Granted Patent B2

US 8,658,654 · App. 12/455,867 · Granted Feb 25, 2014

Abstract

Claims (60)

1. A method of treating a disease or a disorder associated with abnormal cellular activities, wherein the disease is non-small cell lung cancer or prostate cancer, and wherein an ephrin, KDR, Flt-1, EGFR, or ErbB2 receptor tyrosine kinase is implicated, the method comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula I,

or a single stereoisomer, racemate, enantiomer, or diastereomer, thereof and optionally as a pharmaceutically acceptable salt thereof, wherein,

R 1 is methyl;

R 2 is selected from halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —N(R 3 )R 4 , —S(O) 0-2 R 4 , —SO 2 N(R 3 )R 4 , —CO 2 R 3 , —C(═O)N(R 3 )R 4 , —N(R 3 )SO 2 R 4 , —N(R 3 )C(═O)R 3 , —N(R 3 )CO 2 R 4 , —C(═O)R 3 , lower alkyl, lower alkenyl, and lower alkynyl;

R 3 is —H or R 4 ;

R 4 is selected from lower alkyl; lower alkyl substituted with one, two, or three halogen; aryl; aryl substituted with one, two, or three halogen; and unsubstituted lower arylalkyl; or

R 3 and R 4 , when taken together with a common nitrogen to which they are attached, form morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl optionally substituted by one, two, or three alkyl;

q is 0, 1, 2, 3, 4, or 5;

Z is —NR 5 —;

R 5 is —H;

M 1 -M 2 -M 3 -M 4 - together are according to formula II:

wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, said saturated bridged ring system containing up to three annular heteroatoms represented by any of X 1 , X 2 , and X 3 ; wherein,

each X 1 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;

each X 2 is independently a bridgehead methine optionally substituted with R 6 , or a bridgehead nitrogen;

each X 3 is independently selected from —C(R 6 )R 7 —, —O—, —S(O) 0-2 —, and —NR 8 —;

provided, for X 1 , X 2 , and X 3 , there are no nitrogen-nitrogen annular bonds nor geminal di-nitrogen substitutions;

E is absent;

Y is —CH 2 — provided that Y is not directly attached to any heteroatom represented by X 1 , X 2 or X 3 ;

m and p are each independently 1, 2, 3, or 4;

n is 0, 1, or 2, when n is zero, then there is a direct single bond between the two bridgehead X 2 's;

R 6 and R 7 are each independently selected from —H, halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —N(R 3 )R 4 , —S(O) 0-2 R 4 , —SO 2 N(R 3 )R 4 , —CO 2 R 3 , —C(O)N(R 3 )R 4 , —N(R 3 )SO 2 R 4 , —N(R 3 )C(O)R 3 , —NCO 2 R 3 , —C(O)R 3 , lower alkyl, aryl, and unsubstituted lower arylalkyl; or

R 6 and R 7 , when taken together are oxo; or

R 6 and R 7 , when taken together with a common carbon to which they are attached, form a three- to seven-membered spirocyclyl optionally containing at least one additional heteroatom selected from N, O, S, and P and wherein the spirocyclic ring is optionally substituted with one or two alkyl; and

R 8 is selected from R 3 , —SO 2 N(R 3 )R 4 , —CO 2 R 3 , —C(O)N(R 3 )R 4 , —SO 2 R 4 , and —C(O)R 3 ;

with the proviso that when Y is a C 1-3 alkylene linker, E is absent, Z is —NH— or —N(CH 3 )—, R 1 is a C 1-3 alkyl, R 2 is —H or halogen, n=0, and the atoms X 1 of one bridge of the saturated bridged ring system, when combined with both bridgehead atoms, X 2 , of the saturated bridged ring system, represent:

either a pyrrolidine ring or a piperidine ring, and any atom, X 1 or X 2 , of either of said pyrrolidine ring or said piperidine ring is attached to Y; then the other bridge of said saturated bridged ring system cannot be any one of —OC(O)CH 2 —, —CH 2 OC(O)—, —OC(O)CH 2 CH 2 —, —CH 2 OC(O)CH 2 —, —CH 2 CH 2 OC(O)—, —OC(O)CH 2 NH—, —OC(O)CH 2 N(C 1-4 alkyl)-, and —OC(O)CH 2 O—; and

either a piperazine ring or a 4-(C 1-4 alkyl)-piperazine ring, and any atom, X 1 or X 2 , of either of said piperazine ring or said 4-(C 1-4 alkyl)-piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 2- and the 3-position of either of said piperazine ring or said 4-(C 1 - 4 alkyl)-piperazine ring, cannot be one of —CH 2 OC(O)CH 2 —, —CH 2 CH 2 OC(O)—, and either of the two aforementioned bridges substituted by one or two C 1-2 alkyl groups; and

a piperazine ring, and any atom, X 1 or X 2 , of said piperazine ring is attached to Y; then the other bridge of said saturated bridged ring system, only when attached via the 3- and the 4-position of said piperazine ring, cannot be —C(O)OCH 2 CH 2 —, —CH 2 OC(O)CH 2 —, —C(O)OCH 2 CH 2 — substituted with one or two C 1-2 alkyl groups, or —CH 2 OC(O)CH 2 — substituted with one or two C 1-2 alkyl groups (but only when the four above mentioned bridges are attached to the 3-position of said piperazine ring via their left-hand end as depicted above); and

a 2-oxomorpholine ring, said 2-oxomorpholine ring attached to Y via its 4-position; then the other bridge of said saturated bridged ring system, only when attached via the 5- and the 6-position of said 2-oxomorpholine ring, cannot be one of —(CH 2 ) g —, —CH 2 WCH 2 —, —CH 2 WCH 2 CH 2 —, and —CH 2 CH 2 WCH 2 —, wherein W is —O—, —S(O) 0-2 —, —NH—, or —N(C 1-4 alkyl)- and wherein g is 2, 3, or 4;

optionally together with a pharmaceutically acceptable carrier.

2. The method of claim 1 , comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula I, wherein

R 2 is selected from halogen, trihalomethyl, —CN, —NO 2 , —OR 3 , and lower alkyl; q is 1, 2, or 3 ; and

M 1 -M 2 -M 3 -M 4 - together are according to formula II wherein X 1 , X 2 , and optionally X 3 , represent the atoms of a saturated bridged ring system, wherein said saturated bridged ring system is according to either formula V or formula VI;

wherein R 8 is selected from —H, lower alkyl, —CO 2 R 3 , —C(O)N(R 3 )R 4 , —SO 2 R 4 , and —C(O)R 3 ;

or a single stereoisomer, racemate, enantiomer, or diastereomer, thereof, optionally as a pharmaceutically acceptable salt thereof, and optionally together with a pharmaceutically acceptable carrier.

3. The method of claim 1 , comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula I wherein the compound is selected from:

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-(1-methylethyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

7-({[(3aR,5r,6aS)-2-acetyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-{[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-ylmethyl]oxy}quinazolin-4-amine;

ethyl (3aR,5r,6aS)-5-[({4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl}oxy)methyl]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;

N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2- is methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)quinazolin-4-amine;

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5s,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazo lin-4-amine;

N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazo lin-4-amine;

N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(3-chloro-2,4-difluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta-[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4,5-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-5-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-2,3-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(3,4-dichlorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methyl}oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-3-chloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-ethyloctahydrocyclopenta[c]pyrrol-5-yl]methyl }oxy)-6-(methyloxy)quinazolin-4-amine;

N-(4-bromo-3-chloro-2-fluorophenyl)-6-(methyloxy)-7-({[(3aR,5r,6aS)-2-(2-methylpropyl)octahydrocyclopenta[c]pyrrol-5-yl]methyl }oxy)quinazolin-4-amine; and

1,1-dimethylethyl (3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyl-oxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate;

N-(3,4-dichloro-2-fluorophenyl)-6-(methyloxy)-7-{[[(3aR,5r,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]methyl]oxy}quinazolin-4-amine; and

1,1-dimethylethyl (3aR,6aS)-5-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl) hexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate; and

a single stereoisomer, racemate, enantiomer, or diastereomer, thereof, optionally as a pharmaceutically acceptable salt thereof, and optionally together with a pharmaceutically acceptable carrier.

4. The method of claim 1 , comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula I, wherein the compound is named N-(3,4-dichloro-2-fluorophenyl)-7-({[(3aR,5r,6aS)-2-methyloctahydrocyclo-penta[c]pyrrol-5-yl]methyl }oxy)-6-(methyloxy)quinazo lin-4-amine optionally as a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier.

5. The method of claim 1 , comprising administering, to a mammal in need thereof, a therapeutically effective amount of a compound of Formula I, or a single stereoisomer, racemate, enantiomer, or diastereomer, thereof, optionally as a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Assignments (10)