US 2002/0177601 A1 · Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them

Abstract

A compound of formula (I) 1 wherein Ra, Rb, Rc, A, B, C, D, and X are as defined herein, or a tautomer, stereoisomer, or salt thereof, particularly a physiologically acceptable salt thereof. In addition, pharmaceutical compositions comprising an effective amount of a compound of formula (I), methods for the treatment or prophylaxis of benign or malignant tumors, diseases of the airways and lungs, polyps, diseases of the gastrointestinal tract, bile duct, gall bladder, kidneys, and skin, and methods for making compounds of formula (I) are disclosed.

A compound of formula (I)

10
wherein:
Ra is a hydrogen atom or a Cl1-4-alkyl group;
Rb is a phenyl, benzyl, or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by R1, R2, and R3, wherein:
R1 and R2, which are identical or different, each are:
(i) a hydrogen, fluorine, chlorine, bromine, or iodine atom,
(ii) a C1-4-alkyl, hydroxy, C1-4-alkoxy, C3-6-cycloalkyl, C4-6-cycloalkoxy, C2-5-alkenyl, or C2-5-alkynyl group,
(iii) an aryl, aryloxy, arylmethyl, or arylmethoxy group,
(iv) a C3-5-alkenyloxy or C3-5-alkynyloxy group, wherein the unsaturated moiety thereof is not linked to the oxygen atom,
(v) a C1-4-alkylsulfenyl, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, C1-4-alkylsulfonyloxy, trifluoromethylsulfenyl, trifluoromethylsulfinyl, or trifluoromethylsulfonyl group,
(vi) a methyl or methoxy group substituted by 1 to 3 fluorine atoms,
(vii) an ethyl or ethoxy group substituted by 1 to 5 fluorine atoms, or
(viii) a cyano or nitro group or an amino group optionally substituted by one or two C1-4-alkyl groups, wherein the substituents are identical or different, or
R1 together with R2, if they are bound to adjacent carbon atoms, are a —CH═CH—CH═CH, —CH═CH—NH, or —CH═N—NH group, and
R3 is a hydrogen, fluorine, chlorine, or bromine atom, or a C1-4-alkyl, trifluoromethyl, or C1-4-alkoxy group;
X is a methine group substituted by a cyano group or a nitrogen atom;
A is a group consisting of:
(a) —O—C1-6-alkylene, —O—C4-7-cycloalkylene, —O—C1-3-alkylene-C3-7-cycloalkylene, —O—C4-7-cycloalkylene-C1-3-alkylene, or —O—C1-3-alkylene-C3-7-cycloalkylene-C1-3-alkylene group, wherein the oxygen atom thereof in each case is linked to the bicyclic heteroaromatic moiety of formula (I),
(b) an —O—C1-6-alkylene group substituted by an R6O—CO or R6O—CO—C1-4-alkyl group, wherein the oxygen atom of the —O—C1-6-alkylene group is linked to the bicyclic heteroaromatic moiety of formula (I),
(c) an —O—C2-6-alkylene group substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, or 4-(C1-4-alkyl)-piperazino group, wherein the oxygen atom of the —O—C2-6-alkylene group is linked to the bicyclic heteroaromatic moiety of formula (I),
(d) a —C1-6-alkylene group,
(e) an —NR4—C1-6-alkylene, —NR—C3-7-cycloalkylene, —NR4—C1-3-alkylene-C3-7-cycloalkylene, —NR4—C3-7-cycloalkylene-C1-3-alkylene, or —NR4—C1-3-alkylene-C3-7-cycloalkylene-C1-3-alkylene group, wherein the —NR4— moiety thereof in each case is linked to the bicyclic heteroaromatic moiety of formula (I),
(f) an oxygen atom linked to a carbon atom of the group B, or
(g) a NR4 group linked to a carbon atom of the group B,
B is a group consisting of:
(a) an R6O—CO-alkylene-NR5, (R7O—PO—OR8)-alkylene-NR5, or (R7O—PO—R9)-alkylene-NR5 group, wherein in each case the alkylene moiety, which is straight-chained and contains 1 to 6 carbon atoms, is additionally optionally substituted by one or two C1-2-alkyl groups or by an R6O—CO or R6O—CO—C1-2-alkyl group,
(b) a 4- to 7-membered alkyleneimino group substituted by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(c) a 4- to 7-membered alkyleneimino group substituted by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6OCO group and an R6O—CO—C1-4-alkyl group,
(d) a piperazino or homopiperazino group substituted in each case at the 4 position by R10 and additionally substituted at a cyclic carbon atom thereof by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(e) a piperazino or homopiperazino group substituted in each case at the 4 position by R10 and additionally substituted at cyclic carbon atoms thereof by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(f) a piperazino or homopiperazino group substituted in each case at the 4 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4alkyl group,
(g) a piperazino or homopiperazino group substituted in each case at the 4 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group and additionally substituted at cyclic carbon atoms thereof by one or two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(h) a morpholino or homomorpholino group substituted in each case by an R6O—CO, R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(i) a morpholino or homomorpholino group substituted in each case by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(j) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by R10, wherein the 5 to 7-membered rings thereof in each case are additionally substituted at a carbon atom thereof by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(k) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by R10, wherein the 5 to 7-membered rings thereof in each case are additionally substituted at carbon atoms thereof by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(l) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(m) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group, wherein the 5- to 7-membered rings thereof in each case are additionally substituted at carbon atoms thereof by one or two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(n) a 2-oxomorpholino group substituted by 1 to 4 C1-2-alkyl groups,
(o) a 2-oxomorpholinyl group substituted at the 4 position by a hydrogen atom, or by a C1-4-alkyl, R6O—CO—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group, wherein the 2-oxomorpholinyl group thereof is linked to a carbon atom of the group A, and
(p) an R11NR5 group, or
A together with B are a group consisting of:
(a) a hydrogen, fluorine, or chlorine atom,
(b) a C1-6-alkoxy group,
(c) a C2-6-alkoxy group substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4-(C1-4-alkyl)-piperazino, homopiperazino, 4-(C1-4-alkyl)-homopiperazino, or 1-imidazolyl group,
(d) a C1-4-alkoxy group substituted by a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted at the 1 position by R10,
(e) a C1-6-alkoxy group substituted by an R6O—CO, (R7O—PO—OR8), or (R7O—PO—R9) group,
(f) a C3-7-cycloalkoxy or C3-7-cycloalkyl-C1-4-alkoxy group,
(g) an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4-(C1-4-alkyl)-piperazino, homopiperazino, or 4-(C1-4-alkyl)-homopiperazino group, and
(h) a 2-oxomorpholino group optionally substituted by 1 or 2 methyl groups;
C is a group consisting of:
(a) an —O—C1-6-alkylene, —O—C4-7-cycloalkylene, —O—C1-3-alkylene-C3-7-cycloalkylene, —O—C4-7-cycloalkylene-C1-3-alkylene, or —O—C1-3-alkylene-C3-7-cycloalkylene-C1-3-alkylene group, wherein the oxygen atom thereof in each case is linked to the bicyclic heteroaromatic moiety of formula (I),
(b) an —O—C1-6-alkylene group substituted by an R6O—CO or R6O—CO—C1-4-alkyl group, wherein the oxygen atom of the —O—C1-6-alkylene group is linked to the bicyclic heteroaromatic moiety of formula (I),
(c) an —O—C2-6-alkylene group substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, or 4-(C1-4-alkyl)-piperazino group and the oxygen atom of the —O—C2-6-alkylene group is linked to the bicyclic heteroaromatic moiety of formula (I),
(d) a —C1-6-alkylene group,
(e) an —NR4—C1-6-alkylene, —NR4—C3-7-cycloalkylene, —NR4—C1-3-alkylene-C3-7-cycloalkylene, —NR4—C3-7-cycloalkylene-C1-3-alkylene, or —NR4—C1-3-alkylene-C3-7-cycloalkylene-C1-3-alkylene group, wherein the —NR4— moiety thereof in each case is linked to the bicyclic heteroaromatic moiety of formula (I),
(f) an oxygen atom linked to a carbon atom of the group D, and
(g) a NR4 group linked to a carbon atom of the group D,
D is a group consisting of:
(a) an R6O—CO-alkylene-NR5, (R7O—PO—OR8)-alkylene-NR5, or (R7O—PO—R9)-alkylene-NR5 group wherein in each case the alkylene moiety thereof, which is straight-chained and contains 1 to 6 carbon atoms, is additionally optionally substituted by one or two C1-2-alkyl groups or by an R6O—CO or R6O—CO—C1-2-alkyl group,
(b) a 4- to 7-membered alkyleneimino group substituted by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(c) a 4- to 7-membered alkyleneimino group substituted by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6OCO group and an R6O—CO—C1-4-alkyl group,
(d) a piperazino or homopiperazino group in each case substituted at the 4 position by R10 and additionally substituted at a cyclic carbon atom thereof by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(e) a piperazino or homopiperazino group in each case substituted at the 4 position by R10 and additionally substituted at cyclic carbon atoms thereof by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(f) a piperazino or homopiperazino group substituted in each case at the 4 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(g) a piperazino or homopiperazino group substituted in each case at the 4 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group and additionally substituted at cyclic carbon atoms thereof by one or two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(h) a morpholino or homomorpholino group substituted in each case by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(i) a morpholino or homomorpholino group substituted in each case by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(j) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by R10, wherein the 5- to 7-membered rings thereof in each case are additionally substituted at a carbon atom by an R6O—CO, (R7O—PO—OR8), (R7O—PO—R9), R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(k) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by R10, wherein the 5- to 7-membered rings thereof in each case are additionally substituted at carbon atoms thereof by two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(l) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group,
(m) a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted in each case at the 1 position by an R6O—CO—C1-4-alkyl, bis-(R6O—CO)—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group, wherein the 5- to 7-membered rings thereof in each case are additionally substituted at carbon atoms thereof by one or two R6O—CO or R6O—CO—C1-4-alkyl groups or by an R6O—CO group and an R6O—CO—C1-4-alkyl group,
(n) a 2-oxomorpholino group optionally substituted by 1 to 4 C1-2-alkyl groups,
(o) a 2-oxomorpholinyl group substituted at the 4 position by a hydrogen atom, or by a C1-4-alkyl, R6O—CO—C1-4-alkyl, (R7O—PO—OR8)—C1-4-alkyl, or (R7O—PO—R9)—C1-4-alkyl group, wherein the 2-oxomorpholinyl group is linked to a carbon atom of the group C, and
(p) an R11NR5 group, or
C and D together are a group consisting of:
(a) a hydrogen, fluorine, or chlorine atom;
(b) a C1-6-alkoxy group,
(c) a C2-6-alkoxy group substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4-(C1-4-alkyl)-piperazino, homopiperazino, 4-(C1-4-alkyl)-homopiperazino, or 1-imidazolyl group,
(d) a C1-4-alkoxy group substituted by a pyrrolidinyl, piperidinyl, or hexahydroazepinyl group substituted at the 1 position by R10,
(e) a C1-6-alkoxy group substituted by an R6O—CO, (R7O—PO—OR8), or (R7O—PO—R9) group,
(f) a C3-7-cycloalkoxy or C3-7-cycloalkyl-C1-4-alkoxy group,
(g) an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, hexahydroazepino, morpholino, homomorpholino, piperazino, 4-(C1-4-alkyl)-piperazino, homopiperazino, or 4-(C1-4-alkyl)-homopiperazino group, and
(h) a 2-oxomorpholino group optionally substituted by 1 or 2 methyl groups,
with the proviso that:
(i) at least one of the groups B or D, or A together with B, or C together with D contains an optionally substituted 2-oxomorpholinyl group, an (R7O—PO—OR8) or (R7O—PO—R9) group, or
(ii) that at least one of the groups B or D contains an optionally substituted 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, 2-oxotetrahydropyran-3-yl, 2-oxotetrahydropyran-4-yl, or 2-oxotetrahydropyran-5-yl group, or
(iii) that at least one of the groups A, B, C, or D, or A together with B, or C together with D contains an R6O—CO group and additionally one of the groups A, B, C, or D, or A together with B, or C together with D contains a primary, secondary, or tertiary amino function, wherein the nitrogen atom of this amino function is not linked to a carbon atom of an aromatic group,
Rc and Rd, which are identical or different, each are a hydrogen, fluorine, or chlorine atom, or a methoxy group or a methyl group optionally substituted by a methoxy, dimethylamino, diethylamino, pyrrolidino, piperidino, or morpholino group;
Re and Rf, which are identical or different, in each case are a hydrogen atom or a C1-4-alkyl group;
Rg is a C1-4-alkyl, C3-7-cycloalkyl, C1-4-alkoxy, or C5-7-cycloalkoxy group;
R4 is a hydrogen atom or a C1-4-alkyl group;
R5 is a hydrogen atom,
a C1-4-alkyl group optionally substituted by an R6O—CO, (R7O—PO—OR8), or (R7O—PO—R9) group,
a C2-4-alkyl group substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, or di-(C1-4-alkyl)-amino group, or by a 4- to 7-membered alkyleneimino group, wherein a methylene group at the 4 position of the 6- to 7-membered alkyleneimino group is optionally replaced by an oxygen or sulfur atom, or by a sulfinyl, sulfonyl, imino, or N—(C1-4-alkyl)-imino group, or
a C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl group;
R6, R7, and R8, which are identical or different, in each case are a hydrogen atom,
a C1-8-alkyl group optionally substituted at a position other than position 1 by a hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, or di-(C1-4-alkyl)-amino group or by a 4- to 7-membered alkyleneimino group, wherein a methylene group at the 4 position of the 6- to 7-membered alkyleneimino group is optionally replaced by an oxygen or sulfur atom, or by a sulfinyl, sulfonyl, imino, or N—(C1-4-alkyl)-imino group,
a C4-7-cycloalkyl group optionally substituted by 1 or 2 methyl groups,
a C3-5-alkenyl or C3-5-alkynyl group, wherein the unsaturated moiety thereof is not linked to the oxygen atom, or
a C3-7-cycloalkyl-C1-4-alkyl, aryl, aryl-C1-4-alkyl, or RgCO—O—(ReCRf) group;
R9 is a C1-4-alkyl, aryl, or aryl-C1-4-alkyl group;
R10 is a hydrogen atom, or a C1-4-alkyl, formyl, C1-4-alkylcarbonyl, or C1-4-alkylsulfonyl group;
R11 is a 2-oxotetrahydrofuran-3-yl, 2-oxotetrahydrofuran-4-yl, 2-oxotetrahydropyran-3-yl, 2-oxotetrahydropyran-4-yl, or 2-oxotetrahydropyran-5-yl group each optionally substituted by one or two methyl groups;
R12 is a cyano, carboxy, C1-4-alkoxycarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, di-(C1-4-alkyl)-aminocarbonyl, C1-4-alkylsulfenyl, C1-4-alkylsulfinyl, C1-4-alkylsulfonyl, hydroxy, C1-4-alkylsulfonyloxy, trifluoromethyloxy, nitro, amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C1-4-alkylcarbonylamino, N—(C1-4-alkyl)—C1-4-alkylcarbonylamino, C1-4-alkylsulfonylamino, N—(C1-4-alkyl)-C1-4-alkylsulfonylamino, aminosulfonyl, C1-4-alkylaminosulfonyl, or di-(C1-4-alkyl)-aminosulfonyl group or a carbonyl group substituted by a 5- to 7-membered alkyleneimino group, wherein a methylene group at the 4 position of the 6- to 7-membered alkyleneimino group is optionally replaced by an oxygen or sulfur atom, or by a sulfinyl, sulfonyl, imino, or N—(C1-4-alkyl)-imino group;
and
R13 is a fluorine, chlorine, bromine, or iodine atom, or a C1-4-alkyl, trifluoromethyl, or CR1-4-alkoxy group, or two groups R13, if they are bound to adjacent carbon atoms, together are a C3-5-alkylene, methylenedioxy, or 1,3-butadien-1,4-ylene group,
wherein the aryl moieties of the abovementioned groups are identical or different phenyl groups optionally monosubstituted by R12, mono-, di-, or trisubstituted by R13, or monosubstituted by R12 and additionally mono- or disubstituted by R13, wherein the substituents are identical or different,
or a tautomer, stereoisomer, or salt thereof.

106 more elements

Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them

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Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them

Life of this patent

Abstract

Claims13