6,7,8,9-Substituted 1-phenyl-1,5-dihydro-pyrido[3,2-b]indol-2-ones useful as anti-infective pharmaceutical agents

A compound of formula (I):

• the N-oxides, salts, quaternary ammonium salts, stereoisomeric forms, racemic mixtures, pro drugs, esters and metabolites thereof,
• wherein
• n is 1, 2 or 3;
• R1 is hydrogen, cyano, halo, amino carbonyl, hydroxycarbonyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, arylaminocarbonyl, N-(aryl)-N—(C1-4alkyl)aminocarbonyl, methanimidamidyl, N-hydroxymethanimidamidyl, mono- or di(C1-4alkyl)methanimidamidyl, Het1 or Het2;
• X is a bivalent radical NR2, O, S, SO, SO2,;
• R2 is:
• i) hydrogen, C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, wherein said C1-10alkyl, C2-10alkenyl and C3-7cycloalkyl, each individually and independently, may be optionally substituted with a substituent selected from the group consisting of cyano, N(R16aR16b), pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C1-4alkyl)-piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, ary, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, hydroxycarbonyl, C1-4alkylcarbonyl, N(R16aR16b)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;
• or R2 is
• ii) aryl substituted with a radical —COOR4;
• or R2 is
• iii) C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, each of said C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, each individually and independently, being substituted with aryl wherein said aryl is substituted with a radical —COOR4;
• or R2 is
• iv) C1-10alkyl, C2-10alkenyl, C3-7cycloalkyl, each individually and independently, substituted with a radical selected from —NR5a—C(═NR5b)—NR5cR5d, —NR5a—C(═NR5e)—R5f, —O—NR5a—C(═NR5b)—NR5cR5d, —O—NR5a—C(═NR5e)—R5f, -sulfonyl-R6, —NR7R8, —NR9R10, a radical
• wherein
• each Q1 independently is a direct bond, —CH2—, or —CH2—CH2—;
• each Q2 independently is O, S, SO or SO2;
• each R4 independently is hydrogen, C1-4alkyl, arylC1-4alkyl;
• each R5a, R5b, R5c, R5d independently is hydrogen, C1-4alkyl or arylC1-4alkyl;
• each R5e, R5f independently is hydrogen, C1-4alkyl or arylC1-4alkyl, or R5e and R5f, taken together may form a bivalent alkanediyl radical of formula —CH2—CH2— or —CH2—CH2—CH2—;
• R6 is C1-4alkyl, —N(R5aR5b), C1-4alkyloxy, pyrrolidin-1-yl, piperidin-1-yl, homopiperidin-1-yl, piperazin-1-yl, 4-(C1-4alkyl)-piperazin-1-yl, morpholin-4-yl-, thiomorpholin-4-yl-, 1-oxothiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl;
• R7 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl or C1-4alkylcarbonyloxyC1-4alkyl;
• R8 is hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, C1-4alkylcarbonyloxyC1-4alkyl, aryl or arylC1-4alkyl;
• R9 is hydrogen or C1-4alkyl;
• R10 is Het1, Het2 or a radical
• R11 is aryl, arylC1-4alkyl, formyl, C1-4alkylcarbonyl, arylcarbonyl, arylC1-4alkylcarbonyl, C1-4alkyloxycarbonyl, arylC1-4alkyloxycarbonyl, R5aR5bN-carbonyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, arylC1-4alkyloxyC1-4alkyl, aryloxyC1-4alkyl, Het2;
• each R12 independently is hydroxy, C1-4alkyl, arylC1-4alkyl, C1-4alkyloxy, arylC1-4alkyloxy, oxo, spiro(C2-4alkanedioxy), spiro(diC1-4alkyloxy), —NR5aR5b;
• R13 is hydrogen, hydroxy, C1-4alkyl, C1-4alkyloxy, or arylC1-4alkyloxy;
• or
• R13a is C1-4alkyl, arylC1-4alkyl, C1-4alkyloxycarbonyl or arylC1-4alkyloxycarbonyl;
• each R13b is hydrogen or C1-4alkyl;
• or R2 is
• iv) a radical of formula:
• —CpH2p—CH(OR14)—CqH2q—R15 (b-3);
• —CH2—CH2—(O—CH2—CH2)m—OR14 (b-4);
• —CH2—CH2—(O—CH2—CH2)m—NR17aR17b (b-5);
• wherein in radical (b-3) one of the hydrogen atoms in —CpH2p— and one of the hydrogen atoms in —CH(OR14)-CqH2q—, that is not part of R14, may be replaced by a direct bond or a C1-4alkanediyl group;
• p is 1, 2 or 3;
• q is 0, 1, 2 or 3;
• each m independently is 1 to 10;
• each R14 independently is hydrogen, C1-4alkyl, aryl C1-4alkyl, aryl, C1-4alkylcarbonyl, —SO3H, —PO3H2;
• R15 is a substituent selected from the group consisting of cyano, NR16aR16b, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, 4-(C1-4alkyl)-piperazinyl, 4-(C1-4alkylcarbonyl)-piperazinyl, 4-(C1-4alkyloxycarbonyl)-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, hydroxy-carbonyl, C1-4alkylcarbonyl, N(R16aR16b)carbonyl, C1-4alkyloxycarbonyl, pyrrolidin-1-yl-carbonyl, piperidin-1-ylcarbonyl, homopiperidin-1-ylcarbonyl, piperazin-1-yl-carbonyl, 4-(C1-4alkyl)-piperazin-1-ylcarbonyl, morpholin-1-yl-carbonyl, thiomorpholin-1-yl-carbonyl, 1-oxothiomorpholin-1-ylcarbonyl and 1,1-dioxo-thiomorpholin-1-ylcarbonyl;
• or R15 may additionally be aryl substituted with a radical —COOR4;
• or a radical selected from —NR5a—C(═NR5b)—NR5cR5d, —NR5a—C(═NR5e)—R5f, —O—NR5a—C(═NR5b)—NR5cR5d, —O—NR5a—C(═NR5e)—R5f, -sulfonyl-R6, —NR7R8, —NR9R10, a radical (a-1), (a-2), (a-3), (a-4) or (a-5);
• wherein R4, R5a, R5b, R5c, R5d, R6, R7, R3, R9, R10, and the radicals (a-1),(a-2) (a-3), (a-4), (a-5) independently are as defined above;
• R16a and R16b independently from one another are hydrogen, C1-6alkyl or C1-6alkyl 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, 1,1-dioxo-thiomorpholinyl and aryl;
• R17a and R17b independently from one another are hydrogen, C1-4alkyl or arylC1-4alkyl;
• or R17a and R17b together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, piperazinyl, 4-C1-4alkyl-piperazinyl, 4-(C1-4alkylcarbonyl)-piperazinyl, 4-(C1-4alkyloxycarbonyl)-piperazinyl ring;
• each R18 independently is hydrogen, C1-4alkyl, arylC1-4alkyl, C1-4alkylcarbonyl or C1-4alkyloxycarbonyl;
• R19 is hydrogen, hydroxy, C1-4alkyl or a radical —COOR4;
• -a1=a2-a3=a4- represents a bivalent radical of formula
• —CH═CH—CH═CH— (c-1);
• —N═CH—CH═CH— (c-2);
• —CH═N—CH═CH— (c-3);
• —CH═CH—N═CH— (c-4);
• —CH═CH—CH═N— (c-5);
• wherein one, two, three or four of the hydrogen atoms in (c-1) is replaced by a radical, C1-6alkyl, C1-4alkoxy, halo, hydroxy, (R5g)(R5h)N—(C1-4alkanediyl)-O—, (R7)(R8)N—(C1-4alkanediyl)-O—, (R8)(R9)N—(C1-4alkanediyl)-O—, trifluoromethyl, cyano, a radical —COOR4, (R5a)(R5b)N-carbonyl, (R5a)(R5b)N-sulfonyl, pyrrolidinylsulfonyl, piperidinylsulfonyl, homopiperidinylsulfonyl, formyl, C1-6alkylcarbonyl, nitro, hydroxyC1-6alkyl, C1-4alkoxyC1-6alkyl, (R4OOC)—C1-6alkyl, a radical —N(R5a)(R5b), —N(R7)(R8), —N(R9)(R10), a radical
• morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo-thiomorpholinyl, (R5g)(R5h)N—(C1-4alkanediyl)-N(R5c)—, (R7)(R8)N—(C1-4alkanediyl)-N(R5c)—, (R9)(R10)N—(C1-4alkanediyl)-N(R5c)—, C1-6alkylcarbonylamino, C1-6alkyloxycarbonylamino, trifluoroacetylamino, C1-6alkylsulfonylamino, (R5a)(R5b)N—C1-4alkyl;
• aryl;
• Het1 or Het2;
• R20 is hydrogen, hydroxy, C1-4alkyl, arylC1-4alkyl, C1-4alkyloxy, arylC1-4alkyloxy, oxo, spiro(C2-4alkylenedioxy), spiro(diC1-4alkyloxy), —NR5gR5h;
• each R5g or R5h independently is hydrogen, C1-4alkyl or arylC1-4alkyl, or R5g and R5h together with the nitrogen to which they attached form a pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C1-4alkylpiperazinyl radical;
• wherein each of said pyrrolidinyl, piperidinyl, homopiperidinyl, morfolinyl, piperazinyl or 4-C1-4alkylpiperazinyl radical may optionally be substituted with hydroxy or oxo;
• or
• wherein one or more of the hydrogen atoms in (c-2), (c-3), (c-4) or (c-5) may be replaced with a radical selected from halo and C1-6alkyl;
• 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-hydroxymethanimidamidyl or Het1;
• 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, oxadiazolyl, thiadiazolyl and triazolyl moieties may optionally be substituted with C1-4alkyl;
• and
• Het2 is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, wherein any ring carbon atom of each of said 6-membered nitrogen containing aromatic rings may optionally be substituted with a substituent selected from the group consisting of C1-4alkyl.