CH2) - NHI ower d ky I (C, - C3) , - NH- (CH2)p- N(l ower d kyl (C( - C3))2 , -NH-(CH2)p- / \ -NH-(CH„)-N n-i 2 p \____/ / \ - NH- (CH ) - N O 2 p \___/ and the pharmaceutically acceptable salts forms thereof. 11. A pharmaceutical composition useful for treating disease in a mammal characterized by excess renal reabsorption of water, the pharmaceutical composition comprising an effective amount of a compound of Claim 10, or a pharmaceutically acceptable salt, ester or prodrug form thereof, and a suitable pharmaceutical carrier.
15
A tricyclic benzazepine vasopressin antagonist, substantially as 5 hereinbef ore described with reference to any one of the examples.
17
A method for the treatment of disease characterised by excess renal in reabsorption of water in a mammal in need of said treatment, comprising administering to said mammal an effective amount of a compound according to any one of claims 1, 3, 4, 6-10 or 12-15. or of a pharmaceutical composition according to any one of claims 2, 5, 11 or 16.
18
A compound according to any one of claims 1, 3, 4, 6-10 or 12-15 or a 15 composition according to any one of claims 2, 5, 1 1 or 16 when used for the treatment of disease characterised by excess renal reabsorption of water in a mammal.
19
The use of a compound according to any one of claims 1, 3, 4, 6-10 or 12- 15 for the manufacture of a medicament for the treatment of disease in a mammal characterised by excess renal reabsorption of water.

Independent claims10

3,539 paragraphs in 684 sections, as filed

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 congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

Background of the Invention

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

Vasopressin is involved in some cases of congestive heart failure where peripheral resistance is

|R:\LIBZ]()5389.doc:hin

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-2increased. νχ antagonists may decrease systemic vascular resistance, increase cardiac output and prevent vasopressin induced coronary vasoconstriction. Thus, in conditions with vasopressin induce increases in total peripheral resistance and altered local blood flow, νχantagonists may be therapeutic agents. Vi antagonists may decrease blood pressure, induced hypotensive effects and thus be therapeutically useful in treatment of some types of hypertension.

The blockage of V2 receptors is useful in treating diseases characterized by excess renal reabsorption of free water. Antidiuresis is regulated by the hypothalamic release of vasopressin (antidiuretic hormone) which binds to specific receptors on renal collecting tubule cells. This binding stimulates adenylyl cyclase and promotes the cAMP-mediated incorporation of water pores into the luminal surface of 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

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-3hemorrhage-stroke, thrombosis-bleeding and abnormal states of water retention.

The following prior art references describe peptide vasopressin antagonists: M. Manning et al., <£. Med. Chem.. 3S.< 382 (1992); M. Manning et al., J. Med.

Chem., 35, 3895(1992); H. Gavras and B. Lammek, U.S. Patent 5,070,187 (1991); M. Manning and

W.H. Sawyer, U.S. Patent 5,055,448(1991) F.E. Ali, U.S. Patent 4,766,108(1988); R.R. Ruffolo et al., Drug

News, and Perspective, 4(4), 217, (May) (1991) . P.D. Williams et al., have reported on potent hexapeptide oxytocin antagonists [£.. Med. Chem. , 35. 3905(1992)] which also exhibit weak vasopressin antagonist activity in binding to Vi and V2 receptors. Peptide vasopressin antagonists suffer from a lack of oral activity and many of these peptides are not selective antagonists since they also exhibit partial agonist activity.

Non-peptide vasopressin antagonists have recently been disclosed, Y. Yamamura et al., Science, ·

252, 579(1991); Y. Yamamura et al., Br. Pharmacol,

105, 787(1992); Ogawa et al., (Otsuka Pharm Co., LTD.) EP 0514667-Al; EPO 382185-A2; WO9105549 and

U.S.5,258,510; WO 9404525 Yamanouchi Pharm.Co.,Ltd., WO 9420473; WO 9412476; WO 9414796; Fujisawa Co. Ltd.,

EP 620216-Al Ogawa et al, (Otsuka Pharm. Co.) EP 470514A disclose carbostyril derivatives and pharmaceutical compositions containing the same. Non-peptide oxytocin and vasopressin antagonist have been disclosed by Merck and Co.; M.G. Bock and P.D. Williams, EP 0533242A; M.G.

Bock et al., EP 0533244A; J.M. Erb, D.F. Verber, P.D. Williams, EP 0533240A; K. Gilbert et al., EP 0533243A.

Premature birth can cause infant health problems and mortality and a key mediator in the mechanism of labor is the peptide hormone oxytocin. On the basis of the pharmacological action of oxytocin, antagonists of this hormone are useful in the prevention of preterm labor, B.E. Evans et al., J. Med. Chem. 35. 3919(1992), J. Med. Chem.. 36, 3993(1993) and references therein. The compounds of this invention are antagonists of the peptide hormone oxytocin and are useful in the control of premature birth.

The present invention relates to novel tricyclic derivatives which exhibit antagonist activity at V| and/or V2 receptors and exhibit in vivo vasopressin antagonist activity. The compounds also exhibit antagonist activity at oxytocin receptors.

SUMMARY OF THE INVENTION

There are disclosed herein new compounds selected from those of the general formula I:

wherein Y is a moiety selected from; -(CH2)n- wherein n is an integer from 0 to 2,

O

I I —CHIoweralkyl(CrC3) and —c—

A-B is a moiety selected from —(CH2)mN— — N—(CH2)m—

I q Io

R and R wherein m is an integer from 1 to 2 provided that when Y is -(CH2)n- and n is 2, m may 2o 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 be two;

and the moiety:

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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 or (C1-C3)lower alkylamino; (2) a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from Ο, N or 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, halogen or (C1-C3)lower alkoxy;

the moiety:

E

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C1-C3)lower alkyl, hydroxy, -COCCI3, -COCF3,

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-60 -ch=ch-no2, -(CH_)NO2 , 11

-C-0-lower alkyl^-Cg), -(CH2)qN\^ Rb ’

-(CH2)q-N 0

-(CH2)q -0-lower alkyl (CfC3), -(CH2)q0H,

I

-C-lower alkyl (C^-C^),

-CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower alkylamino, CONH-lower alkyl(C1-C3) , and -CON[lower

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-7alkyl(Ci-C3) 12; q is one or two; Rb is independentlyselected from hydrogen, -CH3 or -C2H5;

PCT/US97/10736

-10wherein p is one to five and X is selected from O, S, NH, NCH3; wherein R1 and r2 are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-11wherein 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, -CO25 lower alkyl(C1-C3) , and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr’ wherein Rc is selected from halogen, (C^Cg) lower alkyl, -O-lower al kyl (C^-Cp, OH,

II

-O-C-lower alkyl(C^-Cp, -S-lower alkyl(C^Cj),

wherein Ra and Rb are as hereinbefore defined and Ar' is selected from moieties of the formula:

WO 97/49707

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is selected from 0, wherein W'

S, NH, N-lower alkyl (ΟχC3), NHCO-lower alkyl (C1-C3 ) , and NSO21ower alkyl(ΟχC3) ;

r8 and are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen,

-NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2< -OCF3,

-OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3) ,

II

-O-C-(CrC3)

-N(Rb) (CH2) vN(Rb) 2 / and CF3 wherein v is one to three and;

R1® is selected from hydrogen, halogen and lower alkyl(C1-C3); is

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-13- O-low er alkyl (C3-Cg) branched or unbranched ,

-NH lower alkyl(C3-C8) branched or unbranched ,

-z-Ru z~R SO_N\

-NH-CH2(CH2)n—, \_ Rt

- NHCO —<Z 7

-NCO

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wherein n is 0 or 1; q is 1 or 2; Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (C1-C3)lower alkyl, (Οχ5 C3) lower alkoxy and halogen; R^5 is hydrogen, (C1-C3) lower alkyl, (C1-C3)-lower alkoxy and halogen; R^O is hydrogen, halogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy, NH2, -NH(C1-C3) lower alkyl, -N-[(C1-C3) lower alkyl]2/

N—lower alkyΙ(Οχ---C3) —NH—(CH2)P—NHIower alkylfC-,—C3) —NH—(CH2)P—N[lower alky 1(0-,—C3)]2

—NH—(CH2)p—N N—lower alkyl(CrC3)

and the pharmaceutically acceptable salts thereof.

In a first embodiment, this invention relates to compounds selected from those of the formula:

| R:\LIBZ ]05389.doc:lam

15a rv~N e

ZO >=F

Oa-b wherein Y is CH2 ;

A-B is a moiety selected from

-(CH2)n- and -N-(CH2)'3 L R R3 and the moiety :

o zo represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

15b

II

-CH=CH-NO2,-(CH2)qNO2

-C-0-lower alkyl(CrC3), - (CH2)q

-(CH2)q -0-lower alkyl (C^Cp, -(CH2)qOH,

II <=i

-C-lower alkyl (C.-C ), -CH-Nx^N -CH,-Nx o 1 J i ά N ·· ·· • · ·· • · · ···· ···· • · ···· ···· ··· • ·· • · *

···»

A ···· • · ···· ···· ··

A

-CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower alkylamino, CONH-lower alkyl(C1-C3), arid -CONflower alkyl (C1-C3 ) ] 2 ; <3 is one or two;

15c

Rb is independently selected from hydrogen, -CH3 or -C2H5;

Rc is H, lower alkyl(Ci-C3), hydroxyethyl, -CH2CO2R50, -CH2C(CH2OH)3; R?<> is H or lower alkyl (C1-C4);

R·’ is a moiety of the formula:

O

II —C—Ar wherein Ar is a moiety selected from the group consisting of r2°

R20

R2

ΙΟ • · · • ·· · • · · · • · • · • · · · • · · · • · · · • · · · • · · • · • 9

R4 is selected from hydrogen, lower alkyl(C j-C3); -CO-lower alkyl (C1-C3);

R20 is hydroxy;

R2 is selected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy, hydroxy and halogen;

R6 is selected from (a) moieties of the formula:

15d

-NCOAr’, -NCOCH2Ar', -NCONAr',

99 9

- NCO-(CH2)n-cycl oal kyl ,

-NH-C-O-1 ower alkyl (C3~CQ) straight or branched, 0

- NH- C-1 ower al kyl (C3- Cg) strai ght or branched, -NHSO2-lower alkyl(C3-C8) straight or branched, i?

-NH-C-O-1ower alkenyl(C3-C8) straight or branched, 0

-NH-C-lower alkenyl (C3-C8) straight or branched, -NHSO2-lower alkenyl (C3-C8) straight or branched,

15e wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; R;| is independently selected from hydrogen, -CH3, -C2H5, zRb —(CH2)q—N Kb

-(CH2)M-O-lower alkyl(C)-C3) and -CH2CH2OH;

q is one or two;

R1 is selected from hydrogen, (C1-C3) lower alkyl, (C1-C3) lower alkoxy, hydroxy and halogen;

J

R and R|, are as hereinbefore defined;

(b) moieties of the formula:

wherein R7 is lower alkyl(C3-C8), lower alkenyl(C3-Cs), -(CH2)p-cycloalkyl(C3-C6),

R1

|R:\LIBZ]05389.doc:lam

I5f wherein p is one to five and X is selected from 0, s,

NH, NGH3; wherein rT and r2 are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

I5g

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, -C02~ 5 lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

R

13

-N-COCHAr'

R c wherein Rc is selected from halogen, (C}-C3) lower alkyl, -0-low er alkyl (C)-C3), OH,

-O-C-lower al kyl (C C 3), -S-lower al kyl (C}-C3),

-NH(CH2)q-CON

-NH(CH2)q-N

-O-CCH,)^

and Ra and Rb are as hereinbefore defined wherein Ar* is selected from moieties of the formula:

15h

wherein W' is selected from 0, S, NH, N-lower alkyl(CiC3), NHCO-lower alkyl(C1-C3), and NS021ower alkyl(CiC3) ;

R8 and R9 are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3) , -N-[lower alkyl(C1-C3 ) ] 2 , -OCF3, -OH, -CN, -S-CF3, -NO2/ -NH2 , 0-lower alkyl(C1-C3) ,

-O-C-(C,-C3) ,

-N(Rt>) (CH2 ) vN (Rb) 2 < and CF3 wherein v is one to three and;

R10 is selected from hydrogen, halogen and lower alkyl(C1-C3);

15i

R14 is

-0-low er alkyl(C3-C8) branched or unbranched ,

-OCH2-(CH2)n-0^ J

-NH lower al kyl (C3- Cg) branched or unbranched ,

15.1

q is 1 or 2;

wherein n is 0 or 1;

15k

Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (Ci-C3)lower alkyl, (Ci-C3)lower alkoxy and halogen;

R^S is hydrogen, (Ci-C3)lowcr alkyl, (C]-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (C j-C3)lower alkyl, (C 1-C3)lowcr alkoxy, NH2. -NH(C C3)lowcr alkyl, -N-[(C]-C3)lowcr alkyl)2.

N-1 ower d kyl <C]- C3)

- NH- (CH2) - NHI ower d kyl (C, - C3) ,

- NH-(CH2)p- N(lower d kyl(Cr C3))2 ,

-NH- (CH

- NH- (CH2)p- N

- NH- (CH2)p- N \

N-1 ower d kyl (Ct- C3) ,

and the pharmaceutically acceptable salts thereof.

a In a second embodiment, this invention relates to compounds selected from those of the formula:

151

<td colspan="3"> wherein Y is CH2;</td>

<td> Λ-B is a moiety selected from</td><td></td><td></td>

<td> and the moiety:</td><td> 0</td><td></td>

represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C]-C3)lower alkyl, halogen, amino, (Ci-C3)lower alkoxy or (C]-C3)lowcr

alkylamino; the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic riu-g wherein D, E and F are selected from carbon and nitrogen and wherein the carbon atoms m4y be optionally substituted by a substituent selected from:

Rb

Rc

-(CHA-N

q is one or two;

Rb is independently selected from hydrogen, -CH3 or -C2H5;

Rc is hydroxycthyl, -CH2CO2R^®, or -CI42C(CH2OH)3;

R^O is H or lower alkyl(C] -C4);

R3 is a moiety of the formula:

O

-C- Ar wherein Ar is a moiety selected from the group consisting of

is selected from hydrogen, lower alkyl(Ci-C3); -CO-lower alkyl(C I-C3);

R1 and R3 are independently selected from hydrogen, (Ci-C3)lower alkyl, (CiC3)lower alkoxy, hydroxy and halogen;

is selected from (a) moieties of the formula:

<td> NCOAr' I 7</td><td> — NCOCH?Ar' . l *</td>

— NCONAr'

I I

Ra Rb

2()

15η

NCOLCH^ — cycloalkyl

-NCO

II — NH~ C~O~ lower alkyl (Cj-Cg) straight or branched ~ NH~ C~ lower alkyl (C3-C8) straight or branched 5 ^SO2 lower alkyl (C,-C8) , ~NSO2— lower alkenyl (CrC8) ,

O

II

NH C ~ O ~ lower alkenyl (C3-Cg) straight or branched 5 O

II or NH- C ~ lower alkenyl (C3-Cg) straight or branched wherein cycloalkyl is defined as C3 to Cg cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

15ο

-(CH2)q

- (CH2)q-

-(CII?)q-O-lower alkyl(C I-C3) and -CH2CH2OH;

q is one or two;

R1, ^2 and Rb arc as hereinbefore defined; or (b) inoictics of the formula:

wherein is selected from lower alkyl(C3-C8), lower alkenyl(C3-Cs), -(CH2)pcycloalkyl(C3-C6),

wherein p is one to five;

X is selected from O, S, NH, NCH3;

R1 and are as hereinbefore defined; or

15p (c) a moiety of the formula:

-N-OOJ wherein J is Ra, lower alkyl(C3-Cg) branched or unbranchcd, lower alkcnyl(C3-Cg) branched or unbranchcd, O-lowcr alkyl(C3-Cg) branched or unbranchcd, -O-lowcr alkciiyl(C3-C.'s) branched or unbranchcd, tetrahydrofuran, tetrahydrothiophene, the moieties·

or -CH2-K’ wherein K' is (C1-C3) lower alkoxy, halogen, 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, (Ci-C3)lower alkyl, hydroxy, -CO-Iower alkyl(C]-C3), CHO, (C]-C3)lower alkoxy, -CO2-lower alkyl(Ci-C3), and Ra and Rb are as hereinbefore defined; or

5q (d) a moiety of the formula:

wher ei n R J s s el ed ed f r orn hd ogen (C, - C ) c I 3 •·· · I 5 • · · · • · • · • · · · ···· • · · · • · · · • · · • · • · / R

-NH(CH„)-N\ 0

R, b

/R,

-NH(CH) -CCbK 2 q R b

and Ra and R^ are as hereinbefore defined wherein Ar' is selected from moieties of the formula:

I5r

end

wherein W is selected from O, S, NIL N-lower alkyl(C 1-C3), NHCO-lowcr alkyl(C 1-C3), and NSO2>ower alkylfCj -C3);

R8 and R^ arc independently selected from hydrogen, lower alkyl(C 1-C3), -S-lowcr alkyl(C 1-C3), halogen, -ΝΉ-lower alky l(C 1-C3), -N-[lower alkyl(C 1 -C3))2, -OCF3, -OH, CN, -S-CF3, -NO2, -NH2, 0-lower alky 1(C 1-C3),

O

-oc-(q-q) ,

-N(Rb)(CH2)vN(Rb)2, and CF3 wherein v is one to three and;

R10 is selected from hydrogen, halogen and lower alkyl(C 1-C3);

R14 is

15s

-O-lower d ky I (C3-C8) trenched or entrenched,

R

- NH I ower d k yI (C3- C8) tr cnched or untr onched,

5t ···· • · · · • · ·· • · · ···· • ·

2() • ·· · ·· ···· ·· · • · • · all

q is 1 or 2;

n is 0 or 1;

15u

Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (Ci-C3)Iower alkyl, (C1 -C3)lOWcr alkoxy and halogen;

R^S is hydrogen, (Cj-C3)lower alkyl, (Cj-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (Ci-C3)lower alkyl, (C )-C3)lo\ver alkoxy, ΝΉ2, -NH(CiC3)lower alkyl, -N-[(Ci-C3)lower alky I ]2,

I ower d kyl (C(-C3)

dkyltC.-q) , dkyl(Cr C3))2 ,

and the pharmaceutically acceptable salts forms thereof. 7

In a third embodiment, this invention relates to compounds selected from those of the formula:

15v

wherein Y is CH2;

A-B is a moiety selected from

end

-N-(CH2)and the moiety:

XSedn,fr„Ph7' .r ^bSti‘“,ed Phenyl °P,iOnally SUbS!1,U,ed by One °r substituents m( 1 3) °wer alkyl, halogen, amino, (C[-C3)lower alkoxy or (Cj-C3)lower alkylamino;

the moiety:

15w

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F arc selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (Ci-C3)lowcr alkyl, hydroxy, -COCCI3, COCF3,

O

-C-O-lower alkyl (C,-C3)

-CH=CH-NO2 -(CH2)qNO2

-(CH2)q-N

-(CH2)q-0-lower alkyl (C,-C3)

O

-C-lower alkyl (C]-C3)

15x

-CHO, amino, (C j -C3)lowcr alkoxy, (Ci -C3)lowcr alkylamino, CONH-lowcr alkyl(Ci -C3), and -CON[lower alkyl(C 1-C3))2;

q is one or two;

Rb is independently selected from hydrogen, -CH3 or -C2H5;

Re is selected from H, lower alkyl (C1-C4), hydroxyethyl, -CHqCOqR^O or CH2C(CH2OH)3;

is H or lower alkylfC 1-C4);

R^ is a moiety of the formula: ·

O

II

-C-Ar wherein Ar is the moiety:

is selected from hydrogen, lower alkyl(Ci-C3); -CO-lower alkyl(Ci-C3); R^and are independently selected from hydrogen, (Ci-C3)lower alkyl, (C1C3)lower alkoxy, hydroxy and halogen;

15y

R14 is selected from:

q is 1 or 2;

n is 0 or 1;

Ra is hydrogen, -CH3 or-C2H5; R’ is hydrogen, (Cj-C3)lower alkyl, (Ci-C3)lower alkoxy and halogen;

R4^ is hydrogen, (C[-C3)lower alkyl, (C]-C3)lower alkoxy and halogen;

R^O is hydrogen, halogen, (Ci-C3)lower alkyl, (C]-C3)lower alkoxy, NH2, -NH(C]C3)lower alkyl, -N-[(Ci-C3)lower alkyl]2,

15z

/ \

I ower d kyI (Ct- C3)

- NH- (CH2)p NHI ower d kyI (C, - Cp ,

- NH- (CH2)p- N(l ower d kyI (C( - C3))2 ,

-NH-(CH

- NH- (CH2)p- N N-1 ower d kyI (C,- C3) ,

- NH- (CH ) - N O 2 p \____/

and the pharmaceutically acceptable salts forms thereof.

DETAILED DESCRIPTION OF THE INVENTION

Within the group of the compounds defined by formula 1, certain subgroups of compounds are broadly preferred. Broadly preferred are those compounds wherein R3 is the moiety:

3d and Ar is selected from the moieties:

O

II —CAr

Y is (Cl-E)» and n is one or zero;

wherein R20, R2, R4, R6 and R14 are as hereinbefore defined.

Especially preferred are compounds wherein RJ is the moiety:

····

II

CAr and

Ar is selected from the moieties:

R1 R1

Y is - (CH?),! and n is one and m is one; wherein R1. R2, R4, R6 and R14 are as hereinbefore defined.

Especially preferred are compounds wherein R3 is the moiety:

O —CAr and

2ii Ar is selected from the moieties:

|R\I.IBZ|(J53S9.dl»c:lam

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one or zero;

I -NCOAr',

-NCOCHjAr’, Ra Rb

I I

R b

-NCONAr',

-X-R? } - NCO-(CH2)n-cycloalkyl ;

where Ar' is selected from the group:

and R14, X, W', Ra, Rb and cycloalkyl are as previously described.

More particularly preferred are compounds of the formulae:

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from a phenyl, thiophene, furan, pyrrole, or is selected pyridine ring;

R3 is the moiety:

Ar wherein Ar is selected from the

moieties:

R6 is

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-NCOAr',

-NCOCH2Ar’, Ra

-NCONAr',

-X-R7t -NCO-(CH2)n-cycloalkyl ; and Ar' is selected from the moieties:

wherein X, Ra, Rb< R^, R^, R&, R^, R·^, cycloalkyl and

W' are as hereinbefore described;

R^1 is selected from hydrogen, halogen, (C1-C3) lower alkyl, hydroxy,

-<CH2)qr<^ Kb

I

-C-low er al kyl (C^C^,

-CHO, and (C1-C3)lower alkoxy; and r!2 is selected from 10 hydrogen, (C1-C3)lower alkyl, halogen and (C1-C3) lower alkoxy.

Also particularly preferred are compounds of the formulae:

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wherein m is one or two; the moiety:

is selected from a phenyl, thiophene, furan, pyrrole or pyridine ring;

is the moiety:

- 2Ar wherein Ar is selected from the moieties:

R^ is

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-24-NCOAr', -NCOCH2Ar’, -NCONAr',

-X-R7t -NCO-(CH2)n-cycloalkyl ;

(CH2)n cycloalkyl; Ar' is selected from the moieties:

wherein X, Ra, Rb' R^, r6.

W' are as hereinbefore defined;

R1* is selected from hydrogen, halogen, (C1-C3) lower alkyl, hydroxy,

-(CH2)qN<bRb

-C-lower al kyl (C1-C3),

-CHO, and (C1-C3)lower alkoxy; and r!2 is selected from hydrogen, (C1-C3)lower alkyl, halogen and (C1-C3)lower alkoxy.

More particularly preferred are compounds of the formulae :

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R3 is the moiety:

-CAr wherein

Ar is selected from the moieties:

R6 is

-NCOAr',

-NCOCH2Ar’,

-NCONAr',

-X-R

-NCO- (CH2)n- eye I oal kyl ;

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wherein n is 0 or 1; Ra is hydrogen, -CH3 or -C2H5; R‘ is hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen; R20 is hydrogen, halogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy, NH2, -NH(Ci-C3) lower alkyl, -N[(C1-C3) lower alkyl]2»

-N

I

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-27wherein cycloalkyl is defined as C3-C6 cycloalkyl, cyclohexenyl or eyelopentenyl; Rb is hydrogen; Ra is independently selected from hydrogen, -CH3, -C2H5 or -(CH2)qN(CH3)2; Ar' is selected from the moieties:

wherein q, X, Ra, Rb» R5» R7, R8» R9, R10, R11 and W' are as hereinbefore described;

Ri2 and r13 are independently selected from hydrogen, (C1-C3) lower alkyl, halogen, amino, (C1-C3) lower alkoxy or (C1-C3) lower alkylamino.

Also particularly preferred are compounds of the formulae:

wherein m is one or two;

R3 is the moiety:

wherein Ar is selected from the moieties:

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-NCOAr ,

-NCONAr',

-NCOCH2Ar',

R ia

-NCO-(CH2)n-cycloalkyl ;

-X-R7

J cycloalkyl is defined as C3-C6 cycloalkyl, wherein cyclohexenyl or cyclopentenyl; Rfe is hydrogen; Ra is independently selected from hydrogen, -CH3, -C2H5 or

- (CH2) qN(CH3 ) 2; and Ar* is selected from the moieties:

R5, R7,

R8

rH, rI^ and W' selected from hydrogen, amino, (C1-C3) lower wherein q, are as hereinbefore defined;

r!2 and r13 are independently (C1-C3) lower alkyl, halogen, alkoxy or (C1-C3) lower alkylamino.

The most highly broadly preferred of the compounds are those of the formula:

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wherein Y is a moiety -(CH2)-;

A-B is a moiety:

-N-(CH2)— ' 3

R the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring optionally substituted by halogen, (C1-C3)lower alkyl, and -(CH2)q-N(Rb)2 wherein 10 D is carbon; q is 1 or 2; Rb is independently selected from hydrogen, -CH3, and C2H5;

R3 is a moiety of the formula:

wherein Ar is a moiety selected from the group consisting of

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-30r! and R^ are independently selected from hydrogen, (ΟχC3)lower alkyl, (C1-C3)lower alkoxy and halogen; R14 is selected from a moiety of the formula:

wherein Ra is hydrogen; R^-θ is selected from hydrogen, halogen, and (C1-C3)lower alkyl; R^ is selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(Οχ10 C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3), CF3, and

II

-O-C-(C,-C3) ;

and the pharmaceutically acceptable salts, esters and 15 pro-drug forms thereof.

-31compounds formula :

Preferred group I. Among the more preferred disclosed herein are those selected from the

-d-'e i

F

-wherein Y is CH2;

A-B is a moiety selected from and

-N-(CH2)♦ 9

R3 and the moiety:

substituted phenyl optionally represents phenyl or substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

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-32-C-0-lower al kyl(C

-CH=CH-N02,-(CH2)N02 , / Rb -(CH2)q< , Kb

-(CH2)q-N 0

-(CH2)q -O-lower alkyl (C^Cp, -(CH2)qOH,

II 1=1 f=

-C-lower alkyl (C^Cj), -CH^N-^N , -CH2-

Ν=η , ~ (CH2)q-

- (CH2)q- N N

-,(CH2)q-<^ e

•<ch2),-nQ>-<£

-CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower alkylamino, CONH-lower alkyl(C1-C3), and -CONflower alkyl(C1-C3)]2; q is one or two;

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-33Rb is independently selected from hydrogen, -CH3 or -C2H5;

Re is H, lower alkyl(C1-C3), hydroxyethyl, -CH2CO2R^0, -CH2C(CH2OH)3;

r50 is H or lower alkyl(C1-C4);

R3 is a moiety of the formula:

-> Ar wherein Ar is a moiety selected from the group consisting of

R4 is selected from hydrogen, lower alkyl(C1-C3); -COlower alkyl(C1-C3);

r1 and R2 are independently selected from hydrogen, (Ci~

C3)lower alkyl, (C1-C3)lower alkoxy, hydroxy and halogen; R3 is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formula:

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-34ia

-NCOAr’,

R a

I

-NCOCH^r’,

R ia 1 -NCONAr’,

I’

- NCO- (CH2)n- eye I oal kyl

- NH- C- Ο-1 ower al kyl (C,- Cn) strai ght or branched, 0

-NH-C-lower alkyl(C3-C8) straight or branched,

- NHSO2-1 ower al kyl (C3- C8) straight or branched,

-NH-C-0-1 ower alkenyl(C3-C8) straight or branched, 0

II

-NH-C-lower alkenyl(C3-C8) straight or branched,

- NHSO2-1 ower al kenyl (C3-C8) strai ght or branched,

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PCT/US97/10736 wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

-(0Η2)ς.θ

-(CH2)q-N 0

-(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rfc are as hereinbefore defined;

(b) moieties of the formula:

- X- R7 ,

wherein R7 is lower alkyl(C3-C8),

-(CH2)p-cycloalkyl(C3-C6), lower alkenyl(C3-C8),

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-36wherein p is one to five and X is selected from 0, S, NH, NCH3; wherein R1 and r2 are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl(C3-C3) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-37wherein 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, (Ci~C3)lower alkoxy, -CO25 lower alkyl(C1-C3), and Ra and Rfc are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr'

R c wherein Rc is selected from halogen, (C^Cj) lower alkyl, -0-lower alkyl(C1-C3), OH,

II

-O-C-lower alkyl(C^Cg), -S-lower alkyl(C^Cj),

-S-(CH2)2-N<Rb

-NH(CH2)q-C0N

-NH(CH2)q-N

-0- (CH,)^

and Ra and Rfo are as hereinbefore defined wherein Ar' is selected from moieties of the formula:

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wherein W' is selected from O, S, NH, N-lower alkyl (C]_C3), NHCO-lower alkyl(C1-C3), and NS021ower alkyl(C1C3) ;

r8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2> -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3),

-41Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (CiC3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R45 is hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (C1-C3)lower alkyl, (CiC3)lower alkoxy, NH2, -NH(C1-C3)lower alkyl, -N-[(CiC3)lower alkyl]2»

-N 0

- N N-1 ower al kyl (C^C3)

- NH- (CH2)p- NHI ower al kyl (C,- C3),

-NH-(CH2)p-N[lower alkyl(CfC3)]2 ,

-NH-(CH2)p-N

-NH-(CH2)p-N N-lower alkyl (C^-Cj),

- NH- (CH2)p- N 0

and the pharmaceutically acceptable salts, esters and 10 pro-drug forms thereof.

Within preferred group I above are the following preferred sub-groups 1, 2 and 3 of compounds:

1. wherein the moiety A-B is:

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wherein R2 is as defined in preferred group I above;

2. wherein R2 is the moiety:

and Ar is

wherein R2·, R2 and R2·^ are as defined in preferred group I above;

3. wherein R2 is the moiety:

and Ar is

wherein R2, R2, and R® are as defined in preferred group I above.

-43Preferred group II. Among the most preferred compounds disclosed herein are those selected from the formula:

wherein Y is CH2;

A-B is a moiety selected from

-n-ch2and the moiety:

represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are carbon and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (Ci~ C3)lower alkyl, hydroxy, -COCCI3, -COCF3,

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-44o -CH=CH-N02,-(CH2)qN02 , II

-C-0-lower alkyl(CfC3), -(CH2)qN^ Rb

•(CH2)q -0-lower alkyl (C^Cg), -(CH2)qOH,

Γ=1 F=1

-C-lower alkyl (C^-Cg), -CH^Nx^N -CH2-

N=1

CH2- N , -(CH2)q-

-(CH2)q- N N

-(CH2)q-K^ e

-((:ΗΛ-θ-Ν<^ ^00

-CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower alkylamino, CONH-lower alkyl(C1-C3), and -C0N[lower alkyl(C1-C3)]2; q is one or two;

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-45Rfr is independently selected from hydrogen, -CH3 or -C2H5;

Re is H, lower alkyl(C1-C3), hydroxyethyl, -CH2CO2R50, -CH2C(CH2OH)3;

r50 is H or lower alkyl(C1-C4);

r3 is a moiety of the formula:

2-Ar wherein Ar is a moiety selected from the group consisting of

R4 is selected from hydrogen, lower alkyl(C1-C3) ; -COlower alkyl(C1-C3);

R1 and r2 are independently selected from hydrogen, (Ci~ C3)lower alkyl, (C1-C3)lower alkoxy, hydroxy and halogen; is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

r6 is selected from (a) moieties of the formula:

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-46- NCOAr- NCOCH2Ar- NCONAr

-NCO—C iCHA

-NH-C-O-lower alkyl(C3-Cg) straight or branched, 0

I

-NH-C-1ower alkyl(C3-C8)straight or branched,

- NHSO2-1ower al kyl (C3-C8) strai ght or branched,

- NH-C- 0-1 ower al kenyl (C3- C8) straight or branched,

I

-NH-C-1ower alkenyl(C3-C8) straight or branched, -NHS02-lower alkenyl(C3-C8) straight or branched,

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-47wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

-(ΟΗ^-(CH2)q-N 0

-(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rfa are as hereinbefore defined;

(b) moieties of the formula:

-X-R7,

wherein is lower alkyl(C3-C8), lower alkenyl(C3-C8),

- (CH2)p-cycloalkyl(C3-C6),

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wherein p is one to five and X is selected from 0, S,

NH, NCH3; wherein and R^ are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-49wherein 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, -CO25 lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr'

R c wherein Rc is selected from halogen, (C^-Cg) lower alkyl, -O-lower alkyl(C^Cg), OH,

II

-O-C-lower alkyl(C^-Cg), -S-lower alkyl(C^Cg),

-S-(CH2)2-N<bKb

-NH(CH2)q-CON

-NH(CH2)q-N<^RbRb

-0- (ΟΗ^,Ν

and Ra and Rb are as hereinbefore defined wherein Ar1 is selected from moieties of the formula:

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wherein W' is selected from 0, S, NH, N-lower alkyl (C]_C3), NHCO-lower alkyl(C1-C3), and NS021ower alkyl(ΟχC3) ;

r8 and are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3),

II

-O-C-(C,-C3) ,

-N(Rb)(CH2)vN(Rb)2» and CF3 wherein v is one to three and;

rIO is selected from hydrogen, halogen and lower alkyl(C1-C3); R1^ is

V

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C3) lower alkoxy, NH2, -NH(C].-C3) lower alkyl, -N-[(CiC3)lower alkyl]2/

- NH- (CH2)p- NHI ower al kyl (Cf C3),

- NH- (CH2)p- N[l ower al kyl (C,- C3)]2 ,

-NH-(CH2)p-N

-NH-(CH2)p-N N-1 ower al kyl (C^-Cg),

and the pharmaceutically acceptable salts, esters and 10 pro-drug forms thereof.

Within preferred group II above are the following preferred sub-groups 1 and 2 of compounds:

1. wherein R8 is the moiety:

-540

I

-C-Ar and Ar is

wherein Rl, R^ and R^ are as defined in preferred group 5 II above;

2. wherein R^ is the moiety:

-CAr and Ar is

wherein R% R^ and R^ are as defined in in preferred group II above.

Preferred group III. Among the preferred compounds disclosed herein are those selected from those of the formulae:

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-55wherein Y is CH2;

A-B is a moiety selected from

and -N-(CH2)-

and the moiety:

represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

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-560 -CH=CH-NO2,-(CH2)qNO2 ,

-C-0-lower alkyl(C,-0^,

-(CH2)q-N 0

- (CH2)q -Ο-1 ower al kyl (C ,-C3), - (CH2)qOH,

I r=i 1=1

-C-lower alkyl (C1-C3), -CH2-N^.N . -CH2-

N=1

-Cn^-N^N

-(CH2)q-

J

-CHO, amino, (C1-C3)lower alkoxy, (C1-C3)lower alkylamino, CONH-lower alkyl(C1-C3), and -C0N[lower alkyl(C1-C3)]2; Q is one or two;

L

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Rb is independently selected from hydrogen, -CH3 or -C2H5;

Re is H, lower alkyl(C1-C3), hydroxyethyl, -CH2CO2R50, -CH2C(CH2OH)3;

R50 is H or lower alkyl(C1-C4);

R3 is a moiety of the formula:

wherein Ar is a moiety selected from the group consisting of

R^ is selected from hydrogen, lower alkyl(C1-C3); -COlower alkyl(C1-C3);

R2 is selected from hydrogen, (C1-C3) lower alkyl, (Ci~

C3)lower alkoxy, hydroxy and halogen; R3 is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formula:

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-58-NCOAr', -NCOCH2Ar',

- NCO- (CH2)n- cycl oal kyl ,

-NCONAr’,

-NH-C-O-lower alkyl(C3-C8) straight or branched, 0

II

- NH-C-1 ower al kyl (C3- C8) straight or branched,

-NHSO2-1 ower al kyl (C3- C8) strai ght or branched,

-NH-C-0-1 ower al kenyl (C3- C8) straight or branched, 0

II

-NH-C-lower alkenyl(C3-C8) straight or branched, -NHS02-lower alkenyl(C3-C8) straight or branched,

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-59wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

-(CH2)q-t<^ , -(CH^-nQ»

-(CH2)q-N_2) , -(CH2)q5 -(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rb are as hereinbefore defined;

<td> (b) moieties of the</td><td colspan="2"> formula:</td><td></td>

wherein R2 is lower alkyl(C3-Cs), lower alkenyl(C3-C8),

-(CH2)p-cycloalkyl(C3-C6),

S

R

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-60wherein p is one to five and X is selected from O, s, NH, NCH3; wherein Ri and R3 are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl(C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K’ wherein K* is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-61wherein 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, -CO25 lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr’

R c wherein Rc is selected from halogen, (C^Cg) lower alkyl, -O-lower alkyl (C^C^, OH,

II

-O-C-lower alkylCC^Cg), -S-lower alkyl(C.pCg),

-S-(CH2)2-N

-NH(CH2)q-CON

J

-NH(CH2)q-N

and Ra and Rb are as hereinbefore defined wherein Ar‘ is selected from moieties of the formula:

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wherein W’ is selected from O, S, NH, N-lower alkyl(ΟχC3), NHCO-lower alkyl(C1-C3), and NSO21ower alkyl(ΟχC3);

r8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2· -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3),

-65wherein n is 0 or 1;

Ra is hydrogen, -CH3 or -C2H5; R- is hydrogen, (CjC3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R45 is hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy 5 and halogen;

R20 is hydrogen, halogen, (C1-C3)lower alkyl, (Ci~ C3)lower alkoxy, NH2, -NH(C1-C3)lower alkyl, -N-[(Ci~ C3)lower alkyl]2#

O Ό . -Ο

- N N-1ower al kyl (C^ C3)

- NH- (CH2)p- NHI ower al kyl (C,- C3),

- NH- (CH2)p- NDower al kyl (C,- C3)]2,

-NH- (CH2)p- N N-1 ower al kyl (Cy C3),

and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

Within the preferred group III above are the following preferred sub-groups 1, 2 and 3 of compounds:

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-661. wherein A-B is a moiety:

R3 where R^ is as defined in preferred group III above;

2. wherein A-B is the moiety:

-N-CI-L1r3 is a moiety wherein

Ar is:

defined

R6 wherein above;

R2 and

R6 are in in preferred group III

3. wherein

R2 is a moiety of the formula:

wherein

Ar is :

wherein R3ancj R14 are defined in preferred group III above .

Preferred group IV. Among the preferred compounds disclosed herein are those selected from those of the formula:

wherein Y is CH2;

A-B is a moiety selected from

<td> and the moiety:</td><td></td><td></td>

<td> represents phenyl or</td><td colspan="2"> substituted phenyl optionally</td>

substituted by one or two substituents selected from (C1-C3)lower alkyl·, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

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-68is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring where D is carbon and E and F are selected from carbon and nitrogen and wherein the carbon atoms may be optionally substituted by a substituent selected from halogen, (C1-C3)lower alkyl, hydroxy, -COCCI3, -COCF3,

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-690 - CH=CH- N02, - (CH2)qN02 ,

-C-0-lower alkyKC^Cg),

r~\

-(CH2)q-N 0

-(CH2)q -Ο-1ower alkyl (CrC3), - (CH2)qOH,

I

-C-1ower alkyl (Cj-Cj), r=i f=i

-CH-N^N 2 > z N

N=1 'CH2-N^N ,

-(CH2)q-

-(CH2)q- N N

-CHO, amino, (C1-C3) lower alkoxy, (Ci-C3)lower alkylamino, CONH-lower alkyl(C1-C3), and -CON[lower alkyl(C1-C3)]2; q is one or two;

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-70Rb is independently selected from hydrogen, -CH3 or -C2H5;

Re is H, lower alkyl(C1-C3), hydroxyethyl, -CH2CO2R50, -CH2C(CH2OH)3;

r50 is H or lower alkyl(C1-C4);

R3 is a moiety of the formula:

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

OH

R4 is selected from hydrogen, lower alkyl(C1-C3); -COlower alkyl(C1-C3);

R2 is selected from hydrogen, (C1-C3)lower alkyl, (Cl~ 15 C3)lower alkoxy, hydroxy and halogen; R3 is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formula:

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-74wherein 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, -CO25 lower alkyl (C1-C3) , and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr' Rc wherein Rc is selected from halogen, (C^Cg) lower alkyl, -O-lower alkyl (C^Cg), OH,

II

-0-C-lower alkyl(C^-Cg), -S-lower alkyl(C-j-Cg),

-S-(CH2)2-N<RbRb

-NH(CH2)q-C0N

-NH(CH2)q-N

and Ra and Rb are as hereinbefore defined wherein Ar' is selected from moieties of the formula:

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wherein W' is selected from O, S, NH, N-lower alkyl(CiC3), NHCO-lower alkyl (C3.-C3 ) , and NSO21ower alkyl(ΟχC3) ;

R3 and r9 are independently selected from hydrogen, lower alkyl(Ci-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl (C1-C3),

II

-O-C-(C,-C3) ,

-N(Rb)(CH2)vN(Rb)2< and CF3 wherein v is one to three and;

R10 is selected from hydrogen, halogen and lower alkyl(C1-C3); R2^ is

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-76-0-1ower al kyl (C3-C8) branched or unbranched ,

-NH lower alkyl(C3-Cg) branched or unbranched ,

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-NCOfCH^-/ y—R20

q is 1 or 2;

wherein n is 0 or 1;

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-78Ra is hydrogen, -CH3 or -C2H5; R· is hydrogen, (CiC3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R45 is hydrogen, (C1-C3)lower alkyl, (Ci-C3)lower alkoxy and halogen;

R^O is hydrogen, halogen, (C1-C3) lower alkyl, (Ci~ C3)lower alkoxy, NH2> -NH(C1-C3)lower alkyl, -N-[(CiC3)lower alkyl]2/ •O Ό -O.

N-1ower al kyl (C,C3)

- NH- (CH2)p- NHIower al kyl (Cr C3),

- NH- (CH2)p- N[l ower al kyl (Cr C3)]2 ,

-NH-(CH2)p-N

-NH-(CH2)p-N N-1 ower al kyl ((^-C3) r

and the pharmaceutically acceptable salts, esters and 10 pro-drug forms thereof.

Within the preferred group IV above are the following preferred sub-groups 1 and 2 of compounds:.

1. wherein A-B is the moiety:

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-79-n-ch2I «

I 9

R3 is a moiety of the formula:

wherein Ar is:

wherein R2 and R14 are defined in preferred group IV above;

2. wherein A-B is the moiety:

-n-ch2I 1

R3 is a moiety of the formula:

wherein Ar is:

-80wherein R^ and R14 are defined in preferred group rv above.

Preferred group V. Among the more preferred compounds disclosed herein are chose selected from the formula:

wherein Y is CH2 ;

A-B is and the moiety:

represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy 15 or (C1-C3)lower alkylamino;

the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are carbon wherein the carbon atoms may be optionally substituted by a substituent selected from

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-81- CH=CH- N02, - (CH2)qNO2 , . (CH2)q<^ RbRb

-(CH2)q-N 0

-(CH2)q -O-lower alkyl (CrC3), -(CH2)qOH,

-CHO, and (C1-C3) lower alkylamino;

q is one or two;

Rb is independently selected from hydrogen, -CH3 or -C2H5;

R3 is a moiety of the formula:

wherein Ar is a moiety selected from the group consisting of

R4 is selected from hydrogen, lower alkyl (C1-C3) ; -COlower alkyl(C1-C3);

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-82r! and R^ are independently selected from hydrogen, (CiC3)lower alkyl, (C1-C3)lower alkoxy, hydroxy and halogen; R^ is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R6 is selected from (a) moieties of the formula:

-NCOAr’,

-NCOCH2Ar',

-NCO-(CH2)n-cycloalkyl ,

wherein W' is selected from O, S, NH, N-lower alkyl(Ci10 C3), NHCO-lower alkyl(C1-C3), and NSO2lower alkyl(C1~

C3) ;

R8 and R8 are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3) , halogen,

-NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2· -OCF3,

-OH, -CN, -S-CF3, -NO2, -NH2. O-lower alkyl(C1-C3),

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-830

II

-O-C-(C,-C3)

-N(Rb)(CH2)vN(Rb)2· and CF3 wherein v is one to three and;

R10 is selected from hydrogen, halogen and lower alkyl(C1-C3);

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or eyelopenteny1; Ra is independently selected from hydrogen, -CH3, -C2H5,

-(CH2)q-<R‘ ,

-(CH2)q-N^ , -<CH2)q-N^O

-(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rb are as hereinbefore defined;

PCT/US97/10736

-86-N-COCHAr' Rc whereinRc is selectedfrom halogen, (C^-Cj) lower alkyl, -0-lower al kyl ((^-Cp, OH,

II

-O-C-lower alkyl(C^Cj), -S-lower alkyl(CC3),

-S-(CH2)2-N

-NH(CH2)q-N

-0- (CH,)^

and Ra and Rb are as hereinbefore defined;

and

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-87wherein W' is selected from 0, S, NH, N-lower alkyl (Cj.C3), NHCO-lower alkyl(C1-C3), and NSO21ower alkyl(CiC3) ;

r8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen,

-NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3) ]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, 0-lower alkyl(C1-C3),

II

-O-C-(C,-C3) ,

-N(Rb) (CH2)vN(Rb>2/ and CF3 wherein v is one to three 10 and;

R10 is selected from hydrogen, halogen and lower alkyl(C1-C3);

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-88R^4 is

-Ο- low er al kyl (C3~ Cg) branched or unbranched ,

-NH lower alkyl(C3-Cg) branched or unbranched ,

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q is 1 or 2;

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-90wherein n is 0 or 1;

Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (Ci~

C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

r45 is hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy 5 and halogen;

r20 is hydrogen, halogen, (C1-C3) lower alkyl, (Cj.C3)lower alkoxy, NH2, -NH(C1-C3)lower alkyl, -N-[(Ci~

C3)lower alkyl]2/

-N ΙΨIower al kyl ((^-C3)

- NH- (CH2)p- NHI ower al kyl (C,- C3),

- NH- (CH2)p- NO ower al kyl (C,- C3)]2 ,

-NH-(CH2)p-N N-1ower al kyl(C^Cp

wherein W' is selected from 0, S,

NH, N-lower alkyl(CiC3) , NHCO-lower alkyl (C1-C3 ) , and NS021ower alkyl (C]_C3) ;

r8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3), halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C1-C3),

II

-O-C-(C,-C3)

-N(Rb) (CH2) vN (Rb) 2» and CF3 wherein v is one to three and;

rIO is selected from hydrogen, halogen and lower alkyl(C1-C3);

wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

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-95-(CH2)q-N<Rbt ,

-(CHz)q-N^2) , * <CHz>q-, ~(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rb are as hereinbefore defined;

<td colspan="4"> (b) moieties of the formula:</td>

lower alkenyl(C3-C8), wherein R7 is lower alkyl(C3-Cs),

wherein p is one to five and X is selected from 0, S,

NH, NCH3; wherein R1 and R2 are as hereinbefore defined;

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-96-N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -O-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran,

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic 10 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,

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-97-CO-lower alkyl(C1-C3), CHO, (Ci~C3)lower alkoxy, -CO2lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr’

R c

wherein Rc is selected from halogen, (0,-Cg) lower alkyl, -0-lower al kyl^-Cg), OH,

II

-O-C-lower alkyl (C^-Cg), -S-lower alkyl (C^Cg),

-S-(CH2),-N<fRbRb

-NH(CH2)q-CON

-NH(CH2)q-N<^RbRb

-O-iCH,)^

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-98and Ra and Rb are as hereinbefore defined;

wherein W* is selected from 0, S, NH, N-lower alkyl (C]_C3), NHCO-lower alkyl(C1-C3), and NS021ower alkyl(Οχ5 C3) ;

r8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl (C1-C3) , halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2, -OCF3, -OH, -CN, -S-CF3, -NO2, -NH2, O-lower alkyl(C1-C3),

II -O-C-(C,-C3) ,

-N(Rb) (CH2)vN(Rb) 2 < and CF3 wherein v is one to three and;

R10 is selected from hydrogen, halogen and lower alkyl(C1-C3);

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-99R14 is

-0-lower alkyl(C3-Cg) branched or unbranched ,

- 0- CH2- (CHz)n- 0

-NH lower alkyl(C3-Cg) branched or unbranched ,

-NCO

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-100-

q is 1 or 2;

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-101wherein n is 0 or 1;

Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (ΟχC3) lower alkyl, (CX-C3) lower alkoxy and halogen;

R45 is hydrogen, (CX-C3)lower alkyl, (CX-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (CX-C3)lower alkyl, (ΟχC3)lower alkoxy, NH2, -NH(Cx-C3)lower alkyl, -Ν-[(ΟχC3)lower alkyl]2·

- 1 ower al kyl (Cr C3)

- NH- (CH2)p-NHIower al kyl (Cf C3),

- NH- (CH2)p- NO ow er al kyl (C,- 0,)¾.,

-NH-(CH2)p-N

-NH-(CH2)p-N N-1ower al kyl C3),

and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

-102within preferred group VI above are the following preferred sub-groups I and 2 of compounds:

1. wherein Ar is:

and R2 and R^ are defined in preferred group VI above;

2. wherein Ar is:

and R2 and R2^ are as defined in preferred group VI above .

Preferred group VII. Among the preferred compounds disclosed herein are those selected from the formula :

wherein Y is CH2;

A-B is a moiety selected from

and the moiety:

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-103represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D, E and F are carbon and wherein the carbon atoms may be substituted by a substituent selected from -CH-CH-NO., -(CH,)„NO optionally t

-(CH2)q-(CH2)q-N

q is one or

Rb is independently selected from hydrogen,

-C2H5;

Re is H, lower alkyl(C1-C3), hydroxyethyl, -CH2CO2R50,

-CH2C(CH2OH)3;

R50 is H or lower alkyl(C1-C4) ;

R3 is a moiety of the formula:

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-1040

2-Ar wherein Ar is a moiety selected from the group consisting of

is selected from hydrogen, lower alkyl(C1-C3); -COlower alkyl(C1-C3);

r! and R2 are independently selected from hydrogen, (CiC3)lower alkyl, (C1-C3)lower alkoxy, hydroxy and halogen; is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

r6 is selected from (a) moieties of the formula:

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-105- NCOAr- NCOCH,Ar - NCONAr

-NH-C-0-1 ower alkyl(C,-C„) straight or branched, 0

I

-NH-C-lower alkyl(C3-C8) straight or branched,

-NHS02-lower alkyl(C3-C8) straight or branched,

-NH-C-0-1 ower alkenyl (C3-C8) straight or branched, 0 I

-NH-C-lower alkenyl(C3-Cg) straight or branched, -NHS02-lower alkenyl (C3-C8) straight or branched,

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PCT/US97/10736 wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

-106-

-(Ctyq-(CH2)q-N 0

-(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rb are as hereinbefore defined;

(b) moieties of the formula:

-X-R7,

wherein R7 is lower alkyl (C3-C8), lower alkenyl(C3-C8),

- (CH2)p-cycloalkyl(C3-C6),

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-107wherein p is one to five and X is selected from 0, S, NH, NCH3; wherein κΛ and R2 are as hereinbefore defined;

-N-COJ wherein J is Ra, lower alkyl (C3-C8) branched or unbranched, lower alkenyl(C3-C8) branched or unbranched, 0-lower alkyl(C3-C8) branched or unbranched, -0-lower alkenyl(C3-C8) branched or unbranched, tetrahydrofuran, tetrahydrothiophene, the moieties:

or -CH2-K' wherein K' is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-108wherein 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, (Ci~C3)lower alkoxy, -CO25 lower alkyl(C1-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr' Re wherein Rc is selectedfrom halogen, (C^Cg) lower alkyl, -0-lower alkyl^-Cj), OH,

II

-O-C-lower alkyl(C1-C3), -S-1ower alkyl(C1-C3),

-S-(CH

-NH(CH2)q-CON

-NH(CH2)q-N

-O-CCH,)^

and Ra and Rb are as hereinbefore defined wherein Ar' is selected from moieties of the formula:

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wherein W' is selected from O, S, NH, N-lower alkyl (Ci~ C3), NHCO-lower alkyl(Ci-C3) , and NS021ower alkyKCiC3) ;

R8 and R^ are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3) , halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2» -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, 0-lower alkyl(C1-C3),

II

-O-C-(C,-C3) ,

-N(Rb) (CH2) vN (Rb) 2 < and CF3 wherein v is one to three and;

rIO is selected from hydrogen, halogen and lower alkyl(C1-C3);

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-110R14 is

-0-lower alkyl(C3-C8) branched or unbranched ,

-NH lower alkyl(C3-Cg) branched or unbranched ,

-NCO

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-111-

R

-NCO(CH2)n—y—R20

q is 1 or 2;

wherein n is 0 or 1;

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-112Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (C1C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R45 is hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (C1-C3)lower alkyl, (Ci~

C3)lower alkoxy, NH2, -NH(Ci-C3) lower alkyl, -N-[(Ci~

C3)lower alkyl]2,

-N 0

- N N-1ower al kyl (C,-C3)

- NH- (CH2)p- NHIower al kyl (C^ C3),

-NH-(CH2)p-N[lower alkyl(CfC3)]2 ,

-NH-(CH2)p-N

-NH-(CH2)p-N N-1 ower alkyl ((^-C3),

-NH-(CH2)p-N 0

and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.

-113Preferred group. VIII. Among the more preferred compounds disclosed herein are those selected from the formula:

wherein Y is CH2 ;

A-B is a moiety selected from and

and the moiety:

represents phenyl or substituted phenyl optionally substituted by one or two substituents selected from (C1-C3)lower alkyl, halogen, amino, (C1-C3)lower alkoxy or (C1-C3)lower alkylamino;

the moiety:

is a five membered aromatic (unsaturated) nitrogen containing heterocyclic ring wherein D,is carbon arid E and F are selected from carbon or nitrogen and wherrein. the carbon atoms may be optionally substituted by a substituent selected from

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-114-CH=CH-NO2,-(CH2)qNO2 ,

-(CH2)q-<J‘ _ -(CH2)q<^bF

C<:

Rb

q is one or two;

Rb is independently selected from hydrogen, -CH3 or -C2H5;

Re is H, lower alkyl (C1-C3 ) , hydroxyethyl, -0112002^50, -CH2C(CH2OH)3;

r50 is H or lower alkyl(C1-C4);

R^ is a moiety of the formula:

->Ar wherein Ar is a moiety selected from the group consisting of

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-115R4 is selected from hydrogen, lower alkyl(C1-C3); -COlower alkyl(C1-C3);

r! and R3 are independently selected from hydrogen, (C]_C3)lower alkyl, (C3.-C3) lower alkoxy, hydroxy and halogen; R^ is selected from hydrogen, (C1-C3)lower alkyl, (C1-C3)lower alkoxy and halogen;

is selected from (a) moieties of the formula:

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-116-NCOAr', -NCOCH2Ar',

-NCONAr’,

- NH-C-Ο-1ower al kyl (0,-CR) straight or branched, 0

I

-NH-C-lower alkyl(C3-C8) straight or branched,

-NHS02-lower alkyl(C3-C8) straight or branched,

-NH-C-0-1 ower alkenyl (C3-C8) straight or branched, 0

I

-NH-C-lower alkenyl(C3-C8) straight or branched, -NHS02-lower alkenyl (C3-Cg) straight or branched,

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-117wherein cycloalkyl is defined as C3 to C6 cycloalkyl, cyclohexenyl or cyclopentenyl; Ra is independently selected from hydrogen, -CH3, -C2H5,

-(CH2)q-<RRbb , -Wq-Γθ ,

-<CH2)q -(CH2)q- N 0

-(CH2)q-O-lower alkyl(C1-C3) and -CH2CH2OH, q is one or two, and Ri, R2 and Rfr are as hereinbefore defined;

(b) moieties of the formula:

-X-R7 ,

R

wherein is lower alkyl(C3-C8), lower alkenyl(C3-C8)<

-(CH2)p-cycloalkyl(C3-C6),

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-118wherein p is one to five and x is selected from 0, s,

NH, NCH3; wherein and R2 are as hereinbefore defined;

or -CH2-K' wherein K1 is (C1-C3) lower alkoxy, halogen, tetrahydrofuran, tetrahydrothiophene or the heterocyclic ring moiety:

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-119wherein 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, (Ci-C3)lower alkoxy, -CO25 lower alkyl(Ci-C3), and Ra and Rb are as hereinbefore defined;

(d) a moiety of the formula:

-N-COCHAr wherein Rc is selected from halogen, (C^Cj) lower alkyl, -O-lower alkyl(C1-C3), OH,

II

-O-C-lower alkyl(C^Cj), -S-lower alkyl(C,-C3),

-0- (CH

and Ra and Rb are as hereinbefore defined wherein Ar' is selected from moieties of the formula:

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wherein W' is selected from O, S, NH, N-lower alkyl(CiC3), NHCO-lower alkyl(C1-C3 ), and NS021ower alkyl(CiC3) ;

R8 and R9 are independently selected from hydrogen, lower alkyl(C1-C3), -S-lower alkyl(C1-C3) , halogen, -NH-lower alkyl(C1-C3), -N-[lower alkyl(C1-C3)]2> -OCF3, -OH, -CN, -S-CF3, -N02, -NH2, 0-lower alkyl(C1-C3),

-123wherein n is 0 or 1;

Ra is hydrogen, -CH3 or -C2H5; R' is hydrogen, (ΟχC3)lower alkyl, (C1-C3)lower alkoxy and halogen;

r45 is hydrogen, (CX-C3)lower alkyl, (CX-C3)lower alkoxy and halogen;

R20 is hydrogen, halogen, (CX-C3)lower alkyl, (ΟχC3) lower alkoxy, ΝΗ2» -NH(Cx-C3) lower alkyl, -Ν-[(ΟχC3)lower alkyl]2,

-Ό - Ό . -C° ·

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-130Scheme 3

13a 13b

The compounds of Formula I wherein Y, A-B,

R1, R2 and R2 are as defined and the Ar moiety of R2

Z, (-COAr) is

may be prepared, as shown in Scheme 4, by reacting an activated ester of the pyridine-3-carboxylic acid 14.

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-136Scheme 6

12a

12b

KF

KF qyca) z° =0

OY'N

ZO o

ZD^P ! t

F

18a

NH2R7;

HN-R7;

I j ch3 z°r w

19a

X=NH; X_R

NCH3; 7

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-137As an alternative method for synthesis of compounds of this invention as depicted in Formula I wherein Y, A-B, D, E, F and Z are as previously described and R2 is

is the coupling of pyridinyl carboxylic acids 20 with the tricyclic derivatives 3a and 3b to give 21a and 21b.

The pyridine carboxylic acids are activated for coupling by conversion to an acid chloride, bromide or anhydride or by first reacting with an activating reagent such as H,N-dicyclocarbodiimide, diethyl cyanophosphonate and related peptide type activating reagents. The method of activating the acids 20 for coupling to the tricyclic derivatives 3a and 3b is chosen on the basis of compatibility with other substituent groups in the molecule. The method of choice is the conversion of the 3-pyridinyl carboxylic acids 20 to the corresponding 3-pyridinylcarbonyl chlorides. The 3-pyridinylcarbonyl chlorides 22. may be prepared by standard procedures known in the art, such as reaction with thionyl chloride, oxalyl chloride and the like. The coupling reaction is carried out in solvents such as halogenated hydrocarbons, toluene, xylene, tetrahydrofuran, or dioxane in the presence of pyridine or tertiary bases such as triethylamine and the like (Scheme 7). Alternatively, the 3-pyridinylcarbonyl chlorides 22., prepared from the carboxylic acids 20, may be reacted with derivatives Jia and 3b in pyridine with or without 4-(dimethylamino)pyridine.

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-138In general, when the 3-pyridinyl carboxylic acids 20 are activated with peptide type activating reagents, higher temperatures are required than when the 3-pyridinylcarbonyl chlorides are used.

Scheme 7

R16

-coch3

40c _17

R = halogen,CHO -coch3

a) ArCO

b) Ph-CH2CO

▼ * 41c

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-144Scheme 9 (cont'd)

43.

Reagent

Ar’COCI

Ar'CH^COd

Ar'NCOCI

I ▼ +

Ar ΓΟΝΗ

ArOH2CONH

Ar'-N-CONH

The compounds of this invention wherein R3 is the moiety:

- ZAr and the Ar group is the moiety:

The compounds of this invention wherein R8 is the moiety:

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-148-CAr and the Ar group is the moiety:

and R-*-4, Rg, Rb- Y, R1, R^, Z and Ar' are as previously defined and wherein R1! is selected from the moieties:

-ch2-n

-151Scheme 10b fcont'd)

-CH2-ON\r^ , -CH2-O-tO

PCT/US97/10736

-155Scheme 10d (cont’d)

154 ch3no2

-161-

6 wherein R and R are defined hereinabove; and R , is selected from a moiety of the formula:

PCT/US97/1O736

-164with alkali metal boroydride or alkyl metal trialkoxyborohydride reagents according to the procedure described by Kardos and Genet in Tetrahedron: Asymmetry, Vol 5., No.8, 1525 (1994), and also by Kruse and Hilbert in Heterocycles, Vol. 20, No.7, 1373 (1983), to prepare a compound of Formula 152 or Formula 156. respectively; wherein R1, R2, R6, and R14 are defined hereinabove.

PCT/US97/10736

-167Scheme 11

zD* zO /^F —Xch^-N

▼ v

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PCT/US97/10736 -168As shown in Scheme 11, reaction of tricyclic derivatives of Formula Jia and 3b with substituted and unsubstituted arylcarbonyl chlorides 50. wherein r1, r2 and R14 are hereinbefore defined gives compounds 51 and 5 52 which are vasopressin antagonists.

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-169Scheme 12

NO 2

54a

V

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-170Scheme 12 (cont'd) zD*e \ ' zD* ryY-< f zoi

N—(CH2)m =0

R’

nh2

55a

R2

-173-

- N N-1 ower al kyl (Cx- C3)

- NH- (CH2)p- NHI ower al kyl (Cr C3) ,

-NH-(CH2)p-NOower al kyl (Cr C,)], ,

-NH-(CH2)p_N

J

- NH- (CH2)p- N N -1 ow er al kyl (Cf C3)

-NH-(CH2)p-N 0

Preparation of some tricyclic diazepines useful for starting materials for the synthesis of compounds of this invention are shown in Schemes 8 and

9. Other tricyclic diazepines are prepared by literature procedures or by methods known in the art or by procedures reported for the synthesis of specific known tricyclic diazepines. These diazepine ring systems discussed below when subjected to reaction conditions shown in Schemes 1, 2, 3, 4, 5, 6, 7, 9 and 10 give the compounds of this invention.

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-174The tricyclic diazepine ring system, 10,11dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine,

is reported by G. Stefancich, R. Silvestri and M.

Artico, 2. Het. Chem. 30. 529 (1993); ring substitution on the same ring system is reported by G. Stefancich, M. Artico, F. Carelli, R. Silvestri, G. deFeo, G. Mazzanti, I. Durando,

Carelli,

R. Silvestri, G. deFeo, G.

Palmery, IL Farmaco, ££., £2.,

429(1985).

X=H,-OCH3,-OCH2C6H5 ; Y=H,

synthesis of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a][1,4]diazepin-9-one

Cl, -och3 ; x,y=o-ch2-o15

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-175-

is reported by F. Povazunec, B. Decroix and J. Morel, J.. Het. Chem. 29, 1507(1992) and is reduced to give the tricyclic heterocycle 9,10-dihydro-4H-furo[2,35 e]pyrrolo[l,2-a][1,4]diazepine.

The tricyclic 5,10-dihydro-4H-pyrazolo [5,1-c][1,4]benzodiazepine ring system is reported by L. Cecchi and G. Filacchioni, A- Het. Chem. . 20, 871 (1983);

H

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-176The synthesis of 9-oxo-9,10-dihydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepine is reported by A. Daich and B. Decroix, Bull. Soc. Chim. Fr 129, 360(1992);

and is reduced with boron-dimethylsulfide to give 9,10dihydro-4H-pyrrolo[l,2-a]thieno[2,3-e][1,4]diazepine.

Also reported by A. Daich and B. Decroix is 5-oxo-4,5dihydropyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

which is also reduced to give 4,10-dihydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine

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-177-

H

Reported by B. Decroix and J. Morel, J. Het. Chem.. 28. 81(1991) are 5H-pyrrolo[l,2-a]thieno[3,2-e][l,4]diazepine;

and 4H-pyrrolo[1,2-a]thieno[2,3-e] [1,4]diazepine. The 10fi-pyrrolo [1,2-a] thieno [3,4—jsJ [1,4] diazepine is reported by A. Daich, j. Morel and B. Decroix, <1, Heterocyclic Chem., 31. 341(1994) . Reduction by hydrogen-Pd/C or chemical reduction with reagents such as sodium cyanoborohydride and acetic acid gives the dihydro tricyclic heterocycles

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-178-

The synthesis of the tricyclic 1,5-benzodiazepine ring system, 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine, has been reported by F. Chimenti, S. Vomero, R.

Giuliano and M. Artico, IL Farmaco. Ed. Sc.. 32. 339(1977). Annelated 1,5-benzodiazepines containing five membered rings have been reviewed by A. Chimirri, R. Gitto, S. Grasso, A.M. Monforte, G. Romeo and M. Zappala, Heterocycles. 3£, No. 3, 604(1993), and the ring system 6,7-dihydro-5H-pyrrolo[ 1,2-a][1,5]benzodiazepine is described.

H

The preparation of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-^][1,5]benzodiazepin-5-ones from 1,215 dihydro-3H-4-dimethylamino-l,5-benzodiazepin-2-ones has been described by M. DiBroccio, G. Roma, G. Grossi, M.

Ghia, and F. Mattioli Eur. £. Med. Chem: 26. 489(1991).

Reduction of 5,6-dihydro-4H-[1,2,4]triazolo[4,3-^]WO 97/49707

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-179[1,5]benzodiazepin-5-ones with diborane or lithium hydride gives the tricyclic 5,6-dihydro derivatives.

R21 = H, CH3

The compounds of this invention and their preparation can be understood further by the following examples, but should not constitute a limitation thereof .

Reference Example 1

1-(2-Nitrophenvl)-lH-pvrrole-2-carboxaldehvde

To a solution of 3.76 g of l-(2-nitrophenyl)pyrrole in 20 ml of N,N-dimethylformamide at 0°C is added dropwise with stirring 3 ml of phosphorus oxychloride. Stirring is continued for 30 minutes and the reaction mixture is heated at 90°C for 1 hour.

After cooling to room temperature the mixture is treated with crushed ice and the pH adjusted to 12 with 2 N sodium hydroxide. The resulting suspension is filtered, washed with water and dried to give 5.81 g of the desired product as a light yellow solid, m.p. 119°122°C.

Reference Example 2

4,5-Dihvdro-pyrrolo-11,2-al-Quinoxaline

To a solution of 1.0 g of 1-(2-nitrophenyl)lH-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for

A solution of 2.0 g of o-trifluoromethylbenzoic acid in 21 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a residue.

Reference Example 10 2-MethvlDhenvlacetvl chloride

A solution of 2.0 g of o-tolylacetic acid in 27 ml of thionyl chloride is heated at reflux for 1 hour. The volatiles are evaporated in vacuo to give a residue which is concentrated from toluene three times and dried under vacuum to give 2.1 g of the desired product as a light brown oil.

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-183Reference_Examole 11

3--Methvl-4^nit-ro-benzovl chloride

A mixture of 1.81 g of 3-methyl-4-nitrobenzoic acid and 1.25 g of thionyl chloride in 75 ml of chloro5 form is heated at reflux under argon for 48 hours. The volatiles are removed in vacuo to a residue which is evaporated with toluene several times in vacuo. The residue is partially dissolved in methylene chloride and filtered free of solids and the filtrate evaporated in vacuo to give 1.47 g of the desired acid chloride.

Reference Example 12

1-(o-Nitrobenzvl)-imidazole-2-carboxaldehvde

A 2.0 g portion of sodium hydride (60% in oil) is washed with pentane two times. To the residue is added 110 ml of Ν,Ν-dimethylformamide under argon. With stirring and external cooling, 4.80 g of 2-imidazolecarboxaldehyde is added and the cooling bath removed. Slight external heating results in a yellow solution. The reaction mixture is chilled in ice and 10.8 g of 220 nitrobenzyl bromide is added. The reaction mixture is stirred at 0°C for 18 hours. The volatiles are removed In vacuo to a residue which is stirred with ice water, filtered and the cake washed well with water and suction dried to give 10.9 g of the desired product as a solid,

m.p. 141-144°C. MH+ 232.

Reference Example 13

10, ll-Dihvdro_-5H-imidazoF2 .1-cl Fl. 4)benzodiazepine

A 5.0 g sample of 1-(o-nitrobenzyl)-imidazole2-carboxaldehyde is dissolved in 150 ml of hot ethyl alcohol, cooled to room temperature and filtered. To the filtrate is added 0.5 g of 10% Pd/C and the mixture hydrogenated at 48 psi for 4 hours. An additional 0.5 g of 10% Pd/C is added and hydrogenation continued for 25 hours at 65 psi. The mixture is filtered through diatomaceous earth and the cake washed with ethyl acetate. The filtrate is evaporated in vacuo to a

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-184residue which is dissolved in methylene chloride, treated with activated carbon, filtered through diatomaceous earth and hexanes added to the filtrate at the boil to give 1.86 g of the desired product as a crystalline solid, m.p. 164-170°C.

-187extract is concentrated to dryness to give 0.8 g of solid, m.p. 214-218°C. To a suspension of the preceding compound (1.19 g) in 20 ml of dry tetrahydrofuran is added 0.2 g of sodium hydride (60% in oil). After the hydrogen evolution, the mixture is stirred and refluxed for 4.5 hours, cooled and poured into ice-water. The precipitated solid is filtered and the solid triturated with petroleum ether (bp 30-60°C) to give 0.75 g of

4,10-dihydro-4,10-dioxo-5H-pyrrolo-[1,2-a]thieno[3,2e][1,4]diazepine as a solid, m.p. 280-290°C. The preceding compound (0.362 g) is added to an ice-water cooled solution of 1 M diborane in tetrahydrofuran. The mixture is stirred at room temperature for 65 hours. The solution is concentrated to dryness and ice-water added to the residue. The mixture is acidified with dilute HC1, stirred and then basified with solid NaHCO3. The mixture is filtered to give 0.223 g of a solid (foam) m.p. 80-85°C.

Reference Example 22

10,ll-Dihvdro-5H-l,2,4-triazolor3,4-clJU41 benzodiazepine

A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry Ν,Ν-dimethylformamide is heated at 150155°C for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70-78°C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 5.0 ml of methanol. The mixture is shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-lH-l,4benzodiazepin-3-one as a yellow solid, m.p. 167-170°C.

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-188A mixture of the preceding compound (1.6 g) and 0.84 g of phosphorus pentasulfide in 10 ml of dry (dried over KOH) pyridine is stirred and heated at 8085°C for 15 minutes. The mixture is poured into water and stirred for 30 minutes. Filtration gives 1.0 g of 1,2,4,5-tetrahydro-3H-l,4-benzodiazepin-3-thione as yellow solid, m.p. 150-153°C.

The preceding compound (0.5 g) and 0.5 g of Nformylhydrazine in 6 ml of dry n-butanol is refluxed for

16 hours and the solvent removed. The gummy residue is triturated with cold water and the mixture filtered. The solid is triturated with acetone to give 0.19 g of yellow solid, m.p. 232-237°C.

Reference Example 36

6-Γ(3-Methvl-2-thienvlcarbonvl)aminolpvridine-3carboxvlic acid

Reference Example 37

6-Γ(2-Methvl-3-thienylcarbonvl) amino1pvridine-3carboxvlic acid

Reference Example 38

6-F(3-Methvl-2-furanvlcarbonvl)aminolpyridine-3carboxvlic acid

Reference Example 39

6-F(2-Methvl-3-furanvlcarbonvl)aminolpyridine-3carboxvlic acid

Reference Example 40

6-[(3-fluoro-2-methvlbenzovl)amino1pvridine-3-carboxylic acid

Reference Example 41

6-Γ(2-Methvlbenzovl)aminolpyridine-3-carboxvlic acid

Reference Example 42

6-Γ(2-chlorobenzoyl)amino]pvridine-3-carboxylic acid

Reference Example 43

6-Γ(2-Fluorobenzovl)aminolpvridine-3-carboxvlic acid Reference Example 44

6-Γ(2-Chloro-4-fluorobenzovl)aminolpyridine-3-carboxvlic

Reference Example 45

6-Γ(2.4-Dichlorobenzovl)aminolpyridine-3-carboxylic acid

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-195Reference Example 46

6-Γ(4-Chloro-2-fluorobenzovl) amino1ovridine-3-carboxylic acid

Reference Example 47

6- Γ (3 ,JL5_-Trimethoxvbenzovl) amino lpvridine-3-carboxylic acid

Reference Example 48

6-Γ (2, ArDiflnorobenzovl) aminolpyridine-3-carboxvlic acid

Reference Example 49

6-Γ C2rBr.Qmob.enz.ovl laminol pyridine-3-carboxy lie acid

Reference Example 50

6- Γ (2-Chloro-4-nitrobenzovl) aminolovridine-3-carboxylic acid

Reference Example 51

6-f(Tetrahvdrofuranvl-2-carbonvl)aminolpvridine-3carboxvlic acid

Reference Example 52

6-Γ (Tetrahvdrothienvl-2-carbonyl) aminolpvridine-3carboxvlic acid

Reference Example 53

6-Γ (Cvclohexvlcarbonvl)aminolnvridine-3-carboxylic acid

Reference Example 54

6- Γ (cvclohex-3-enecarbonyl) aminolovridine-3-carboxylic acid

Reference Example 55

6-[ (5-Fluoro-2-methvlbenzeneacetvl) aminol ovridine-3carboxvlic acid

Reference Example 56

6- Γ (2-Chlorobenzeneacetvl) amino lovridine-3-carboxylic .acid

Reference Example 57

6-Γ (cvclopentvlcarbonvl) aminolPvridine-3-carboxylic acid

Reference Example 58

6-Γ (cvclohexvlacetvl) amino!PYridine-3-carboxylic acid

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-196Reference_Example 59

6- Γ (3-Methvl_-2 -thienvlacetvl) amino 1 pyridine-3 -carboxylic acid

Reference Example 60

6^1. (2-Methy 1.-3-thienvlacetvl) amino 1 pvridine-3-carboxylic acid

Reference Example 61

- Γ (3 -Methyl-2 -furanvlacetvl) amino 1 pvridine-3 -carboxylic acid

Example 62

6-1(2 -Methvl -3 -furanvlacetvl) amino 1 pvridine-3 -carboxylic acid

Reference Example 63

6-Γ(3-Methvl-2-tetrahvdrothienvlacetvl )aminolpvridine-3carboxylic acid

Reference Example 64

6-F(2-Methvl-3-tetrahvdrothienvlacetvl)aminolpvridine~3carboxvlic acid

Reference Example 65

6-F(2,5-Dichlorobenzovllaminolpvridine-3-carboxvlic acid

Reference Example 66

6-F(3.5-Dichlorobenzovl)amino 1pvridine-3-carboxylic acid

Reference Example 67

6- Γ (2-Methvl-4-chlorobenzovl) amino 1 pvridine-3-carboxylic acid

Reference Example 68

6-F(2,3-Dimethvlbenzovl)amino1pvridine-3-carboxylic acid

Reference Example 69 .6- L.(2.-Methoxvben2;ovl) amino 1 pvridine-3-carboxylic acid

Reference Example 70

6-F(2-Trifluoromethoxvbenzovl)aminolovridine-3carboxylic acid

Reference Example 71

6-F(4-Chloro-2-methoxvbenzovl)amino1ovridine-3carboxvlic acid

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-197Reference Example 72

6-_Li2z (.Trif luo-E.Qm.ethv.1) benzovl 1 amino 1 pvridine-3 carboxylic acid

Reference Example 73

6-Γ (2 ._6_-Dichlorobenzovl) amino!pvridine-3-carboxylic acid

Reference Example 74

6-f (2,6-Dimethvlbenzovl) amino! pvridine-3-carboxvlic acid

Reference Example 75

6- f (2-Kethvlthiobenz.ovl) amino! Dvridine-3-carboxvlic acid

Reference Example 76

6- 1 (4-Fluoro-2- (trifluoromethvl)benzovl)aminolovridine3-carboxylic acid

Reference Example 77

6-1(2.3-Dichlorobenzovl)amino!pvridine-3-carboxylic acid Reference Example 78

6-1 (4-Fluoro-2-methvlbenzovl) amino! pvridine-3-carboxylic acid

Reference Example 79

6-Γ(2,3.5-Trichlorobenzoyl)amino! pvridine-3-carboxylic acid

Reference Example 80

6-1(5-Fluoro-2-chlorobenzovl)aminolovridine-3-carboxylic acid

Reference Example 81

6- Γ (2-Fluoro-5- (trif luoromethvl) benzovl) amino! pyridine 3-carboxylic acid

Reference Example 82

6- 1 (5-Fluoro-2-methvlbenzovl)amino1pvridine-3-carbonv 1

A mixture of 6.2 g of 6-[(5-fluoro-2-methylbenzoyl)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

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-198process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.

As described for Reference Example 82, the following 6-(acyl)amino)pyridine-3-carbonyl chlorides are prepared.

Reference Example 83

6- F (3-Methvl-2-thienvlcarbonvl)aminolpvridine-3-carbonvl chloride

Reference Example 84

6-F(2-Methvl-3-thienvlcarbonvl)aminolpvridine-3-carbonvl chloride

Reference Example 85

6-Γ(3-Methvl-2-furanvlcarbonvl)aminolnvridine-3-carbonvl chloride

Reference Example 86

6-Γ(2-Methvl-3-furanvlcarbonvl)amino1pyridine-3-carbonvl chloride

Reference Example 87

6-F(3-Fluoro-2-methvlbenzovl) amino1pvridine-3-carbonvl chloride

Reference Example 88

6-F(2-Methvlbenzovl)aminolpvridine-3-carbonvl chloride Reference Example 89

6-F(2-Chlorobenzovl)amino1pvridine-3-carbonvl chloride, white crystals

Reference Example 90

6-F(2-Fluorobenzovl)amino1pvridine-3-carbonvl chloride Reference Example 91

6-Γ(2-Chloro-4-fluorobenzovl)aminolpvridine-3-carbonvl chloride

Reference Example 92

6-F(2.4-Dichlorobenzovl) amino 1pvridine-3-carbonvl chloride

Reference Example 93

6-F(4-Chloro-2-fluorobenzovl)aminolpvridine-3-carbonvl chloride

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-199Reference Example 94

6- Γ .(3..,-4. ,..5-Trimethoxvbenzovl) amino 1 pyridine-3 -carbonyl chloride

Reference Example 95

6-(.(2.,21-Di f luorobenzovl) amino 1 pyridine-3 -carbonyl chloride

Reference Example 9.6

6- f..(2rBromobenzovl) amino!pyridine-3-carbonyl chloride

Reference Example 97

6-.LI2-Chloro--4-nitrobenzovl) amino! pvridine-3-carbonvl chloride

Reference Example 98

6- i (Te.trahvdrcfuranvl-2-carbonvl) amino!pyridine-3carbonvl chloride

Reference Example 99

6-i(Tetrahvdrothienvl-2-carbonvl) amino!pvridine-3carbonvl chloride

Reference Example 100

6-Γ(Cvclohexvlcarbonvl)aminolovridine-3-carbonvl .Chloride

Reference Example 101

6-Γ(Cvclohex-3-enecarbonyl)amino!pvridine-3-carbonvl chloride

Reference Example 102

6-Γ(2-Methvlbenzeneacetvl)amino1pvridine-3-carbonvl chloride

Reference Example 103

6-J.( 2-ChlQrahe.nzeneacetvl) amino!ovridine-3-carbonvl -chl-oride

Reference Example 104 f (CvclopentvlcarbonvJJamino!Dyridine-3-carbonvl chloride

Reference Example 125

6-UCvclohexvlacetvl)amino!pvridine-3-carbonvl chloride

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Lt Γ (3_-Methvl-2-thienvlacetvl) amino lpvridine-3-carbonvl shl.oride

Reference Example 107

6- Γ (2-Methvl-3-thienvlacetvl)amino!pyridine-3-carbonv 1 chloride

Reference Example 108

6- Γ (3-Methvl-2-furanvlacetvl) amino!pyridine-3-carbonvl .chloride

Reference Example 109

6-F (2-Me.thv_l-3-furanvlacetvl)aminolPvridine-3-carbonyl chloride

Reference Example 110

6-Γ(2-Methvl-5-fluorobenzeneacetvl)amino!ovridine-3-carbonvl chloride

Reference Example 111

6- F (3-Methvl-2-tetrahvdrothienvlacetvl) aminolpyridine-3carbonvl chloride

Reference Example 112

6- f U-Methvl-B-tetrahydrothienvlacetvllaminolovridine-Bcarbonvl chloride

Reference Example 113

6-Γ(2,5-Dichlorobenzovl)aminolpvridine-3-carbonvl chloride

Reference Example 114

6-Γ(3, 5-Dichlorobenzovl)aminolpvridine-3-carbonvl chloride

Reference Example 115

6-r (2-Methvl-4-chlorobenzovl)aminolpvridine-3-carbonvl chloride

Reference Example, 1.1.6

6- Γ (2.3-Dimethvlbenzovl) aminolovridine-3-carbonvl chloride

Reference Example 117

6-Γ(2-Methoxvbenzovl)amino!pvridine-3-carbonvl chloride

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-201Referen.ce Example 118

6- r (2,-Trifluoromethoxvbenzovl) amino 1 nvridine-3-carbonvl sblcride

Reference Example 119

6- [ (A-ChlQr.Q-2-methQXV.benz.Qvl)aminol pvridine-3-carbonvl chloride

Reference .Example. 120

6- Γ Γ2-- (TrifLuoromet.byJJ-benzovl 1 amino 1 ovridine-3-carbonvl chloride

Reference Example 121

6-1(2,6-Dichlorobenzovl) amino 1pvr idine-3-carbonvl chloride

Reference Example 122

6- Γ (2,6-Dimethvlbenzovl) amino 1 pvridine-3 -carbonvl chloride

Reference Example 123

6- Γ (2-Methvlthiobenzovl) amino 1 pvridine-3-carbonvl £b.lo.ricte

Reference Example 124

6-ί(4-Fluoro-2-(trifluoromethvl)benzovl)aminolovridine3-carbonvl chloride

Reference Example 125

- Γ (2,3-Dichlorobenzovl)amino 1 Pvridine-3-carbonvl chloride

Reference Example 126

6- ί (4-Fluoro-2-methvlbenzovl) amino 1 pvridine-3-carbonyl chloride

Reference Example 127

6- ί (2,3,5-Trichlorobenzovl) aminoΊpyridine-3-carbonvl chloride

Reference Example 128

- ί (5-Fluoro-2-chlorobenzovl) amino 1 pvridine-3-carbonvl chloride

Reference Example 129

6- ί (2-Fluoro-5- (trif luoromethvl)benzovl)aminolovridine3-carbonyl chloride

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-202Reference Example 13 0

1-(3-Nitro-2-pvridinvl)-lH-pvrrole-2-carboxaldehvde

A sample (3.6 g) of sodium hydride (60% in oil) is washed with hexane under argon. To the sodium 5 hydride is added 100 ml of dry N,N-dimethylformamide. The mixture is cooled in an ice bath and 7.8 g of 1Hpyrrole-2-carboxaldehyde is added in small portions.

After the addition the cooled mixture is stirred for 15 minutes and 13.0 g of 2-chloro-3-nitropyridine is added.

The mixture is heated at 120°C for 16 hours. The solvent is removed under vacuum at 80°C and to the dark residue is added 200 ml of ethyl acetate. The mixture is filtered and to the filtrate is added 100 ml of water. The mixture is filtered through diatomaceous earth and then filtered through a thin pad of hydrous magnesium silicate. The filtrate is diluted with water, the organic layer separated, washed 2 times with 100 ml of water and once with 100 ml of brine and then dried (Na2SO4). The solvent is removed under vacuum to give

16 g of solid. The solid is chromatographed on a silica gel column with hexane-ethyl acetate (2:1) as solvent to give crystals which are recrystalizzed from ethyl acetate-hexane (97:3) to give 8.5 g of product as crystals, m.p. 122°-125°C.

-205NH4OH. The separated solid is filtered and washed with water to give 18 g of solid; mass spectrum: 218 (M+) .

i Reference Example 158

Methvl 6-amino-5-bromopvridine-3-carboxylate

6-Amino-5-bromopyridine-3-carboxylic acid (10 g, 50 mmol) is dissolved in saturated methanolic HC1 (100 ml) and refluxed for 24 hours. The solvent, methanol, is re-moved under reduced pressure and the residue is dis-solved in ice cold water. The aqueous 10 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 Example 159

IQ^rLe.-ChlarQ^-PYridinvlLcarbonvl]-10,ll-dihvdro-5Hpy.r.r_olo.[ 2.1-cl Γ1.41 benzodiazepine

To a mixture of 1.84 g of 10,ll-dihydro-5Hpyrrolo[2, l-£] [1,4]benzodiazepine and 1.52 g of triethylamine in 20 ml of dichloromethane is added a solu20 tion of 2.11 g of 6-chloronicotinyl chloride in 5 ml of dichloromethane. The mixture is stirred at room temperature for 2 hours and quenched with 30 ml of IN sodium hydroxide. The mixture is diluted with 20 ml of dichloromethane and the organic layer separated. The 25 organic layer is washed twice with 20 ml of 1 N sodium hydroxide, washed with brine and dried (Na2SO4). The solvent is removed under vacuum and the residue triturated with ether to give 3.22 g of white solid; mass spectrum (CI) 324 (M+H).

, 30 Reference Example 160 , 10 - LL.6 Ul· (2 -dimethvlaminoethvl) amino 1 -3 pvridinvll.carbonyl 1 -10, ll-dihvdro-5H-Pvrrolor2,1-cl Λ 11,41 benzodiaz eoine > A mixture of 10-[[6-chloro-3-pyridinyl] j 35 carbonyl]-10, ll-dihydro-5H-pyrrolo[2 , l-£] [1,4]benzodiazepine (3.2 g) , K2CO3 (5 g) and the 2-dimethvlaminoWO 97/49707

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-206ethylamine (5 ml) is heated in dimethylsulfoxide (80 ml) for 6 hours at 100°C (with stirring). The reaction mixture is quenched with water and the solid which separates, is filtered off and washed well with water.

Examination of the TLC (CHCI3:MeOH; 3:1) showed the products to be sufficiently pure to be used for further reactions without purification. Yield 3.2 g, 85%, mass spectrum (CI) 376 (M+l).

Reference Example 161

6- Γ (2-Methvlbenzeneacetvl) amino lpvridine-3-carboxylic acid

To a cooled (0°C) mixture of 5.0 g methyl 6aminopyridine-3-carboxylate, 12.6 ml of N,N-diisopropylethylamine in 40 ml of dichloromethane is added a solution of 12.2 g of 2-methylbenzeneacetyl chloride in 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 concentrated to dryness. The residue (9.0 g) is chromatographed 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.

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-207Reference Example 162

6- f (2-MethvJLbenzeneacetvl) aminol cvridine-3-carbonv 1 chloride

A mixture of 4.5 g of 6-[ (2-methylbenzene5 acetyl)amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 1 hour and then concentrated to dryness under vacuum. To the residue is added 20 ml of toluene and the solvent removed under vacuum. The addition and removal of toluene is repeated and the residual solid dried at room temperature under vacuum to give 5.3 g of dark brown solid.

Reference Example 163

6- f (2-Methvlbenzeneacetvl) aminolt>vridine-3-carboxvlic

To a chilled solution (0°C) of 5.0 g of methyl

6-aminopyridine-3-carboxylate and 12.6 ml of diisopropylethylamine in 40 ml of dichloromethane under argon is added 12.2 g of 2-methylbenzeneacetyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature 16 hours and diluted with 200 ml of dichloromethane and 50 ml of water. The organic layer is separated and 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 concentrated to dryness. The residue (9.0 g) is purified by chromatography on silica gel with hexaneethyl acetate (3:1) as eluent to give 0.70 g of methyl 6-[[bis(2-methylbenzeneacetyl)] amino]pyridine-3-carboxylate and 8.6 g of a mixture of methyl 6-[(2-methyl30 benzeneacetyl)amino]pyridine-3-carboxylate and the bis acylated product. The above mixture (8.6 g) of mono and bis acylated product is dissolved in 60 ml of tetrahydro fur an -methanol (1:1) and 23 ml of 5 N NaOH is added. The solution is stirred at room temperature for

16 hours, concentrated under vacuum, diluted with 25 ml of H2O and acidified with cold 1 N HC1. The precipiWO 97/49707

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Methyl 4-Γ(f1,1'-Biphenvll-2-carbonyl)aminol-210 chlorobenzoate

A solution of 2.37 g of [1,1'-biphenyl]-2carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.84 g of methyl 4-amino-2-chlorobenzoate and 1.49 g of N,N15 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 Example 173

4-I (Γ1,1'-Biphenvll-2-carbonvl)aminol-2-chlorobenzoic

Acid

A mixture of 3.0 g of methyl 4-[([l,l'~ 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

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-217resulting solid is collected and dried to give 1.92 g of the desired product as a crystalline solid, m.p. 136138°C.

Reference Example 191

3-Methoxy.-4- Γ ί Γ4_1 -_trif luoromethvl) Γ1,1 -biphenvll -2carbonvl)amino1 benzoic 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. Water is added to obtain a solution which is extracted with methylene chloride. The aqueous phase is acidified with acetic acid and the resulting solid collected and dried in vacuo at 80°C to give 3.49 g of the desired product as a crystalline solid, m.p. 213215°C.

Reference Example 192

Methyl 3-Methoxv-4-Γ ( [ 4 1-trifluoromethvl) ί 1,1' biphenyl]-2-carbonyl)amino1 benzoate

A solution of 3.56 g of [41 - (trifluoromethyl) [1,1'-biphenyl]-2-carbonyl chloride in 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 Ν,Ν-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCC>3 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 Example 193

2-Chloro-4-Γ(Γ41 -(trifluoromethvl) Γ1,11-biphenvll -2carbonvl)amino1 benzoyl Chloride

A mixture of 1.39 g of 2-chloro-4-[([4 1 (trifluoromethyl) (1,1'-biphenyl]-2-carbonyl)amino]WO 97/49707

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-218benzoic 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 194

2-Chloro-4-f(Γ4 1 -(trifluoromethvl) [1,11-biphenyl1-2carbonvl)aminolbenzoic acid

A mixture of 3.83 g of methyl 2-chloro-410 [([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. 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. 187189°C.

Reference Example, 195

Methyl 2-Chloro-4-Γ([41 — (trifluoromethvl) Γ1,11 biphenvl1-2-carbonyl) aminolbenzoate

A solution of 3.56 g of [4(trifluoromethyl) [1,1 ’-biphenyl]-2-carbonyl chloride in 10 ml of methylene chloride is added dropwise to an ice cold solution of 1.86 g of methyl 2-chloro-4-aminobenzoate and 1.6 g of Ν,Ν-diisopropylethylamine in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 18 hours and washed with water, saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through a pad of hydrous magnesium silicate(3X) and hexane added to the filtrate at the boil to give 4.0 g of the desired product as a crystalline solid, m.p. 130-132°C.

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-219Reference Example 196

4-f(Γ4‘-(Trifluoromethyl)Γ1.1’biphenvll carbonvl) amino 1 benzoic Acid A mixture of 3.0 g of methyl 4-[ ([41 -(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.

Reference Example 197

Methyl 6-f 13- (2_-methvlpvridinvl) carbonvl1aminolnvridine3-carboxylate

To a stirred solution of 3 g of methyl 6aminopyridine-3-carboxylate and 4 ml of N, N-diisopropylethylamine in 100 ml of methylene chloride is added dropwise a solution of 6.4 g of 2-methylpyridine-3carbonyl 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+=39O.

Reference Example 198 .6.-( [3- (2-metbYlpyridinvl) carbonyl] aminolpvridine.-3carboxvlic Acid

To a solution of 6.5 g of methyl 6-((3-(-2methylpyridinyl) 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 in vacuo to a residue. The residue is dissolved in water and neutralized with acetic acid.

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-220The separated solid is filtered and air-dried to give 3.0 g of the desired product. M+=257.

Reference Example 199

Methyl 6-Γ(Γ1.1'-biphenvll-2-carbonyl)amino1-pvridine-35 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 Ν,Ν-diisopropylethylamine at room temperature. To the stirred reaction mixture is slowly 10 added a solution of 2.5 g of [1,1 *-biphenyl]-2-carbonyl chloride. The reaction mixture is stirred at room temperature for 4 hours and then quenched with water. The organic layer is washed well with water and dried over anhydrous MgSO4, filtered and evaporated in vacuo 15 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 200

6-F(Γ1,11-Biphenvll-2-carbonvl)amino1pvridine-320 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 201

Methvl 2-(2-Pvridinvl)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

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Reference-Example 202

2-,(2τΕνχϊάΐην1)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 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+l=200.

Example 1 . N-f 5-(SH-Pyrrolo Γ.2. l-cl Γ1,41benzodiazepin-10(11H)vlcarbonvl )^2-pyridinvl1-5-fluoro-2-methvlbenzamide

A mixture of thionyl chloride (100 ml) and 6[(5-fluoro-2-methylbenzoy1) amino]py ri d ine-3 -carboxylie acid (2.7 g, 10 mmol) is heated to reflux for 5 hours. At the end, excess thionyl chloride is removed and the acid chloride is dissolved in CH2CI2 (100 ml). At room temperature, the methylene chloride solution of the 6[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours and quenched with ice cold water. The reaction mixture is washed with 0.1 N NaOH and subsequently washed with water. The CH2CI2 layer is separated; dried (MgSO4)> filtered and concentrated. The product is purified by silica gel column chromatography by eluting first with 10% ethyl acetate-hexane (1 L) and then with 30% ethyl acetatehexane. The product is crystallized from ethyl acetatehexane. Yield 1.0 g, 46 ; mass spectrum (FAB), M+1 441; M+Na: 462.

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PCT/US97/10736 -222As described for Example 1, the following are prepared (Table C) .

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A mixture of 0.44 g of N-[5- (5H-pyrrolo[2, l-£.] [1,4]benzodiazepin-10 (1W -ylcarbonyl) -2 pyridinyl]-5-fluoro-2-methylbenzamide, 5 ml of a 40% of a drop of glacial acetic acid. The mixture is concentrated under vacuum and the residue extracted with aqueous solution of dimethylamine and 5 ml of an aqueous solution of formaldehyde in 50 ml of tetrahydrofuranmethanol (1:1) is refluxed for 16 hours in the presence

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-230chloroform. The extract is washed with water, dried (MgSO4) and the solvent removed. The residue is purified by column chromatography on silica gel with 5% methanol in chloroform as eluent to give 0.45 g of solid: mass spectrum (CI) 499 (M+l).

The following Examples are prepared as described for Example 120 with formaldehyde and the appropriate amine.

Example 121

N-Γ 5-Γ Γ3-Γ(Dimethvlamino)methvl1 -F5H-pvrrolor2,1-cl [1,41benzodiazepin-10(11H)1-vll carbonvll-2-pvridinvll -5.chloro-2-methvlbenzamide

Example 122

Ν-Γ5-Γr 3-Γ(Dimethvlamino)methvll-r5H-pyrrolor2,l-c1fl, 41benzodiazep.inr.10 (11H) 1-vllcarbpnvll-2-pvridinvll -3fluoro-2-methvlbenzamide

Example 123

W— Γ5 — Γi3 — Γ(Dimethvlamino)methvl1 -Γ 5H~pyrrolo(2,1-cl Γ1,41 benzodiazepin-10(11H)-vllcarbonvll-2-nvridinvll -2chloro-4-fluorobenzamide

Example 124

Μ-Γ5 — Γ Γ3 — Γ(Dimethvlamino)methvll-r5H-pvrrolor2,1-cl L1,41 benzodiazepin-10 (11H) 1 -vll carbonvll -2-pvridinvll -2chloro-5-fluorobenzamide

Example 125

N-Γ 5 — ΓΓ 3 — Γ(Dimethvlamino)methvll-Γ 5H-pvrrolo f2,l-clΓ1,41 benzodiazepin-10 (11H) 1 -vllcarbonvll -2-pvridinvll -2chlorobenzamide

Example 126

N-Γ5-Γ Γ3-i(Dimethvlamino)methvll-Γ 5H-ovrrolo Γ2,1-cl Γ1,41 benzodiazepin-10 (11H) 1 -vllcarbonvll -2-pvridinvll -2fluoro-5-chlorobenzamide

Example 127

N-Γ5-Γ Γ3 — Γ(Dimethvlamino)methvll-Γ5H-pyrroloΓ2,1-cl Γ1.41 benzodiazepin-10 (11H) 1 -vll carbonvll -2-pvridinvll 2,4-dichlorobenzamide

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N- f 5-.Γ f 3- (l-Pyrrolidinvlmethvl) -5H-pvrrolo i2.1-cl ί 1,41 benzodiazepin-10 (11H) -vl 1 carbonvl 1-2-pvridinvll -2chloro-4-fluorobenzamide

Example 129

N- Γ 5 - LLl^-JLiDimethvlamino) methvl 1 - Γ 5H-pvrrolo f2,l-clΓ1.41ben.zndiazepinrlO (11H) l-vllcarbonvll-2-pvridinvll -2chlorobenzeneacetamide

Example 130

N-Γ2-(DimethYlamino)ethvll-N-F5-(5H-pvrrolof2.1-c1f 1,41benzodlazepin-10 (11H) -ylcarbonvl) -2-pvridinvll-5fluo.ro-2-methvlbenzamide

To a solution of 0.75 g of 10-[[6-[2(dimethylamino) ethylamino]-3-pyridinyl]carbonyl]-10,11dihydro-5H-pyrrolo [2,1-&] [1,4] benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane is added (slowly) 0.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and the solution washed well with water. The organic layer is dried (MgSO4) and the solvent removed under vacuum. The residue is purified by column chromatography on silica gel with 30% methanol in chloroform as eluent to give 0.80 g of yellow solid; mass spectrum (CI), 511 (M+l).

Example 131

N-_L3 - .(Dimethv_l.amin.o) propvll -N-Γ 5-(5H-nvrrolo f 2.1-clri,-41benzodiazepin-10 (11H) -vlcarbonvl) -2-pvridinvll t5fluoro-2-methvlbenzamide

A solution of 6.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane is added to a solution of 2 mmol of 10-[[6-[3-(dimethylamino)propylamino] -3-pyridinyl] carbonyl] -10, ll-dihydro-5H~ pyrrolo [2, l-£] [1,4]benzodiazepine and 5 ml of diisopropyl ethylamine in 75 ml of dichloromethane. The solution is stirred 16 hours at room temperature, washed with water, dried (MgSCM) and the solvent removed. The

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Example 132

N-Γ 2 - (Dimethvlamino) methvl 1 -N-5 - (5H-ovrrolo r2.1-clΓ1,41benzodiazeoin-10(11H) -vlcarbonvl) -2-pyridinvl)-5f luoro-3-methvlbenzamide

As described for Example 130, a solution of 2 mmol of 10-[ [6-[2-(dimethylamino)methylamino]-3-pyridinyl] carbonyl] -10, ll-dihydro-5H-pyrrolo[2, l-£] [1,4]benzodiazepine, 8 ml of diisopropylethylamine, and 2.2 mmol of 5-fluoro-2-methylbenzoyl chloride in 100 ml of dichloromethane is stirred at room temperature for 16 hours. The solvent is removed and the product purified by chromatography on silica gel to give a solid.

Example 133

N-Γ5-Γ Γ3 — Γ(Dimethvlamino)methvl1 -Γ5H-pvrrolo[2,1-clri,41benzodiazepin-.10(llH) 1 vll carbonvl1-2-pyridinvll3.4.5-trimethoxvbenzamide

A mixture of 1.0 g of [5-(5H-pyrrolo[2,1£.] [1,4 ] benzodiazepin-10 (11H) -ylcarbonyl) -2-pyridinyl] 3,4,5-trimethoxybenzamide, 10 ml of 40% aqueous dimethylamine, 10 ml of 35% aqueous formaldehyde in 50 ml of tetrahydrofuran-methanol (1:1) plus 1 drop of acetic acid is refluxed for 16 hours. The mixture is concentrated and the residue extracted with chloroform. The extract is washed with water, dried (MgSO4), concentrated and the residue purified by column chromatography (silica gel) with 5% methanol in chloroform as eluent. The fractions containing product are combined to give 0.80 g of solid; mass spectrum (CZ) 556 (M+l).

-235Examole 171

N-F5-(Pvrrolof1.2-alouinoxalin-5(4H)-vlcarbonvl)-2pvridinvll-5-fluoro-2-methylbenzamide

To a chilled (0°C) solution of 0.341 g of 4,5dihydropyrrolo[1,2-^]quinoxaline and 1.11 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6- [ (5-f luoro-2-methylbenzoyl) amino]pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours. The mixture is diluted with 50 ml of dichloromethane and 20 ml of water and the organic layer is separated. The organic layer is washed with 20 ml each of 1 M NaHCO3 and brine and dried (Na2SO4) . The solution is filtered through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated and the residue purified on silica gel prep-plates with ethyl acetate-hexane (1:1) as solvent to give a solid. The solid is crystallized from ethyl acetate to give 0.38 g of crystals, m.p. 190-196°C.

As described for Example 171 the following compounds are prepared (Table G).

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Examole 208

N-Γ5-(4H~PvrazoloF5.l-clfl, 41benzodiazepin-5 (10H)vlcarbonvl)-2-pvridinvll-5-f luoro-2-methvlbenzamide

To a chilled (0°C) solution of 0.37 g of 5,10dihydro-4H-pyrazolo[5,l-£][1,4]benzodiazepine and 836 microliters of triethylamine in 5 ml of dichloromethane is added 0.761 g of 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride. The mixture is stirred at room temperature under argon for 5 hours. An additional 420 microliters of triethylamine and 0.38 g of 6-[ (5-fluoro-2-methylbenzoyl)amino]pyridine-3carbonyl chloride is added and the mixture stirred 16 hours. The mixture is diluted with 60 ml of dichloromethane and washed with 25 ml each of H2O, 1 M NaHCC>3, brine and dried (Na2SO4). The solution is filtered (twice) through a thin pad of hydrous magnesium silicate and the pad washed with dichloromethane. The filtrate is concentrated to give a yellow glass (0.68 g) which is crystallized from ethyl acetate to give 0.38 g of white crystals, m.p. 250-260°C; mass spectrum (FABL) 442.4 (M+H).

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Example 328

N-i 4-(5H-Pvrrolo Γ2,1-clil,41benzodiazepin-10(11H)-vlcarbonvl) -3-chlorophenvll -2-methvl-pyridine-3carboxamide

A mixture of 1.1 g of 10,ll-dihydro-10-(4amino-2-chlorobenzoyl)-5H-pyrrolo[2,l-£][1,4]benzodiazepine and 3 ml of N,N-di isopropyl ethylamine in 100 ml of methylene chloride is stirred while a solution of 600 mg of 2-methylpyridine-3-carbonyl chloride in 15 ml of methylene chloride is added slowly. The reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is quenched with water and the organic layer washed with water, dried(MgSO4), filtered and evaporated in vacuo to a residue. The product is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give the desired product as a pale yellow residue. M+=456.

Example 3 29

N- Γ5--(5ΗτΡυτγο1οΤ2,1-cl Γ1.41 benzodiazepin-10 (11H) vlcarbonvll -2-ovridinvll -2-methvlPvridine-3-carboxamide

A mixture of 2.5 g of 6-[ [3-(2-methylpyridinyl)carbonyl]amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 3 hours and the mixture evaporated to dryness in vacuo to give a solid. A solution of the solid in 50 ml of methylene chloride is added to 2 g of 10,ll-dihydro-5H-pyrrolo[2,l-£][1,4]benzodiazepine dissolved in 50 ml of dichloromethane containing 3 ml of N,N-diisopropylethylamine at room temperature. The reaction mixture is stirred at room temperature for 2 hours and quenched with water; washed with water; dried (MgSO4), filtered and evaporated in vacuo to a residue. The residue is purified by column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane to give 2.0 g of the desired product as a solid. M+=423.

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Example 33Q

N-F5-(5H-Pvrrolo_F2, l-cl Γ1,41benzodiazepin-10 (11H) vlcarbonvll -2-ovridinvll -2 -methvlovridine-3-carboxamide

Hydr.Qbhl.Qr ids

To a solution of 1.0 g of N-[5- (5H-pyrrrolo[2,1-s.J [l,4]benzodiazepin-10 (11H) -ylcarbonyl)-2pyridinyl]-2-methylpyridine-3-carboxamide in 50 ml of methanol is added hydrogen chloride gas. The mixture is stirred at room temperature for 30 minutes and the solvent removed under vacuum. The residue is triturated with ether to give 1.0 g of the desired product as a solid: mass spectrum(CC1);459 (M+) .

Example 331

N- f 4-..(5H-J*zxro.lof 2,l-clΓ1,41benzodiazeoin-lO (11H)vlcarbonvlJphenvl-1-2- FN-methvlpiperazinvll -pvridine-3-CarbQ.xami.de Hydrochloride

The method of Example 330 is used to prepare the desired product as a solid: M+=543.

Example 332

N- F 4-(5H-Pyrrolo F2,l-clil,41 benzodiazepin-10(11H)vlcarbonvDjohenvll - 2- (dimethvlamino) -pvridine-3carboxamide Hydrochloride

The method of Example 330 is used to prepare the desired product as a solid: M+=487.

Example 333

N- F4- (5H-Pvrrolo F2 l-cl Fl, 41benzodiazepin-10 (11H)~ vlcarbonvl-lphenvll -2-chloropvridine-3-carboxamide

To a stirred solution of 6.06 g of 10,11dihydro-10- (4-aminobenzoyl) -5H-pyrrolo[2,1-q] [1,4]benzodiazepine and 10 ml of N,N-diisopropylethylamine is added a solution of 4.0 g of 2-chloropyridine-3-carbonyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched with water and the organic layer washed well with water. The organic layer is dried, filtered and evaporated in vacuo to a pale yellow

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-256product which is crystallized from 1:1 ethyl acetate:hexane to give 7.0 g of the desired product; M+=442.

Example 334

ΝτΠ^ί5ΗτΡνΓΓθ·1ο_Γ2., 1-cl LL41 benzodiazepin-10 (11H) ylcarbonyl)phenvll -2- (me.thvlamino)pvridine-3-carboxamide

A mixture of 1 g of N- [4-(5H~pyrrolo [2, 1-p.] [1,4] benzodiazepin-10 (11H) -ylcarbonyl) phenyl] -2-chloropyridine-3-carboxamide, 1 g of K2CO3 and 10 ml of a 40% solution of monomethylamine is heated in 25 ml of dimethylsulfoxide for 8 hours at 100°C. The reaction mixture is poured over water and the pale yellow solid separated. The reaction mixture is filtered and the collected solid washed well with water. After drying the solid is purified by column chromatography on silica gel by elution with 9:1 ethyl acetate:methanol to give 850 mg of the desired product as a pale yellow solid:M+=437.

Example. 335

N- F4-(5H-pvrrolo f2.1-clΓ1,41 benzodiazepin-10(11H)vlcarbonvl)phenvl1-2-F(3-dimethvlaminooropvlLaminol pyridine-3-carboxamide

Using'the conditions of Example 334 and N-[4-(5Hpyrrolo[2,1-p][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 3-(dimethylamino ) propylamine gives 900 mg of the desired product:M+=508.

Example 336

N- F4- (5H-Pvrrolo Γ2,1-clΓ1,41 benzodiazepin-10(11H1yj^arbonyl)phenvl 1 -2- (1-piperidinvl) -pyridine-3carboxamide

Using the conditions of Example 334 and 1 g of N-[4-(5H-pyrrolo[2,1-p][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of piperidine gives 700 mg of the desired product:M+=491.

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-257Example 337

N-[4-.i.5H-PvrrolpJ.2, l-_cl Fl,41benzodiazeDin-lQ.(llH) YlcarbQDYllphenvJ,L-2- (4-methyl-l-Diperazinvl) -uvridine3-carboxamide

Using the conditions of Example 334 and 1 g of N-[4-(5E-pyrrolo[2,l-£][1,4]benzodiazepin-10(11H)ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide and 5 ml of N-methylpiperazine gives 1 g of the desired product:M+=500.

Exampie 3.3$

N-J4-- (5H-PvrrQlQ.F2,1-cl Fl.41 benzodiazepin-10 (11H) vl carbonyl lDhenvll -2- (dimethvlamino) -pvridine-3carbQxamide

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<td></td><td> Example 346 N- L4- CSH-Pyrrolo L2_._l-clJ 1,41 benzodiazepin-10 (11H) -</td>

<td> 5</td><td> vlcarbpnvlLphenvl1-2-(4-chlorophenvloxv)pvridine-3carboxamide The conditions of Example 325 are used with 2(4-chlorophenyloxy)pyridine-3-carbonyl chloride to give the desired product as a crystalline solid, m.p. 211212°C (M+Na) = 557.3.</td>

<td> 10</td><td> Example 347 N-L4-L5H-Pvrr.oLQl.2.,JLrcl JI, 41 benzodiazepin-10 (11H) - Ylcarbgn.vJ.Lphenvll -2-methvl-2- (4- chlorophenvloxv) propionamide</td>

<td> 15</td><td> The conditions of Example 325 are used with 2(4-chlorophenoxy)-2-methylpropionyl chloride to give the desired product as a solid. M+-499. Example 348 10-f Γ6-(1,1-dimethvlethvllaminol-3-nvridinvl)carbonvl]- 10,ll-dihvdro-5H-nvrroloi2,1-cli1,41 benzodiazepine</td>

<td> 20</td><td> Using the conditions of Example 273 and tbutylamine gives the desired product as a beige solid. MS (CI): 361(M+H). Example 349</td>

<td> 25</td><td> 1-0- i 16 _UrMethvlethvl) amino) -3 -ovridinvl) carbonvl 1 - IQ., ll-_dihvdro^5H_-pyrroloi2, 1-cl Γ1,41 benzodiazepine Using the conditions of Example 273 and isopropylamine gives the desired product as a white solid. MS(CI): 347(M+H).</td>

<td> 30</td><td> Example 3 50 10-Γ[6-(1-lndanvlaminol-3-ovridinvl)carbonvll -10,11-</td>

<td> μ-</td><td> dihvdro-5H-pvrrolo Γ2,1-c1 Γ1,41 benzodiazepine Using the conditions of Example 273 and 1aminoindan gives the desired product as a beige solid. MS (CI): 421(M+H).</td>

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Example 351

10- Γ [6-_i2.4--Dimethoxvphenvlamino) -3-pvridinvllcarbonyl1 IQ. llzdihv.dro-5H-pyrrQlol2_JL-cl Γ1,41 benzodiazepine

Using the conditions of Example 273 with 2,4dimethoxybenzylamine gives the desired product as a light yellow solid. MS(CI): 455(M+H).

Example 352

IQ- Γ L£--L2_-Brornophenvlamino) -3-pvridinvll carbonvll -10.11dihy.dro-5HzPYrral.oJ2,1-cl fl, 41 benzodiazepine

Using the conditions of Example 273 and 2bromobenzylamine gives the desired product as an offwhite solid. MS(CI): 474(M+H).

Example 353

N- i 5- (5H-Pyrrol0.12,1-c) ί 1,41benzodiazepin-10 (11H) vlc-arb_onvl) -2 -pvridinvll -2 -methvlf urane-3 -carboxamide Using the conditions of Example 1 with Reference Example 39 to give Reference Example 86 and stirring overnight gives the desired product as white crystals after column chromatography on silica gel by elution with 1:1 ethyl acetate:hexane and crystallization from ethyl acetate, m.p. 210-212°C.

Example 354

Ντ iS-.tSEL^wailaia.Jl-c.Li 1., 4j.be.nzQdia.?gpi.ojJ..QLLl.H]·vlcarbonvl)-2-pvridinvll-2-aminobenzamide

A room temperature solution of 1.0 g of N-[5(5H-pyrrolo[2,l-£][1,4]benzodiazepin-10(11H)ylcarbonyl)-2-pyridinyl]-2-nitrobenzamide in 100 ml of ethyl alcohol is hydrogenated over 200 mg of 10% Pd/C in a Parr apparatus under 40 psi of hydrogen for 2 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with additional ethyl alcohol. The combined filtrates are concentrated in vacuo and the residue purified by crystallization from 2:1 ethyl acetate: hexane to give the desired product as pale yellow crystals: M+Na 445:M+423.

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-262Example 3 55 (3-Chloro-4- Γ 3-dimethvlaminomethvl) -5H, llH-Pvrrolo[2^1-_cl Γ1,41-benzodiazepine-10-carbonvll -phenvl)bl·Phenvl·--2.rcaI·bO-χvliCacid amide

To a solution of the product from Example 319, (2.23 g, 4.32 mmol) in 1:1 methanol/tetrahydro furan (40 ml) was added Ν,Ν,Ν' ,N'-tetramethyl-diaminomethane (1.19 ml, 8.64 mmol), paraformaldehyde (0.519 g, 17.3 mmol), and acetic acid (0.516 ml, 8.6 mmol). The suspension was stirred at room temperature overnight. The solvent was removed, and the residue was dissolved in dichloromethane, washed with water, 5% sodium bicarbonate, and water. All aqueous washings were backwashed with dichloromethane. The combined organic solutions were dried (MgSO4), and the solvent removed to give crude product (1.68 g) . Puri.f i-cation by flash chromatography on silica gel (50 g) in 18% methanol/ethyl acetate gave the product, which was recrystallized from ethyl acetate-hexane to give pur© sample (1.06 g) mp 138-141°. MS (+FAB) m/z: 575/577 (M+H) .

Analysis for: C32H21CIN3O3 Calcd: C, 73.10, H: 5.43. N: 9.74. Found C, 71.57, H: 5.21, N: 9.41.

Example 356 < 3 -Chloro-4-_L3 -.(4 rmethvlpjperazin-l-vlmethvl) 5H JLIHpvrrolo [2,1.-C1.I VAlbenzodiazepine-10-carbonvl) 1 -phenvl.) biphenvl-2-carboxvlic acid amide

To a solution of the product from Example 319, (0.54 g, 1.08 mmol) in 1:1 methanol-tetrahydrofuran (8 ml) was added N-methylpiperazine (0.48 g, 4.32 mmol), paraformaldehyde (0.194 g), and acetic acid (0.13 ml, 2.16 mmol) in that order. The mixture was allowed to stir at 60° for 21 hours. The solvent was removed under vacuum, and the residue was partitioned between dichloromethane and water. The organic phase was washed . 35

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-263with sodium bicarbonate and water, dried (MgSO4), and the solvent removed to yield crude product (0.48 g). The 5 experiment was repeated to obtain 0.43 g of the crude product. The two batches were combined (0.9 g) and purified by silica gel chromatography (25g) with methanol-ethyl acetate (1:4) to give on crystallization from ethyl acetate-hexane 0.45 g of desired product. MS (+FAB) m/z: 653 (M+Na)+ .

Example 357

Γ4- (3-Dimethvlaminomethvl-5H, llH-PvrroloΓ2.1-cl ί1,41benzodiazepine-lO-carbonvl)-3-methoxv-phenvl 1 biphenvJ.-2-carboxylic acid amide

Step a) 2-methoxy-4-nitrobenzoic acid methyl ester Thionyl chloride (13.9 ml, 190 mmol) was added via syringe to a solution of 2-methoxy-4-nitrobenzoic acid (50 g, 250 mmol) in methanol which was stirred at room temperature for 16 hours. The volatiles were removed in vacuo. The residue dissolved in dichloromethane, washed with (IN) sodium hydroxide, and the organic layer separated and dried (MgSO4).

Evaporation in vacuo gave a light yellow solid (50 g, 93%) mp 80-81°C, which was taken directly to the next step.

Analysis for: C9 Hg N O5

Calcd: C, 51.19; H, 4.30; N, 6.63.

Found: C, 50.97; H, 4.11; N, 6.51.

Step b) 4-amino-2-methoxy-benzoic acid methyl ester

A mixture of 2-methoxy-4-nitrobenzoic acid methyl ester (12 g, 57 mmol), palladium (10% on activated carbon), and ethanol (150 ml) was shaken at room temperature under 50psi of hydrogen for 2 hours. The reaction was filtered through diatomaceous earth, and the diatomaceous earth washed with chloroform. Evaporation of the chloroform washings gave a yellow

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-264solid; purification by crystallization gave a light yellow crystalline solid (8.76 g, 85%) mp 148-149°C. Analysis for: Cg Ηχι N O3

-267Found: C, 74.46; H, 6.35; N, 11.24.

Example 359 (2-Methoxv-4-Γ3- (4-methvl-pinerazin-l-vlmethvl)-5H, 11Hpvrrolo Γ2.1-cl F1,41benzodiazepine-10-carbonvll-phenvl)biphenvl-2-carboxylic acid amide

The compound of Example 359 was prepared in substantially the same manner as described in Example 357. In step 357a, 4-nitro-3-methoxybenzoic acid was substituted for 4-nitro-2-methoxybenzoic acid. In step 357f, N-methyl piperazane was used in place of Ν,Ν,Ν' , N'- tetramethyl-di aminomet hane. The product was obtained as a colorless solid, mp 104-105°C.

Analysis for: C39 H39 N5 O3 + 1.0 H2O

Calcd: C, 73.43; H, 6.59; N, 10.88. Found: C, 73.01; H, 6.17; N, 10.92.

Example 360

F4-(3-Dimethvlaminomethvl-5H, HH-pvrroloF2,lcl f 1.41benzodiazepine-10-carbonvl) -2-methoxv-phenvll biphenvl-2-carboxvlic acid amide

The compound of Examle 360 was prepared in substantially the same manner as described in Example 357. In step 357a, 4-nitro-3-methoxybenzoic acid was substituted for 4-nitro-2-methoxybenzoic acid. The title compound was obtained as a colorless solid, m.p. 114-116°C.

Analysis for: C36 H34 N4 O3 + 0.25 H2O

Calcd: C, 75.17; H, 6.05; N, 9.74. Found: C, 74.98; H, 5.89; N, 9.69.

Example 3 61 (3-Bromo-4- Γ3- (dimethvl-amino-methvl) -5H, 11Hpyrrolo F2.1-cl F1,41benzodiazepine-10-carbonvl1 -phenvlbiphenvl-2-carboxvlic acid amide

Step a) .2-Bromo-4-nitrobenzoic acid methyl ester Thionyl chloride (3.99 ml, 54.6 mmol) was added via syringe at room temperature to a methanol solution (500 ml) of 2-bromo-4-nitrobenzoic acid (Chem.

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-268Ber. 1961, 835) (17.9 g, 72.9 mmol). The reaction was stirred at room temperature for 16 hours. The volatiles were removed in vacuo, the residue dissolved in dichloromethane, washed with IN sodium hydroxide, and the organic layer separated and dried (MgSO4).

Evaporation gave a light yellow solid (10.9 g, 83%) m.p. 73-74°C, which was used without further purification in Example 361, step b.

<td> Analysis</td><td> for: C8</td><td> H6</td><td> Br N</td><td> 04</td>

<td> Calcd: C,</td><td> 34.17;</td><td> H,</td><td> 1.64;</td><td> N, 5.69.</td>

<td> Found: C,</td><td> 33.92;</td><td> H,</td><td> 1.49;</td><td> N, 5.67.</td>

Step b) (3-Bromo-4-[3-(dimethyl-amino-methyl)-5H, 11Hpyrrolo [2,1-c] [1,4] benzodiazepine-10-carbonyl] -phenyl}bipheny1-2-carboxylic acid amide

The compound of Example 3 61, step b was prepared in substantially the same manner as Example 357, following the steps b through f. In Example 357 step b, the product of Example 361, step a, was substituted for the product of Example 357, step a.

Also in Example 357, step b, Raney nickel was substituted for palladium on carbon and the reaction time increased to 24 hours. The product was obtained as a colorless solid, m.p. 138-140°C.

Analysis for: C35 H31 Br N4 02

Calcd: C, 67.85; H, 5.04; N, 9.04.

Found: C, 67.94; H, 5.24; N, 8.84.

Example 3 62 i-3-Bromo-4-(3- (4-methvl-oiperazin-l-vlmethvl) -5H, 11HpvrroloΓ2,1-cl Γ1.41 benzodiazeoin.e-10-carbonvl] -ohenvllbiohenvl-2-carboxvlic acid amide

The compound of Example 3 62 was prepared in substantially the same manner as described in Example 357, following the steps b through f. In Example 357 step b, the product of Example 3 61, step a, was substituted for the product of Example 3 57, step a.

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-269Also in Example 357, step b, Raney nickel was substituted for palladium on carbon and the reaction time increased to 24 hours. In Example 357, step f, Nmethylpiperazane was substituted for Ν,Ν,Ν',Ν'tetramethyldiaminomethane. The product was obtained as a colorless solid, m.p. 149-150°C.

<td colspan="3"> Analysis for: C38 H36 Br N5 0</td>

<td> Calcd: C, 67.65; H, 5.38;</td><td> N,</td><td> 10.38.</td>

<td> Found: C, 67.28; H, 5.52;</td><td> N,</td><td> 10.13.</td>

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-272The title compound was prepared in substantially the same manner as described in Example 357 steps c through e. In step 357c, 1-(pyridin-2yl)benzoic acid (G. Timari, et.al,, Chem. Ber. 1992,125,929) was used in place of 2-biphenylcarboxylic acid. In step 357e 5H,10H-pyrazolo[5,lc][1,4benzodiazepine (L. Cecchi and G. Filacchioni, J. Heterocyclic Chem. 1983,20, 871) was used in place of 10,ll-dihydro-5H-pyrrolo[2,l-c][1,4]benzodiazepine. The title compound was obtained as a pale pink solid (0.23 g, 37%). MS (+FAB) m/z: 516 (M+H).

Analysis for: C31H25N5O3

Calcd: C, 72.22; H, 4.89; N, 13,58. Found: C, 71.47;, H, 4.63; N, 12.95.

Example 366

N-i3-Chloro-4-(51L llH-pvrroloΓ2,1-clί1,41benzodiazeoine10-carbonvl)-ohenvll-2-thioohen-2-vl-benzamide

Step a) 2-Bromobenzoyl chloride

To a solution of 2-bromobenzoic acid (1.88 g, 9.35 mmol) in anhydrous tetrahydrofuran (20 ml), under nitrogen, was added 1 drop of dimethylformamide followed by addition of oxalyl chloride (1 ml, 11.4 mmol). The mixture was stirred at room temperature until gas evolution ceased and then heated to reflux. The solution was cooled to room temperature before being concentrated in vacuo to produce a golden colored oil (1.87 g, 91%) which was used without further purification.

Step b) 2-Bromo-N-[3-chloro-4-(10,ll-dihydro-5Hpyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]benzamide

To a stirred solution of the product of 10,11dihydro-10- (2-chloro-4-aminobenzoyl) -5H-pyrrolo [2, Ιο] [1, 4] benzodiazepine (2.25 g. 6.66 mmol) in dichloromethane (40 ml) , under nitrogen, was added triethylamine (1.19 ml, 8.53 mmol). The mixture was cooled to 0°C ' 35

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-2738.52 mmol) in dichloromethane (20 ml) was added dropwise. The cooling bath was removed and stirring wascontinued for 14 hours. The reaction mixture was poured into water. The organic layer was separated and sequentially washed with water, saturated aqueous sodium bicarbonate, and water. The organic solution was dried (Na2SO4) and concentrated in vacuo to yield a pale orange foam (2.0 g, 58%). Purifi-cation by flash chromatography on silica gel with hexane-ethyl acetate (1:1) as the mobile phase resulted in a colorless powder (1.39 g, 40%), m.p. 188-189°C. MS (El),m/z:: 519 (M+)

Analysis for: C26H19BrClN3O2 + 0.5 H20 Calcd: C, 58.93; H, 3.80; N, 7.93.

Found: C, 59.12; H, 3.62; N, 7.75. Step c) N- [3-Chloro-4-(5H, llH-pyrrolo[2, Ιο] [1,4] benzodiazepine -10-carbonyl) -phenyl] -2-thiophen2-y1-benzamide

The 2-bromo-N-[3-chloro-4-(10,11-dihydro-5Hpyrrolo[2,1-c] [1,4]benzodiazepine-10-carbonyl)-phenyl]benzamide (1.04 g, 2.0 mmol) and thiophene-2-boronic acid (0.32 g, 2.4 mmol), and barium hyroxide octahydrate (0.88 g, 2.8 mmol) was suspended in ethylene glycol dimethyl ether (28.8 ml) and water (4.8 ml). The heterogeneous mixture was stirred at room temperature and purged with nitrogen for ten minutes before bis(triphenylphosphine) palladium (II) chloride (0.17 g, 0.24 mmol) was added. The reaction was capped with a nitrogen balloon and heated in an oil bath at 70°C. After 20 hours, additional thiophene-2-boronic acid (0.13 g, 1 mmol) was added to the reaction. After 24 hours additional bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol) was added to the reaction flask. The reaction was cooled to room temperature and the mixture was extracted into benzene.

The combined organic extracts were washed with brine,

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-274dried (MgS04), filtered and concentrated in vacuo to yield a brown solid (1.42 g) . The solid was triturated with ethyl acetate and filtered. The filtrate was purified by flash chromatography using silica gel with hexane-ethyl acetate (1:1) as the mobile phase to afford a pale yellow solid (0.59 g, 56%), which was dried under vacuum at 78°C for two days, m.p. 132-136°C. MS (El),m/z: 523 (M+).

Analysis for: C30H22CIN3O2S + 0.5 H2O Calcd: C, 67.53; H, 4.36; N, 7.88.

Found: C, 67.53; H, 4.08; N, 7.90.

Example 367

N-i3-Chloro-4-(5H.llH-pyrroloΓ2,1-cl Γ1,41benzodiazeoine-lOcarbonvJJ^phenvll -2-Pvridin-3-vl-benzamide

The compound of Example 367 was prepared in substantially the same manner as described in Example 3 66 following the steps 366a and 365b. In Step 366a, 2(pyridin-3-yl)-benzoic acid was substituted for 2bromobenzoic acid. Preparation of 2-(pyridin-3-yl)-benzoic acid was carried out in the manner of Timari, et al (Chem. Ber. 1992, 125, 929) substituting 3-bromopyridine in place of 2-bromopyridine. The title compound was obtained as an offwhite powder (0.21 g, 40%) m.p. 155-158°C.

Analysis for: C31H23CIN4O2 + 0.85 H2O Calcd: C, 69.68; H, 4.66; N, 10.49. Found: C, 69.69; H, 4.70; N, 10.16.

Example 368

N-r3-Chloro-4-(5H.llH-PvrroloΓ2,1-cl il.41 benzodiazepine-liL· carbonyl) -phenvll -2-pvridin-4-vl-benzamide.

The compound of Example 368 was prepared in substantially the same manner as described in Example 366 following steps 366a and 366b. In Step 366a, 2-(pyridineyl)-benzoic acid was substituted for 2-bromobenzoic acid. Preparation of 2-(pyridin-4-yl)-benzoic acid was carried out in the manner of Timari, et al (Chem. Ber. 1992, 125, 929)

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-275substituting 4-bromopyridine hydrochloride and an additional equivalent of base in place of 2-bromopyridine. The title compound was obtained as a pale yellow solid (1.21 g, 53%) m.p. 165-168°C.

Analysis for: C31H23CIN4O2 + 0.47 H2O Calcd: C, 70.59; H, 4.57; N, 10.62.

Found: C, 70.58; H, 4.50; N, 10.33.

Example 369

N-F4-(3-Methoxv-5H,llH-pyrroloΓ2. Ιοί fl, 41benzodiazeDine-10-carbonvl) -phenvll -2-pvridin-2vl-benzamide

Step a) 2-Methoxy-4-[ (2-pyridin-2-ylbenzoyl)amino] benzoyl chloride

To a solution of 2-methoxy-4-[(2-pyridin-2ylbenzoyl)amino]benzoic acid (0.92 g, 2.64 mmol) in anhydrous tetrahydrofuran (25 ml), under nitrogen, was added 1 drop of dimethylformamide followed by addition of oxalyl chloride (0.28 ml, 3.17 mmol). The mixture was stirred at room temperature until gas evolution ceased. The solution was concentrated in vacuo to produce a tan solid (1.16 g) which was used without further purification in Example 369 step b.

Step b) N-[4-(3-Methoxy-5H,llH-pyrrolo[2, Ιο] [1,4] benzodiazepine-10-carbonyl) -phenyl] -2-pyridin-2yl-benzamide >

To a stirred solution of the product from Reference Example 6, 10,ll-dihydro-5H-pyrrolo[2,Ιο] [1,4]benzodiazepine (0.405 g. 2.20 mmol) in dichloromethane (30 ml), under nitrogen, was added triethylamine (0.37 ml, 2.64 mmol). The mixture was cooled to 0°C and a solution of the crude 2-methoxy-4-[(2-pyridin-2ylbenzoyl)-amino]benzoyl chloride (1.16g) in dichloromethane (30 ml) was added dropwise. After 5 hours the reaction mixture was poured into water. The organic layer was separated and sequentially washed twice with water and aqueous sodium bicarbonate, and

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-27610 once with water. The organic solution was dried (Na2SC>4) and concentrated in vacuo to give a marron solid (1.1 g, 94%). Purification by flash chromatography on silica gel with hexane-ethyl acetatemethlyene chloride-methanol (3:6:2:0.5) as a mobile phase, followed by concentration in vacuo, resulted in a pale purple solid (0.88 g, 76%) , m.p. 138-140°C. MS (FAB),m/z : 515 (M+H).

Analysis for: C32H26N4O3 + 0.43 H2O

Calcd: C, 73.58; H, 5.18; N, 10.73. Found: C, 73.59; H, 5.05; N, 10.47.

Example 370

N-Γ4-(3-Dimethvlaminomethvl-5H,llH-pyrrolo Γ2,1-cl ί1.41benzodiazepine-10-carbonvl)-3-methoxv-phenvll -2pyridin-2-vl-benzamide

Into a flask equipped with a reflux condenser was placed under nitrogen product of Example 369 step b, N-[4-(3-methoxy-5H,llH-pyrrolo[2,Ιο] [1, 4]benzodiazepine-10-carbonyl)-phenyl]-2-pyridin-2yl-benzamide (0.37 g, 0.71 mmol), Ν,Ν,Ν',Ν'tetramethyldiaminomethane (0.15 mg, 1.4 mmol), paraformaldehyde (85 g, 2.8 mmol), tetrahydrofuran (5 ml) and methanol (5 ml). After stirring at room temperature for two minutes glacial acetic acid (85m g, 1.4 mmol) was added. The solution was stirred at room temperature for 14 hours. The reaction was concentrated in vacuo, redissolved in dichloromethane and washed sequentially with saturated aqueous sodium bicarbonate, water, saturated aqueous sodium bicarbonate and water. The organic solution was dried (Na2SO4) and concentrated in vacuo to afford an off-colorless foam (0.39 g, 96%). Purification by flash chromatography using silica gel with dichloromethane-methanol (9:1) as the mobile phase, afforded a colorless foam. The foam was redissolved in dichloromethane, filtered through diatomaceous earth, concentrated in vacuo and dried under vacuum at 78°C

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-277overnight to afford an off-white solid (0.24 g, 59%), m.p. 132-134°C (dec).

Analysis for: C35H33N5O3 + 0.89 H2O Cald'd: C, 71.53; H, 5.97; N, 11.92. Found: C, 71.52; H, 5.63; N, 11.89.

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-28010 brine and dried (MgS04). Evaporation in vacuo gave a dark residue, which was adsorbed onto silica gel and purified by flash chromatography (eluting solvent hexane-ethyl acetate 2:1) to give a colorless solid (2.25 g, 64%) m.p. 194-196°C.

Analysis for: C32 H25 N3 O3 + 0.25 H2O

Calcd: C, 76.24; H, 5.10; N, 8.34.

Found: C, 76.16; H, 5.00; N, 8.31.

Step b) [4-(3-Dimethylaminomethyl-3-hydroxy-5H, 11Hpyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-phenyl]biphenyl-2-carboxylic acid amide

The compound of Example 371 step b was prepared in the same manner as described in Example 357 step f, substituting the product of Example 371 step a for the product of Example 357 step e. The product was obtained as a colorless solid, m.p. 135-137°C.

<td colspan="2"> Analysis for: C35 H32 N4 O3</td><td> + 0.25H2O</td>

<td> Calcd: C, 74.91; H,</td><td> 5.84; N,</td><td> 9.98.</td>

<td> Found: C, 74.61; H,</td><td> 5.94; N,</td><td> 9.93.</td>

<td></td><td colspan="2"> Example 373</td>

Γ4-(3-Γ1.41lBipiperidinvl-l·-vlmethvl-5H.11HpyrrolQ[2, l~d_[1,41 benzodiazepine-10-carbonvl)-3chloro-.p.henvll-biphenvl-2-carboxylic acid amide

The product from Example 319, (2.07 g, 4 mmol) was treated sequentially with 4-piperidinopiperidine (2.02 g, 12 mmol), trifluoroacetic acid (2.73 g, 24 mmol), and 37% aqueous formaldehyde (formalin) (4 ml, 50 mmol) in methanol (50-75 ml). After stirring for one hour at room temperature, the reaction mixture was diluted with dichloromethane (500 ml) , extracted with saturated aqueous sodium bicarbonate (200 ml) and water (4 x 200 ml), and dried (Na2SO4). The product was purified through a short silica gel plug by gradient elution filtration, (ethyl acetate to methanol-ethyl acetate 1:4). The appropriate fractions were combined and evaporated, redissolved and refiltered from ethyl

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-281acetate, and the solvent evaporated in vacuo to afford 1.34 g (1.9 mmol, 48%) of a colorless solid.

_ Trituration with ether-hexane and filtration afforded, after drying in vacuo overnight at 50*C, 1.30 g (1.86 mmol, 47%) of the title compound as a colorless, amorphous powder, m.p. 193-195’C. MS (+FAB), m/z : 720 (M+Na) .

Analysis for: C43H44CIN5O2

Calcd: C, 73.96; H, 6.35; N, 10.03. Found: C, 73.23; H, 6.31; N, 9.81.

Example 374 (3-Chloro-4-(3-F(2-hvdroxv-l,1-bis-hydroxymethylethvlamino)-methvll-5H,llH-ovrrolof2.1-cl

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-284Calcd: C, 72.99; H, 6.13; N, 10.64.

Found: C, 72.66; H, 6.01, N, 10.45.

Example 377

N-Γ .Chloro-4-(5H.11H-Dvrrolo{2.Ιοί il, 4Ι^βηζοάΐβζβΏ1ηβ-10-θΒ^οην1) -phenvll -2-Pvrrol-lvl-benzamide

A solution of 1-(2-carboxyphenyl)pyrrole (188 mg, 1 mmol) and triphenylphosphine (264 mg, 1 mmol) in dichloromethane (6 ml) was cooled to 0°C. To this solution was added, portionwise, N-chlorosuccinimide (131 mg, 0.9 mmol). The solution was stirred for 30 minutes and allowed to warm to room temperature. To this solution was added a solution of 10,ll-dihydro-10(2-chloro-4-aminobenzoyl)-5H-pyrrolo[2, Ιο] [1,4]benzodiazepine (338 mg, 1 mmol) and triethylamine (0.15 ml, 1.06 mmol) in 15 ml of a mixture of a tetrahydrofuran-dichloromethane (1:2). The reaction was stirred for two hours at room temperature and then was concentrated to a solid in vacuo. The solid was disolved in ether (100 ml) and filtered. The filtrate was concentrated in vacuo and chromatographed over silica gel with ethyl acetate-hexane (1:1) as the mobile phase to afford 270 mg of the product as a yellow solid. Recrystallization from ethyl acetate-ether-hexane gave 180 mg of the product as a colorless solid. MS (El),m/z 506/508 (M+).

Example 378 Ouinoline-8-carboxvlic acid Γ4-(5H,llH-pyrroloΓ2,1-cl il,41benzodiazenine-10-carbonvl) -3-phenvl)-amide The compound of Example 378 was prepared in substantially the same manner as described in Example 366, Steps 366a and 366b. In Step 366a, quinoline-8-carboxylic acid was substituted for 2-bromobenzoic acid. The title compound was obtained as a colorless powder (0.69 g, 37%) m.p. 230-231°C.

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-285Analysis for: C29H21CIN4O2 + 0.33 H2O Calcd: C, 69.81; H, 4.38; N, 11.23. Found: C, 69.81; H, 4.09; N, 11.14.

Example 379 i 3-Chloro-4-13-dimethvlaminomethvl-5H.llH-pvrrolo Γ 21-c 1 fl, 41 benzodiazepine-lO-carbonvl) -phenyl 1 -2-phenvlcvclopent-l-enecarboxvlic acid amide

Step a) [2-Phenyl-cyclopent-l-enecarboxylic acid]

Sodium hydroxide (IN) (10.7 ml, 11.8 mmol) was added to a refluxing solution of 2-phenyl-cyclopent-lenecarboxylic acid methyl ester (2.32 g, 10.7 mmol) (Lin et al., J. Chin. Chem. Soc., 1993, 40, 273) in methanol (40 ml). The reaction was refluxed for 2 hours. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate and (IN) HCI. The aqueous layer was re-extracted with ethyl acetate, and the combined organic extracts combined and dried (MgSO4). Evaporation of the solution in vacuo gave a pale yellow solid, which was recrystallized from acetone-hexane to give a colorless solid (1.27 g, 63%) m.p. 145-146°C.

Analysis for: C12 H12 02 Calcd: C, 76.57; H, 6.43. Found: C, 76.47; H, 6.35.

Step b) 2-Phenyl-cyclopent-l-enecarbonyl chloride

To solution of 2-phenyl-cyclopent-l-enecarboxylic acid (0.43 g, 2.28 mmol) in dichloromethane (20 ml) was added dimethylformamide (1 drop) and then neat oxalyl chloride (0.4 ml, 4.56 mmol). The reaction was stirred at room temperature for 2 hours and then the volatiles were removed in vacuo. The residue was redisolved in dichloro-methane, concentrated in vacuo and dried under high vacuum for 15 minutes to give an amber oil which was used directly in the next step without further purification.

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-286Step c) [4-(5H,llH-Pyrrolo-[2,1-c][1,4]benzodiazepine10-carbonyl) -3-chloro-phenyl] -2-phenyl-cyclopent-1enecarboxylic acid amide

The product from Example 379 step b, 2-phenylcyclopent-l-enecarbonyl chloride was dissolved in dichloromethane (20 ml) was added at room temperature to a solution of the product of Reference Example 6, 10,11dihydro-10- (2-chloro-4-aminobenzoyl) -5H-pyrrolo[2, Ιο] [1, 4] benzodiazepine (0.77 g, 2.28 mmol), 4-dimethylaminopyridine in dichloromethane (20 ml) . Triethylamine (0.38 ml, 2.74 mmol) was then added via syringe. The reaction was stirred for 16 hours, diluted with dichloromethane and washed with sodium bicarbonate, (IN) HCI, and brine. The dichloromethane solution was dried (MgSO4> and concentrated in vacuo to give a yellow solid. Purification by flash chromatography (eluting solvent chloroform-methanol 50:1 and hexane-ethyl acetate 2:1) afforded a colorless solid (0.70 g, 60%) m.p. 121-122°C.

Analysis for: C31 H26 Cl N3 O2 Calcd: C, 73.29; H, 5.16; N, 8.27. Found: C, 73.18; H, 5.02; N, 8.11.

Example 380

Biohenvl-2-carboxylic acid (3-chloro-4-Γ3-(2-nitroethvl) -5H,llH-pyrrolo ί 2,1-cl Γ1,41benzodiazepjne-10carbonvl)-phenvl)-amide

A solution of sodium metal (115 mg, 5 mmol) dissolved in ethanol (10 ml) was treated with nitromethane (1.52 g, 25 mmol) . To the resulting white suspension was added (10-{4-[(Biphenyl-2-carbonyl)amino] -2-chloro-benzoyl] -10, ll-dihydro-5H-pyrrolo [2,1-c] [1,4] benzodiazepin-3-ylmethy 1) - trimethyl-ammonium (1 mmol) and the mixture heated to 78°C for 7 5 minutes. After evaporation of the reaction mixture in vacuo, the residue was dissolved in dichloromethane, washed with IN HCI and water, and dried (MgSO4) . Filtration through a

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Radioligand Binding Experiments with Human Platelet Membranes '

Platelet Source: Hudson Valley Blood Services, Westchester Medical Center, Valhalla, NY.

Platelet Membrane Preparation: , ’

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

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Table 4

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-311TABLE 5 *

.5 Rat Urine Volume Data and Binding Assay to Membranes of Mouse

Fibroblast Cell Line ( LV-2) Transfected with the cDNA Expressing the Human V2 Receptor

<td> Example Number</td><td> Urine Volume (ml/4 hrs) 10 mg/kg rat p.</td><td> Vasopressin Binding Human V2 Receptor o. nM</td>

*Volume of urine produced in a 4 hour time perion by the oral administration of 10 mg/kg dose to rats.

The compounds of the present invention can be 20 used in the form of salts derived from pharmaceutically .

or physiologically acceptable acids or bases. These salts include, but are not limited to, the following: salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the 25 case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds can also be used in the form of esters, carbamates and other conventional , “pro-drug forms, which, when administered in such form, convert to the active moiety in vivo.

When the compounds are employed for the above utilities, they may be combined with one or more . pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered J orally in such forms as tablets, capsules, dispersible

WO 97/49707

PCT/US97/10736

-31210 powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.

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

PCT/US97/10736

-313tants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.

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

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exits. It must be stable under conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil.

WO 97/49707 PCT/US97/10736

-314The new tricyclic non-peptide vasopressin antagonists of this invention are useful in treating conditions where decreased vasopressin levels are desired, such as in congestive heart failure, in disease conditions with excess renal water reabsorption and in conditions with increased vascular resistance and coronary vasoconstriction.

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

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

WO 97/49707

PCT/US97/10736

-315-

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57 members in 26 offices

This recordMember, by publication datePriority claim16 more offices are in the list below

Priority claims8

Priority claims
Document	Office	Kind	Date
67215096	United States of America	A	1996-06-27
67215096	United States of America	A	1996-06-27
9710736	United States of America	W	1997-06-20
9710736	United States of America	W	1997-06-20
08672150	–	–	–
PCTUS9710736	–	–	–
US19960672150	–	–	–
WO1997US10736	–	–	–

Members57

Family members, oldest first
Document	Office	Kind
IL116775D0	Israel	D0	1996-05-14
US5536718A	United States of America	A	1996-07-16
CA2210631A1	Canada	A1	1996-07-25
WO9622293A1	World Intellectual Property Organization (WIPO)	A1	1996-07-25
AU4769896A	Australia	A	1996-08-07
US5610156A	United States of America	A	1997-03-11
US5612334A	United States of America	A	1997-03-18
ZA96297B	South Africa	B	1997-07-15
EP0804438A1	European Patent Office (EPO)	A1	1997-11-05
BR9607182A	Brazil	A	1997-11-11
CZ224997A3	Czechia	A3	1997-12-17
US5700796A	United States of America	A	1997-12-23
EA199700117A1	Eurasian Patent Organization (EAPO)	A1	1997-12-30
CA2258885A1	Canada	A1	1997-12-31
WO9749707A1	World Intellectual Property Organization (WIPO)	A1	1997-12-31
WO9749708A1	World Intellectual Property Organization (WIPO)	A1	1997-12-31
AR002022A1	Argentina	A1	1998-01-07
AU3406397A	Australia	A	1998-01-14
AU3641497A	Australia	A	1998-01-14
US5753648A	United States of America	A	1998-05-19
MX9705313A	Mexico	A	1998-07-31
HU9800646A2	Hungary	A2	1998-08-28
CN1198746A	China	A	1998-11-11
HK1004132A1	Hong Kong, China	A1	1998-11-20
HU9800646A3	Hungary	A3	1998-12-28
JPH11500106A	Japan	A	1999-01-06
NZ302111A	New Zealand	A	1999-04-29
EP0915876A1	European Patent Office (EPO)	A1	1999-05-19
AU707982B2	Australia	B2	1999-07-22
BR9710087A	Brazil	A	1999-08-10
IL116775A	Israel	A	1999-08-17
CN1231666A	China	A	1999-10-13
IL127470D0	Israel	D0	1999-10-28
KR20000022297A	Republic of Korea	A	2000-04-25
JP2000510154A	Japan	A	2000-08-08
TW403752B	Taiwan Province of China	B	2000-09-01
HU0001162A2	Hungary	A2	2000-09-28
NZ332605A	New Zealand	A	2000-09-29
EA001143B1	Eurasian Patent Organization (EAPO)	B1	2000-10-30
HU0001162A3	Hungary	A3	2001-02-28
AU731925B2This record	Australia	B2	2001-04-05
CN1065244C	China	C	2001-05-02
MXPA99000214A	Mexico	A	2002-07-22
UA54383C2	Ukraine	C2	2003-03-17
KR100443438B1	Republic of Korea	B1	2004-10-14
CA2210631C	Canada	C	2006-03-14
EP0804438B1	European Patent Office (EPO)	B1	2006-03-15
AT320429T	Austria	T	2006-04-15
DE69635922D1	Germany	D1	2006-05-11
DK0804438T3	Denmark	T3	2006-06-12
PT804438E	Portugal	E	2006-07-31
ES2258267T3	Spain	T3	2006-08-16
DE69635922T2	Germany	T2	2006-08-17
SI0804438T1	Slovenia	T1	2006-08-31
CZ297797B6	Czechia	B6	2007-04-04
JP2008101012A	Japan	A	2008-05-01
JP4163252B2	Japan	B2	2008-10-08

2 legal events, as the office reported them to INPADOC

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Events

Legal events, newest first
	Event	Code
2003-01-23	Patent ceased section 143(a) (annual fees not paid) or expiredExpiredMK14	MK14
2001-08-02	Letters patent sealed or granted (standard patent)GrantedFGA	FGA