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Title:
AZITHROMYCIN DERIVATIVES CONTAINING A PHOSPHONIUM ION AS ANTIBACTERIAL AGENTS
Document Type and Number:
WIPO Patent Application WO/2018/193126
Kind Code:
A1
Abstract:
The invention relates to compounds that can be used to treat bacterial infections. The compounds comprise azithromycin derivatives having a phosphonium ion tethered to the azithromycin macrocycle. The invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds. The compounds comprise an ion of formula (I) or a pharmaceutically acceptable salt thereof: (formula I)

Inventors:
SPAREY TIM (GB)
RATCLIFFE ANDREW (GB)
STEVENSON BRETT (GB)
LAGASSE FRANZ (GB)
COCHRANE EDWARD (GB)
FROIDBISE ALEXANDRE (DE)
LASSALLE GILBERT (DE)
Application Number:
PCT/EP2018/060247
Publication Date:
October 25, 2018
Filing Date:
April 20, 2018
Export Citation:
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Assignee:
NOVINTUM BIOTECHNOLOGY GMBH (CH)
International Classes:
C07H17/00; A61K31/7052; A61P31/04
Domestic Patent References:
WO2004101590A12004-11-25
Foreign References:
EP0941998A21999-09-15
Other References:
YAN XUE ET AL: "Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 16, no. 2, 6 February 2015 (2015-02-06), pages 3626 - 3655, XP055493340, DOI: 10.3390/ijms16023626
KANAZAWA A ET AL: "Synthesis and antimicrobial activity of dimethyl- and trimethyl-substituted phosphonium salts with alkyl chains of various lengths", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 38, no. 5, 1 May 1994 (1994-05-01), pages 945 - 952, XP002554246, ISSN: 0066-4804
Attorney, Agent or Firm:
HGF LIMITED (Leeds West Yorkshire LS11 9DX, GB)
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Claims:
CLAIMS

1 . A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

-L1- is independently selected from: -0-, -NR6-, -OC(O)-, -NR5C(0)-, NR5S(0)2-, - OC(0)NR5-, -NR5C(0)0- and NR5C(0)NR5;

-L3- is independently at each occurrence either absent or selected from: -0-, -S-, -NR6-, - C(0)-, -0C(0)-, -C(0)0-, -S(0)2-, -S(0)-, -NR5C(0)-, -C(0)NR5, -NR5S(0)2-, -S(0)2NR5-, - OC(0)NR5-, -NR5C(0)0-, NR5C(0)NR5, -CR7=CR7- and -C≡C-;

-L2- and -L4- are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R8 groups; provided that any -L2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-; n is an integer selected from 0, 1 , 2, 3, 4 and 5; wherein L1, L2, L3, L4, and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;

R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1 d groups; and wherein said C3 to Cs-cycloalkyl, d-Cs-alkyl and 4- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1 e groups; wherein R1 a and R1 b are optionally connected to each other via a bond or a group selected from -0-, N R6a, and Ci-C3-alkylene;

R2a, R2b and R2c are each independently selected from H and Ci-C6-alkyl;

R3a is independently at each occurrence selected from H , Ci-C6-alkyl or C(0)-Ci-C6-alkyl;

R3b is independently at each occurrence selected from H or C(0)-Ci-C6-alkyl;

R4a and R4b are each independently selected from: H , Ci-C6-alkyl or C(0)-Ci-C6-alkyl; or R4a and R4b together from C(O);

R5 and R6a are each independently at each occurrence selected from H and Ci-C6-alkyl;

R6 and R1 1 are each independently at each occurrence selected from: H , Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl;

R7 is independently at each occurrence selected from H , Ci-C4-alkyl and halo;

R8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, OR9, S R10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)2R10 and S(O)2N R10R10;

R9 is independently at each occurrence selected from: H , Ci-C6-alkyl and Ci-C6-haloalkyl;

R10 is independently at each occurrence selected from: H and Ci-C6-alkyl;

R1 d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°, S(O)2N R10R10, OC(O)N R10R10 and N R10C(O)OR10;

R1 e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)Ri S(0)2R10, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci- Ce-haloalkyl, ORa, NRaRb, SRa, C(0)ORa, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, S(0)2Ra, S(0)Ra and S(0)2NRaRa; wherein Ra is independently at each occurrence selected from: H and Ci-C6-alkyl; and Rb is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl.

2. A compound of claim 1 , wherein L1 is -NR5C(0)0-.

3. A compound of claim 1 or claim 2, wherein L3 is at each occurrence absent.

4. A compound of any one of claims 1 to 3, wherein L1 , L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.

5. A compound of any one of claims 1 to 4, wherein R4a is H and R4b is H.

6. A compound of any one of claims 1 to 4, wherein R4a and R4b together form C(O).

7. A compound of any one of claims 1 to 6, wherein R2a is methyl and R2c is methyl.

8. A compound of any one of claims 1 to 7, wherein R2b is methyl.

9. A compound of any one of claims 1 to 8, wherein R3a is H and R3b is H.

10. A compound of any one of claims 1 to 8, wherein R3a is H and R3b is C(0)CH3.

1 1 . A compound of any one of claims 1 to 10, wherein R1a, R1 b and R1c are each substituted phenyl.

12. A compound of any one of claims 1 to 10, wherein R1a, R1 b and R1c are each unsubstituted phenyl.

13. A compound of any one of claims 1 to 10, wherein R1a, R1 b and R1c are each C3 to Cs-cycloalkyl.

14. ,A compound of any one of claims 1 to 10, wherein R1a, R1 b and R1c are each benzyl.

15. A compound of any one of claims 1 to 10, wherein R1a and R1 b are each unsubstituted phenyl and R1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci- Cs-alkyl and 4- to 8-membered heterocycloalkyi.

16. A compound of any one of claims 1 to 10, wherein R1a and R1b are each C3 to Cs cycloalkyl and R1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6 , 9- or 10- membered heteroaryl, d-Cs-alkyl and 4- to 8-membered heterocycloalkyi

17. A compound of any one of claims 1 to 10, wherein at least one of R1a, R1b and R1c is Ci-C6-alkyl.

18. A compound of claim 17, wherein any of R1a, R1b and R1c that are not Ci-C6-alkyl are phenyl.

19. A compound of claim 1 , wherein the ion of formula (I) is selected from:

102

105

108

109

110

112

113

114

20. A compound of any one of claims 1 to 19, wherein the compound is for medical use.

21 . A compound of any one of claims 1 to 19, wherein the compound is for use in the treatment of a bacterial or mycobacterial infection.

22. A compound for use of claim 21 , wherein the bacterial infection is caused by a Gram- negative bacteria.

23. A compound for use of claim 21 , wherein the bacterial infection is caused by a Gram- positive bacteria.

24. A compound for use of any one of claims 21 to 23 , wherein the infection is caused by a strain of bacteria or mycobacteria that is resistant to at least one antibiotic.

25. A method for the treatment of a bacterial or mycobacterial infection, wherein the method comprises the administration of a therapeutically effective amount of a compound of any one of claims 1 to 19.

26. A method of claim 25, wherein the bacterial infection is caused by a Gram-negative bacteria.

27. A method of claim 25, wherein the bacterial infection is caused by a Gram-positive bacteria.

28. A method of any one of claims 25 to 27, wherein the infection is caused by a strain of bacteria or mycobacteria that is resistant to at least one antibiotic.

29. A pharmaceutical composition, wherein the composition comprises a compound of any one of claims 1 to 19 and one or more pharmaceutically acceptable excipients.

Description:
AZITHROMYCIN DERIVATIVES CONTAINING A PHOSPHONIUM ION AS

ANTIBACTERIAL AGENTS

[0001] This invention relates to ions and compounds comprising said ions that can be used to treat bacterial infections, and particularly infections caused by Gram-negative bacterial strains that are resistant to other antibiotics. The ions are azithromycin derivatives having a phosphonium ion tethered to the azithromycin macrocycle. The invention also relates to methods of using said ions and compounds and to pharmaceutical formulations comprising said ions and compounds.

BACKGROUND

[0002] Until comparatively recently, bacterial infections were one of the most common causes of death, disfigurement and disablement. During the 19 th century a series of antibiotic drug classes were developed, meaning that the successful treatment of bacterial infections has become routine. However, microbial resistance to antibiotics is becoming a significant problem and many consider that this will become one of the most significant challenges to human health. Indeed, in some bacterial pathogens, multidrug resistance has already become common.

[0003] While resistant strains of Staphylococcus aureus (e.g. Methicillin Resistant Staphylococcus Aureus (MRSA)) have become most well-known, S. Aureus is a Gram- positive bacteria and infections caused by Gram-positive bacteria can be treated effectively by a broader range of antibiotics than can be used to treat infections caused by Gram-negative bacteria. Gram-negative bacteria have an outer membrane that Gram-positive bacteria lack and this outer membrane provides protection against a range of antibiotics. Thus, in some respects, there is a greater medical need for the development of treatments for multidrug resistant Gram-negative bacteria, for which there is already a smaller antibiotic arsenal available. In Feb 2017, the World Health Organisation (WHO) issued a prioritised list of bacterial pathogens to assist member states in focusing research and development in this area to the areas of greatest need. All of the bacteria that the WHO classed as a critical priority were Gram-negative: carbapenem resistant Acinetobacter Baumannii, carbapenem resistant Pseudomonas aeruginosa and carbapenem resistant and 3 rd generation cephalosporin resistant Enterobacteriaceae (a class of bacteria that includes Klebsiella pneumonia and Escherichia coli). A number of Gram-negative bacteria that were identified as high priority included clarithromycin-resistant Helicobacter pylori, fluoroquinolone-resistant Campylobacter, fluoroquinolone-resistant Salmonella spp., and 3 rd generation cephalosporin- resistant and fluoroquinolone-resistant Neisseria gonorrhoeae. [0004] Azithromycin is a broad-spectrum antibiotic. It is widely used for treating bacterial infections caused by both Gram-negative and Gram-positive bacteria.

Azithromycin [0005] It is an aim of certain embodiments of this invention to provide antibacterial compounds, and particularly compounds that are active against Gram-negative bacteria. It is an aim of certain embodiments of this invention to provide compounds that are active against bacterial strains, and particularly Gram-negative bacterial strains, that are resistant to one or more other antibiotics. BRIEF SUMMARY OF THE DISCLOSURE

In a first aspect of the present invention there is provided a compound comprising an ion of formula I) or a pharmaceutically acceptable salt thereof:

wherein -L 1 - is independently selected from: -0-, -NR 6 -, -0C(0)-, -NR 5 C(0)-, NR 5 S(0) 2 -, -OC(0)NR 5 -, -NR 5 C(0)0- and NR 5 C(0)NR 5 ;

-L 3 - is independently at each occurrence either absent or selected from: -0-, -S-, -NR 6 -, - C(0)-, -OC(O)-, -C(0)0-, -S(0) 2 -, -S(0)-, -NR 5 C(0)-, -C(0)NR 5 , -NR 5 S(0) 2 -, -S(0) 2 NR 5 -, - OC(0)NR 5 -, -NR 5 C(0)0-, NR 5 C(0)NR 5 , -CR 7 =CR 7 - and -C≡C-;

-L 2 - and -L 4 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 8 groups; provided that any -L 2 - or -L 4 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C 2 -C 4 -alkylene-;

n is an integer selected from 0, 1 , 2, 3, 4 and 5;

wherein L 1 , L 2 , L 3 , L 4 , and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;

R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Ce-alkyI and 4- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 1e groups; wherein R 1a and R 1b are optionally connected to each other via a bond or a group selected from -0-, NR 6a , and Ci- Cs-alkylene;

R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl;

R 3a is independently at each occurrence selected from H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;

R 3b is independently at each occurrence selected from H or C(0)-Ci-C6-alkyl;

R 4a and R 4b are each independently selected from: H, Ci-C 6 -alkyl or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b together from C(O);

R 5 and R 6a are each independently at each occurrence selected from H and Ci-C6-alkyl;

R 6 and R 11 are each independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0) 2 -Ci-C 6 -alkyl;

R 7 is independently at each occurrence selected from H, Ci-C 4 -alkyl and halo;

R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0) 2 R 10 and S(O) 2 NR 10 R 10 ;

R 9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl; R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl;

R 1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0)R 10 , S(0) 2 R 1 °, S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;

R 1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0)R i S(0) 2 R 1 °, S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;

and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6-alkenyl, C1-C6- haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR a , S(0) 2 R a , S(0)R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C6-alkyl; and R b is independently at each occurrence selected from: H, C1-C6- alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl. [0006] A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:

wherein -L 1 - is independently selected from: -0-, -N R 6 -, -0C(0)-, -N R 5 C(0)-, N R 5 S(0) 2 -, -OC(0)N R 5 -, -N R 5 C(0)0- and N R 5 C(0)N R 5 ;

-L 3 - is independently at each occurrence either absent or selected from: -0-, -S-, -N R 6 -, - C(0)-, -OC(O)-, -C(0)0-, -S(0) 2 -, -S(0)-, -N R 5 C(0)-, -C(0)N R 5 , -N R 5 S(0) 2 -, -S(0) 2 N R 5 -, - OC(0)N R 5 -, -N R 5 C(0)0-, N R 5 C(0)N R 5 , -CR 7 =CR 7 - and -C≡C-;

-L 2 - and -L 4 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 8 groups; provided that any -L 2 - or -L 4 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C 2 -C 4 -alkylene-; n is an integer selected from 0, 1 , 2, 3, 4 and 5; wherein L 1 , L 2 , L 3 , L 4 , and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;

R 1 a , R 1 b and R 1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1 d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Ce-alkyI and 5- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 1 e groups;

R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl; R 3a is independently at each occurrence selected from H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;

R 3b is independently at each occurrence selected from H or C(0)-Ci-C6-alkyl;

R 4a and R 4b are each independently selected from: H, Ci-C 6 -alkyl or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b together from C(O);

R 5 is independently at each occurrence selected from H and Ci-C6-alkyl; R 6 and R 1 1 are each independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0) 2 -Ci-C 6 -alkyl;

R 7 is independently at each occurrence selected from H , Ci-C 4 -alkyl and halo; R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0) 2 R 10 and S(O) 2 NR 10 R 10 ;

R 9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl; R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl;

R 1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0)R 10 ' S(0) 2 R 1 °, S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;

R 1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0)R i S(0) 2 R 10 , S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6-alkenyl, C1-C6- haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR a , S(0) 2 R a , S(0)R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C6-alkyl; and R b is independently at each occurrence selected from: H, C1-C6- alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl.

[0007] For the absence of doubt, where n is greater than 1 , each -L 3 -L 4 - unit is selected independently of the other each -L 3 -L 4 - unit or -L 3 -L 4 - units. Thus, each -L 3 -L 4 - unit may be the same or they may be different.

[0008] For the absence of doubt the atom length of the linkers formed by L 1 , L 2 , L 3 and L 4 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the carbon atom via which the linker is attached to the azithromycin portion of the molecules. The length does not include any substituents or branching that might be present on the chain.

[0009] For the absence of doubt where a bivalent group (e.g. L 1 , L 2 , L 3 , L 4 or a combination thereof) is represented in text, the left-hand portion of the linker group is attached, either directly or indirectly, to the carbon atom via which the linker is attached to the azithromycin macrocyclic portion of the ion and the right hand portion of the linker group is attached, either directly or indirectly, to the phosphorous atom of the phosphonium.

[0010] In embodiments the ion of formula (I) is an ion of formula (la):

[0011] In embodiments the ion of formula (I) is an ion of formula (lb)

[0012] In embodiments the ion of formula (I) is an ion of formula (II):

L 5 is a Ci-Ci5-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 5 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 5 may be unsubstituted. [0013] In embodiments the ion of formula (I) is an ion of formula

wherein L 6 is a Ci-Cis-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 6 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 6 may be unsubstituted. [0014] In embodiments the ion of formula (I) is an ion of formula (IV):

wherein L 7 is a Ci-Cis-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 7 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 7 may be unsubstituted. [0015] In embodiments the ion of formula (I) is an ion of formula (V):

wherein L 8 is a Ci-Cis-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 8 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 8 may be unsubstituted. [0016] In embodiments the ion of formula (I) is an ion of formula (VI):

wherein L 9 is a Ci-Cis-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 9 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 9 may be unsubstituted. [0017] The following statements apply to compounds of any of formulae (I) to (VI). These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described in one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this invention in this specification.

[0018] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, 5- or 6- membered heteroaryl and C3 to Cs-cycloalkyl, wherein said phenyl, biphenyl and 5- or 6- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1d groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R 1e groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0019] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with from 1 to 5 independently selected R 1d groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R 1e groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0020] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 1d groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R 1e groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0021] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1d groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0022] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, optionally substituted with from 1 to 5 independently selected R 1d groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0023] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 independently selected R 1d groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0024] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 R 1d groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.

[0025] In embodiments, R 1a , R 1b and R 1c are each independently selected from C3 to Cs cycloalkyi, Ci-Cs-alkyI and 4- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyI and 4- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 1e groups.

[0026] In embodiments, R 1a , R 1b and R 1c are each independently selected from C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 1e groups.

[0027] In embodiments R 1a , R 1b and R 1c are different or the same.

[0028] In embodiments, R 1e is independently at each occurrence selected from Ci-C6-alkyl, halo, OR 9 , NR 10 R 11 and S(0) 2 OR 1 °.

[0029] In embodiments, R 1e is independently at each occurrence selected from OCH3, OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.

[0030] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 1d groups, wherein R 1d is independently at each occurrence selected from Ci-C 6 -alkyl, halo, OR 9 , NR 10 R 11 and S(0) 2 OR 10 . [0031] In embodiments, R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 1d groups, wherein R 1d is independently at each occurrence selected from OCH 3 , OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.

[0032] In embodiments, R 1a is C 3 to Cs-cycloalkyI, R 1b is C 3 to Cs-cycloalkyI and R 1c is C 3 to Cs-cycloalkyI .

[0033] In embodiments, R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C 3 to Cs-cycloalkyI, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi. [0034] In embodiments, R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C 3 to Cs-cycloalkyI, Ci-Cs-alkyI and 5- to 8-membered heterocycloalkyi.

[0035] In embodiments, R 1a and R 1b are each unsubstituted phenyl and R 1c is substituted phenyl.

[0036] In embodiments, R 1a and R 1b are each unsubstituted phenyl and R 1c is pyridyl.

[0037] In embodiments, R 1a and R 1b are each C 3 to Cs-cycloalkyI and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi.

[0038] In embodiments, R 1a and R 1b are each C 3 to Cs-cycloalkyI and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyI and 5- to 8-membered heterocycloalkyi.

[0039] In embodiments, R 1a and R 1b are each cyclohexyl and R 1c is substituted biphenyl.

[0040] In embodiments, R 1a , R 1b and R 1c are each substituted phenyl. It may be that R 1a , R 1b and R 1c are each fluorophenyl, e.g. para-fluorophenyl. It may be that R 1a , R 1b and R 1c are each chlorophenyl, e.g. para-chlorophenyl. It may be that R 1a , R 1b and R 1c are each methoxyphenyl, e.g. para-methoxyphenyl.

[0041] In embodiments, R 1a , R 1b and R 1c are each C 3 to Cs-cycloalkyI . In embodiments, R 1a , R 1b and R 1c are each cyclohexyl.

[0042] In embodiments, R 1a R 1b and R 1c are each benzyl. [0043] In embodiments, R 1a R 1b and R 1c are each unsubstituted phenyl. [0044] In embodiments, at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi. In embodiments, at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi group comprises at least one nitrogen atom in the ring. In embodiments, at least one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not heteroaryl or heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.

[0045] In embodiments, at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi. In embodiments, at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi group comprises at least one nitrogen atom in the ring. In embodiments, at least one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not heteroaryl or heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.

[0046] In embodiments, at least one of R 1a , R 1b and R 1c is Ci-C 6 -alkyl (e.g. methyl). It may be that a single one of R 1a , R 1b and R 1c is Ci-C6-alkyl (e.g. methyl). It may be that two or more of R 1a , R 1b and R 1c is Ci-C 6 -alkyl (e.g. methyl). It may be that each of R 1a , R 1b and R 1c is Ci- C6-alkyl (e.g. methyl). In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not Ci-C6-alkyl are phenyl, e.g. unsubstituted phenyl.

[0047] It may be that R 1a and R 1b are connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene. It may be that R 1a and R 1b are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are connected to each other via a bond. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond. [0048] It may be that R 1a and R 1b are not connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene.

[0049]

In embodiments, - + PR 1a R 1b R 1c is selected from - + P(Ph) 3 ,

[0050] n embodiments, R 2a is C1-C6 alkyl.

[0051] n embodiments R a is methyl.

[0052] n embodiments R 2b is Ci-C 6 alkyl.

[0053] n embodiments R is methyl.

[0054] n embodiments R 2a is Ci-C 6 alkyl and R 2b is Ci-C 6 alkyl

[0055] n embodiments R a is methyl and R is methyl

[0056] n embodiments R 2c is Ci-C 6 alkyl.

[0057] n embodiments R c is methyl.

[0058] n embodiments R a , R and R c are each methyl.

[0059] n embodiments R 3a is H.

[0060] n embodiments R 3 is H.

[0061] n embodiments R 3b is C(0)CH 3 .

[0062] n embodiments R 3a is H and R 3b is C(0)CH 3 .

[0063] n embodiments R 3a is H and R 3b is H.

[0064] n embodiments R 4a is H.

[0065] n embodiments R 4b is H.

[0066] n embodiments R 4a is H and R 4b is H.

[0067] n embodiments and R 4b together form C(O).

[0068] n embodiments R 3b is H and R 4a and R 4b together form C(O).

[0069] n embodiments R 2a , R 2b and R 2c are each methyl and R 3a is H.

[0070] n embodiments R 2a , R 2b and R 2c are each methyl, R 3a is H and R 3b is H or C(0)CH 3

In embodiments, R 2a , R 2b and R 2c are each methyl, R 3a is H and R 3b is H. [0071] In embodiments, R 2a , R 2b and R 2c are each methyl and R 4a and R 4b are H or together form C(O).

[0072] In embodiments, R 2a , R 2b and R 2c are each methyl, R 3a is H, R 3b is H or C(0)CH 3 and R 4a and R 4b are H or together form C(O). In embodiments, R 2a , R 2b and R 2c are each methyl, R 3a is H, R 3b is H and R 4a and R 4b are H or together form C(O).

[0073] In embodiments, L 1 is selected from -O-C(O)-, -NR 5 C(0)-, -NR 5 S(0) 2 - and - OC(0)NR 5 -. In embodiments, L 1 is-OC(0)NR 5 -, e.g. -OC(0)NH-. In embodiments, L 1 is - NR 5 C(0)- e.g. -NHC(O)-. In embodiments, L 1 is -NR 5 S(0) 2 - e.g. -NHS(0) 2 -.

[0074] In certain embodiments, L 3 is at each occurrence absent. Thus, the group -L 2 -(L 3 - L 4 ) n - may form an alkylene linker group.

[0075] In embodiments, L 3 is at each occurrence -0-.

[0076] In certain embodiments, L 3 is at each occurrence -O- and -L 4 - is at each occurrence -C2-C4-alkylene-. Thus, the group -(L 3 -L 4 ) n - may form an ether or polyether linker group. -L 4 - may at each occurrence represent -CH2CH2- or-Ch Ch CI- -. Thus, the group -(L 3 -L 4 ) n - may form an ethylene glycol, polyethyleneglycol, propyleneglycol or polypropylene glycol linker group.

[0077] In certain embodiments, L 3 is at each occurrence -NR 5 C(0)-, -C(0)NR 5 . Thus, the group— (L 3 -L 4 ) n - may form a peptide linker group. In these embodiments, it may be that -L 4 - is at each occurrence -Ci-alkylene-. [0078] In embodiments, L 1 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.

[0079] In embodiments -L 1 -L 2 -(L 3 -L 4 ) n - represents -OC(0)NH(CH 2 )io-, -OC(0)NH(CH 2 ) 8 -, - OC(0)NH(CH 2 ) 6 -, -OC(0)NH(CH 2 )ii-, -OC(0)NH(CH 2 ) 9 -, -OC(0)NH(CH 2 ) 7 -, OC(0)NH(CH 2 ) 5 -, -C(0)(CH 2 )io-, -C(0)(CH 2 ) 8 -, -C(0)(CH 2 ) 6 -, -C(0)(CH 2 )n-, -C(0)(CH 2 ) 9 -, - C(0)(CH 2 ) 7 -, or -C(0)(CH 2 ) 5 -.

[0080] In embodiments -L 1 -L 2 -(L 3 -L 4 ) n represents -OC(0)NH(CH 2 )io-, -OC(0)NH(CH 2 ) 8 -, - OC(0)NH(CH 2 ) 6 -, -OC(0)NH(CH 2 )ii-, -OC(0)NH(CH 2 ) 9 -, -OC(0)NH(CH 2 ) 7 -, or - OC(0)NH(CH 2 ) 5 -.

[0081] In embodiments -L 1 -L 2 -(L 3 -L 4 ) n - represents -C(0)(CH 2 )io-, -C(0)(CH 2 ) 8 -, -C(0)(CH 2 ) 6 -, -C(0)(CH 2 )ii-, -C(0)(CH 2 ) 9 -, -C(0)(CH 2 ) 7 -, or -C(0)(CH 2 ) 5 -. [0082] In embodiments -L 1 -L 2 -(L 3 -L 4 ) n - represents -OC(0)NH(CH 2 )io-, -OC(0)NH(CH 2 ) 8 -, - OC(0)NH(CH 2 ) 6 - or-C(0)(CH 2 ) 7 -.

[0083] In embodiments -L 1 -L 2 -(L 3 -L 4 ) n represents -OC(0)NH(CH 2 )io-, -OC(0)NH(CH 2 ) 8 -, or - OC(0)NH(CH 2 ) 6 -. [0084] In embodiments, R 4a and R 4b togetherform C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl, R 2c is Ci-C 6 alkyl, R 3a is H and R 3b is C(0)-Ci-C 6 -alkyl.

[0085] In embodiments, R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl, R 2c is methyl, R 3a is H and R 3b is C(0)CH 3 .

[0086] In embodiments, R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl, R 2c is methyl, R 3a is H, R 3b is C(0)CH 3 and L 1 is O, L 3 is C(0)NR 10 , R 10 is H, R 1a is phenyl, R 1b is phenyl and R 1c is phenyl.

[0087] In embodiments, L 5 is a Ci-Cis-alkylene group. L 5 may be C6-alkylene. L 5 may be Cs- alkylene. L 5 may be Cio-alkylene.

[0088] In embodiments, L 6 is a Ci-Cis-alkylene group. L 6 may be C6-alkylene. L 6 may be Cs- alkylene. L 6 may be Cio-alkylene.

[0089] In embodiments, L 7 is a Ci-Cis-alkylene group. L 7 may be C6-alkylene. L 7 may be Cs- alkylene. L 7 may be Cio-alkylene.

[0090] In embodiments, L 8 is a Ci-Cis-alkylene group. L 8 may be C6-alkylene. L 8 may be Cs- alkylene. L 8 may be Cio-alkylene. [0091] In embodiments, L 9 is a Ci-Cis-alkylene group. L 9 may be C6-alkylene. L 9 may be Cs- alkylene. L 9 may be Cio-alkylene.

[0092] In embodiments, R 5 is at any particular occurrence H. In embodiments, R 5 is at each occurrence H.

[0093] In embodiments, R 5 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 5 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[0094] In embodiments, R 6 is at any particular occurrence H. In embodiments, R 6 is at each occurrence H. [0095] In embodiments, R 6 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 6 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[0096] In embodiments, R 7 is at any particular occurrence H. In embodiments, R 7 is at each occurrence H.

[0097] In embodiments, R 7 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 7 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[0098] In embodiments, L 2 and L 4 are both unsubstituted.

[0099] In embodiments, R 8 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 8 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[00100] In embodiments, R 9 is at any particular occurrence H. In embodiments, R 9 is at each occurrence H.

[00101] In embodiments, R 9 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 9 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[00102] In embodiments, R 10 is at any particular occurrence H. In embodiments, R 10 is at each occurrence H.

[00103] In embodiments, R 10 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 10 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[00104] In embodiments, R 11 is at any particular occurrence H. In embodiments, R 11 is at each occurrence H.

[00105] In embodiments, R 11 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 11 is at each occurrence Ci-C4-alkyl, e.g. methyl.

[00106] In an embodiment, the ion of formula (I) is an ion selected from:

[00108] The cation of formula (I) will be associated with an anionic counter ion. For administration to a subject, the cation of formula (I) will be associated with a

pharmaceutically acceptable anionic counterion. The first aspect of the invention also, therefore, provides a compound comprising the ion of formula (I) and a pharmaceutically acceptable anion. The anion may have a single negative charge. For example, the anion may be selected from: halo (e.g. CI, Br and I), BF 4 , PF 6 , CF 3 C(0)0, HC(0)0, HC0 3 ,

(CF 3 S0 2 ) 2 N, (C 2 F 5 ) 3 PF3, HS0 4 , Ci-Ci 5 -alkylS0 4 , CH 3 C(0)0, CF 3 S0 3 , Tosyl-O, C(CN) 3 ,

N(CN) 2 or the carboxylate anion of a proteinogenic amino acid. For the avoidance of doubt each anion listed in the preceding sentence possesses a single negative charge. The anion may have multiple negative charges, e.g. P0 4 3" or C0 3 2" . The anion may be derived from a di- or tri-acid, e.g. glutamic acid, succinic acid, malic acid, citric acid, tartaric acid. It may be a mono-carboxylate of said di- or tri-acid. The remaining carboxylic acid groups may be in the form of protonated carboxylic acids, Ci-Ci2-alkylesters, or they may likewise be carboxylate anions. Said carboxylate anions may each be accompanied by a

pharmaceutically acceptable metal cation or by another cation of formula (I).

[00109] The anions associated with the cations of the invention can be quite labile. It may be therefore that the cation of the invention is present associated with two or more different anions. Ion exchange processes can be used to control the identity of the anion associated with the cation of the invention.

[00110] In embodiments the anion is CI, Br, I, PF 6 , CF 3 C(0)0, or HC(0)0.ln an aspect of the invention, the compounds of the invention are for medical use.

[00111] In an aspect, the compounds of the present invention are for use in treating a bacterial or mycobacterial infection. [00112] In a further aspect of the invention, there is provided a method for the treatment of a bacterial or mycobacterial infection, wherein the method comprises the administration of a therapeutically effective amount of a compound of the present invention.

[00113] In a further aspect of the invention, there is provided a use of the compounds of the invention for the manufacture of a medicament for the treatment of a bacterial or mycobacterial infection.

[00114] The bacterial infection may be a Gram-negative bacterial infection. The bacterial infection may be a Gram-positive bacterial infection. The bacterial or mycobacterial infection, e.g. the Gram-negative bacterial infection or the Gram-positive bacterial infection, may be resistant to at least one antibiotic (e.g. azithromycin). Exemplary Gram-positive bacteria include Staphylococcus aureus and Streptococcus pneumoniae. Exemplary Gram-negative bacteria include Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa.

[00115] The "treatment" of an infection may be taken to include prevention. Treatment also encompasses any improvement of pathology, symptoms or prognosis that is achieved in respect of an infection in a subject receiving compounds of the invention. Treatment may be indicated by a partial improvement of such indications (e.g., the reduction of infection following medical use of the compounds of the invention), or by a total improvement (i.e. the absence of infection following medical use of the compounds of the invention).

[00116] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and one or more pharmaceutically acceptable excipients.

[00117] In an embodiment, the pharmaceutical composition may be a combination product comprising one or more different pharmaceutically active agents. The one or more additional pharmaceutically active agents may be other antibiotics. The one or more pharmaceutically active agents may include a compound that increases the effectiveness of an antibiotic, e.g. by sensitising the bacteria to the antibiotic.

[00118] The present invention also contemplates the following numbered clauses.

1 . A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

-L 1 - is independently selected from: -0-, -N R 6 -, -0C(0)-, -N R 5 C(0)-, N R 5 S(0) 2 -, -OC(0)N R 5 -, -N R 5 C(0)0- and N R 5 C(0)N R 5 ; -L 3 - is independently at each occurrence either absent or selected from: -0-, -S-, -N R 6 -, - C(0)-, -OC(O)-, -C(0)0-, -S(0) 2 -, -S(0)-, -N R 5 C(0)-, -C(0)N R 5 , -N R 5 S(0) 2 -, -S(0) 2 N R 5 -, - OC(0)N R 5 -, -N R 5 C(0)0-, N R 5 C(0)N R 5 , -CR 7 =CR 7 - and -C≡C-;

-L 2 - and -L 4 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 8 groups; provided that any -L 2 - or -L 4 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C 2 -C 4 -alkylene-; n is an integer selected from 0, 1 , 2, 3, 4 and 5; wherein L 1 , L 2 , L 3 , L 4 , and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms; R 1 a , R 1 b and R 1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1 d groups; and wherein said C3 to Cs-cycloalkyl, d-Cs-alkyl and 5- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 1 e groups;

R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl; R 3a is independently at each occurrence selected from H , Ci-C6-alkyl or C(0)-Ci-C6-alkyl;

R 3b is independently at each occurrence selected from H or C(0)-Ci-C6-alkyl;

R 4a and R 4b are each independently selected from: H, Ci-C 6 -alkyl or C(0)-Ci-C 6 -alkyl; or R 4a and R 4b together from C(O); R 5 is independently at each occurrence selected from H and Ci-C6-alkyl;

R 6 and R 11 are each independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0) 2 -Ci-C 6 -alkyl;

R 7 is independently at each occurrence selected from H , Ci-C 4 -alkyl and halo;

R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C 2 -C6- alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0) 2 R 10 and S(O) 2 NR 10 R 10 ;

R 9 is independently at each occurrence selected from: H , Ci-C6-alkyl and Ci-C6-haloalkyl;

R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl;

R 1d is independently at each occurrence selected from: Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0)R i S(0) 2 R 10 , S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;

R 1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0)R i S(0) 2 R 10 , S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ; and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6-alkenyl, C1-C6- haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR a , S(0) 2 R a , S(0)R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C6-alkyl; and R b is independently at each occurrence selected from: H, C1-C6- alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl. 2. A compound of clause 1 , wherein L 1 is -NR 5 C(0)0-.

3. A compound of clause 1 or clause 2, wherein L 3 is at each occurrence absent.

4. A compound of any one of clauses 1 to 3, wherein L 1 , L 2 , L 3 , L 4 , L 5 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.

5. A compound of any one of clauses 1 to 4, wherein R 4a is H and R 4b is H.

6. A compound of any one of clauses 1 to 4, wherein R 4a and R 4b together form C(O).

7. A compound of any one of clauses 1 to 6, wherein R 2a is methyl and R 2c is methyl.

8. A compound of any one of clauses 1 to 7, wherein R 2b is methyl.

9. A compound of any one of clauses 1 to 8, wherein R 3a is H and R 3b is H.

10. A compound of any one of clauses 1 to 8, wherein R 3a is H and R 3b is C(0)CH3.

1 1 . A compound of any one of clauses 1 to 10, wherein R 1a , R 1b and R 1c are each substituted phenyl.

12. A compound of any one of clauses 1 to 10, wherein R 1a , R 1b and R 1c are each unsubstituted phenyl.

13. A compound of any one of clauses 1 to 10, wherein R 1a , R 1b and R 1c are each C3 to Cs-cycloalkyl.

14. ,A compound of any one of clauses 1 to 10, wherein R 1a , R 1b and R 1c are each benzyl.

15. A compound of any one of clauses 1 to 10, wherein R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyI and 5- to 8- membered heterocycloalkyi.

16. A compound of any one of clauses 1 to 10, wherein R 1a and R 1b are each C3 to Cs- cycloalkyl and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyI and 5- to 8-membered heterocycloalkyi. 17. A compound of any one of clauses 1 to 10, wherein at least one of R 1a , R 1b and R 1c is d-Ce-alkyl.

18. A compound of clause 17, wherein any of R 1a , R 1b and R 1c that are not Ci-C6-alkyl are phenyl.

19. A compound of any one of clauses 1 to 18, wherein the compound is for medical use. 20. A compound of any one of clauses 1 to 18, wherein the compound is for use in the treatment of a bacterial or mycobacterial infection. A compound for use of clause 20, wherein the bacterial infection is caused by a Gram- negative bacteria.

A compound for use of clause 20, wherein the bacterial infection is caused by a Gram- positive bacteria.

A compound for use of any one of clauses 20 to 22 , wherein the infection is caused by a strain of bacteria or mycobacteria that is resistant to at least one antibiotic.

A method for the treatment of a bacterial or mycobacterial infection, wherein the method comprises the administration of a therapeutically effective amount of a compound of any one of clauses 1 to 18.

A method of clause 24, wherein the bacterial infection is caused by a Gram-negative bacteria.

A method of clause 24, wherein the bacterial infection is caused by a Gram-positive bacteria.

A method of any one of clauses 24 to 26, wherein the infection is caused by a strain of bacteria or mycobacteria that is resistant to at least one antibiotic.

A pharmaceutical composition, wherein the composition comprises a compound of any one of clauses 1 to 18 and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION

[00119] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

[00120] The term "halo" or "halogen" refers to an atom selected from fluorine, chlorine, bromine and iodine. "Halo" or "halogen" may refer to an atom selected from CI and F. "Halo" or "halogen" may refer to fluorine.

[00121] The term "alkyi" refers to a linear or branched hydrocarbon chain. The term "C-i-Cs alkyi" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The term "C1-C6 alkyi" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The term "C1-C6 alkyi" for example refers to methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The "alkyi" group may be substituted or unsubstituted by one or more substituents. Substituents for the alkyi group may be halo (for example fluorine, chlorine, bromine and iodine), OH and C1-C6 alkoxy. In addition, alkylene groups may be linear or branched and may have two places of attachment to the remainder of the molecule. [00122] The term "alkylene" refers to a divalent group which is a linear or branched hydrocarbon chain. With the "alkylene" group being divalent, the group must form two bonds to other groups. The term "d-Cs-alkylene" may refer to -CH2-, -CH2CH2-, -CH2CH2CH2-, - CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-,

CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2- or substituted equivalents thereof. The alkylene group may be unsubstituted or substituted by one or more substituents.

[00123] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. The term "C3- Cs cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane. The term "cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and indane. The cycloalkyl group may be substituted with one or more substituents.

[00124] The term "haloalkyi" refers to a linear or branched hydrocarbon chain which is substituted with at least one halogen atom which are independently selected at each occurrence from fluorine, chlorine, bromine and iodine. For example, the term "C1-C6 haloalkyi" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The halogen atom may be substituted at any position on the hydrocarbon chain. The term "C1-C6 haloalkyi" may refer to, for example, fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl (such as 1 ,2,2-trichloroethyl and 2,2,2- trichloroethyl), fluoropropyl and chloropropyl. The haloalkyi group may be substituted with one or more substituents.

[00125] The term "alkenyl" refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having at least two carbon atoms. The term "C2-C6 alkenyl" refers to a linear or branched hydrocarbon chain containing at least one carbon- carbon double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond or double bonds may be E or Z isomers. The double bond may be present at any possible position of the hydrocarbon chain. The term "C2-C6 alkenyl" may refer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl group may be substituted or unsubstituted by one or more substituents.

[00126] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system. The term "C3-C8 cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring may contain more than one double bond. The term cycloalkenyl may refer to, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloocatadienyl. The cycloalkenyl group may be substituted with one or more substituents. [00127] The term "alkynyl" refers to a linear or branched hydrocarbon chain contain at least one carbon-carbon triple bond and having at least two carbon atoms. The term "C2-C6 alkynyl" refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond or triple bonds may be present at any possible position of the hydrocarbon chain. The term "C2-C6 alkynyl" may refer to, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl group may be unsubstituted or substituted by one or more substituents.

[00128] The term "heteroalkyi" refers to a linear or branched hydrocarbon chain containing at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain. The term "C1-C6 heteroalkyi" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain. The heteroalkyi may be attached to another group by the heteroatom or the carbon atom. The term "C1-C6 heteroalkyi" may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2. The heteroalkyi group may be unsubstituted or substituted by one or more substituents.

[00129] The term "heterocycloalkyi" refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S. The term "5- to 8- membered heterocycloalkyi" refers to a saturated hydrocarbon ring with 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom. The "heterocycloalkyi" group may also be denoted as a "3 to 10 membered heterocycloalkyi" which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one being a heteroatom. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in chromane. The "heterocycloalkyi" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "heterocycloalkyi" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "heterocycloalkyi" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and chromane.

[00130] The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S. The term "C3-C8 heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom selected from N, O or S. There may be more than one double bond present. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. There may also be more than 1 heteroatom present. For example, there may be 1 , 2 or 3 heteroatoms present. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran. The heterocycloalkenyl may be attached to another group by any carbon or heteroatom. The term heterocycloalkenyl may refer to, for example, tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene and indoline. The heterocycloalkenyl group may be substituted with one or more substituents.

[00131] The term "aryl" refers to an aromatic hydrocarbon ring system which satisfies Huckel's rule for aromaticity or that contains a ring system which satisfies Huckel's rule for aromaticity. As such an aryl group may be a single ring or a bi-cyclic or tri-cyclic ring system. The term "aryl" may refer to, for example, phenyl, naphthyl, indane, tetralin and anthracene. The aryl group may be unsubstituted or substituted with one or more substituents. Any aryl group may be a phenyl ring.

[00132] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom selected from N, O or S which satisfies Huckel's rule for aromaticity or a ring system that contains a heteroatom and an aromatic hydrocarbon ring. The heteroaryl may be a single ring system or a fused ring system. The term "5-, 6-, 9- or 10- membered heteroaryl" refers to an aromatic ring system within 5, 6, 9, or 10 members selected from carbon, N, O or S either in a single ring or a bicyclic ring system. The term heteroaryl may refer to, for example, imidazole, thiazole, oxazole, isothiazole, isoxazole, triazole, tetraazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone and isoquinoline.

[00133] The term "alkoxy" refers to an alkyl group which is linked to another group by oxygen. The alkyl group may be linear or branched. The term "C1-C6 alkoxy" refers to an alkyl group containing 1 , 2, 3, 4, 5 or 6 carbon atoms which is linked to another group by oxygen. The alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert- butyl, n-pentyl and n-hexyl. The term "C1-C6 alkoxy" may refer to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl group may be substituted or unsubstituted by one or more substituents.

[00134] A bond terminating in a " " means that the bond is connected to another group that is not shown. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[00135] Where a group is substituted, it may be substituted at any point on the group where chemically possible and consistent with valency requirements. The group may be substituted by one or more substituents. For example, the group may be substituted with 1 , 2, 3 or 4 substituents. Where there are two or more substituents, the substituents may be the same or different. Substituent(s) may be, for example, halo, CN, nitro, oxo, Ci-C6-alkyl, C2-C6-alkynyl, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR a , S(0) 2 R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C6-alkyl; and R b is independently at each occurrence selected from: H, d-Ce-alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl.

[00136] If chemically possible to do so, a cyclic substituent may be substituted on a group so as to form a spiro-cycle.

[00137] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.

[00138] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " ".

[00139] "Meta" substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the roups below are meta substituted.

[00140] "Para" substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent. For example the groups below are para substituted.

[00141] The ion of formula (I) will be associated with a pharmaceutically acceptable anionic counter ion for administration to a subject. Nevertheless, where either the ion of formula (I) or the anionic counter ion comprise either basic or acidic groups, those groups may themselves be protonated or deprotonated and associated with an appropriate counter ion.

[00142] Suitable acid addition salts are formed from acids which form non-toxic salts, for example, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1 ,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[00143] Suitable base salts are formed from bases which form non-toxic salts, for example include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00144] The salt may be an acid addition salt.

[00145] The salts may be formate or hydrochloride.

[00146] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of the following methods:

(i) reacting the compound of formula (I) with the desired acid or base;

(ii) removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

(iii) converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. [00147] The reactions above are typically carried out in solution and the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised.

[00148] The compounds may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

[00149] Complexes are contemplated, such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts are also contemplated. The resulting complexes may be ionised, partially ionised, or non-ionised. A review of such complexes is found in J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00150] Compounds, ions and salts described in this specification may be isotopically-labelled (or "radio-labelled"). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include 2 H (also written as "D" for deuterium), 3 H (also written as "T" for tritium), 11 C, 13 C, 14 C, 15 0, 17 0, 18 0, 18 F and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays, 3 H or 14 C are often useful. For radio-imaging applications, 11 C or 18 F are often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. And in some embodiments, the radionuclide is 18 F.

[00151] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00152] The compounds include a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.

[00153] Before purification, the compounds may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus, the compounds cover individual enantiomers as well as mixtures thereof. [00154] For some of the steps of the process of preparation of the compounds of formula (I), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

[00155] Also, the compounds as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as crystallization or chromatography.

[00156] The compounds and formulations of the invention can be used to treat both Gram positive and Gram negative bacterial infections such as infections of the genitourinary system, the respiratory tract, the gastrointestinal tract, the ear, the skin (including wounds), the throat, soft tissue, bone and joints. The compounds can be used to treat pneumonia, sinusitis, acute bacterial sinusitis, bronchitis, acute bacterial exacerbation of chronic bronchitis, anthrax, chronic bacterial prostatitis, acute pyelonephritis, pharyngitis, tonsillitis, cellulitis, acnes, cystitis, infectious diarrhoea, typhoid fever, infections caused by anaerobic bacteria, peritonitis, bacterial vaginosis, pelvic inflammatory disease, pseudomembranous colitis, acute gingivitis, Crohn's disease, rosacea, fungating tumours, impetigo. The compounds can be used prophylactically, e.g. before surgery (including dental surgery).

[00157] The bacterial infection may be caused by Gram-positive bacteria (e.g. a strain of a Gram-positive bacteria that is resistant to an antibiotic). The bacterial infection may be caused by a bacteria selected from: Staphylococcus aureus, Enterococcus faecium, Clostridium difficile and Streptococcus pneumonia.

[00158] The bacterial infection may be caused by Gram-negative bacteria (e.g. a strain of a Gram-negative bacteria that is resistant to an antibiotic). The bacterial infection may be caused by a bacteria selected from Acinetobacter Baumannii, Pseudomonas aeruginosa, Enterobacteriaceae (a class of bacteria including Klebsiella pneumonia, Escherichia coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp, Morganella spp), Helicobacter pylori, Campylobacter spp., Salmonella spp, Neisseria gonorrhoeae, Shigella spp. and Haemophilus Influenzae. [00159] The compounds of the invention can be used to treat mycobacterial infections, e.g. mycobacterial infections caused by resistant strains of mycobacteria. Thus, they can be used to treat TB or leprosy. The compounds may be used to treat resistant strains of TB, e.g. MDR- TB (i.e. TB infections caused by strains which are resistant to isoniazid and rifampicin), XDR- TB (i.e. TB infections caused by strains which are resistant to isoniazid, rifampicin, at least one fluoroquinolone and at least one of kanamycin, capreomycin and amikacin) and/or TDR- TB (i.e. TB infections caused by strains which have proved resistant to every drug tested against it with the exception of a compound of the invention).

[00160] The compounds of the invention may be used to treat infections caused by bacterial or mycobacterial strains that are resistant to at least one antibiotic. The term 'resistant' is intended to refer to strains of bacteria or mycobacteria that have shown non-susceptibility to one or more known antibiotic drug. A non-susceptible strain is one in which the MIC of a given compound or class of compounds for that strain has shifted to a higher number than for corresponding susceptible strains. In certain embodiments, the term 'resistant' is used to mean a strain to such an extent that the use of the antibiotic in treating that strain is associated or is expected to be associated with a high likelihood of therapeutic failure.

[00161] The bacterial strain may be resistant to an antibiotic selected from: a fluoroquinolone, a β-lactam (e.g. penicillin, methicillin, ampicillin), a carbapenem, a cephalosporin, vancomycin, clarithromycin and azithromycin. [00162] The compounds of the invention can be used to treat mycobacterial infections, e.g. mycobacterial infections caused by strains of mycobacteria that are resistant to an antimycobacterial agent. Thus, they can be used to treat TB or leprosy. The compounds may be used to treat resistant strains of TB (e.g. strains which are resistant to at least one of isoniazid, rifampicin, a fluoroquinolone, kanamycin, capreomycin and amikacin). [00163] The compounds of the invention may also be useful in treating other forms of infectious disease, e.g. fungal infections, parasitic infections and/or viral infections.

[00164] The compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc.

[00165] The compounds of the invention may be administered in combination with another antibiotic or with a compound that increases the effectiveness of an antibiotic. Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products may be administered so that the combination is provided in a therapeutically effective amount, for example the compounds of this invention may be administered within a therapeutically effective dosage range described herein and the other pharmaceutically-active agent may be administered in a therapeutically effective amount, including in amount less than or within its approved dosage range.

[00166] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[00167] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ^g(microgram)/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00168] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00169] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (percent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

[00170] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00171] For oral administration, the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00172] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also, liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[00173] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00174] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[00175] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication (including the location of the infection in the body), age, and co-morbid medical conditions of the patient.

[00176] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00177] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00178] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

METHODS FOR SYNTHESISING COMPOUNDS

[00179] Certain ions of the invention can be synthesised according to or analogously to methods described in the General Schemes below and/by other techniques known to those of ordinary skill in the art. Certain ions of the invention can be synthesised according to or analogously to the methods described in the Examples.

[00180] Compound (1 ) and compound (29) may be prepared by the procedure described in European Journal of Medicinal Chemistry 40, 201 1 , 5196. Compound (9) and compound (24) may be prepared by the procedure described in WO2004/101590.

[00181] Certain compounds of formula (I) can be made by Scheme A.

Scheme A

[00182] Reaction of imidazolecarboxylate (1 ) with phosphonium amine (2) (L 5 is a C2-C13- alkylene group optionally substituted with from 0 to 10 R 8 groups) can furnish phosphonium carbamate (3). The reaction can be performed in the presence of a non- nucleophilic base, such as DBU, in an organic solvent, such as DMF, at room temperature.

[00183] Phosphonium amine (2) can be furnished by Scheme B.

Scheme B

[00184] Reaction of halo isoindoline-1 ,3-dione (4) (where X = CI or Br) with phosphine (5) can deliver phosphonium isoindoline-1 ,3-dione (6). The reaction can be performed by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C. Reaction of the phosphonium isoindoline-1 ,3-dione (6) with hydrazine hydrate in an alcoholic solvent, such as EtOH, at a temperature from 50 to 75 °C can furnish phosphonium amine (2).

[00185] Certain compounds of formula (I) can be made by Scheme C.

Scheme C

[00186] Deprotection of the cyclic carbonate and acetate in (3) (prepared as described in Scheme A) to give (7) can be accomplished by base, such as K2CO3, in a h O/MeOH mixed solvent, at a temperature of 25 to 50 °C.

[00187] Certain compounds of formula (I) can be made by Scheme D. „

(8)

Scheme D

[00188] Selective removal of the acetate in (3) (prepared as described in Scheme A) to give cyclic carbonate (8) can be accomplished by heating in an alcoholic solvent, such as MeOH, at a temperature from 50 to 65 °C.

[00189] Certain compounds of formula (I) can be made by Scheme E.

(12)

Scheme E

[00190] Reaction of amine (9) with phosphonium acid (1 1 ) (L 6 is a C2-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups) can furnish phosphonium amide (12). The reaction can be performed using standard peptide coupling agents, such as 1 ,3- dicyclohexylcarboiimide (DCC), in a chlorinated solvent, such as DCM at room temperature. Addition of DMAP is optional. Phosphonium acid (1 1 ) can be prepared from reaction of halide (10) (X = CI or Br) with phosphine PR 1a R 1b R 1c (5). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. [00191] Certain compounds of formula (I) can be made by Scheme F.

[00192] Scheme F

[00193] Cyclic carbonate protection of amine (9) to give (13) can be acomplished by reaction with ethylene carbonate in the presence of a base, such as K2CO3, in an organic solvent, such as toluene, at a temperature of 70 to 100 °C. Cyclic carbonate amine (13) can be transformed to phosphonium amide (14). The reaction can be performed using phosphonium acid (1 1 ) and standard peptide coupling agents, such as 1 ,3-dicyclohexylcarboiimide (DCC), in DMS, at room temperature. Addition of DMAP is optional. [00194] Certain compounds of formula (I) can be made by Scheme G.

Scheme G

[00195] Reaction of amine (9) with halo sulphonic acid (15) (where X = CI or Br; (L 7 is a C2- Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups)) can furnish halo sulphonamide (16). The reaction can be performed using SOC in an organic solvent, such as DMF or DCM, at a temperature from 20 to 60 °C. Reaction of phosphine (5) with halo sulphonamide (16) can deliver phosphonium sulphonamide (17). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.

[00196] Replacement of amine (9) in Scheme G with cyclic carbonate amine (13) can provide phosphonium sulphonamide (18), a subset of compounds of formula (I).

[00197] Certain compounds of formula (I) can be made by Scheme H.

Scheme H

[00198] Reaction of amine (9) with phosphonium chlorocarbonate (22) (L 8 is a C2-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups) can furnish phosphonium carbamate (19). The reaction can be accomplished in the presence of a base, such as pyridine, in an organic solvent, such as DCM, at a temperature from 0 °C to room temperature. Phosphonium chloroacetate (22) can be synthesised from phosphonium alcohol (21 ) through treatment with triphosgene in the presence of a base, such as DIEA, in an organic solvent, such as THF, at a temperature from -5 to 5 °C. Phosphonium alcohol (21 ) can be synthesised from halo alcohol (20) (where X = CI or Br) and phosphine PR 1a R 1b R 1c (5). . The reaction can be accomplished by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C [00199] Replacement of amine (9) in Scheme H with cyclic carbonate amine (13) can provide phosphonium carbamate (23), a subset of compounds of formula (I).

[00200] Replacement of amine (9) in Scheme E, F, G and H with isomer amine (24) can provide phosphonium compounds (25), (26), (27) and (28), which represent a subset of compounds of formula (I):

[00201] Certain compounds of formula (I) can be made by Scheme I.

[00202] Scheme I

[00203] Reaction of alcohol (29) with phosphonium acid (1 1 ) can furnish phosphonium ester (30). The reaction can be performed using standard coupling agents for ester formation, such as N-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCI (EDAC.HCI) in the presence of DMAP, in an organic solvent, such as DCM, at room temperature.

[00204] Certain compounds of formula (I) can be made by Scheme J.

[00205] Selective removal of the acetate in (30) to give cyclic carbonate (31 ) can be accomplished by heating in an alcoholic solvent, such as MeOH, at a temperature from 25 to 50 °C. Deprotection of the cyclic carbonate in (31 ) to give phosphonium ester (32) can be performed in the presence of a base, such as K2CO3, in an alcoholic solvent, such as MeOH, at a temperature from 25 to 80 °C.

Experimental

Analytical methods [00206] NMR spectra were obtained on a 400 MHz Bruker AV III

[00207] UPLC/MS was carried out using a Waters Acquity QDa mass detector and Methods A, I , J or Waters SQ mass detector and Methods B, C, D, E, F, H or Agilent 6120 MSD and Method G

[00208] Method A [00209] Column: Waters Acquity UPLC CSH C18, 1 .7 pm, 2.1 x 30 mm; Gradient Eluent: 5- 95% MeCN/H 2 0 containing 0.1 % HCOOH; Time: 0-10 min

[00210] Method B

[00211] Column: Waters Acquity UPLC CSH C18, 1 .7 pm, 2.1 x 50 mm; Gradient Eluent: 2- 98% MeCN/H 2 0 containing 0.02% HCOOH; Time: 0-4.5 min [00212] Method C

[00213] Column: Waters Acquity UPLC CSH C18, 1 .7 pm, 2.1 x 50 mm; Gradient Eluent: 2- 98% MeCN containing 0.035% TFA/H2O containing 0.05% TFA; Time: 0-4.5 min

[00214] Method D

[00215] Column: Waters Acquity UPLC CSH C18, 1.7 pm, 2.1 x 100 mm; Gradient Eluent: 2- 98% MeCN containing 0.035% TFA/H2O containing 0.05% TFA; Time: 0-15 min

[00216] Method E

[00217] Column: Waters Acquity UPLC BEH C18, 1 .7 pm, 2.1 x 30 mm; Gradient Eluent: 5- 95% MeCN/H 2 0 containing 10 mM (NH 4 ) 2 C0 3 ; Time: 0-3 min

[00218] Method F [00219] Column: Waters Acquity UPLC CSH C18, 1 .7 pm, 2.1 x 50 mm; Gradient Eluent: 2- 100% MeCN containing 0.035% TFA/H2O containing 0.05% TFA; Time: 0-3 min [00220] Method G

[00221] Column: Waters Acquity UPLC CSH C18, 2.5 m, 4.6 x 30 mm; Gradient Eluent: 5- 95% MeCN/h O containing 0.1 % HCOOH; Time: 0-3 min

[00222] Method H [00223] Column: Waters Acquity UPLC BEH C18, 1 .7 m, 2.1 x 30 mm; Gradient Eluent: 5- 95% MeCN/H 2 0 containing 10 mM (NH 4 ) 2 C0 3 ; Time: 0-15 min

[00224] Method I

[00225] Column: Waters Acquity UPLC BEH C18, 1 .7 Mm, 2.1 x 30 mm; Gradient Eluent: 5- 95% MeCN/H 2 0 containing 10 mM (NH 4 ) 2 C0 3 ; Time: 0-3 min [00226] Method J

[00227] Column: Waters Acquity UPLC CSH C18, 1.7 Mm, 2.1 x 30 mm; Gradient Eluent: 5- 95% MeCN/H 2 0 containing 0.1 % HCOOH; Time: 0-3 min

[00228] Preparative HPLC was carried out using a ZQ Mass Spectrometer and Method A or Gilson PLC2020 and Method B,C [00229] Method A

[00230] Waters X-Select Prep-C18, 5 Mm, 19 x 50 mm eluting with MeCN/H 2 O/0.1 % HCOOH

[00231] Method B

[00232] Gemini NX-C18, 10 Mm, 30 x 250 mm eluting with a mixture of MeCN/0.035% TFA and H 2 O/0.05% TFA [00233] Method C

[00234] Gemini NX-C18, 10 Mm, 50 x 300 mm eluting with a mixture of MeCN/H 2 O/0.1 % TFA

[00235] The following abbreviations have been used in the examples and in the description: toluenesulfonate (Ts); dimethylformamide (DMF); trifluoroacetic acid (TFA); dichloromethane (DCM); dimethyl sulfoxide (DMSO); Ν,Ν-Diisopropylethylamine (DIEA); tetrahydrofuran (THF); 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU); 4-Dimethylaminopyridine (DMAP); dimethyl sulfide (DMS). [00236] Example 1 - (2S,3R,4S,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4- ethyl-11 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-({[10- (triphenylphosphoniumyl)decyl]carbamoyl}oxy)oxan-2-yl]oxy}-3 a,7,9,11 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate

[00237] [10-(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)decylltriphenylphosphonium bromide

[00238] A mixture of 2-(10-bromodecyl)isoindoline-1 ,3-dione (1 .43 g, 5.46 mmol) and triphenylphosphine (2 g, 5.46 mmol) in MeCN (15.6 mL) was heated at 70 °C overnight. On cooling the solvent was removed in vacuo and the resulting residue purified by column chromatography eluting with 0-10% MeOH in DCM to give [10-(1 ,3-dioxo-2,3-dihydro-1 H- isoindol-2-yl)decyl]triphenylphosphonium bromide (1 g, 29%).

[00239] LC-MS (Method B) 548.4 [M] + ; RT 2.06 min [00240] (10-aminodecvDtriphenylphosphonium bromide

[00241] To a solution of [10-(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2- yl)decyl]triphenylphosphonium bromide (prepared as described in Example 1 step (a)) (800 mg, 1.27 mmol) in EtOH (10 mL) was added hydrazine hydrate (1 .53 mL). The resulting reaction mixture was refluxed for 16 h. On cooling the solvent was removed under vacuo and the resulting residue purified by column chromatography eluting with 0-20% MeOH/5% NH3 in DCM to give (l O-aminodecyl)triphenylphosphonium bromide (385 mg, 61 %) as a white solid.

[00242] LC-MS (Method F) 418.4 [M] + ; RT 1.52 min

[00243] (2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hvdroxy- 8-{r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5-({ri0-

(triphenylphosphoniumyl)decyllcarbamoyl)oxy)oxan-2-ylloxy )-3a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan- 10-vHoxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate trifluoroacetate

[00244] A solution of (2S ! 3S ! 4R ! 6R)-6-{[(3aR ! 4R ! 7R ! 8S ! 9S ! 10R,1 1 R,13R,16R,16aR)-10- {[(2S ! 3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyloxan -2-yl]oxy}-4-ethyl-1 1 -hydroxy- 3a ! 7 ! 9 ! 1 1 ! 13 ! 15 ! 16-heptamethyl-2 ! 6-dioxo-tetradecahydro-2H-[1 ! 3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl 1 H imidazole-1 -carboxylate (prepared as described in European Journal of Medicinal Chemistry 40, 201 1 , 5196) (150 mg, 0.16 mmol) and (l O-aminodecyl)triphenylphosphonium bromide (prepared as described in Example 1 step (b)) (124 mg, 0.25 mmol) in DMF (1.5 mL) was treated with DBU (27 μΙ_, 0.20 mmol). After stirring at room temperature for 20 h the reaction mixture was quenched with aqueous saturated NaHCC>3 (1 mL) and extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na2S0 4 and solvent removed under vacuo. The resulting crude residue was purified by preparative HPLC (Method B) to give (2S,3R,4S,6R)-2- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4- methoxy-4,6-dimethyl-5-({[10-(triphenylphosphoniumyl)decyl]c arbamoyl}oxy)oxan-2-yl]oxy}- 3a,7,9,1 1 ,13,15,16-heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate Example 1 (161 mg, 61 %) as a TFA salt as a white solid.

[00245] LC-MS (Method D) 1260.9 [M] + ; RT 6.80 min

[00246] Example 2 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[10-

(triphenylphosphoniumyl)decyl]carbamate trifluoroacetate

[00247] To a solution of the TFA salt of (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[10-(triphenylphosphoniumyl)decyl]c arbamoyl}oxy)oxan-2-yl]oxy}- 3a ! 7 ! 9 ! 1 1 ! 13 ! 15 ! 16-heptamethyl)-2 ! 6-dioxo-tetradecahydro-2H-[1 ! 3]dioxolo[4,5-c]1-oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate (prepared as described in Example 1 ) (106 mg, 0.07 mmol) in H2O (0.05 mL) and MeOH (0.5 mL) was added K2CO3 (91 mg, 0.66 mmol). After stirring at room temperature for 16 h the solvent was removed under vacuo. The resulting crude residue was purified by preparative HPLC (Method C) to give (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,1 1 R,12S,13S,14R)-11- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacy clopentadecan-13-yl]oxy}-4- methoxy-2,4-dimethyloxan-3-yl N-[10-(triphenylphosphoniumyl)decyl]carbamate trifluoroacetate (32 mg, 32%) as a TFA salt as a white solid.

[00248] LC-MS (Method C) 1 192.7 [M] + ; RT 2.01 min [00249] Example 3 - (2S,3S,4R,6R)-6-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9 A 1 A 3,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[10- (triphenylphosphoniumyl)decyl]carbamate bromide

[00250] (2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hvdroxy- 8-{r(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5- ri0-

(triphenylphosphoniumyl)decyllcarbamoyl)oxy)oxan-2-ylloxy )-3a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan- 10-ylloxy -(dimethylamino)-6-methyloxan-3-yl acetate bromide

[00251] Prepared following the procedure described in Example 1 step (c) but with addition of DMAP and purification of the crude by column chromatography using 0-10% MeOH/0.7M NH 3 in DCM.

[00252] (2S,3S,4R,6R)-6-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10- {r(2S,3R,4S,6R)-4-(dimethylamino)-3-hvdroxy-6-methyloxan-2-y lloxy)-4-ethyl-1 1 -hvdroxy- 3a,7,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahvdro-2H-ri,3ldioxo lor4,5-cl1 -oxa-6- azacvclopentadecan-8-ylloxy)-4-methoxy-2,4-dimethyloxan-3-yl N-H 0-

(triphenylphosphoniumvDdecyllcarbamate bromide

[00253] A solution of (2S,3R ! 4S ! 6R)-2-{[(3aR ! 4R,7R ! 8S,9S,10R,1 1 R,13R,16R,16aR)-4- ethyl-1 1 -hydroxy-8-{[(2R ! 4R,5S ! 6S)-4-methoxy-4,6-dimethyl-5-({[10- (triphenylphosphoniumyl)decyl]carbamoyl}oxy)oxan-2-yl]oxy}-3 a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described by Example 3 step (a)) (70 mg, 0.05 mmol) in MeOH (1 mL) was heated at 64 °C for 15 h. After cooling to room temperature the solvent was removed under vacuo to give (2S,3S,4R,6R)-6- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6- dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4- methoxy-2,4-dimethyloxan-3-yl N-[10-(triphenylphosphoniumyl)decyl]carbamate bromide Example 3 (63 mg, 88%) as a white foam.

[00254] LC-MS (Method E) 1219.1 [M] + ; RT 2.1 1 min

[00255] Example 4 - (3R,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4-ethyl-11 - hydroxy-8-{[(2R,5S)-4-methoxy-4,6-dimethyl-5-({[8-

(triphenylphosphoniumyl)octyl]carbamoyl}oxy)oxan-2-yl]oxy }-3a,7,9,11 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate [00256] [8-(1 ,3-dioxo-2,3-dihvdro-1 H-isoindol-2-yl)octylltriphenylphosphonium bromide

[00257] Prepared following the procedure of Example 1 step (a) using 2-(8- bromooctyl)isoindole-1 ,3-dione.

[00258] LC-MS (Method B) 520.3 [M] + ; RT 1.85 min [00259] (8-aminooctyl)triphenylphosphonium bromide

[00260] Prepared following the procedure of Example 1 step (b) using [8-(1 ,3-dioxo-2,3- dihydro-1 H-isoindol-2-yl)octyl]triphenylphosphonium bromide (prepared as described in Example 4 step (a)). [00261] LC-MS (Method B) 390.3 [M] + ; RT 0.72 min

[00262] (2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hvdroxy- 8-{r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5- r8-

(triphenylphosphoniumyl)octyllcarbamoyl)oxy)oxan-2-ylloxy )-3a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan- 10-ylloxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate trifluoroacetate

[00263] Prepared following the procedure of Example 1 step (c) using (8- aminooctyl)triphenylphosphonium bromide (prepared as described in Example 4 step (b)). The title compound was isolated as a TFA salt as a white solid. [00264] LC-MS (Method D) 1260.8 [M + 28] + ; RT 6.81 min [00265] Example 5 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[8- (triphenylphosphoniumyl)octyl]carbamate trifluoroacetate

[00266] Prepared following the procedure of Example 2 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[8-(triphenylphosphoniumyl)octyl]ca rbamoyl}oxy)oxan-2-yl]oxy}- 3a ! 7 ! 9 ! 1 1 ! 13 ! 15 ! 16-heptamethyl)-2 ! 6-dioxo-tetradecahydro-2H-[1 ! 3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate (prepared as described in Example 4). The title compound was isolated as a TFA salt as a white solid.

[00267] LC-MS (Method C) 1 164.7 [M] + ; RT 1.89 min [00268] Example 6 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13, 15,16-heptamethyl-2, 6-dioxo-tetradecahydro-2H-[1 , 3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[8- (triphenylphosphoniumyl)octyl]carbamate bromide

[00269] Prepared following the procedure of Example 3 step (b) using (2S.3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[8-(triphenylphosphoniumyl)octyl]ca rbamoyl}oxy)oxan-2-yl]oxy}- 3aJ,9,1 1 ,13,15,16-heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate bromide (prepared as described in Example 3 step (a) using (8-aminooctyl)triphenylphosphonium bromide (prepared as described in Example 4 step (b)). The title compound was isolated as a white solid. [00270] LC-MS (Method E) 1 191.0 [M] + ; RT 2.02 min

[00271] Example 7 - (2S,3R,4S,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4- ethyl-11 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-({[6- (triphenylphosphoniumyl)hexyl]carbamoyl}oxy)oxan-2-yl]oxy}-3 a,7,9,11 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate

[00272] Prepared following the procedure of Example 1 step (c) using (6- aminohexyl)triphenylphosphonium bromide (prepared as described in WO2016025725). The title compound was isolated as a TFA salt as a white solid.

[00273] LC-MS (Method B) 1204.9 [M] + ; RT 1.31 min

[00274] Example 8 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[6- (triphenylphosphoniumyl)hexyl]carbamate trifluoroacetate

Me—

Me * ¾Μβ [00275] Prepared following the procedure of Example 2 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[6-(triphenylphosphoniumyl)hexyl]ca rbamoyl}oxy)oxan-2-yl]oxy}- 3a ! 7 ! 9 ! 1 1 ! 13 ! 15 ! 16-heptamethyl)-2 ! 6-dioxo-tetradecahydro-2H-[1 ! 3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate trifluoroacetate (prepared as described in Example 7). The title compound was isolated as a TFA salt as a white solid.

[00276] LC-MS (Method B) 1 136.8 [M] + ; RT 1.03 min

[00277] Example 9 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9 A 1 A 3,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[6- (triphenylphosphoniumyl)hexyl]carbamate bromide

[00278] Prepared following the procedure of Example 3 step (b) using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[6-(triphenylphosphoniumyl)hexyl]ca rbamoyl}oxy)oxan-2-yl]oxy}- 3a ! 7 ! 9 ! 1 1 ! 13 ! 15 ! 16-heptamethyl)-2 ! 6-dioxo-tetradecahydro-2H-[1 ! 3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate bromide (prepared as described in Example 3 step (a) using (6-aminohexyl)triphenylphosphonium bromide) (prepared as described in WO2016025725). The title compound was isolated as a white solid.

[00279] LC-MS (Method E) 1 163 [M] + ; RT 2.0-2.3 min [00280] Example 10 - (2S,3R,4S,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4- ethyl-11 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[({8-[tr is(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]ox y}- 3a,7,9 ,11 ,13 ,15 ,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa- 6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methylox an-3-yl acetate bromide

[00281] Γ8-Μ ,3-dioxo-2,3-dihvdro-1 H-isoindol-2-yl)octylltris(4 methoxyphenvQphosphonium bromide

[00282] A mixture of 2-(8-bromodecyl)isoindoline-1 ,3-dione (0.91 g, 2.70 mmol) and tris(4- methoxyphenyl)phosphine (1 g, 2.84 mmol) in MeCN (10 mL) was heated at 70 °C overnight. On cooling the solvent was removed in vacuo and the resulting residue purified by column chromatography eluting with 10% MeOH in DCM to give [8-(1 ,3-dioxo-2,3-dihydro-1 H- isoindol-2-yl)octyl]tris(4-methoxyphenyl)phosphonium bromide (1.56 g, 82%) as a white foam. [00283] 1 H NMR (Method A) (DMSO-d 6 ): δ (delta) ppm 7.88-7.81 (4H, m), 7.65 (6H, m), 7.28 (6H, m), 3.88 (9H, s), 3.54 (2H, t), 3.31 (2H, m), 1.61 -1 .36 (6H, m), 1.23 (6H, m); 31 P NMR (162 MHz, DMSO-de): δ (delta) ppm +21 .7 ppm; LC-MS (Method G) 610 [M] + ; RT 2.13 min

[00284] (8-aminooctyl)tris(4-methoxyphenyl)phosphonium bromide

[00285] To a solution of [8-(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)octyl]tris(4- methoxyphenyl)phosphonium bromide (prepared as described in Example 10 step (a)) (1.56 g, 2.26 mmol) in EtOH (20 mL) was added anhydrous hydrazine in THF (1 M, 5.65 mL). The resulting reaction mixture was refluxed for 18 h. On cooling the solvent was removed under vacuo and the resulting residue purified by column chromatography eluting with 0-100% EtOAc in DCM followed by 0-10% MeOH in DCM to give (8-aminooctyl)tris(4- methoxyphenylphosphonium bromide (0.65 g, 48%) as a white foam.

[00286] 1 H NMR (Method A) (DMSO-de): δ (delta) ppm 7.70-7.63 (6H, m), 7.62 (2H, broad s), 7.29 (6H, m), 3.89 (9H, s), 3.36 (2H, m), 2.78-2.70 (2H, t), 1.59-1.35 (6H, m), 1 .20 (6H, m); 31 P NMR (162 MHz, DMSO-d 6 ): δ (delta) ppm +21 .7 ppm; LC-MS (Method G) 480 [M] + ; RT 1 .28 min

[00287] (2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hvdroxy-

8-{r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5-r({8-rtris(4- methoxyphenyl)phosphoniumylloctyl)carbamoyl)oxyloxan-2-yllox y)-3a,7,9,1 1 ,13,15.16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacvclopentadecan-

10-vHoxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide

[00288] Prepared following the procedure of Example 1 step (c). Purification effected by column chromatography eluting with 0-10% MeOH/0.7 M NH 3 in DCM to give the title compound as a white foam. [00289] 1 H NMR (Method A) (DMSO-d 6 ): δ (delta) ppm 7.67 (dd, 6H), 7.29 (dd, 6H), 6.95 (t, J = 5.8 Hz, 1 H), 6.77 (s, 1 H), 4.90 (d, J = 4.9 Hz, 1 H), 4.79 (dd, J = 9.4, 3.2 Hz, 1 H), 4.60-4.50 (m,2H), 4.39 (d, J= 9.8 Hz, 1H), 4.29-4.15 (m, 3H), 4.04 (hept, J = 1.6, 0.8 Hz, 1H), 3.89 (s, 9H), 3.69-3.57 (m, 1H), 3.42 (d, J= 6.9 Hz, 1H), 3.40-3.31 (m, 2H), 3.25 (s, 3H), 3.18-2.99 (m, 1H), 2.98-2.83 (m, 1H), 2.82-2.74 (m, 1H), 2.68-2.58 (m, 1H), 2.37-2.28 (m, 2H), 2.27-2.20 (m, 1H), 2.18 (s, 6H), 2.08 (s, 3H), 1.95 (s, 3H), 1.92-1.86 (m, 1H), 1.86-1.78 (m, 2H), 1.78- 1.64 (m, 2H), 1.63-1.53 (m, 1H), 1.50-1.40 (m, 6H), 1.38-1.30 (m, 4H), 1.28-1.07 (m, 17H), 1.06-0.92 (m, 9H), 0.84 (t, J = 7.4 Hz, 9H); 31 P NMR (162 MHz, DMSO-d 6 ) δ +21.68 (s); LC- MS (Method E) 1323 [M] + ; RT 2.24 min

[00290] Example 11 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1-oxa-6-azacy clopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamate bromide

[00291] Prepared following the procedure of Example 2 using (2S,3R,4S,6R)-2-

{[(3aR,4RJR,8S,9S,10R,1 1 R,13R,16R,16aRH-ethyl-1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4- methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]ox y}-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-

10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in

Example 10). Purification effected by millipore filtration to give the title compound as a white foam. [00292] LC-MS (Method E) 1255.06 [M] + ; RT 2.07 min

[00293] Example 12 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13, 15,16-heptamethyl-2, 6-dioxo-tetradecahydro-2H-[1 , 3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-{8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamate bromide

[00294] Prepared following the procedure of Example 3 step (b) using (2S,3R,4S,6R)-2-

{[(3aR,4RJR,8S,9S,10R,1 1 R,13R,16R,16aRH-ethyl-1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4- methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]ox y}-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-

10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in

Example 10) to give the title compound as a white foam.

[00295] (LC-MS (Method E) 1281 .97 [M] + ; RT 2.10 min Example 13 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13, 15,16-heptamethyl-2, 6-dioxo-tetradecahydro-2H-[1 , 3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[7- (triphenylphosphoniumyl)heptyl]carbamate bromide |7-(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)heptylltriphenylphosphonium bromide

Prepared following the procedure of Example 1 step (a) using 2-(7-bromoheptyl)isoindole- 1 ,3-dione.

LC-MS (Method J) 506 [M] + ; RT 1 .18 min (7-aminoheptyl)triphenylphosphonium bromide

Prepared following the procedure of Example 1 step (b) using [7-(1 ,3-dioxo-2,3-dihydro-1 H- isoindol-2-yl)heptyl]triphenylphosphonium bromide (prepared as described in Example 13 step (a)).

LC-MS (Method I) 376 [M] + ; RT 1 .07 min (2S,3S,4R,6R)-6-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10-{r(2S,3R,4S,6R)-4-

(dimethylamino)-3-hvdroxy-6-methyloxan-2-ylloxyV4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan-8- vHoxy)-4-methoxy-2,4-dimethyloxan-3-yl N-[7-(triphenylphosphoniumyl)heptyllcarbamate bromide

Prepared by synthesis of (2S ! 3R ! 4S ! 6R)-2-{[(3aR ! 4R ! 7R ! 8S ! 9S ! 10R,1 1 R,13R,16R,16aR)-4- ethyl-1 1 -hydroxy-8-{[(2R ! 4R ! 5S ! 6S)-4-methoxy-4,6-dimethyl-5-({[7- (triphenylphosphoniumyl)heptyl]carbamoyl}oxy)oxan-2-yl]oxy}- 3a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide following the procedure of Example 1 step (c) using (7-aminoheptyl)triphenylphosphonium bromide (prepared as described in Example 13 step (b)) and DMAP, followed by removal of the acetate using the procedure of Example 3 step (b). Title compound isolated as a white solid.

LC-MS (Method H) 1 177 [M] + ; RT 8.78 min

Example 14 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[7- (triphenylphosphoniumyl)heptyl]carbamate bromide

Prepared following the procedure of Example 2 using (2S,3S,4R,6R)-6- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6- dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4- methoxy-2,4-dimethyloxan-3-yl N-[7-(triphenylphosphoniumyl)heptyl]carbamate bromide (prepared as described in Example 13). Title compound isolated as a white solid.

LC-MS (Method H) 1 151 [M] + ; RT 8.47 min

Example 15 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[9- (triphenylphosphoniumyl)nonyl]carbamate bromide

(9-aminononyl)triphenylphosphonium bromide

Prepared following the procedure of Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro-1 H- isoindol-2-yl)nonyl]triphenylphosphonium bromide (prepared as described in Chemistry - A European Journal 19 (39), 13017-13029, 2013).

LC-MS (Method I) 404 [M] + ; RT 1.26 min

(2S,3S,4R,6R)-6-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10-{r(2S,3R,4S,6R)-4- (dimethylamino)-3-hvdroxy-6-methyloxan-2-ylloxyV4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan-8- vHoxy)-4-methoxy-2,4-dimethyloxan-3-yl N-[9-(triphenylphosphoniumyl)nonyllcarbamate bromide

Prepared by synthesis of (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4- ethyl-1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-({[9- (triphenylphosphoniumyl)nonyl]carbamoyl}oxy)oxan-2-yl]oxy}-3 a,7,9,1 1 ,13,15,16- heptamethyl)-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide following the procedure of Example 1 step (c) using (9-aminononyl)triphenylphosphonium bromide (prepared as described in Example 15 step (a)) and DMAP, followed by removal of the acetate using the procedure of Example 3 step (b). Title compound isolated as a white solid. LC-MS (Method H) 1205 [M] + ; RT 9.50 min

Example 16 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[9- (triphenylphosphoniumyl)nonyl]carbamate bromide

Prepared following the procedure of Example 2 using (2S,3S,4R,6R)-6- { aR^RJR^S^S OR I R SR eR eaR^I O-i S^R^S^RH-idimethylamino)^- hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6- dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4- methoxy-2,4-dimethyloxan-3-yl N-[9-(triphenylphosphoniumyl)nonyl]carbamate bromide (prepared as described in Example 15). Title compound isolated as a white solid.

LC-MS (Method H) 1 179 [M] + ; RT 9.27 min

Example 17 - (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-4-ethyl-11 - hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-({[9-

(methyldiphenylphosphoniumyl)nonyl]carbamoyl}oxy)oxan-2-y l]oxy}- 3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa- 6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methylox an-3-yl acetate bromide [9-(1 ,3-dioxo-2,3-dihvdro-IH-isoindol-2-vO bromide

Prepared following the procedure in Example 1 step (a) using methyldiphenylphosphine. Purification by 0-10% MeOH in DCM.

LC-MS (Method J) 472 [M] + ; RT 1.49 min

(9-aminononyl)(methyl)diphenylphosphonium bromide

Prepared following the procedure in Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro-IH- isoindol-2-yl)nonyl](methyl)diphenylphosphonium bromide (prepared as described in

Example 17 step (a)). Purification by 0-100% EtOAc in DCM.

LC-MS (Method I) 342 [M] + ; RT 0.88 min

(2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R.1 1 R.13R.16R.16aR)-4-ethyl-1 1 -hydroxy-8- {r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5- r9- (methyldiphenylphosphoniumyl)nonyllcarbamoyl)oxy)oxan-2-yllo xy)-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan- 10-ylloxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide

Prepared following the procedure of Example 1 step (c) using (9- aminononyl)(methyl)diphenylphosphonium bromide (prepared as described in Example 17 step (b)). Purification by 0-3% MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.

LC-MS (Method H) 1085 [M] + ; RT 9.28 min

Example 18 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[9- (methyldiphenylphosphoniumyl)nonyl]carbamate bromide

Prepared following the procedure in Example 2 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H-hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[9-(methyldiphenylphosphoniumyl)non yl]carbamoyl}oxy)oxan-2- yl]oxy^3aJ,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-meth yloxan-3-yl acetate bromide (prepared as described in Example 17). Purification by 0-10% MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.

LC-MS (Method H) 1 1 17 [M] + ; RT 8.06 min

Example 19 - (2S,3S,4R,6R)-6-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-[9- (methyldiphenylphosphoniumyl)nonyl]carbamate bromide

Prepared following the procedure in Example 3 step (b) using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[9-(methyldiphenylphosphoniumyl)non yl]carbamoyl}oxy)oxan-2- yl]oxy}-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-meth yloxan-3-yl acetate bromide (prepared as described in Example 17). Title compound isolated as a white solid.

LC-MS (Method H) 1 143 [M] + ; RT 8.76 min

Example 20 - (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-8- {[(2R,4R,5S,6S)-5-[({9-[dimethyl(phenyl)phosphoniumyl]nonyl} carbamoyl)oxy]-4- methoxy-4,6-dimethyloxan-2-yl]oxy}-4-ethyl-11 -hydroxy-3a,7,9,11 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan -3-yl acetate bromide

[9-(1 ,3-dioxo-2,3-dihvdro-IH-isoindol-2-yl)nonylldimethylphenylph osphonium bromide

Prepared following the procedure in Example 1 step (a) using dimethylphenylphosphine. Purification by 0-20% MeOH in DCM.

LC-MS (Method J) 410 [M] + ; RT 1.09 min

(9-aminononyl)dimethylphenylphosphonium bromide

Prepared following the procedure in Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro-IH- isoindol-2-yl)nonyl]dimethylphenylphosphonium bromide (prepared as described in Example 20 step (a)). Purification by 0-100% EtOAc in DCM followed by 0-40% MeOH in DCM. LC-MS (Method I) 280 [M] + ; RT 0.61 min

(2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-8-{r(2R,4R,5S,6S)-5-r({9- [dimethyl(phenyl)phosphoniumyllnonyl)carbamoyl)oxyl-4-methox y-4,6-dimethyloxan-2- ylloxy)-4-ethyl-1 1 -hvdroxy-3aJ.9.1 1.13.15.16-heptamethyl-2.6-dioxo-tetradecahvdro-2H- [1 ,3ldioxolo[4,5-cl1 -oxa-6-azacvclopentadecan-10-vHoxy)-4-(dimethylamino)-6-meth yloxan- 3-yl acetate bromide

Prepared following the procedure of Example 1 step (c) using (9- aminononyl)dimethylphenylphosphonium bromide (prepared as described in Example 20 step (b)). Purification by 0-10% MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.

LC-MS (Method H) 1 123 [M] + ; RT 8.59 min

Example 21 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{9-

[dimethyl(phenyl)phosphoniumyl]nonyl}carbamate bromide

Prepared following the procedure in Example 2 using (2S,3R,4S,6R)-2- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-8-{[(2R,4R,5S,6S)-5-[({9- [dimethyl(phenyl)phosphoniumyl]nony^

yl]oxy}-4-ethyl-1 1 -hydroxy-3a ,7,9 ,1 1 ,13 ,15 ,16-heptamethyl-2,6-dioxo-tetradecahydro-2H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-met hyloxan- 3-yl acetate bromide (prepared as described in Example 20). Purification by 0-10%

MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.

LC-MS (Method H) 1055 [M] + ; RT 7.50 min

Example 22 - (2S,3S,4R,6R)-6-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-y l]oxy}-4-ethyl-11 - hydroxy-3a,7,9 A 1 A 3,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethylox an-3-yl N-{9- [dimethyl(phenyl)phosphoniumyl]nonyl}carbamate bromide

Prepared following the procedure in Example 3 step (b) using (2S,3R,4S,6R)-2- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-8-{[(2R,4R,5S,6S)-5-[({9- [dimethyl(phenyl)phosphoniumyl]nonyl}carbamoyl)oxy]-4-methox y-4,6-dimethyloxan-2- yl]oxy}-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-met hyloxan- 3-yl acetate bromide (prepared as described in Example 20). Purification by 0-10%

MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white solid.

LC-MS (Method H) 1081 [M] + ; RT 7.79 min [00296] Antibacterial susceptibility testing

[00297] The minimum inhibitory concentration (MICs) versus planktonic bacteria are determined by the broth microdilution procedure according to the guidelines of the Clinical and Laboratory Standards Institute (Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard- 10 th Ed. CLSI document M7-A10, 2015). The broth dilution method involves a two-fold serial dilution of compounds in 96-well microtitre plates, giving a final concentration range of 0.25-128 μg (micrograms)/ml_ and a maximum final concentration of 1 % DMSO. The bacterial strains tested include the Gram-positive strains Staphylococcus aureus ATCC 29213, Staphylococcus aureus NRS 384, Streptococcus pneumoniae ATCC49619, Streptococcus pneumoniae 5174.00 and the Gram negative strains Acinetobacter baumannii ATCC BAA 747, Acinetobacter baumannii NCTC 13301 , Escherichia coli ATCC 25922, Escherichia coli ATCC BAA-2469, Klebsiella pneumoniae ATCC 43816, Klebsiella pneumoniae ATCC BAA-2146, Neisseria gonorrhoeae ATCC49226, Neisseria gonorrhoeae NCTC 13481 , Pseudomonas aeruginosa ATCC 27853, Pseudomonas aeruginosa N CTC 13437.

[00298] Strains were grown in cation-adjusted Muller-Hinton broth (caMHB) in Corning #3370 polystyrene, non-treated, flat bottomed 96-well plates. For testing Streptococcus pneumoniae, caMHB was supplemented with 5% v/v lysed horse blood, and testing performed in U-well plates (Corning #3788). For testing Neisseria gonorrhoeae assays were performed using agar-incorporation of test articles. Stock test compound solutions were prepared in sterile DMSO and diluted in the appropriate growth medium to provide a test range of 128 to 0.25 μg(micrograms)/mL and maximum final concentration of 1 % DMSO. Doxycycline was prepared in sterile water. Azithromycin was prepared in 95% EtOH.

[00299] Assay plates were incubated at 37 °C in air for 16 to 20 h, except for Streptococcus pneumoniae (which was incubated for 20 to 24 h) and Neisseria gonorrhoeae (which was incubated for 20 to 24 h under 5% CO2). Endpoints were determined visually (all assays) and by spectrophotometer at 600 nm (all assays except Streptococcus pneumoniae and Neisseria gonorrhoeae). The MIC is determined as the lowest concentration of test compound that completely inhibits visible growth of the bacteria and is reported in Table 1. In Table 1 an MIC (in μg (micrograms)/ml_) of less or equal to 1 is assigned the letter A; a MIC of from 1 to 10 is assigned the letter B; a MIC of from 10 to 50 is assigned the letter C; a MIC of from 50 to 100 assigned the letter D; and a MIC of over 100 is assigned the letter E.

[00300] The compounds of the invention all showed activity against bacterial pathogens with many showing improved activity relative to azithromycin. In particular, many of the compounds showed good activity against resistant strains of Gram-negative bacteria against which the established antibiotics doxycycline and azithromycin were only poorly active. Examples

Strain

1 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Doxycydine Azithromycin

E. coli

B B B C B B E C B B B B B B B A C

ATCC 25922

E. coli

B B B B B D D C B B B B D B B C D

ATCC BAA-2469

P. aeruginosa

B B B B B C E c B B B B C B B C D

ATCC 27853

P. aeruginosa

B B B C B C E c B B B B C B B E D

NCTC 13437

/ . baumannii

B B B B B B E B B B B B B B A A B

ATCC BAA 747

/ . baumannii

C B D C C D E D D C C C E B C A D

NCTC 13301

K. pneumoniae

B B B C B C E C B B B B C B B B C

ATCC 43816

K. pneumoniae

B B B C B C E C B B B B D B B D D

ATCC BAA-2146

Λ/. gonorrhoeae

B B B B B B B B B B B A A

ATCC 49226

Λ/. gonorrhoeae

B B B B A B B B B B B A A

NCTC 13841

S. aureus

A B A A A B A B A A A A A A A A B

ATCC 29213

S. aureus

A A B B A B B B A B B B B B B A E

NRS 384

S. pneumoniae

A A A A A A A A A A A A A A A A A

ATCC 49619

S. pneumoniae

A A A A A A A A B A A A A A A B B

5174-00

Table 1