Spectinamides as anti-tuberculosis agents

1. A compound of Formula (I):

wherein:

R 1 and R 2 are each independently H, alkoxycarbonyl, or aralkoxycarbonyl;

R 3 is alkyl;

R 4 is H, hydroxy, alkyl, or alkoxy; and

R 5 is —C(═O)R 6 , wherein R 6 is:

(a) selected from the group consisting of —CH 2 NHC(CH 3 ) 3 , —CH(NH 2 )CH(CH 3 )CH 2 CH 3 , —CH(NH 2 )CH(CH 3 ) 2 , —CH(CH 2 C 6 H 5 )NHC(═O)CH 2 NH 2 , —CH 2 CH 2 NHC(═O)C 6 H 5 , and —CH 2 CH 2 NHC(═O)CH 2 C 6 H 5 ; or

(b) selected from the group consisting of heteroaryl, substituted heteroaryl, 2-substituted phenyl, 4-halo-substituted phenyl, —CH 2 R 7 , and —C(R 8 ) 2 ; wherein R 7 is selected from the group consisting of aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, and substituted phenyl, wherein said substituted phenyl is selected from the group consisting of fluoro-substituted phenyl, alkyl-substituted phenyl, 2-substituted phenyl, 3-mono-substituted phenyl, 2,3-di-substituted phenyl, and di-substituted phenyl wherein two phenyl carbons are together substituted with an alkylene; and each R 8 is independently aryl or substituted aryl; and

wherein said heteroaryl and said substituted heteroaryl are selected from the group consisting of pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, triazolyl, triazinyl, benzofuranyl, pyrrolyl, imidazoyl, pyrazole, thiazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, and benzothiazolyl,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 and R 2 are each H.

3. The compound of claim 1 , wherein R 1 and R 2 are each aralkoxycarbonyl selected from the group consisting of benzyloxycarbonyl and benzyloxycarbonyl substituted by one or more halo, alkoxy, and nitro groups.

4. The compound of claim 3 , wherein R 1 and R 2 are each benzyloxycarbonyl.

5. The compound of claim 1 , wherein R 3 is methyl or butyl.

6. The compound of claim 1 , wherein R 4 is H, OH, methyl, or methoxy.

7. The compound of claim 1 , wherein R 6 is 4-fluorophenyl or 2-fluorophenyl.

8. The compound of claim 1 , wherein R 6 is —C(R 8 ) 2 , wherein each R 8 is phenyl or substituted phenyl.

9. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (Ia):

wherein:

R 1 and R 2 are each independently H, alkoxycarbonyl, or aralkoxycarbonyl;

R 3 is alkyl;

R 4 is H, hydroxy, alkyl, or alkoxy; and

R 7 is selected from the group consisting of aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, and substituted phenyl, wherein said substituted phenyl is selected from the group consisting of fluoro-substituted phenyl, alkyl-substituted phenyl, 2-substituted phenyl, 3-mono-substituted phenyl, 2,3-di-substituted phenyl, and di-substituted phenyl wherein two phenyl carbons are together substituted with an alkylene; and

wherein said heteroaryl and said substituted heteroaryl are selected from the group consisting of pyridyl, triazolyl, triazinyl, pyrimidinyl, pyridazinyl, oxazolyl, furanyl, benzofuranyl, thiophenyl, pyrrolyl, imidazoyl, thiazolyl, quinolinyl, isoquinolinyl, benzoxazolyl, and benzothiazolyl,

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 , wherein R 7 is substituted phenyl selected from the group consisting of 4-fluorophenyl, 4-methylphenyl, 3-methylphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-methylenedioxyphenyl, and 2,3-difluorophenyl.

11. The compound of claim 9 , wherein the heteroaryl group of R 7 is substituted heteroaryl, wherein the heteroaryl is substituted with one or more of the group consisting of NH 2 , OH, alkylamino, arylamino, nitro, halo, alkyl, substituted alkyl, alkoxy, perhaloalkoxy, aralkyl, acyl, aryl, aryloxy, and substituted aryl.

12. The compound of claim 11 , wherein the heteroaryl group of R 7 is substituted heteroaryl, wherein the heteroaryl is substituted with one or more of the group consisting of fluoro, chloro, bromo, methoxy, methyl, nitro, trifluoromethoxy, phenylamino, phenyl, and trifluoromethyl.

13. The compound of claim 9 , wherein R 7 is aralkyl or substituted aralkyl, wherein said aralkyl or substituted aralkyl comprises a heteroaryl or substituted heteroaryl group.

14. The compound of claim 9 , wherein the heteroaryl group of R 7 comprises a nitrogen-containing heteroaryl group and the compound of Formula (Ia) has a structure of one of Formulas (Ib), (Ic), or (Id):

wherein:

R 1 and R 2 are each independently H, alkoxycarbonyl, or aralkoxycarbonyl;

R 3 is alkyl;

R 4 is H, hydroxy, alkyl, or alkoxy;

X 1 is CH or N;

X 2 and X 3 are each O, S, or NH;

R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 are independently selected from the group consisting of H, halo, hydroxy, nitro, N(R 15 ) 2 , alkyl, substituted alkyl, alkoxy, perhaloalkoxy, aralkyl, substituted aralkyl, aralkoxy, aryl, aryloxy, acyl and substituted aryl;

or wherein R 9 and R 10 together or R 11 and R 12 together are alkylene; and

each R 15 is independently selected from the group consisting of H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl;

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1 , wherein the compound is selected from the group consisting of:

3′-dihydro-3′-deoxy-4(R)-(3-pyridin-3-yl)propionylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyridin-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-4-fluorobenzoylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-furan-2-carboxylicamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(4-fluorophenyl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyridin-3-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-pyridin-2-carboxylicamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-p-tolylacetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(3-methoxy-phenyl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-[3,4-(methylene dioxy)phenyl]acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-m-tolylacetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyridin-4-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyrimidin-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(thiazol-4-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(2-aminothiazol-4-yl)acetylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-(5-fluoropyridin-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(2,3-difluorophenyl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(2-methoxyphenyl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyridazin-3-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(pyrazine-2-yl)carboxylicamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(benzooxazol-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(1H-imidazol-4-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-[3(R)-amino-3-(4-fluorophenyl)]propanoylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(thiazol-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(5-nitropyridin-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(benzothiazol-2-yl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(2-fluorobenzene-1-yl)carboxylicamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(2,2-diphenyl)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(5-bromopyridin-2-yl)acetylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-(2-phenylthiazol-4-yl)acetylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-(pyridin-2-yl)propanoylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(5-phenylpyridin-2-yl)acetylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-(2-(phenylamino)thiazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(5-(4-chlorophenyl)pyridin-2-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(quinoline-8-yl)carbonylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-2-(1-benzyl-1H-1,2,3-triazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(2-((4-fluorophenyl)amino)thiazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(2-((3-fluorophenyl)amino)thiazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(2-((4-(trifluoromethoxy)phenyl)amino)thiazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(2-((4-(trifluoromethyl)phenyl)amino)thiazol-4-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(5-(4-fluorophenyl)pyridin-2-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(5-(3-methoxyphenyl)pyridin-2-yl)acetylamino spectinomycin;

3′-Dihydro-3′-deoxy-4(R)-(4-chloropyridin-2-yl)acetylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-(tert-butylamino)acetylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(3-methyl)butanoylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-[(2S,3S)-2-amino-3-methyl]pentanoylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-[2(S)-amino-3-methyl]butanoylamino spectino-mycin;

3′-dihydro-3′-deoxy-4(R)-[2(S)-(2-aminoacetamido)-3-phenyl]propanoyl-amino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-3-benzamido propanoylamino spectinomycin; and

3′-dihydro-3′-deoxy-4(R)-3-(2-phenylacetamido)propanoylamino spectinomycin;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound is a pharmaceutically acceptable salt.

17. The compound of claim 16 , wherein the compound is a hydrochloride or hydrobromide salt.

18. A pharmaceutical formulation comprising:

(a) a compound of claim 1 ; and

(b) a pharmaceutically acceptable carrier.

19. The pharmaceutical formulation of claim 18 , wherein the pharmaceutically acceptable carrier is pharmaceutically acceptable in humans.

20. The pharmaceutical formulation of claim 18 , further comprising an additional antibacterial compound.

21. The pharmaceutical formulation of claim 20 , wherein the additional antibacterial compound is an anti-tuberculosis compound.

22. The pharmaceutical formulation of claim 20 , wherein the additional antibacterial compound is selected from the group consisting of isoniazid, ethambutol, rifampicin, kanamycin, capreomycin, linezolid, and streptomycin.

23. The pharmaceutical formulation of claim 18 , wherein the formulation is for oral or topical administration.

24. A compound selected from the group consisting of:

3′-dihydro-3′-deoxy-4(R)-cyclopropylmethylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-furan-2-yl-methylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(3-methoxy)benzylamino spectinomycin;

3′-dihydro-3′-deoxy-4(R)-(4-fluoro)benzylamino spectinomycin; and

3′-dihydro-3′-deoxy-4(R)-2-phenylethylamino spectinomycin;

or a pharmaceutically acceptable salt thereof.