The present invention concerns heteroaromatic antibacterial compounds, pharmaceutical compositions containing them and uses of these compounds in the manufacture of medicaments for the treatment of bacterial infections. These compounds are useful antimicrobial agents effective against a variety of human and veterinary pathogens, especially Gram negative aerobic and anaerobic bacteria. The compounds of the present invention can optionally be employed in combination, either sequentially or simultaneously, with one or more therapeutic agents effective against bacterial infections.

The intensive use of antibiotics has exerted a selective evolutionary pressure on microorganisms to produce genetically based resistance mechanisms. Modern medicine and socio-economic behaviour exacerbate the problem of resistance development by creating slow growth situations for pathogenic microbes, e.g. in artificial joints, and by supporting long-term host reservoirs, e.g. in immune-compromised patients. In hospital settings, an increasing number of strains of Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp., Enterobacteriaceae such as Klebsiella pneumonia, Acinetobacter baumannii and Pseudomonas aeruginosa, major sources of infections, are becoming multi-drug resistant and therefore difficult if not impossible to treat. This is particularly the case for Gram-negative organisms where the situation is getting worrisome since no novel agents have been approved for decades and the development pipeline looks empty.

Therefore, there is an important medical need for new antibacterial compounds addressing Gram-negative resistant bacteria, in particular third generation cephalosporins- and carbapenem- resistant Klebsiella pneumoniae and multi-drug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. One way to tackle the problem of cross resistance to established classes of antibiotics is to inhibit a new essential target. In this respect, LpxC, which is an enzyme in the biosynthesis of lipopolysaccharides (a major constituent of the outer membrane of Gram-negative bacteria), has received some attention.

In WO2015132228 and WO2017037221 we have reported certain antibacterial derivatives. 1 ) One embodiment of the invention relates to compounds of formula I

I, wherein

M rep

wherein

the symbol " * " denotes the point of attachment to the pyrroloimidazolone bicyclic ring system and the symbol " ** " denotes the point of attachment to the group A;

X represents sulfur or oxygen;

R ^3C represents hydrogen, halogen (especially fluorine) or (Ci-C3)alkyl (especially methyl);

A represents a group selected from a list consisting of A ^A , A ^B , A ^c , A ^D , A ^E , A ^F , A ^G and A ^H as defined below:

A ^D A ^E A ^F

A ^G A ^H

wherein

the symbol "***" denotes the point of attachment to the group M;

R ^1A represents hydrogen, to-hydroxy-(Ci-C3)alkyl, 1 -ami nocycloprop- 1 -yl , 1-(3-fluoroazetidin-1- yl)methylcycloprop-1-yl, 1-(3-hydroxyazetidinecarbonyloxymethyl)cycloprop-1-yl, 1 -hydroxycycloprop-1 -yl, 1- hydroxymethylcycloprop-1-yl, 2-(1 ,2-dihydroxyethyl)cycloprop-1-yl, 3-hydroxy-oxetan-3-yl, 3- (hydroxymethyl)oxetan-3-yl, 1-methylazetidin-3-yl, 1-(morpholin-4-yl-methyl)cycloprop-1-yl, or 1- (tetrahydrofuran-3-yl)oxycarbonylazetidin-3-yl;

R ^1B represents -hydroxy-(Ci-C3)alkyl , 1 -hydroxymethylcycloprop-1 -yl or 2-(1 ,2-dihydroxyethyl) cycloprop-1- yi;

R ^1C represents hydroxy, ω-hydroxy-(C1-C3)alkyl, 3-hydroxy-oxetan-3-yl, 3-(hydroxymethyl)oxetan-3-yl, 1- hydroxycycloprop-1-yl, 1-hydroxymethylcycloprop-1-yl, 2-(1 ,2-dihydroxyethyl)cycloprop-1-yl, 1-oxoprop-1-yl, 1 -(3-fluoroazetidin-1 -yl)prop-1 -yl, 1 -(3-fluoroazetidin-1 -yl)methylcycloprop-1 -yl, 1 -(3-hydroxyazetidine carbonyloxymethyl)cycloprop-1 -yl or 1 -(morpholin-4-yl-methyl)cycloprop-1 -yl;

R ^1D represents methyl or 2-hydroxyethyl;

R ^3E represents hydrogen, to-hydroxy-(Ci-C3)alkyl, oxetan-3-yl, 1 ,2-dihydroxyethyl, 1-(oxetan-3- yl methyl )azetid in-3-y I , (1-methyl)azetidin-3-yl or (3-fluoroazetidin-1-yl)methyl-;

R ^2F represents hydrogen or ω-hydroxy-(C1-C3)alkyl;

R ^5H represents hydrogen; and

R ¹ represents hydrogen, -P(0)(OH) ₂ , -S(0)2(OH), phosphonooxymethyl or L represented below:

L

wherein

R ² represents (Ci-C4)alkylamino(Ci-C4)alkyl, [di(Ci-C4)alkylamino](Ci-C4)alkyl, phosphonooxy(Ci-C4)alkyl, phosphonooxymethoxy, 2-(phosphonooxy-(Ci-C4)alkyl)-phenyl, (2-(phosphonooxy)-phenyl)-(Ci-C4)alkyl (especially 2-(2-(phosphonooxy)-phenyl)-ethyl) or [2-(phosphonooxy-(Ci-C4)alkyl)-phenyl]-(Ci-C4)alkyl;

or salts (in particular pharmaceutically acceptable salts) thereof. It is understood that compounds of formula I, wherein R ¹ is -P(0)(OH)2 , -S(0)2(OH), phosphonooxymethyl or L represent prodrugs.

In particular:

the prodrug comprising the group (di(Ci-C4)alkylamino)-(Ci-C4)alkyl-carbonyloxy (occurring when R ² represents [di(Ci-C4)alkylamino](Ci-C4)alkyl)) notably refers to dimethylaminoacetoxy;

❖ the prodrug comprising the group [2-(phosphonooxy-(Ci-C4)alkyl)-phenyl]-carbonyloxy (occurring when R ² represents 2-(phosphonooxy-(Ci-C4)alkyl)-phenyl) notably refers to one of the groups represented below

the prodrug comprising the group [(2-phosphonooxy-phenyl)-(Ci-C4)alkyl]-carbonyloxy (occurring when R ² represents (2-(phosphonooxy)-phenyl)-(Ci-C4)alkyl) notably refers to one of the groups represented below

It is understood that further prodrugs may be formed by substituting a hydrogen of a hydroxy group, wherein said hydroxy group is present in R ^A , R ^B , R ^C , R ^D , R ^3E or R ^2F ; by any one of -P(0)(OH) ₂ , -S(0) ₂ (OH), phosphonooxymethyl or L.

2) Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R ¹ represents hydrogen.

3) Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R ¹ represents -P(0)(OH) ₂ .

4) Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R ¹ represents -S(0) ₂ (OH).

5) Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R ¹ represents phosphonooxymethyl. 6) Another embodiment of the invention relates to compounds according to embodiment 1 ) wherein R ¹ represents L as defined in embodiment 1 ).

7) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^A .

8) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^B .

9) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^c .

10) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^D .

11 ) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^E .

12) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^F .

13) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^G .

14) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^H .

15) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M'.

16) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^J .

17) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^A , M ^B or M ^c .

18) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^D , M ^E , M ^F M ^G , M ^H or M'.

19) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents M ^A , M ^B , M ^c M ^D , M ^F or M'.

20) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 15) or 17) to 19), wherein X represents sulfur.

21 ) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 15) or 17) to 19), wherein X represents oxygen.

22) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein R ^1A represents hydrogen, 1 -hydroxycycloprop-1 -yl, 1 -a m i n ocy cl o pro p- 1 -yl , 3-hydroxy-oxetan-3-yl, 1- hydroxymethylcycloprop-1 -yl, 3-(hydroxymethyl)oxetan-3-yl or 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl;

R ^1B represents 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl;

R ^1C represnts -hydroxy-(Ci-C3)alkyl, 2-(1 ,2-dihydroxyethyl)cycloprop-1 -yl, 3-hydroxy-oxetan-3-yl, 1- hydroxymethylcycloprop-1-yl, 1 -hydroxycycloprop-1 -yl or 1-oxoprop-1-yl;

R ^3E represents -hydroxy-(Ci-C3)alkyl, 1 ,2-dihydroxyeth-2-yl or (3-fluoroazetidin-1 -yl)methyl; and

R ^2F represents hydrogen.

23) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^A .

24) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^B .

25) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^c .

26) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^D .

27) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^E .

28) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^F .

29) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^G .

30) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to

21 ) , wherein A represents A ^H .

31 ) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^A , A ^B , A ^c , A ^E , A ^F or A ^G .

32) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to

22) , wherein A represents A ^A , A ^c or A ^D .

33) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^A , A ^B , A ^c , A ^E or A ^F .

34) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^A , A ^B , A ^c , A ^E or A ^F ; and R ^1A , R ^1B R ^1C , R ^3E and R ^2F are as defined in embodiment 22). 35) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^A , A ^B , A ^c , A ^E or A ^G .

36) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^E ; and R ^3E is as defined in embodiment 22).

37) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^A or A ^E .

38) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^A or A ^E ; and R ^1A and R ^3E are as defined in embodiment 22).

39) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 22), wherein A represents A ^E , A ^F or A ^H .

40) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^E or A ^F .

41 ) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 21 ), wherein A represents A ^E or A ^F ; and R ^3E and R ^2F are as defined in embodiment 22).

42) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M ^A , M ^B , M ^E , M ^F or M'; and A represents A ^A , A ^B , A ^E , A ^F or A ^c .

43) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M ^D , M ^E , M ^F , M ^G , M ^H or M'; and A represents A ^A , A ^B , A ^F , A ^E or A ^c .

44) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), 20) or 22); wherein M represents M ^A , M ^B or M ^c ; and A represents A ^A , A ^B , A ^F , A ^E or A ^c .

45) Another embodiment of the invention relates to compounds according to any one of embodiments 1 ) to 6), wherein M represents the group M ^c ; X represents sulfur; A represents A ^A ; and R ^1A represents hydrogen, 1 -hydroxycycloprop-1 -yl , 1-aminocycloprop-1 -yl, 3-hydroxy-oxetan-3-yl, 1- hydroxymethylcycloprop-1-yl, 3-(hydroxymethyl)oxetan-3-yl or 2-( 1 ,2-d i h yd roxy ethyl )cycl o prop- 1 -y I . 46) Another embodiment of the invention relates to compounds according to embodiment 1 ), selected from the group consisting of:

(2R)-4-(6-(5-ethynylthiophen-3-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide;

(2R)-4-(6-(4-ethynylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide;

(2R)-4-(6-(5-ethynylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide;

(2R)-4-(6-(4-ethynylfuran-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide; (2R)-4-(6-(4-cyclopropylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A -hydroxy-2-methyl-2- (methylsulfonyl)butanamide;

(2R)-4-(6-(5-cyanothiophen-2-yl)-3-oxo-1 H-pyrrolo^

(methylsulfonyl)butanamide;

(2R)-4-(6-(5-cyanothiophen-2-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-4-(6-(4-((1-aminocyclopropyl)ethynyl)thiophen-2-yl)- 3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-4-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol- 2(3/-/)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-4-(6-(5-ethynylfuran-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-

2- methyl-2-(methylsulfonyl)butanamide;

(2R)-N-hydroxy-4-(6-(5-((methoxyimino)methyl)thiophen-3-y l)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy -(6-(4-(3-hydroxyprop-1-yn-1-yl)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy4-(6-(4-((1 S*,2S*)-2-(hydroxymethyl)cyclopropyl)thiophen-2-yl)-

3- 0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

(2R,E)-A/-hydroxy-4-(6-(4-(3-hydroxyprop-1 -en-1-yl)thiophen-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

(2R)-A/-hydroxy4-(6-(5-(2-hydroxyethyl)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(3-oxo-6-(2-phe nyloxazol-4-yl)-

1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-4-(6-(4-((E)-2-((1 S,2S)-2-((2R)-1 ,2-dihydroxyethyl)cyclopropyl)vinyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(3-oxo-6-(2-phe nylthiazol-5-yl)-

1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-4-(6-(4-(((1 S,2S)-2-(1 ,2-dihydroxyethyl)cyclopropyl)ethynyl)thiophen-2-yl)- 3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl ) butanamide;

(2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phe nylthiazol-2-yl)-

1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-N-hydroxy-4-(6-(4-(3-hydroxypropyl)thiophen-2-yl)-3-oxo -

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(3-oxo-6-(5- phenylthiazol-2-yl)-

1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide; (2R)-4-(6-(4-fluoro-5-(3-hydroxypropyl)thiophen-2-yl)-3-oxo- 1 - -pyrrolo[1 ,2-c]imidazol-2(3 V)-yl)-A-hydroxy-2-methyl-2-(methylsulfonyl)butanaiTiide; (2R)-A/-hydroxy-4-(6-(4-((3-hydroxyoxetan-3-yl)ethynyl)furan -2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-W-hydroxy-2-methyl-2-(methylsulfonyl) -(3-oxo-6-(5-(thiophen-2-yl)isoxazol-3-yl)-1 H-pyTO c]imidazol-2(3/-/)-yl)butanamide;

(2R)-A/-hydroxy-4-(6-(5-(3-hydroxypropyl)thiophen-3-yl)-3-ox o- 1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-4-(6-(5-(4-(2-hydroxyethyl)phenyl)thiophe n-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-ph enylisoxazol-3-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-ph enyloxazol-2-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5 -phenyloxazol-2-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-ph enylisoxazol-5-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl) -(3-oxo-6-(3-phenylisoxazol-5-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-ph enylisoxazol-5-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-ph enylthiophen-2-yl)- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-4-(6-(5-cyclopropylisoxazol-3-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)- A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-

4-(3-oxo-6-(3-phenyl-1 ,2,4-oxadiazol-5-yl)-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-4-(6-(4-(2-((1 R,2S)-2-((2R)-1 ,2-dihydroxyethyl)cyclopropyl)ethyl)thiophen-2-yl)- 3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-4-(6-(5-((1-aminocyclopropyl)ethynyl)thiazol-2-yl)-3 -oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide;

(2R)-4-(6-(5-((1-aminocyclopropyl)ethynyl)thiazol-2-yl)-3 -oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide; (2R)-A/-hydroxy -(6-(5-((1 -(hydroxymethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-

1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide; (2R)-N-hydroxy -(6-(3-(4-(2-hydroxyethyl)phenyl)isoxazol-5-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy -(6-(4-((1 -(hydroxymethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy4-(6-(5-((3-(hydroxymethyl)oxetan-3-yl)eth ynyl)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy4-(6-(5-(2-(3-(hydroxymethyl)oxetan-3-yl)ethy l)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy4-(6-(5-((3-hydroxyoxetan-3-yl)ethynyl)thioph en-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e;

(2R)-A/-hydroxy-4-(6-(5-(2-(3-hydroxyoxetan-3-yl)ethyl)thiop hen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy4-(6-(5-(2-(1 -(hydroxymethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-4-(6-(5-((E)-2-((1 S,2S)-2-((2R)-1 ,2-dihydroxyethyl)cyclopropyl)vinyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-A/-hydroxy-2-methyl-4-(6-(4-((1 -methylazetidin-3-yl)ethynyl)thiophen-2-yl)-3-oxo-

1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-(methylsulfonyl)butanamide;

(2R)-4-(6-(4-(azetidin-3-ylethynyl)thiophen-2-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-A/-hydroxy-4-(6-(5-(4-(2-hydroxyethyl)phenyl)thiazol-2- yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-4-(6-(2-(4-(2-hydroxyethyl)phenyl)thiazol-5- yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-4-(6-(5-(((1 S,2S)-2-(- (2R)-1 ,2-dihydroxyethyl)cyclopropyl)ethynyl)thiophen-2-yl)-

3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(6-(4-(4-(ox etan-3-yl)phenyl)thiophen-

2- yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(6-(5-(4-(ox etan-3-yl)phenyl)thiophen- 2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide;

(2R)-4-(6-(5-(((1 S,2S)-2-((2R)-1 ,2-dihydroxyethyl)cyclopropyl)ethyl)thiophen-2-yl)-

3- 0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide; (2R,E)-A/-hydroxy-4-(6-(4-(2-(1 -(hydroxymethyl)cyclopropyl)vinyl)thiophen-2-yl)-

3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-4-(6-(5-((1 -hydroxycyclopropyl)ethynyl)thiophen-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide; (2R)-A/-hydroxy-4-(6-(5-((1 -(hydroxymethyl)cyclopropyl)ethynyl)furan-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-4-(6-(5-((1 -(hydroxymethyl)cyclopropyl)ethynyl)furan-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy -(6-(4-(2-(1 -(hydroxymethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy -(6-(4-(2-(1 -(hydroxymethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-A/-hydroxy-4-(6-(5-(2-(1 -hydroxycyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e;

(2R)-W-hydroxy-2-methyl-2-(methylsulfonyl) -(3-oxo-6-(5-(3-oxopentyl)thiophen-2-yl)-1 H-pyrrolo[1 ,2 c]imidazol-2(3/-/)-yl)butanamide;

(2R)-A/-hydroxy-4-(6-(5-(2-(1 -hydroxycyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-(1 -((5-(2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4-oxob utyl)-3-oxo-

2,3-dihydro-1 /-/-pyrrolo[1 ,2-c]imidazol-6-yl)thiophen-2-yl)ethynyl)cyclopropyl)methyl

3-hyd roxyazetid i ne- 1 -carboxy late ;

(2R)-4-(6-(5-((3RS)-3-(3-fluoroazetidin-1-yl)pentyl)thiophen -2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-4-(6-(4-fluoro-5-((3-hydroxyoxetan-3-yl)ethynyl)thio phen-2-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-4-(6-(2-(4-((2S)-1 ,2-dihydroxyethyl)phenyl)thiazol-5-yl)-3-oxo-

1 H-pyrrolo[1 ,2-c]imidazol-2(3/^-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

(2R)-4-(6-(2-(4-((2R)-1 ,2-dihydroxyethyl)phenyl)thiazol-5-yl)-3-oxo- 1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide;

(2R)-A -hydroxy-2-methyl-2-(methylsulfonyl)-4-

(6-(5-((1 -(morpholinomethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo- 1 - -pyrrolo[1 ,2-c]imidazol-2(3 -/)- yl)butanamide;

(2R)-4-(6-(5-((1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl) ethynyl)thiophen-2-yl)- 3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl)4-(6-(2-(4-(ox etan-3-yl)phenyl)thiazol-5- yl)-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)butanamide;

(2R)-A/-hydroxy4-(6-(5-((1 -(hydroxymethyl)cyclopropyl)ethynyl)thiazol-2-yl)-

3-0X0-1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanam ide;

(2R)-4-(6-(4-cyclopropylthiazol-2-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide; (2R)-W-hydroxy -(6-(5-(((2-hydroxyethoxy)imino)methyl)thiophen-3-yl)-3-oxo- 17-pyrrolo[1 ,2-c]imidazol-2(3V)-yl)-2-methyl-2-(methylsulfonyl)butanamid e;

(2R)-W-hydroxy-2-methyl-4-(6-(2-(4-(1-methylazetidin-3-yl)ph enyl)thiazol-5-yl)-3-oxo- 1/-/-pyrrolo[1,2-c]imidazol-2(3/-/)-yl)-2-(methylsulfonyl)bu tanamide;

(2R)-W-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(2-(4-(1-(ox etan-3-ylmethyl)azetidin- 3-yl)phenyl)thiazol-5-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2( 3/-/)-yl)butanamide;

(2R)-4-(6-(5-(2-(1-((3-fluoroazetidin-1-yl)methyl)cyclopropy l)ethyl)thiophen-2-yl)-

3- oxo-1 --pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-/V-hydroxy-2-methyl-2-(methylsulfony l)butanamid;

(2R)-4-(6-(5-(2-(1-((3-fluoroazetidin-1-yl)methyl)cyclopropy l)ethyl)thiophen-2-yl)- 3-oxo-1 --pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-/V-hydroxy-2-methyl-2-(methylsulfony l)butanamide;

(2R)-A/-hydroxy-2-methyl-2-(methylsulfonyl) -(6-(5-(2-

(1-(morpholinomethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-o xo-1 --pyrrolo[1 ,2-c]imidazol-2(3-)- yl)butanamide;

(2RS)-tetrahydrofuran-3-yl 3-((5-(2-((2R) -(hydroxyamino)-3-methyl-3- (methylsulfonyl)-4-oxobutyl)-3-oxo-2,3-dihydro-1 H-pyrrolo[1 ,2-c]imidazol-6-yl)thiophen-2- yl)ethynyl)azetidine-1-carboxylate;

(2R)-/V-hydroxy-2-methyl-2-(methylsulfonyl)-

4- (6-(5-(2-(1-(morpholinomethyl)cyclopropyl)ethyl)thiophen-2-y l)-3-oxo-1 --pyrrolo[1 ,2-c]imidazol-2(3-)- yl)butanamide; and

(2R) -(6-(4-((1-((1-fluoroazetidin-3-yl)methyl)cyclopropyl)ethyny l)furan-2-yl)-3-oxo-1H-pyrrol^ c]imidazol-2(3/-/)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl )butanamide;

or salts (in particular pharmaceutically acceptable salts) thereof.

47) Another embodiment of the invention relates to a compound according to embodiment 1), which is (2R)- 2-(3-((4-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1H-pyrrolo[1,2 -c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)butanamido)oxy)-3-oxopropyl)phenyl dihydrogen phosphate; or a salt (in particular pharmaceutically acceptable salts) thereof.

Based on the dependencies of the different embodiments 1) to 47) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form: 2+1, 3+1 , 4+1 , 5+1 , 6+1 , 7+1 , 7+2+1 , 7+3+1 , 7+4+1 , 7+5+1 , 7+6+1 , 8+1 , 8+2+1 , 8+3+1 , 8+4+1 , 8+5+1 , 8+6+1 , 9+1 , 9+2+1, 9+3+1, 9+4+1, 9+5+1, 9+6+1, 10+1, 10+2+1, 10+3+1, 10+4+1, 10+5+1, 10+6+1, 11+1, 11+2+1, 11+3+1, 11+4+1, 11+5+1, 11+6+1, 12+1, 12+2+1, 12+3+1, 12+4+1, 12+5+1, 12+6+1, 13+1, 13+2+1, 13+3+1, 13+4+1, 13+5+1, 13+6+1, 14+1, 14+2+1, 14+3+1, 14+4+1, 14+5+1, 14+6+1, 15+1, 15+2+1, 15+3+1, 15+4+1, 15+5+1, 15+6+1, 16+1, 16+2+1, 16+3+1, 16+4+1, 16+5+1, 16+6+1, 17+1, 17+2+1, 17+3+1, 17+4+1, 17+5+1, 17+6+1, 18+1, 18+2+1, 18+3+1, 18+4+1, 18+5+1, 18+6+1, 19+1, 19+2+1, 19+3+1, 19+4+1, 19+5+1, 19+6+1, 20+1, 20+2+1, 20+3+1, 20+4+1, 20+5+1, 20+6+1, 20+7+1, 20+7+2+1, 20+7+3+1, 20+7+4+1, 20+7+5+1, 20+7+6+1, 20+8+1, 20+8+2+1, 20+8+3+1, 20+8+4+1, 20+8+5+1, 20+8+6+1, 20+9+1, 20+9+2+1, 20+9+3+1, 20+9+4+1, 20+9+5+1, 20+9+6+1, 20+10+1, 20+10+2+1, 20+10+3+1, 20+10+4+1, 20+10+5+1, 20+10+6+1, 20+11+1, 20+11+2+1, 20+11+3+1, 20+11+4+1, 20+11+5+1, 20+11+6+1, 20+12+1, 20+12+2+1, 20+12+3+1, 20+12+4+1, 20+12+5+1, 20+12+6+1, 20+13+1, 20+13+2+1, 20+13+3+1, 20+13+4+1, 20+13+5+1, 20+13+6+1, 20+14+1, 20+14+2+1, 20+14+3+1, 20+14+4+1, 20+14+5+1, 20+14+6+1, 20+15+1, 20+15+2+1, 20+15+3+1, 20+15+4+1, 20+15+5+1, 20+15+6+1, 20+16+1, 20+16+2+1 20+16+3+1, 20+16+4+1, 20+16+5+1, 20+16+6+1, 20+17+1, 20+17+2+1, 20+17+3+1, 20+17+4+1, 20+17+5+1 20+17+6+1, 20+18+1, 20+18+2+1, 20+18+3+1, 20+18+4+1, 20+18+5+1, 20+18+6+1, 20+19+1, 20+19+2+1 20+19+3+1, 20+19+4+1, 20+19+5+1, 20+19+6+1, 21+1, 21+2+1, 21+3+1, 21+4+1, 21+5+1, 21+6+1, 21+7+1 21+7+2+1, 21+7+3+1, 21+7+4+1, 21+7+5+1, 21+7+6+1, 21+8+1, 21+8+2+1, 21+8+3+1, 21+8+4+1, 21+8+5+1 21+8+6+1, 21+9+1, 21+9+2+1, 21+9+3+1, 21+9+4+1, 21+9+5+1, 21+9+6+1, 21+10+1, 21+10+2+1, 21+10+3+1 21+10+4+1, 21+10+5+1, 21+10+6+1, 21+11+1, 21+11+2+1, 21+11+3+1, 21+11+4+1, 21+11+5+1, 21+11+6+1 21+12+1, 21+12+2+1, 21+12+3+1, 21+12+4+1, 21+12+5+1, 21+12+6+1, 21+13+1, 21+13+2+1, 21+13+3+1 21+13+4+1, 21+13+5+1, 21+13+6+1, 21+14+1, 21+14+2+1, 21+14+3+1, 21+14+4+1, 21+14+5+1, 21+14+6+1 21+15+1, 21+15+2+1, 21+15+3+1, 21+15+4+1, 21+15+5+1, 21+15+6+1, 21+16+1, 21+16+2+1, 21+16+3+1 21+16+4+1, 21+16+5+1, 21+16+6+1, 21+17+1, 21+17+2+1, 21+17+3+1, 21+17+4+1, 21+17+5+1, 21+17+6+1 21+18+1, 21+18+2+1, 21+18+3+1, 21+18+4+1, 21+18+5+1, 21+18+6+1, 21+19+1, 21+19+2+1, 21+19+3+1 21+19+4+1, 21+19+5+1, 21+19+6+1, 22+1, 22+2+1, 22+3+1, 22+4+1, 22+5+1, 22+6+1, 22+7+1, 22+7+2+1, 22+7+3+1 22+7+4+1, 22+7+5+1, 22+7+6+1, 22+8+1, 22+8+2+1, 22+8+3+1, 22+8+4+1, 22+8+5+1, 22+8+6+1, 22+9+1, 22+9+2+1 22+9+3+1, 22+9+4+1, 22+9+5+1, 22+9+6+1, 22+10+1, 22+10+2+1, 22+10+3+1, 22+10+4+1, 22+10+5+1, 22+10+6+1 22+11+1, 22+11+2+1, 22+11+3+1, 22+11+4+1, 22+11+5+1, 22+11+6+1, 22+12+1, 22+12+2+1, 22+12+3+1 22+12+4+1, 22+12+5+1, 22+12+6+1, 22+13+1, 22+13+2+1, 22+13+3+1, 22+13+4+1, 22+13+5+1, 22+13+6+1 22+14+1, 22+14+2+1, 22+14+3+1, 22+14+4+1, 22+14+5+1, 22+14+6+1, 22+15+1, 22+15+2+1, 22+15+3+1 22+15+4+1, 22+15+5+1, 22+15+6+1, 22+16+1, 22+16+2+1, 22+16+3+1, 22+16+4+1, 22+16+5+1, 22+16+6+1 22+17+1, 22+17+2+1, 22+17+3+1, 22+17+4+1, 22+17+5+1, 22+17+6+1, 22+18+1, 22+18+2+1, 22+18+3+1 22+18+4+1, 22+18+5+1, 22+18+6+1, 22+19+1, 22+19+2+1, 22+19+3+1, 22+19+4+1, 22+19+5+1, 22+19+6+1 22+20+1, 22+20+2+1, 22+20+3+1, 22+20+4+1, 22+20+5+1, 22+20+6+1, 22+20+7+1, 22+20+7+2+1, 22+20+7+3+1 22+20+7+4+1, 22+20+7+5+1, 22+20+7+6+1, 22+20+8+1, 22+20+8+2+1, 22+20+8+3+1, 22+20+8+4+1, 22+20+8+5+1 22+20+8+6+1, 22+20+9+1, 22+20+9+2+1, 22+20+9+3+1, 22+20+9+4+1, 22+20+9+5+1, 22+20+9+6+1, 22+20+10+1 22+20+10+2+1, 22+20+10+3+1, 22+20+10+4+1, 22+20+10+5+1, 22+20+10+6+1, 22+20+11+1, 22+20+11+2+1 22+20+11+3+1, 22+20+11+4+1, 22+20+11+5+1, 22+20+11+6+1, 22+20+12+1, 22+20+12+2+1, 22+20+12+3+1 22+20+12+4+1, 22+20+12+5+1, 22+20+12+6+1, 22+20+13+1, 22+20+13+2+1, 22+20+13+3+1, 22+20+13+4+1 22+20+13+5+1, 22+20+13+6+1, 22+20+14+1, 22+20+14+2+1, 22+20+14+3+1, 22+20+14+4+1, 22+20+14+5+1 22+20+14+6+1, 22+20+15+1, 22+20+15+2+1, 22+20+15+3+1, 22+20+15+4+1, 22+20+15+5+1, 22+20+15+6+1 22+20+16+1, 22+20+16+2+1, 22+20+16+3+1, 22+20+16+4+1, 22+20+16+5+1, 22+20+16+6+1, 22+20+17+1 22+20+17+2+1, 22+20+17+3+1, 22+20+17+4+1, 22+20+17+5+1, 22+20+17+6+1, 22+20+18+1, 22+20+18+2+1 22+20+18+3+1, 22+20+18+4+1, 22+20+18+5+1, 22+20+18+6+1, 22+20+19+1, 22+20+19+2+1, 22+20+19+3+1 22+20+19+4+1, 22+20+19+5+1, 22+20+19+6+1, 22+21+1, 22+21+2+1, 22+21+3+1, 22+21+4+1, 22+21+5+1 22+21+6+1, 22+21+7+1, 22+21+7+2+1, 22+21+7+3+1, 22+21+7+4+1, 22+21+7+5+1, 22+21+7+6+1, 22+21+8+1 22+21+8+2+1, 22+21+8+3+1, 22+21+8+4+1, 22+21+8+5+1, 22+21+8+6+1, 22+21+9+1, 22+21+9+2+1, 22+21+9+3+1 22+21+9+4+1, 22+21+9+5+1, 22+21+9+6+1, 22+21+10+1, 22+21+10+2+1, 22+21+10+3+1, 22+21+10+4+1 22+21+10+5+1, 22+21+10+6+1, 22+21+11+1, 22+21+11+2+1, 22+21+11+3+1, 22+21+11+4+1, 22+21+11+5+1 22+21+11+6+1, 22+21+12+1, 22+21+12+2+1, 22+21+12+3+1, 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43+20+19+3+1, 43+20+19+4+1, 43+20+19+5+1, 43+20+19+6+1, 43+21+1 , 43+21+2+1 43+21+3+1, 43+21+4+1, 43+21+5+1, 43+21+6+1, 43+21+7+1, 43+21+7+2+1, 43+21+7+3+1, 43+21+7+4+1 43+21 +7+5+1 , 43+21 +7+6+1 , 43+21 +8+1 , 43+21 +8+2+1 , 43+21 +8+3+1 , 43+21 +8+4+1 , 43+21 +8+5+1 ,43+21 +8+6+1 43+21+9+1, 43+21+9+2+1, 43+21+9+3+1, 43+21+9+4+1, 43+21+9+5+1, 43+21+9+6+1, 43+21+10+1, 43+21+10+2+1 43+21+10+3+1, 43+21+10+4+1, 43+21+10+5+1, 43+21+10+6+1, 43+21+11+1, 43+21+11+2+1, 43+21+11+3+1 43+21+11+4+1, 43+21+11+5+1, 43+21+11+6+1, 43+21+12+1, 43+21+12+2+1, 43+21+12+3+1, 43+21+12+4+1 43+21+12+5+1, 43+21+12+6+1, 43+21+13+1, 43+21+13+2+1, 43+21+13+3+1, 43+21+13+4+1, 43+21+13+5+1 43+21+13+6+1, 43+21+14+1, 43+21+14+2+1, 43+21+14+3+1, 43+21+14+4+1, 43+21+14+5+1, 43+21+14+6+1 43+21+15+1, 43+21+15+2+1, 43+21+15+3+1, 43+21+15+4+1, 43+21+15+5+1, 43+21+15+6+1, 43+21+16+1 43+21+16+2+1, 43+21+16+3+1, 43+21+16+4+1, 43+21+16+5+1, 43+21+16+6+1, 43+21+17+1, 43+21+17+2+1 43+21+17+3+1, 43+21+17+4+1, 43+21+17+5+1, 43+21+17+6+1, 43+21+18+1, 43+21+18+2+1, 43+21+18+3+1 43+21+18+4+1, 43+21+18+5+1, 43+21+18+6+1, 43+21+19+1, 43+21+19+2+1, 43+21+19+3+1, 43+21+19+4+1 43+21+19+5+1, 43+21+19+6+1, 44+6+1, 44+20+1, 44+20+2+1, 44+20+3+1, 44+20+4+1, 44+20+5+1, 44+20+6+1 44+20+7+1, 44+20+7+2+1, 44+20+7+3+1, 44+20+7+4+1, 44+20+7+5+1, 44+20+7+6+1, 44+20+8+1, 44+20+8+2+1 44+20+8+3+1, 44+20+8+4+1, 44+20+8+5+1, 44+20+8+6+1, 44+20+9+1, 44+20+9+2+1, 44+20+9+3+1, 44+20+9+4+1 44+20+9+5+1, 44+20+9+6+1, 44+20+10+1, 44+20+10+2+1, 44+20+10+3+1, 44+20+10+4+1, 44+20+10+5+1 44+20+10+6+1, 44+20+11+1, 44+20+11+2+1, 44+20+11+3+1, 44+20+11+4+1, 44+20+11+5+1, 44+20+11+6+1 44+20+12+1, 44+20+12+2+1, 44+20+12+3+1, 44+20+12+4+1, 44+20+12+5+1, 44+20+12+6+1, 44+20+13+1 44+20+13+2+1, 44+20+13+3+1, 44+20+13+4+1, 44+20+13+5+1, 44+20+13+6+1, 44+20+14+1, 44+20+14+2+1 44+20+14+3+1, 44+20+14+4+1, 44+20+14+5+1, 44+20+14+6+1, 44+20+15+1, 44+20+15+2+1, 44+20+15+3+1 44+20+15+4+1, 44+20+15+5+1, 44+20+15+6+1, 44+20+16+1, 44+20+16+2+1, 44+20+16+3+1, 44+20+16+4+1 44+20+16+5+1, 44+20+16+6+1, 44+20+17+1, 44+20+17+2+1, 44+20+17+3+1, 44+20+17+4+1, 44+20+17+5+1 44+20+17+6+1, 44+20+18+1, 44+20+18+2+1, 44+20+18+3+1, 44+20+18+4+1, 44+20+18+5+1, 44+20+18+6+1 44+20+19+1, 44+20+19+2+1, 44+20+19+3+1, 44+20+19+4+1, 44+20+19+5+1, 44+20+19+6+1, 44+21+1 , 44+21+2+1 44+21+3+1, 44+21+4+1, 44+21+5+1, 44+21+6+1, 44+21+7+1, 44+21+7+2+1, 44+21+7+3+1, 44+21+7+4+1 44+21+7+5+1, 44+21+7+6+1, 44+21+8+1, 44+21+8+2+1, 44+21+8+3+1, 44+21+8+4+1, 44+21+8+5+1 , 44+21+8+6+1 44+21+9+1, 44+21+9+2+1, 44+21+9+3+1, 44+21+9+4+1, 44+21+9+5+1, 44+21+9+6+1, 44+21+10+1, 44+21+10+2+1 44+21+10+3+1 44+21+10+4+1 , 44+21+10+5+1 44+21+10+6+1 44+21+11+1 44+21+11+2+1, 44+21+11+3+1

44+21+11+4+1 44+21+11+5+1 , 44+21+11+6+1 44+21+12+1 44+21+12+2+1 44+21+12+3+1, 44+21+12+4+1

44+21+12+5+1 44+21+12+6+1 , 44+21+13+1, 44+21+13+2+1 44+21+13+3+1 44+21+13+4+1, 44+21+13+5+1

44+21+13+6+1 44+21+14+1, 44+21+14+2+1, 44+21+14+3+1 44+21+14+4+1, 44+21+14+5+1, 44+21+14+6+1

44+21+15+1, 44+21+15+2+1, 44+21+15+3+1, 44+21+15+4+1, 44+21+15+5+1, 44+21+15+6+1 , 44+21+16+1

44+21+16+2+1 44+21+16+3+1 , 44+21+16+4+1 44+21+16+5+1 44+21+16+6+1 44+21+17+1, 44+21+17+2+1

44+21+17+3+1 44+21+17+4+1 , 44+21+17+5+1 44+21+17+6+1 44+21+18+1, 44+21+18+2+1, 44+21+18+3+1

44+21+18+4+1 44+21+18+5+1 , 44+21+18+6+1 44+21+19+1 44+21+19+2+1 44+21+19+3+1, 44+21+19+4+1

44+21+19+5+1 44+21+19+6+1, 45+1,46+1,47+1

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "7+2+1" for example refers to embodiment 7) depending on embodiment 2), depending on embodiment 1), i.e. embodiment "7+2+1" corresponds to embodiment 1) further characterized by the features of the embodiments 2) and 7).

Definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of embodiments 1) to 45), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or a preferred definition of a term or expression defines and may replace the respective term or expression independently of (and in combination with) any definition or preferred definition of any or all other terms or expressions as defined herein.

The term "halogen" refers to fluorine, chlorine, bromine or iodine. It refers preferably to fluorine or chlorine and more preferably to fluorine.

The term "alkyl", used alone or in combination, refers to a straight or branched chain alkyl group containing from one to four carbon atoms. The term "(C _x -C _y )alkyl" (x and y each being an integer) refers to a straight or branched chain alkyl group containing x to y carbon atoms. For example, a (Ci-C3)alkyl group contains from one to three carbon atoms. Representative examples of alkyl groups include methyl, ethyl, propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl and iert-butyl. Preferred are methyl and ethyl. Most preferred is methyl.

When used as a substituent for group "A", the term "oo-hydroxy(Ci-C3)alkyl" means a linear alkyl group which contains from one to three carbon atoms in which one terminal hydrogen atom is replaced with hydroxy. Examples of oo-hydroxy(Ci-C3)alkyl groups are hydroxy methyl, 2-hydroxyethyl and 3-hydroxypropyl; notably hydroxymethyl.

The term "alkylamino", used alone or in combination, refers to an amino group wherein one of the two hydrogen atoms has been replaced by an alkyl group as defined before. The term "(C _x -C _y )alkylamino" (x and y each being an integer) refers to an alkylamino group as defined before wherein the alkyl group contains x to y carbon atoms. For example, a (Ci-C4)alkylamino group is an alkylamino group as defined before wherein the alkyl group contains from one to four carbon atoms. Representative examples of alkylamino groups include methylamino, ethylamino and /so-propyl-amino; notably methylamino and ethylamino; and especially methylamino. The term "dialkylamino", used alone or in combination, refers to an amino group wherein each hydrogen atom has been replaced by an alkyl group as defined before, whereby the alkyl groups may be the same or different. The term "di(C _x -C _y )alkylamino" (x and y each being an integer) refers to a dialkylamino group as defined before wherein each alkyl group independently contains x to y carbon atoms. For example, a di(Ci- C4)alkylamino group is a dialkylamino group as defined before wherein each alkyl group independently contains from one to four carbon atoms. Representative examples of dialkylamino groups include dimethylamino, diethylamino, N-ethyl-N-methyl-amino and N-iso-propyl-N-methyl-amino; notably dimethylamino and diethylamino; especially dimethylamino.

The term "(Ci-C4)alkylamino(Ci-C4)alkyl" refers to an alkyl group containing from one to four carbon atoms as defined before wherein one of the hydrogen atoms has been replaced by a (Ci-C4)alkylamino group as defined before. Representative examples of (Ci-C4)alkylamino-(Ci-C4)alkyl groups include methylaminomethyl, 2-methylamino-ethyl, 3-methylamino-propyl, 4-methylamino-butyl, ethylaminomethyl, 2-ethylamino-ethyl, 3-ethylamino-propyl, 4-ethylamino-butyl, n-propylaminomethyl, 2-(n-propylamino)-ethyl and 3-(n-propylamino)-propyl; preferred are methylaminomethyl, 2-methylamino-ethyl and 3-methylamino- propyl; most preferred is methylaminomethyl.

The term "[di(Ci-C4)alkylamino]-(Ci-C4)alkyl" refers to an alkyl group containing from one to four carbon atoms as defined before wherein one of the hydrogen atoms has been replaced by a di(Ci-C4)alkylamino group as defined before. Representative examples of [di(Ci-C4)alkylamino]-(Ci-C4)alkyl groups include dimethylaminomethyl, 2-(dimethylamino)-ethyl, 3-(dimethylamino)-propyl, 4-(dimethylamino)-butyl, diethylaminomethyl, 2-(diethylamino)-ethyl, 3-(diethylamino)-propyl, 4-(diethylamino)-butyl, di(n-propyl)aminomethyl, 2-(di(n-propyl)amino)-ethyl and 3-(di(n-propyl)amino)-propyl; notably dimethylaminomethyl, 2-(dimethylamino)-ethyl and 3-(dimethylamino)-propyl; especially dimethylaminomethyl.

The point of attachment of R ^3C to M ^c can be either adjacent to the pyrroloimidazolone bicyclic ring system or to A; especially to A.

The term "quinolone-resistant", when used in this text, refers to a bacterial strain against which ciprofloxacin has a Minimal Inhibitory Concentration of at least 16 mg/L (said Minimal Inhibitory Concentration being measured with the standard method described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7 ^th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006)).

The term "carbapenem-resistant", when used in this text, refers to a bacterial strain against which imipenem has a Minimal Inhibitory Concentration of at least 16 mg/L (said Minimal Inhibitory Concentration being measured with the standard method described in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006)). The term "multi-drug resistant", when used in this text, refers to a bacterial strain against which at least three antibiotic compounds selected from three distinct antibiotic categories have Minimal Inhibitory Concentrations (MICs) over their respective clinical breakpoints, whereby said three distinct antibiotic categories are chosen among penicillins, combinations of penicillins with beta-lactamase inhibitors, cephalosporins, carbapenems, monobactams, fluoro-quinolones, aminoglycosides, phosphonic acids, tetracyclins and polymixins. Clinical breakpoints are defined according to the latest available list published by Clinical and Laboratory Standards Institute (Wayne, PA, USA). Accordingly, clinical breakpoints are the levels of MIC at which, at a given time, a bacterium is deemed either susceptible or resistant to treatment by the corresponding antibiotic or antibiotic combination.

The present invention also includes isotopically labeled, especially 2H (deuterium) labeled compounds of formula I, which compounds are identical to the compounds of formula I except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labeled, especially 2H (deuterium) labeled compounds of formula I and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula I are not isotopically labeled, or they are labeled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula I are not isotopically labeled at all. Isotopically labeled compounds of formula I may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example 'Handbook of Pharmaceutical Salts. Properties, Selection and Use , P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH (2008) and 'Pharmaceutical Salts and Co-crystals', Johan Wouters and Luc Quere (Eds.), RSC Publishing (2012).

The compounds of formula I may encompass compounds with one or more asymmetric centers, such as one or more asymmetric carbon atoms, which are allowed to be present in (R)- as well as (S)-configuration. The compounds of formula I may further encompass compounds with one or more double bonds which are allowed to be present in Z- as well as E-configuration and/or compounds with substituents at a ring system which are allowed to be present, relative to each other, in cis- as well as trans-configuration. The compounds of formula I may thus be present as mixtures of stereoisomers or preferably in stereoisomerically enriched form, especially as essentially pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, cis- or trans- designations are to be understood as referring to the respective stereoisomer in enriched, especially essentially pure, form. Likewise, in case a particular compound (or generic structure) is designated as Z- or E- stereoisomer (or in case a specific double bond in a compound is designated as being in Z- or E- configuration), such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, stereoisomeric form (or to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of the double bond). The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The term "essentially pure", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The term "prevent" or "prevention" or "preventing" used with reference to a disease means either that said disease does not occur in the patient or animal, or that, although the animal or patient is affected by the disease, part or all the symptoms of the disease are either reduced or absent. The terms "prevention" and "preventing" may be understood to mean "prophylaxis".

The term "treat" or "treatment" or "treating" used with reference to a disease means either that said disease is cured in the patient or animal, or that, although the animal or patient remains affected by the disease, part or all the symptoms of the disease are either reduced or eliminated. Besides, the term "room temperature" as used herein refers to a temperature of 25°C. Whenever the word "between" is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1 , 2, 3, or

Unless used regarding temperatures, the term "about" placed before a numerical value "X" refers in the current application to an interval extending from X minus 10% of X to X plus 10% of X, and preferably to an interval extending from X minus 5% of X to X plus 5% of X. In the particular case of temperatures, the term "about" placed before a temperature "Y" refers in the current application to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and preferably to an interval extending from Y minus 5°C to Y plus 5°C.

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof exhibit antibacterial activity, especially against Gram-negative organisms and are therefore suitable to treat bacterial infections in mammals, especially humans. Said compounds may also be used for veterinary applications, such as treating infections in livestock and companion animals. They may further constitute substances for preserving inorganic and organic materials in particular all types of organic materials for example polymers, lubricants, paints, fibres, leather, paper and wood. Furthermore, the compounds of formula I or salts thereof may be used for disinfecting any hard surface, liquid, or semi-liquid.

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may therefore be used for the treatment or prevention of infectious disorders caused by fermentative or non-fermentative Gram negative bacteria, especially those caused by susceptible and multi-drug resistant Gram-negative bacteria. Examples of such Gram-negative bacteria include Acinetobacter spp. such as Acinetobacter baumannii or Acinetobacter haemolyticus, Actinobacillus actinomycetemcomitans, Achromobacter spp. such as Achromobacter xylosoxidans or Achromobacter faecalis, Aeromonas spp. such as Aeromonas hydrophila, Bacteroides spp. such as Bacteroides fragilis, Bacteroides theataioatamicron, Bacteroides distasonis, Bacteroides ovatus or Bacteroides vulgatus, Bartonella hensenae, Bordetella spp. such as Bordetella pertussis, Borrelia spp. such as Borrelia Burgdorferi, Brucella spp. such as Brucella melitensis, Burkholderia spp. such as Burkholderia cepacia, Burkholderia pseudomallei or Burkholderia mallei, Campylobacter spp. such as Campylobacter jejuni, Campylobacter fetus or Campylobacter coli, Cedecea, Chlamydia spp. such as Chlamydia pneumoniae, Chlamydia trachomatis, Citrobacter spp. such as Citrobacter diversus (koseri) or Citrobacter freundii, Coxiella burnetii, Edwardsiella spp. such as Edwarsiella tarda, Ehrlichia chafeensis, Eikenella corrodens, Enterobacter spp. such as Enterobacter cloacae, Enterobacter aerogenes, Enterobacter agglomerans, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus spp. such as Haemophilus influenzae (beta-lactamase positive and negative) or Haemophilus ducreyi, Helicobacter pylori, Kingella kingae, Klebsiella spp. such as Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum beta-lactamases (hereinafter "ESBLs"), carbapenemases (KPCs), cefotaximase-Munich (CTX-M), metallo-beta-lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, beta-lactams, and beta-lactam/beta-lactamase inhibitor combinations), Klebsiella rhinoscleromatis or Klebsiella ozaenae, Legionella pneumophila, Mannheimia haemolyticus, Moraxella catarrhalis (beta-lactamase positive and negative), Morganella morganii, Neisseria spp. such as Neisseria gonorrhoeae or Neisseria meningitidis, Pasteurella spp. such as Pasteurella multocida, Plesiomonas shigelloides, Porphyromonas spp. such as Porphyromonas asaccharolytica, Prevotella spp. such as Prevotella corporis, Prevotella intermedia or Prevotella endodontalis, Proteus spp. such as Proteus mirabilis, Proteus vulgaris, Proteus penneri or Proteus myxofaciens, Porphyromonas asaccharolytica, Plesiomonas shigelloides, Providencia spp. such as Providencia stuartii, Providencia rettgeri or Providencia alcalifaciens, Pseudomonas spp. such as Pseudomonas aeruginosa (including ceftazidime-, cefpirome- and cefepime-resistant P. aeruginosa, carbapenem-resistant P. aeruginosa or quinolone-resistant P. aeruginosa) or Pseudomonas fluorescens, Ricketsia prowazekii, Salmonella spp. such as Salmonella typhi or Salmonella paratyphi, Serratia marcescens, Shigella spp. such as Shigella flexneri, Shigella boydii, Shigella sonnei or Shigella dysenteriae, Streptobacillus moniliformis, Stenotrophomonas maltophilia, Treponema spp., Vibrio spp. such as Vibrio cholerae, Vibrio parahaemolyticus, Vibrio vulnificus, Vibrio alginolyticus, Yersinia spp. such as Yersinia enterocolitica, Yersinia pestis or Yersinia pseudotuberculosis.

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof are thus useful for treating a variety of infections caused by fermentative or non-fermentative Gram-negative bacteria, especially infections such as: nosocomial pneumonia (related to infection by Legionella pneumophila, Haemophilus influenzae, or Chlamydia pneumonia); urinary tract infections; systemic infections (bacteraemia and sepsis); skin and soft tissue infections (including burn patients); surgical infections; intraabdominal infections; lung infections (including those in patients with cystic fibrosis); Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.); endocarditis; diabetic foot infections; osteomyelitis; otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Haemophilus influenzae or Moraxella catarrhalis; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by Actinobacillus haemolyticum; sexually transmitted diseases related to infection by Chlamydia trachormatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neisseria gonorrheae; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae or H. influenzae; gastroenteritis related to infection by Campylobacter jejuni; persistent cough related to infection by Bordetella pertussis and gas gangrene related to infection by Bacteroides spp. Other bacterial infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford et al., "The Sanford Guide to Antimicrobial Therap , 26th Edition, (Antimicrobial Therapy, Inc., 1996).

The preceding lists of infections and pathogens are to be interpreted merely as examples and in no way as limiting. The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may therefore be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection, in particular for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria.

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may more especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria selected from the group consisting of Citrobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Stenotrophomonas maltophilia and Pseudomonas aeruginosa bacteria (notably of a bacterial infection caused by Gram-negative bacteria selected from the group consisting of Klebsiella pneumoniae and Pseudomonas aeruginosa bacteria, and in particular of a bacterial infection caused by Pseudomonas aeruginosa bacteria).

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may thus especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, systemic infections (such as bacteraemia and sepsis), skin and soft tissue infections (including burn patients), surgical infections; intraabdominal infections and lung infections (including those in patients with cystic fibrosis).

The compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof may more especially be used for the preparation of a medicament, and are suitable, for the prevention or treatment of a bacterial infection selected from urinary tract infections, intraabdominal infections and lung infections (including those in patients with cystic fibrosis), and in particular for the prevention or treatment of a bacterial infection selected from urinary tract infections and intraabdominal infections.

Besides, the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof display intrinsic antibacterial properties and have the ability to improve permeability of the outer membrane of Gram- negative bacteria to other antibacterial agents. Their use in combination with another antibacterial agent might offer some further advantages such as lowered side-effects of drugs due to lower doses used or shorter time of treatment, more rapid cure of infection shortening hospital stays, increasing spectrum of pathogens controlled, and decreasing incidence of development of resistance to antibiotics. The antibacterial agent for use in combination with a compound of formula I according to this invention will be selected from the group consisting of a penicillin antibiotic (such as ampicillin, piperacillin, penicillin G, amoxicillin, or ticarcillin), a cephalosporin antibiotic (such as ceftriaxone, cefatazidime, cefepime, cefotaxime) a carbapenem antibiotic (such as imipenem, or meropenem), a monobactam antibiotic (such as aztreonam), a fluoroquinolone antibiotic (such as ciprofloxacin, moxifloxacin or levofloxacin), a macrolide antibiotic (such as erythromycin or azithromycin), an aminoglycoside antibiotic (such as amikacin, gentamycin or tobramycin), a glycopeptide antibiotic (such as vancomycin or teicoplanin), a tetracycline antibiotic (such as tetracycline, oxytetracycline, doxycycline, minocycline or tigecycline), and linezolid, clindamycin, telavancin, daptomycin, novobiocin, rifampicin and polymyxin. Preferably, the antibacterial agent for use in combination with a compound of formula I according to this invention will be selected from the group consisting of vancomycin, tigecycline and rifampicin.

The compounds of formula I according to this invention, or the pharmaceutically acceptable salt thereof, may moreover be used for the preparation of a medicament, and are suitable, for the prevention or treatment (and especially the treatment) of infections caused by biothreat Gram negative bacterial pathogens as listed by the US Center for Disease Control (the list of such biothreat bacterial pathogens can be found at the web page (https://www.selectagents.gov/SelectAgentsandToxinsList.html ), and in particular by Gram negative pathogens selected from the group consisting of Yersinia pestis, Francisella tularensis (tularemia), Burkholderia pseudomallei and Burkholderia mallei.

One aspect of this invention therefore relates to the use of the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to any one of embodiments 1 ) to 47) for the manufacture of a medicament for the prevention or treatment of a bacterial infection (in particular one of the previously mentioned infections caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria). Another aspect of this invention relates to the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to any one of embodiments 1 ) to 47) for the prevention or treatment of a bacterial infection (in particular for the prevention or treatment of one of the previously mentioned infections caused by Gram-negative bacteria, especially by multi-drug resistant Gram-negative bacteria). Yet another aspect of this invention relates to the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to any one of embodiments 1 ) to 47) for use as a medicament. Yet a further aspect of this invention relates to a pharmaceutical composition containing, as active ingredient, a compound of formula I according to any one of embodiments 1 ) to 47), or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. As well as in humans, bacterial infections can also be treated using compounds of formula I (or pharmaceutically acceptable salts thereof) in other species like pigs, ruminants, horses, dogs, cats and poultry.

The present invention also relates to pharmacologically acceptable salts and to compositions and formulations of compounds of formula I.

Any reference to a compound of formula I in this text is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

A pharmaceutical composition according to the present invention contains at least one compound of formula I (or a pharmaceutically acceptable salt thereof) as the active ingredient and optionally carriers and/or diluents and/or adjuvants, and may also contain additional known antibiotics.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such as especially oral) or parenteral (including topical application or inhalation) administration. The compounds of formula I are suitable for inhibiting the LpxC enzyme of bacteria and thus for the prevention and/or treatment of bacterial infections in mammals, such as especially humans.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, nontoxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Another aspect of the invention concerns a method for the prevention or the treatment of a Gram-negative bacterial infection in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to any one of embodiments 1 ) to 47) or a pharmaceutically acceptable salt thereof. Accordingly, the invention provides a method for the prevention or the treatment of a bacterial infection caused by Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant Acinetobacter baumannii _: quinolone-resistant Escherichia coli bacteria or quinolone-resistant Klebsiella pneumoniae bacteria) in a patient, comprising the administration to said patient of a pharmaceutically active amount of a compound of formula I according to one of embodiments 1 ) to 47) or a pharmaceutically acceptable salt thereof.

Moreover, the compounds of formula I according to this invention may also be used for cleaning purposes, e.g. to remove pathogenic microbes and bacteria from surgical instruments, catheters and artificial implants or to make a room or an area aseptic. For such purposes, the compounds of formula I could be contained in a solution or in a spray formulation.

This invention, thus, relates to the compounds of formula I as defined in embodiment 1 ), or further limited under consideration of their respective dependencies by the characteristics of any one of embodiments 2) to 47), and to pharmaceutically acceptable salts thereof. It relates furthermore to the use of such compounds as medicaments, especially for the prevention or treatment of a bacterial infection, in particular for the prevention or treatment of a bacterial infection caused by Gram-negative bacteria (notably for the prevention or treatment of a bacterial infection caused by Acinetobacter baumannii bacteria, Escherichia coli bacteria, Klebsiella pneumoniae bacteria or Pseudomonas aeruginosa bacteria, and in particular for the prevention or treatment of a bacterial infection caused by quinolone-resistant Acinetobacter baumannii _: quinolone-resistant Escherichia coli bacteria , quinolone-resistant Klebsiella pneumoniae bacteria or quinolone-resistant Pseudomonas aeruginosa).

The compounds of formula I can be manufactured in accordance with the present invention using the procedures described hereafter.

PREPARATION OF THE COMPOUNDS OF FORMULA I Abbreviations:

The following abbreviations are used throughout the specification and the examples:

Ac acetyl

AcOH acetic acid

aq. aqueous

bis(pinacolato)diboron 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane

CC column chromatography over silica gel

CD I carbonyldiimidazole

Cipro ciprofloxacin

Cp cyclopentadienyl Cy cyclohexyl

DAD diode array detection

dba dibenzylideneacetone

DCC dicyclohexylcarbodiimide

DCE 1 ,2-dichloroethane

DCM dichloromethane

DEA diethylamine

DIPEA A/,A/-diisopropylethylamine

DMAP 4-dimethylamino-pyridine

DME 1 ,2-dimethoxyethane

DMF A/,A/-dimethylformamide

DMSO dimethylsulfoxide

dppb 1 ,4-bis(diphenylphosphino)butane

dppf bis(diphenylphosphino)ferrocene

DSC A/,/V-disuccinimidyl carbonate

EA ethyl acetate

EDC A/-(3-dimethylaminopropyl)-A/-ethylcarbodiimide hydrochloride

ELSD evaporative light scattering detector

ESI electron spray ionisation

Et ethyl

Et ₂ 0 diethyl ether

EtOH ethanol

h hour(s)

HATU 0-(7-azabenzotriazol-1 -y I )-Λ , Λ , Λ ', Λ '-te tra methyluronium hexafluorophosphate

Hept heptane

Hex hexane

HOBT hydroxybenzotriazole

HPLC high performance liquid chromatography

iPr isopropyl

iPrOH isopropanol IT internal temperature

LC-MS liquid chromatography - mass spectroscopy

MCPBA 3-chloro perbenzoic acid

Me methyl

MeCN acetonitrile

MeOH methanol

MIDA W-methyliminodiacetic acid

min minute(s)

MS mass spectroscopy

NBS W-bromosuccinimide

NCS W-chlorosuccinimide

n-Bu n-butyl

NMR Nuclear Magnetic Resonance

org. organic

Pd/C palladium on carbon

PIFA bis(trifluoroacetoxy)iodobenzene

PG protecting group

Ph phenyl

PPTS para-toluenesulfonic acid pyridinium salt

prep-HPLC preparative HPLC

Pyr pyridine

Q-phos 1 ,2,3 ,4,5-pentaphenyl-1 '-(di-iert-butylphosphino)ferrocene rt room temperature

sat. saturated

SK-CC01 -A 2'-(dimethylamino)-2-biphenylyl-palladium(ll) chloride dinorbornylphosphine complex

S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

T3P n-propylphosphonic cyclic anhydride

TBAF tetra-n-butylammonium fluoride

TBDMSCI iert-butyldimethylsilyl chloride

TBDPSCI iert-butyldiphenylsilyl chloride TBME iert-butylmethyl ether

f-Bu iert-butyl

i-BuOH iert-butyl alcohol

TEA triethyl amine

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyranyl

TLC thin layer chromatography

TMP 2,2,6,6-tetramethyl piperidine

TMSE 2-(trimethylsilyl)ethyl

tR retention time

UV ultra violet

General reaction techniques:

Genera! ..reaction . techn

removal):

The protecting groups of hydroxamic acid ester derivatives (CONHOPG) or the protecting groups of phosphonic acid ester derivatives (P(0)(OPG')2) are removed as follows:

- When PG or PG' is THP, (2-methylpropoxy)ethyl, methoxymethyl, f-Bu, COOf-Bu or COf-Bu: by acidic treatment with e.g. TFA or HCI in an org. solvent such as DCM, dioxane, Et20 or MeOH between 0°C and rt or by treatment with PPTS in EtOH between rt and +80°C;

When PG or PG' is trityl: by treatment with diluted acid such as citric acid or HCI in an org. solvent such as MeOH or DCM;

When PG or PG' is TMSE: by using fluoride anion sources such as BF3.etherate complex in MeCN at 0°C, TBAF in THF between 0°C and +40°C or HF in MeCN or water between 0°C and +40°C, or using acidic conditions such as AcOH in THF/MeOH or HCI in MeOH;

When PG or PG' is allyl: by treatment with Pd(PP i3)4 in a solvent such as MeOH in presence of K2CO3 or a scavenger such as dimedone, morpholine or tributyltin hydride.

Further general methods to remove hydroxamic acid protecting groups have been described in T.W. Greene & P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3 ^rd Ed (1999), 23-147 (Publisher: John Wiley and Sons, Inc., New York, N.Y.). Gene.raJ .reaction tech nig ue.2.(-N H _: C( OJ.- bond or .-0-C(0) _: . bond formation) :

The carboxylic acid is reacted with the hydroxylamine or amine derivative in the presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride (T3P), HATU or DSC, in a dry aprotic solvent such as DCM, MeCN or DMF between -20°C and 60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991 ), vol. 6, p. 381 ). Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between -20° and 60°C. Further activating agents can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2 ^nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).

General .reaction tech nig ue.3.(Suzu ki. cross-coupling .reaction);

The aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, i-BuONa or i-BuOK between 20°C and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%). Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PP i3)4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCy3 or P(i-Bu)3), dialkylphosphinobiphenyls (e.g. S-Phos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01 -A) or /V-heterocyclic carbene complexes (e.g. PEPPSI™-IPr). The reaction can also be performed by using the corresponding aromatic triflate. Further variations of the reaction are described in Miyaura and Suzuki, Chem. Rev. (1995), 95, 2457-2483, Bellina et al., Synthesis (2004), 2419-2440, Mauger and Mignani, Aldrichimica Acta (2006), 39, 17-24, Kantchev et al., Aldrichimica Acta (2006), 39, 97-1 1 1 , Fu, Acc. Chem. Res. (2008), 41 , 1555-1564, and references cited therein. General .reaction tech nig ue.4.(red uctiye ami nation);

The reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgSC>4 or Na2SC>4). Such solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH. The reaction can be catalyzed by traces of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C. The reaction is carried out between -10°C and 1 10°C, preferably between 0°C and 60°C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex {Tetrahedron (2004), 60, 7899-7906). GeneraJ reaction technjgu

When the ester side chain is a linear alkyl, the hydrolysis is usually performed by treatment with an alkali hydroxide such as LiOH, KOH or NaOH in a water-dioxane or water-THF mixture between 0°C and 80°C. When the ester side chain is f-Bu, the release of the corresponding acid can also be performed in neat TFA or diluted TFA or HCI in an org. solvent such as ether or THF. When the ester side chain is the allyl group, the reaction is performed in the presence of tetrakis(triphenylphosphine)palladium(0) in the presence of an allyl cation scavenger such as morpholine, dimedone or tributyltin hydride between 0°C and 50°C in a solvent such as THF. When the ester side chain is benzyl, the reaction is performed under hydrogen in the presence of a noble metal catalyst such as Pd/C in a solvent such as MeOH, THF or EA. Further strategies to introduce other acid protecting groups and general methods to remove them have been described in T.W. Greene & P.G.M. Wuts, Protecting Groups in Organic Synthesis, 3 ^rd Ed. (1999), 369-441 (Publisher: John Wiley and Sons, Inc., New York, N.Y.).

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures.

The sections hereafter describe general methods for preparing compounds of formula I. If not indicated otherwise, the generic groups A, M, M ^A , M ^B , M ^c , M ^D , M ^E , M ^F , M ^G , M ^H , M ¹ , M ^J , R ¹ , R ² , R ^1A , R ^{1 B} , R ^1C , R ^1D , R ^2F , R ^3C , R ^3E and R ^5H are as defined for formula I. General synthetic methods used repeatedly throughout the text below are referenced to and described in the above section entitled "General reaction techniques". In some instances certain generic groups might be incompatible with the assembly illustrated in the procedures and schemes below and so will require the use of protecting groups. The use of protecting groups is well known in the art (see for example T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 ^rd Ed (1999), Wiley-lnterscience).

Preparation pf the∞^

The compounds of formula I wherein R ¹ = H can be obtained by deprotecting a compound of formula II

II

wherein A and M have the same meaning as in formula I and PG ¹ represents THP, TMSE, trityl, (2- methylpropoxy)ethyl, methoxymethyl, allyl, f-Bu, COOi-Bu or COi-Bu using general reaction technique 1. The reaction can also be performed with racemic material and the (R) enantiomer can be obtained by chiral HPLC separation.

If desired, the compounds of formula I thus obtained may be converted into their salts, and notably into their pharmaceutically acceptable salts using standard methods.

Besides, whenever the compounds of formula I are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art, e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 μιη) column, a Daicel ChiralCel OD-H (5-10 μ m) column, or a Daicel ChiralPak IA (10 μ m) or AD-H (5 μ m) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in the presence or absence of an amine such as DEA or TEA) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min. Preparation of the c ^

The compounds of formula I wherein R ¹ ≠ H can be obtained by: a) reacting a compound of formula I wherein R ¹ = H, and A and M are as defined in formula I with a compound of formula III

(PG ^A 0) ₂ P-N(iPr) ₂

III

wherein PG ^A represents iert-butyl. The reaction is performed in presence of a base such as tetrazole in a solvent such as acetonitrile at a temperature of about 0°C. An oxidation reaction is subsequently performed adding an oxidizing agent such as hydrogen peroxide in water or MCPBA (this sequence can also be performed with racemic compound of formula I wherein R ¹ = H and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product). Functional groups present on A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction. Final cleavage of PG ^A can be performed using general reaction technique 1 leading to compounds of formula I wherein R ¹ = PO3H2. b) reacting a compound of formula I wherein R ¹ = H, and A and M are as defined in formula I with a compound of formula IV

HOC(0)R ²

IV

wherein R ² has the same meaning as in formula I. The reaction can be performed using general reaction technique 2 leading to compounds of Formula I wherein R ¹ = C(0)R ² (this reaction can also be performed with racemic compound of formula I wherein R ¹ = H and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product). Functional groups present on R ² and A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction. c) reacting a compound of formula I wherein R ¹ = H, and A and M are as defined in formula I with a compound of formula V

Y ^a -(CH ₂ )-0-P(0)(OPG ^A ) ₂

V

wherein Y ^a represents iodine, bromine or chlorine and PG ^A has the same meaning as in formula III. The reaction can be performed in presence of a mineral base such as NaH or K2CO3 or in presence of an organic base such as TEA or DIPEA in a solvent such as THF at a temperature ranging between about -50°C and rt. Functional groups present on A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction. This sequence can also be performed with racemic compound of formula I wherein R ¹ = H and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product. Final cleavage of PG ^A can be performed using general reaction technique 1 leading to compounds of formula I wherein R ¹ = CH2-O-PO3H2. d) reacting a compound of formula I wherein R ¹ = H, and A and M are as defined in formula I with Pyr.SC complex or Me2NCHO.SC>3 complex in a solvent such as DMF or pyridine leading to compounds of formula I wherein R ¹ = SO3H. Functional groups present on A that would be incompatible with the reaction conditions abovementioned can be protected before performing said reaction and deprotected after performing said reaction. This sequence can also be performed with racemic compound of formula I wherein R ¹ = H and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product.

If desired, the compounds of formula I thus obtained may be converted into their salts, and notably into their pharmaceutically acceptable salts using standard methods.

Besides, whenever the compounds of formula I are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to one skilled in the art, e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 μ m) column, a Daicel ChiralCel OD-H (5-10 μ m) column, or a Daicel ChiralPak IA (10 μ m) or AD-H (5 μ m) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in the presence or absence of an amine such as DEA or TEA) and eluent B (Hex), at a flow rate of 0.8 to 150 mL/min. The compounds of formula II can be obtained by: i) reacting a compound of formula VI

VI

wherein A and M are as defined in formula I with a compound of formula VII

H ₂ N-OPG ¹

VII

wherein PG ¹ has the same meaning as in formula II using general reaction technique 2 (this reaction can also be performed with racemic compound of formula VI and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product), whereby functional groups present on A that would be incompatible with the coupling conditions mentioned in general reaction technique 2 can be protected before performing said reaction and deprotected after performing said reaction; or reacting a boron derivative of formula Villa or VI I lb

Villa Vlllb

wherein A and M have the same respective meanings as in formula I, D ¹ and D ² represent H, methyl or ethyl or D ¹ and D ² together represent CH ₂ C(Me)2CH2 or C(Me)2C(Me)2 with a compound of formula IX

IX

wherein Y represents a halogen such as bromine or iodine and PG ¹ has the same meaning as in formula II, using general reaction technique 3 (this reaction can also be performed with racemic compound of formula IX and the (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product); or reacting a compound of formula X

H

/

-M

wherein A has the same meaning as in formula I, M represents M ^F , M ^H or M ^J , with a compound of formula IX wherein Y represents a halogen such as bromine or iodine. The compound of formula X is first treated with a strong base such as TMPMgCI.LiCI, n-BuLi or NaOi-Bu at a temperature ranging between -78°C and rt. The resulting magnesio, lithio or sodio species can be further reacted with ZnC before it is reacted with a compound of formula IX in presence of Pd(PP i3)4 or a palladium salt and an appropriate ligand.

Preparation the _^ syn hesisjnte Compounds of formula VI:

The compounds of formula VI can be prepared as summarised in Scheme 1 hereafter.

VI 1-4 Scheme 1

In Scheme 1 , A and M are as defined in formula I.

The derivatives of formula I-3 can be obtained (Scheme 1 ) by reaction of the pyrrole aldehydes of formula 1-1 with the amine of formula I-2 using general reaction technique 4. The derivatives of formula I-4 can be obtained from the derivatives of formula I-3 by treatment with CDI in a solvent such as THF in the presence of a base such as NaH; this reaction can be performed at a temperature ranging from 0°C to 50°C, and ideally at rt. The compounds of formula 1-4 can be transformed into the compounds of formula VI using general reaction technique 5. These reactions can also be performed with racemic material and the (R) enantiomer can be obtained by chiral HPLC separation at any step when suitable. Compounds of formula VII:

The compounds of formula VII are commercially available (PG ¹ = methoxymethyl, THP, TMSE, trityl, f-Bu, COOi-Bu or allyl) or can be prepared according to WO 2010/060785 (PG ¹ = (2-methylpropoxy)ethyl) or Marmer and Maerker, J. Org. Chem. (1972), 37, 3520-3523 (PG ¹ = COi-Bu).

Compounds of formula Villa and Vlllb:

The compounds of formula Villa are commercially available or can be prepared as summarised in Scheme 2 hereafter.

Scheme 2 In Scheme 2, A and M are as defined in formula I, Y ^c represents bromine or iodine, D ¹ and D ² represent H, methyl or ethyl or D ¹ and D ² together represent CH ₂ C(Me)2CH ₂ or C(Me) ₂ C(Me) ₂ , R ³ represents a (Ci-C ₄ )alkyl group such as isopropyl.

The compounds of formula Villa can be obtained from the compounds of formula 11-1 by treatment with a strong base such as n-BuLi in an aprotic solvent such as THF at a temperature ranging from -78°C to 0°C, the resulting lithio species is subsequently reacted with a compound of formula 11-3. Alternatively, the compounds of formula Villa can be obtained reacting a compound of formula 11-2 with a reagent of formula 11-4 according to general reaction technique 3.

The potassium trifluoroborate salts of formula Vlllb wherein A and M have the same meanings as in formula I, can be prepared from the compounds of Villa wherein D ¹ and D ² represent each (Ci-C ₂ )alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 by treatment with an aqueous solution of potassium hydrogen difluoride.

Compounds of formulae IX:

The compounds of formula IX can be prepared as summarised in Scheme 3 hereafter.

Scheme 3

In Scheme 3, Y represents a halogen (such as iodine or bromine), R represents (Ci-C4)-alkyl and PG ¹ has the same meaning as in formula II. The reactions can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

The compounds of formula 111-1 wherein Y = Br (Scheme 3) can be transformed to the compounds of formula 111-1 wherein Y = iodine by reaction with Nal in the presence of a copper (I) salt and a ligand such as trans- Λ ,Λ '-dimethylcyclohexa-l ,2-diamine in a solvent such as dioxane at a temperature ranging between rt and 100°C, or in a microwave oven at 150°C. The compounds of formula 111-1 can be transformed to the compounds of formula III-2 using general reaction technique 5. The compounds of formula III-2 can be further reacted with the compounds of formula VII using general reaction technique 2, thus affording the compounds of formula IX. The compounds of formula IX wherein Y represents iodine can be obtained from the compounds of formula IX wherein Y = bromine by reaction with Nal in the presence of a copper (I) salt and a ligand such as irans-A/,A/'-dimethylcyclohexa-1 ,2-diamine in a solvent such as dioxane at a temperature ranging between rt and 100°C, or in a microwave oven at about 150°C.

The compounds of formula X are commercially available or can be prepared by standard methods known to one skilled in the art.

Other synt^ The compound of formula 1-2 can be prepared as described in the section entitled "EXAMPLES" hereafter (see Preparation A), or by standard methods known to one skilled in the art.

The compounds of formula 1-1 can be prepared as summarised in Scheme 4 hereafter.

Scheme 4

In Scheme 4, Y represents iodine or bromine and A and M have the same respective meanings than in formula I.

The derivatives of formula 1-1 can be obtained (Scheme 4) by reaction of the pyrrole aldehydes of formula IV- 1 wherein Y represents bromine or iodine by reaction with compounds of formula Villa or VI lib using general reaction technique 3.

The compounds of formula 111-1 wherein Y ^b represents bromine or iodine and R represent f-Bu can be prepared as summarised in Scheme 5 hereafter.

Scheme 5

In Scheme 5, Y represents bromine or iodine.

The derivatives of formula V-1 can be obtained (Scheme 5) by reaction of the pyrrole aldehydes of formula IV- 1 with the amine of formula I-2 using general reaction technique 4. The derivatives of formula 111-1 can then be obtained from the derivatives of formula V-1 by treatment with CD I in the presence of a base such as NaH in a solvent such as THF; this reaction can be performed at a temperature ranging from 0°C to 50°C, and ideally at rt.

Alternatively, the compounds of formula 111-1 can be prepared as summarised in Scheme 6 hereafter.

111-1

Scheme 6

In Scheme 6, Y represents bromine or iodine and R represents (Ci-C4)alkyl. The oxime of formula VI-1 can be obtained (Scheme 6) by reaction of the pyrrole aldehydes of formula IV-1 with hydroxylamine in AcOH in the presence of NaOAc. The oxime derivatives of formula VI-1 can be reduced to the amine derivatives of formula VI-2 by treatment with Zn in a solvent such as AcOH. The derivatives of formula VI-3 can be obtained from the derivative of formula VI-2 by treatment with CD I in a solvent such as THF in the presence of a base such as NaH. This reaction can be performed at a temperature ranging from 0°C to 50°C, and ideally at rt. The compound of formula VI-3 can then be transformed into the compounds of formula 111-1 by treatment with the bromide of formula VI-4 in the presence of a base such as NaH and in a solvent such as THF or DMF.

The compounds of formula III, IV and V are commercially available or can be prepared by standard methods known to one skilled in the art. The compounds of formula IV-1 wherein Y ^b is bromine or iodine are commercially available or can be prepared by standard methods known to one skilled in the art. The compounds of formula 1-2, 11-3, 11-4 and VI-4 are commercially available or can be prepared by standard methods known to one skilled in the art.

Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail without limiting its scope in any way. EXAMPLES

PREPARATIONS:

All temperatures are stated in °C. Unless otherwise indicated, the reactions take place at rt. The combined org. layers resulting from the liquid-liquid extraction during the work-up procedure of a reaction mixture are, unless otherwise indicated, washed with a minimal volume of brine, dried over MgSC>4, filtered and evaporated to dryness to provide a so-called evaporation residue.

Analytical TLC characterisations were performed with 0.2 mm plates: Merck, Silica gel 60 F254. Elution is performed with EA, Hept, DCM, MeOH or mixtures thereof. Detection was done with UV or with a solution of KMn0 ₄ (3 g), K2CO3 (20 g), 5% NaOH (3 mL) and H ₂ 0 (300 mL) with subsequent heating.

CCs were performed using Brunschwig 60A silica gel (0.032-0.63 mm) or using an ISCO CombiFlash system and prepacked S1O2 cartridges, elution being carried out with either Hept-EA or DCM-MeOH mixtures with an appropriate gradient. When the compounds contained an acid function, 1 % of AcOH was added to the eluent(s). When the compounds contained a basic function, 25% aq. NH4OH was added to the eluents.

The compounds were characterized by ¹ H-NMR (300 MHz, Varian Oxford; 400 MHz, Bruker Avance 400 or 500 MHz, Bruker Avance 500 Cryoprobe). Chemical shifts δ are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hex = hexet, hep = heptet, m = multiplet, br = broad; coupling constants J are given in Hz. Alternatively or additionally compounds were characterized by LC-MS (MS1 : Thermo MSQ Plus with Dionex HPG-3200RS Pump, binary pump, DAD and ELSD; MS2: Thermo MSQ Plus with Waters iCIass BSM), binary pump, DAD and ELSD.

The analytical LC-MS data have been obtained using the following respective conditions:

· MS 1 :

o Column: Zorbax RRHD, 1.8 μιτι, 3.0 x 50 mm;

o Injection volume: 0.15 μί;

o Column oven temperature: 40°C;

o Detection: UV 210 nm, ELSD and MS;

o MS ionization mode: ESI+; o Eluents: A: H ₂ 0; and B: MeCN;

o Flow rate: 0.8 mL/min;

o Gradient: 5% B to 95% B (0.0 min - 1.2 min), 95% B (1.2 min - 1.9 min).

• MS 2:

o Column: Zorbax SB-Aq, 30.5 μιη, 4.6 x 50 mm;

o Injection volume: 1 μί.;

o Column oven temperature: 40°C;

o Detection: UV 210 nm, ELSD and MS;

o MS ionization mode: ESI+;

o Eluents: A: H ₂ 0 + 0.04% TFA; and B: MeCN;

o Flow rate: 4.5 mL/min;

o Gradient: 5% B to 95% B (0.0 min - 1.0 min), 95% B (1.0 min - 1.45 min).

The number of decimals given for the corresponding [M+H ⁺ ] peak(s) of each tested compound depends upon the accuracy of the LC-MS device actually used. The prep-HPLC purifications were performed on a Gilson HPLC system, equipped with a Gilson 215 autosampler, Gilson 333/334 pumps, Dionex MSQ Plus detector system, and a Dionex UVD340U (or Dionex DAD-3000) UV detector, using the following respective conditions:

• Method 1 :

o Column: Waters XBridge C18, 10 μιτι, 30x75 mm;

o Flow rate: 75 mL/min;

o Eluents: A: H ₂ 0 + 0.5% NH ₄ OH solution (25%); B: MeCN;

o Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

• Method 2:

o Column: Agilent Zorbax SB-AQ, 5 μιη, 30 ^χ 75 mm;

o Flow rate: 75 mL/min;

o Eluents: A: H ₂ 0 + 0.5% HCOOH; B: MeCN;

o Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

Besides, semi-preparative and analytical chiral HPLCs were performed using the conditions herafter.

Semi-preparative chiral HPLC Method A:

The semi-preparative chiral HPLC is performed on a Daicel ChiralPak AS-H column (250 x 20 mm, 20 μιη) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak AS-H column (250 x 4.6 mm, 5 μιη) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

Semi-preparative chiral HPLC Method B:

The semi-preparative chiral HPLC is performed on a Daicel ChiralPak IA column (30 x 250 mm, 5 μιη) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralPak IA column (4.6 x 250 mm, 5 μιη) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol.

Semi-preparative chiral HPLC Method C:

The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OJ-H column (20 x 250 mm; 5 μιη) using the eluent mixture, flow rate and detection conditions indicated between brackets in the corresponding experimental protocol. The retention times are obtained by elution of analytical samples on a Daicel ChiralCel OJ-H column (4.6 x 250 mm; 5 μιη) using the same eluent mixture with the flow rate indicated between brackets in the corresponding experimental protocol. Procedures: Procedure A:

The boronic acid (0.86 mmol), the halo-derivative (0.57 mmol), PdCI ₂ (dppf).DCM (0.06 g; 0.075 mmol), K ₃ P0 ₄ (0.367 g; 1.73 mmol) are dissolved in THF (5 mL). The reaction mixture is stirred 2h under reflux. The reaction mixture is partitioned between EA-MeOH (9-1 , 30 mL) and H2O (15 mL). The evaporation residue is purified by CC using an appropriate solvent.

Procedure. B:

To a solution of the THP-protected hydroxamic acid derivative (0.06 mmol) in MeOH (0.3 mL) is added 2M HCI (0.22 mL; 0.44 mmol). The reaction mixture is stirred until completion. The reaction mixture, after neutralization with aqueous ammonia, can be directly purified by prep-HPLC using a suitable method. Alternatively, the evaporation residue can purified by CC (DCM-MeOH gradient).

Procedure.C:

A mixture of the halo-derivative (0.32 mmol), the boronic acid or boronate ester derivative (0.37 mmol), K2CO3 (0.140 g; 1.01 mmol) and Pd(PPh ₃ ) ₄ (0.039 g; 0.33 mmol) is flushed with nitrogen for 15 min. Dioxane (1.3 mL) and water (0.32 mL) are added and the mixture is refluxed until completion. After cooling, water (15 mL) and EA (20 mL) are added and the two layers are separated. The aq. layer is extracted with EA (2 x 20 mL) and the combined org. layers are washed with brine, dried over MgSC>4 and concentrated to dryness. The residue is then purified by CC using an appropriate eluent.

Procedure. D:

The boronic acid or boronate ester (0.21 mmol), the halo-derivative (0.17 mmol), PdCl2(dppf).DCM (0.015 g; 0.018 mmol), CS2CO3 (0.1 16 g; 0.357 mmol) and silver oxide (0.04 g; 0.27 mmol) are dissolved in dioxane (0.53 mL) and water (0.02 mL). The reaction mixture is stirred under reflux until completion. The reaction mixture is partitioned between EA (15 mL) and H2O (10 mL). The evaporation residue is purified by CC using an appropriate solvent.

Procedure.E:

To the THP-protected hydroxamic acid derivative (0.06 mmol) in EtOH (2 mL) is added PPTS (0.008 g; 0.032 mmol). The mixture is stirred at 80°C for 2 h, cooled to rt and directly purified by CC (DCM-MeOH gradient) or by prep-HPLC using a suitable method.

PREPARATIONS:

Preparation A: (2RS)-ferf-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate A/ ^' . (2RS)-tert-Butyl 2-(methylsulfonyl)propanoate:

To a suspension of sodium methanesulfinate (100 g; 929 mmol) in i-BuOH (350 mL) was added iert-butyl 2- bromopropionate (150 mL; 877 mmol). The reaction mixture was stirred at 90°C for 24 h under nitrogen atmosphere, then cooled to rt and concentrated to dryness. The residue was partitioned between water (750 mL) and EA (600 mL). The aq. layer was extracted with EA (2 x 500 mL). The evaporation residue afforded the title compound (175 g, 96% yield) as a yellowish solid.

¹ H NMR (DMSO-cie) δ: 4.24 (q, J = 7.2 Hz, 1 H); 3.1 1 (s, 3H); 1.45 (s, 9H); 1.40 (d, J = 7.2 Hz, 3H).

A/7. (2RS)-tert-Butyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate:

To an ice-chilled suspension of intermediate A.i (130 g; 626 mmol) in DMF (750 mL) was added portionwise NaH (60% in mineral oil; 32.1 g; 802 mmol) over 1.5 h, keeping IT below 7°C. The mixture was stirred at 0°C for 1.5 h, allowed to reach rt and stirred at rt for 0.5 h. The mixture was cooled down to 12°C with an ice bath and 1 ,2-dibromoethane (166 mL; 1.9 mol) was then added dropwise, keeping IT below 22°C. The reaction mixture was stirred at rt for 2 h. The mixture was poured into cold water (1 L) and Et20 (1 L) and the aq. layer was extracted with Et20 (2 x 750 mL). The org. layer was washed with cold water (2 x 500 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (1 16.8 g; 59% yield) as a pale yellowish oil. ¹ H NMR (DMSO-cie) δ: 3.71-3.63 (m, 1 H); 3.45-3.37 (m, 1 H); 3.12 (s, 3H); 2.72-2.62 (m, 1 H); 2.43-2.33 (m, 1 H); 1.49 (s, 3H); 1.46 (s, 9H).

A. Hi. (2RS)-ten-Butyl 4-azido-2-methyl-2-(methylsulfonyl)butanoate:

To a solution of intermediate A.ii (70.3 g; 223 mmol) in DMF (400 mL) was added NaN ₃ (54.6 g; 831 mmol). The reaction mixture was stirred at 80°C overnight, before being cooled to rt. Water (500 mL) and EA (500 mL) were added. The aq. layer was extracted with EA (2 x 500 mL) and the org. layer was washed with water (2 x 500 mL). The evaporation residue was triturated in Hept, filtered and washed with Hept to afford the title compound (59.6 g; 96% yield) as a white solid.

¹ H NMR (DMSO-cie) δ: 3.66-3.60 (m, 1 H); 3.35-3.29 (overlapped m, 1 H); 3.1 1 (s, 3H); 2.49-2.43 (m, 1 H); 2.04- 1.96 (m, 1 H); 1.46 (s, 9H); 1.44 (s, 3H).

MS2 (ESI, m/z): 278.95 [M+H ⁺ ] for C10H19N3O4S; t _R = 0.80 min.

A. iv. (2RS)-tert-Butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

A solution of intermediate A.iii (45 g; 162 mmol) in a mixture of i-BuOH-EA (1-1 , 900 mL) was treated with 10% Pd/C (2.3 g). The suspension was stirred at rt under hydrogen for 4 h. Then 10% Pd/C (0.5 g) was added to the suspension and the reaction was stirred under hydrogen for 2 days. The catalyst was filtered off and the filtrate concentrated to dryness to afford the crude material (40.6 g, 99% yield) as a grey solid.

1H NMR (DMSO-cie) δ: 3.06 (s, 3H); 2.75-2.63 (m, 1 H); 2.53-2.40 (overlapped m, 1 H); 2.28-2.16 (m, 1 H); 1.85- 1.74 (m, 1 H); 1.44 (s, 9H); 1.40 (s, 3H).

MS2 (ESI, m/z): 252.0 [M+H ⁺ ] for C10H21 NO4S; t _R = 0.45 min. Preparation B: (2R)-iert-butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate

B. i. (2R)-tert-Butyl 4-azido-2-methyl-2-(methylsulfonyl)butanoate:

Intermediate A.iii (184 g) was separated by semi-preparative chiral HPLC Method A (Hept-iPrOH 4-1 ; flow rate: 570 mL/min; UV detection at 235 nm); the respective retention times were 8.3 and 10.7 min. The title (R)-enantiomer (90.7 g), identified as the second eluting compound, was obtained as a light orange oil. ¹ H NMR (DMSO-cie) δ: 3.66-3.60 (m, 1 H); 3.35-3.29 (overlapped m, 1 H); 3.1 1 (s, 3H); 2.50-2.43 (overlapped m, 1 H); 2.04-1.97 (m, 1 H); 1.46 (s, 9H); 1.44 (s, 3H).

B.ii. (2R)-tert-Butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

Starting from intermediate B.i (45 g; 162 mmol) and proceeding in analogy to Preparation A, step A.iv, the title compound (40.6 g; 99% yield) was obtained as a grey solid.

1H NMR (DMSO-cie) δ: 3.06 (s, 3H); 2.75-2.63 (m, 1 1 H); 2.53-2.40 (overlapped m, 1 H); 2.28-2.16 (m, 1 H); 1.85-1.74 (m, 1 H); 1.44 (s, 9H); 1.40 (s, 3H). MS2 (ESI, m/z): 252.0 [M+H ⁺ ] for C10H21 NO4S; t _R = 0.45 min.

Preparation C: ferf-butyl (2 ?)-4-(6-iodo-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)butanoate

FIRST METHOD: C.i. (2RS)4ert-Butyl 4-(((4-iodo-1H yriOl-2-yl)methyl)am^

To a solution of the compound of Preparation A (24.631 g; 98 mmol) in dry THF (470 mL) was added 4-iodo- 1/-/-pyrrole-2-carbaldhehyde (20.625 g; 93.3 mmol, commercial). The reaction mixture was stirred 2 h. MeOH (144 mL) was added and the resulting mixture was cooled to -20°C. NaBhU (3.578 g, 94.6 mmol) was added portionwise. Once the addition completed, the reaction proceeded at 0°C for 1 h. Ice-water (330 mL) was added portionwise, keeping IT below 10°C. DCM (600 mL) was added. The two layers were separated and the the aq. layer was extracted twice with DCM (2 x 250 mL). The combined org. layers were washed with sat. aq. NaHCC>3 (300 mL). The evaporation residue was further co-evaporated twice with toluene (2 x 150 mL) to afford, after drying under high vacuum, of the crude title product (43.87 g; > 95% yield) as a brown oil.

1H NMR (DMSO-cie) δ: 10.88 (br s, 1 H); 6.77 (s, 1 H); 5.97 (s, 1 H); 3.63-3.49 (m, 2H); 3.06 (s, 3H); 2.60-2.55 (overlapped m, 1 H); 2.42-2.34 (m, 1 H); 2.32-2.24 (m, 1 H); 2.05-1.95 (overlapped m, 1 H); 1.84-1.76 (m, 1 H); 1.40 (s, 9H); 1.38 (s, 3H).

MS2 (ESI, m/z): 456.6 [M+H ⁺ ] for C15H25N2O4IS; t _R = 0.63 min.

C.ii. (2RS)-tei1 utyl 4-(6-bromo-3-oxo-1H yrrolo[1,2-c]imid^^

2-(methylsulfonyl)butanoate:

To a solution of intermediate C.i (60.88 g; 124 mmol) in dry THF (329 mL) was added, at 0°C, CDI (21.12 g; 130 mmol). The reaction mixture was then stirred at rt for 3 h. After cooling to 0°C, NaH (60% dispersion in oil, 0.758 g; 17.4 mmol) was added portion wise. After 2 h stirring, a second portion of NaH (60% dispersion in oil, 0.758 g; 17.4 mmol) was added. The reaction proceeded 2 h and sat. aq. NH4CI (300 mL) was carefully added. The mixture was further diluted with water (200 mL) and EA (1 L). The two phases were separated and the aq. phase was extracted twice with EA (2 x 500 mL). The evaporation residue was purified by CC (DCM-EA gradient) to afford the title compound (40.2 g, 67% yield) as a white solid.

1H NMR (CDC ) δ: 7.20 (d, J = 0.9 Hz, 1 H); 6.16 (q, J = 1.4 Hz, 1 H); 4.43 (m, 1 H); 4.29 (m, 1 H); 3.80 (m, 1 H); 3.57 (m, 1 H); 3.05 (s, 3H); 2.58 (m, 1 H); 2.18 (m, 1 H); 1.71 (s, 3H); 1.43 (s, 9H).

MS2 (ESI, m/z): 482.8 [M+H ⁺ ] for C16H23N2O5IS; t _R = 0.89 min. C. iii. tert-Butyl (2R)-4-(6-iodo-3-oxo-1Hwrrolo[1,2-c]imidazo

Intermediate C.ii (22.8 g) was separated by semi-preparative chiral HPLC Method B (MeOH-EtOH 1 -1 ; flow rate: 100 mL/min; UV detection at 243 nm); the respective retention times were 6.2 and 6.8 min. The title (R)-enantiomer (9.5 g), identified as the second eluting compound, was obtained as a white solid.

1H NMR (CDC ) δ: 7.20 (d, J = 0.9 Hz, 1 H); 6.16 (q, J = 1.4 Hz, 1 H); 4.43 (m, 1 H); 4.29 (m, 1 H); 3.80 (m, 1 H); 3.57 (m, 1 H); 3.05 (s, 3H); 2.58 (m, 1 H); 2.18 (m, 1 H); 1.71 (s, 3H); 1.43 (s, 9H).

MS2 (ESI, m/z): 482.8 [M+H ⁺ ] for C16H23N2O5IS; t _R = 0.89 min.

SECOND METHOD:

Alternatively, starting from the compound of Preparation B (3.8 g; 15 mmol) and 4-iodo-1 - -pyrrole-2- carbaldehyde (3.5 g; 15.8 mmol) and proceeding as described in steps C.i (55% yield) and C.ii (75% yield), the title compound (3.15 g) was obtained as a white solid.

The product obtained by the SECOND METHOD had NMR data equivalent to those reported for the compound obtained by the FIRST METHOD.

Preparation D: (2 ?H-(6-iodo-3-oxo-1H^yrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-A/- ((2 ?S)-(tetrahydro-2H-pyran-2-yl)oxy)butanamide

D. i. (2R)-4-(6-lodo-3-oxo-1H yrrolo[1,2 ]imidazol-2(3H)-^

To an ice-chilled solution of the compound of Preparation C (40 g; 85.2 mmol) in DCM (238 mL) was added Et ₃ SiH (14.6 mL; 91.4 mmol) and TFA (182 mL, 2.3 mol) over 15 min. The resulting solution was stirred at rt for 5 h. The reaction mixture was cooled to 0°C and dry Et20 (450 mL) was added dropwise over 1 h. The resulting suspension was stirred 1 h, filtered and washed with Et20 (3 x 100 mL). The solid was dried to afford the title compound (33.56 g; 95% yield) as an off-white solid.

¹ H NMR (DMSO-cie) δ: 13.81 (m, 1 H); 7.32 (d, J = 0.9 Hz, 1 H); 6.23 (m, 1 H); 4.47-4.35 (m, 2H); 3.59 (m, 1 H); 3.53-3.40 (overlapped m, 1 H); 3.12 (s, 3H); 2.59-2.48 (overlapped m, 1 H); 2.04 (m, 1 H); 1.53 (s, 3H).

MS2 (ESI, m/z): 426.9 [M+H ⁺ ] for C12H15N2O5IS; t _R = 0.69 min. D.ii. (2R)-4-(6-lodo-3-oxo-1H yrrolo[1,2-c]imidazol-2(3 ^

(tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a suspension of intermediate D.i (33.56 g; 78.7mmol) in THF (380 mL) were added DIPEA (74 mL; 433 mmol) and THPO-NH ₂ (14.56 g; 118 mmol). The mixture was cooled down to 0°C and T3P (50% solution in EA, 72 mL; 181 mmol) was added over 30 min. After 1 h at 0°C, DIPEA (12 mL; 70 mmol) and T3P (50% solution in EA, 30 mL, 75 mmol) were added. The reaction proceeded further 1 h and sat. aq. NaHC03 (200 mL) was added at 0°C. The mixture was diluted with water (100 mL) and EA (200 mL). The two layers were separated and the aq. layer was extracted with EA (200 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (32.46 g; 78% yield) as a white solid.

1H NMR (DMSO-c¼) (mixture of steroisomers) δ: 1 1.37 (m, 0.5H); 1 1.34 (m, 0.5H); 7.32 (d, J = 7.9 Hz, 1 H); 6.21 (dd, J = 1.3, 3.0 Hz, 1 H); 4.86 (s, 0.5H); 4.484.38 (m, 2.5H); 4.05-4.00 (m, 0.5H); 3.98-3.92 (m, 0.5H); 3.55-3.42 (overlapped m, 3H); 3.07 (s, 1.5H); 3.04 (s, 1.5H); 2.70-2.55 (overlapped m, 1 H); 2.01 -1.92 (m, 1 H); 1.70-1.61 (m, 2H); 1.57-1.45 (m, 7H).

MS2 (ESI, m/z): 525.9 [M+H ⁺ ] for C17H24N3O6IS; t _R = 0.78 min.

Preparation E: trimethyl((5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophen^-yl)ethynyl)silan

A mixture of 4-bromothiophene-2-boronic acid pinacol ester (0.500 g; 1.57 mmol), trimethylsilylacetylene (0.333 mL; 2.36 mmol), piperidine (0.466 mL; 4.72 mmol), Cul (0.0299 g, 0.157 mmol) and Pd(PPh ₃ ) ₄ (0.09 g, 0.078 mmol) in THF (7.9 mL) was stirred overnight at rt. The mixture was diluted in EA (50 mL) and filtered through a short pad of silica gel. The filtrate was concentrated in vacuo and the evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.1 14 g, 24% yield) as an orange brown oil. ¹ H NMR (DMSO-cie) δ: 8.17 (d, J = 1.1 Hz, 1 H); 7.48 (d, J = 1.1 Hz, 1 H); 1.28 (s, 12H); 0.21 (s, 9H). Preparation F: trimethyl((5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophen-2-yl)ethynyl)silane

Starting from 5-bromothiophene-2-boronic acid (1 g; 3.15 mmol) and proceeding in analogy to Preparation E, the title compound (0.259 g; 27% yield) was obtained after purification by CC (Hept-EA gradient) as a brownish solid.

¹ H NMR (cfe-DMSO) δ: 7.45 (d, J = 1.1 Hz, 1 H); 7.42 (d, J = 1.1 Hz, 1 H); 1.28 (s, 12H); 0.23 (s, 9H). Preparation G: (2 ?) -(6-(4-bromothiophen-2-yl) -oxo-1H^yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)-N-(((2 ?S)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

Starting from the compound of Preparation D (1.2 g; 2.28 mmol) and 4-bromo-2- thienylboronic acid (commercial, 0.567 g; 2.74 mmol), and proceeding in analogy to Procedure C, the title compound was obtained after purification by CC (Hept-EA-MeOH gradient) as a beige solid (0.608 g, 47% yield).

MS1 (ESI, m/z): 561.8 [M+H ⁺ ] for C2iH ₂ 6N ₃ 06BrS2; t _R = 0.97 min.

Preparation H: fert-butyldimethyl(3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)thiophen-2- yl)propoxy)silane

H. i. 3-( 5-Bromothiophen-2-yl)propan- 1 -ol:

To an ice-chilled solution of 3-(thiophen-2-yl)propan-1-ol (1.5 g; 1 1.7 mmol) in toluene (15 mL) was added NBS (2.083 g; 1 1.7 mmol) in portions. The reaction proceeded at rt overnight. 10% aq. KOH (50 mL) was added and the reaction mixture was extracted with DCM (2 x 50 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.925 g, 36% yield) as a brown oil.

1H NMR (DMSO-cie) δ: 6.87 (d, J = 3.7 Hz, 1 H); 6.59 (dt, J = 1.0, 3.6 Hz, 1 H); 3.72 (t, J = 6.3 Hz, 2H); 2.91 - 2.86 (m, 2H); 1.95-1.89 (m, 2H). H.ii. (3-(5-Bromothiophen-2-yl)propoxy)(tert-butyl)dimethylsilane:

To a solution of intermediate H.i (0.925 g; 4.18 mmol) in DCM (7 mL) was added imidazole (0.573 g; 8.37 mmol) and TBDMSCI (0.946 g; 6.28 mmol). The reaction mixture was stirred at rt for 1 h. Water (15 mL) and DCM (10 mL) were added. The two phases were separated and the organic layer was washed with water (15 mL). The evaporation residue was purified by CC (Hept-EA gradient) to give the title compound (1.167 g, 83% yield) as a light brown oil.

¹ H NMR (DMSO-cie) δ: 6.86 (d, J = 3.6 Hz, 1 H); 6.57 (dt, J= 1.0, 3.6 Hz, 1 H); 3.66 (t, J = 6.1 Hz, 2H); 2.85 (td, J = 0.8, 7.6 Hz, 2H); 1.89-1.82 (m, 2H); 0.92 (s, 9H); 0.07 (s, 6H).

H.iii. tert-Butyldimethyl(3-(5-(4 ,5,5-tetramethyl-1,3,2-dioxaborolan^

A mixture of intermediate H.ii (0.500 g; 1.49 mmol), bis(pinacolato)diboron (0.454 g; 1.79 mmol), Pd(dppf)Cl2 (0.109 g; 0.149 mmol) and KOAc (0.585 g; 5.96 mmol) was in dioxane (8.7 mL) was heated to 95°C for 1.5 h. After cooling to rt, EA (50 mL) was added and the resulting mixture was filtered over a pad of silica. The filtrate concentrated to dryness. The evaporation residue was purified by prep-HPLC (Method 2) to afford the title compound (0.189 g, 33% yield) as a colorless oil.

¹ H NMR (DMSO-cie) δ: 7.48 (d, J = 3.4 Hz, 1 H); 6.89 (d, J = 3.4 Hz, 1 H); 3.67 (t, J = 6.1 Hz, 2H); 2.95 (t, J = 7.6 Hz, 2H); 1.94-1.88 (m, 2H); 1.35 (s, 12H); 0.92 (s, 9H); 0.06 (s, 6H).

MS1 (ESI, m/z): 383.2 [M+H ⁺ ] for C19H35O3BSS; t _R = 1.31 min.

Preparation I: methyl (2 ?)-4-(6-iodo-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)butanoate

To an ice-chilled solution of intermediate D.i (3.35 g; 7.86 mmol) in MeOH (55 mL) and DCM (55 mL) was added drop wise trimethylsilyldiazomethane (2M in hexane, 20 mL; 40 mmol). The solution was stirred at 0°C for 2 h. AcOH (2.7 mL) was added and the mixture was evaporated and then coevaporated with cyclohexane (2 x 300 mL) to afford the title compound (3.5 g, >95% yield) as a yellow solid.

¹ H NMR (DMSO-cie) δ: 7.33 (d, J = 0.7 Hz, 1 H); 6.24 (d, J = 1.2 Hz, 1 H); 4.38 (s, 2H); 3.60 (m, 1 H); 3.52 (s, 3H); 3.47 (m, 1 H); 3.13 (s, 3H); 2.61 (m, 1 H); 2.07 (m, 1 H); 1.59 (s, 3H).

MS2 (ESI, m/z): 440.9 [M+H ⁺ ] for C13H17N2O5IS; t _R = 0.78 min.

Preparation J: 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )thiazole To a solution of 2-cyclopropyl-1 ,3-thiazole (0.5 g; 3.99 mmol) in THF (10 mL) cooled at -78°C, was added nBuLi (1.6M in hexanes; 3 mL; 4.79 mmol). The mixture was stirred at -78°C for 45 min before 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1.22 mL; 5.99 mmol) was added. The reaction was allowed to warm to rt over 2 h. Water (10 mL) and EA (20 mL) were added. The evaporation residue was purified by CC (Hept- EA gradient) to afford the title compound (0.091 g; 9% yield) as a colorless oil.

¹ H NMR (DMSO-cie) δ: 8.03 (s, 1 H); 2.41 (m, 1 H); 1.35 (s, 12H); 1.23-1.16 (m, 2H); 1.15-1.09 (m, 2H).

Preparation K: ((1 ?*,2 ?*)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cycloprop yl)methyl benzoate

K.i. ((1R*,2R*)-2-(4,4,5,5-Tetramethyl-1,3,2<Jioxalx)rolan-2^

To a solution of ierf-butyldimethyl(((1 R*,2R*)-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)cyclopropyl)methoxy)silane (prepared as described by Volgraf, M and a/, in J.Med.Chem. 2016, 59, 2760, 5.93 g, crude) in THF (36 mL) was added TBAF (1 M in THF, 66 mL). The mixture was stirred at rt for 6 h. The reaction mixture was concentrated to dryness. The crude residue was partitionned between water (50 mL) and DCM-MeOH (9-1 , 70 mL). The evaporation residue was purified by CC (Hex-TBME gradient) to afford the title compound (2.45 g, 74% yield) as colorless oil.

1H NMR (CDCI ₃ ) 6: 3.46 (d, J = 6.7 Hz, 2H); 1.35 (m, 1 H); 1.22 (s, 12H); 0.76 (m, 1 H); 0.55 (m, 1 H); 0.24 (dt, J = 5.8, 9.7 Hz, 1 H).

K.H. ((1R*,2R*)-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cy clopro

To a solution of intermediate K.i (2.44 g; 12.3 mmol) in THF (75 mL), cooled at 0°C, were added TEA (3.6 mL; 25.9 mmol) and DMAP (0.161 g; 1.31 mmol). Benzoyl chloride (1.7 mL; 14.5 mmol) was added drop wise over 2 min at 0°C. The reaction mixture was stirred at rt for 3 h 30. The reaction was poured onto sat. aq. NaHCC>3 (35 mL) and the aq. layer was extracted with EA (3 x 40 mL). The evaporation residue was purified by CC (Hex-EA gradient) to afford the title compound (2.17 g, 58% yield) as a colorless oil.

1H NMR (CDC ) δ: 8.06-8.03 (m, 2H); 7.55 (m, 1 H); 7.41-7.46 (m, 2H); 4.31 (dd, J = 6.1 , 1 1.4 Hz, 1 H); 4.06 (dd, J = 7.6, 1 1.4 Hz, 1 H); 1.49 (m, 1 H); 1.22 (s, 12H); 0.82 (td, J = 3.9, 6.8 Hz, 1 H); 0.70 (m, 1 H); -0.07 (m, 1 H).

Preparation L: fert-butyldimethyl(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)thiophen-2- yl)ethoxy)silane

Ll(2-(5-Bromothiophen-2-yl)ethoxy)(tert-butyl)dimethylsil ane

To a solution of 2-(5-bromothiophen-2-yl)ethan-1 -ol (1 g; 4.83 mmol) in DCM (14 mL) was added imidazole (0.661 g; 9.66 mmol) and TBDMSCI (1.09 g; 7.24 mmol). The reaction proceeded at rt for 30 min. Water (15 mL) and DCM (10 mL) were added. The two phases were separated. The evaporation residue afforded the title compound (1.55 g, >95 yield) as a colorless oil. ¹ H NMR (CDCI3) δ: 6.87 (d, J = 3.6 Hz, 1 H); 6.60 (d, J = 3.6 Hz, 1 H); 3.80 (t, J = 6.4 Hz, 2H); 2.96 (t, J = 6.4 Hz, 2H); 0.91 (s, 9H); 0.05 (s, 6H).

Lii. tert-Butyldimethyl(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan^

To a mixture of intermediate L.i (1 g; 3.11 mmol), bis(pinacolato)diboron (0.948 g; 3.73 mmol), Pd(dppf)Cl2 (0.228 g, 0.311 mmol) and KOAc (1.22 g, 12.4 mmol was added dioxane (18 mL). The reaction proceeded at 95°C for 2 h. The reaction mixture was cooled to rt and partitioned between EA (10 mL) and water (10 mL). The aq. layer was extracted with EA (10 mL). The evaporation residue was was purified by prep-HPLC (Method 2) to afford the title compound (0.367 g, 32% yield) as an orange oil.

¹ H NMR (CDC ) δ: 7.49 (d, J = 3.4 Hz, 1 H); 6.93 (d, J = 3.4 Hz, 1 H); 3.84 (t, J = 7.2 Hz, 2H); 3.08 (t, J = 7.1 Hz, 2H); 1.34 (s, 12H); 0.90 (s, 9H); 0.04 (s, 6H).

MS1 (ESI, m/z): 369.0 [M+H ⁺ ] for GerbOsBSSi; t _R = 1.31 min.

Preparation M: 2-((£)-2-((1 S _! 2S)-2-((2 ?)-2,2-dimethyl-1,3-dioxolan-4-yl)cyclopropyl)vinyl)-4,4,5,5 - tetramethyl-1 ,3,2-dioxaborolane

Ml (4R)-4-((1S,2R)-2^thynylcyclopropyl)-2,2-dimethyl-1,3-d^

A suspension of (1 R,2S)-2-((4R)-2,2-dimethyl-1 ,3-dioxolan-4-yl)cyclopropane-1-carbaldehyde (prepared as described by Gauvin, J.-C. and al. in WO2015/036964, 0.9 g; 5.3 mmol) and K2CO3 (1.462 g; 10.6 mmol) in MeOH (48.3 mL) was treated dropwise with dimethyl (1-diazo-2oxopropyl)phosphonate (1.1 1 g, 5.82 mmol). The reaction proceeded at rt for 2 h. The solvent was evaporated and the residue was dissolved in DCM (200 mL) and water (100 mL). The evaporation residue was carried on without further purification.

1H NMR (CDCb) δ: 4.13 (dd, J = 6.0, 8.1 Hz, 1 H); 3.77 (m, 1 H); 3.68 (m, 1 H); 1.83 (d, J = 2.1 Hz, 1 H); 1.44 (s, 3H); 1.34 (m, 1 H); 1.35 (s, 3H); 1.25 (m, 1 H); 1.02-0.92 (m, 2H).

Ml. 2-((E)-2-((1S,2S)-2-((2R)-2,2-Dimthyl-1,3 ioxofa

dioxaborolane:

To a mixture of intermediate M.i (0.837 g; 5.04 mmol) and TEA (0.0712 mL; 0.511 mmol) were added 4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (0.785 mL, 5.25 mmol) and Cp ₂ ZrHCI (0.136 g; 0.504 mmol). The reaction proceeded at 50°C for 2 h. The reaction mixture was diluted with EA, filtered and evaporated to dryness. The evaporation residue was purified by CC (pentane-EA gradient) to afford the title compound (0.5 g, 34% yield) as a colorless oil.

¹ H NMR (CDCb) δ: 6.12 (dd, J = 9.0, 17.9 Hz, 1 H); 5.49 (d, J = 17.9 Hz, 1 H); 4.09 (dd, J = 5.9, 8.0 Hz, 1 H); 3.69 (m, 1 H); 3.63 (m, 1 H); 1.47 (m, 1 H); 1.44 (s, 3H); 1.35 (s, 3H); 1.27 (s, 12H); 1.15 (m, 1 H); 0.96 (dt, J = 5.1 , 8.5 Hz, 1 H); 0.87 (dt, J = 4.9, 8.4 Hz, 1 H). Preparation N: 2-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiazole

To a solution of 2-phenylthiazole (0.5 g; 3.1 mmol) in THF (10 mL) at -78°C was added nBuLi (1.6M in hexanes, 2.33 mL, 3.72 mmol). The reaction mixture was stirred at -78°C for 45 min before 2-isopropoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.949 mL; 4.65 mmol) was added. The reaction was allowed to warm to rt. After 1.5 h, the reaction mixture was partitioned between water (10 mL) and EA (20 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.3 g; 34% yield) as a white solid.

¹ H NMR (CDCb) δ: 8.29 (m, 1 H); 8.04-8.01 (m, 2H), 7.50-7.45 (m, 3H); 1.39 (s, 12H).

Preparation O: fert-butyl(3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor olan-2-yl)thiophen-2- yl)propoxy)dimethylsilane

01 Ethyl (E)-3-(3-fluorothiophen-2-yl)acrylate:

To an ice-chilled suspension of NaH (60% dispersion in oil, 0.784 g; 19.6 mmol) in 1 ,2-dimethoxyethane (50 mL) was slowly added triethylphosphonoacetate (4.33 mL; 21.4 mmol). The mixture was stirred at rt for 30 min before 3-fluorothiophene-2-carbaldehyde (commercial, 2.32 g; 17.8 mmol) was added. After 1.5 h, the reaction mixture was partitioned between diethyl ether (100 mL) and water (50 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (2.6 g; 73% yield) as a yellowish solid. ¹ H NMR (CDCb) δ: 7.77 (d, J = 15.8 Hz, 1 H); 7.27 (m, 1 H); 6.85 (d, J = 5.6 Hz, 1 H); 6.22 (d, J = 15.8 Hz, 1 H); 4.27 (q, J = 7.1 Hz, 2H); 1.35 (t, J = 7.1 Hz, 3H).

MS1 (ESI, m/z): 201.2 [M+H ⁺ ] for C9H9O2FS; t _R = 0.94 min.

O.ii. 3-(3-Fluorothiophen-2-yl)propan-1-ol:

To a solution of intermediate O.i (2.6 g; 13 mmol) in EtOH (50 mL) was added portion wise NaBH4 (2.94 g; 78 mmol). After stirring for 2 days, the reaction mixture was partitioned between EA (200 mL) and sat. NaHCC (50 mL). The evaporation residue was taken up in MeOH (50 mL). 10% Pd/C (0.3 g) was added and the mixture was stirred under hydrogen atmosphere for 1 h. The catalyst was removed by filtration. The evaporation residue afforded the title alcohol (1.42 g; 68% yield) as a colorless oil.

¹ H NMR (CDCb) δ: 7.00 (m, 1 H); 6.76 (d, J = 5.5 Hz, 1 H); 3.72 (t, J = 6.9 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H); 1.92 (quint, J = 6.9 Hz, 2H), 1.46 (br s, 1 H).

O.iii. tert-Butyl(3-(3-fluorothiophen-2-yl)propoxy)dimethylsilane:

To a solution of intermediate O.ii (1420 g; 8.86 mmol) in DCM (50 mL) was added TBDMSCI (1.6 g; 10.6 mmol) and imidazole (0.9 g; 13.3 mmol). The reaction proceeded at rt overnight. The reaction mixture was partitioned between water (20 mL) and DCM (50 mL). The org. layer was washed with sat. NaHCCb (30 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (2.2 g; 90% yield) as a colorless oil.

¹ H NMR (CDCb) δ: 7.00 (m, 1 H); 6.74 (d, J = 5.5 Hz, 1 H); 3.67 (t, J = 6.9 Hz, 2H); 2.81 (t, J = 6.9 Hz, 2H); 1.92 (quint, J = 6.9 Hz, 2H); 0.92 (s, 9H); 0.07 (s, 6H).

MS1 (ESI, m/z): 275.1 [M+H ⁺ ] for C13H23OFSS1; t _R = 1.24 min.

O.iv. tert-Butyl(3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxabor ote^^

Starting from intermediate O.iii (0.5 g; 1.82 mmol) and proceeding as described in Preparation N, the title compound (0.69 g; 95% yield) was obtained after purification by CC (Hept-EA gradient) as a yellowish oil. ¹ H NMR (CDCb) δ: 7.25 (s, 1 H); 3.67 (t, J = 6.9 Hz, 2H); 2.85 (t, J = 6.9 Hz, 2H); 1.87 (quint, J = 6.9Hz, 2H); 1.35 (s, 12H); 0.92 (s, 9H); 0.07 (s, 6H).

MS1 (ESI, m/z): 401.1 [M+H ⁺ ] for C19H34O3FSS1 ; t _R = 1.33 min.

Preparation P: fert-butyldimethyl(3-(4-(4,4,5,54etramethyl-1,3,2-dioxaborol an-2-yl)thiophen-2- yl)propoxy)silane

Starting from 3-(4-bromothiophen-2-yl)propan-1-ol (1 g; 4.52mmol) and proceeding successively in analogy to Preparation L, steps L.i (94% yield) and L.ii (59% yield), the title compound (0.47 g) was obtained after filtration through a pad of silica gel (EA) as a yellowish oil.

¹ H NMR (CDCb) δ: 7.72 (d, J = 1.0 Hz, 1 H); 7.10 (s, 1 H); 3.68 (t, J = 6.2 Hz, 2H); 2.91 (t, J = 7.6 Hz, 2H); 1.87-1.94 (m, 2H); 1.35 (s, 12H); 0.92 (s, 9H); 0.07 (s, 6H).

MS1 (ESI, m/z): 383.2 [M+H ⁺ ] for C19H35O3BSS; t _R = 1.31 min. Preparation Q: fert-butyldiphenyl(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan-2-yl)thiophen-2- yl)phenethoxy)silane

Starting from (4-bromophenethoxy)(iert-butyl)diphenylsilane (2.0 g; 4.55 mmol) and 2-thiophene boronic acid (0.641 g; 5.0 mmol) and proceeding successively in analogy to Procedure C (89% yield) and Preparation J (47% yield), the title compound (0.3 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

¹ H NMR (CDCb) δ: 7.62-7.54 (m, 7H); 7.44-7.33 (m, 7H); 7.19-7.16 (m, 2H); 3.87 (t, J = 6.8 Hz, 2H); 2.88 (t,

J = 6.8 Hz, 2H); 1.38 (s, 12H); 1.04 (s, 9H).

MS1 (ESI, m/z): 569.3 [M+H ⁺ ] for C ₃ 4H ₄ i0 ₃ BSSi; t _R = 1.43 min.

Preparation R: 4,4,5,5-tetramethyl-2-(3-methyl-5-phenylthiophen-2-yl)-1,3,2 -dioxaborolane Starting from 2-bromo-3-methyl-5-phenylthiophene (prepared as described by Join, B. and a/ in Angewandte Chemie, Int. Ed. 2009, 48, 3644-3647, 1.1 g; 4.35 mmol) and proceeding in analogy to Preparation H, step H.iii (41 % yield), the title compound (0.53 g) was obtained after purification by CC (Hept gradient) as a off- white solid.

¹ H NMR (CDCb) δ: 7.66-7.62 (m, 2H); 7.41-7.36 (m, 2H); 7.30 (m, 1 H); 7.22 (s, 1 H); 2.49 (s, 3H); 1.37 (s, 12H).

MS1 (ESI, m/z): 300.1 [M+H ⁺ ] for C17H21O2BS; t _R = 1.20 min.

Preparation S: fert-butyldimethyl(3-(4-(4,4,5,54etramethyl-1,3,2-dioxaborol an-2-yl)thiophen-2- yl)propoxy)silane

Starting from 3-(4-bromothiophen-2-yl)propan-1 -ol (commercial, 1 g; 4.52 mmol) and proceeding successively in analogy to Preparation O, step O.iii (94% yield) and Preparation H, step H.iii (59% yield), the title compound (0.47 g) was obtained after purification by CC (Hept-EA gradient) as a yellowish oil.

¹ H NMR (CDCb) δ: 7.71 (m, 1 H); 7.09 (s, 1 H); 3.68 (t, J = 6.2 Hz, 2H); 2.91 (t, J = 7.6 Hz, 2H); 1.94-1.88 (m,

2H); 1.34 (s, 12H); 0.92 (s, 9H); 0.06 (s, 6H).

MS1 (ESI, m/z): 383.2 [M+H ⁺ ] for C19H35O3BSS; t _R = 1.31 min.

Preparation T: ferf-butyl (1-(thiazol-5-ylethynyl)cyclopropyl)carbamate A mixture of 5-bromothiazole (0.300 g; 1.83 mmol), ferf-butyl (l-ethynylcyclopropyl)carbamate (0.497 g; 2.74 mmol), Cul (0.03 g; 0.146 mmol), PdCI ₂ (PPh ₃ ) ₂ (0.064 g; 0.0914 mmol) and TEA (9.03 mL; 64.9 mmol) was heated to 100°C for 30 min. The reaction mixture was partitioned between water (20 mL) and EA (50 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.42 g, 87% yield) as a orange oil.

1H NMR (CDCb) δ: 8.85 (br s, 1 H); 8.01 (br s, 1 H); 5.13 (br s, 1 H); 1.49 (s, 9H); 1.37-1.31 (m, 2H); 1.27-1.21 (m, 2H).

MS1 (ESI, m/z): 265.1 [M+H ⁺ ] for Ci ₃ Hi ₆ N ₂ 0 ₂ S; t _R = 0.89 min. Preparation U: 5-(3-((fert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)thiazole

Starting from 5-bromothiazole (0.300 g; 1.83 mmol), ierf-butyldimethyl(prop-2-yn-1-yloxy)silane (0.748 g; 4.39 mmol) and proceeding in analogy to Preparation T, the title compound (0.4 g, 87% yield), was obtained after purification by CC (Hept-EA gradient) as a brownish oil.

¹ H NMR (CDCb) δ: 8.73 (br s, 1 H); 7.98 (br s, 1 H); 4.57 (s, 2H); 0.95 (s, 9H); 0.18 (s, 6H).

MS1 (ESI, m/z): 254.1 [M+H ⁺ ] for C12H19NOSS1; t _R = 1.14min.

Preparation V: (2 ?H-(6-(5-bromothiophen-2-yl) -oxo-1H^yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)-A/-(((2 ?S)-tetrahydro-2H-pyran-2-yl)oxy)butanamide Starting from the compound of Preparation D (1.2 g; 2.28 mmol) and 5-bromo-2- thienylboronic acid (commercial, 0.567 g; 2.74 mmol), and proceeding in analogy to Procedure C, the title compound was obtained after purification by CC (Hept-EA-MeOH gradient) as a beige solid (0.643 g, 50% yield).

MS1 (ESI, m/z): 560.0 [M+H ⁺ ] for C2iH ₂ 6N ₃ 06BrS2; t _R = 0.98 min. Preparation W: 3-(4-(2-((fert-butyldiphenylsilyl)oxy)ethyl)phenyl)-5-(tribu tylstannyl)isoxazole

W.i. 4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)benzaldehyde:

To a solution of 4-(2-hydroxyethyl)benzaldehyde (1 g; 6.66 mmol) in DCM (20 mL) was added imidazole (0.907 g; 133 mmol) and TBDPSCI (1.9 mL; 7.32 mmol). The reaction proceeded at rt for 30 min. Water (15 mL) and DCM (10 mL) were added. The two phases were separated. The evaporation residue was purified by CC (Hept-EA gradient) afforded the title compound (1.50 g, 58% yield) as a colorless oil.

¹ H NMR (CDC ) δ: 10.0 (s, 1 H); 7.82-7.79 (m, 2H); 7.76-7.73 (m, 2H); 7.59-7.57 (m, 4H); 7.46-7.34 (m, 6H); 3.91 (t, J = 6.5 Hz, 2H); 2.94 (t, J = 6.5 Hz, 2H); 1.03 (s, 9H).

W.ii. (E)-4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)benzaldehyde oxime:

To a solution of intermediate W.i (0.7 g; 1.8 mmol) in MeCN-water mixture (2-1 , 15 mL) was added NH2OH.HCI (0.25 g; 3.6 mmol). The reaction proceeded overnight at rt. The reaction mixture was partitioned between EA (50 mL) and water (10 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title oxime (0.49 g; 67 yield) as a colorless oil.

¹ H NMR (CDCb) δ: 8.14 (s, 1 H); 7.60-7.57 (m, 4H); 7.51 -7.48 (m, 2H); 7.45-7.41 (m, 2H); 7.38-7.34 (m, 4H); 7.21-7.18 (m, 2H); 3.87 (t, J = 6.7 Hz, 2H); 2.88 (t, J = 6.7 Hz, 2H); 1.29 (br s, 1 H); 1.03 (s, 9H). W.iii. 3-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)phenyl)-5-(trib^

To a solution of intermediate W.ii (0.490 g; 1.21 mmol) in DCM (10 mL) were added tributyl(ethynyl)stannane (0.383 g, 1.21 mmol), KHCO3 (0.182 g; 1.82 mmol) and NCS (0.178 g, 1.34 mmol). The mixture was stirred at rt overnight. The crude mixture was directly subjected to CC (Hept-EA gradient) to afford the title isoxazole (0.79 g; 91 % yield) as a colorless oil.

MS1 (ESI, m/z): 718.2 [M+H ⁺ ] for CsgHssNC SiSn; t _R = 1.53 min.

Preparation X: ieri-butyl((3-ethynyloxetan-3-yl)oxy)dimethylsilane

Starting from 3-ethynyloxetan-3-ol (0.2 g; 2.0 mmol) and proceeding in analogy to Preparation H, step H.ii (> 95% yield), the title compound (0.444 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

1H NMR (DMSO-cfe) δ: 4.66-4.64 (m, 2H); 4.56 (d, J = 6.9 Hz, 2H); 3.89 (s, 1 H); 0.89 (s, 9H); 0.13 (s, 6H). Preparation Y: 5-(4-(2-((fert-butyldiphenylsilyl)oxy)ethyl)phenyl)thiazole

Y.i. tert-Butyldiphenyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phe

Starting from (4-bromophenethoxy)(iert-butyl)diphenylsilane (prepared as reported in Bur, D. and al. WO2004105762, 1.5 g; 3.41 mmol) and proceeding in analogy to Preparation H, step H.iii (76% yield), the title compound (1.27 g) was obtained after purification by CC (Hept-EA gradient) as a yellowish oil.

¹ H NMR (CDCb) δ: 7.74-7.71 (m, 2H); 7.62-7.59 (m, 4H); 7.44-7.40 (m, 2H); 7.39-7.34 (m, 4H); 7.19-7.17 (m, 2H); 3.86 (t, J = 6.9 Hz, 2H); 2.88 (t, J = 6.9 Hz, 2H); 1.36 (s, 12H); 1.04 (s, 9H).

Y.ii. 5-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)phenyl)thiazole:

Starting from intermediate Y.i (0.65 g; 1.34 mmol) and 5-bromothiazole (0.22 g; 1.34 mmol) and proceeding in analogy to Procedure C (48% yield), the title compound (0.286 g) was obtained after purification by CC (Hept- EA gradient) as a yellowish oil.

¹ H NMR (CDCb) δ: 8.80 (s, 1 H); 8.08 (s, 1 H); 7.62-7.58 (m, 4H); 7.51 -7.49 (m, 2H); 7.46-7.41 (m, 2H); 7.38- 7.34 (m, 4H); 7.24-7.21 (m, 2H); 3.88 (t, J = 6.9 Hz, 2H); 2.89 (t, J = 6.9 Hz, 2H); 1.04 (s, 9H).

MS1 (ESI, m/z): 444.2 [M+H ⁺ ] for C ₂₇ H ₂ 9NOSSi; t _R = 1.39 min. Preparation Z: 2-(4-(2-((fert-butyldiphenylsilyl)oxy)ethyl)phenyl)-5-(4,4,5 ,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)thiazole

Z.i. 2-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)phenyl)thiazole:

Starting from intermediate Y.i (0.65 g; 1.34 mmol) and 2-bromothiazole (0.22 g; 1.34 mmol) and proceeding in analogy to Procedure C (82% yield), the title compound (0.488 g) was obtained after purification by CC (Hept- EA gradient) as a colorless oil.

¹ H NMR (CDCb) δ: 7.90-7.86 (m, 3H); 7.62-7.58 (m, 4H); 7.46-7.41 (m, 2H); 7.38-7.32 (m, 5H); 7.27-7.24 (m, 2H); 3.90 (t, J = 6.7 Hz, 2H); 2.91 (t, J = 6.6 Hz, 2H); 1.04 (s, 9H).

MS1 (ESI, m/z): 444.2 [M+H ⁺ ] for C ₂₇ H ₂ 9NOSSi; t _R = 1.34 min.

Z.ii. 2-(4-(2-((tert-Butyldiphenylsilyl)oxy)ethyl)phenyl)-5-(4,4,5 ,5^

Starting from intermediate Z.i (0.48 g; 1.08 mmol) and proceeding in analogy to Preparation J (58% yield), the title compound (0.360 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

1H NMR (CDCb) δ: 8.27 (s, 1 H); 7.92-7.90 (m, 2H); 7.60-7.57 (m, 4H); 7.44-7.40 (m, 2H); 7.38-7.34 (m, 4H); 7.26-7.24 (m, 2H), 3.89 (t, J = 6.7 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H), 1.39 (s, 12H); 1.04 (s, 9H).

MS1 (ESI, m/z): 570.2 [M+H ⁺ ] for C ₃ 3H ₄ oN0 ₃ BSSi; t _R = 1.41 min. Preparation AA (£)-fert-butyldiphenyl((1-(2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)vinyl)cyclopropyl)methoxy)silane

Starting from iert-butyl((1 -ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 2.0 g; 5.98 mmol), and proceeding in analogy to Preparation M, step M.ii (67% yield), the title compound (1.85 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

¹ H NMR (CDC ) δ: 7.67-7.64 (m, 4H); 7.45-7.36 (m, 6H); 6.40 (d, J = 18.4 Hz, 1 H), 5.37 (d, J = 18.4 Hz, 1 H), 3.81 (s, 2H); 1.27 (s, 12H); 1.06 (s, 9H); 0.92-0.87 (m, 4H).

MS1 (ESI, m/z): 570.2 [M+H ⁺ ] for C ₃ 3H ₄ oN0 ₃ BSSi; t _R = 1.41 min.

Preparation AB: (2 ?H-(6-(4-bromofuran-2-yl) -oxo-1H^yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)-N-((( ?S)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

Starting from the compound of Preparation D (0.5 g; 0.952 mmol) and 2-(4-bromofuran-2-yl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (0.312 g; 1.14 mmol) and proceeding in analogy to Procedure C (53% yield), the title compound (0.275 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a beige solid. MS1 (ESI, m/z): 545.6 [M+H ⁺ ] for C2iH ₂ 6N30 ₇ BrS; t _R = 0.94 min. Preparation AC: (2 ?)-4-(6-(5-bromofuran-2-yl)-3-oxo-1H-pyrrolo[1,2-c]imidazol- 2(3H)-yl)-2-methyl-2- (methylsulfonyl)-N-((( ?S)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

Starting from the compound of Preparation D (0.5 g; 0.952 mmol) and 2-(5-bromofuran-2-yl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane (0.312 g; 1.14 mmol) and proceeding in analogy to Procedure C (57% yield), the title compound (0.296 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a yellow foam.

MS1 (ESI, m/z): 545.6 [M+H ⁺ ] for C2iH ₂ 6N30 ₇ BrS; t _R = 0.94 min. Preparation AD: 5-(4-(oxetan-3-yl)phenyl)thiazole

Starting from 4,4,5,5-tetramethyl-2-(4-(oxetan-3-yl)phenyl)-1 ,3,2-dioxaborolane (commercial, 0.634 g; 2.44 mmol) and 5-bromothiazole (0.4 g; 2.44 mmol) and proceeding in analogy to Procedure C (92% yield), the title compound (0.488 g) was obtained after purification by CC (Hept-EA gradient) as an amorphous white solid.

¹ H NMR (CDCb) δ: 8.80 (s, 1 H); 8.1 1 (s, 1 H); 7.64-7.59 (m, 2H); 7.51 -7.46 (m, 2H); 5.13 (dd, J = 6.1 , 8.4 Hz,

2H); 4.80 (dd, J = 6.1 , 6.7 Hz, 2H); 4.28 (m, 1 H).

MS1 (ESI, m/z): 218.1 [M+H ⁺ ] for C12H11 NOS; t _R = 0.83 min. Preparation AE: ferf-butyl((3-((3-fluoro-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)thiophen-2- yl)ethynyl)oxetan-3-yl)oxy)dimethylsilane

AE. i. 2-Ethynyl-3-fluorothiophene:

Starting from 3-fluorothiophene-2-carbaldehyde (2.4 g; 18.4 mmol) and proceeding in analogy to Preparation M, step Mi, the title compound (0.35 g; 15% yield) was obtained as a yellowish oil.

¹ H NMR (CDCb) δ: 7.15 (dd, J = 4.0, 5.6 Hz, 1 H); 6.79 (dd, J = 0.8, 5.6 Hz, 1 H); 3.51 (d, J = 0.8 Hz, 1 H).

AE.ii. 3-((3-Fluorothiophen-2-yl)ethynyl)oxetan-3-ol:

To a solution of intermediate AE.i (0.32 g; 2.54 mmol) in THF (5 mL), cooled at -78°C was slowly added n- BuLi (1.6M in hexanes, 1.6 mL; 2.54 mmol). After 20 min, a solution of 3-oxetanone (0.366 g; 5.07 mmol) in THF (1 mL) was added.The reaction mixture was allowed to gradually warm up to rt over 2h. The reaction mixture was partitioned between water (15 mL) and EA (50 mL) and the aq. layer was extracted with EA (50mL). The evaporation residue was purified by chromatography (Hept-EA gradient) to afford the title compound (0.376 g, 75% yield) as a colorless oil.

¹ H NMR (CDCb) δ: 7.20 (dd, J = 4.0, 5.6 Hz, 1 H); 6.80-6.82 (m, J = 0.5, 5.7 Hz, 1 H); 4.95 (d, J = 7.1 Hz, 2H); 4.81 (d, J = 7.1 Hz, 2H); 2.70 (s, 1 H).

AE.iii. tert-Butyl((3-((3-fluorothiophen-2-yl)ethynyl)oxetan-3-yl)ox y)dim^

Starting from intermediate AE.ii (0.37 g; 1.87 mmol) and proceeding in analogy to Preparation H, step H.ii, the title compound (0.48 g, 82% yield) was obtained, after purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (CDCb) δ: 7.18 (dd, J = 4.0, 5.6 Hz, 1 H); 6.81 (dd, J = 0.7, 5.6 Hz, 1 H); 4.88 (d, J = 6.8 Hz, 2H); 4.78 (d, J = 6.8 Hz, 2H); 0.95 (s, 9H); 0.19 (s, 6H).

AE.iv. tert-butyl((3-((3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxab oro

yl)oxy)dimethylsilane:

Starting from intermediate AE.iii (0.48 g;1.54 mmol) and proceeding in analogy to Preparation J, the title compound (0.638 g, 95% yield) was obtained after purification by CC (Hept-EA gradient) as a yellowish oil. ¹ H NMR (CDCb) δ: 7.25 (s, 1 H); 4.89 (d, J = 6.5 Hz, 2H); 4.78 (d, J = 6.5 Hz, 2H); 1.36 (s, 12H); 0.95 (s, 9H); 0.18 (s, 6H)

Preparation AF: (2S)-2-(4-(2,2,3 _! 3 _! 8 _! 8 _! 9 _! 9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)phenyl)thi azole

Starting from (2S)-1-(4-bromophenyl)ethane-1 ,2-diol (2.58 g; 11.9 mmol) and proceeding successively in analogy to Preparation H, steps H.ii (68% yield) and H.iii (70% yield) and Preparation Z, step Z.i (46% yield), the title compound (0.11 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (CDCI3) δ: 7.94 (d, J = 8.1 Hz, 2H); 7.88 (d, J = 3.3 Hz, 1 H); 7.45 (d, J = 8.1 Hz, 2H); 7.34 (d, J = 3.3 Hz, 1 H); 4.75 (t, J = 6.1 Hz, 1 H); 3.71 (dd, J = 6.8, 10.1 Hz, 1 H); 3.58 (dd, J = 5.5, 10.1 Hz, 1 H); 0.91 (s, 9H); 0.88 (s, 9H); 0.10 (s, 3H); -0.01 (s, 6H); -0.03 (s, 3H).

Preparation AG: (2 ?)-2-(4-(2,2,3 _! 3 _! 8 _! 8 _! 9 _! 9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)phenyl)thi azole Starting from (2R)-1 -(4-bromophenyl)ethane-1 ,2-diol (1.53 g; 7.05 mmol) and proceeding successively in analogy to Preparation H, steps H.ii (48% yield) and H.iii (57% yield) and Preparation Z, step Z.i (46% yield), the title compound (0.20 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

1H NMR (CDC ) δ: 7.94 (d, J = 8.1 Hz, 2H); 7.88 (d, J = 3.3 Hz, 1 H); 7.45 (d, J = 8.1 Hz, 2H); 7.34 (d, J = 3.3 Hz, 1 H); 4.75 (t, J = 6.1 Hz, 1 H); 3.71 (dd, J = 6.8, 10.1 Hz, 1 H); 3.58 (dd, J = 5.5, 10.1 Hz, 1 H); 0.91 (s, 9H); 0.88 (s, 9H); 0.10 (s, 3H); -0.01 (s, 6H); -0.03 (s, 3H).

Preparation AH : 2-(4-(oxetan-3-yl)phenyl)thiazole

Starting from 4,4,5,5-tetramethyl-2-(4-(oxetan-3-yl)phenyl)-1 ,3,2-dioxaborolane (commercial, 0.634 g; 2.44 mmol) and 2-bromothiazole (0.4 g; 2.44 mmol) and proceeding in analogy to Procedure C (75% yield), the title compound (0.396 g) was obtained after purification by CC (Hept-EA gradient) as an amorphous white solid.

¹ H NMR (CDCb) δ: 8.00 (d, J = 8.3 Hz, 2H); 7.90 (d, J = 3.3 Hz, 1 H); 7.51 (d, J = 8.1 Hz, 2H); 7.36 (d, J = 3.3 Hz, 1 H); 5.14 (dd, J = 6.1 , 8.4 Hz, 2H); 4.82 (dd, J = 6.1 , 6.4 Hz, 2H).

MS1 (ESI, m/z): 218.1 [M+H ⁺ ] for C12H11 NOS; t _R = 0.79 min.

Preparation Al: 5-((1-(((ferf-butyldiphenylsilyl)oxy)methyl)cyclopropyl)ethy nyl)thiazole

Starting from iert-butyl((1 -ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.918 g; 2.74 mmol) and 5-bromothiazole (0.3 g; 1.83 mmol), and proceeding in analogy to Preparation T (91 % yield), the title compound (0.697 g) was obtained after purification by CC (Hept-EA gradient) as a yellowish oil.

MS1 (ESI, m/z): 418.1 [M+H ⁺ ] for C25H27NOSS1; t _R = 1.34 min. Preparation AJ: ferf-butyl 3-(4-(thiazol-2-yl)phenyl)azetidine-1-carboxylate

Starting from ferf-butyl 3-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)azetidine-1 -carboxylate (commercial, 1.31 g; 3.66 mmol) and 2-bromothiazole (0.6 g; 3.66 mmol) and proceeding in analogy to Procedure C (37% yield), the title compound (0.396 g) was obtained after purification by CC (Hept-EA gradient) as an amorphous white solid. ¹ H NMR (CDCI3) δ: 7.99 (d, J = 8.3 Hz, 2H); 7.90 (d, J = 3.3 Hz, 1 H); 7.43 (d, J = 8.2 Hz, 2H); 7.37 (d, J = 3.3 Hz, 1 H); 4.38 (t, J = 8.7 Hz, 2H); 4.02 (dd, J = 6.0, 8.6 Hz, 2H); 3.77-3.83 (m, 1 H); 1.50 (s, 9H).

MS1 (ESI, m/z): 317.1 [M+H ⁺ ] for C17H20N2O2S; t _R = 1.03 min.

Preparation AK: (3 ?S)-tetrahydrofuran-3-yl 3-ethynylazetidine-1-carboxylate AK.i. (3RS)-2,5-Dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl) carbonate:

To a solution of (3RS)-3-hydroxy-tetrahydrofuran (0.459 mL, 5.62 mmol) in MeCN (33.3 mL) was added TEA (1.56 mL; 1 1.2 mmol) and DSC (4.545 g; 16.9 mmol). The reaction mixture was stirred at rt for 2h. The reaction mixture was concentrated to dryness and the residue was diluted with EtOAc (50 mL). The org. layer washed with 1 M aq. citric acid (3x20 mL), water (30 mL), brine (30 mL), dried over MgSC>4, filtered and evaporated to dryness. The evaporation residue was purified by CC (Hexane-EA-MeOH gradient) to afford the title compound (1.28 g; 99% yield) as a colorless oil.

¹ H NMR (DMSO-cie) δ: 5.41 (m, 1 H); 3.79-3.87 (m, 3H); 3.76 (td, J = 4.5, 8.6 Hz, 1 H); 2.82 (s, 4H); 2.27 (m, 1 H); 2.03 (m, 1 H).

AK.H. (3RS)-Tetrahydrofuran-3-yl 3-ethynylazetidine-1-carboxylate:

To a solution of intermediate AK.i (0.770 g; 3.36 mmol) in DCM (35 mL) were added TEA (0.935 mL, 6.72 mmol) and 3-ethynylazetidine hydrochloride (commercial, 0.435 g; 3.7 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted in DCM (20mL), washed with sat. aq. NaHCC (3x40mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.225 g, 34% yield) as a colorless oil.

1H NMR (DMSO-ci ₆ ) δ: 5.09 (m, 1 H); 4.17-4.10 (m, 2H); 3.79-3.64 (m, 6H); 3.44 (m, 1 H); 3.29 (d, J = 2.5 Hz, 1 H); 2.08 (dd, J = 6.3, 13.6 Hz, 1 H); 1.85 (m, 1 H).

MS1 (ESI, m/z): 196.2 [M+H ⁺ ] for C10H13NO3; t _R = 0.64 min.

Preparation AL: (2 ?)-4-(6-(5-bromothiophen-2-yl)-3-oxo-1H-pyrrolo[1,2-c]imidaz ol-2(3H)-yl)-A/-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation V (0.2 g; 0.357 mmol) and proceeding in analogy to Procedure E, the title compound (0.120 g; 70% yield) was obtained, after filtration and drying to a constant weight, as a yellowish solid.

¹ H NMR (DMSO-ci ₆ ) δ: 10.95 (br s, 1 H); 9.20 (br s, 1 H); 7.48 (s, 1 H); 7.15 (m, 1 H); 7.12 (m, 1 H); 6.37 (d, J = 1.3 Hz, 1 H), 4.46 (s, 2H); 3.49 (m, 1 H); 3.36 (overlapped m, 1 H); 3.07 (s, 3H); 2.61 (m, 1 H); 1.96 (m, 1 H); 1.52 (s, 3H).

MS1 (ESI, m/z): 478.0 [M+H ⁺ ] for t _R = 0.83 min. Preparation AM: 2-(4-(((ieri-butyldimethylsilyl)oxy)methyl)phenyl)thiazole

Starting from 4-(iert-butyldimethylsilyloxymethyl)phenylboronic acid (0.649 g; 2.44 mmol) and 2-bromothiazole (0.4 g; 2.44 mmol) and proceeding in analogy to Procedure C (79% yield), the title compound (0.586 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil.

1H NMR (CDC ) δ: 7.97-7.95 (m, 2H); 7.88 (d, J = 3.3 Hz, 1 H); 7.44-7.41 (m, 2H); 7.46-7.41 (m, 2H), 7.34 (d, J = 3.3Hz, 1 H); ), 4.80 (s, 2H), 2.91 (t, J = 6.6 Hz, 2H), 0.97 (s, 9H); 0.14 (s, 6H).

MS1 (ESI, m/z): 306.0 [M+H ⁺ ] for C27H29NOSS1; t _R = 1.22 min.

EXAMPLES OF COMPOUNDS ACCORDING TO THE INVENTION: Example 1 : (2 ?)-4-(6-(5-ethynylthiophen-3-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide:

11 (2R)4-(6-(5-Formylthiophen-3-yl)-3-oxo-1H^ynolo[1^

(((R)-tetrahydro-2H-pyran-2-yl)oxy)butanamide

Starting from the compound of Preparation D (0.302 g; 0.57 mmol) and 2-formylthiophene-4-boronic acid (commercial, 0.135 g; 0.86 mmol), and proceeding in analogy to Procedure A (15% yield), the title compound (0.044 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a beige foam.

MS1 (ESI, m/z): 510.1 [M+H ⁺ ] for C22H27N3O7S2; t _R = 0.84 min.

1.H. (2R)-4-(6-(5^thynylthiophen-3-yl)-3-oxo-1H yrrolo[1^

N-(((R)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

A suspension of intermediate 1.i (0.044 g; 0.086 mmol) and K2CO3 (0.024 g; 0.173 mmol) in MeOH (0.8 mL) cooled to 0°C was treated drop wise with dimethyl (1 -diazo-2oxopropyl)phosphonate (0.0183 g; 0.0954 mmol). The reaction mixture was stirred at rt overnight. The solution was partitioned in DCM (10 mL) and water (10 mL). The aq. layer was extracted with DCM (10 mL). The evaporation residue was purified by CC (Hept-EA-MeOH gradient) to afford the title compound (0.0307 g, 70% yield) as a light yellow solid. MS1 (ESI, m/z): 506.1 [M+H ⁺ ] for C23H27N3O6S2; t _R = 0.94 min.

1.iii. (2R)-4-(6-(5^thynylthiophen-3-yl)-3-oxo-1H yrrolo[1^^

(methylsulfonyl)butanamide:

Starting from intermediate 1.ii (0.030 g; 0.06 mmol), and proceeding in analogy Procedure B (71 % yield), the title compound (0.05 g), was obtained after purification by prep-HPLC (Method 1 ) as a yellow solid.

1H NMR (DMSO-cie) δ: 9.14 (br s, 1 H); 7.71 (d, J = 1.1 Hz, 1 H); 7.67 (d, J = 1.1 Hz, 1 H); 7.58 (s, 1 H); 6.47 (d, J = 1.0 Hz, 1 H); 4.57 (s, 1 H); 4.46 (s, 2H); 3.50 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.96 (m, 1 H); 1.52 (s, 3H).

MS2 (ESI, m/z): 422.0 [M+H ⁺ ] for C18H19N3O5S2; t _R

Example 2: (2 ?)-4-(6-(4-ethynylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide 21. (2R)-2-Methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4^

c]imidazol-2(3H)-yl)-M-(((2RS)4etrahyd -2H^yran-2-yl^

Starting from the compound of Preparation D (0.17 g; 0.32 mmol) and the compound of Preparation E (0.135 g; 0.86 mmol), and proceeding in analogy to Procedure C (25% yield), the title compound (0.044 g), was obtained after purification by CC (Hept-EA-MeOH gradient) as a beige foam.

MS2 (ESI, m/z): 578.0 [M+H ⁺ ] for C25H33N3O6S2S; t _R = 0.97 min.

211 (2R) -(6-(4-Ethynylthiophen-2-yl)-3-oxo-1H^ynolo[1^

N-(((2RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a solution of intermediate 2.i (0.0448 g; 0.0775 mmol) in THF (0.32 mL) was added TBAF (1 M in THF, 0.32 mL; 0.32 mmol). The solution was stirred at rt for 30 min. Water (10 mL) and EA (10 mL) were added. The evaporation resdue was purified by CC (Hept-EA-MeOH gradient) to afford the title product (0.035 g; 98% yield) as a beige gum.

MS2 (ESI, m/z): 506.1 [M+H ⁺ ] for C23H27N3O6S2; t _R = 0.84 min.

21ii. (2R)-4-(6-(4^thynylthiophen-2-yl)-3-oxo-1H yrrolo[1,2-^

(methylsulfonyl)butanamide:

Starting from intermediate 2.ii (0.035 g; 0.066 mmol), and proceeding in analogy Procedure B (47% yield), the title compound (0.013 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellow solid.

1H NMR (DMSO-cie) δ 9.1 1 (br s, 1 H); 7.65 (d, J = 1.2 Hz, 1 H); 7.51 (d, J = 0.6 Hz, 1 H); 7.34 (d, J = 1.3 Hz, 1 H); 6.40 (d, J = 1.3 Hz, 1 H); 4.46 (s, 2H); 4.13 (s, 1 H); 3.50 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.96 (m, 1 H); 1.52 (s, 3H).

MS2 (ESI, m/z): 422.0 [M+H ⁺ ] for C18H19N3O5S2; t _R = 0.79 min. Example 3: (2 ?)-4-(6-(5-ethynylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.29 g; 0.55 mmol) and the compound of Preparation F (0.2 g; 0.65 mmol), and proceeding in analogy to Procedure C (37 % yield), Example 2, step 2.ii (83% yield) and Procedure B (23% yield), the title compound (0.013 g) was obtained after purification by prep-HPLC (Method 1 ) as a beige amorphous solid.

¹ H NMR (DMSO-cie) δ: 9.16 (br s, 1 H); 7.55 (d, J = 0.8 Hz, 1 H); 7.28 (d, J = 3.8 Hz, 1 H); 7.23 (d, J = 3.7 Hz, 1 H); 6.40 (d, J = 1.3 Hz, 1 H); 4.57 (s, 1 H); 4.46 (s, 2H); 3.50 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H).

MS2 (ESI, m/z): 422.0 [M+H ⁺ ] for C18H19N3O5S2; t _R = 0.79 min.

Example 4: (2 ?)-4-(6-(4-ethynylfuran-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.30 g; 0.57 mmol) and 4-formylfuran-2-boronic acid (commercial, 0.096 g; 0.68 mmol), and proceeding successively in analogy to Procedure C (17% yield), Example 1 , step 1.ii (54% yield) and Procedure B (62% yield) the title compound (0.014 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as an amorphous white solid.

¹ H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.16 (br s, 1 H); 7.99 (s, 1 H); 7.42 (s, 1 H); 6.75 (s, 1 H); 6.39 (d, J = 1.0 Hz, 1 H); 4.46 (s, 2H); 4.16 (s, 1 H); 3.49 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H), 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 406.2 [M+H ⁺ ] for CieHigNsOeS; t _R = 0.76 min.

Example 5: (2 ?)-4-(6-(4-cyclopropylthiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation G (0.10 g; 0.18 mmol) and cyclopropylboronic acid (commercial, 0.018 g; 0.357 mmol), and proceeding successively in analogy to Procedure D (69% yield) and Procedure B (32% yield) the title compound (0.017 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.36 (s, 1 H); 7.01 (d, J = 1.2 Hz, 1 H); 6.91 (d, J = 1.1 Hz, 1 H); 6.32 (d, J = 1.1 Hz, 1 H); 4.45 (s, 2H); 3.50 (m, 1 H); 3.37 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.89 (m, 1 H); 1.53 (s, 3H); 0.90-0.83 (m, 2H); 0.68-0.61 (m, 2H).

MS1 (ESI, m/z): 438.2 [M+H ⁺ ] for C19H23N3O5S2; t _R = 0.84 min. Example 6: (2 ?)-4-(6-(5-cyanothiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.150 g; 0.28 mmol) and 5-cyanothiophene-2-boronic acid (commercial, 0.053 g; 0.34 mmol), and proceeding successively in analogy to Procedure C (12% yield) and Procedure B (67% yield), the title compound (0.010 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.91 (d, J = 3.9 Hz, 1 H); 7.77 (s, 1 H); 7.46 (d, J = 3.9 Hz, 1 H); 6.50 (s, 1 H); 4.49 (s, 2H); 3.51 (m, 1 H); 3.40 (m, 1 H); 3.07 (s, 3H); 2.61 (m, 1 H); 1.98 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 423.1 [M+H ⁺ ] for C17H18N4O5S2; t _R = 0.74 min.

Example 7: (2 ?)-4-(6-(5-cyanothiophen-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.3 g; 0.57 mmol) and the compound of preparation H (0.262 g; 0.685 mmol), and proceeding successively in analogy to Procedure C (48% yield), Example 2, step 2.ii (65% yield) and Procedure B (79% yield) the title compound (0.063 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 9.15 (br s, 1 H); 7.32 (s, 1 H); 7.05 (d, J = 3.4 Hz, 1 H); 6.74 (d, J = 3.4 Hz, 1 H); 6.31 (d, J = 1.1 Hz, 1 H); 4.51 (t, J = 5.0 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.47-3.42 (m, 2H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.79 (t, J = 7.6 Hz, 2H); 2.58 (m, 1 H); 1.96 (m, 1 H); 1.78-1.72 (m, 2H); 1.52 (s, 3H).

MS1 (ESI, m/z): 456.1 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.67 min.

Example 8: (2 ?)-4-(6-(4-((1-aminocyclopropyl)ethynyl)thiophen-2-yl)-3-oxo -1H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

81 Methyl (2R)-4-(6-(4-bromothiophen-2-yl)-3-oxo-1H yrroW

(methylsulfonyl)butanoate:

Starting from the compound of Preparation I (2.88 g; 6.54 mmol) and 4-bromo-2-thienylboronic acid (1.42 g; 6.86 mmol), and proceeding successively in analogy to Procedure C (42% yield), the title compound (1.3 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as an off-white solid.

MS1 (ESI, m/z): 475.0 [M+H ⁺ ] for CuH^I^OsB^; t _R = 0.98 min.

8.H. Methyl (2R)-4-(6-(4-((1-((tert-butoxycarbonyl)amino)cyclopropyl)eth yn

pyrrolo[ 1, 2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoate:

Intermediate 8.i (0.2 g; 0.42 mmol), iert-butyl (l -ethynylcyclopropyl)carbamate (commercial, 0.152 g; 0.84 mmol), KOAc (0.103 g; 1.0 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'- biphenyl)[2-(2'-amino-1 ,r-biphenyl)]palladium(ll) (CAS 130584-14-5, 0.003 g; 0.004 mmol) in DMF (1.4 mL) was stirred at 50°C for 4.5h. After evaporation to dryness, the residue was purified by CC (Hept-EA-MeOH gradient) to afford the title compound (0.17 g, 70% yield) as a brown solid.

MS1 (ESI, m/z): 576.1 [M+H ⁺ ] for C27H33N3O7S2; t _R = 1.03 min. 8.iii. (2R)-4-(6-(4-((1-((tert-Butoxycarbonyl)amino)cyclopropyl)eth yn

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid:

To a solution of intermediate 8.ii (0.184 g, 0.319 mmol) in THF (2 mL) and water (1.31 mL) was added LiOH.h O (0.0358 g; 0.478 mmol). The solution was stirred at rt for 30min. The solution was acidified with sat. NaHSC>4 to pH = 1 -2 and extracted with EA (2 x 20 mL). The evaporation residue afforded the title compound (0.175 g, 98 % yield) as a brown gum.

MS1 (ESI, m/z): 562.1 [M+H ⁺ ] for C26H31 N3O7S2; t _R = 0.95 min.

8./V. tert-Butyl (1-((5-(2-((3l)-3- ethyl-3-( ethylsulfonyl)-4-oxo ^

yl)oxy)amino)butyl)-3-oxo-2,3-dihydro-1H-pyrrolo[1,2^]M

yl)ethynyl)cyclopropyl)carbamate:

To a solution of intermediate 8.iii (0.175 g; 0.312 mmol) in DMF (3 mL) and DIPEA (0.163 mL; 0.935 mmol) was added EDC.HCI (0.131 g; 0.685 mmol), THPO-NH ₂ (0.0547 g; 0.467 mmol) and HOBt (0.0842 g; 0.623 mmol). The mixture was stirred at rt over night. After evaporation to dryness, the residue was dissolved in EA (50 mL) and washed with water (2 x30 mL). The evaporation residue was purified by CC (Hept-EA- MeOH gradient) to afford the title compound (0.14 g, 68% yield) as a beige solid.

MS1 (ESI, m/z): 562.1 [M+H ⁺ ] for C31H40N4O8S2; t _R = 1.02 min.

8.v. (2R)-4-(6-(4-((1-Aminocyclopropyl)ethynyl)thiophen^

hydroxy-2-methyl-2-(methylsulfonyl)butanamide:

A solution of intermediate 8.iv (0.120 g; 0.182 mmol) in EA (0.5 mL) was added to the previous solution (3M HCI in EA, 3 mL) and the reaction proceeded at rt for 10 min. Aq. NH4OH was added until pH =8-9. The volatiles were removed in vacuo and the evaporation residue was purified by prep-HPLC (Method 1 ) to afford the title compound (0.042 g, 49% yield) as a light beige amorphous solid.

¹ H NMR (DMSO-cie) δ: 9.19 (br s, 1 H); 7.48 (s, 1 H), 7.44 (d, J = 1.1 Hz, 1 H); 7.23 (d, J = 1.1 Hz, 1 H); 6.39 (d, J = 1.0 Hz, 1 H); 4.46 (s, 2H); 3.49 (m, 1 H); 3.38 (overlapped m, 1 H); 3.07 (s, 3H); 2.58 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H); 0.90-0.87 (m, 2H); 0.85-0.82 (m, 2H).

MS1 (ESI, m/z): 477.2 [M+H ⁺ ] for C21H24N4O5S2; t _R = 0.57 min. Example 9: (2 ?)-4-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.16 g; 0.3 mmol) and the compound of Preparation J (0.092 g; 0.365 mmol), and proceeding successively in analogy to Procedure C (42% yield) and Procedure B (43% yield), the title compound (0.024 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.5 (br s, 1 H); 9.15 (br s, 1 H); 7.74 (s, 1 H); 7.71 (s, 1 H); 6.35 (s, 1 H); 4.46 (s, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 2.35 (m, 1 H); 1.97 (m, 1 H); 1.52 (s, 3H); 1.12-1.07 (m, 2H); 0.97-0.92 (m, 2H).

MS1 (ESI, m/z): 439.1 [M+H ⁺ ] for C18H22N4O5S2; t _R = 0.66 min.

Example 10: (2 ?)-4-(6-(5-ethynylfuran-2-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-N-hydroxy-2- methyl-2-(methylsulfonyl)butanamide

101 (2R)-4-(6-(5-Formylfuran-2-yl)-3-oxo-1H yrrolo[1,2-c]^

(((2RS)-tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a mixture of the compound of Preparation D (0.300 g; 0.571 mmol), 5-formyl-2-furanboronic acid MIDA ester (0.244 g; 0.971 mmol), S-Phos (0.0234 g; 0.0571 mmol) and Pd(OAc) ₂ (0.0077 g, 0.0345 mmol) were added dioxane (6.9 mL) and 3M K3PO4 (1.44 mL; 4.32 mmol). The reaction proceeded at 60°C overnight. After cooling, the reaction mixture was partitioned between EA (30 mL) and water (20 mL). The evaporation residue was purified by CC (Hept-EA-MeOH gradient) to afford the title compound (0.0608 g, 22% yield) as a beige solid.

MS2 (ESI, m/z): 494.2 [M+H ⁺ ] for C22H27N3O8S; t _R = 0.72 min.

10.H. (2R)-4-(6-(5^thynylfuran-2-yl)-3-oxo-1H yrrolo[1,2-c]^

(methylsulfonyl)butanamide:

Starting from intermediate 10.L (0.061 g; 0.12 mmol) and proceeding successively in analogy to Example 1 , step 1.ii (65% yield) and Procedure B (19% yield), the title compound (0.006 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 9.17 (br s, 1 H); 7.46 (s, 1 H); 6.88 (d, J = 3.5 Hz, 1 H); 6.68 (d, J = 3.5 Hz, 1 H); 6.41 (d, J = 1.3 Hz, 1 H); 4.75 (s, 1 H); 4.47 (s, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 4H); 2.60 (overlapped m, 1 H); 1.99 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 406.2 [M+H ⁺ ] for C18H19N3O5S2; t _R = 0.70 min.

Example 11 : (2 ?)-A/-hydroxy-4-(6-(5-((methoxyimino)methyl)thiophen-3-yl)-3 -oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide To a solution of intermediate 1.i (0.097 g; 0.19 mmol) in MeCN (0.776 mL) and water (0.388 mL) was added MeONhb.HCI (0.0175 g; 0.209 mmol). The solution was stirred for 1 h. The reaction mixture was directly purified by prep-HPLC (Method 1 ) to afford the title compound (0.0549 g, 63% yield) as a white amorphous solid.

1H NMR (DMSO-c(6) δ: 9.17 (br s, 1 H); 8.37 (s, 0.5H); 7.89 (s, 0.5H); 7.84 (s, 0.5H); 7.80 (d, J = 1.2 Hz, 0.5H); 7.69 (s, 0.5H); 7.66 (d, J = 1.0 Hz, 0.5H), 7.52 (s, 0.5H); 7.50 (s, 0.5H); 6.46 (d, J = 1.1 Hz, 0.5H); 6.44 (d, J = 1.1 Hz, 0.5H); 4.47 (s, 2H); 3.98 (s, 1.5H); 3.85 (s, 1.5H); 3.50 (m, 1 H), 3.37 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H), 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 455.1 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.77 min. Example 12: (2 ?)-A/-hydroxy-4-(6-(4-(3-hydroxyprop-1 -yn-1 -yl)thiophen-2-yl)-3-oxo-1 H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanarnide

121 (2R)-4-(6-(4 romothiophen-2-yl)-3-oxo-1H yrrolo[1,2^^

N-((2RS)-(tetrahydro-2H-pyran-2-yl)oxy)butanamide:

Starting from the compound of Preparation D (0.4 g; 0.76 mol) and 4-bromo-2-thienylboronic acid (0.189 g; 0.914 mmol) and proceeding in analogy to Procedure C (44% yield), the title compound (0.188 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a yellowish foam.

MS1 (ESI, m/z): 562.0 [M+H ⁺ ] for C2iH ₂ 6N ₃ 06BrS2; t _R = 0.96 min.

1211 (2R)-N ydroxy-4-(6-(4-(3-hydroxyprop-1-yn-1-yl)thioph

yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 12. i (0.14 g; 0.24 mol) and iert-butyldimethyl(2-propynyloxy)silane (0.10 mL; 0.49 mmol) and proceeding successively in analogy to Example 8, step 8.ii (21 % yield), Example 2, step 2.ii (79% yield) and Procedure B (22% yield), the title compound (0.005 g) was obtained after purification by prep- HPLC (Method 1 ) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 7.56 (d, J = 1.1 Hz, 1 H); 7.50 (s, 1 H); 7.30 (d, J = 1.2 Hz, 1 H); 6.39 (s, 1 H); 5.31 (t, J = 6.0 Hz, 1 H); 4.46 (s, 2H); 4.27 (d, J = 6.0 Hz, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.52 (s, 3H).

MS1 (ESI, m/z): 452.1 [M+H ⁺ ] for C19H21 N3O6S2; t _R = 0.68 min.

Example 13: (2 ?)-A/-hydroxy-4-(6-(4-((1 S*,2S*)-2-(hydroxymethyl)cyclopropyl)thiophen-2-yl)-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e 131 ((1S\2S 2-(5-(2-((2R)-3-Methyl-3-( ethylsulfonyl) -oxo^

yl)oxy)amino)butyl)-3 ixo-2,3-dihydro-1H-pyrrolo[1,2-c]imidaz^^^

benzoate:

Starting from intermediate 12. i (0.15 g; 0.27 mmol) and the compound of Preparation K (0.097 g; 0.32 mmol), and proceeding in analogy to Procedure D (52% yield), the title compound (0.091 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a yellowish foam.

MS1 (ESI, m/z): 656.1 [M+H ⁺ ] for C32H37N3O8S2; t _R = 1.08 min.

1311 (2R)-4-(6-(4-((1S^2S*)-2-(Hydroxymethyl)cyclopropyl)thiophen ^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-(((2RS)-tetrahyd^

To a solution of intermediate 13.i (0.091 g; 0.14 mmol) in MeOH (0.77 mL) was added K2CO3 (0.0379 g; 0.275 mmol). The reaction mixture was stirred at rt for 3h. The brown solution was diluted with DCM (10 mL) and washed with aq. 10% NaHSC>4 solution (10 mL). The aq. layer was extracted with DCM-MeOH (9-1 , 3 x 10 mL) and EA (10 mL). The evaporation residue was purified by CC (DCM-MeOH gradient) to afford the title compound (0.0606 g, 79% yield) as a yellowish foam.

MS1 (ESI, m/z): 552.2 [M+H ⁺ ] for C25H33N3O7S2; t _R = 0.82 min.

131H. (2R)-M-Hyd xy-4-(6-(4-((1S*,2S 2-(hyd xymethyl)cyclop p

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 13.ii (0.06 g; 0.1 mmol) and proceeding in analogy to Procedure B (58% yield), the title compound (0.029 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.36 (s, 1 H); 7.00 (s, 1 H); 6.88 (s, 1 H); 6.32 (s, 1 H); 4.59 (t, J = 5.6 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.44-3.33 (m, 3H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.76 (m, 1 H); 1.53 (s, 3H); 1.27 (m, 1 H); 0.82-0.77 (m, 2H).

MS1 (ESI, m/z): 467.9 [M+H ⁺ ] for C20H25N3O6S2; t _R = 0.70 min. Example 14 (2 ?,£)-A/-hydroxy-4-(6-(4-(3-hydroxyprop-1 -en-1 -yl)thiophen-2-yl)-3-oxo-1 H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide 141 (2R)-4-(6-(4-((E)-3-((tert-Butyldimethylsilyl)ox^^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl^

Starting from intermediate 12.i (0.2 g; 0.357 mmol) and (E)-ferf-butyldimethyl((3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)allyl)oxy)silane (0.160 g; 0.535 mmol) and proceeding in analogy to Procedure C (82% yield), the title compound (0.190 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a brownish foam.

MS1 (ESI, m/z): 652.1 [M+H ⁺ ] for C30H45N3O6S2S; t _R = 1.19 min.

1411 (2R,E)^ ydroxy-4-(6-(4-(34iydroxyprop-1-en-1-yl)thiophen-2-yl)-3-o^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 14.L (0.066 g; 0.1 mmol), and proceeding successively in analogy to Example 2, step 2.ii (90% yield) and Procedure B (57% yield), the title compound (0.023 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.49 (s, 1 H); 7.43 (s, 1 H); 7.22 (s, 1 H); 6.49 (d, J = 15.9 Hz, 1 H); 6.38 (s, 1 H); 6.23 (dt, J = 5.1 , 15.9 Hz, 1 H); 4.84 (t, J = 5.5 Hz, 1 H); 4.47 (s, 2H); 4.10-4.06 (m, 2H); 3.50 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 454.1 [M+H ⁺ ] for C19H21 N3O6S2; t _R = 0.69 min.

Example 15 (2 ?)-A/-hydroxy-4-(6-(5-(2-hydroxyethyl)thiophen-2-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.3 g; 0.57 mmol) and the compound of preparation L (0.31 g; 0.857 mmol), and proceeding successively in analogy to Procedure C (33% yield), Example 2, step 2.ii (74% yield) and Procedure B (84% yield), the title compound (0.051 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.87 (br s, 1 H); 9.17 (br s, 1 H), 7.32 (s, 1 H); 7.06 (d, J = 3.4 Hz, 1 H); 6.76 (d, J = 3.4 Hz, 1 H); 6.32 (d, J = 1.1 Hz, 1 H); 4.80 (t, J = 5.3 Hz, 1 H); 4.45 (s, 2H); 3.63-3.58 (m, 2H); 3.49 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.88 (t, J = 6.8 Hz, 2H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 442.2 [M+H ⁺ ] for C18H23N3O6S2; t _R = 0.66 min. Example 16: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(2-phen yloxazol-4-yl)-1 H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and 2-phenyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)oxazole (0.12 g; 0.45 mmol), and proceeding successively in analogy to Procedure C (17% yield) and Procedure E (84% yield), the title compound (0.017 g) was obtained, after filtration and drying to a constant weight, as a white solid.

¹ H NMR (DMSO-cie) δ: 10.87 (br s, 1 H); 9.17 (br s, 1 H), 8.05-8.01 (m, 2H); 7.59-7.56 (m, 2H); 7.44 (s, 1 H); 6.47 (br s, 1 H); 4.50 (s, 2H); 3.52 (m, 1 H); 3.40 (m, 1 H); 3.08 (s, 3H); 2.61 (m, 1 H); 1.99 (m, 1 H); 1.53 (s, 3H). MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C21 H22N4O6S; t _R = 0.79 min. Example 17: (2 ?H-(6-(4-((£)-2-((1S _! 2S)-2-((2 ?)-1 ,2-dihydroxyethyl)cyclopropyl)vinyl)thiophen-2-yl) oxo-1H^yrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

171 (2R)-4-(6-(4-((E)-2-((1S,2S)-2-((R)-2,2-DimethyM

1H yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(me^

yl)oxy)butanamide:

Starting from intermediate 12. i (0.2 g; 0.36 mmol) and the compound of Preparation M (0.157 g; 0.53 mmol), and proceeding successively in analogy to Procedure C (88% yield), the title compound (0.20 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a yellowish thick oil.

MS1 (ESI, m/z): 648.1 [M+H ⁺ ] for C3iH ₄ iN ₃ 08S2; t _R = 1.03 min.

17.H. (2R)-4-(6-(4-((E)-2-((1S _: 2S)-2-((2R)-1 _: 2-Dihyd^

pyrrolo[ 1, 2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl) butan

Starting from intermediate 17.i (0.052 g; 0.08 mmol) and proceeding in analogy to Procedure B (94% yield), the title compound (0.039 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.17 (br s, 1 H); 7.40 (d, J = 1.0 Hz, 1 H); 7.39 (s, 1 H); 7.06 (d, J = 1.0 Hz, 1 H); 6.37-6.33 (m, 2H); 5.76 (dd, J = 9.0, 15.7 Hz, 1 H); 4.54 (d, J = 4.9 Hz, 1 H); 4.50 (t, J = 5.6 Hz, 1 H); 4.46 (s, 2H); 3.49 (m, 1 H); 3.37-3.35 (m, 3H); 3.17 (m, 1 H); 3.07 (s, 3H); 2.60-2.56 (m, 2H); 1.96 (m, 1 H); 1.52 (s, 3H); 1.45 (m, 1 H); 1.00 (m, 1 H); 0.81 (m, 1 H).

MS1 (ESI, m/z): 524.1 [M+H ⁺ ] for C23H29N3O7S2; t _R = 0.68 min. Example 18: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(2-phen ylthiazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation N (0.131 g; 0.457 mmol), and proceeding successively in analogy to Procedure C (40% yield) and Procedure E (76% yield), the title compound (0.017 g) was obtained, after filtration and drying to a constant weight, as a white solid.

¹ H NMR (DMSO-cie) δ: 10.87 (br s, 1 H); 9.20 (br s, 1 H), 8.11 (s, 1 H), 7.94-7.90 (m, 2H); 7.60 (s, 1 H); 7.54- 7.46 (m, 2H); 6.49 (br s, 1 H); 4.50 (s, 2H); 3.52 (m, 1 H); 3.41 (m, 1 H); 3.08 (s, 3H); 2.61 (m, 1 H); 1.99 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 475.1 [M+H ⁺ ] for C21 H22N4O5S2; t _R = 0.81 min.

Example 19: (2 ?)-4-(6-(4-(((1 S,2S)-2-(1 ,2-dihydroxyethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

Starting from intermediate 12. i (0.2 g; 0.36 mmol) and the intermediate M.i (0.1 19 g; 0.71 mmol), and proceeding successively in analogy to Example 8, steps 8.ii (47% yield) and 8.v (7% yield), the title compound (0.039 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.94 (br s, 1 H); 9.17 (br s, 1 H); 7.46 (s, 1 H); 7.44 (s, 1 H); 7.25 (s, 1 H); 6.38 (s, 1 H); 4.65 (d, J = 5.0 Hz, 1 H); 4.58 (t, J = 5.5 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.38-3.35 (overlapped m, 3H); 3.07 (s, 3H); 2.59 (overlapped m, 2H); 1.96 (m, 1 H); 1.53 (s, 3H); 1.44 (m, 1 H); 1.28 (m, 1 H); 0.90 (m, 1 H); 0.74 (m, 1 H).

MS1 (ESI, m/z): 522.1 [M+H ⁺ ] for C23H27N3O7S2; t _R = 0.68 min.

Example 20: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phen ylthiazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

201 (2R)-2-Methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4 he

((tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To an ice-chilled solution of 4-phenylthiazole (0.077 g; 0.478 mmol) in THF (2 mL) was slowly added a freshly prepared solution of TMPMgCI.LiCI (0.8M in THF, 0.7 mL, 0.564 mmol). The mixture was stirred for 45 min at 0°C before ZnC (1 M in THF, 0.6 mL, 0.6 mmol) was added. After stirring for another 30 min at rt, the compound of Preparation D (0.220 g; 0.419 mmol), Pd(dba) ₂ (0.013 g; 0.023 mmol) and P(o-furyl) ₃ (0.01 1 g; 0.046 mmol) were added. The reaction was warmed to 50°C. The reaction mixture was partitioned between (EA (20 mL) and water (10 mL). The evaporation residue was purified by CC (EA-Hept gradient) and subsequently by prep-HPLC (Method 1 ) to afford the title product (0.005 g, 2% yield) as an amorphous solid. MS1 (ESI, m/z): 559.2 [M+H ⁺ ] for C26H30N4O6S2; t _R = 0.97 min. 20.H. (2R)^ydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phen^

2(3H)-yl)butanamide:

Starting from intermediate 20.i (0.005 g; 0.009 mmol) and proceeding successively in analogy to Procedure E (47% yield), the title compound (0.002 g) was obtained, after precipitation, as a white amorphous solid. MS1 (ESI, m/z): 475.1 [M+H ⁺ ] for C21 H22N4O5S2; t _R = 0.82 min.

Example 21 : (2 ?)-A/-hydroxy-4-(6-(4-(3-hydroxypropyl)thiophen-2-yl)-3-oxo- 1H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

211 (2R)-4-(6-(4-(3-((tei1 utyldimethylsilyl)oxy)propy^

yl)-2-methyl-2-(methylsulfonyl)^-(((2RS)-tetrahydro-2H^yr afc

To a solution of intermediate 14.i (0.185 g; 0.284 mmol) in EA (1.1 mL) and MeOH (3.5 mL) was added 10% Pd/C (0.03 g). The reaction mixture was stirred at rt for 3.5h under H2 atmosphere. The reaction mixture was filtered through celite. The evaporation residue was purified by CC (Hept-EA-MeOH gradient) to afford the title compound (0.1729 g, 93% yield) as a white gum.

MS1 (ESI, m/z): 654.2 [M+H ⁺ ] for C30H47N3O7S2S; t _R = 1.20 min. 21. ii. (2R)-N ydroxy -(6-(4-(3-hydroxypropyl)thiophen-2-yl)-3-oxo

methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 21. i. (0.173 g; 0.26 mmol), and proceeding successively in analogy to Example 2, step 2.ii (62% yield) and Procedure B (57% yield), the title compound (0.04 g) was obtained after filtration and trituration in MeCN as a white amorphous solid.

1H NMR (DMSO-c¼) δ: 10.94 (br s, 1 H); 9.19 (br s, 1 H); 7.36 (s, 1 H); 7.13 (d, J = 0.6 Hz, 1 H); 6.95 (s, 1 H); 6.33 (d, J = 0.9 Hz, 1 H); 4.49-4.43 (m, 3H); 3.50 (m, 1 H); 3.45-3.40 (m, 2H); 3.37 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 2.59-2.53 (m, 2H); 1.97 (m, 1 H); 1.75-1.70 (m, 2H); 1.53 (s, 3H).

MS1 (ESI, m/z): 442.2 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.68 min.

Example 22: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-phen ylthiazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from 5-phenylthiazole (0.077 g; 0.478 mmol) and the compound of Preparation D (0.220 g; 0.419 mmol), and proceeding successively in analogy to Example 20, step 20.i (62% yield) and Procedure E (79% yield), the title compound (0.1 10 g) was obtained after precipitation, filtration and drying to a constant weight as a white amorphous solid.

1H NMR (DMSO-cie) δ: 10.94 (br s, 1 H); 9.19 (br s, 1 H); 8.18 (s, 1 H); 7.73 (s, 1 H); 7.71 -7.67 (m, 2H); 7.49- 7.43 (m, 2H); 7.37 (m, 1 H); 6.57 (s, 1 H); 4.53-4.49 (m, 2H); 3.53 (m, 1 H); 3.42 (m, 1 H); 3.08 (s, 3H); 2.64 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H). MS1 (ESI, m/z): 475.1 [M+H ⁺ ] for C21 H22N4O5S2; t _R = 0.79 min.

Example 23: (2 ?)-4-(6-(4-fluoro-5-(3-hydroxypropyl)thiophen-2-yl)-3-oxo-1H -pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.3 g; 0.57 mmol) and the compound of Preparation O (0.274 g; 0.187 mmol), and proceeding successively in analogy to Procedure C (49% yield), Example 2, step 2.ii (92% yield) and Procedure E (82% yield), the title compound (0.1 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.94 (br s, 1 H); 9.19 (br s, 1 H); 7.45 (s, 1 H); 7.12 (s, 1 H); 6.34 (s, 1 H); 4.54 (t, J = 5.1 Hz, 2H); 4.46 (s, 2H); 3.50 (m, 1 H); 3.47-3.43 (overlapped m, 2H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.72 (t, J = 7.6 Hz, 2H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.74-1.67 (m, 2H); 1.53 (s, 3H).

MS1 (ESI, m/z): 474.1 [M+H ⁺ ] for C19H24N3O6FS2; t _R = 0.70 min.

Example 24: (2 ?)-A/-hydroxy-4-(6-(4-((3-hydroxyoxetan-3-yl)ethynyl)furan-2 -yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

Starting from 3-ethynyloxetan-3-ol (commercial, 0.074 g; 0.75 mmol) and the compound of Preparation AB (0.203 g; 0.37 mmol), and proceeding successively in analogy to Example 8, step 8.ii (82% yield) and Procedure E (1 1 % yield), the title compound (0.014 g) was obtained after purification by prep-HPLC (Method 2) as a beige solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 8.00 (d, J = 0.6 Hz, 1 H); 7.44 (s, 1 H); 6.76 (s, 1 H); 6.61 (s, 1 H); 6.40 (d, J = 1.2 Hz, 1 H); 4.71 (d, J = 6.5 Hz, 2H); 4.58 (d, J = 6.6 Hz, 2H); 4.47 (s, 2H); 3.49 (m, 1 H); 3.39 (m, 1 H), 3.07 (s, 3H); 2.60 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 478.1 [M+H ⁺ ] for C21H23N3O8S; t _R = 0.66 min.

Example 25: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-(thi ophen-2-yl)isoxazol-3-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

25./ ^' tert-Butyl (2R)-4-(6-formyl-3-oxo-1H yrrolo[1,2-c]imidazol-2^

(methylsulfonyl)butanoate:

A vial was charged with the compound of Preparation C (0.6 g; 1.24 mmol), N-formyl saccharin (0.394 g; 1.87 mmol), dppb (0.024 g; 0.056 mmol), Pd(OAc) ₂ (0.008 g; 0.037 mmol) and Na ₂ C0 ₃ (0.2 g, 1.87 mmol). DMF (4.5 mL) and EfeSiH (0.258 mL; 1.62 mmol) were added. The reaction proceeded at 75°C over night. The reaction mixture was partitioned between EA (25 mL) and water (10 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title aldehyde (0.19 g; 40% yield) as a reddish solid.

MS1 (ESI, m/z): 385.2 [M+H ⁺ ] for C17H24N2O6S; t _R = 0.80 min. 25.H. tert-Butyl (2R,E)-4-(6-((hydroxyimino)methyl)-3-oxo-1H^yrroW

(methylsulfonyl)butanoate:

To a solution of intermediate 25. i. (0.450 g; 1.17 mmol) in a MeCN-h O mixture (2-1 , 8 mL) was added NH2OH.HCI (0.163 g; 2.34 mmol). The reaction proceeded 1 h at rt. The reaction mixture was partitioned between EA (25 mL) and water (10 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.32 g; 70% yield) as a colorless solid.

MS1 (ESI, m/z): 400.2 [M+H ⁺ ] for C17H25N3O6S; t _R = 0.75 min.

25.;;; ^' . tert-Butyl (2R)-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-(thiophen^

c]imidazol-2(3H)-yl)butanoate: To a suspension of intermediate 25.ii (0.18 g; 0.451 mmol) in MeOH (5 mL) was added thiopheneacetylene (0.244 g; 2.25 mmol). PIFA (0.233 g, 0.541 mmol) was added in three portions. After 3h, the reaction mixture was directly subjected to CC (Hept-EA gradient) to afford the title compound (0.08 g; 35% yield) as a yellowish solid.

MS1 (ESI, m/z): 506.1 [M+H ⁺ ] for C23H27N3O6S2; t _R = 1.04 min. 25 (2R)-N^ydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo

c]imidazol-2(3H)-yl)butanamide:

Starting from the intermediate 25.iii (0.08 g; 0.158 mmol) and proceeding successively in analogy to Preparation D, steps D.i (63% yield), D.ii (75% yield) and Procedure E (60% yield), the title compound (0.021 g) was obtained, after filtration and drying to a constant weight, as a white amorphous solid.

1H NMR (DMSO-c¼) δ: 10.94 (br s, 1 H); 9.19 (br s, 1 H); 7.84 (d, J = 4.9 Hz, 1 H); 7.79 (s, 1 H); 7.66 (d, J = 3.3 Hz, 1 H); 7.27 (t, J = 4.4 Hz, 1 H); 7.24 (s, 1 H); 6.52 (s, 1 H); 4.51 (s, 2H); 3.53 (m, 1 H); 3.41 (m, 1 H); 3.08 (s, 3H); 2.62 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 465.0 [M+H ⁺ ] for C19H20N4O6S2; t _R = 0.78 min.

Example 26 (2 ?)-A/-hydroxy-4-(6-(5-(3-hydroxypropyl)thiophen-3-yl)-3-oxo- 1H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation P (0.238 g; 0.419 mmol), and proceeding successively in analogy to Procedure C (31 % yield), Example 2, step 2.ii (36% yield) and Procedure B (79% yield), the title compound (0.004 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

1H NMR (DMSO-cie) δ: 10.87 (br s, 1 H); 9.17 (br s, 1 H), 7.44 (s, 1 H); 7.36 (s, 1 H); 7.15 (s, 1 H); 6.42 (s, 1 H); 4.53 (t, J = 5.2 Hz, 1 H); 4.45 (s, 2H); 3.53-3.43 (m, 3H); 3.39 (overlapped m, 1 H); 3.07 (s, 3H); 2.81 (t, J = 7.7 Hz, 2H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.81-1.74 (m, 2H); 1.53 (s, 3H). MS1 (ESI, m/z): 456.1 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.66 min.

Example 27 (2 ?)-A/-hydroxy-4-(6-(5-(4-(2-hydroxyethyl)phenyl)thiophen-2-y l)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation Q (0.175 g; 0.457 mmol), and proceeding successively in analogy to Procedure C (10% yield), Example 2, step 2.ii (29% yield) and Procedure E (79% yield), the title compound (0.018 g) was obtained, after filtration and drying to a constant weight, as a slightly orange amorphous solid.

¹ H NMR (DMSO-c¼) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H), 7.54 (d, J = 8.1 Hz, 2H), 7.48 (s, 1 H), 7.40 (d, J = 3.7 Hz, 1 H), 7.28-7.25 (m, 3H); 6.41 (s, 1 H); 4.66 (t, J = 5.2 Hz, 1 H), 4.48 (s, 2H), 3.64-3.59 (m, 2H); 3.52 (m, 1 H); 3.41 (m, 1 H); 3.08 (s, 3H); 2.74 (t, J = 6.9 Hz, 2H); 2.61 (m, 1 H); 1.99 (m, 1 H); 1.81 -1.74 (m, 2H); 1.54 (s, 3H).

MS1 (ESI, m/z): 518.1 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.80 min.

Example 28 (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-phen ylisoxazol-3-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide: Starting from intermediate 25. ii (0.098 g; 0.245 mmol) and phenylacetylene (0.125 g; 1.23 mmol) and proceeding successively in analogy to Example 25, step 25.ii, Preparation D, steps D.i (73% yield, two steps) and D.ii (72% yield), and Procedure E (54% yield), the title compound (0.026 g) was obtained, after filtration and drying to a constant weight, as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H), 7.86-7.83 (m, 2H), 7.77 (s, 1 H), 7.59-7.52 (m, 3H), 7.41 (s, 1 H), 6.53 (d, J = 0.9 Hz, 1 H); 4.52 (s, 2H), 3.64-3.59 (m, 2H); 3.53 (m, 1 H); 3.42 (m, 1 H); 3.08 (s, 3H); 2.64 (m, 1 H); 1.99 (m, 1 H); 1.81 -1.74 (m, 2H); 1.55 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C19H25N3O6S2; t _R = 0.81 min.

Example 29: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-phen yloxazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide 291 (2R)-2-Methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4 he

((tetrahydro-2H-pyran-2-yl)oxy)butanamide:

To a mixture of the compound of Preparation C (0.300 g, 0.622 mmol) and 4-phenyloxazole (commercial, 0.181 g, 1.24 mmol) were added NaOi-Bu (0.12 g; 1.24 mmol), Pd(PPh ₃ )4 (0.07 g, 0.062 mmol) and dioxane (4 mL). The reaction proceeded at 100°C for 1 h. The reaction mixture was partitioned between (EA (20mL) and water (10mL). The evaporation residue was purified by CC (EA-Hept gradient) to afford the title product (0.23 g, 74% yield) as an orange solid.

MS1 (ESI, m/z): 500.1 [M+H ⁺ ] for C25H29N2O6S; t _R = 1.04 min. 29.H. (2R)^ydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(4-pheny^

2(3H)-yl)butanamide:

Starting from intermediate 29.i (0.23 g; 0.46 mmol) and proceeding successively in analogy to Preparation D, steps D.i (54% yield) and D.ii (65% yield), and Procedure E (54% yield), the title compound (0.054 g) was obtained, after filtration and drying to a constant weight, as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.19 (br s, 1 H); 8.60 (s, 1 H); 7.80-7.85 (m, 2H); 7.71 (s, 1 H); 7.46 (t, J = 7.6 Hz, 2H); 7.35 (t, J = 7.4Hz, 1 H); 6.61 (s, 1 H); 4.53 (s, 2H); 3.53 (m, 1 H); 3.43 (m, 1 H); 3.08 (s, 3H); 2.64 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C21 H22N4O6S; t _R = 0.76 min. Example 30: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-phen yloxazol-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

To a mixture of the compound of Preparation C (0.300 g, 0.622 mmol) and 5-phenyloxazole (commercial, 0.181 g, 1.24 mmol) and proceeding successively in analogy to Example 29, step 29.i (32% yield), Preparation D, steps D.i (74% yield) and D.ii (68% yield) and Procedure E (64% yield), the title compound (0.027 g) was obtained after purification by CC (DCM-MeOH gradient) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H); 7.82-7.78 (m, 3H); 7.73 (s, 1 H); 7.50-7.47 (m, 2H); 7.35 (m, 1 H); 6.61 (s, 1 H); 4.53 (s, 2H); 3.53 (m, 1 H); 3.43 (m, 1 H); 3.08 (s, 3H); 2.64 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C21 H22N4O6S; t _R = 0.77 min. Example 31 : (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-phen ylisoxazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and 3-phenyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)isoxazole (commercial, 0.124 g; 0.457 mmol), and proceeding successively in analogy to Procedure C (6% yield) and Procedure B (46% yield), the title compound (0.004 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H); 7.90-7.85 (m, 3H); 7.75 (s, 1 H); 7.57-7.51 (m, 3H); 7.25 (m, 1 H); 6.56 (s, 1 H); 4.53 (s, 2H); 3.53 (m, 1 H); 3.42 (m, 1 H); 3.08 (s, 3H); 2.64 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C21 H22N4O6S; t _R = 0.80 min. Example 32: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-phen ylisoxazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and (2-phenyloxazol-5-yl)boronic acid (commercial, 0.108 g; 0.57 mmol), and proceeding successively in analogy to Procedure C (45% yield) and Procedure E (46% yield), the title compound (0.051 g) was obtained, after filtration and drying to a constant weight, as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H); 8.07-8.04 (m, 2H); 7.65 (s, 1 H); 7.57-7.51 (m, 3H); 7.50 (s, 1 H); 6.52 (m, 1 H); 4.51 (s, 2H); 3.53 (m, 1 H); 3.41 (m, 1 H); 3.08 (s, 3H); 2.62 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C21 H22N4O6S; t _R = 0.77 min.

Example 33: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-phen ylisoxazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation R (0.229 g; 0.76 mmol), and proceeding successively in analogy to Procedure C (23% yield) and Procedure E (76% yield), the title compound (0.051 g) was obtained after purification by CC (DCM-MeOH gradient) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H); 7.63-7.59 (m, 2H); 7.43-7.38 (m, 2H); 7.36 (s, 1 H); 7.31-7.26 (m, 2H); 6.32 (s, 1 H); 4.50 (s, 2H); 3.53 (m, 1 H); 3.39 (m, 1 H); 3.08 (s, 3H); 2.62 (m, 1 H); 2.32 (s, 3H); 2.00 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 459.1 [M+H ⁺ ] for C23H25N3O5S2; t _R = 0.93 min.

Example 34: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(5-phen ylthiophen-2-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and 5-phenyl-2-thienylboronic acid (0.333 g; 0.45 mmol), and proceeding successively in analogy to Procedure C (28% yield) and Procedure B (5% yield), the title compound (0.002 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H), 7.67-7.62 (m, 2H), 7.49 (s, 1 H), 7.46 (m, 1 H); 7.45- 7.39 (m, 2H); 7.33-7.28 (m, 1 H); 6.42 (s, 1 H); 4.48 (s, 2H), 3.51 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.62 (m, 1 H); 2.32 (s, 3H); 2.00 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 474.1 [M+H ⁺ ] for C22H23N3O5S2; t _R = 0.89 min.

Example 35: (2 ?)-4-(6-(5-cyclopropylisoxazol-3-yl)-3-oxo-1H-pyrrolo[1,2-c] imidazol-2(3H)-yl)-A/- hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 25. ii (0.16 g; 0.4 mmol) and cyclopropylacetylene (70% in toluene, 0.24 mL; 2 mmol) and proceeding successively in analogy to Example 25, step 25.W (43% yield), Preparation D, steps D.i (58% yield) and D.ii (72% yield), and Procedure B (50% yield), the title compound (0.015 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous foam.

1H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.19 (br s, 1 H); 7.65 (s, 1 H); 6.54 (s, 1 H); 6.42 (s, 1 H); 4.48 (s, 2H); 3.51 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.64 (m, 1 H); 2.12 (m, 1 H), 1.99 (m, 1 H); 1.81-1.74 (m, 2H); 1.53 (s, 3H); 1.09-1.04 (m, 2H); 0.90-0.85 (m, 2H).

MS1 (ESI, m/z): 423.1 [M+H ⁺ ] for GeHa^OeS; t _R = 0.70 min.

Example 36: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-(3-phen yl-1 ,2,4-oxadiazol-5-yl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from 3-phenyl-1 ,2,4-oxadiazole (0.065 g; 0.444 mmol) and the compound of Preparation C (0.193 g; 0.4 mmol), and proceeding successively in analogy to Example 20, step 20.i (6% yield), Preparation D, steps D.i (82% yield) and D.ii (93% yield), and Procedure E (59% yield), the title compound (0.017 g) was obtained, after filtration and drying to a constant weight, as a white amorphous solid.

1H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.19 (br s, 1 H); 8.09-8.03 (m, 3H); 7.65-7.57 (m, 3H); 6.74 (s, 1 H); 4.56 (s, 2H); 3.55 (m, 1 H); 3.46 (m, 1 H); 3.08 (s, 3H); 2.66 (m, 1 H); 2.01 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 460.1 [M+H ⁺ ] for C20H21 N5O6S; t _R = 0.78 min.

Example 37: (2 ?)-4-(6-(4-(2-((1 ?,2S)-2-((2 ?)-1,2-dihydroxyethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo - 1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide 371 (2R)-4-(6-(4-(2-((1R,2S)-2-((2R)-2,2-Dimethyl-1,3-d^

1H yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(me^

yl)oxy)butanamide:

To an inertized solution of intermediate 17. i (0.080 g; 0.123 mmol) in EA (0.48 mL) and MeOH (1.6 mL) was added Pt02 (Adam's catalyst, 0.0277 g). The reaction proceeded at rt for 28h under normal H2 atmosphere. The reaction mixture was filtered through celite and the filtrate was evaporated to afford the title compound (0.073 g, 91 % yield) as a yellow gum.

MS1 (ESI, m/z): 650.2 [M+H ⁺ ] for C31 H43N3O8S2; t _R = 1.05 min.

37M. (2R)-4-(6-(4-(2-((1R,2S)-2-((2R)-1,2-Dihydroxyethyl)cyc^

pyrrolo[1 _: 2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsul fon Starting from intermediate 37.i (0.070 g; 0.108 mmol) and proceeding in analogy to Procedure B (37% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 2) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.94 (br s, 1H); 9.18 (brs, 1H); 7.35 (s, 1H); 7.39 (s, 1H); 7.13 (d, J=1.2Hz, 1H); 6.94 (s, 1 H); 6.33 (m, 1 H); 4.45 (s, 2H); 4.41 (t, J = 5.4 Hz, 1 H); 4.36 (d, J = 4.7 Hz, 1 H); 3.50 (m, 1 H); 3.40- 3.30 (overlapped m, 3H); 3.07 (s, 3H); 2.94 (m, 1H); 2.59 (overlapped t, J = 7.5 Hz, 2H); 1.97 (m, 1H); 1.56 (m, 1H); 1.53 (s,3H); 1.44 (m, 1H);0.64(m, 1 H); 0.58 (m, 1 H); 0.41 (m, 1H); 0.17 (m, 1H).

MS1 (ESI, m/z): 526.1 [M+H ⁺ ] for C23H31N3O7S2; t _R = 0.69 min.

Example 38: (2?)-4-(6-(5-((1-aminocyclopropyl)ethynyl)thiazol-2-yl)-3-ox o-1H-pyrrolo[1,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation T (0.115 g; 0.434 mmol) and the compound of Preparation D (0.205 g; 0.391 mmol), and proceeding successively in analogy to Example 20, step 20. i (64% yield) and Example 8, step 8.v (77% yield), the title compound (0.1 g) was obtained after purification by prep-HPLC (Method 1) as a white amorphous solid.

1H NMR (DMSO-cie) δ: 10.94 (br s, 1H); 9.19 (br s, 1H); 7.83 (s, 1H); 7.74 (d, J = 0.5Hz, 1H); 6.53 (d, J = 1.3 Hz, 1H); 4.49 (s, 2H); 3.53 (m, 1H); 3.42 (m, 1H); 3.07 (s, 3H); 2.62 (m, 1H); 1.98 (m, 1H); 1.54 (s, 3H).

MS1 (ESI, m/z): 475.1 [M+H ⁺ ] for C20H23N5O5S2; t _R = 0.79 min.

Example 39: (2?)-4-(6-(5-((1-aminocyclopropyl)ethynyl)thiazol-2-yl)-3-ox o-1H-pyrrolo[1,2-c]imidazol- 2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation U (0.110 g; 0.434 mmol) and the compound of Preparation D (0.205 g; 0.391 mmol), and proceeding successively in analogy to Example 20, step 20.i (45% yield), Example 2, step 2.ii (58% yield) and Procedure B (79% yield), the title compound (0.04 g) was obtained after purification by prep-HPLC (Method 1) as a white amorphous foam.

1H NMR (DMSO-cie) δ: 10.94 (brs, 1H); 9.19 (brs, 1H); 7.94 (s, 1H); 7.78 (s, 1H); 6.53 (d, J=1.3Hz, 1H); 5.45 (t, J = 6.1 Hz, 1H); 4.50 (s, 2H); 4.35 (d, J = 6.0 Hz, 2H); 3.53 (m, 1H); 3.42 (m, 1H); 3.07 (s, 3H); 2.62 (m, 1H); 1.98 (m, 1H); 1.54 (s,3H).

MS1 (ESI, m/z): 453.2 [M+H ⁺ ] for C18H20N4O6S2; t _R = 0.60 min.

Example 40: (2?)-N-hydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethyny l)thiophen-2-yl)-3-oxo-1H- pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl) butanamide 401. (2R) -(6-(5-((1-(((tert-Butyldiphenylsilyl)oxy)me^

pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methy^^

yl)oxy)butanamide:

Starting from iert-butyl((1 -ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.477 g; 1.43 mmol) and the compound of Preparation V (0.400 g; 0.714 mmol), and proceeding in analogy to Example 8, step 8.ii (88% yield), the title compound (0.518 g) was obtained after purification by CC (Hept-EA gradient) as an orange oil.

MS1 (ESI, m/z): 814.1 [M+H ⁺ ] for C43H51 N ₃ 0 ₇ S ₂ Si; t _R = 1.30 min.

40.H. (2R)-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl)thiophen -2-yl)^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-((tetrahydro

Starting from intermediate 40.i (0.255 g; 0.31 mmol) and proceeding in analogy to Example 2, step 2.ii (55% yield), the title compound (0.098 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as an orange solid.

MS1 (ESI, m/z): 576.1 [M+H ⁺ ] for C27H33N3O7S; t _R = 0.90 min. 4011 (2R)^ ydroxy -(6-(5-((1-(hydmymethyl)cydopropyl)ethynyl)thioph

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 40. ii (0.0.098 g; 0.17 mmol) and proceeding in analogy to Procedure E (50% yield), the title compound (0.042 g) was obtained after purification by prep-HPLC (Method 2) as a yellowish amorphous solid.

1H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.49 (s, 1 H); 7.16 (d, J = 3.7 Hz, 1 H); 7.10 (d, J = 3.7 Hz, 1 H); 6.37 (d, J = 1.3 Hz, 1 H); 4.95 (t, J = 6.0 Hz, 1 H); 4.46 (s, 2H); 3.49 (m, 1 H); 3.41 (d, J = 6.0 Hz, 2H); 3.38 (overlapped m, 1 H); 3.06 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H); 0.90-0.86 (m, 4H).

MS1 (ESI, m/z): 492.1 [M+H ⁺ ] for C22H25N3O6S2; t _R = 0.77 min. Example 41 : (2 ?)-A/-hydroxy-4-(6-(3-(4-(2-hydroxyethyl)phenyl)isoxazol-5-y l)-3-oxo-1H-pyrrolo[1,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanarnide

411. tert-Butyl (2R)-4-(6-(3-(4-(2-((teii-butyldiphenylsilyl)oxy)e^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoate :

A vial was charged with the compound of Preparation C (0.53 g; 1.1 mmol), the compound of Preparation W (0.787 g; 1.1 mmol), (i-Bu ₃ P) ₂ Pd (0.056 g, 0.1 1 mmol), CsF (0.334 g, 2.2 mmol) and dioxane (9 mL). The mixture was heated to 80°C over night. The reaction mixture was partitioned between EA (50 mL) and sat. NaHCC>3 (25 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.3 g, 35% yield) as a yellowish solid.

MS1 (ESI, m/z): 782.3 [M+H ⁺ ] for C43H51 N3O7SS; t _R = 1.34 min.

41. ii. (2R)-N-hydroxy-4-(6-(3-(4-(2-hydroxyethyl)phenyl)isoxazol^

yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 41. i (0.30 g; 0.38 mmol) and proceeding successively in analogy to Preparation D, step D.i (60% yield), Example 8, step 8.iv (53%), Example 2, step 2.ii (82% yield) and Procedure E (75% yield), the title compound (0.040 g) was obtained, after precipitation from water, filtration and drying to a constant weight, as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.89 (br s, 1 H); 9.20 (br s, 1 H); 7.77 (d, J= 8.2Hz, 2H); 7.74 (s, 1 H); 7.39 (d, J= 8.2Hz, 2H); 7.22 (s, 1 H); 6.56 (d, J= 1.2Hz, 1 H); 4.70 (t, J= 5.2Hz, 1 H); 4.53 (s, 2H); 3.68-3.62 (m, 2H); 3.53 (m, 1 H); 3.42 (m, 1 H); 3.08 (s, 3H); 2.79 (t, J = 6.9Hz, 2H); 2.64 (m, 1 H); 2.00 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 503.1 [M+H ⁺ ] for C23H26N4O7S; t _R = 0.71 min.

Example 42: (2 ?)-A/-hydroxy-4-(6-(4-((1-(hydroxymethyl)cyclopropyl)ethynyl )thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e Starting from intermediate 12. i (0.27 g; 0.48 mmol) and iert-butyl((1- ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.32 g; 0.96 mmol), and proceeding successively in analogy to Example 8, steps 8.ii (42% yield), Example 2, step 2.ii (88% yield) and Procedure E (56% yield), the title compound (0.042 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

1H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.47 (s, 1 H); 7.45 (d, J = 1.3 Hz, 1 H); 7.25 (d, J = 1.3 Hz, 1 H); 6.39 (d, J = 1.3 Hz, 1 H); 4.91 (t, J = 6.0 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.41 (d, J = 6.0 Hz, 2H); 3.40 (overlapped m, 1 H); 3.06 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H); 0.86-0.83 (m, 4H).

MS1 (ESI, m/z): 492.1 [M+H ⁺ ] for C22H25N3O6S2; t _R = 0.76 min. Example 43: (2 ?)-A/-hydroxy-4-(6-(5-((3-(hydroxymethyl)oxetan-3-yl)ethynyl )thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e 431. (2R)-4-(6-(5-((3-(Hydmymethyl)oxetan-3-yl)et ynyl)M^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-((tetrahydro-2H y^

Starting from iert-butyl((3-ethynyloxetan-3-yl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.413 g; 1.18 mmol) and the compound of Preparation V (0.33 g; 0.59 mmol), and proceeding successively in analogy to Example 8, step 8.ii (46% yield) and Example 2, step 2.ii (86% yield), the title compound (0.04 g) was obtained after purification by CC (Hept-EA gradient) as a yellowish foam. MS1 (ESI, m/z): 592.1 [M+H ⁺ ] for C27H33N3O8S2; t _R = 0.85 min.

43.il (2R)^ydroxy-4-(6-(5-((3-(hydroxymethyl)oxetan-3-yl)ethyn

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 43. i (0.119 g; 0.14 mmol) and proceeding in analogy to Procedure E (54% yield), the title compound (0.022 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

1H NMR (DMSO-cie) δ: 10.9 (br s, 1 H); 9.19 (m, 1 H); 7.54 (s, 1 H); 7.21 (m, 2H); 6.40 (d, J = 1.3 Hz, 1 H); 5.44 (t, J = 5.8 Hz, 1 H); 4.62 (d, J = 5.6 Hz, 2H); 4.57 (d, J = 5.6 Hz, 2H); 4.47 (s, 2H); 3.73 (d, J = 5.9 Hz, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.61 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 508.1 [M+H ⁺ ] for C22H25N3O7S2; t _R = 0.70 min.

Example 44: (2 ?)-A/-hydroxy-4-(6-(5-(2-(3-(hydroxymethyl)oxetan-3-yl)ethyl )thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from intermediate 43. i (0.04 g; 0.067 mmol) and proceeding in analogy to Example 37, step 37.L (80% yield) and Procedure E (43% yield), the title compound (0.012 g) was obtained after purification by prep- HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.9 (br s, 1 H); 9.19 (br s, 1 H); 7.34 (s, 1 H); 7.06 (d, J = 3.4 Hz, 1 H); 6.79 (d, J = 3.5 Hz, 1 H); 6.33 (d, J = 1.3 Hz, 1 H); 4.91 (t, J = 5.3 Hz, 1 H); 4.45 ( s, 2H) 4.31 (d, J = 5.8 Hz, 2 H ); 4.27 (d, J = 5.8 Hz, 2H); 3.61 (d, J = 5.3 Hz, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.80-2.73 (m, 2H); 2.59 (m, 1 H); 2.01-1.93 (m, 3H); 1.54 (s, 3H)

MS1 (ESI, m/z): 512.1 [M+H ⁺ ] for C22H29N3O7S2; t _R = 0.68 min.

Example 45: (2 ?)-A/-hydroxy-4-(6-(5-((3-hydroxyoxetan-3-yl)ethynyl)thiophe n-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

451 (2R)-4-(6-(5-((3^ydroxyoxetan-3-yl)ethynyl)thiophen-2^

me /-2-(me /su/fony/J-W-(((2RSJ-ieirahydro-2H-pyran-2-y/JoxyJbuianam/ ^' cie:

Starting from the compound of Preparation X (0.379 g; 1.78 mmol) and the compound of Preparation V (0.5 g; 0.89 mmol), and proceeding successively in analogy to Example 8, step 8.ii (45% yield) and Example 2, step 2.ii (77% yield), the title compound (0.09 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a yellowish foam.

MS1 (ESI, m/z): 578.1 [M+H ⁺ ] for C26H31 N3O8S2; t _R = 0.84 min.

45.il (2R)-N^ydroxy-4-(6-(5-((3-hydroxyoxetan-3-yl)ethynyl)thiop^^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 45. i (0.19 g; 0.034 mmol) and proceeding in analogy to Procedure E (62% yield), the title compound (0.010 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

1H NMR (DMSO-c¼) δ: 10.9 (br s, 1 H); 9.20 (br s, 1 H); 7.57 (s, 1 H); 7.28 (d, J = 3.66 Hz, 1 H); 7.26 (d, J= 3.66 Hz, 1 H); 6.67 (s, 1 H); 6.42 (d, J = 1.3 Hz, 1 H); 4.74 (d, J = 6.6 Hz, 2H); 4.59 (d, J = 6.6 Hz, 2H); 4.48 (s, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.08 (s, 3H); 2.61 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H)

MS1 (ESI, m/z): 494.1 [M+H ⁺ ] for C21H23N3O7S2; t _R = 0.70 min.

Example 46: (2 ?)-A/-hydroxy-4-(6-(5-(2-(3-hydroxyoxetan-3-yl)ethyl)thiophe n-2-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

Starting from intermediate 45.i (0.073 g; 0.127 mmol) and proceeding in analogy to Example 37, step 37.L (84% yield) and Procedure E (41 % yield), the title compound (0.02 g) was obtained after purification by prep- HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.9 (br s, 1 H); 9.20 (br s, 1 H); 7.34 (m, 1 H); 7.06 (m, 1 H); 6.79 (d, J = 3.3 Hz, 1 H); 6.33 (s, 1 H); 5.72 (m, 1 H); 4.46 (s, 2H); 4.41 (d, J= 6.5 Hz 2 H); 4.33 (d, J = 6.5 Hz, 2H); 3.50 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.85-2.78 (m, 2H); 2.60 (m, 1 H); 2.08-2.03(m, 2H); 1.97 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 498.1 [M+H ⁺ ] for C21H27N3O7S2; t _R = 0.67 min.

Example 47: (2 ?)-A/-hydroxy-4-(6-(5-(2-(1-(hydroxymethyl)cyclopropyl)ethyl )thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

471 (2R) -(6-(5-(2-(1-(Hydroxymethyl)cyclopropyl)ethyl)thioph

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-(((R)-tetrahyd

Starting from intermediate 40.i (1.44 g; 1.77 mmol) and proceeding successively in analogy to Example Example 2, step 2.ii (79% yield), Example 37, step 37. i. (>95% yield), the title compound (0.4 g) was obtained as a yellowish foam.

MS1 (ESI, m/z): 580.0 [M+H ⁺ ] for C27H37N3O7S2; t _R = 0.92 min. 47.H. (2R)^ydroxy-4-(6-(5-(2-(1-(hydroxymethyl)cyclopropyl)ethyl)

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from intermediate 47.i (0.06 g; 0.1 mmol) and proceeding in analogyProcedure E (37% yield), the title compound (0.019 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

1H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.19 (br s, 1 H); 7.31 (s, 1 H); 7.04 (d, J = 3.4 Hz, 1 H); 6.73 (d, J = 3.5 Hz, 1 H); 6.31 (d, J = 1.3 Hz, 1 H); 4.53 (t, J = 5.6 Hz, 1 H); 4.44 (s, 2H); 3.49 (m, 1 H); 3.38 (m, 1 H); 3.26 (d, J = 5.6 Hz, 2H); 3.07 (s, 3H); 2.83-2.80 (m, 2H); 2.59 (m, 1 H); 1.96 (m, 1 H); 1.68-1.63 (m, 2H); 1.53 (s, 3H); 0.34-0.32 (m, 2H); 0.30-0.27 (m, 2H).

MS1 (ESI, m/z): 496.1 [M+H ⁺ ] for C22H29N3O6S2; t _R = 0.78 min. Example 48: (2 ?H-(6-(5-((£)-2-((1S,2S)-2-((2 ?)-1 ,2-dihydroxyethyl)cyclopropyl)vinyl)thiophen-2-yl^ oxo-1 H^yrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide

Starting from the compound of Preparation V (0.2 g; 0.36 mmol) and the compound of Preparation M (0.157 g; 0.53 mmol), and proceeding successively in analogy to Procedure C (34% yield) and Procedure B (40% yield), the title compound (0.025 g) was obtained after purification by prep-HPLC (Method 2) as a yellowish solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.19 (br s, 1 H); 7.39 (s, 1 H); 7.10 (d, J = 3.6 Hz, 1 H); 6.82 (d, J = 3.7 Hz, 1 H); 6.53 (d, J = 15.6 Hz, 1 H); 6.33 (d, J = 1.3 Hz, 1 H); 5.57 (dd, J = 9.0, 15.6 Hz, 1 H); 4.55 (d, J = 4.9 Hz, 1 H); 4.51 (t, J = 5.6 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.39-3.34 (overlapped m, 3H); 3.17 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.96 (m, 1 H); 1.53 (s, 3H); 1.47 (m, 1 H); 1.02 (m, 1 H); 0.81 (m, 1 H); 0.59 (m, 1 H).

MS1 (ESI, m/z): 523.6 [M+H ⁺ ] for C23H29N3O7S2; t _R = 0.69 min.

Example 49: (2 ?)-A/-hydroxy-2-methyl-4-(6-(4-((1-methylazetidin-3-yl)ethyn yl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-(methylsulfonyl)butanamide

491 (2R)-4-(6-(4-(Azetidin-3-ylethynyl)thiophen-2-yl)-3-ox

methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 12.i (0.2 g; 0.36 mmol) and iert-butyl 3-ethynylazetidine-1 -carboxylate (0.129 g; 0.71 mmol), and proceeding successively in analogy to Example 8, steps 8.ii (67% yield) and 8.v (43% yield), the title compound (0.045 g) was obtained after purification by prep-HPLC (Method 1 ) as a white solid.

MS1 (ESI, m/z): 477.1 [M+H ⁺ ] for C21H24N4O5S2; t _R = 0.57 min. 49.il (2R)-N ydroxy-2-methyl-4-(6-(4-((1-methylazetidin-3^

c]imidazol-2(3H)-yl)-2-(methylsulfonyl)butanamide: To a suspension of intermediate 49. i (0.0457 g; 0.0959 mmol) in MeOH (1 mL) and DCM (1 mL) was added 37% aq. formaldehyde (0.01 12 mL, 0.144 mmol). NaBH(OAc) ₃ (0.061 g; 0.288 mmol) was added and stirred at rt for 80 min. The reaction mixture was directly purified by prep-HPLC (Method 1 ) to afford the title compound (0.0309 g, 66% yield) as a white freeze dried solid.

1H NMR (DMSO-cie) δ: 10.91 (br s, 1 H); 9.17 (br s, 1 H); 7.51 (d, J = 1.2 Hz, 1 H); 7.48 (s, 1 H); 7.29 (d, J = 1.2Hz, 1 H); 6.39 (d, J = 1.3 Hz, 1 H); 4.46 (s, 2H); 3.55-3.52 (m, 2H); 3.48 (m, 1 H); 3.38 (m, 1 H); 3.09 (overlapped m, 1 H); 3.07 (s, 3H); 2.99-2.96 (m, 2H); 2.58 (m, 1 H); 2.20 (s, 3H); 1.96 (m, 1 H); 1.53 (s, 3H). MS1 (ESI, m/z): 491.1 [M+H ⁺ ] for C22H26N4O5S2; t _R = 0.58 min.

Example 50: (2 ?)-A/-hydroxy-4-(6-(5-(4-(2-hydroxyethyl)phenyl)thiazol-2-yl )-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

501 (2R)-4-(6-(4-(4-(2-((teii-Butyldiphenylsilyl^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-(((R)-tetrah

To a solution of the compound of Preparation Y (0.286 g; 0.645 mmol) in THF (3 mL), cooled at -78°C, was slowly added n-BuLi (1.6M in hexanes, 0.44 mL, 0.709 mmol). The mixture was stirred for 45 min, before ZnC (1 M in THF, 0.6 mL, 0.6 mmol) was added. After stirring for another 30 min at rt, the compound of Preparation D (0.271 g; 0.516 mmol), Pd(dba) ₂ (0.018 g; 0.032 mmol) and P(o-furyl) ₃ (0.015 g; 0.064 mmol) were added. The reaction was warmed to 50°C. The reaction mixture was partitioned between EA (20 mL) and water (10 mL). The evaporation residue was purified by CC (EA-Hept gradient) to afford the title product (0.208 g, 38% yield) as a yellow solid.

MS1 (ESI, m/z): 841.4 [M+H ⁺ ] for C44H52N ₄ 0 ₇ S2Si; t _R = 1.30 min.

50.il (2R)^ydroxy-4-(6-(5-(4-(2-hydroxyethyl)phenyl)thiazol-2^

yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 50. i (0.208 g; 0.24 mmol) and proceeding successively in analogy to Example 2, step 2.ii (91 % yield) and Procedure B (69% yield), the title compound (0.080 g) was obtained after purification by prep-HPLC (Method 1 ) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.91 (br s, 1 H); 9.21 (br s, 1 H); 8.13 (s, 1 H); 7.71 (s, 1 H); 7.57 (d, J = 8.2 Hz, 2H); 7.30 (d, J = 8.3 Hz, 2H); 6.57 (d, J = 1.3 Hz, 1 H); 4.69 (t, J = 5.2 Hz, 1 H); 4.51 (s, 2H); 3.65-3.59 (m, 2H); 3.52 (m, 1 H); 3.42 (m, 1 H); 3.08 (s, 3H); 2.75 (t, J = 6.9 Hz, 2H); 2.63 (m, 1 H); 1.99 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 519.1 [M+H ⁺ ] for C23H26N4O6S2; t _R = 0.72 min. Example 51 : (2 ?)-A/-hydroxy-4-(6-(2-(4-(2-hydroxyethyl)phenyl)thiazol-5-yl )-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation Z (0.39 g; 0.68 mmol), and proceeding successively in analogy to Procedure D (59% yield), Example 2, step 2.ii (65% yield) and Procedure B (73% yield), the title compound (0.055 g) was obtained, after precipitation from water, filtration and drying to a constant weight, as a white solid.

1H NMR (DMSO-c¼) δ: 10.91 (br s, 1 H); 9.21 (br s, 1 H); 8.08 (s, 1 H); 7.82 (d, J = 8.2 Hz, 2H); 7.59 (s, 1 H); 7.36 (d, J = 8.3 Hz, 2H); 6.49 (d, J = 1.3 Hz, 1 H); 4.70 (t, J = 5.2 Hz, 1 H); 4.50 (s, 2H); 3.67-3.62 (m, 2H); 3.51 (m, 1 H); 3.40 (m, 1 H); 3.08 (s, 3H); 2.78 (t, J = 6.9 Hz, 2H); 2.63 (m, 1 H); 1.99 (m, 1 H); 1.55 (s, 3H).

MS1 (ESI, m/z): 519.1 [M+H ⁺ ] for C23H26N4O6S2; t _R = 0.71 min.

Example 52: (2 ?)-4-(6-(5-(((1S,2S)-2-((2 ?)-1 ,2-dihydroxyethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-oxo- 1H^yrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-methyl-2-(methylsulfonyl )butanamide

521 (2R)-4-(6-(5-(((1S,2S)-2-((2R)-2,2-Dimethyl-1,3-d^

1H yrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methy^^

yl)oxy)butanamide:

Starting from the compound of Preparation V (0.369 g; 0.658 mmol) and intermediate M.i (0.219 g; 1.32 mmol), and proceeding in analogy to Example 8, step 8.ii (60% yield), the title compound (0.255 g) was obtained after purification by CC (Hept-EA gradient) as an orange oil.

MS1 (ESI, m/z): 646.0 [M+H ⁺ ] for C31 H39N3O8S2; t _R = 1.02 min.

52.H. (2R)-4-(6-(5-(((1S,2S)-2-((2R)-1,2-Dihydroxyethyl)cy^

pyrrolo[1 _: 2-c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsul fon

Starting from intermediate 52. i (0.04 g; 0.061 mmol) and proceeding successively in analogy to Procedure B (28% yield), the title compound (0.009 g) was obtained after purification by prep-HPLC (Method 2) as a yellowish solid.

¹ H NMR (DMSO-cie) δ: 10.91 (br s, 1 H); 9.21 (br s, 1 H); 7.49 (s, 1 H); 7.17 (d, J = 3.7 Hz, 1 H); 7.10 (d, J = 3.7 Hz, 1 H); 6.37 (d, J = 1.3 Hz, 1 H); 4.68 (d, J = 5.0 Hz, 1 H); 4.61 (t, J = 5.6 Hz, 1 H); 4.46 (s, 2H); 3.49 (m, 1 H); 3.43-3.29 ( overlapped m, 4H); 3.08 (s, 3H); 2.63 (m, 1 H); 1.99 (m, 1 H); 1.55 (s, 3H); 1.51 (m, 1 H); 1.32 (m, 1 H); 0.94 (m, 1 H); 0.79 (m, 1 H).

MS1 (ESI, m/z): 522.1 [M+H ⁺ ] for C23H27N3O7S2; t _R = 0.69 min.

Example 53: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(4-(4-(oxetan -3-yl)phenyl)thiophen-2-yl)- 3-OXO-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide Starting from intermediate 12.i (0.150 g; 0.268 mmol) and 4,4,5,5-tetramethyl-2-(4-(oxetan-3-yl)phenyl)-1 ,3,2- dioxaborolane (commercial, 0.104 g; 0.40 mmol), and proceeding successively in analogy to Procedure C (45% yield) and Procedure E (60% yield), the title compound (0.036 g) was obtained after purification by prep- HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.96 (br s, 1 H); 9.20 (br s, 1 H); 7.76 (d, J = 1.3 Hz, 1 H); 7.74 (d, J = 8.2 Hz, 2H); 7.69 (d, J = 1.3 Hz, 1 H); 7.51 (s, 1 H); 7.45 (d, J = 8.2 Hz, 2H); 6.45 (d, J = 1.2 Hz, 1 H); 4.95 (dd, J = 5.9, 8.4 Hz, 2H); 4.66-4.63 (m, 2H); 4.48 (s, 2H); 4.27 (m, 1 H); 3.51 (m, 1 H); 3.39 (m, 1 H); 3.08 (s, 3H); 2.61 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 530.1 [M+H ⁺ ] for C25H27N3O6S2; t _R = 0.87 min.

Example 54: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(5-(4-(oxetan -3-yl)phenyl)thiophen-2-yl)- 3-OXO-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide Starting from the compound of Preparation V (0.150 g; 0.268 mmol) and 4,4,5,5-tetramethyl-2-(4-(oxetan-3- yl)phenyl)-1 ,3,2-dioxaborolane (commercial, 0.104 g; 0.40 mmol), and proceeding successively in analogy to Procedure C (51 % yield) and Procedure E (43% yield), the title compound (0.029 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.96 (br s, 1 H); 9.19 (br s, 1 H); 7.64 (d, J = 8.2 Hz, 2H); 7.49 (s, 1 H); 7.45 (dd, J = 2.1 , 6.0 Hz, 3H); 7.29 (d, J = 3.7 Hz, 1 H); 6.42 (d, J = 0.9 Hz, 1 H); 4.964.93 (m, 2H); 4.62 (t, J = 6.5 Hz, 2H); 4.48 (s, 2H); 4.26 (m, 1 H); 3.51 (m, 1 H); 3.39 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 530.1 [M+H ⁺ ] for C25H27N3O6S2; t _R = 0.88 min.

Example 55: (2 ?)-4-(6-(5-(((1S,2S)-2-((2 ?)-1,2-dihydroxyethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo - 1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

Starting from intermediate 52.i (0.215 g; 0.333 mmol) and proceeding in analogy to Example 37, step 37.L (74% yield) and Procedure B (28% yield), the title compound (0.015 g) was obtained after purification by prep- HPLC (Method 2) as a yellowish solid.

¹ H NMR (DMSO-cie) δ: 10.9 (br s, 1 H); 9.20 (br s, 1 H); 7.32 (m, 1 H); 7.05 (m, 1 H); 6.75 (m, 1 H); 6.32 (d, J = 1.2 Hz, 1 H); 4.47-4.42 (m, 3H); 4.39 (d, J = 4.7 Hz, 1 H); 3.49 (m, 1 H); 3.38-3.33 (m, 2H); 3.06-3.07 (m, 3H); 2.94 (m, 1 H); 2.85-2.78 (m, 2H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.59 (m, 1 H); 1.53 (s, 3H); 1.46 (m, 1 H); 0.68 (m, 1 H); 0.60(m, 1 H); 0.58-0.63 (m, 1 H); 0.436 (m, 1 H); 0.21 (m, 1 H).

MS1 (ESI, m/z): 526.1 [M+H ⁺ ] for C23H31 N3O7S2; t _R = 0.70 min.

Example 56: (2 ?,£)-A/-hydroxy-4-(6-(4-(2-(1-(hydroxymethyl)cyclopropyl)vi nyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e 561. (2R)-4-(6-(4-((E)-2-(1-(Hydroxymethyl)cyclopropyl)vinyl)^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)^-(((2RS)-tetrahyd^

Starting from intermediate 12.i (0.442 g; 0.789 mmol) and the compound of Preparation AA (0.438 g; 0.946 mmol), and proceeding successively in analogy to Procedure C (75% yield) and Example 2, step 2.ii (90% yield), the title compound (0.31 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as a white foam.

MS1 (ESI, m/z): 578.1 [M+H ⁺ ] for C27H35N3O7S2; t _R = 0.90 min.

56.il (2R,E)^ydroxy-4-(6-(4-(2-(1-(hydroxymethyl)cyclopropy^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 56. i (0.1 g; 0.173 mmol) and proceeding in analogy to Procedure E (73% yield), the title compound (0.062 g) was obtained, after precipitation from water, filtration and drying to a constant weight, as a white solid.

¹ H NMR (DMSO-cie) δ: 10.96 (br s, 1 H); 9.20 (br s, 1 H); 7.42 (d, J = 12.8 Hz, 2H); 7.09 (d, J = 1.1 Hz, 1 H); 6.37-6.33 (m, 2H); 6.01 (d, J = 16.2 Hz, 1 H); 4.62 (t, J = 5.8 Hz, 1 H); 4.46 (s, 2H); 3.51 (m, 1 H); 3.48 (d, J = 6.0 Hz, 2H); 3.40 (overlapped m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H), 0.77-0.75 (m, 2H); 0.62-0.60 (m, 2H).

MS1 (ESI, m/z): 494.1 [M+H ⁺ ] for C22H27N3O6S2; t _R = 0.77 min.

Example 57: (2 ?)-A/-hydroxy-4-(6-(5-((1-hydroxycyclopropyl)ethynyl)thiophe n-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e 571 (2R)-4-(6-(5-((1^ydroxycyclopropyl)ethynyl)thiophen-2-yl^^

me /-2-(me /su/fony/J-W-(((2RSJ-ieirahydro-2H-pyran-2-y/JoxyJbuianam/ ^' cie:

Starting from 1-ethynylcyclopropan-1-ol (0.103 g; 1.25 mmol) and the compound of Preparation V (0.35 g; 0.62 mmol), and proceeding in analogy to Example 8, step 8.ii (74% yield), the title compound (0.260 g) was obtained after purification by CC (Hept-EA-MeOH gradient) as an orange foam.

MS1 (ESI, m/z): 562.1 [M+H ⁺ ] for C26H31 N3O7S2; t _R = 0.89 min.

57. ii. (2R)-NΉydroxy-4-(6-(5-((1-hydroxycyclopropyl)ethynyl)thioph en-2-yl)-3-oxo-1H^

2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide:

Starting from intermediate 57. ii (0.05 g; 0.089 mmol) and proceeding in analogy to Procedure E (1 1 % yield), the title compound (0.0045 g) was obtained after purification by prep-HPLC (Method 2) as a yellowish solid. ¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.19 (m, 1 H), 7.53 (s, 1 H), 7.19 (dd, J=3.7 Hz, J=18.3 Hz, 2H), 6.40-6.35 (m, 2H), 4.48-4.45 (m, 2H), 3.50 (m, 1 H), 3.40 (m, 1 H), 3.07 ( s, 3H), 2.6(m, 1 H), 1.97 (m, 1 H), 1.53 ( s, 3H), 1.02-0.94 (m, 4H).

MS1 (ESI, m/z): 478.1 [M+H ⁺ ] for C21 H23N3O6S2; t _R = 0.76 min.

Example 58: (2 ?)-A/-hydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl )furan-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e 581 (2R)-4-(6-(4-((1-(Hydroxymethyl)cyclopropyl)ethynyl)furan^

yl)-2-methyl-2-(methylsulfonyl)^-(((2RS)-tetrahydro-2H^yr an-2-y^^

Starting from iert-butyl((1 -ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.55 g; 1.65 mmol) and the compound of Preparation AB (0.448 g; 0.82 mmol), and proceeding in analogy to Example 8, step 8.ii (19% yield), Example 2, step 2.ii (71 % yield), the title compound (0.06 g) was obtained after purification by CC (Hept-EA gradient) as a beige foam.

MS1 (ESI, m/z): 560.1 [M+H ⁺ ] for C27H23N3O8S; t _R = 0.87 min.

58.il (2R)-N^ydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl )fuw^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 58. i (0.08 g; 0.143 mmol) and proceeding in analogy to Procedure E (19% yield), the title compound (0.0375 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.84 (d, J = 0.7 Hz, 1 H); 7.39 (s, 1 H); 6.66 (s, 1 H); 6.37 (d, J = 1.3 Hz, 1 H); 4.91 (t, J = 6.0 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.40 (d, J = 6.0 Hz, 2H); 3.40 (overlapped m, 1 H); 3.06 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H), 0.85-0.81 (m, 4H).

MS1 (ESI, m/z): 476.1 [M+H ⁺ ] for C22H25N3O7S; t _R = 0.73 min.

Example 59: (2 ?)-A/-hydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl )furan-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from iert-butyl((1 -ethynylcyclopropyl)methoxy)diphenylsilane (prepared as described in Chapoux, G. and al. WO2015132228, 0.364 g; 1.09 mmol) and the compound of Preparation AC (0.296 g; 0.544 mmol), and proceeding in analogy to Example 8, step 8.ii (45% yield), Example 2, step 2.ii (65% yield) and Procedure E (55% yield), the title compound (0.0375 g) was obtained after purification by prep-HPLC (Method 2) as a yellowish solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.19 (br s, 1 H); 7.42 (d, J = 0.7 Hz, 1 H); 6.7 (d, J = 3.5 Hz, 1 H); 6.63 (d, J = 3.4 Hz, 1 H); 6.39 (d, J = 1.3 Hz, 1 H); 4.99 (t, J = 6.0 Hz, 1 H); 4.46 (s, 2H); 3.49 (m, 1 H); 3.42 (d, J = 6.1 Hz, 2H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H), 0.93-0.88 (m, 4H).

MS1 (ESI, m/z): 476.1 [M+H ⁺ ] for C22H25N3O7S; t _R = 0.74 min.

Example 60: (2 ?)-A/-hydroxy-4-(6-(4-(2-(1-(hydroxymethyl)cyclopropyl)ethyl )thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

60.i (2R)-4-(6-(4-(2-(1-(Hydroxymethyl)cyclopropyl)ethyl)thiop^

yl)-2-methyl-2-(methylsulfonyl)^-(((2RS)-tetrahydro-2H yrafr

To a solution of intermediate 56.i (0.181 g; 0.313 mmol) in EA (4 mL) and MeOH (2 mL) was added 10% Pd/C (0.1 15 g). The reaction mixture was stirred at rt for 8 h under H ₂ atmosphere. The reaction mixture was filtered through celite and the filtrate was evaporated to afford the title compound (0.168 g, 92% yield) as a yellowish foam.

MS1 (ESI, m/z): 580.1 [M+H ⁺ ] for C27H37N3O7S2; t _R = 0.92 min.

60.H. (2R)-N ydroxy-4-(6-(4-(2-(1-(hydroxyme1 yl)cyclopropy^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e:

Starting from intermediate 60. i (0.16 g; 0.276 mmol) and proceeding in analogy to Procedure E (75% yield), the title compound (0.103 g) was obtained after purification by prep-HPLC (Method 2) as a white solid.

1H NMR (DMSO-c(6) δ: 10.95 (br s, 1 H); 9.20 (br s, 1 H); 7.36 (d, J = 0.7 Hz, 1 H); 7.12 (d, J = 1.3 Hz, 1 H); 6.93 (d, J = 1.1 Hz, 1 H); 6.33 (d, J = 1.3 Hz, 1 H); 4.49 (t, J = 5.7 Hz, 1 H); 4.45 (s, 2H); 3.49 (m, 1 H); 3.37 (m, 1 H); 3.27 (d, J = 5.7 Hz, 2H); 3.07 (s, 3H); 2.64-2.57 (m, 3H); 1.97 (m, 1 H); 1.65-1.60 (m, 2H); 1.53 (s, 3H), 0.34- 0.32 (m, 2H); 0.28-0.25 (m, 2H).

MS1 (ESI, m/z): 496.1 [M+H ⁺ ] for C22H29N3O6S2; t _R = 0.78 min.

Examples 61 and 62: (2 ?)-A/-hydroxy-4-(6-(5-(2-(1-hydroxycyclopropyl)ethyl)thiophe n-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e and (2R)-/V-hydroxy-2-methyl- 2-(methylsulfonyl)-4-(3-oxo-6-(5-(3-oxopentyl)thiophen-2-yl) -1H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)butanamide

Starting from intermediate 57. i (0.21 g; 0.374 mmol) and proceeding in analogy to Example 37, step 37.ii (95% yield) and Procedure E (75% yield), the title compounds (Example 61 : 0.017 g; Example 62: 0.018 g) were obtained after purification and separation by prep-HPLC (Method 1 ) as a beige solids. Example 61

¹ H NMR (DMSO-cie) δ: 10.9 (s, 1 H); 9.19 (s, 1 H); 7.32 (d, J = 0.7 Hz, 1 H); 7.05 (d, J = 3.4 Hz, 1 H); 6.75 (d, J = 3.5 Hz, 1 H); 6.32 (d, J = 1.3 Hz, 1 H); 5.18 (s, 1 H); 4.47-4.45 (m, 2H); 3.49 (m, 1 H); 3.37 (m, 1 H); 3.08 (s, 3H); 2.95-2.91 (m, 2H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.79-1.76 (m, 2H); 1.53 (m, 3H); 0.57-0.53 (m, 2H); 0.40- 0.36 (m, 2H).

MS1 (ESI, m/z): 482.1 [M+H ⁺ ] for C21H27N3O6S2; t _R = 0.74 min. Example 62

¹ H NMR (DMSO-cie) δ: 10.9 (s, 1 H); 9.19 (m, 1 H); 7.33 (s, 1 H); 7.05 (d, J = 3.4 Hz, 1 H); 6.74 (d, J = 3.4 Hz, 1 H); 6.32 (d, J = 1.3 Hz, 1 H); 5.18 (s, 1 H); 4.464.44 (m, 2H); 3.49 (m, 1 H); 3.34 (overlapped m, 1 H); 3.08 (s, 3H); 2.95-2.91 (m, 2H); 2.95 (t, J = 7.2 Hz, 2H); 2.81 (t, J = 7.2 Hz, 2H); 2.54 (overlapped m, 1 H); 1.54 (s, 3H); 0.93 (t, J = 7.3 Hz, 3H).

MS1 (ESI, m/z): 482.1 [M+H ⁺ ] for C21 H27N3O6S2; t _R = 0.81 min.

Example 63: (2 ?)-A/-hydroxy-4-(6-(5-(2-(1-hydroxycyclopropyl)ethyl)thiophe n-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from the compound of Preparation D (0.193 g; 0.368 mmol) and the compound of Preparation AD (0.1 g; 0.46 mmol) proceeding successively in analogy to Example 50, step 50.i (18% yield) and Procedure E (42% yield), the title compound (0.019 g) was obtained, after precipitation from water, filtration and drying to a constant weight, as a brownish solid.

¹ H NMR (DMSO-cie) δ: 10.9 (br s, 1 H); 9.19 (br s, 1 H); 8.18 (s, 1 H); 7.72 (d, J = 1.0 Hz, 1 H); 7.69-7.66 (m, 2H); 7.51-7.48 (m, 2H); 6.57 (d, J = 1.3 Hz, 1 H); 4.96 (dd, J = 6.0, 8.4 Hz, 2H); 4.64 (dd, J = 6.0, 6.7 Hz, 2H); 4.52 (br s, 2H); 4.29 (m, 1 H); 3.52 (m, 1 H); 3.43 (m, 1 H); 3.08 (m, 3H); 2.64 (m, 1 H); 1.99 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 531.1 [M+H ⁺ ] for C24H26N4O6S2; t _R = 0.79 min.

Example 64: (2 ?)-(1-((5-(2-(4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4 -oxobutyl)-3-oxo-2,3- dihydro-1H-pyrrolo[1,2-c]imidazol-6-yl)thiophen-2-yl)ethynyl )cyclopropyl)methyl 3-hydroxyazetidine-1- carboxylate

641 2,5-Dioxopyrrolidin-1-yl ((1^-(2-((R)-3-methyl-3-(methylsulfonyl) -oxo-^

yl)oxy)amino)butyl)-3wo-2,3<li ydro-1H-pyrrolo[^

carbonate:

To a solution of intermediate 57.i (0.150 g; 0.261 mmol) in MeCN (3 mL) were added TEA (0.0725 mL; 0.521 mmol) and DSC (0.211 g; 0.782 mmol). The reaction mixture was stirred at rt for 1 h30. The reaction mixture was concentrated to dryness and the residue was diluted with EA (50 mL), washed with 1 M aq. citric acid (25 mL), water (50 mL), brine (50 mL), dried over Na2SC>4 and evaporated to dryness. The residue was purified by CC (Hept-EA-MeOH gradient) to afford the title product (0.175 g, 93% yield) as a yellow foam. MS1 (ESI, m/z): 717.2 [M+H ⁺ ] for C32H36N4O11S2; t _R = 0.95 min. 64.H. (1-((5-(2-((2R)-3-Methyl-3-(methylsulfonyl)-4-oxo^

3-οχο-2,3-ά^γ&ο-1Η γ οΙο[1,2-ο]Μίά3ζοΙ-6-γΙ)Μ^βη^ 3-hydroxyazetidine- 1-carboxylate:

To a solution of intermediate 64. i (0.175 g, 0.244 mmol) in DCM (3 mL) were added 3-hyd roxyazetidine. H CI (0.0273 g; 0.244 mmol) and TEA (0.068 mL; 0.488 mmol) and the reaction proceeded 1 h at rt. The reaction mixture was diluted in DCM (50 mL), washed with sat. NaHCC>3 sat. (3 x 50 mL), brine (50 mL), dried over Na2SC>4 and evaporated. The residue was purified by CC (Hept-EA gradient) to afford the title product as a yellow solid (0.043 g; 26 % yield).

MS1 (ESI, m/z): 675.1 [M+H ⁺ ] for C31H38N4O9S2; t _R = 0.91 min.

64.iii. (2R)-(1^-(2-(4-(Hydroxyamino)-3-methyl-3-(methylsulfony^

pyrrolo[1,2-c]imidazol-6-yl)thiophen-2-yl)ethynyl)cyclopr opyl^^

Starting from intermediate 64. ii (0.043 g; 0.0637 mmol) and proceeding in analogy to Procedure E (31 % yield), the title compound (0.011 g) was obtained after purification by prep-HPLC (Method 2) as a white solid. ¹ H NMR (DMSO-cie) δ: 10.9 ( s br, 1 H); 9.18 (m, 1 H); 7.52 (s, 1 H); 7.19 (d,J =3.7 Hz, 1 H); 7.15 (d, J=3.7Hz, 1 H) , 6.39 (d, J = 1.1 Hz, 1 H); 5.72 (d, J = 6.4 Hz, 1 H); 4.47-4.45 (m, 3H); 4.164.08 (m, 2H); 3.96 (s, 2H); 3.72-3.66 (m, 2H); 3.50(m, 1 H); 3.40 (m, 1 H); 3.07 (s, 3H); 2.59 (m, 1 H); 1.97 (m, 1 H); 1.54 (s, 3H); 1.02 (d, J = 7.8 Hz, 4H).

MS1 (ESI, m/z): 591.1 [M+H ⁺ ] for C26H30N4O8S2; t _R = 0.78 min.

Example 65: (2 ?)-4-(6-(5-((3 ?S)-3-(3-fluoroazetidin-1-yl)pentyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

To a solution of Example 62 (0.013 g; 0.027 mmol) in DCM-MeOH (9-1 , 0.1 mL) was added 3- fluoroazetidine.HCI (0.0033g, 0.0297 mmol) and TEA (0.0042 mL, 0.03 mmol). NaBH(OAc) ₃ (0.008 g, 0.038 mmol) was added. The reaction proceeded overnight at rt. The solvent was removed in vacuo and the residue was purified by prep HPLC (Method 1 ) ) to afford the title compound (0.004 g; 23 % yield) as a freeze dried solid.

MS1 (ESI, m/z): 541.1 [M+H ⁺ ] for C24H33N4O5FS2; t _R = 0.62 min. Example 66: (2 ?)-4-(6-(4-fluoro-5-((3-hydroxyoxetan-3-yl)ethynyl)thiophen- 2-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

Starting from the compound of Preparation D (0.2 g; 0.38 mmol) and the compound of Preparation AE (0.167 g; 0.381 mmol), and proceeding successively in analogy to Procedure C (26% yield), Example 2, step 2.ii (53% yield) and Procedure E (38% yield), the title compound (0.010 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.18 (br s, 1 H), 7.44 (s, 1 H); 7.68 (d, J = 1.0 Hz, 1 H), 7.34 (s, 1 H); 6.72 (s, 1 H); 6.44 (d, J = 1.3Hz, 1 H), 4.74 (d, J = 6.8 Hz, 2H), 4.60 (d, J = 6.8 Hz, 2H), 4.48 (s, 2H), 4.53 (t, J = 5.2 Hz, 1 H); 4.45 (s, 2H); 3.50 (m, 1 H); 3.40 (m, 1 H), 3.07 (s, 3H), 2.59 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 512.1 [M+H ⁺ ] for C21H22N3O7FS2; t _R = 0.72 min.

Example 67: (2 ?)-4-(6-(2-(4-((2S)-1 ,2-dihydroxyethyl)phenyl)thiazol-5-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

Starting from the compound of Preparation D (0.103 g; 0.19 mmol) and the compound of Preparation AF (0.1 1 g; 0.245 mmol), and proceeding successively in analogy to Example 50, step 50. i (41 % yield), Example 2, step 2.ii (65% yield) and Procedure B (58% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.20 (br s, 1 H); 8.09 (s, 1 H); 7.86 (d, J = 8.3 Hz, 2H); 7.59 (s, 1 H); 7.47 (d, J = 8.2 Hz, 2H); 6.49 (d, J = 1.3Hz, 1 H); 5.38 (d, J = 4.3 Hz, 1 H); 4.79 (t, J = 6.0 Hz, 1 H); 4.59 (m, 1 H); 4.50 (s, 2H); 3.54-3.37 (m, 4H); 3.07 (s, 3H); 2.62 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 535.1 [M+H ⁺ ] for C23H26N4O7S2; t _R = 0.63 min.

Example 68: (2 ?)-4-(6-(2-(4-((2 ?)-1 ,2-dihydroxyethyl)phenyl)thiazol-5-yl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

Starting from the compound of Preparation D (0.187 g; 0.35 mmol) and the compound of Preparation AG (0.1 1 g; 0.245 mmol), and proceeding successively in analogy to Example 50, step 50. i (38% yield), Example 2, step 2.ii (68% yield) and Procedure B (48% yield), the title compound (0.030 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.20 (br s, 1 H); 8.09 (s, 1 H); 7.86 (d, J = 8.3 Hz, 2H); 7.59 (s, 1 H); 7.47 (d, J = 8.2 Hz, 2H); 6.49 (d, J = 1.3Hz, 1 H); 5.38 (d, J = 4.3 Hz, 1 H); 4.79 (t, J = 6.0 Hz, 1 H); 4.59 (m, 1 H); 4.50 (s, 2H); 3.54-3.37 (m, 4H); 3.07 (s, 3H); 2.62 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 535.1 [M+H ⁺ ] for C23H26N4O7S2; t _R = 0.63 min. Example 69: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(5-((1-

(morpholinomethyl)cyclopropyl)ethynyl)thiophen-2-yl)-3-ox o-1H-pyrrolo[1,2-c]imidazol-2(3H)- yl)butanamide

691 (2R)-4-(6-(5-((1-Formylcyclopropyl)ethynyl)thiophen^

me /-2-fme /su/fony/J-W-fff2RSJ-ieirahydro-2H-pyran-2-y/JoxyJbuianam/ ^' cie:

To a solution of intermediate 40.ii (0.277 g; 0.481 mmol) in DCM (2.36 mL), cooled at -10°C, was added DIPEA (0.152 mL; 0.885 mmol). Pyr.SOs (0.187 g; 0.529 mmol) in DMSO (0.438 mL) was then added dropwise. The reaction mixture was stirred for 2h at rt. The reaction mixture was partitioned between water (10 mL) and DCM (10mL). The two layers were decanted and the aq. layer was extracted with DCM (10 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.1606 g, 58 % ) as a white foam.

MS1 (ESI, m/z): 574.1 [M+H ⁺ ] for C27H31 N3O7S2; t _R = 0.96 min.

69. ii. (2R)-2-methyl-2-(methylsulfonyl)-4-(6-(5-((1-(morpholinome^

1H yrrolo[1,2 ]imidazol-2(3H)-yl)-N-(((2RS)-tetrahyd^

A mixture of intermediate 69.i (0.072 g; 0.126 mmol), morpholine (0.0141 mL, 0.163 mmol) and sodium NaBH(OAc)3 (0.040 g; 0.188 mmol) in DCM (1 mL) was stirred at rt for 2h. The reaction mixture was concentrated to dryness and the residue was directly purified by prep HPLC (Method 1 ) to afford the title compound(0.045 g, 56 % yield) as a white amorphous solid.

MS1 (ESI, m/z): 645.2 [M+H ⁺ ] for C31H40N4O7S2; t _R = 0.73 min.

69. Hi (2R)-N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(5-((1-(morp holinome

2-yl)-3-oxo-1H-pyrrolo[1 _: 2-c]imidazol-2(3H)-yl)butanamide:

Starting from intermediate 69. ii (0.045 g; 0.07 mmol) and proceeding in analogy to Procedure B (84% yield), the title compound (0.030 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous solid.

1H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.20 (br s, 1 H); 7.51 (s, 1 H); 7.17 (d, J = 3.7 Hz, 1 H); 7.09 (d, J = 3.7 Hz, 1 H); 6.39 (d, J = 1.3 Hz, 1 H); 5.38 (d, J = 4.3 Hz, 1 H); 4.46 (s, 2H); 3.63-3.57 (m, 4H); 3.50 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.60 (m, 1 H); 2.50 (overlapped m, 4H); 2.38 (s, 2H); 1.97 (m, 1 H); 1.54 (s, 3H); 1.02-0.97 (m, 2H); 0.86-0.82 (m, 2H).

MS1 (ESI, m/z): 456.1 [M+H ⁺ ] for C26H32N4O6S2; t _R = 0.63 min. Example 70: (2 ?)-4-(6-(5-((1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl)et hynyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

Starting from intermediate 69.i (0.087 g; 0.15 mmol) and 3-fluoroazetidine.HCI (0.020 g, 0.17 mmol) and proceeding successively in analogy to Example 69, step 69.ii (58% yield) and Procedure B (89% yield), the title compound (0.043 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.20 (br s, 1 H), 7.51 (s, 1 H), 7.17 (d, J = 3.7 Hz, 1 H), 7.1 1 (d, J = 3.7 Hz, 1 H), 6.38 (d, J = 1.3 Hz, 1 H), 5.22-5.11 (m, 1 H), 5.38 (d, J = 4.3 Hz, 1 H), 4.46 (s, 2H), 3.71 -3.61 (m, 2H); 3.50 (m, 1 H); 3.38 (m, 1 H), 3.21 -3.12 (m, 2H), 3.07 (s, 3H), 2.60 (m, 1 H); 2.50 (overlapped m, 2H), 1.97 (m, 1 H), 1.54 (s, 3H), 0.92-0.89 (m, 2H), 0.85-0.82 (m, 2H).

MS1 (ESI, m/z): 549. 1 [M+H ⁺ ] for C25H29N4O6FS2; t _R = 0.64 min.

Example 71 : (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(2-(4-(oxetan -3-yl)phenyl)thiazol-5-yl)-3- oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from the compound of Preparation D (0.193 g; 0.37 mmol) and the compound of Preparation AH (0.1 g; 0.245 mmol), and proceeding successively in analogy to Example 50, step 50.i (19% yield) and Procedure E (63% yield), the title compound (0.030 g) was obtained after purification by prep-HPLC (Method 1 ) as a colorless amorphous solid.

1H NMR (DMSO-cie) δ: 10.90 (br s, 1 H); 9.20 (br s, 1 H); 8.11 (s, 1 H); 7.91-7.93 (d, J = 8.3 Hz, 2H); 7.60 (d, J = 0.2 Hz, 1 H); 7.55 (d, J = 8.3 Hz, 2H); 6.50 (d, J = 1.3 Hz, 1 H); 4.98 (dd, J = 6.0, 8.4 Hz, 2H); 4.65 (t, J = 6.5 Hz, 2H); 4.50 (s, 2H); 4.33 (m, 1 H); 3.51 (m, 1 H); 3.40 (m, 1 H); 3.08 (s, 3H); 2.61 (m, 1 H); 1.99 (m, 1 H); 1.54 (s, 3H).

MS1 (ESI, m/z): 535.0 [M+H ⁺ ] for C24H26N4O6S2; t _R = 0.81 min. Example 72: (2 ?)-A/-hydroxy-4-(6-(5-((1-(hydroxymethyl)cyclopropyl)ethynyl )thiazol-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from the compound of Preparation D (0.352 g; 0.67 mmol) and the compound of Preparation Al (0.35 g; 0.838 mmol), and proceeding successively in analogy to Example 50, step 50. i (52% yield), Example 2, step 2.ii (71 % yield) and Procedure B (65% yield), the title compound (0.1 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.80 (br s, 1 H); 9.19 (br s, 1 H); 7.84 (s, 1 H); 7.74 (s, 1 H); 6.53 (d, J = 1.3 Hz, 1 H); 5.02 (t, J = 6.0 Hz, 1 H); 4.50 (s, 2H); 3.51 (m, 1 H); 3.42 (d, J = 6.0 Hz, 2H); 3.42 (m, 1 H); 3.07 (s, 3H); 2.61 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H) 0.96-0.87 (m, 4H).

MS1 (ESI, m/z): 493.1 [M+H ⁺ ] for C21H24N4O6S2; t _R = 0.69 min. Example 73: (2 ?)-4-(6-(4-cyclopropylthiazol-2-yl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy- 2-methyl-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation D (0.205 g; 0.39 mmol) and 4-cyclopropylthiazole (0.055 g; 0.434 mmol), and proceeding successively in analogy to Example 50, step 50. i (41 % yield) and Procedure B (38% yield), the title compound (0.1 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.80 (br s, 1 H); 9.19 (br s, 1 H); 7.59 (s, 1 H); 7.12 (s, 1 H); 6.48 (d, J = 1.2 Hz, 1 H); 4.49 (s, 2H); 3.51 (m, 1 H); 3.40 (overlapped m, 1 H); 3.07 (s, 3H); 2.61 (m, 1 H); 2.07 (m, 1 H); 1.98 (m, 1 H); 1.54 (s, 3H) 0.92-0.81 (m, 4H).

MS1 (ESI, m/z): 439.1 [M+H ⁺ ] for C18H22N4O5S2; t _R = 0.69 min.

Example 74: (2 ?)-A/-hydroxy-4-(6-(5-(((2-hydroxyethoxy)imino)methyl)thioph en-3-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e Starting from intermediate 1.i (0.103 g; 0.2 mmol) and 2-aminooxyethanol (0.017 g; 0.221 mmol), the solution was stirred for 1 h. The reaction mixture was directly purified by prep-HPLC (Method 1 ) to afford the title compound (0.084 g, 86% yield) as a white amorphous solid.

MS1 (ESI, m/z): 485.1 [M+H ⁺ ] for C19H24N4O7S2; t _R = 0.65 min.

Example 75: (2 ?)-A/-hydroxy-2-methyl-4-(6-(2-(4-(1-methylazetidin-3-yl)phe nyl)thiazol-5-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-(methylsulfonyl)butanamide

751 (2R)-4-(6-(2-(4-(Azetidin-3-yl)phenyl)thiazol^

methyl-2-(methylsulfonyl)butanamide:

Starting from the compound of Preparation D (0.571 g; 1.09 mmol) and the compound of Preparation AJ (0.43 g; 1.36 mmol), and proceeding successively in analogy to Example 50, step 50.i (29% yield) and Example 8, step 8.v (24% yield), the title compound (0.073 g) was obtained after purification by prep-HPLC (Method 1 ) as a yellowish solid.

MS1 (ESI, m/z): 530.1 [M+H ⁺ ] for C24H27N5O5S2; t _R = 0.58 min.

75.H. (2R)^ydroxy-2-methyl-4-(6-(2-(4-(1-methylazetidin-3-yl^

c]imidazol-2(3H)-yl)-2-(methylsulfonyl)butanamide:

To a suspension of intermediate 75. i (0.068 g, 0.128 mmol) in MeOH (1.3 mL) and DCM (1.3 mL) was added 37% aq. formaldehyde (0.015 mL; 0.193 mmol). NaBH(OAc) ₃ (0.0816 g; 0.385 mmol) were added: The reaction proceeded at rt for 1 h30. The volatiles were removed in vacuo and the residue was purified by prep- HPLC (Method 1 ) to afford the title compound (0.002 g, 3% yield) as a yellowish amorphous solid.

¹ H NMR (DMSO-cie) δ: 10.97 (br s, 1 H), 9.17 (br s , 1 H), 8.09 (s, 1 H), 7.87 (d, J = 8.2 Hz, 2H), 7.59 (s, 1 H), 7.48 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 1.2 Hz, 1 H), 4.50 (s, 2H), 3.64-3.59 (m, 3H), 3.51 (m, 1 H), 3.41 (m, 1 H), 3.10-3.09 (m, 2H), 3.08 (s, 3H), 2.60 (m, 1 H), 2.28 (s, 3H), 1.98 (m, 1 H), 1.53 (s, 3H).

MS1 (ESI, m/z): 544.1 [M+H ⁺ ] for C25H29N5O5S2; t _R = 0.59 min. Example 76: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(2-(4-(1-(oxe tan-3-ylmethyl)azetidin-3- yl)phenyl)thiazol-5-yl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from intermediate 75. i (0.080 g; 0.151 mmol) and oxetane-3-carbaldehyde (0.02 g; 0.227 mmol), and proceeding in analogy to Example 75, step 75.ii (9% yield), the title compound (0.008 g) was obtained after purification by prep-HPLC (Method 1 ) as a white solid.

¹ H NMR (DMSO-cie) δ: 9.16 (br s, 1 H); 8.08 (s, 1 H); 7.86 (d, J = 8.4 Hz, 2H); 7.59 (s, 1 H); 7.45 (d, J = 8.4 Hz, 2H); 6.48 (d, J = 1.3 Hz, 1 H); 4.63-4.60 (m, 2H); 4.49 (s, 2H); 4.28 (t, J = 6.0 Hz, 2H); 3.68-3.58 (m, 3H); 3.51 (m, 1 H): 3.41 (m, 1 H); 3.12-3.08 (overlapped m, 2H); 3.07 (s, 3H); 2.96 (m, 1 H); 2.72 (d, J = 7.5 Hz, 2H); 2.60 (m, 1 H); 1.97 (m, 1 H); 1.53 (s, 3H). Example 77: (2 ?)-4-(6-(5-(2-(1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl) ethyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

771. (2R)-4-(6-(5-(2-(1-Formylcyclopropyl)ethyl)thiophen^

me /-2-(me /su/fony/J-W-(((2RSJ-ieirahydro-2H-pyran-2-y/JoxyJbuianam/ ^' cie:

Starting from intermediate 47.i (0.243 g; 0.419 mmol) and proceeding in analogy to Example 69, step 69.L (43% yield), the title compound (0.104 g; 43% yield) was obtained after purification by CC (Hept-EA gradient) as a yellowish foam.

MS1 (ESI, m/z): 578.2 [M+H ⁺ ] for C27H35N3O7S2; t _R = 0.98 min.

77.H. (2R)-4-(6-(5-(2-(1-((3-Fluoroazetidin-1-yl)me^

c]/m/dazo/-2(3HJ-y/J-W-hydroxy-2-meihy/-2-(meihy/su/fony/ Jbuianam/ ^' cie:

Starting from intermediate 77. i (0.05 g; 0.086 mmol) and proceeding in analogy to Example 70 (18% yield, two steps), the title compound (0.009 g) was obtained after purification by prep-HPLC (Method 1 ) as a white solid. ¹ H NMR (DMSO-cie) δ: 10.7 (br s, 1 H), 9.18 (br s, 1 H), 7.32 (m, 1 H), 7.04 (d, J = 3.4Hz, 1 H), 6.72 (d, J = 3.4Hz, 1 H), 6.31 (m, 1 H), 5.25-5.08 (m, 1 H), 4.45 (br s, 2H), 3.66-3.55 (m, 2H), 3.48 (m, 1 H), 3.33 (overlapped m, 1 H), 3.08 (m, 3H), 3.08 (overlapped m, 1 H), 3.03 (m, 1 H), 2.83-2.76 (m, 2H), 2.59 (m, 1 H), 2.34 (s, 2H), 1.96 (m, 1 H), 1.61-1.56 (m, 2H), 1.53 (m, 3H), 0.33-0.22 (m, 4H).

MS1 (ESI, m/z): 553.2 [M+H ⁺ ] for C25H33N4O5FS2; t _R = 0.65 min.

Example 78: (2 ?)-4-(6-(5-(2-(1-((3-fluoroazetidin-1-yl)methyl)cyclopropyl) ethyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

781 2,5-Dioxopyrrolidin-1-yl ((i-(2-(5-(2-((2RJ-3-meihy/-3-(meihy/su/fony/J-4-oxo-4-((((2 RSJ-ieirahyciro-2H- pyran^-yljoxyjaminojbutylj-SKixo^S^ihydro-IH yffololl^^

yl)ethyl)cyclopropyl)methyl) carbonate: To a solution of intermediate 47.i (0.130 g; 0.224 mmol) in MeCN (3 mL) was added TEA (0.0624 mL, 0.448 mmol) and DSC (0.172 g, 0.673 mmol) . The reaction mixture was stirred at rt for 3h The reaction mixture was concentrated to dryness and the residue was diluted with EtOAc (50 mL). The org layer was washed with 1 M aq. citric acid (25 mL), water (50 mL), brine (50 mL), dried over Na ₂ SC>4 and concentrated to dryness. The evaporation residue was purified by CC (Hept-EA-MeOH gradient) to afford the title product (0.136 g, 84 % yield) as a yellow foam.

MS1 (ESI, m/z): 721.3 [M+H ⁺ ] for C32H40N4O11S2; t _R = 1.01 min.

78.H. (1-(2-(5-(2-((2R)-3-methyl-3-(methylsulfonyl)-4-oxo^

yl)oxy)amino)butyl)-3<)xo-2,3 ihydro-1H yirolo[1,2 ]imfa 3- hydroxyazetidine- 1 -carboxylate:

To a solution of intermediate 78. i (0.136 g; 0.189 mmol) in DCM (3 mL) were added 3-hydroxyazetidine.HCI (0.021 g; 0.189 mmol) and TEA (0.0525 mL; 0.377 mmol). The reaction proceeded for 1 h30 at rt. The reaction mixture was diluted in DCM (50mL), washed with NaHCC>3 sat. aq. (3x50 mL). The evaporation residue was purified by prep HPLC (method 1 ) to afford the title product as a yellow oil (0.048g, 37% yield).

MS1 (ESI, m/z): 675.1 [M+H ⁺ ] for C31 H38N4O9S2; t _R = 0.91 min.

78.///. (2R)-4-(6-(5-(2-(1-((3-fluoroazetidin-1-yl)methyl)cy ^^^

c]imidazol-2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl )butanam

Starting from intermediate 78. ii (0.048 g; 0.419 mmol) and proceeding in analogy to Procedure E (75% yield, two steps), the title compound (0.031 g; 75% yield) was obtained after purification by prep-HPLC (Method 2) as a white solid.

¹ H NMR (DMSO-c(6) 6: 10.9 (m, 1 H), 9.21 (m, 1 H), 7.32 (m, 1 H), 7.05 (d, J = 3.4 Hz, 1 H), 6.74 (d, J = 3.5 Hz, 1 H), 6.32 (d, J = 1.3 Hz, 1 H), 5.71 (m, 1 H), 4.46-4.44 (m, 2H), 4.42 (m, 1 H), 4.18-3.99 (m, 2H), 3.87 (s, 2H), 3.76-3.58 (m, 2H), 3.50 (m, 1 H), 3.38 (m, 1 H), 3.07 (m, 3H), 2.87-2.81 (m, 2H), 2.60 (m, 1 H), 1.97 (m, 1 H), 1.68-1.62 (m, 2H),1.53 (m, 3H), 0.49-0.39 (m, 4H).

MS1 (ESI, m/z): 595.1 [M+H ⁺ ] for C26H34N4O8S2; t _R = 0.08 min.

Example 79: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(5-(2-(1-

(morpholinomethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo- 1H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)butanamide

Starting from intermediate 77. i (0.05 g; 0.086 mmol) and morpholine (0.010 g, 0.097 mmol) and proceeding successively in analogy to Example 69, step 69.ii (59% yield) and Procedure B (60% yield), the title compound (0.001 g) was obtained after purification by prep-HPLC (Method 1 ) as a white amorphous solid. ¹ H NMR (DMSO-cie) δ: 10.9 ( brs., 1 H) , 9.19 (brs. , 1 H), 7.33 (s, 1 H), 7.05 (d, J = 3.4 Hz, 1 H), 6.74 (d, J = 3.5 Hz, 1 H), 6.32 (d, J = 1.3 Hz, 1 H), 4.45 (s, 2H), 3.59 (t, J = 4.4 Hz, 4H), 3.53-3.46 (m, 2H), 3.38 (m, 1 H), 3.07 ( s, 3H), 2.87-2.81 (m, 2H), 2.58 (m, 1 H), 2.53 ( m, 1 H), 2.39 ( m, 2H), 2.17 (s, 2H), 1.97 (m, 1 H),

1.66-1.61 (m, 2H), 1.53 (s, 3H), 0.39-0.18 (m, 4H).

MS1 (ESI, m/z): 565.2 [M+H ⁺ ] for C26H36N4O6S2; t _R = 0.65 min.

Example 80: (2 ?S)-tetrahydrofuran-3-yl 3-((5-(2-((2 ?)-4-(hydroxyamino)-3-methyl-3-(methylsulfonyl)-4- oxobutyl)-3-oxo-2,3-dihydro-1H^yrrolo[1,2^]imidazol-6-yl)thi ophen-2-yl)ethynyl)azetidine-1- carboxylate

Starting from the compound of Preparation AK (0.097 g; 0.49 mmol) and the compound of Preparation AL (0.1 18 g; 0.248 mmol), and proceeding in analogy to Example 8, step 8.ii (74% yield), the title compound (0.0045 g) was obtained after purification by prep-HPLC (Method 1 ) as a beige solid.

1H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.19 (s, 1 H); 7.53 (s, 1 H); 7.21 (s, 2H); 6.39 (d, J = 1.3 Hz, 1 H); 5.11 (m, 1 H); 4.46 (s, 2H), 4.25-4.16 (m, 2H); 3.93-3.86 (m, 2H); 3.77-3.73 (m, 4H); 3.72-3.64 (m, 3H); 3.07 (s, 3H); 2.60 (m, 1 H); 2.09 (m, 1 H); 1.97 (m, 1 H); 1.88 (m, 1 H); 1.53 (s, 3H).

MS1 (ESI, m/z): 591.1 [M+H ⁺ ] for C26H30N4O8S2; t _R = 0.84 min.

Example 81 : (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-(5-(2-(1- (morpholinomethyl)cyclopropyl)ethyl)thiophen-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)- yl)butanamide

Starting from the compound of Preparation AM (0.3 g; 0.982 mmol) and the compound of Preparation D (0.413 g; 0.786 mmol), and proceeding successively in analogy to Example 50, step 50.i (36% yield), Example 2, step 2.ii (66% yield), Example 69, step 69.i (40% yield), Example 77, step 77.ii (81 % yield) and Procedure B (49% yield), the title compound (0.021 g) was obtained, after purification by prep-HPLC (Method 1 ) as an off-white solid.

¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.21 (m, 1 H), 8.09 (m, 1 H), 7.86 (d, J = 8.2 Hz, 2H), 7.60 (m, 1 H), 7.41 (d, J = 8.2 Hz, 2H), 6.49 (d, J = 1.3 Hz, 1 H), 5.19 (m, 1 H), 4.50-4.47 (m, 2H), 3.68 (s, 2H), 3.60-3.49 (m, 3H), 3.40 (m, 1 H), 3.19 (m, 1 H), 3.14 (m, 1 H), 3.08 (s, 3H), 2.61 (m, 1 H), 1.99 (m, 1 H), 1.55 (s, 3H).

MS1 (ESI, m/z): 562.2.1 [M+H ⁺ ] for C25H28N5O5FS2; t _R = 0.59 min.

Example 82: (2 ?)-4-(6-(4-((1-((1-fluoroazetidin-3-yl)methyl)cyclopropyl)et hynyl)furan-2-yl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

Starting from intermediate 58.i (0.099 g; 0.177 mmol) and and proceeding successively in analogy to Example 69, step 69-i (67% yield), Example 77, step 77. ii (81 % yield) and Procedure B (57% yield), the title compound (0.029 g) was obtained, after purification by prep-HPLC (Method 1 ) as an off-white solid.

¹ H NMR (DMSO-cie) δ: 10.95 (br s, 1 H); 9.18 (br s, 1 H); 7.84 (d, J = 0.6 Hz, 1 H); 7.39 (s, 1 H); 6.66 (s, 1 H); 6.37 (d, J = 1.2 Hz, 1 H); 5.28-5.06 (m, 1 H); 4.46 (s, 2H); 3.70-3.60 (m, 2H); 3.49 (m, 1 H); 3.39 (m, 1 H); 3.21 - 3.10 (m, 2H); 3.06 (s, 3H); 2.61 (m, 1 H); 2.46-2.40 (ovelapped m, 2H); 1.96 (m, 1 H); 1.53 (s, 3H); 0.87-0.83 (m, 2H); 0.81-0.76 (m, 2H).

MS1 (ESI, m/z): 533.2 [M+H ⁺ ] for C25H29N4O6FS; t _R = 0.62 min. Example 83: (2 ?)-2-(3-((4-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1H-pyrrolo[ 1,2-c]imidazol-2(3H)-yl)-2- methyl-2-(methylsulfonyl)butanamido)oxy)-3-oxopropyl)phenyl dihydrogen phosphate

831 (2R)-di-tert-butyl (2-(3^-(6-(2-cyclopropylthiazol-5-yl)-3-oxo-1H y^^

methyl-2-(methylsulfonyl)butanamido)oxy)-3-oxopropyl)phen yl) phosphate:

To a solution of the compound of Example 9 (0.0627 g; 0.143 mmol) in DMF (0.8 mL) and TEA (0.0597 mL; 0.429 mmol) was added EDC.HCI (0.055 g; 0.286 mmol), HOBt (0.0438 g; 0.286 mmol) and 3-(2-((di-iert- butoxyphosphoryl)oxy)phenyl)propanoic acid (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.0615 g; 0.172 mmol). The solution was stirred at rt for 16h. EA (20 mL) and water (10 mL) were added. The two layers were separated. The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound (0.065 g, 58% yield) as a yellowish foam.

MS2 (ESI, m/z): 779.3 [M+H ⁺ ] for C35H47N4O10PS2; t _R = 1.06 min.

83.H. (2R)-2-(3-((4-(6-(2-cyclopropylthiazol-5-yl)-3-ox^^^

(methylsulfonyl)butanamido)oxy)-3-oxopropyl)phenyl dihydrogen phosphate:

A solution of intermediate 83.i (0.065 g; 0.083 mmol) in MeCN (0.3mL) was treated with 4M HCI in dioxane (0.31 mL). The reaction proceeded at rt for 10 min. The resulting solution was directly purified by prep-HPLC (Method 2) to afford the title compound (0.044 g, 77% yield) as a white solid.

¹ H NMR (DMSO-cie) δ: 12.29 (br s, 1 H); 7.75 (s, 1 H); 7.44 (s, 1 H); 7.31-7.18 (m, 3H); 7.06 (m, 1 H); 6.38 (d, J = 1.3 Hz, 1 H); 4.52-4.41 (m, 2H); 3.57 (overlapped m, 1 H); 3.43 (overlapped.m, 1 H); 3.10 (s, 3H); 2.94-2.88 (m, 2H); 2.80-2.75 (m, 2H); 2.59 (m, 1 H); 2.35 (m, 1 H); 2.04 (m, 1 H); 1.62 (s, 3H); 1.12-1.07 (m, 2H); 0.97- 0.91 (m, 2H).

MS2 (ESI, m/z): 667.2 [M+H ⁺ ] for C27H31 N4O10PS2; t _R = 0.69 min.

Pharmacological properties of the invention compounds

Bacterial growth minimal inhibitory concentrations: Experimental methods:

Minimal Inhibitory Concentrations (MICs; mg/L) were determined in cation-adjusted Mueller-Hinton Broth by a microdilution method following the description given in "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Approved standard, 7th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006).

Results:

All Reference Example compounds were tested against against several Gram negative bacteria. K. pneumoniae A-651 is a multiply resistant strain (in particular quinolone-resistant), while E. coli ATCC25922 and P. aeruginosa ATCC27853 are quinolone-sensitive strains. The corresponding antibacterial test results are given in Table 1 hereafter (MICs in mg/L).

38 1 4 4 61 0.125 2 0.25

39 4 4 4 62 0.125 2 0.25

40 0.25 0.5 0.25 63 0.125 8 0.5

41 0.25 1 2 64 2 4 2

42 0.25 1 1 65 0.5 8 1

43 0.5 2 2 66 1 2 1

44 2 2 4 67 1 2 2

45 0.5 1 0.5 68 1 2 2

46 1 2 2 69 1 8 2

47 0.25 1 0.25 70 0.5 4 1

48 0.5 2 2 71 0.125 >8 >8

49 2 2 4 72 >8 2 >8

50 < 0.063 2 0.5 73 2 >8 4

51 < 0.063 0.5 0.25 74 4 4 4

52 0.25 1 1 75 4 8 8

53 < 0.063 8 1 76 0.25 4 4

54 < 0.063 >8 0.25 77 0.5 8 1

55 0.5 2 1 78 1 8 2

56 1 4 2 79 0.25 8 1

57 0.125 1 0.25 80 0.25 4 0.5

58 0.5 1 1 81 < 0.063 2 0.5

59 4 8 4 82 2 4 2

60 0.5 4 1 Cipro 0.063 0.25 8

The compound of Example 83 was tested against wild-type E. coli A-1261 in: the presence of alkaline phosphatase (from bovine intestinal mucosa: Sigma P6774-2KU, Lot: SLBJ7151V); the presence of esterase (from porcine liver: Sigma E2884-5KU, Lot: SLBD0030V); the presence of the above-mentioned alkaline phosphatase and esterase; the absence of the above mentioned alkaline phosphatase and esterase. The corresponding antibacterial test results are given in Table 2 hereinafter (MICs in mg/L). - Ill -

Table 2