Imidazopyridine derivatives as modulators of TNF activity

Patent metadata

Field	Value
Publication number	US-9309243-B2
Application number	US-201314414287-A
Country	US
Kind code	B2
Filing date	Jul 5, 2013
Priority date	Jul 13, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

A series of imidazo[1,2-a]pyridine derivatives of formula (I), being potent modulators of human TNFa activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

First claim

The invention claimed is:

1. A compound represented by formula (IIB) or a pharmaceutically acceptable salt thereof:

wherein
E represents —N(R 5 ), —CH 2 —, —CH(OH)—, —CH(OCH 3 )—, —CH(OCH 2 CO 2 H)—, —CH(NH 2 )—, —CH(NHCOCH 3 )—, —CH(CO 2 H)—, —CH(CO 2 benzyl)—, —CH(CH 3 )— or -C(CH 3 )(OH)—;
Q represents a covalent bond; or Q represents —CH 2 —, —CH(CN)—, —CH(OH)—, —CH(OCH 3 )—, —CH 2 O—,—CH 2 N(R 6 )— or —H 2 OCH 2 —;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups is optionally substituted by one or more substituents; or Z represents —Z 1 —Z 2 or —Z 1 —C(O)—Z 2 , either of which moieties is optionally substituted by one or more halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, oxo, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-3 alkylenedioxy, C 1-6 alkylsulfonyl, amino, di(C 1-6 )alkylamino, di(C 1-6 )alkylamino(C 1-6 )alkyl, C 2-6 alkylcarbonylamino, C 1-6 alkyl-sulfonylamino, formyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylamino-carbonyl, di(C 1-6 )alkylaminocarbonyl, aminocarbonylamino, and hydrazinocarbonyl;
Z 1 represents a divalent radical derived from an aryl, C 3-7 heterocycloalkyl or heteroaryl group;
Z 2 represents aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl;
V represents C—R 22 or N;
R 5 and R 6 independently represent hydrogen or C 1-6 alkyl;
R 12 represents hydrogen, halogen, trifluoromethyl or C 1-6 alkyl optionally substituted with C 2-6 alkoxycarbonyl;
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, arylamino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 alkylaminosufonyl;
R 21 represents hydrogen, halogen, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoro-methyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy,(C 1-6 )alkoxy-(C 1-6 )alkyl, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C 3-7 )cycloalkyloxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, amino, amino-(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, N-[(C 1-6 ) -alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino-(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, N-[(C 1-6 )alkyl]-N-[carboxy(C 1-6 )alkyl]amino, carboxy(C 3-7 )cycloalkylamino, carboxy(C 3-7 )cycloalkyl(C 1-6 )alkylamino, C 1-6 alkyl-sulphonylamino, C 1-6 alkylsulphonylamino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, (C 2-6 )alkylcarbonyloxy(C 1-6 )alkyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, C 2-6 alkoxycarbonyl-methylidenyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl or di(C 1-6 )alkylaminosulphonyl; or R 21 represents (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-6 )alkyl, (C 4-7 )cycloalkenyl, (C 4-9 )bicycloalkyl, (C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkenyl, (C 4-9 )heterobicycloalkyl or (C 4-9 )spiroheterocycloalkyl, any of which groups is optionally substituted by one, two or three substituents independently selected from C 1-6 alkyl, oxo, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, tetrazolyl, tetrazolyl(C 1-6 )alkyl, halogen, halo(C 1-6 )alkyl, cyano, nitro(C 1-6 )alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, C 1-6 alkylsulphonyl, amino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, formyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonylmethylidenyl, hydroxyoxadiazolyl, C 1-6 alkoxyaminocarbonyl, C 1-6 alkylsulphonylaminocarbonyl, aminosulphonyl and C 2-6 alkylcarbonylaminosulphonyl;
R 22 represents hydrogen, halogen or C 1-6 alkyl; and
R 23 represents hydrogen, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy.

2. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof wherein R 21 represents hydroxy(C 1-6 )alkyl.

3. The compound as claimed in claim 1 represented by formula (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (IIJ), (IIK) or (IIL) or a pharmaceutically acceptable salt thereof:

wherein
T represents —CH 2 — or —CH 2 CH 2 —;
U represents C(O) or S(O) 2 ;
W represents O, S, S(O), S(O) 2 , N(R 31 ) or C(R 32 )(R 33 );
-M-represents —CH 2 — or —CH 2 CH 2 —;
R 31 represents hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, trifluoroethyl, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminocarbonyl, C 1-6 alkylamino-carbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, (C 1-6 )alkylaminosulphonyl, di(C 1-6 )alkyalaminosulphonyl or tetrazolyl(C 1-6 )alkyl;
R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, carboxy, carboxy (C 1-6 )alkyl, C 2-6 alkylcarbonyl, C 2-6 alkoxycarbonyl, (C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkoxyaminocarbonyl,(C 1-6 )alkyl-sulphonylaminocarbonyl, (C 2-6 )alkylcarbonlaminosulphonyl, hydroxyoxadiazolyl or tetrazolyl;
R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, amino or carboxy;
R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, (C 2-6 )alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, (C 1-6 )alkylsulphonylamino, or (C 1-6 )alkylsulphonylamino(C 1-6 )alkyl.

4. The compound as claimed in claim 3 or a pharmaceutically acceptable salt thereof, wherein R 34 represents hydrogen or hydroxy.

5. The compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R 15 represents difluoromethoxy.

6. A compound according to claim 1 that is,
N-(2,5-Dichlorophenyl)-6-(6-methoxypyridin-3-yl)-2-methylimidazo[1,2-a]pyridin-3-amine,
3-[2-(Difluoromethoxy)benzyl]-6-(6-methoxy-5-methylpyridin-3-yl)-2-methyl -imidazo[1,2-a]pyridine,
5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-a]pyridin-6-yl}-3-methyl-pyridin-2(1H)-one,
3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[1,2-a]pyridine,
3-[2-(Difluoromethoxy)benzyl]-6-(6-methoxypyridin-3-yl)-2-methylimidazo[1,2-a]-pyridine,
{3-[2-(Difluoromethoxy)benzyl]-6-(6-methoxypyridin-3-yl)imidazo[1,2-a]pyridin-2-yl}-methanol,
3-[2-(Difluoromethoxy)benzyl]-2-methyl-6-[2-(piperazin-1-yl)pyrimidin-5-yl]-imidazo[1,2-a]pyridine,
4-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-a]pyridin-6-yl}pyrimidin-2-yl)piperazin-2-one,
3-[2-(Difluoromethoxy)benzyl]-6-[2-(1,1-dioxidothiomorpholin-4-yl)pyrimidin -5-yl]-2-methylimidazo[1,2-a]pyridine,
5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-a]pyridin-6-yl}pyridin-2(1H)-one,
4-(5-{3-[2-(Difluoromethoxy)benzyl]-2-methylimidazo[1,2-a

Assignees

• Ucb Biopharma Sprl

Inventors

• Bentley Jonathan Mark
• Brookings Daniel Christopher
• Brown Julien Alistair
• Cain Thomas Paul
• Chovatia Praful Tulshi
• Foley Anne Marie
• Gallimore Ellen Olivia
• Gleave Laura Jane
• Heifetz Alexander
• Horsley Helen Tracey
• Hutchings Martin Clive
• Jackson Victoria Elizabeth
• Johnson James Andrew
• Johnstone Craig
• Kroeplien Boris
• Lecomte Fabien Claude
• Leigh Deborah
• Lowe Martin Alexander
• Madden James
• Porter John Robert
• Quincey Joanna Rachel
• Reed Laura Claire
• Reuberson James Thomas
• Richardson Anthony John
• Richardson Sarah Emily
• Selby Matthew Duncan
• Shaw Michael Alan
• Zhu Zhaoning

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title