.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 6,297,258

« Back to Dashboard

Details for Patent: 6,297,258

Title: Substituted 3-cyanoquinolines
Abstract:This invention provides compounds of formula I having the structure ##STR1## wherein G.sub.1, G.sub.2, R.sub.1, R.sub.4, Z, n, and X are defined in the specification or a pharmaceutically acceptable salt thereof which are useful as antineoplastic agents and in the treatment of polycystic kidney disease.
Inventor(s): Wissner; Allan (Ardsley, NY), Tsou; Hwei-Ru (New City, NY), Berger; Dan M. (New City, NY), Floyd, Jr.; Middleton B. (Suffern, NY), Hamann; Philip R. (Gernerville, NY), Zhang; Nan (Eastchester, NY), Frost; Philip (Morris Township, NJ)
Assignee: American Cyanamid Company (Madison, NJ)
Filing Date:Aug 01, 2000
Application Number:09/630,270
Claims:1. A compound of Formula 1 having the structure: ##STR44##

wherein:

X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalky of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

Z is --NH--, --O--, --S--, or --NR--;

R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;

G.sub.1, G.sub.2, R.sub.1, and R.sub.4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, ##STR45##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y--

with the proviso that either G.sub.1 or G.sub.2 or both G.sub.1 and G.sub.2 must be a radical selected from the group ##STR46##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R'.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y--, or ##STR47##

Y is a divalent radical selected from the group consisting of ##STR48##

R.sub.7 is --NR.sub.6 R.sub.6, --J, --OR.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6);

R'.sub.7 is --N(OR.sub.6), --N(R.sub.6).sub.3.sup.+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms,

N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,

N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms, or N,N-dialkynylamino of 6-12 carbon atoms with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

M is >NR.sub.6, --O--, >N--(C(R.sub.6).sub.2).sub.p NR.sub.6 R.sub.6, or >N--(C(R.sub.6).sub.2).sub.p --OR.sub.6 ;

W is >NR.sub.6, --O-- or is a bond;

Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and ##STR49##

wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R.sub.6, optionally mono- or di-substituted on carbon with hydroxy, --N(R.sub.6).sub.2, or --OR.sub.6, optionally mono or di-substituted on carbon with the mono-valent radicals --(C(R.sub.6).sub.2).sub.S OR.sub.6 or --(C(R.sub.6).sub.2).sub.S N(R.sub.6).sub.2, or optionally mono or di-substituted on a saturated carbon with divalent radicals --O-- or --O(C(R.sub.6).sub.2).sub.S O--;

R.sub.6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;

R.sub.2, is selected from the group consisting of ##STR50## ##STR51##

R.sub.3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR52##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that at least one of the R.sub.3 groups is selected from the group ##STR53##

R'.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that for said at least one R.sub.3 group the moiety Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2)r-- cannot be morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl piperidino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, or azacycloalkyl-N-alkyl of 3-11 carbon atoms;

R.sub.5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR54##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

R.sub.8, and R.sub.9 are each, independently, --(C(R.sub.6).sub.2).sub.r NR.sub.6 R.sub.6, or --(C(R.sub.6).sub.2).sub.r OR.sub.6 ;

J is independently hydrogen, chlorine, fluorine, or bromine;

Q is alkyl of 1-6 carbon atoms or hydrogen;

a=0 or 1;

g=1-6;

k=0-4;

n is 0-1;

p=2-4;

q=0-4;

r=1-4;

s=1-6;

u 0-4 and v=0-4, wherein the sum of u+v is 2-4;

or a pharmaceutically acceptable salt thereof,

provided that

when R.sub.6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

and further provided that

when Y is --NR.sub.6 -- and R.sub.7 is --NR.sub.6 R.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6), then g 2-6;

when M is --O-- and R.sub.7 is --OR.sub.6, then p=1-4;

when Y is --NR.sub.6 --, then k=2-4;

when Y is --O-- and M or W is --O--, then k=1-4;

when W is not a bond with Het bonded through a nitrogen atom, then q=2-4;

and when W is a bond with Het bonded through a nitrogen atom and Y is --O-- or --NR.sub.6 --, then k=2-4.

2. The compound according to claim 1 wherein Z is --NH-- and n=0 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein X is optionally substituted phenyl or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3 wherein R.sub.1 and R.sub.4 are hydrogen or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is:

a) 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

b) N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-(N-allyl-N-methylamino )-2-butynamide or a pharmaceutically acceptable salt thereof;

c) N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-(N-methoxyethyl-N-meth ylamino)-2-butynamide or a pharmaceutically acceptable salt thereof;

d) N-[4-[(3-Bromophenyl)amino]-3-cyano-6-quinolinyl]-4-(bis-(2-methoxyethyl)a mino)-2-butynamide or a pharmaceutically acceptable salt thereof;

e) 4-Methoxymethoxy-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

f) 4-(4-Chloro-2-fluoro-phenylamino)-6-methoxy-7-(2-pyridin-4-yl-ethoxy)-1-qu inoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

g) 4-(2-Methoxy-ethoxy)-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

h) 4-((2S)-2-Methoxymethylpyrrolidin-1-yl)but-2-ynoic Acid[4-(3-bromophenylamino)-3-cyanoquinolin-6-yl]amide or a pharmaceutically acceptable salt thereof;

i) 4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)but-2-ynoic Acid[4-(3-Bromophenylamino)-3-cyanoquinolin-6-yl]amide or a pharmaceutically acceptable salt thereof;

j) 4-(3-Bromo-phenylamino)-6-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-quinol ine-3-carbonitrile or a pharmaceutically acceptable salt thereof;

k) 4-[(2-Methoxy-ethyl)-methyl-amino]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

l) (S)-4-(2-Methoxymethyl-pyrrolidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide dihydrochloride or a pharmaceutically acceptable salt thereof;

m) 4-(3-Hydroxymethyl-piperidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

n) 4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

o) 4-(2-Hydroxymethyl-piperidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

p) 4-Bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

q) 4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-7-(3-pyridin-4-yl-propoxy)-qu inoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

r) 4-Diallylamino-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3cyano-7-methoxy-quinolin-6-yl]-ami de or a pharmaceutically acceptable salt thereof;

s) 4-[Bis-(2-methoxy-ethyl)-amino]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

t) 4-([1,3]Dioxolan-2-ylmethyl-methyl-amino)-but-2-enoic acid3-cyano-7-methoxy-quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

u) 4-[Bis-(2-hydroxy-ethyl)-amino]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy- quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

v) 4-Thiomorpholin-4-yl-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

w) 4-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy- quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

x) 4-(1,4,7-Trioxa-10-aza-cyclododec-10-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy- quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

y) 4-(Methoxy-methyl-amino)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

z) 4-(4-Hydroxy-piperidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

aa) 4-[1,4']Bipiperidinyl-1'-yl-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

bb) 4-Thiazolidin-3-yl-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

cc) 3-{3-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-ylcar bamoyl]-allyl}-4-methyl-thiazol-3-ium bromide or a pharmaceutically acceptable salt thereof;

dd) 4-(2,6-Dimethyl-piperidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

ee) 4-[Bis-(2-hydroxy-propyl)-amino]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

ff) 4-(3-Hydroxy-pyrrolidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

gg) 4-[(2-Hydroxy-ethyl)-methyl-amino]-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

hh) 4-(2,5-Dimethyl-pyrrolidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

ii) 4-(4,4-Dihydroxy-piperidin-1-yl)-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-am ide or a pharmaceutically acceptable salt thereof;

jj) 4-(3-Chloro-4-fluoro-phenylamino)-7-methoxy-6-pyrrolidin-1-yl-quinoline-3- carbonitrile or a pharmaceutically acceptable salt thereof;

kk) 4-(3-Chloro-4-fluroanilino)-7-methoxy-6-(1H-pyrrol-1-yl)-3-quinolinecarbon itrile or a pharmaceutically acceptable salt thereof;

ll) 6-(1-Aziridinyl)-4-(3-chloro-4-fluoroanilino)-7-methoxy-3-quinolinecarboni trile or a pharmaceutically acceptable salt thereof;

mm) 4-[(2-Methoxy-ethyl)-methyl-amino]-but-2-enoic acid[4-(3-bromo-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-amide or a pharmaceutically acceptable salt thereof;

nn) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(4-hydroxy-piperidin-1-yl)-pro poxy]-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

oo) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{3-[4-(2-hydroxy-ethyl)-piperazin -1-yl]-propoxy}-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

pp) 4-(2-Bromo-4-chloro-phenylamino)-7-{2-[(2-hydroxy-ethyl)-methyl-amino]-eth oxy}-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

qq) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{3-[(2-hydroxy-ethyl)-methyl-amin o]-propoxy}-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

rr) 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-(3-thiomorpholin-4-yl-p ropoxy)-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

ss) 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(2-methoxy-ethylamin o)-propoxy]-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

tt) 4-(2,4-Dichloro-5-methoxy-phenylamino)-6-methoxy-7-[3-(4-methyl-piperidin- 1-yl)-propoxy]-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

uu) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(2,6-dimethyl-morpholin-4-yl)- propoxy]-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

vv) 4-(2-Bromo-4-chloro-phenylamino)-7-{2-[4-(2-hydroxy-ethyl)-piperazin-1-yl] -ethoxy}-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

ww) 4-(2-Bromo-4-chloro-phenylamino)-7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6 -methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

xx) 4-(2-Bromo-4-chloro-phenylamino)-6-methoxy-7-(2-thiomorpholin-4-yl-ethoxy) -quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

yy) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(2,5-dimethyl-pyrrolidin-1-yl) -propoxy]-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

zz) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(3-hydroxy-propylamino)-propox y]-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

aaa) 1-{3-[3-Cyano-4-(2,4-dichloro-5-methoxy-phenylamino)-6-methoxy-quinolin-7- yloxy]-propyl}-piperidine-4-carboxylic acid ethyl ester or a pharmaceutically acceptable salt thereof;

bbb) 7-[3-(4-acetyl-1-piperazinyl)propoxy]-4-[(2,4-dichloro-5-methoxyphenyl)ami no]-6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

ccc) 4-(3-chloro-4-fluoroanilino)-7-methyoxy-6(4-morpholinyl)-3-quinolinecarbon itrile or a pharmaceutically acceptable salt thereof;

ddd) 7-[3-(4-Benzyl-piperazin-1-yl)-propoxy]-4-(2,4-dichloro-5-methoxy-phenylam ino)-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

eee) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-[3-(2-hydroxy-ethylamino)-propoxy ]-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

fff) 4-(2,4-Dichloro-5-methoxy-phenylamino)-7-{3-[ethyl-(2-hydroxy-ethyl)-amino ]-propoxy}-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

ggg) 7-{3-[Bis-(2-methoxy-ethyl)-amino]-propoxy}-4-(2,4-dichloro-5-methoxy-phen ylamino)-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

hhh) 7-{3-[Bis-(2-hydroxy-ethyl)-amino]-propoxy}-4-(2,4-dichloro-5-methoxy-phen ylamino)-6-methoxy-quinoline-3-carbonitrile or a pharmaceutically acceptable salt thereof;

iii) 4-(3-chloro-4-fluoroanilino)-7-(4-morpholinyl)-6-nitro-3-quinolinecarbonit rile or a pharmaceutically acceptable salt thereof;

jjj) N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-(4-morpholinyl)-6-quinolinyl]-2- butynamide or a pharmaceutically acceptable salt thereof;

kkk) 6-amino-4-(3-chloro-4-fluoroanilino)-7-(4-morpholinyl)-3-quinolinecarbonit rile or a pharmaceutically acceptable salt thereof;

lll) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-(3-{[2-(4-morpholinyl)ethyl] amino}propoxy)-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

mmm) 7-{3-[(2-anilinoethyl)amino]propoxy}-4-(2,4-dichloro-5-methoxyanilino)-6-m ethoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

nnn) N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-(4-morpholinyl)-6-quinolinyl]acr ylamide or a pharmaceutically acceptable salt thereof;

ooo) 4-(3-chloro-4-fluoroanilino)-7-{4-[2-(dimethylamino)ethyl]-1-piperazinyl}- 6-nitro-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

ppp) 6-amino-4-(3-chloro-4-fluoroanilino)-7-{4-[2-(dimethylamino)ethyl]-1-piper azinyl}-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

qqq) N-(4-(3-chloro-4-fluoroanilino)-3-cyano-7-{4-[2-(dimethylamino)ethyl]-1-pi perazinyl}-6-quinolinyl)acrylamide or a pharmaceutically acceptable salt thereof;

rrr) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-({2-[4-(2-methoxyethyl)-1-pi perazinyl]ethyl}amino)-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

sss) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(2H-1,2,3-triazol-2-yl)pr opoxy]-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

ttt) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(1H-1,2,3-triazol-1-yl)pr opoxy]-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

uuu) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-(3-thienyl)-3-quinolinecarbo nitrile or a pharmaceutically acceptable salt thereof;

vvv) 4-[(E)-2-(2-quinolinyl)ethenyl]aniline or a pharmaceutically acceptable salt thereof;

www) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-{[2-(2H-1,2,3-triazol-2-yl)e thyl]amino}-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

xxx) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-{[2-(1H-1,2,3-triazol-1-yl)e thyl]amino}-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

yyy) 4-(2,4-dichloro-5-methoxyanilino)-7-(3-thienyl)-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

zzz) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(1H-1,2,4-triazol-1-yl)pr opoxy]-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

aaaa) 4-(2,4-dichloro-5-methoxyanilino)-7-[3-(1H-imidazol-1-yl)propoxy]-6-methox y-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

bbbb) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(1H-pyrazol-1-yl)propoxy] -3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

cccc) N-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl]-N-[4- (4-ethyl-1-piperazinyl)butyl]acetamide or a pharmaceutically acceptable salt thereof;

dddd) N-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl]-N-(3- (4-ethyl-1-piperazinyl)propyl)acetamide or a pharmaceutically acceptable salt thereof;

eeee) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-{3-[4-(2-methoxyethyl)-1-pip erazinyl]propoxy}-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

ffff) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-(1H-pyrrol-1-yl)-3-quinoline carbonitrile or a pharmaceutically acceptable salt thereof;

gggg) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

hhhh) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[2-(2H-1,2,3-triazol-2-yl)ethoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

iiii) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(1H-tetraazol-1-yl)propox y]-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

jjjj) 4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-[3-(2H-tetraazol-2-yl)propox y]-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

kkkk) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[2-(1H-1,2,3-triazol-1-yl)ethoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof;

llll) 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-[2-(2H-1,2,3-triazol-2-yl)ethoxy]- 3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof; or

mmmm) 4-(2,4-dichloro-5-methoxyanilino)-7-{3-[[2-(dimethylamino)ethyl](methyl)am ino]propoxy}-6-methoxy-3-quinolinecarbonitrile or a pharmaceutically acceptable salt thereof.

6. A method of treating, inhibiting the growth of, or eradicating a neoplasm in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula 1 having the structure ##STR55##

wherein:

X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalky of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

Z is --NH--, --O--, --S--, or --NR--;

R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;

G.sub.1, G.sub.2, R.sub.1, and R.sub.4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, ##STR56##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y-- with the proviso that either G.sub.1 or G.sub.2 or both G.sub.1 and G.sub.2 must be a radical selected from the group ##STR57##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R'.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y--, or ##STR58##

Y is a divalent radical selected from the group consisting of ##STR59##

R.sub.7 is --NR.sub.6 R.sub.6, -J, --OR.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6);

R'.sub.7 is --NR.sub.6 (OR.sub.6), --N(R.sub.6).sub.3.sup.+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms,

N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,

N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms, or N,N-dialkynylamino of 6-12 carbon atoms with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

M is >NR.sub.6, --O--, >N--(C(R.sub.6).sub.2).sub.p NR.sub.6 R.sub.6, or >N--(C(R.sub.6).sub.2).sub.p --OR.sub.6 ;

W is >NR.sub.6, --O-- or is a bond;

Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and ##STR60##

wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R.sub.6, optionally mono- or di-substituted on carbon with hydroxy, --N(R.sub.6).sub.2, or --OR.sub.6, optionally mono or di-substituted on carbon with the mono-valent radicals --(C(R.sub.6).sub.2).sub.s OR.sub.6 or --(C(R.sub.6).sub.2).sub.s N(R.sub.6).sub.2, or optionally mono or di-substituted on a saturated carbon with divalent radicals --O-- or --O(C(R.sub.6).sub.2).sub.s O--;

R.sub.6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;

R.sub.2, is selected from the group consisting of ##STR61## ##STR62##

R.sub.3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR63##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that at least one of the R.sub.3 groups is selected from the group ##STR64##

R'.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that for said at least one R.sub.3 group the moiety Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r -- cannot be morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl piperidino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, or azacycloalkyl-N-alkyl of 3-11 carbon atoms;

R.sub.5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR65##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

R.sub.8, and R.sub.9 are each, independently, --(C(R.sub.6).sub.2).sub.r NR.sub.6 R.sub.6, or --(C(R.sub.6).sub.2).sub.r OR.sub.6 ;

J is independently hydrogen, chlorine, fluorine, or bromine;

Q is alkyl of 1-6 carbon atoms or hydrogen;

a=0 or 1;

g=1-6;

k=0-4;

n is 0-1;

p=2-4;

q=0-4;

r=1-4;

s=1-6;

u 0-4 and v=0-4, wherein the sum of u+v is 2-4;

or a pharmaceutically acceptable salt thereof, provided that

when R.sub.6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

and further provided that

when Y is --NR.sub.6 -- and R.sub.7 is --NR.sub.6 R.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6), then g=2-6;

when M is --O-- and R.sub.7 is -OR.sub.6, then p=1-4;

when Y is --NR.sub.6 --, then k=2-4;

when Y is --O-- and M or W is --O--, then k=1-4;

when W is not a bond with Het bonded through a nitrogen atom, then q=2-4;

and when W is a bond with Het bonded through a nitrogen atom and Y is --O-- or --NR.sub.6 --, then k=2-4.

7. The method according to claim 6 wherein the neoplasm is selected from the group consisting of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, and lung.

8. A method of treating, inhibiting the progression of, or eradicating polycystic kidney disease in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure ##STR66##

wherein:

X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalky of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

Z is --NH--, --O--, --S--, or --NR--;

R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;

G.sub.1, G.sub.2, R.sub.1, and R.sub.4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, ##STR67##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y-- with the proviso that either G.sub.1 or G.sub.2 or both G.sub.1 and G.sub.2 must be a radical selected from the group ##STR68##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R'.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y--, or R.sub.2 --N.sup.H--;

Y is a divalent radical selected from the group consisting of ##STR69##

R.sub.7 is --NR.sub.6 R.sub.6, --J, --OR.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6),

R'.sub.7 is --NR.sub.6 (OR.sub.6), --N(R.sub.6).sub.3.sup.+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms, or N,N-dialkynylamino of 6-12 carbon atoms with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

M is >NR.sub.6, --O--, >N--(C(R.sub.6).sub.2).sub.p NR.sub.6 R.sub.6, or >N--(C(R.sub.6).sub.2).sub.p --OR.sub.6 ;

W is >NR.sub.6, --O-- or is a bond;

Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and ##STR70##

wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R.sub.6, optionally mono- or di-substituted on carbon with hydroxy, --N(R.sub.6).sub.2, or --OR.sub.6, optionally mono or di-substituted on carbon with the mono-valent radicals --(C(R.sub.6).sub.2).sub.s OR.sub.6 or --(C(R.sub.6).sub.2).sub.s N(R.sub.6).sub.2, or optionally mono or di-substituted on a saturated carbon with divalent radicals --O-- or --O(C(R.sub.6).sub.2).sub.s O--;

R.sub.6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;

R.sub.2, is selected from the group consisting of ##STR71## ##STR72##

R.sub.3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR73##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that at least one of the R.sub.3 groups is selected from the group ##STR74##

R'.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that for said at least one R.sub.3 group the moiety Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r -- cannot be morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl piperidino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, or azacycloalkyl-N-alkyl of 3-11 carbon atoms;

R.sub.5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR75##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

R.sub.8, and R.sub.9 are each, independently, --(C(R.sub.6).sub.2).sub.r NR.sub.6 R.sub.6, or --(C(R.sub.6).sub.2).sub.r OR.sub.6 ;

J is independently hydrogen, chlorine, fluorine, or bromine;

Q is alkyl of 1-6 carbon atoms or hydrogen;

a=0 or 1;

g=1-6;

k=0-4;

n is 0-1;

p=2-4;

q=0-4;

r=1-4;

s=1-6;

u=0-4 and v=0-4, wherein the sum of u+v is 2-4;

or a pharmaceutically acceptable salt thereof,

provided that

when R.sub.6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

and further provided that

when Y is --NR.sub.6 -- and R.sub.7 is --NR.sub.6 R.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6), then g=2-6;

when M is --O-- and R.sub.7 is --OR.sub.6, then p=1-4;

when Y is --NR.sub.6 --, then k=2-4;

when Y is --O-- and M or W is --O--, then k=1-4;

when W is not a bond with Het bonded through a nitrogen atom, then q=2-4;

and when W is a bond with Het bonded through a nitrogen atom and Y is --O-- or --NR.sub.6 --, then k=2-4.

9. A pharmaceutical composition which comprises a compound of formula 1 having the structure ##STR76##

wherein:

X is cycloalkyl of 3 to 7 carbon atoms, which may be optionally substituted with one or more alkyl of 1 to 6 carbon atom groups; or is a pyridinyl, pyrimidinyl, or phenyl ring wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- di-, or tri-substituted with a substituent selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms, carboalkoxyalky of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, methylmercapto, and benzoylamino;

Z is --NH--, --O--, --S--, or --NR--;

R is alkyl of 1-6 carbon atoms, or carboalkyl of 2-7 carbon atoms;

G.sub.1, G.sub.2, R.sub.1, and R.sub.4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino, ##STR77##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y-- with the proviso that either G.sub.1 or G.sub.2 or both G.sub.1 and G.sub.2 must be a radical selected from the group ##STR78##

R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.k --Y--, R'.sub.7 --(C(R.sub.6).sub.2).sub.g --Y--, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.k --Y--, Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.k --Y--, or ##STR79##

Y is a divalent radical selected from the group consisting of ##STR80##

R.sub.7 is --NR.sub.6 R.sub.6, -J, --OR.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6);

R'.sub.7 is --NR.sub.6 (OR.sub.6), --N(R.sub.6).sub.3.sup.+, alkenoxy of 1-6 carbon atoms, alkynoxy of 1-6 carbon atoms,

N-alkyl-N-alkenylamino of 4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,

N-alkyl-N-alkynylamino of 4 to 12 carbon atoms, N-alkenyl-N-alkynylamino of 4 to 12 carbon atoms, or N,N-dialkynylamino of 6-12 carbon atoms with the proviso that the alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

M is >NR.sub.6, --O--, >N--(C(R.sub.6).sub.2).sub.p NR.sub.6 R.sub.6, or >N--(C(R.sub.6).sub.2).sub.p --OR.sub.6,

W is >NR.sub.6, --O-- or is a bond;

Het is a heterocycle selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan, thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane, tetrahydropyran, and ##STR81##

wherein the heterocycle is optionally mono- or di-substituted on carbon or nitrogen with R.sub.6, optionally mono- or di-substituted on carbon with hydroxy, --N(R.sub.6).sub.2, or --OR.sub.6, optionally mono or di-substituted on carbon with the mono-valent radicals --(C(R.sub.6).sub.2).sub.s OR.sub.6 or --(C(R.sub.6).sub.2).sub.s N(R.sub.6).sub.2, or optionally mono or di-substituted on a saturated carbon with divalent radicals --O-- or --O(C(R.sub.6).sub.2).sub.s O--;

R.sub.6 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionally substituted with one or more halogen, alkoxy of 1-6 carbon atoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms;

R.sub.2, is selected from the group consisting of ##STR82## ##STR83##

R.sub.3 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR84##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that at least one of the R.sub.3 groups is selected from the group ##STR85##

R'.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

with the proviso that for said at least one R.sub.3 group the moiety Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r -- cannot be morpholino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, piperidino-N-alkyl wherein the alkyl group is 1-6 carbon atoms, N-alkyl piperidino-N-alkyl wherein either alkyl group is 1-6 carbon atoms, or azacycloalkyl-N-alkyl of 3-11 carbon atoms;

R.sub.5 is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms, ##STR86##

R.sub.7 --(C(R.sub.6).sub.2).sub.s --, R.sub.7 --(C(R.sub.6).sub.2).sub.p --M--(C(R.sub.6).sub.2).sub.r --, R.sub.8 R.sub.9 --CH--M--(C(R.sub.6).sub.2).sub.r --, or Het-(C(R.sub.6).sub.2).sub.q --W--(C(R.sub.6).sub.2).sub.r --;

R.sub.8, and R.sub.9 are each, independently, --(C(R.sub.6).sub.2).sub.r NR.sub.6 R.sub.6, or --(C(R.sub.6).sub.2).sub.r OR.sub.6 ;

J is independently hydrogen, chlorine, fluorine, or bromine;

Q is alkyl of 1-6 carbon atoms or hydrogen;

a=0 or 1;

g=1-6;

k=0-4;

n is 0-1;

p=2-4;

q=0-4;

r=1-4;

s=1-6;

u=0-4 and v=0-4, wherein the sum of u+v is 2-4;

or a pharmaceutically acceptable salt thereof,

provided that

when R.sub.6 is alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbon atoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygen atom through a saturated carbon atom;

and further provided that

when Y is --NR.sub.6 -- and R.sub.7 is --NR.sub.6 R.sub.6, --N(R.sub.6).sub.3.sup.+, or --NR.sub.6 (OR.sub.6), then g=2-6;

when M is --O-- and R.sub.7 is -OR.sub.6, then p=1-4;

when Y is --NR.sub.6 --, then k=2-4;

when Y is --O-- and M or W is --O--, then k=1-4;

when W is not a bond with Het bonded through a nitrogen atom, then q=2-4;

and when W is a bond with Het bonded through a nitrogen atom and Y is --O-- or --NR.sub.6 --, then k=2-4.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc