Quinolone analogs and methods related thereto

1. A compound of Formula (I),

or a pharmaceutically acceptable salt or ester thereof;

wherein indicates an optionally unsaturated bond;

each of B, X, A or V is absent if Z 1 , Z 2 , Z 3 and Z 4 , respectively, is N; and

each of B, X, A and V is independently H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , —R 3 , —W, -L-W, —W 0 , -L-N(R)—W 0 , A 2 or A 3 , when each of Z 1 , Z 2 , Z 3 and Z 4 , respectively, is C;

Z is O, S, CR 4 2 , CR 4 NR 4 , or CR 4 ;

each of Z 1 , Z 2 , Z 3 and Z 4 is independently C or N, provided any three N are non-adjacent;

Z 5 is C; or Z 5 may be N when Z is N;

Y is an optionally substituted 5-6 membered carbocyclic or heterocyclic ring;

U 1 is —C(=T)N(R)—, —C(=T)N(R)O—, or —C(=T)-, where T is O, S, or NH; or U 1 may be a bond when Z 5 is N or U 2 is H;

U 2 is H, or C3-C7 cycloalkyl, C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl group, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic; or U 2 is -L-W, -L-N(R)—W 0 , or A 2 ;

in each —NR 1 R 2 , R 1 and R 2 together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member;

R 1 is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O;

R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring;

R 3 is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring;

each R 4 is independently H, or C1-C6 alkyl; or R 4 may be —W, -L-W or -L-N(R)—W 0 ;

each R and R 0 is independently H or C1-C6 alkyl;

L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

W is an optionally substituted 4-7 membered azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member;

W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted with from 1 to 4 fluorine atoms;

provided one of V, A, X and B is a secondary amine A 2 or a tertiary amine A 3 , wherein

the secondary amine A 2 is —NH—W 0 , and

the tertiary amine A 3 is a fully saturated and optionally substituted six-membered or seven-membered azacyclic ring optionally containing an additional heteroatom selected from N, O or S as a ring member, or the tertiary amine A 3 is a partially unsaturated or aromatic optionally substituted five-membered azacyclic ring, optionally containing an additional heteroatom selected from N, O or S as a ring member;

with the proviso that when Z 1 is N, Z 2 and Z 4 are C, Z 5 is C, U 1 is —C(O)NH—, U 2 is -L-W, and L is an ethylene linker, one of V, A, and X is independently an optionally substituted aryl, heteroaryl, or 7-membered azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member, if W is pyrrolidin-1-yl, N-methyl-pyrrolidin-2-yl, piperidin-1-yl or morpholin-1-yl.

2. The compound of claim 1 , wherein Z 1 is N, and each of Z 2 , Z 3 and Z 4 is C.

3. The compound of claim 1 , wherein U 2 is -L-W, where W is an optionally substituted 5-6 membered unsaturated or aromatic azacyclic ring, optionally containing an additional heteroatom selected from N, O and S; or W is an optionally substituted 5-7 membered saturated azacyclic ring containing an additional heteroatom selected from N and S.

4. The compound of claim 1 , wherein U 2 is -L-N(R)—W 0 .

5. The compound of claim 1 , wherein Y is an optionally substituted phenyl ring.

6. A compound of Formula (II),

or a pharmaceutically acceptable salt or ester thereof;

wherein indicates an optionally unsaturated bond;

each of A and X is independently H, halo, azido, —CN, —CF 3 , —CONR 1 R 2 , —NR 1 R 2 , —SR 2 , —OR 2 , —R 3 , —W, -L-W, —W 0 , -L-N(R)—W 0 , A 2 or A 3 ;

Z is O, S, CR 4 2 , NR 4 CR 4 , CR 4 NR 4 or NR 4 ;

Y is an optionally substituted 5-6 membered carbocyclic or heterocyclic ring;

U 1 is —C(=T)N(R)—, —C(=T)N(R)O—, or —C(=T)-, where T is O, S, or NH; or U 1 may be a bond when U 2 is H;

U 2 is H, or C3-C7 cycloalkyl, C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl or C2-C10 heteroalkenyl group, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic; or U 2 is -L-W, -L-N(R)—W 0 , or A 2 ;

in each —NR 1 R 2 , R 1 and R 2 together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member;

R 1 is H or C1-C6 alkyl, optionally substituted with one or more halogens, or ═O;

R 2 is H, or C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, or C2-C10 heteroalkenyl, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-7 membered carbocyclic or heterocyclic ring;

R 3 is an optionally substituted C1-C10 alkyl, C2-C10 alkenyl, C5-C10 aryl, or C6-C12 arylalkyl, or a heteroform of one of these, each of which may be optionally substituted with one or more halogens, ═O, or an optionally substituted 3-6 membered carbocyclic or heterocyclic ring;

each R 4 is independently H, or C1-C6 alkyl; or R 4 may be —W, -L-W or -L-N(R)—W 0 ;

each R and R 0 is independently H or C1-C6 alkyl;

L is a C1-C10 alkylene, C1-C10 heteroalkylene, C2-C10 alkenylene or C2-C10 heteroalkenylene linker, each of which may be optionally substituted with one or more substituents selected from the group consisting of halogen, oxo (═O), or C1-C6 alkyl;

W is an optionally substituted 4-7 membered azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member;

W 0 is an optionally substituted 3-4 membered carbocyclic ring, or a C1-C6 alkyl group substituted with from 1 to 4 fluorine atoms;

provided X is a secondary amine A 2 or a tertiary amine A 3 , wherein

the secondary amine A 2 is —NH—W 0 , and

the tertiary amine A 3 is a fully saturated and optionally substituted six-membered or seven-membered azacyclic ring optionally containing an additional heteroatom selected from N, O or S as a ring member, or the tertiary amine A 3 is a partially unsaturated or aromatic optionally substituted five-membered azacyclic ring optionally containing an additional heteroatom selected from N, O or S as a ring member;

with the proviso that when U 1 is —C(O)NH—, U 2 is -L-W, and L is an ethylene linker, one of A and X is independently an optionally substituted aryl, heteroaryl, or 7-membered azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member, if W is pyrrolidin-1-yl, N-methyl-pyrrolidin-2-yl, piperidin-1-yl or morpholin-1-yl.

7. The compound of claim 6 , wherein at least one of A and X is a tertiary amine A 3 .

8. The compound of claim 7 , wherein A 3 is selected from the group consisting of imidazole, imidazoline, pyrroline, piperidine, piperazine, morpholine, thiomorpholine and homopiperazine.

9. The compound of claim 6 , wherein U 1 is a —C(=T)N(R)—, T is O, and U 2 is -L-W or -L-N(R)—W 0 .

10. The compound of claim 6 , which is selected from the group consisting of

or a pharmaceutically acceptable salt or ester thereof.

11. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient.

12. The compound of claim 6 , wherein X is —NR 1 R 2 , and R 1 and R 2 together with N may form an optionally substituted azacyclic ring, optionally containing an additional heteroatom selected from N, O and S as a ring member.

13. The compound of claim 12 , wherein A is H or halo.

14. The compound of claim 13 , wherein U 1 is a —C(=T)N(R)—, T is O, and R is H or C1-C6 alkyl.

15. The compound of claim 14 , wherein U 2 is -L-W, where L is a C1-C10 alkylene, and W is an optionally substituted 5-6 membered unsaturated or aromatic azacyclic ring, optionally containing an additional heteroatom selected from N, O and S; or W is an optionally substituted 5-7 membered saturated azacyclic ring containing an additional heteroatom selected from N and S.

16. The compound of claim 15 , wherein Z is S.

17. The compound of claim 16 , wherein Y is an optionally substituted phenyl ring.

18. A pharmaceutical composition comprising a compound of claim 6 , or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient.