Novel therapeutic targets for the treatment of mycobacterial infections and compounds useful therefor

A mycobacterial serine/threonine protein kinase inhibitor compound having the general formula (I):

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• wherein
• Y represents C or S;
• wherein
• R1 represents R2, —NH—CO—R16, —NH2, —N═CH—R15, —N═CH—R16, —NH-CH2—R14, —NH—CH2—R16, —NH—SO2—R14, —NH—CO—NH—R14, —NH—CS—NH—CH(CCl3)—NH—CO—R16, —NH—CH(CCl3)—NH—CO—R12, —NH—CS—NH—R12, —N═CH—R12,
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• R2 represents —COOR12, —CONR12R12, —CONR12R14, —C≡N, —COCOOR12, —COCH2Cl, —COCONHNH2,
• R3, R4, R5 represent independently of each other —R11, —R12, —R12′, —OR12, —SR12, —NO2, —CO—R12, —NO, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —COOR12, —COCN, —CONR12R12′, —NR12R12′, —SOR12, —SO2R12, —SO3R12, —CH2OR12;
• in one case R6 represents —R11, —R12, —R12′, —OR12, —SR12, —NO2, —CO—R12, —NO, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —COOR12, —COCN, —CONR12R12′, —NR12R12′, —SOR12, —SO2R12, —SO3R12, and R6 is hydrogen;
• in the other case R6 and R6′ together represent a carbonyl oxygen or a oximo residue ═N—OH or ═N—OOC—R12;
• R7, R8, R9, R10 represent independently of each other —R11, —R12, —OR12, —SR12, —NO2, —CO—R12, —COOR12, —OOCR16;
• R11 represents —F, —Cl, —Br, —I;
• R12, R12′ represent independently of each other —H, —CH3, —C(R11)3, —C2H5, —C3H7, —CH(CH3)2, —CH2—CH═CH2, —CCH3═CH2, —CH═C(CH3)2, —CH═CH—CH3, —CH═CHC2H5, —CH(CH3)C2H5, —(CH2)n—C≡C—R5, —C4H9, —C(CH3)3, -Ph, —CH2—R15;
• —C2H4OH with n being an integer from 0-2;
• R13 represents —CF2CHF2, —C5H11, —C6H11, —C6H13, —C7H15, —C8H17, —C9H19, —C10H21, —C11H23, —C12H25, —C13H27, —CH2SPh, —CH2R11, —C2H4R11, —C3H6R11, —C4H8R11, —C2H4Ph, —CH═CH—COOR12, —CH2COOR12, —C2H4COOR12, —C3H6COOR12, —CH(Ph)-SPh, —C3H5, —CH2CH(Ph)2, —C4H7, —C5H9, —C(CH3)2CH2R11, —CH2CH(CH3)2, —CH(R11)Ph, —CH2CH(CH3)CH2C(CH3)3, —CH(C2H5)—C4H9, —CH(R11)2, —CH(Ph)—C2H5, —CH2C(CH3)3,
• R14 represents
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• R15 represents
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• R16 is R12,
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• R13, R15,
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• —CH2O—R14, —CH═CH—R14, —CH2CH(R14)—CO—R12, —C2H4O—R14, —C3H6O—R14, —C2H4S—CO—R12, —CH2S—CO—R12;
• —COOR12,
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• nitrobenzyl, particularly p-nitrobenzyl;
• R17 represents —H, —CO—R12, —CO—R13, —CO—R14, —CO—NH—R12, —CO—NH—R13, —CO—NH—R14, —SO2—R14, —CO—NH—CH2—COO—R12, —CO—CH2—O—R14, —CO—CH═CH—R14,
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• or R1 and R2 together represent a heterocyclic ring system having the following formula
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• R18 represents R12,
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• R19 represents R3, R14, —SCH2—R3, —SCH2—CO—R14, —SCH2—CO—NH—R14, —SCH2—CO—NH—CH2—R12, —NH—CO—CH2—OR14, —CO—NH—N═CHR12(R14),
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• R20 represents R12, —NH—CO—R12, —N═CH—R15;
• R21 represents R15,
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• and pharmaceutically acceptable salts of these compounds.

A mycobacterial serine/threonine protein kinase inhibiting compound having the formula (II):

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• wherein:
• R1 and R2 are independently of each other —(CH2)p—NH—(CH2)n—R9, —(CH2)s—S—(CH2)mR10, —(CH2)m—O—(CH2)p—R11, —(CH2)rR3, —CH═CH—R11, —(CH2)m—CH(OH)—(CH2)p—R11, —(CH2)q—R11, —R9, —R10, —R12, —R13,
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• R3, R4, R5, R6, R7, and R8 are independently of each other —H, , —Cl, —Br, —I, —SO3H, —SO3NH2, —(CH2)S—COOR16, —(CH2)p—COOR17, —OR16, —SR16, —NR16R17, —OOCR16, —OOCR17, —NH—CO—R16, —NH—CO—R17, —CO—NH—R16, —CO—NH—R17, —NO2, —N3, —CN, —OCN, —NCO, —SCN, —NCS, —CO—R16, —CO—R17, —COCN, —CONR16R17, —SOR16, —SOR17, —SO2R16, —SO2R17, —SO3R16, —SO3R17, —OCF3;
• R9, R10, and R11 are independently of each other —CN, —NR16R17, —NHR16, —NHR17,
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• R12 l , R13, R14, and R15 are independently of each other —R3, —R4, —R5, —R6, —R16, —R17, —CH(COOR16)(COOR17), —CH(CN)(COOR16),
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• R16 and R17 are independently of each other —H, —CH3, —C2H5, —C3H7, —CH(CH3)2, —C4H9, —C5H13, —C6H13, -cyclo-C6H11, -cyclo-C5H9, -Cyclo-C4H7, -cyclo-C3H5, —(CH2)rCH(CH3)2, —CH(CH3)C2H5, —C(CH3)3, —CH═CH2, —CH2—CH═CH2, -Ph, —CH2Ph, —C2H4Ph, —CH(CN)2, —CF3, —CCl3, —CBr3, —C2F5, —(CH2)r—OH, —CH2F, —CH2Cl, —CH2Br, —CH2I, —CHF2, —CHCl2, —CHBr2, —(CH2)r—SH, —C6H4—CH3, —C6H3(CH3)2,
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• m, n, p, q, s are independently of each other integer from 0-6,
• r is an integer from 1-6,
• and the corresponding N-oxides in position 1 and/or 4 of these compounds;
• and the corresponding reduced forms of these compounds wherein the double bond in position 1 and/or 3 is hydrogenated;
• and pharmaceutically acceptable salts of these compounds.