Tricyclic Gyrase inhibitors

A compound having the structure of Formula I

• or pharmaceutically suitable salts thereof, wherein
• L is:
• a) O or S;
• or
• b) NH, CH2, CHF, CF2, SCH2, OCH2, NHCH2, CH═CH, CH2CH2, SCH2CONH, OCH2CONH, NHCH2CONH, OCH2CH═CH, or SCH2CH═CH;
• R8 is:
• a) H or an interacting substituent selected from the group consisting of H, F, Cl, Br, NH2, OH, 1-3C alkyl, amino-1-3C alkyl, aminocyclopropyl, OCH3, OCH2CH3, cyclopropyl, CH2cyclopropyl, CH2Cl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, NHNH2, NHOH, NHNHCH3, NHOCH3, NHCD3, SCH3, NHCOH, CHCl2, and CHCH2;
• or
• b) a substituent having the following structure:
• wherein R8a is H or an interacting substituent selected from the group consisting of H, methyl, ethyl, and cyclopropyl;
• wherein R8b and R8c are independently H or C1-C6 alkyl;
• wherein R8d is
• wherein Q is CH or N;
• wherein R8e is (CR8g2)n-basic amine, wherein each R8g is independently H or C1-C3 alkyl;
• wherein n is 0-2;
• wherein R8f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH2;
• alternatively wherein R8e and R8f join to form a C3-C12 hydrocarbyl ring containing 0-3 heteroatoms selected from O, N and S;
• wherein R8j and R8k are independently H or C1-C8 hydrocarbyl residue;
• c) a substituent having the following structure:
• R9 is H;
• R2 is
• a) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R2 has a CH at each position immediately adjacent the position where R2 attaches to L, if L is O or S;
• b) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R2 has a CF at each positions immediately adjacent the position where R2 attaches to L, if L is O or S;
• c) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents, wherein the 6-membered aryl or heteroaryl ring of R2 has a CH or CF independently at each position immediately adjacent the position where R2 attaches to L, if L is NH, CH2, CHF, or CF2;
• d) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents;
• wherein the 5-membered heteroaryl ring of R2 has O, S, N, NH, CH, CF, or
• CCl, independently at each of the positions immediately adjacent the position where R2 attaches to L, if L is O, S, NH, CH2, CHF, or CF2;
• e) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents;
• wherein the 6-membered or 5-membered non-aryl or non-heteroaryl ring of R2 has O, S, N, NH, CH, CF, or CH2, independently at each position immediately adjacent the position where R2 attaches to L, if L is O, S, NH, CH2, CHF, or CF2;
• f) i) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,
• ii) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents, or
• iii) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally with 0-3 noninterfering substituents,
• when L is selected from the group consisting of SCH2, OCH2, NHCH2, CH═CH, CH2CH2, SCH2CONH, OCH2CONH, NHCH2CONH, OCH2CH═CH, and SCH2CH═CH in any of f)i) to f)iii);
• alternatively wherein 2 adjacent noninterfering substituents of R2 in a)-f) form one or more fused rings with the 6-membered aryl or heteroaryl ring, the 5-membered heteroaryl ring, or the 6-membered or 5-membered non-aryl or non-heteroaryl ring;
• g) a substituent having the following structure:
• wherein R2a contains an oxygen residue derived from an R2 as in a)-f), wherein R2 has an OH group, wherein the R2 OH is replaced with an oxygen residue in R2a, and wherein the oxygen residue is linked to P;
• h)
• wherein R2b, R2c, R2d, R2f, and R2g independently are each N or CR2e wherein R2e is H or C1-C4 alkyl optionally substituted with a noninterfering substituent;
• or
• i) selected from the group consisting of
• wherein the noninterfering substituents in a)-h) of R2 are independently selected from the group consisting of OH, CO2H, CN, NH2, Br, Cl, F, SO3H, SO2NH2, SO2CH3, SOCH3, NHOH, NHOCH3, NO2, and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms optionally substituted with a substituent selected from the group consisting of OH, CN, ═O, NH2, NHOH, ═NOH, ═NNH2, ═NOCH3, Br, F, Cl, SO3H, and NO2;
• R4 is
• a) H;
• b) an optionally substituted ORa;
• wherein Ra is a 5-6 membered aryl or heteroaryl containing 0-3 O, S, or N heteroatoms optionally substituted with 0-3 noninterfering substituents;
• c) an optionally substituted secondary or tertiary amine attached to the C Ring through the secondary or tertiary amine N;
• d) an optionally substituted 5-10 membered unsaturated cyclic or heterocyclic residue containing 0-3 N, O or S heteroatoms;
• wherein the optional substituent is 0-3 noninterfering substituents;
• wherein the R4 substituent of a)-d) does not project greater than about 3 A below the plane of the A, B and C Rings toward the GyrB/ParE binding pocket floor in the bound conformation;
• and
• wherein R4 does not sterically interfere with R2 or Z when the compound is in the bound conformation;
• e) a substituent having the following structure:
• wherein R4a contains an oxygen residue derived from the R4 as in b)-d) or g), wherein the R4 has an OH group, wherein the R4 OH is replaced with an oxygen residue in R4a, and wherein the oxygen residue is linked to P;
• wherein R4′—NH is derived from the R4 as in b)-d) or g), wherein the R4 contains a primary amine and wherein the NH in the primary amine links the R4′ residue to the C═O;
• wherein R4b and R4c are independently H or C1-C6 alkyl;
• wherein R4d is
• wherein Q is CH or N;
• wherein R4e is (CR4g2)n-basic amine, wherein each R4g is independently H or C1-C3 alkyl;
• wherein n is 0-2;
• wherein R4f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH2;
• alternatively wherein R4e and R4f join to form a ring;
• wherein R4j and R4k are independently H or C1-C8 hydrocarbyl residue;
• f) a substituent having the following structure
• g) selected from the group consisting of:
• wherein the noninterfering substituents for R4 are independently selected from the group consisting of OH, CO2H, CN, NH2, Br, Cl, F, SO3H, NO2, and C1-15 hydrocarbyl residue containing 0-5 O, S, or N heteroatoms optionally substituted with OH, CN, ═O, NH2, ═NOH, ═NNH2, ═NOCH3, Br, F, Cl, SO3H, and NO2;
• X is CRX, wherein RX is H or an interacting substituent selected from the group consisting of CH3, Cl, Br, and F;
• Y is CRY, wherein RY is H or an interacting substituent selected from the group consisting of CH3, CHF2, CF3, CN, CH2CH3, Cl, Br, and F;
• Z is:
• CRZ wherein RZ is H or an interacting substituent selected from the group consisting of CH3, CN, Cl, Br, and F;
• provided that the compound of Formula I has at least one of the following moieties i)-iv):
• i) L is NH, CH2, CHF, CF2, SCH2, OCH2, NHCH2, CH═CH, CH2CH2, SCH2CONH, OCH2CONH, NHCH2CONH, OCH2CH═CH, or SCH2CH═CH;
• ii) R8 is:
• a) a substituent having the following structure:
• wherein R8a is H or an interacting substituent selected from the group consisting of H, methyl, ethyl, and cyclopropyl;
• wherein R8b and R8c are independently H or C1-C6 alkyl;
• wherein R8d is
• wherein Q is CH or N;
• wherein R8e is (CR8g2)n-basic amine, wherein each R8g is independently H or C1-C3 alkyl;
• wherein n is 0-2;
• wherein R8f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH2;
• alternatively wherein R8e and R8f join to form a C3-C12 hydrocarbyl ring containing 0-3 heteroatoms selected from O, N and S;
• wherein R8j and R8k are independently H or C1-C8 hydrocarbyl residue;
• or
• b) a substituent having the following structure:
• iii) R2 is
• a) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,
• wherein the 6-membered aryl or heteroaryl ring of R2 has a CF at each position immediately adjacent to the position where R2 attaches to L, if L is 0 or S;
• b) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,
• wherein the 6-membered aryl or heteroaryl ring of R2 has a CH or CF independently at each position immediately adjacent to the position where R2 attaches to L, if L is NH, CH2, CHF, or CF2;
• c) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents;
• wherein the 5-membered heteroaryl ring of R2 has O, S, N, NH, CH, CF, or CCl, independently at each of the positions immediately adjacent to the position where R2 attaches to L, if L is O, S, NH, CH2, CHF, or CF2;
• d) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents;
• wherein the 6-membered or 5-membered non-aryl or non-heteroaryl ring of R2 has O, S, N, NH, CH, CF, or CH2, independently at each position immediately adjacent to the position where R2 attaches to L, if L is O, S, NH, CH2, CHF, or CF2;
• e) i) a 6-membered aryl or heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally substituted with 0-3 noninterfering substituents,
• ii) a 5-membered heteroaryl ring containing 1-4 O, S, or N heteroatoms, optionally substituted with 0-2 noninterfering substituents, or
• iii) a 6-membered or 5-membered non-aryl or non-heteroaryl ring containing 0-3 O, S, or N heteroatoms, optionally with 0-3 noninterfering substituents,
• when L is selected from the group consisting of SCH2, OCH2, NHCH2, CH═CH, CH2CH2, SCH2CONH, OCH2CONH, NHCH2CONH, OCH2CH═CH, and SCH2CH═CH in any of e.i. to e.iii.;
• alternatively wherein 2 adjacent noninterfering substituents of R2 in a)-e) form one or more fused rings with the 6-membered aryl or heteroaryl ring, the 5-membered heteroaryl ring, or the 6-membered or 5-membered non-aryl or non-heteroaryl ring;
• f) a substituent having the following structure:
• wherein R2a contains an oxygen residue derived from an R2 as in a)-e), wherein R2 has an OH group, wherein the R2 OH is replaced with an oxygen residue in R2a, and wherein the oxygen residue is linked to P;
• g)
• wherein R2b, R2c, R2d, R2f and R2g independently are each N or CR2e wherein R2e is H or C1-C4 alkyl optionally substituted with a noninterfering substituent;
• or
• h) selected from the group consisting of
• wherein the noninterfering substitutents for R2 are the same as described above;
• iv) R4 is:
• a) a substituent having the following structure:
• wherein R4a contains an oxygen residue derived from R4 as in b)-d) or g), wherein the R4 has an OH group, wherein the R4 OH is replaced with an oxygen residue in R4a, and wherein the oxygen residue is linked to P;
• wherein R4′—NH is derived from R4 as in b)-d) or g), wherein the R4 contains a primary amine and wherein the NH in the primary amine links the R4′ residue to the C═O;
• wherein R4b and R4c are independently H or C1-C6 alkyl;
• wherein R4d is
• wherein Q is CH or N;
• wherein R4e is (CR4g2)n-basic amine, wherein each R4g are independently H or C1-C3 alkyl;
• wherein n is 0-2;
• wherein R4f is hydrogen or C1-C6 alkyl optionally substituted with OH or NH2;
• alternatively wherein R4e and R4f join to form a ring;
• wherein R4j and R4k are independently H or C1-C8 hydrocarbyl residue:,
• b) a substituent having the following structure
• c) selected from the group consisting of:
• wherein the noninterfering substitutents for R4 are the same as described above.