Novobiocin analogues

1. Compounds according to the formula:

wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl or heterocycle;

wherein R 2 is hydrogen, hydroxy, or —R 8 —OR 9 , wherein R 8 is a covalent bond or alkyl, and R 9 is C-amido or acyl; or R 2 together with R 3 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R 3 is hydrogen, hydroxy, or —R 10 —O—R 11 , wherein R 10 is a covalent bond or alkyl, and R 11 is C-amido or acyl; or R 3 together with R 2 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R 4 is hydrogen, hydroxy, alkyl, carboxyl, —R 12 —O—R 13 , or —R 12 -R 14 , and wherein R 12 is a covalent bond or alkyl, and R 13 is C-amido or acyl, and R 14 is N-amido, —POR 15 R 16 , —SO 2 R 17 , or sulfonamido and wherein R 15 , R 16 , R 17 are independently alkoxy;

wherein R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

wherein R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, or aralkoxy;

wherein X 1 is —O—, —CO—, or —N—;

wherein X 2 is —O—, —N—, —CR 19 — or —CO—, wherein R 19 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 4 is —CR 20 —, wherein R 20 is hydrogen, alkyl, alkenyl, or alkynyl;

wherein X 5 is —CR 21 , wherein R 21 is hydrogen, alky, alkenyl, alkynyl, or alkoxy;

wherein X 6 , is —CR 22 wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein X 8 , is —CR 23 , wherein R 23 is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy;

wherein X 9 is alkyl, alkenyl, alkynyl, ether, secondary or tertiary amino, or sulfanyl;

wherein n is 0, 1, 2, or 3.

2. The compounds according to claim 1 according to:

wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl or heterocycle;

wherein R 2 is hydrogen or hydroxy;

wherein R 3 is hydrogen or hydroxy;

wherein R 4 is hydrogen or methyl;

wherein R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

wherein R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, or aralkoxy;

wherein X 1 is —O— or —N—;

wherein X 2 is —CR 19 — or —CO—, wherein R 19 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 4 is —CR 20 —, wherein R 20 is hydrogen, alkyl alkenyl, or alkynyl;

wherein X 5 , is —CR 2 , wherein R 21 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 6 , is —CR 22 , wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein X 8 , is —CR 23 , wherein R 23 is hydrogen, alkyl, alkenyl, or alkynyl;

wherein X 9 is alkyl, alkenyl, alkynyl, ether, or secondary or tertiary amino; and

wherein n is 0, 1, 2, or 3.

3. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl according to:

wherein R 24 and R 25 are independently hydrogen, alkyl, amino, halo, hydroxy, or alkoxy.

4. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl according to:

wherein R 24 and R 25 are alkoxy.

5. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and wherein R′ is hydrogen and R″ is aryl according to:

wherein R 24 and R 25 are independently hydrogen, alkyl or alkoxy.

6. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and wherein R′ is hydrogen and R″ is aryl selected from the group consisting of

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxybiphenyl-3-carboxamide (28);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-2′-methylbiphenyl-3-carboxamide (29);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-3′-methylbiphenyl-3-carboxamide (30);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-6-methoxy-4′-methylbiphenyl-3-carboxamide (31);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2′,6-dimethoxybiphenyl-3′-carboxamide (32);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (33);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4′,6-dimethoxybiphenyl-3′-carboxamide (34);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2′-hydroxy-6-methoxybiphenyl-3-carboxamide (35);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3 1 -hydroxy-6-methoxybiphenyl-3-carboxamide (36); and

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4′-hydroxy-6-methoxybiphenyl-3-carboxamide (37).

7. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and wherein R′ is hydrogen and R″ is aryl according to:

wherein X is ether or amino;

wherein R 24 is alkoxy;

wherein R 25 is hydrogen, hydroxy, alkoxy, or aryloxy; and

wherein R 26 is hydrogen, alkoxy, aryloxy, or amino.

8. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and wherein R′ is hydrogen and R″ is a an indole according to:

or a R″ is a pendant aryl according to:

9. The compounds according to claim 1 which are selected from the group consisting of:

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26a);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26b);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′,6-dimeth-oxybiphenyl-3-carboxamide (26c);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26d);

N-(8-benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26e);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (260;

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26g);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-3′,6-dimethoxybiphenyl-3-carboxamide (26h).

10. The compounds according to claim 1 which are selected from the group consisting of:

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26i);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-6-propoxy-2H-chromen-3-yl)-1H-indole-2-carboxamide (26j);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-6-isopropoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26k);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-5-methoxy-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26l);

N-(8-benzyl-7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26m);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-2-oxo-8-phenyl-2H-chromen-3-yl)-1H-indole-2-carboxamide (26n);

N-(7-((2S,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methoxy-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26o); and

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-ethyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (26p).

11. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocycle selected from the group consisting of pyridine, benzofuran, indole, and oxazole.

12. The compounds according to claim 1 :

wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocycle selected from the group consisting of pyridine, benzofuran, and indole; and

wherein R 2 is hydroxy; or R 2 together with R 3 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R 3 is hydroxy, or R 3 together with R 2 and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein R 4 is methyl;

wherein R 5 is methyl;

wherein R 6 is methoxy;

wherein X 1 is —O—;

wherein X 2 is —CO—;

wherein X 4 is —CR 20 —, wherein R 20 is hydrogen, alkyl, alkenyl, or alkynyl;

wherein X 5 , is —CR 21 , wherein R 21 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 6 , is —CR 22 , wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein X 8 , is —CR 23 , wherein R 23 is hydrogen, alkyl, alkenyl, alkynyl;

wherein X 9 is ether which is —O—;

wherein n is 1.

13. The compounds according to claim 1 :

wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocycle selected from the group consisting of pyridine, benzofuran, and indole;

wherein R 2 is hydroxy;

wherein R 3 is hydroxy;

wherein R 4 is methyl;

wherein R 5 is methyl;

wherein R 6 is methoxy;

wherein X 1 is —O— or —N—;

wherein X 2 is —CR 19 — or —CO—, wherein R 19 is hydrogen or alkyl;

wherein X 4 is —CR 20 —, wherein R 20 is hydrogen;

wherein X 5 , is —CR 21 , wherein R 21 is hydrogen;

wherein X 6 , is —CR 22 , wherein R 22 is hydrogen;

wherein X 8 , is —CR 23 , wherein R 23 is hydrogen or alkyl;

wherein X 9 is ether which is —O—; and

wherein n is 1.

14. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl or heterocycle according to:

wherein R 29 is hydrogen, alkoxy, or amino; and

wherein R 30 is hydrogen, alkoxy, or aryloxy.

15. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl or heterocycle according to:

wherein R 29 is hydrogen, alkoxy, or amino; and

wherein R 30 is hydrogen, alkoxy, or aryloxy.

16. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocycle according to:

wherein R 27 is hydrogen, hydroxy, alkoxy, or aryloxy; and

wherein R 28 is hydrogen, alkoxy, aryloxy, or amino.

17. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocyle according to:

wherein X 11 is a covalent bond, alkyl, alkenyl, alkynyl, or —OCH 2 —

wherein R 26 is aryl, amino, or hydroxy.

18. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl according to one of the following:

19. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is aryl selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2-phenylacetamide (22);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-phenylpropanamide (23);

Benzyl 7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-ylcarbamate (24); and

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)cinnamamide (25).

20. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is a heterocycle according to one of the following:

21. The compounds according to claim 1 wherein R 1 is an amido which is NR′COR″, and R′ is hydrogen and R″ is heterocycle and selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)picolinamide (40);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)nicotinamide (41);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)isonicotinamide (42);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzofuran-2-carboxamide (43);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (46); and

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-3-carboxamide (47).

22. The compound according to claim 1 which is:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-1H-indole-2-carboxamide (46).

23. The compounds of claim 1 wherein X 1 is —O— and X 2 is —CO—.

24. The compounds of claim 1 wherein X 1 is —CO— and X 2 is —O—.

25. The compounds of claim 1 wherein R 4 and R 5 are both hydrogen.

26. The compounds of claim 1 wherein R 4 and R 5 are independently hydrogen or methyl, and R 6 is hydrogen.

27. The compound of claim 1 which is N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)quinolin-3-yl)-4-methoxy-3-(3-methoxyphenyl)-benzamide (42b).

28. Compounds according to formula:

wherein R 26 is hydrogen, alkyl, alkoxy, aryl, amino; or heterocycle

wherein R 2 is hydrogen or hydroxy;

wherein R 3 is hydrogen or hydroxy,

wherein R 4 is hydrogen, hydroxy, or alkyl;

wherein R 5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

wherein R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, or aralkoxy;

wherein R 20 is hydrogen, alkyl, alkenyl, or alkynyl;

wherein R 21 is hydrogen, alkyl, alkenyl, alkynyl, or alkoxy;

wherein R 22 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein R 23 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or alkoxy.

29. The compounds of claim 28 , wherein R 2 is hydroxy;

wherein R 3 is hydroxy,

wherein R 4 is alkyl;

wherein R 5 is alkyl;

wherein R 6 is alkoxy;

wherein X 1 is —N—, or CR, wherein CR is hydrogen, hydroxy, alkyl, or alkoxy;

wherein R 20 is hydrogen;

wherein R 21 is hydrogen;

wherein R 22 is hydrogen; and

wherein R 23 is hydrogen.

30. Compounds of claim 28 which are selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (8);

-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)biphenyl-2-carboxamide (12);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)biphenyl-3-carboxamide (13);

2-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (18);

3-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (19); and

4-Amino-N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)benzamide (20).

31. Compounds of claim 28 which are selected from the group consisting of:

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-2-methoxybenzamide (9);

N-(7-((2R,3R,4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-3-methoxybenzamide (10); and

N-(7-((2R,3,R4S,5R)-3,4-Dihydroxy-5-methoxy-6,6-dimethyltetrahydro-2H-pyran-2-yloxy)-8-methyl-2-oxo-2H-chromen-3-yl)-4-methoxybenzamide (11).