Methods of preparing quinolone analogs

1. A method for preparing a compound having formula 1:

or a pharmaceutically acceptable salt thereof, wherein:

A, V, and Z are independently H, halo, azido, R 2 , CH 2 R 2 , SR 2 , OR 2 or NR 1 R 2 ;

W is NR 1 R 2 or OR 6 wherein R 6 is a C 1-10 alkyl;

X is S;

each R 1 is H or a C 1-6 alkyl;

each R 2 is H, or a C 1-10 alkyl or C 2-10 alkenyl each optionally substituted with a halogen, a carbocyclic ring, or a heterocyclic ring, wherein each ring is optionally substituted; or

R 1 and R 2 together with N may form an optionally substituted heterocyclic ring containing one or more N, O, or S;

R is a substituent at any position on ring B′; and is H, OR 2 , amino, alkoxy, amido, halogen, or cyano; or R is C 1-6 alkyl, C 2-6 alkenyl, or —CONHR 1 ;

B′ is an optionally substituted phenyl ring; and

n is 0-4;

comprising:

contacting a compound having formula (6A)

wherein each L and L 1 is a leaving group; and A, V, and Z are as defined in formula (1);

with a compound having formula (7) or tautomers thereof

wherein n, X, B′ and R are as defined in formula (1); and

W is OR 6 wherein R 6 is a C 1-10 alkyl; or W is NR 1 R 2 , wherein R 1 and R 2 are as defined in formula (1);

wherein said compound having formula (6A) is contacted with said compound having formula (7) or tautomers thereof in the presence of a non-nucleophilic base to produce a compound having formula (1);

and wherein each optionally substituted group is unsubstituted or is substituted with one or more halo, OR 2 , NR 1 R 2 , C 1-10 alkyl, C 2-10 alkenyl, each optionally substituted by halo, or aryl ; or a carbocyclic or a heterocyclic ring;

where R 1 and R 2 are as defined above.

2. The method of claim 1 , wherein W in formula (1) is OR 6 , and R 6 is a C 1-6 alkyl.

3. The method of claim 2 , further comprising the step of contacting said compound having formula (1) with an amine of the formula

HNR 1 —(CR 1 2 )n—NR 3 R 4   (3)

wherein R 1 and R 3 are independently H or C 1-6 alkyl;

n is 1-6; and

R 4 is H, a C 1-10 alkyl or C 2-10 alkenyl optionally substituted with a carbocyclic or heterocyclic ring; or R 3 and R 4 together with N may form an optionally substituted ring containing one or more N, O or S.

4. The method of claim 3 , wherein R 3 and R 4 together with N form an optionally substituted piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolyl, or aminothiadiazolyl ring.

5. The method of claim 2 , further comprising the step of contacting said compound having formula (1) with an amine of the formula HNR 1 R 2 , provided said amine is not NH 3 .

6. The method of claim 5 , wherein R 1 is H, and R 2 is a C 1-10 alkyl optionally substituted with a C 3-6 cycloalkyl, aryl or a 5-14 membered heterocyclic ring containing one or more N, 0 or S; or R 1 and R 2 together with N may form an optionally substituted heterocyclic ring containing one or more N, O or S.

7. The method of claim 6 , wherein R 2 is a C 1-10 alkyl substituted with a morpholinyl, thiomorpholinyl, imidazolyl, aminothiadiazolyl, pyrrolidinyl, piperazinyl, pyridinyl or piperidinyl ring; or R 1 and R 2 together with N form a piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolyl, or aminothiadiazolyl ring.

8. The method of claim 1 , wherein each R is H or halo.

9. The method of claim 1 , wherein one of A and V is H or halo.

10. The method of claim 9 , wherein said halo is fluoro or chloro.

11. The method of claim 1 , wherein each Z is H, halo, or SR 2 wherein R 2 is C 1-10 alkyl.

12. The method of claim 1 , wherein each L and L 1 is halo.

13. The method of claim 1 , comprising contacting said compound having formula (6A) and said compound having formula (7) to form a mixture, and contacting said mixture with said base.

14. The method of claim 13 , wherein said mixture is cooled to a temperature below room temperature, and contacting the base with said mixture.

15. The method of claim 13 , wherein said base is contacted with said mixture at room temperature or at a temperature above room temperature.

16. The method of claim 1 , wherein said base is an amine.

17. The method of claim 16 , wherein said amine is trialkylamine.

18. The method of claim 1 , wherein said compound having formula (6A) is contacted with said compound having formula (7) to produce a compound having formula (4)

wherein n, W, and R are as defined in formula (1) in claim 1 ;

Z is NR 1 R 2 ; and

each of V and A is independently H or halo.

19. The method of claim 1 , wherein the compound having formula (6A) is contacted with a compound of formula (7) or tautomers thereof in the presence of said non-nucleophilic base and a Lewis acid.

20. The method of claim 19 , wherein said non-nucleophilic base is triethylamine, diisopropyl ethyl amine, diazabicycloundecene, cesium carbonate, 1,8-Bis(dimethylamino)naphthalene or dimethylamino pyridine (DMAP).

21. The method of claim 19 , wherein said Lewis acid has formula ML n , wherein L is a halogen atom or an organic radical, n is 3-5, and M is a group II metal, group III elemental atom, Zr, Ti, Sn, As, Sb, V or Fe.

22. The method of claim 21 , wherein said group III elemental atom is B, or wherein said Lewis acid is MgCl 2 .