Tricyclic compounds for inhibiting the CFTR channel

Patent metadata

Field	Value
Publication number	US-9359381-B2
Application number	US-201314653084-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Dec 19, 2012
Publication date	Jun 7, 2016
Grant date	Jun 7, 2016

Abstract

The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof; and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

The invention claimed is:

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof:

wherein R 1 represents phenyl, (C 4 -C 7 )cycloalkenyl or Het 1 , which R 1 group may be unsubstituted or substituted on one or two carbon atoms by substituents R a , and may further be substituted on a nitrogen atom with a substituent R a1 ;
each R a independently represents (C 1 -C 4 )alkyl, halo, halo(C 1 -C 4 )alkyl, cyano, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, R 6 OC(O)—, or R 6 OC(O)(C 1 -C 4 )alkyl-;
R a1 represents (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-, di[(C 1 -C 4 )alkyl]amino(C 1 -C 4 )alkyl-, aryl(C 1 -C 4 )alkyl or R 6 OC(O)(C 1 -C 4 )alkyl-;
R 2 represents (C 1 -C 6 )alkyl, (C 3 -C 7 )cycloalkyl, (C 4 -C 7 )cycloalkenyl, phenyl, furanyl, thiazolyl or thienyl, which R 2 may be unsubstituted or substituted on from one to three carbon atoms with substituents R b ;
each R b independently represents (C 1 -C 4 )alkyl, halo, halo(C 1 -C 4 )alkyl, cyano, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-, di[(C 1 -C 4 )alkyl]amino(C 1 -C 4 )alkyl-, (R 6 ) 2 NC(O)(C 1 -C 4 )alkyl- or R 6 OC(O)(C 1 -C 4 )alkyl-;
X represents S, Z represents CHR 4a and n represents 1; or
X represents CHR 4b , Z represents NR 5 and n represents 1 or 2; or
X represents CHR 4b , Z represents CHR 4a and n represents 0, 1 or 2; or
X represents C(═CH 2 ), CF 2 or C(CH 3 ) 2 , Z represents CHR 4a and n represents 0 or 1;
each R 3 independently represents methyl or ethyl;
when X represents S, R 4 represents hydrogen, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-, amino(C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-, di[(C 1 -C 4 )alkyl]amino(C 1 -C 4 )alkyl-, phenyl, Het 1 (C 1 -C 4 )alkyl-, Het 2 (C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylS(O) 2 NH(C 1 -C 4 )alkyl-, or R 7 C(O)NH(C 1 -C 4 )alkyl-;
when X represents CHR 4b , each R 4 independently represents hydrogen, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl-, amino(C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-, di[(C 1 -C 4 )alkyl]amino(C 1 -C 4 )alkyl-, amino, (C 1 -C 4 )alkylamino-, di[(C 1 -C 4 )alkyl]amino-, phenyl, Het 1 (C 1 -C 4 )alkyl-, Het 2 (C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylS(O) 2 NH(C 1 -C 4 )alkyl-, or R 7 C(O)NH(C 1 -C 4 )alkyl-;
R 4a represents hydrogen, (C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl-, (C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl-, di[(C 1 -C 4 )alkyl]amino(C 1 -C 4 )alkyl-, Het 1 (C 1 -C 4 )alkyl-, Het 2 (C 1 -C 4 )alkyl-, or R 6 OC(O)—;
R 4b represents hydrogen or methyl;
R 5 represents hydrogen or (C 1 -C 4 )alkyl;
R 6 represents hydrogen or (C 1 -C 4 )alkyl;
R 7 represents (C 1 -C 2 )alkyl, (C 1 -C 2 )alkoxy, (C 1 -C 2 )alkoxy(C 1 -C 2 )alkyl or phenyl;
Het 1 represents a 5- or 6-membered heteroaryl ring comprising a) one oxygen or sulphur atom and optionally one or two nitrogen atoms; or b) from one to four nitrogen atoms; and
Het 2 represents a 4- to 7-membered heterocyclic ring comprising a) 1 or 2 heteroatoms selected from N, O and S; or b) —C(O)— and 1 or 2 heteroatoms selected from N and O.

2. A compound according to claim 1 , wherein R 1 represents phenyl, cyclohexenyl, thiazolyl, pyrazolyl, thienyl, pyrimidin-2-yl or pyridine-2-yl and wherein R 1 may be unsubstituted or substituted on one or two carbon atoms by substituents R a , and may further be substituted on a nitrogen atom with a substituent R a1 .

3. A compound according to claim 1 , wherein R 2 represents phenyl, furanyl, thiazolyl, or thieny, which R 2 may be unsubstituted or substituted on from one to three carbon atoms with substituents R b .

4. A compound according to claim 1 , wherein each R b independently represents (C 1 -C 2 )alkyl, halo, halo(C 1 -C 2 )alkyl, or cyano.

5. A compound according to claim 1 , wherein each R 3 represents methyl.

6. A compound according to claim 1 , wherein R 4 represents hydrogen, methyl, phenyl or HOCH 2 —.

7. A compound according to claim 1 , wherein X represents S, Z represents CHR 4a and n represents 1.

8. A compound according to claim 1 , wherein R 4a represents hydrogen or methyl.

9. A compound according to claim 1 , wherein the compound is of formula (Ia):

10. A compound according to claim 1 which is selected from:
1,3-Dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-Chlorofuran-2-yl)-1,3-dimethyl-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(3-Chlorophenyl)-1,3-dimethyl-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3-Dimethyl-5-phenyl-10-(m-tolyl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-Chlorofuran-2-yl)-1,3-dimethyl-5-(m-tolyl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-(m-tolyl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3-Dimethyl-10-(5-methylthiophen-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3-Dimethyl-10-(4-methylthiophen-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
7-((dimethylamino)methyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-chlorofuran-2-yl)-1,3,8-trimethyl-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
1,3,8-trimethyl-10-(4-methylthiazol-2-yl)-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
3-(10-(5-Chlorofuran-2-yl)-1,3-dimethyl-2,4-dixox-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-5-yl)benzonitrile;
10-(5-Chlorofuran-2-yl)-1,3-dimethyl-5-(methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-Chlorofuran-2-yl)-5-(cyclohex-1-en-1-yl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-Chlorofuran-2-yl)-5-(3,5-difluorophenyl)-1,3-dimethyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
10-(5-Chlorofuran-2-yl)-1,3-diethyl-5-phenyl-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazine-2,4(3H,10H)-dione;
3-Chloro-5-(10-(5-chlorofuran-2-yl)-1,3-dimethyl-2,4-dioxo-2,3,4,7,8,10-hexahydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]thiazin-5-yl)benzonitrile;
10-(2,3-Difluorophenyl)-1,3-dimethyl-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione;
1,3-Dimethyl-10-(5-methylfuran-2-yl)-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione;
1,3-Dimethyl-10-(4-methylthiazol-2-yl)-5-phenyl-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H,3H)-dione;
5-(3-Fluorophenyl)-1,3-dimethyl-10-(5-methylfuran-2-yl)-7,8,9,10-tetrahydropyrimido[4,5-a]indolizine-2,4(1H

Assignees

• Ahmed Mahbub
• Ashall-Kelly Alexander
• Gueritz Louisa
• Mckenna Jeffrey
• Mckenna Joseph
• Mutton Simon
• Parmar Rakesh
• Shepherd Jon
• Wright Paul
• Novartis Ag

Inventors

• Ahmed Mahbub
• Ashall-Kelly Alexander
• Gueritz Louisa
• Mckenna Jeffrey
• Mckenna Joseph
• Mutton Simon
• Parmar Rakesh
• Shepherd Jon
• Wright Paul

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P1/12

  Antidiarrhoeals · CPC title

• A61P13/12

  of the kidneys · CPC title

• C07D487/22

  in which the condensed system contains four or more hetero rings · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title