Inhibitors of bacterial type iii secretion system

A bacterial type III secretion system (T3SS) inhibitor compound of formula I(a):

• wherein:
• A is independently selected from CH or N;
• X is independently selected from hydrogen or halogen;
• Z is O, S, NH;
• or NR′, wherein R′ is alkyl;
• R4 is hydrogen or methyl;
• Y is selected from:
• a divalent straight-chain, branched, or cyclic alkyl, alkenyl or alkynyl radical of from 1 to 6 carbon atoms, which may contain one or more heteroatoms, and which may be unsubstituted or substituted with up to four substituents selected from halo, cyano, hydroxy, amino, alkyl, cycloalkyl, alkylamino, carboxyl, alkoxycarbonyl, carboxamido, acylamino, amidino, sulfonamide, aminosulfonyl, alkylsulfonyl, aryl, heteroaryl, alkoxy, alkylthio;
• aryloxy, and heteroaryloxy;
• oxygen;
• oxime;
• or NR″ where R″ is hydrogen, alkyl or cycloalkyl;
• Ar is an aryl or heteroaryl divalent radical forming a five-membered or six-membered ring which may be additionally fused with from 1 to 3 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings, which Ar radical may be unsubstituted or substituted with up to four substituents selected from halo, cyano, hydroxy, amino, alkyl, cycloalkyl, alkylamino, carboxyl, alkoxycarbonyl, carboxamido, acylamino, amidino, sulfonamido, aminosulfonyl, alkylsulfonyl, aryl, heteroaryl, alkoxy, alkylthio;
• aryloxy, and heteroaryloxy, and wherein any two substituents together may form an aromatic or non-aromatic ring structure fused with said aryl or heteroaryl radical Ar, or alternatively wherein substituents on Ar also may be optionally bonded covalently to either Y or R4, or both Y and R4, to form heterocyclic or carbocyclic ring systems, which ring systems may be aromatic, heteroaromatic, or partly aromatic, (that is, one or more rings being aromatic and one or more rings being non-aromatic (saturated)).
• W is a divalent radical bridging Ar and U selected from the group comprising, —COCH2—, —SO2—, —NHSO2—, —SO2NH—, —CO—, —CH2—, —CH(CH3)—, —NHCO—, —NHCONH— —NCH3CO—, —CONH—, —CONCH3—, —O(CO)—, —(CO)O—, —NH—, or —O—;
• U can be either a nitrogen or a carbon that is part of a non-aromatic heterocyclic ring system of between 4-7 members and containing 1-2 nitrogen atoms, 0-1 oxygen atoms and bearing 0-3 substituents (in addition to the bond between W and the ring carbon/nitrogen and the U and the ring carbon in the formula) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• and additionally W can be either a nitrogen or a saturated carbon that is linked via a chain of 1-4 carbon atoms to a basic nitrogen bearing, independently, hydrogen or aliphatic groups of less than nine carbon atoms that can be optionally substituted with groups selected from haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or aminocarbonyl groups, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• R5 is a monovalent radical selected from the group comprising, —CH2C(CH3)2COOH, —CH2COOH, —CH2COOH, —CH2CH2CH2COOH, —(CyBut)COOH, —CH2(CyPropyl)COOH, CH2(CyPropyl)COOH, —SO2Me, —SO2OH, —SO2CF3

A bacterial type III secretion system (T3SS) inhibitor compound of formula I(b):

• wherein,
• A is CH or N;
• X is independently selected from hydrogen or halogen;
• Y is —CH2—, —CH(CH3)—, or —C(CH3)2—;
• and
• Ar is an aryl or heteroaryl divalent radical forming a five-membered or six-membered ring which may be additionally fused with from 1 to 3 aryl, heteroaryl, cycloalkyl, or heterocycloalkyl rings, which Ar radical may be unsubstituted or substituted with up to four substituents selected from halo, cyano, hydroxy, amino, alkyl, cycloalkyl, alkylamino, carboxyl, alkoxycarbonyl, carboxamido, acylamino, amidino, sulfonamido, aminosulfonyl, alkylsulfonyl, aryl, heteroaryl, alkoxy, alkylthio;
• aryloxy, and heteroaryloxy, and wherein any two substituents together may form an aromatic or non-aromatic ring structure fused with said aryl or heteroaryl radical Ar, or alternatively wherein substituents on Ar also may be optionally bonded covalently to Y;
• to form heterocyclic or carbocyclic ring systems, which ring systems may be aromatic, heteroaromatic, or partly aromatic, (that is, one or more rings being aromatic and one or more rings being non-aromatic (saturated)).
• W is a divalent radical bridging Ar and U selected from the group comprising, —COCH2—, —SO2—, —NHSO2—, —SO2NH—, —CO—, —CH2—, —CH(CH3)—, —NHCO—, —NHCONH— —NCH3CO—, —CONH—, —CONCH3—, —O(CO)—, —(CO)O—, —NH—, or —O—;
• U can be either a nitrogen or a carbon that is part of a non-aromatic heterocyclic ring system of between 4-7 members and containing 1-2 nitrogen atoms, 0-1 oxygen atoms and bearing 0-3 substituents (in addition to the bond between W and the ring carbon/nitrogen and the U and the ring carbon in the formula) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• and additionally W can be either a nitrogen or a saturated carbon that is linked via a chain of 1-4 carbon atoms to a basic nitrogen bearing, independently, hydrogen or aliphatic groups of less than nine carbon atoms that can be optionally substituted with groups selected from haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or aminocarbonyl groups, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• R5 is a monovalent radical selected from the group comprising, —CH2C(CH3)2COOH, —CH2COOH, —CH2COOH, —CH2CH2CH2COOH, —(CyBut)COOH, —CH2(CyPropyl)COOH, CH2(CyPropyl)COOH, —SO2Me, —SO2OH, —SO2CF3

A bacterial type III secretion system (T3SS) inhibitor compound of Formula I(c):

• wherein:
• A is CH or N;
• at least one X is Cl and the other X is hydrogen, F, or Cl;
• W is a divalent radical bridging Ar and U selected from the group comprising, —COCH2—, —SO2—, —NHSO2—, —SO2NH—, —CO—, —CH2—, —CH(CH3)—, —NHCO—, —NHCONH— —NCH3CO—, —CONH—, —CONCH3—, —O(CO)—, —(CO)O—, —NH—, or —O—;
• U can be either a nitrogen or a carbon that is part of a non-aromatic heterocyclic ring system of between 4-7 members and containing 1-2 nitrogen atoms, 0-1 oxygen atoms and bearing 0-3 substituents (in addition to the bond between W and the ring carbon/nitrogen and the U and the ring carbon in the formula) selected from alkyl, cycloalkyl, aryl, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• and additionally W can be either a nitrogen or a saturated carbon that is linked via a chain of 1-4 carbon atoms to a basic nitrogen bearing, independently, hydrogen or aliphatic groups of less than nine carbon atoms that can be optionally substituted with groups selected from haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, sulfinyl, carboxy, alkoxycarbonyl, or aminocarbonyl groups, heteroaryl, haloalkyl, nitro, halogen, alkoxy, alkylthio, haloalkoxy, sulfonyl, or sulfinyl;
• R5 is a monovalent radical selected from the group comprising, —CH2C(CH3)2COOH, —CH2COOH, —CH2COOH, —CH2CH2CH2COOH, —(CyBut)COOH, —CH2(CyPropyl)COOH, CH2(CyPropyl)COOH, —SO2Me, —SO2OH, —SO2CF3