US 2009/0023746 A1Published application

Compounds and their uses 707

AssigneeAstraZeneca AB

InventorsMatthew Hallam, Barrie Martin, Piotr Raubo, Bryan Roberts, Stephen St-Gallay, Paul Willis

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Abstract

The present invention relates to isoquinolinone derivatives of formula (I): wherein R1, R2, R3, R4, R5, R6 and R7 are as herein defined; processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Claims14

Dependent claims

A compound of formula (I):
wherein:
R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)alkynyl, (CH2)a—X—Ar and (CR101R102)a—X—Ar wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo, —OH, -heterocycloalkyl, (C3-C7)cycloalkyl, and —NR8R9;
R2 and R3 are independently selected from H, halo, (C1-C6)alkyl, (C1-C6)alkoxy and (CH2)d—Y;
wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo and —OH;
and wherein said (C1-C6)alkoxy is optionally substituted with 1, 2 or 3 groups independently selected from -halo and —OH;
and provided that when R2 is (CH2)d—Y, R3 is selected from H, halo, (C1-C6)alkyl and (C1-C6)alkoxy;
and provided that when R3 is (CH2)d—Y, R2 is selected from H, halo, (C1-C6)alkyl and (C1-C6)alkoxy;
R4 and R5 are independently selected from H, (C1-C6)alkyl, (C1-C6)alkoxy, halo, CF3, and CN;
R6 is selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl, heteroaryl and OH, wherein said (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl group may be substituted by 1 or more halo atoms;
R7 is selected from H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
Ar is an aryl or heteroaryl ring optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C6)alkynyl, —(CH2)e—O—(C1-C6)alkyl, —(CH2)e—S(O)f—(C1-C6)alkyl, —(CH2)e—N(R10)—(C1-C6)alkyl, —(CH2)e-Z-(C1-C6)alkyl, —O-heterocycloalkyl, —S—(O)b-heterocycloalkyl, —N(R11)-heterocycloalkyl, —CN, —OH, -halo, -phenyl, -heterocycloalkyl, —(C3-C7)cycloalkyl, —C(O)NR8R9, —NR8R9, —C(O)OH and C(O)NR10SO2—(C1-C6)alkyl, wherein each occurrence of (C1-C6)alkyl is, independently, optionally substituted with 1, 2 or 3 groups independently selected from -halo, —OH, —(C1-C6)alkoxy, —NR12R13 and heterocycloalkyl;
X is selected from a single bond, O, NR14 and S(O)g;
Y is selected from heterocycloalkyl, O-heterocycloalkyl, O—(CH2)h—NR16R17, NR18—(CH2)h—NR16R17, S—(O)j-heterocycloalkyl, S—(O)j—(CH2)h—NR16R17, NR16R17, NR15C(O)R16, NR15SO2R16, C(O)NR16R17, OC(O)NR16R17, OC(O)R16, C(O)OR16 and NR15C(O)OR16;
Z is selected from C(O)N(R18), N(R18)C(O), C(O)O, OC(O), SO2N(R18), N(R18)SO2, OC(O)N(R18), N(R18)C(O)O, and OC(O)O;
R8 and R9 are independently selected from H and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo, —OH and NR19R20;
or R8 and R9 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR21, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR19R20;
R12 and R13 are independently selected from H and (C1-C6)alkyl wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR22R23;
or R12 and R13 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR24, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR22R23;
R16 is selected from H, (C1-C6)alkyl and heterocycloalkyl, wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR25R26;
R17 is selected from H and (C1-C6)alkyl;
or R16 and R17 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR27, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR25R26, wherein said —(C1-C6)alkyl is optionally substituted by OH;
R25 and R26 are independently selected from H and (C1-C6)alkyl wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR22R23;
or R25 and R26 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR24, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR22R23;
R27 is selected from H, (C1-C6)alkyl and heterocycloalkyl, wherein said (C1-C6)alkyl is optionally substituted by a substituent selected from —OH, -halo and —NR22R23;
R10, R11, R14, R15, R18, R19, R20R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl;
a is selected from 0, 1, 2, 3, 4, 5 and 6;
d, e and h are independently selected from 0, 1, 2 and 3;
b, f, g and j are independently selected from 0, 1 and 2;
heterocycloalkyl is a C-linked 3 to 7 membered non-aromatic cyclic ring, containing from 1 to 2 NR28 atoms, or one NR28 atom and an S or an O atom, or one S atom, or one O atom;
optionally containing, where possible, 1 or 2 double bonds;
which unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR29R30, wherein said —(C1-C6)alkyl is optionally substituted by —OH;
heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing from 1 to 2 N atoms and, optionally, an NR31 atom, or one NR31 atom and an S or an O atom, or one S atom, or one O atom;
which, unless otherwise stated, may be optionally substituted with 1-3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR38R39;
cycloalkyl is a non-aromatic carbocyclic ring containing the requisite number of carbon atoms, optionally containing, where possible, up to 3 double bonds;
which, unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR34R35;
aryl is an aromatic ring containing 6 or 10 carbon atoms;
which unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR36R37;
R28 and R31 are each independently selected from H, (C1-C6)alkyl and —C(O)O—(C1-C6)alkyl, wherein said (C1-C6)alkyl may be optionally substituted with (C1-C6)alkoxy, —OH, halo, (C3-C7)cycloalkyl and —NR32R33;
R29, R30, R32 and R33 are each independently selected from H and (C3-C6)alkyl;
R34, R35, R36, R37, R38 and R39 are each independently selected from H, and (C1-C6)alkyl;
R101 is (C1-C6)alkyl;
R102 is H or (C1-C6)alkyl;
or a pharmaceutically acceptable salt or N-oxide thereof.

49 more elements

The compound according to claim 1, selected from:
3-(2-Benzyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)-N-cyclopropyl-4-methyl-benzamide;
3-(2-Benzyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)-N-ethyl-4-methyl-benzamide;
3-[2-(4-Bromo-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl-N-cyclopropyl-4-methyl-benzamide;
N-Cyclopropyl-4-methyl-3-{2-[4-(4-methyl-piperazin-1-yl)-benzyl]-1-oxo-1,2-dihydro-isoquinolin-6-yl}-benzamide;
N-Cyclopropyl-3-[2-(4-methanesulfonyl-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide;
4-{4-[6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-1-oxo-1H-isoquinolin-2-ylmethyl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid, tert-butyl ester;
N-Cyclopropyl-4-methyl-3-[1-oxo-2-{4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl}-1,2-dihydro-isoquinolin-6-yl]-benzamide;
N-Cyclopropyl-4-methyl-3-[1-oxo-2-(4-piperidin-4-yl-benzyl)-1,2-dihydro-isoquinolin-6-yl]-benzamide;
N-Methoxy-4-methyl-3-{1-oxo-2-[4-(1,2,3,6-tetrahydro-pyridin-4-yl)-benzyl]-1,2-dihydro-isoquinolin-6-yl}-benzamide;
N-Cyclopropyl-3-{2-[3-(3-dimethylamino-propoxy)-benzyl]-1-oxo-1,2-dihydro-isoquinolin-6-yl}-4-methyl-benzamide;
N-Cyclopropyl-4-methyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzamide;
3-(2-Allyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)-N-cyclopropyl-4-methyl-benzamide;
N-Cyclopropyl-4-methyl-3-[1-oxo-2-(3-pyrrolidin-1-yl-propyl)-1,2-dihydro-isoquinolin-6-yl]-benzamide;
N-Cyclopropyl-3-[2-(4-dimethylaminomethyl-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide;
N-Cyclopropyl-3-[2-(3-dimethylaminomethyl-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide;
N-Cyclopropyl-3-[2-(2-dimethylaminomethyl-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide;
N-Cyclopropyl-3-[2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide,
N-Cyclopropyl-3-(2-(4-((2-(dimethylamino)ethyl)(methyl)carbamoyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-Cyclopropyl-3-(2-(4-(2-(dimethylamino)ethylcarbamoyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-Cyclopropyl-4-methyl-3-(2-(4-(4-methylpiperazine-1-carbonyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-3-(2-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-Cyclopropyl-4-methyl-3-(1-oxo-2-(4-(2-(pyrrolidin-1-yl)ethylcarbamoyl)benzyl)-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-4-methyl-3-(2-(4-(methyl(2-(methylamino)ethyl)carbamoyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-4-methyl-3-(1-oxo-2-(4-(3-(pyrrolidin-1-yl)propylcarbamoyl)benzyl)-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-4-methyl-3-(1-oxo-2-(4-(pyrrolidin-1-ylmethyl)benzyl)-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-4-methyl-3-(2-(4-((4-methylpiperazin-1-yl)methyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide,
3-(2-(4-((Tert-butyl(methyl)amino)methyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide,
3-(2-(4-((Tert-butylamino)methyl)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide,
N-Cyclopropyl-3-(2-((6-(3-(dimethylamino)propoxy)pyridin-3-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-Cyclopropyl-3-(2-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-Cyclopropyl-4-methyl-3-(1-oxo-2-((6-(2-(pyrrolidin-1-yl)ethoxy)pyridin-3-yl)methyl)-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-3-(2-(4-(2-(dimethylamino)ethoxy)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
N-cyclopropyl-4-methyl-3-{1-oxo-2-[3-(2-pyrrolidin-1-ylethoxy)benzyl]-1,2-dihydroisoquinolin-6-yl}benzamide,
N-Cyclopropyl-4-methyl-3-(2-{3-[2-(methylamino)ethoxy]benzyl}-1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide,
N-Cyclopropyl-3-[2-(3-{2-[(2-hydroxyethyl)amino]ethoxy}benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide,
N-Cyclopropyl-4-methyl-3-(2-(4-(2-(methylamino)ethoxy)benzyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)benzamide,
6-(5-(Cyclopropylcarbamoyl)-2-methylphenyl)-2-(cyclopropylmethyl)-1-oxo-N-(piperidin-4-yl)-1,2-dihydroisoquinoline-4-carboxamide,
3-(4-(4-Aminopiperidine-1-carbonyl)-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide,
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-(4-(dimethylamino)piperidine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide,
2-Benzyl-6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-N-(2-(dimethylamino)ethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,
2-Benzyl-6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-1-oxo-N-(2-(piperidin-1-yl)ethyl)-1,2-dihydroisoquinoline-4-carboxamide,
2-Benzyl-6-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-oxo-N-(2-pyrrolidin-1-ylethyl)-1,2-dihydroisoquinoline-4-carboxamide,
2-Benzyl-6-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-N-(1-methylpiperidin-4-yl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,
2-Benzyl-6-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-N-[3-(dimethylamino)propyl]-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,
(R)-3-(4-(3-Aminopyrrolidine-1-carbonyl)-2-benzyl-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide,
6-(5-(Cyclopropylcarbamoyl)-2-methylphenyl)-1-oxo-N-(piperidin-4-yl)-2-(pyridin-4-ylmethyl)-1,2-dihydroisoquinoline-4-carboxamide,
3-(4-(4-Aminopiperidine-1-carbonyl)-1-oxo-2-(pyridin-4-ylmethyl)-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-4-methylbenzamide,
N-Cyclopropyl-3-[2-cyclopropylmethyl-4-(4-methyl-[1,4]diazepan-1-ylmethyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-4-methyl-benzamide,
2-Benzyl-6-(5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl)-N-(2-(dimethylamino)ethyl)-1-oxo-1,2-dihydroisoquinoline-4-carboxamide,
(S)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide
N-Cyclopropyl-3-(2-cyclopropylmethyl-4-[1,4]diazepan-1-ylmethyl-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-methyl-benzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((4-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((4-methyl-1,4-diazepan-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(S)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(R)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-(hydroxymethyl)piperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(R)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((2-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(R)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-(hydroxymethyl)-4-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-1-oxo-4-(piperazin-1-ylmethyl)-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
3-(4-((1,4-Diazepan-1-yl)methyl)-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide
(S)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-(hydroxymethyl)piperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(R)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(s) —N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((2-(hydroxymethyl)piperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(S)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-ethylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(s) —N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((3-(2-hydroxyethyl)piperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
(S)—N-Cyclopropyl-3-(2-(cyclopropylmethyl)-4-((2-methylpiperazin-1-yl)methyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-5-fluoro-4-methylbenzamide
3-(4-(((2R,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)methyl)-2-(cyclopropylmethyl)-1-oxo-1,2-dihydroisoquinolin-6-yl)-N-cyclopropyl-5-fluoro-4-methylbenzamide
and pharmaceutically acceptable salts or N-oxides thereof.

69 more elements

Facts

Application: 12/062,718Filed 4 Apr 2008
Priority: 5 Apr 2007
Published: 22 Jan 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 217/24
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 11/08
Drugs for disorders of the respiratory system: bronchodilators

Family

Application60/910,235Us provisional application · filed 5 Apr 2007
Application60/979,523Us provisional application · filed 12 Oct 2007
US 8,012,979 B2Related patent
US 2009/0023746 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):
wherein:
R1 is selected from H, (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)alkynyl, (CH2)a—X—Ar and (CR101R102)a—X—Ar wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo, —OH, -heterocycloalkyl, (C3-C7)cycloalkyl, and —NR8R9;
R2 and R3 are independently selected from H, halo, (C1-C6)alkyl, (C1-C6)alkoxy and (CH2)d—Y;
wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo and —OH;
and wherein said (C1-C6)alkoxy is optionally substituted with 1, 2 or 3 groups independently selected from -halo and —OH;
and provided that when R2 is (CH2)d—Y, R3 is selected from H, halo, (C1-C6)alkyl and (C1-C6)alkoxy;
and provided that when R3 is (CH2)d—Y, R2 is selected from H, halo, (C1-C6)alkyl and (C1-C6)alkoxy;
R4 and R5 are independently selected from H, (C1-C6)alkyl, (C1-C6)alkoxy, halo, CF3, and CN;
R6 is selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl, heteroaryl and OH, wherein said (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, aryl or heteroaryl group may be substituted by 1 or more halo atoms;
R7 is selected from H, (C1-C6)alkyl, (C1-C6)alkoxy and halo;
Ar is an aryl or heteroaryl ring optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkyl, —(C2-C6)alkenyl, —(C3-C6)alkynyl, —(CH2)e—O—(C1-C6)alkyl, —(CH2)e—S(O)f—(C1-C6)alkyl, —(CH2)e—N(R10)—(C1-C6)alkyl, —(CH2)e-Z-(C1-C6)alkyl, —O-heterocycloalkyl, —S—(O)b-heterocycloalkyl, —N(R11)-heterocycloalkyl, —CN, —OH, -halo, -phenyl, -heterocycloalkyl, —(C3-C7)cycloalkyl, —C(O)NR8R9, —NR8R9, —C(O)OH and C(O)NR10SO2—(C1-C6)alkyl, wherein each occurrence of (C1-C6)alkyl is, independently, optionally substituted with 1, 2 or 3 groups independently selected from -halo, —OH, —(C1-C6)alkoxy, —NR12R13 and heterocycloalkyl;
X is selected from a single bond, O, NR14 and S(O)g;
Y is selected from heterocycloalkyl, O-heterocycloalkyl, O—(CH2)h—NR16R17, NR18—(CH2)h—NR16R17, S—(O)j-heterocycloalkyl, S—(O)j—(CH2)h—NR16R17, NR16R17, NR15C(O)R16, NR15SO2R16, C(O)NR16R17, OC(O)NR16R17, OC(O)R16, C(O)OR16 and NR15C(O)OR16;
Z is selected from C(O)N(R18), N(R18)C(O), C(O)O, OC(O), SO2N(R18), N(R18)SO2, OC(O)N(R18), N(R18)C(O)O, and OC(O)O;
R8 and R9 are independently selected from H and (C1-C6)alkyl, wherein said (C1-C6)alkyl is optionally substituted with 1, 2 or 3 groups independently selected from —(C1-C6)alkoxy, -halo, —OH and NR19R20;
or R8 and R9 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR21, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR19R20;
R12 and R13 are independently selected from H and (C1-C6)alkyl wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR22R23;
or R12 and R13 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR24, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR22R23;
R16 is selected from H, (C1-C6)alkyl and heterocycloalkyl, wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR25R26;
R17 is selected from H and (C1-C6)alkyl;
or R16 and R17 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR27, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR25R26, wherein said —(C1-C6)alkyl is optionally substituted by OH;
R25 and R26 are independently selected from H and (C1-C6)alkyl wherein said (C1-C6)alkyl is optionally substituted with —(C1-C6)alkoxy, —OH, -halo, —(C3-C7)cycloalkyl and —NR22R23;
or R25 and R26 together with the nitrogen atom to which they are attached form a 3 to 7 membered ring, optionally containing a further heteroatom selected from NR24, S and O;
and optionally containing, where possible, 1 or 2 double bonds;
wherein said ring is optionally substituted on carbon by 1 or 2 substituents independently selected from —(C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR22R23;
R27 is selected from H, (C1-C6)alkyl and heterocycloalkyl, wherein said (C1-C6)alkyl is optionally substituted by a substituent selected from —OH, -halo and —NR22R23;
R10, R11, R14, R15, R18, R19, R20R21, R22, R23 and R24 are independently selected from H and (C1-C6)alkyl;
a is selected from 0, 1, 2, 3, 4, 5 and 6;
d, e and h are independently selected from 0, 1, 2 and 3;
b, f, g and j are independently selected from 0, 1 and 2;
heterocycloalkyl is a C-linked 3 to 7 membered non-aromatic cyclic ring, containing from 1 to 2 NR28 atoms, or one NR28 atom and an S or an O atom, or one S atom, or one O atom;
optionally containing, where possible, 1 or 2 double bonds;
which unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR29R30, wherein said —(C1-C6)alkyl is optionally substituted by —OH;
heteroaryl is a 5, 6, 9 or 10 membered aromatic ring, containing from 1 to 2 N atoms and, optionally, an NR31 atom, or one NR31 atom and an S or an O atom, or one S atom, or one O atom;
which, unless otherwise stated, may be optionally substituted with 1-3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR38R39;
cycloalkyl is a non-aromatic carbocyclic ring containing the requisite number of carbon atoms, optionally containing, where possible, up to 3 double bonds;
which, unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR34R35;
aryl is an aromatic ring containing 6 or 10 carbon atoms;
which unless otherwise stated, may be optionally substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C2-C6)alkenyl, —OH, —CN, halo and —NR36R37;
R28 and R31 are each independently selected from H, (C1-C6)alkyl and —C(O)O—(C1-C6)alkyl, wherein said (C1-C6)alkyl may be optionally substituted with (C1-C6)alkoxy, —OH, halo, (C3-C7)cycloalkyl and —NR32R33;
R29, R30, R32 and R33 are each independently selected from H and (C3-C6)alkyl;
R34, R35, R36, R37, R38 and R39 are each independently selected from H, and (C1-C6)alkyl;
R101 is (C1-C6)alkyl;
R102 is H or (C1-C6)alkyl;
or a pharmaceutically acceptable salt or N-oxide thereof.

49 more elements

Facts

Application

12/062,718Filed 4 Apr 2008

Priority

5 Apr 2007

Published

22 Jan 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification13 codes

C07D 217/24
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
A61P 11/00
Drugs for disorders of the respiratory system
A61P 11/06
Drugs for disorders of the respiratory system: antiasthmatics
A61P 11/08
Drugs for disorders of the respiratory system: bronchodilators