# US 7,608,726 B2 · Substituted indolepyridinium as anti-infective compounds

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- Number: US 7,608,726 B2
- Document ID: US7608726B2
- Status: Granted
- Kind: B2
- Application number: 10/535,007
- Filed: 2003-11-14
- Published: 2006-08-03
- Granted: 2009-10-27
- Earliest claimed: 2002-11-15
- Assignees: Tibotec Pharmaceuticals Ltd.
- Inventors: Bart Rudolf Romanie Kesteleyn; Wim Van De Vreken; Natalie Maria Francisca Kindermans; Maxime Francis Jean-Marie Ghislain Canard; Kurt Hertogs; Eva Bettens; Veronique Corine Paul De Vroey; Dirk Edward Désiré Jochmans
- Web page: https://patentgrep.com/patent/US7608726B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention concerns the compounds of formula (I) their N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, wherein n is 1, 2 or 3; R1is H, CN, halo, aminoC(═O), C(═O)OH, C1-4alkyloxyC(═O), C1-4alkylC(═O), mono- or di(C1-4alkyl)aminoC(═O), arylaminoC(═O), N-(aryl)-N—(C1-4alkyl)aminoC(═O), methanimidamidyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, Het1 or Het2; R2 is H, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, wherein said C1-10alkyl, C2-10alkenyl and C3-7cycloalkyl may be optionally substituted; R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxyC(═O), aminoC(═O), C1-4alkyloxyC(═O), mono- or di(C1-4alkyl)aminoC(═O), C1-4alkylC(═O), methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1; for use as a medicine. The invention further relates to a novel subgroup of the compounds of formula (I), and to compositions comprising compounds of formula (I).

## Claims

### Claim 1

A compound of formula (I)
or a pharmaceutically acceptable salt, or stereoisomeric form, wherein n is 1, 2 or 3;
R1 is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, arylaminocarbonyl, N-(aryl)-N—(C1-4alkyl)aminooarbonyl, methanimidamidyl, N-hydroxy-methanimidamidyl, or mono- or di(C1-4alkyl)methanimidamidyl, or Het1;
R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, wherein said C1-10alkyl, C2-10alkenyl and C3-7cyoloalkyl, each individually and independently, may be optionally substituted with a substituent selected from the group consisting of cyano, NR4aR4b, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C1-4alkyl))-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aryl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxycarbonyl, C1-4alkylcarbonyl, N(R4aR4b)carbonyl, C1-4alkyloxycarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(C1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-ylcarbonyl, thiomorpholin-1-ylcarbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl;
R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonyl, methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1;
R4a is hydrogen, C1-4alkyl or C1-4alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C1-4alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxo-thiomorpholinyl;
R4b is hydrogen, C1-4alkyl or C1-4alkyl substituted with a substituent selected from the group consisting of amino, mono- or di(C1-4alkyl)amino, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxo-thiomorpholinyl;
aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C1-6alkyl, C1-4alkoxy, halo, hydroxy, amino, trifluoromethyl, cyano, nitro, hydroxyC1-6alkyl, cyanoC1-6alkyl, mono- or di(C1-4alkyl)amino, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl;
Het1 is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C1-4alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C1-4alkyl, C2-6alkenyl, C3-7cycloalkyl, hydroxy, C1-4alkoxy, halo, amino, cyano, trifluoromethyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, mono- or di(C1-4alkyl)amino, aminoC1-4alkyl mono- or di(C1-4alkyl)aminoC1-4alkyl, arylC1-4alkyl, aminoC2-6alkenyl, mono- or di(C1-4alkyl)aminoC2-6alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonyl, oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadlazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C1-4alkyl provided that the compound of formula (1) is different from 2,5-dihydro-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile, and 2,5-dihydro-5-methyl-1-(4-nitrophenyl)-2-oxo-1H-pyrido[3,2-b]indole-3-carbonitrile.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein n is 1, R3 is nitro, R1is cyano, C1-4alkyloxyoarbonyl or C1-4alkylaminocarbonyl; and R2 is hydrogen or C1-6alkyl.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein
n is 1 or 2:
R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein
R1is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C1-4alkyloxycarbonyl, arylaminocarbonyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, or Het1; and
aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C1-6alkyl, C1-4alkoxy, cyano, nitro; and
Het1is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms; and, where possible, any nitrogen ring member may optionally be substituted with C1-4alkyl; any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C1-4alkyl, C3-7cycloalkyl, halo, cyano, trifluoromethyl, cyanoC1-4alkyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC2-6alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C1-4alkyloxycarbonyl, oxo, thio; and wherein the foregoing isoxazolyl may optionally be substituted with C1-4alkyl.

### Claim 5 (depends on 1)

A compound according to claim 1 wherein
R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl or C1-10alkyl substituted with substituent selected from the group consisting of cyano, NR4aR4b, pyrrolidinyl, piperidinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R4aR4b)carbonyl, C1-4alkyloxycarbonyl or 4-(C1-4alkyl)-piperazin-1-ylcarbonyl; and
R4a is C1-4alkyl; and
R4b is C1-4alkyl or C1-4alkyl substituted morpholinyl.

### Claim 6 (depends on 1)

A compound according to claim 1 wherein
R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl or C1-10alkyl substituted with substituent selected from the group consisting of cyano, NR4aR4b, pyrrolidinyl, piperidinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R4aR4b)carbonyl, C1-4alkyloxycarbonyl or 4-(C1-4alkyl)-piperazin-1-ylcarbonyl; and
aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C1-6alkyl, C1-4alkoxy, cyano, and nitro.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein
R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl or C1-10alkyl substituted with substituent selected from the group consisting of cyano, NR4aR4b, pyrrolidinyl, piperidinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R4aR4b)carbonyl, C1-4alkyloxycarbonyl or 4-(C1-4alkyl)-piperazin-1-ylcarbonyl; and
aryl is phenyl optionally substituted with one or more substituents each individually selected from the group consisting of C1-6alkyl, C1-4alkoxy, cyano, and nitro; and
R4a is C1-4alkyl; and
R4b is C1-4alkyl or C1-4alkyl substituted morpholinyl.

### Claim 8 (depends on 1)

A compound according to claim 1 wherein
R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1; and
Het1is a 5-membered ring system wherein one, two, three or four ring members are heteroatoms each individually and independently selected from the group consisting of nitrogen, oxygen and sulfur, and wherein the remaining ring members are carbon atoms;
and, where possible, any nitrogen ring member may optionally be substituted with C1-4alkyl;
any ring carbon atom may, each individually and independently, optionally be substituted with a substituent selected from the group consisting of C1-4alkyl, C3-7cycloalkyl, halo, cyano, trifluoromethyl, cyanoC1-4alkyl, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC2-6alkenyl, isoxazolyl, aryl, hydroxycarbonyl, C1-4alkyloxycarbonyl, oxo, thio; and wherein the foregoing isoxazolyl may optionally be substituted with C1-4alkyl.

### Claim 9 (depends on 1)

A compound according to claim 1 wherein
n is 1; and
R1 is hydrogen, cyano, halo, aminocarbonyl, hydroxycarbonyl, C1-4alkyloxycarbonyl, arylaminocarbonyl, N-hydroxy-methanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl or, Het1; and
R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl or C1-10alkyl substituted with substituent selected from the group consisting of cyano, NR4aR4b, pyrrolidinyl, piperidinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, aryl, imidazolyl, pyridyl, hydroxycarbonyl, N(R4aR4b)carbonyl, C1-4alkyloxycarbonyl or 4-(C1-4alkyl)-piperazin-1-ylcarbonyl; and
R3 is nitro, cyano, amino, halo, hydroxy, C1-4alkyloxy, hydroxycarbonyl, aminocarbonyl, aminothiocarbonyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, mono- or di(C1-4alkyl)methanimidamidyl, N-hydroxy-methanimidamidyl or Het1.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein the compound has the formula (II)

### Claim 11 (depends on 1)

A compound according to claim 1 wherein R3 is nitro.

### Claim 12 (depends on 1)

A compound according to claim 1 wherein R1 is cyano.

### Claim 13 (depends on 1)

A compound according to claim 1 wherein R1 is C1-4alkyloxycarbonyl or C1-4alkylaminocarbonyl.

### Claim 14 (depends on 1)

A compound according to claim 1 wherein R2 is C2-6alkyl.

### Claim 15 (depends on 1)

A compound according to claim 1 wherein
n is 1,
R1 is cyano, halo or oxadiazolyl optionally substituted with a substituent selected from the group consisting of C1-4alkyl, C2-6alkenyl, C3-7cycloalkyl, hydroxy, C1-4alkoxy, amino, cyano, trifluoromethyl, hydroxyC1-4alkyl, cyanoC1-4alkyl, mono- or di(C1-4alkyl)amino, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC4alkyl, arylC1-4alkyl, aminoC2-6alkenyl, mono- or di(C1-4alkyl)aminoC2-6alkenyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, aryl, hydroxycarbonyl, aminocarbonyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-4alkylcarbonyl, oxo, thio; and wherein any of the foregoing furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadlazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C1-4alkyl;
R2 is C1-6alkyl, hydrogen, or C2-6alkenyl; and
R3 is nitro, C1-6alkyl optionally substituted with piperidinyl, pyrrolidinyl, N(R4aR4b), morpholinyl, pyridyl, cyano, or 4-(C1-4alkyl)-piperazin-1-yl.

### Claim 16 (depends on 1)

A compound according to claim 1 wherein the compound is
5-isobutyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-Allyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-Butyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-Ethyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-(2-Morpholin-4-yl-ethyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-Methyl-1-(4-nitro-phenyl)-1,5-dihydro-pyrido[3,2-b]indol-2-one;
5-But-3-enyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-(2-pyrrolidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-(2-piperidin-1-yl-ethyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-(3-Dimethylamino-propyl)-1-(4nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;
3-Bromo-5-methyl-1-(4-nitro-phenyl)-1,5-dihydro-pyrido[3,2-b]indol-2-one
5-Methyl-1-(3-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-(3piperidin-1-propyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-(4-Morpholin-4-yl-butyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-(4-pyrrolidin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-[3-(4-Methyl-piperazin-1-yl)-propyl]-1-(4-nitro-pheny)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-Cyanomethyl-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-(3-Morpholin-4-yl-propyl)-1-(4-nitro-phenyl)-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]-indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-(4-piperidin-1-yl-butyl)-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
5-(4Dimethylamino-butyl)-1-(4-nitro-phenyl)-2-oxo-2,5- dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
1-(4-Nitro-phenyl)-2-oxo-5-pyridin-4-ylmethyl-2,5-dihydro-1H-pyrido[3,2-b]indole-3-carbonitrile;
3-(5-tert-Butyl-[1,2,4]oxadiazol-3-yl)-5-methyl-1-(4-nitro-phenyl)-1,5-dihydro -pyrido[3,2-b]indol-2-one; or
5-Methyl-1-(4nitro-phenyl)-3-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-1,5-dihydro -pyrido[3,2-b]indol-2-one; or a pharamaceutically acceptable salt or stereoisomer thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition, comprising an effective amount of at least one compound of formula (I) as defined in claim 1 and a pharmaceutically tolerable excipient.