Process for preparing five-membered heterocyclyl tetracycline compounds and methods of use thereof

1. A process for preparing a compound of formula (I)

wherein:

A represents a pyrrole ring optionally substituted by one or more R groups, wherein R is selected from:

halogen, —NRaRb, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, aryl, heteroaryl, hydroxy, —OC 1-6 alkyl, formyl, cyano, trifluoromethyl, —CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, or a C 1-6 alkyl group substituted by one or more groups selected from: hydroxy, —NRaRb, —OC 1-6 alkyl,

—SRa, —CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, wherein:

Ra and Rb independently represent hydrogen or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (II):

with a compound of Formula (III):

under dehydrating conditions.

2. The process of claim 1 , wherein said dehydrating conditions comprise reacting the compound of Formula (II) with the compound of Formula (III) in the presence of sulphuric acid in methanol.

3. The process of claim 1 , wherein R is formyl.

4. The process of claim 1 , wherein R is cyano.

5. The process of claim 1 , wherein R is CHNORa.

6. The process of claim 1 , wherein Ra is hydrogen.

7. The process of claim 1 , wherein Ra is methyl.

8. The process of claim 1 , wherein said compound of formula (I) is [4S-(4aα,5aαα,12aα)]-4-(dimethylamino)-7-(1H-pyrrol-1-yl-3-carboxaldehyde)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

9. The process of claim 1 , wherein said compound of formula (I) is [4S-(4aα,5aαα,12aα)]-4-(dimethylamino)-7-(3-((hydroxymino)-methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

10. The process of claim 1 , wherein said compound of formula (I) is [4S-(4aα,5aαα,12aα)]-7-(3-cyanopyrrol-1-yl)-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

11. The process of claim 1 , wherein said compound of formula (I) is [4S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-(3-((methyloxymino)methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

12. A process for preparing a compound of formula (I)

wherein:

A represents a pyrrole ring optionally substituted by one or more R groups, wherein R is CHNORa, further wherein:

Ra is hydrogen or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (IV):

with NH 2 ORa in water.

13. The process of claim 12 , wherein said compound of formula (I) is [4S-(4aα,5aαα,12aα)]-4-(dimethylamino)-7-(3-((hydroxymino)-methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3, 10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

14. The process of claim 12 , wherein said compound of formula (I) is [4S-(4aα,5aα,12aα)]-4-(dimethylamino)-7-(3-((methyloxymino)methyl)-1H-pyrrol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

15. A process for preparing a compound of formula (I)

wherein:

A represents a pyrrole ring optionally substituted by one or more R groups, wherein R is CH 2 NRaRb, further wherein:

Ra and Rb independently represent hydrogen or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (IV):

with NHRaRb under dehydrating conditions; and

subjecting the product to a reducing agent.

16. The process of claim 15 , wherein said process comprises reacting a compound of Formula (IV) with NHRaRb in the presence of acetic acid, methanol and water.

17. The process of claim 15 , wherein said process comprises subjecting the product to sodium cyanoborohydride.

18. The process of claim 15 , wherein said process comprises reacting a compound of Formula (IV) with NHRaRb in the presence of acetic acid, methanol and water; and subjecting the product to sodium cyanoborohydride.

19. A process for preparing a compound of formula (I)

wherein:

A represents a pyrrole ring optionally substituted by one or more R groups, wherein R is cyano, further wherein:

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (V):

with acetic anhydride and formic acid.

20. A process for preparing a compound of formula (I)

wherein:

A represents a tetrazole ring optionally substituted by one or more R groups, wherein R is selected from:

halogen, —NRaRb, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, aryl, heteroaryl, hydroxy, —OC 1-6 alkyl, formyl, cyano, trifluoromethyl, —CHNORa, —CO 2 Ra, —CONRaRb,

—NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, or a C 1-6 alkyl group substituted by one or more groups selected from: hydroxy, —NRaRb, —OC 1-6 alkyl,

—SRa, —CHNORa, —CO 2 Ra, —CONRaRb, —NRaC(O)Ra, —NRaC(O)ORa, —OC(O)NRaRb, —OC(O)Ra, —OC(O)ORa, wherein:

Ra and Rb independently represent hydrogen or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (II):

with isobutyl nitrite in methanolic hydrochloric acid followed by treatment with a mixture containing sodium azide and triethyl orthoformate in acetic acid.

21. The process of claim 20 , wherein said compound of formula (I) is [4(R,S)-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-(1H-Tetrazol-1-yl)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

22. A process for preparing a compound of formula (I)

wherein:

A represents a 1,2,3-triazole ring optionally substituted by one or more R groups, wherein R is CO 2 Ra, further wherein:

Ra represents hydrogen or C 1-6 alkyl;

R 1 represents hydrogen, C 1-6 alkyl or together R 1 and R 3 represent a CH 2 moiety;

R 2 represents hydrogen, —OC 1-6 alkyl, —O(O)C 1-6 alkyl or hydroxy;

R 3 represents hydrogen, hydroxy or together R 3 and R 1 represent a CH 2 moiety, or a pharmaceutically acceptable salt thereof;

said process comprises reacting a compound of Formula (II):

with isobutyl nitrite in methanolic hydrochloric acid followed by treatment with sodium azide to afford the corresponding 7-azido intermediate; and

subjecting the 7-azido intermediate to a reaction with alkylpropiolate in dioxane under reflux conditions.

23. The process of claim 22 , wherein said compound of formula (I) is [4-S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-[(4-ethoxycarbonyl)-1H-triazol-1-yl]-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.

24. The process of claim 22 , wherein said compound of formula (I) is [4-S-(4aα,5aα,12aα)]-4-(Dimethylamino)-7-[(5-ethoxycarbonyl)-1H-triazol-1-yl 1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide.