Claims for Patent: 6,251,912

Summary for Patent: 6,251,912

Title:	Substituted quinazoline derivatives
Abstract:	This invention provides compounds of formula 1 having the structure ##STR1## wherein: X, R.sub.1, R.sub.2, R.sub.3, R.sub.4, Z, X, and n are as defined hereinbefore in the specification, which are useful as antineoplastic agents and in the treatment of certain kidney diseases, such as polycystic kidney disease.
Inventor(s):	Wissner; Allan (Ardsley, NY), Tsou; Hwei-Ru (New City, NY), Johnson; Bernard D. (Stony Point, NY), Hamann; Philip R. (Garnerville, NY), Zhang; Nan (Suffern, NY)
Assignee:	American Cyanamid Company (Madison, NJ)
Application Number:	09/124,365
Patent Claims:	1. A compound of formula 1 having the structure ##STR31## 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, 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, aminomethyl, N-alkylaminomethyl of 2-7 carbon atoms, N,N-dialkylaminomethyl of 3-7 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; R.sub.1, R.sub.3, 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, 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, Y is a divalent radical selected from the group consisting of ##STR32## R.sub.7 is --NR.sub.6 R.sub.6, or --OR.sub.6 ; 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, optionally mono- or di-substituted on carbon or nitrogen with R.sub.6 and optionally mono-substituted on carbon with --CH.sub.2 OR.sub.6 ; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; 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, 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 ##STR33## ##STR34## 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, 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: Z is NH; n is 0; R.sub.2 is selected from the group consisting of ##STR35## R.sub.5 is independently and exclusively hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; R.sub.1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; R.sub.4 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; and R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; X is not an unsubstituted phenyl ring, or a phenyl ring exclusively substituted with one or more substitutents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms; further provided that when R.sub.2 is ##STR36## and R.sub.5 is hydrogen or alkyl of 1-6 carbon atoms, R.sub.3 is not halogen; and still further 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 finally provided that when Y is --NR.sub.6 -- or R.sub.7 is --NR.sub.6 R.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 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 n=0, Z is --NH--, and X a phenyl ring unsubstituted or substituted with halogen or alkyl of 1-6 carbon atoms or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 2 wherein R.sub.1, R.sub.3, and R.sub.4 are hydrogen. 4. A compound according to claim 1 which is 4-dimethylamino-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1 which is 4-morpholin-4-yl-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-dimethylamino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-diethylamino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-(4-ethyl-piperazin-1-yl)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-(4-methyl-piperazin-1-yl)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-[bis-(2-methoxy-ethyl)-amino]-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, (2-methoxy-ethyl)-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, isopropyl-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, diisopropyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, allyl-methyl-amino-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, or but-2-ynoic acid [4-(3-dimethylamino-phenylamino)-quinazolin-6-yl]-amide or a pharmaceutically accetable salt thereof. 6. A compound of claim 1 which is 4-methoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-(2-methoxy-ethoxy)-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, or 4-methoxymethoxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide or a pharmaceutically accetable salt thereof. 7. A compound of claim 1 which is 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-4-ethoxy-cyclobut-3-ene-1 ,2-dione, 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-4-dimethylamino-cyclobut- 3-ene-1,2-dione, 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-4-methylamino-cyclobut-3- ene-1,2-dione, 3-amino-4-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-cyclobut-3-ene-1, 2-dione, or 3-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-4-morpholin-4-yl-cyclobut -3-ene-1,2-dione or a pharmaceutically accetable salt thereof. 8. A compound of claim 1 which is 4-methoxy-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, or 1-methyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid 4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide or a pharmaceutically accetable salt thereof. 9. A compound of claim 1 which is N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-morpholin-4-ylmethyl-acrylam ide, or 4-diethylamino-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, or a pharmaceutically accetable salt thereof. 10. A compound of claim 1 which is N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-methyldisulfanyl-propionamid e, N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-3-methyldisulfanyl-propionamid e, N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-methyldisulfanyl-acetamide, N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-tert-butyldisulfanyl-acetami de, N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-isobutyldisulfanyl-acetamide , or N-[4-(3-bromo-phenylamino)-quinazolin-6-yl]-2-isopropyldisulfanyl-acetamid e or a pharmaceutically accetable salt thereof. 11. A compound which is 2-{[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-methyl}-acrylic acid methyl ester, or (E)-4-[4-(3-bromo-phenylamino)-quinazolin-6-ylamino]-methyl}-but-2-enoicac id methyl ester or a pharmaceutically acceptable salt thereof. 12. A compound which is 4-chloro-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, 4-hydroxy-but-2-ynoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-3(E)-chloro-2-propenamide, 4-bromo-but-2-enoic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, oxirane-2-carboxylic acid [4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide, or ethenesulfonic acid[4-(3-bromo-phenylamino)-quinazolin-6-yl]-amide or a pharmaceutically acceptable salt thereof. 13. A method of inhibiting the biological effects of a deregulated protein tyrosine kinase in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure ##STR37## 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, 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, aminomethyl, N-alkylaminomethyl of 2-7 carbon atoms, N,N-dialkylaminomethyl of 3-7 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; R.sub.1, R.sub.3, 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, 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, Y is a divalent radical selected from the group consisting of ##STR38## R.sub.7 is --NR.sub.6 R.sub.6, or --OR.sub.6 ; 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, optionally mono- or di-substituted on carbon or nitrogen with R.sub.6 and optionally mono-substituted on carbon with --CH.sub.2 OR.sub.6 ; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; 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, 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 ##STR39## ##STR40## 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, 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: Z is NH; n is 0; R.sub.2 is selected from the group consisting of ##STR41## R.sub.5 is independently and exclusively hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; R.sub.1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; R.sub.4 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; and R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; X is not an unsubstituted phenyl ring, or a phenyl ring exclusively substituted with one or more substitutents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms; further provided that when R.sub.2 is ##STR42## and R.sub.5 is hydrogen or alkyl of 1-6 carbon atoms, R.sub.3 is not halogen; and still further 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 finally provided that when Y is --NR.sub.6 -- or R.sub.7 is --NR.sub.6 R.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 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. 14. A method of treating, inhibiting the growth of, or eradicating neoplasms in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula 1 having the structure ##STR43## 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, 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, aminomethyl, N-alkylaminomethyl of 2-7 carbon atoms, N,N-dialkylaminomethyl of 3-7 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; R.sub.1, R.sub.3, 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, 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, Y is a divalent radical selected from the group consisting of ##STR44## R.sub.7 is --NR.sub.6 R.sub.6, or --OR.sub.6 ; 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, optionally mono- or di-substituted on carbon or nitrogen with R.sub.6 and optionally mono-substituted on carbon with --CH.sub.2 OR.sub.6; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; 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, 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 ##STR45## ##STR46## 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, 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: Z is NH; n is 0; R.sub.2 is selected from the group consisting of ##STR47## R.sub.5 is independently and exclusively hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; R.sub.1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; R.sub.4 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; and R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; X is not an unsubstituted phenyl ring, or a phenyl ring exclusively substituted with one or more substitutents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms; further provided that when R.sub.2 is ##STR48## and R.sub.5 is hydrogen or alkyl of 1-6 carbon atoms, R.sub.3 is not halogen; and still further 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 finally provided that when Y is --NR.sub.6 -- or R.sub.7 is --NR.sub.6 R.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 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. 15. The method according to claim 14 wherein the neoplasm expresses EGFR or erbB2 (Her2). 16. The method according to claim 14 wherein the neoplasm is selected from the group consisting of breast, kidney, bladder, mouth, larynx, esophagus, stomach, colon, ovary, and lung. 17. 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 ##STR49## 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, 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, aminomethyl, N-alkylaminomethyl of 2-7 carbon atoms, N,N-dialkylaminomethyl of 3-7 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; R.sub.1, R.sub.3, 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, 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, Y is a divalent radical selected from the group consisting of ##STR50## ##STR51## R.sub.7 is --NR.sub.6 R.sub.6, or --OR.sub.6 ; 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, optionally mono- or di-substituted on carbon or nitrogen with R.sub.6 and optionally mono-substituted on carbon with --CH.sub.2 OR.sub.6 ; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; 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, 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 ##STR52## ##STR53## 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, 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: Z is NH; n is 0; R.sub.2 is selected from the group consisting of ##STR54## R.sub.5 is independently and exclusively hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; R.sub.1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; R.sub.4 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; and R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; X is not an unsubstituted phenyl ring, or a phenyl ring exclusively substituted with one or more substitutents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms; further provided that when R.sub.2 is ##STR55## and R.sub.5 is hydrogen or alkyl of 1-6 carbon atoms, R.sub.3 is not halogen; and still further 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 finally provided that when Y is --NR.sub.6 -- or R.sub.7 is --NR.sub.6 R.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 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. 18. A pharmaceutical composition which comprises a compound of formula 1 having the structure ##STR56## 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, 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, aminomethyl, N-alkylaminomethyl of 2-7 carbon atoms, N,N-dialkylaminomethyl of 3-7 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; R.sub.1, R.sub.3, 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, 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, Y is a divalent radical selected from the group consisting of ##STR57## R.sub.7 is --NR.sub.6 R.sub.6, or --OR.sub.6 ; 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, optionally mono- or di-substituted on carbon or nitrogen with R.sub.6 and optionally mono-substituted on carbon with --CH.sub.2 OR.sub.6 ; wherein the heterocycle is selected from the group consisting of morpholine, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine, pyrrolidine, aziridine, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, piperazine, tetrahydrofuran, and tetrahydropyran; 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, 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 ##STR58## ##STR59## 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, 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: Z is NH; n is 0; R.sub.2 is selected from the group consisting of ##STR60## R.sub.5 is independently and exclusively hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxy of 1-6 carbon atoms, phenyl, or carboalkyl of 2-7 carbon atoms; R.sub.1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; R.sub.4 is hydrogen, halogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; and R.sub.3 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, or trifluoromethyl; X is not an unsubstituted phenyl ring, or a phenyl ring exclusively substituted with one or more substitutents selected from the group consisting of halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, amino, and alkanoylamino of 1-6 carbon atoms; further provided that when R.sub.2 is ##STR61## and R.sub.5 is hydrogen or alkyl of 1-6 carbon atoms, R.sub.3 is not halogen; and still further 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 finally provided that when Y is --NR.sub.6 -- or R.sub.7 is --NR.sub.6 R.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 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 and a pharmaceutical carrier.