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 WO2017036968 antibacterial 1 ,2-dihydro-3H-pyrolo[1 ,2-c]imidazolones and annulated pyrolidinone derivatives are disclosed.

1 ) One embodiment of the present invention relates to compounds of formula I

I, wherein M represents

M1 or M2,

wherein

the symbol "*" denotes the point of attachment to T;

T represents

^■ mono- or di-substituted cyclopropyl; or

^■ mono-substituted cyclobutyl;

wherein the substituents are independently selected from

> methyl or ethyl;

> u)-hydroxy(Ci-C4)alkyl;

> (C2-C3)alkenyl which is unsubstituted or mono-substituted with cyclopropyl or 1-(oxetan-3- yl)piperidin-4-yl;

> (C ₂ -C ₃ )alkynyl;

> phenyl which is unsubstituted or mono-substituted with fluorine, oxetan-3-yl, 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1-(hydroxymethyl)cycloprop-1-yl, 1 -((3-fluoroazetidin- 1-yl)methyl)cycloprop-1 -yl, 1 -aminocycloprop-1 -yl , (morpholin-4-yl)methyl;

> 5-membered heteroaryl which is unsubstituted or mono-substituted with fluorine, oxetan-3-yl, 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1-(hydroxymethyl)cycloprop-1-yl, 1 - ((3-fluoroazetidin-1-yl)methyl)cycloprop-1-yl, 1 -aminocycloprop-1 -yl, or (morpholin-4-yl)methyl; or salts (especially pharmaceutically acceptable salts) thereof. 2) Another embodiment of the present invention relates to compounds according to embodiment 1 , wherein M represents M1.

3) Another embodiment of the present invention relates to compounds according to embodiment 1 , wherein M represents M2.

4) Another embodiment of the present invention relates to compounds according to any one of

embodiments 1 to 3, wherein T represents a mono-substituted cyclopropyl.

5) Another embodiment of the present invention relates to compounds according to any one of

embodiments 1 to 3, wherein T represents a di-substituted cyclopropyl.

6) Another embodiment of the present invention relates to compounds according to embodiments 1 to 3, wherein T represents a di-substituted cyclopropyl, wherein both substituents are attached to thesame carbon atom and wherein one substituent is methyl and the other is independently selected from

> ethenyl, optionally substituted with cyclopropyl or 1 -(oxetan-3-yl)piperidin-4-yl;

> ethynyl;

> phenyl.optionally mono-substituted with fluorine, oxetan-3-yl, 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1 -(hydroxymethyl)cycloprop-1 -yl, 1 -((3-fluoroazetidin-

1-yl)methyl)cycloprop-1-yl, 1-aminocycloprop-1 -yl, hydroxymethyl or 2-hyd roxyeth - 1 -y I ; or

> thiophenyl;

7) Another embodiment of the present invention relates to compounds according to any one of

embodiments 1 to 3, wherein T represents a mono-substituted cyclobutyl, wherein the substituent is selected from

> ethenyl, optionally substituted with cyclopropyl or 1 -(oxetan-3-yl)piperidin-4-yl;

> ethynyl;

> phenyl.optionally mono-substituted with fluorine, oxetan-3-yl, 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1 -(hydroxymethyl)cycloprop-1 -yl, 1 -((3-fluoroazetidin- 1-yl)methyl)cycloprop-1-yl, 1-aminocycloprop-1 -yl, hydroxymethyl or 2-hyd roxyeth - 1 -y I ; or

> thiophenyl; Another embodiment of the present invention relates to compounds according to embodiment 1 , wherein M represents M1 or M2; T represents CP or CB

wherein

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

R ² represents H or methyl;

A ^cp and A ^CB independently represent SC ^A , SC ^B , SC ^C , SC ^D or SC ^E as defined below

SC ^A SC ^B SC ^C SC ^D SC ^E ;

wherein the symbol "#" denotes the point of attachment to CP or CB;

R ^1A represents hydrogen or fluorine;

R ^3A represents H, oxetan-3-yl, 2-hyd roxyeth- 1 -yl , 1 ,2-dihydroxyethyl, (3-fluoroazetidin-1 -yl)methyl, 1 - (hydroxymethyl)cycloprop-l -yl, 1 -((3-fluoroazetidin-1 -yl)methyl)cycloprop-1 -yl, 1 -aminocycloprop-1 - yl, (morpholin-4-yl)methyl, hydroxymethyl o;

R ^1C represents cyclopropyl or 1-(oxetan-3-yl)piperidine-4-yl;

n represents an integer from 2 to 3.

) Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M1.

0) Another embodiment of the present invention relates to compounds according to any one of embodiments 8 or 9, wherein T represents CP.

1 ) Another embodiment of the present invention relates to compounds according to any one of embodiments 8 to 10, wherein A ^cp represents SC ^A , SC ^B or SC ^C .

2) Another embodiment of the present invention relates to compounds according to any one of embodiments 8 or 9, wherein T represents CB.

3) Another embodiment of the present invention relates to compounds according to any one of embdiments 8, 9 or 12, wherein A ^CB represents SC ^A or SC ^D .

4) Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M2.

5) Another embodiment of the present invention relates to compounds according to embodiment 14, wherein T represents CP.

6) Another embodiment of the present invention relates to compounds according to embodiment 15, wherein A ^cp represents SC ^A , SC ^B or SC ^C (notably SC ^A or SC ^C ).

7) Another embodiment of the present invention relates to compounds according embodiment 14, wherein T represents CB.

8) Another embodiment of the present invention relates to compounds according to embdiment 17, wherein A ^CB represents SC ^A or SC ^D .

9) Another embodiment of the present invention relates to compounds according to embodiment 8, wherein M represents M2 and T represents CP.

0) Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 or M2; T represents CP or CB; and A ^cp or A ^CB independently represent SC ^A , SC ^B or SC ^c .

1 ) Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CP or CB; and A ^cp or A ^CB independentnly represent SC ^A , SC ^B or SC ^c .

2) Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CP; and A ^cp represents SC ^A , SC ^B or SC ^c .

3) Another embodiment of the present invention relates to compounds according to embodiment 8, werein M represents M1 ; T represents CB; and A ^CB represents SC ^A or SC ^C . 24) Another embodiment of the present invention relates to compounds of embodiment 1 , selected from:

(2R)-W-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1 S,2S)-2-phenylcyclopropyl)-4,6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)butanamide;

(2R)-N-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1 R,2R)-2-phenylcyclopropyl)-4,6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)butanamide;

(2R) -(2-((1 S,2S)-2-(2-Fluorophenyl)cyclopro

methyl-2-(methylsulfonyl)butanamide;

(2R) -(2-((1 R,2R)-2-(2-Fluorophenyl)cyclopropyl)-6-oxo ,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2- methyl-2-(methylsulfonyl)butanamide;

(2R) -(2-((1 S,2R)-2-((E)-2-Cyclopropylvinyl)cyd^

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

(2R)-4-(2-((1 R,2S)-2-((E)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4,6-dihyd ro-5H-thi

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

(2R)-W-Hydroxy -(6-((1 S*,2S*)-2-(4-(2-hydroxyethyl)phenyl)cyclopropyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol- 2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanamide amide;

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

(2R)-W-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1 S*,2S*)-2-(4-(oxetan-3-yl)phenyl)cyclopropyl)-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)butanamide;

(2R)-4-(6-((1 R*,2S*)-2-((E)-2-Cyclopropylvinyl)cyclopropyl)-3-oxo-1 H-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-((1 S*,2S*)-2-phenylcyclopropyl)-1 H-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)butanamide;

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

(2R)-A/-Hydroxy-4-(2-((1 S,2S)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6-oxo-4,6-dihy dro-5H-thieno[2,3- c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-A/-Hydroxy-4-(2-((1 R,2R)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6-oxo-4,6-dihy dro-5H-thieno[2,3- c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-A/-Hydroxy-4-(6-((1 S*,2S*)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol- 2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-N-Hydroxy -(6-((^2S 2-(4-(hydro^

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

(2 ^W-Hydrox -2-methyl-2^methylsulfonyl)^(2-((1 S*,2/? ^, )-2-((£)-2-(1 -(oxete^

yl)vinyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]p yrrol-5-yl)butanamide;

(2R)-W-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((1 r,3R)-3-phenylcyclobutyl)-1 H-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)butanamide;

(2R) -(6-((1 r,3R)-3-ethynylcyclobutyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-W-hydroxy-2-me

(methylsulfonyl)butanamide;

(2R)-W-Hydroxy-4-(6-(( 1 r,3f?)-3-(4-(2-hydroxyethyl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)-2-methyl-2-(methylsulfonyl)butanamide;

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

(2R)-N-Hydroxy -(6-((1r,3R)-3-(4-(1 -(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanamide ;

(2R)-N-Hydroxy-4-(6-((1r,3R)-3-(4-(1 -(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3-oxo-1H-pyrr olo[1 ,2- c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanamide ;

(2R)-N-Hydroxy -(6-((1 r,3R)-3-(4-(1 -(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanamide ; or

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

(2R) -(6-((1 r,3R)-3-(4-(1-Aminocyclopropyl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2 hydroxy-2-methyl-2-(methylsulfonyl)butanamide;

(2R)-N-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1 r,3R)-3-(4-(oxetan-3-yl)phenyl)cyclo

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

((2R)-W-Hydroxy -(6-((1s,3R)-3-(3-hydroxypropyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-y methyl-2-(methylsulfonyl)butanamide;

(2R)-W-Hydroxy-4-(6-((1s,3R)-3-(4-hydroxybutyl)cyclobutyl)-3 -oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3^ methyl-2-(methylsulfonyl)butanamide; and

(2R)-W-Hydroxy-2-methyl-2-(methylsulfo^ 1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)butanamide.

Based on the dependencies of the different embodiments 1) to 23) as disclosed hereinabove, the following embodiments are thus possible and intended and herewith specifically disclosed in individualized form: 2+1, 3+1, 4+1, 4+2+1,4+3+1, 5+1, 5+2+1, 5+3+1, 6+1, 6+2+1, 6+3+1, 7+1, 7+2+1, 7+3+1, 8+1, 9+8+1, 10+8+1, 10+9+8+1, 11+8+1, 11+9+8+1, 11 + 10+8+1, 11+10+9+8+1, 12+8+1, 12+9+8+1, 13+8+1, 13+9+8+1, 13+12+8+1, 13+12+9+8+1, 14+8+1, 15+14+8+1, 16+15+14+8+1, 17+14+8+1, 18+17+14+8+1, 19+8+1,

20+8+1, 21+8+1, 22+8+1, 23+8+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, "6+2+1 " for example refers to embodiment 6) depending on embodiment 2), depending on embodiment 1), i.e. embodiment "6+2+1" corresponds to embodiment 1) further characterized by the features of the embodiments 2) and 6).

It is understood that the the hydrogen atom of the hydroxy group in the fragment -NH-OH of formula I can be replaced by R ¹ employing common in the art synthetic methods. R ¹ may be selected from -P(0)(0H)2, - S(0)2(0H), phosphonooxymethyl or PM as defined below

PM

wherein R ^PM 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)-(CrC4)alkyl (especially 2-(2-(phosphonooxy)-phenyl)-ethyl) or [2-(phosphonooxy- (Ci-C ₄ )alkyl)-phenyl]-(Ci-C ₄ )alkyl.

It is further understood that compounds of formula I, wherein R ¹ is -P(0)(0H)2 , -S(0)2(0H), phosphonooxymethyl or PM represent prodrugs.

In particular:

• the prodrug comprising the group (di(Ci-C4)alkylamino)-(Ci-C3)alkyl-carbonyloxy (occurring when R ^PM 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 ^PM 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 ^PM represents (2-(phosphonooxy)-phenyl)-(Ci-C4)alkyl) notably refers to one of the groups represented below

It is also understood that further prodrugs may be formed by replacing a hydrogen of a hydroxy group, wherein said hydroxy group may be attached to a substituent of the group T by any one of: -P(0)(0H)2 , - S(0)2(0H), phosphonooxymethyl or PM.

Definitions provided herein are intended to apply uniformly to the subject matter as defined in any one of embodiments 1 ) to 24), 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 "mono- or di-substituted cyclopropyl" as used throughout the present text means a cyclopropyl ring having one or two single bonds to substituents in addition to the bond to M. The term "mono-substituted cyclobutyl" as used throughout the present text means a cyclobutyl ring having one single bond to a substituent in addition to the bond to M. Notably, the term "mono- or di-substituted cyclopropyl" represents the group CP

CP and the term "mono-substituted cyclobutyl" represents the group CB

CB

wherein the asterisk " * " in both formulae denotes the point of attachment to M;

The term "(C _x -C _y )alkyl" (x and y each being an integer), used alone or in combination, refers to a saturated straight or branched hydrocarbon chain with x to y carbon atoms. Thus, the term "(Ci-C4)alkyl, alone or in combination with other groups, means saturated, branched or straight chain groups with one to four carbon atoms. Examples of "(Ci-C4)alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and t-butyl. . Preferred is methyl.

The term "(C _x -C _y )alkenyl" (x and y each being an integer), used alone or in combination, refers to an unsaturated straight or branched hydrocarbon chain with x to y carbon atoms having one double bond. Thus, the term "(C2-C3)alkenyl, alone or in combination with other groups, means unsaturated, branched or straight chain groups with one to three carbon atoms having one double bond. Examples thereof are ethenyl, prop-1 - en-1-yl, prop-1 -en-2-yl. Preferred are ethenyl and prop-1 -en-1-yl.

The term "(C _x -C _y )alkynyl" (x and y each being an integer), used alone or in combination, refers to an unsaturated straight or branched hydrocarbon chain with x to y carbon atoms having one triple bond. Thus, the term "(C2-C3)alkynyl, alone or in combination with other groups, means unsaturated, branched or straight chain groups with one to three carbon atoms having one triple bond. Examples thereof are ethynyl, prop-1-yn-

1- yl and prop-2-yn-1 yl. Preferred are ethynyl and prop-1-yn-1 -yl.

An "(jd-hydroxy(Ci-C4)alkyl" group as used as a substituent for the group "T", is a linear alkyl group which contains from one to four carbon atoms in which one terminal hydrogen atom has been replaced by hydroxy. Examples of oo-hydroxy(Ci-C4)alkyl groups are hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and

4- hydroxybutyl; especially 2-hydroxyethyl and hydroxymethyl.

The term "5-membered heteroaryl", used alone or in combination, means a 5- membered monocyclic aromatic ring containing one to a maximum of four heteroatoms, each independently selected from oxygen, nitrogen and sulfur. Examples of such 5-membered heteroaryl groups are furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl. Notably, the term "5-membered heteroaryl" refers to thiazolyl and thiophenyl; in particular thiophen-

2- yl, thiophen-3-yl, thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl. A preferred example of an optionally substituted

5- membered heteroaryl group is unsubstituted thiophen-2-yl.

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 alkyi group contains x to y carbon atoms. For example, a (Ci-C4)alkylamino group is an alkylamino group as defined before wherein the alkyi 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 alkyi group as defined before, whereby the alkyi 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 alkyi 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 alkyi 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 alkyi 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 alkyi 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 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 Aerobicallf, 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 ² H (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 ² H (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 expression "between X and Y" , "X to Y" or "from X to Y" is used to describe a numerical range, it is to be understood that the end points X and Y 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 (40 °C to 80 °C) or (from 40 °C to 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 (1 to 4) or (from 1 to 4), this means that the variable is the integer 1 , 2, 3, or 4.

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, they may be used for threating hard surfaces, liquids, or semi-liquids.

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/ SelectAgentsandToxinsL.ist.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 one of embodiments 1 ) to 24) 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 one of embodiments 1 ) to 24) 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 the compounds of formula I or salts (in particular pharmaceutically acceptable salts) thereof according to one of embodiments 1 ) to 24) 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 one of embodiments 1 ) to 24), 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 one of embodiments 1 ) to 24) 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 24), 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 or quinolone-resistant Klebsiella pneumoniae bacteria).

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:

acetyl

AcOH acetic acid

AIBN azobisisobutyronitrile

aq. aqueous

Boc iert-butoxycarbonyl

CC column chromatography over silica gel

CDI carbonyldiimidazole

Cipro ciprofloxacin

DAD diode array detection

dba dibenzylideneacetone

DCC dicyclohexylcarbodiimide

DCE 1 ,2-dichloroethane

DCM dichloromethane

dF(CF ₃ )ppy 3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl

DIPEA A/,A/-diisopropylethylamine

DMA N,N-dimethylacetamide

DMAP 4-dimethylamino-pyridine

DME 1 ,2-dimethoxyethane

DMF A/,A/-dimethylformamide

DMSO dimethylsulfoxide

dppf bis(diphenylphosphino)ferrocene

DSC Α/,/V-disuccinimidyl carbonate

dtbbpy 4,4'-di-ierf-butyl-2,2'-bipyridine

EA ethyl acetate

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

e.e. enantiomeric excess

ELSD evaporative light scattering detector electron spray ionisation

equivalent(s)

ethyl

diethyl ether

ethanol

1 ,2-dimethoxyethane

hour(s)

0-(7-azabenzotriazol-1-yl)-W,W,W',W'-tetramethyluronium hexafluorophosphate heptane

hexane

hydroxybenzotriazole

high performance liquid chromatography

isopropyl

isopropanol

internal temperature

liquid chromatography - mass spectroscopy

lithium diisopropyl amide

Light-emitting diode

lithium hexamethyldisilazide

3-chloro perbenzoic acid

methyl

acetonitrile

methanol

minute(s)

mass spectroscopy

methanesulfonyl (mesyl)

W-bromosuccinimide

n-butyl

A/-methyl-2-pyrrolidone

Nuclear Magnetic Resonance

organic

palladium on carbon

[1 ,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyr idyl)palladium(ll) dichloride

protecting group

phenyl

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

TBAF tetra-n-butylammonium fluoride

TBDPSCI iert-butyldiphenylsilyl chloride

TBME iert-butylmethyl ether

tBu iert-butyl

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

THP tetrahydropyranyl

TLC thin layer chromatography

TMS trimethylsilyl

TMSE 2-(trimethylsilyl)ethyl

tR retention time

Ts para-toluenesulfonyl

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, tBu, COOtBu or COtBu: 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 pyridinium 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 PC is allyl: by treatment with Pd(PPh3)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.).

Generajjeacj n technic 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, 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).

GeneraJ.reactipn.techm 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, tBuONa or tBuOK between 20 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(PPh ₃ )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(tBu)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 W-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, 97-11 1 , Fu, Acc. Chem. Res. (2008), 41 , 1555-1564, and references cited therein.

General..reaction _, . techn i.q ue .4. _(aj kyl . bfom ide-aryj.. bromide ..cross _: cou j i njg)j ..The cross coupling reaction between an alkyl bromide and an aryl bromide can be performed under reductive conditions using catalytic amount of a nickel complex in presence of a reducing agent such as manganese powder as described by Everson, D.A. and al in J. Am. Chem.Soc. (2010) 132, 920-921. Alternatively, an iridium photosensitizer and an amine can be employed in combination with the nickel catalyst to perform the said cross-coupling reaction as described by Paul, A and al in J. Org. Chem. (2017) 82, 1996-2003. Tris(trimethylsilyl)silane can also be used in such a reaction as described by Zhang, P and al in J. Am. Chem. Soc. (2016) 138, 8084-8087. GeneraJ. reason. technjg 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, NaBHCIS , 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).

General .reaction .technique .6 Xtransfo[mati n of an.^ 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-dioxan or water-THF mixture between 0°C and 80°C. When the ester side chain is tBu, 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.).

General _, reacti o n. tech n i qu e .7. a|cp hoj . actjyatjpn).: . The alcohol is reacted with either MsClor TsCI in the presence of a base such as TEA in a dry aprotic solvent such as Pyr, THF or DCM between -30°C and +50°C. In the case of the triflate, Tf20 is used under the same reaction conditions.

General preparation methods:

Pre aration of t e.compou^ 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 all generic groups such as M1 , M2, etc. are as defined in 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).

Pre aration .of the compounds of ormuJ.a .h.The compounds of formula I can be obtained by deprotecting a compound of formula II

wherein T and M have the same meaning as in formula I and PG ¹ represents THP, TMSE, trityl, (2- methylpropoxy)ethyl, methoxymethyl, allyl, tBu, COOtBu or COtBu 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 m) column, a Daicel ChiralCel OD-H (5-10 m) column, or a Daicel ChiralPak IA (10 m) or AD-H (5 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 TEA or diethylamine) 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

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

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 T 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 Vlllb

Villa Vlllb

wherein A ^cp and R ² 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)2with a compound of formula IX

wherein M is as defined in formula I, 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 iii) reacting a bromo derivative of formula X

wherein A ^CB has the same respective meanings as in formula I, with a compound of formula IX using general reaction technique 4 (this reaction can also be performed with racemic compound of formula IX and the trans (R)-enantiomer can then be obtained by chiral HPLC separation of the reaction product);

Pre aration of the s_.nthesisjn.tem

Compounds of formula VI:

The compounds of formula VI wherein M is M1 can be prepared as summarised in Scheme 1 hereafter.

VI 1-4

Scheme 1

In Scheme 1 , T is 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 5. 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 to 50°C, and ideally at rt. The compounds of formula I-4 can be transformed into the compounds of formula VI using general reaction technique 6. 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.

The compounds of formula VI wherein M is M2 can be prepared as summarised in Scheme 2 hereafter.

Scheme 2

In Scheme 2, T has the same meanings as in formula I. 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 derivatives of formula 11-2 can be obtained (Scheme 2) by reaction of the thiophene carboxylic acids of formula 11-1 with the amine of formula I-2 using general reaction technique 2. The derivatives of formula II-2 are treated with NBS in a solvent such as CCU in the presence of a radical initiator such as AIBN; this reaction, usually performed at reflux, affords the bromo-methyl derivatives of formula 11— 3 _ The latter are subsequently transformed to the compounds of formula 11-4 by treatment with a base such as LDA or LiHMDS in a solvent such as THF. The reaction can be carried out at a temperature ranging between -20°C and rt and ideally at rt. The derivatives of formula 11-4 can be transformed into the compounds of formula VI using general reaction technique 6.

Alternatively, the compounds of formula 11-4 can also be prepared as summarised in Scheme 3 hereafter.

Scheme 3

In Scheme 3, T has the same meaning as in formula I. 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 derivatives of formula 11-7 can be obtained (Scheme 3) from the derivatives of formula 11-5 and the amine of formula 1-2 using general reaction technique 5. Alternatively, the derivatives of formula 11-7 can be obtained (Scheme 3) by treating the bromo methyl derivatives of formula 11-6 with the amine of formula 1-2 in tBuOH at a temperature ranging between 50°C and 85°C, ideally at 85°C in presence of a base such as K2CO3. The derivatives of formula 11-7 can spontaneously give rise to the compounds of formula 11-4. Alternatively, the derivatives of formula 11-7 can be transformed to the derivatives of formula 11-4 applying sequentially general reaction techniques 6 and 2.

The derivatives of formula 114 can also be obtained (Scheme 3) by reaction of the dialdehydes derivatives of formula 11-8 with the amine of formula 1-2 in DMF at a temperature ranging between rt and about 60°C, and ideally at about 50°C. Alternatively, this condensation step can be performed in DCM in presence of AcOH at rt. Compounds of formula VII: The compounds of formula VII are commercially available (PG ¹ = methoxymethyl, THP, TMSE, trityl, tBu, COOtBu 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 = COtBu).

Compounds of formula Villa and Vlllb:

The compounds of formula Villa wherein D ¹ and D ² each represent H, (Ci-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 or 1 ,2-phenyl can be prepared as summarized in Schemes 4 and 4a hereafter

Villa

Scheme 4a

In Scheme 4a, A ^cp has the same meaning as in formula I.

The derivatives of formula IV-3 wherein D ¹ and D ² represent each (Ci-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 or 1 ,2-phenyl can be obtained (Scheme 4) from the derivatives of formula IV-1 by addition of boranes of formula IV-2 wherein D ¹ and D ² have the same meaning. The reaction can be catalysed by zirconium complexes such as the Schwartz's reagent (Cp2ZrHCI) in presence of a base such as TEA. The derivatives of formula IV-3 wherein D ¹ and D ² represent each represent 1 ,2-phenyl can be obtained (Scheme 4) from the derivatives of formula IV-1 by addition of catecholborane. The derivatives of formula Villa can then be obtained by zinc promoted cyclopropanation reaction using diiodoethane and TFA as reagents. The reaction can be performed in DCM at a temperature ranging from 0°C to reflux and ideally at rt. The derivatives of formula IV-3 wherein D ¹ and D ² represent each H can be obtained (Scheme 4) from the derivatives of formula IV-3 wherein D ¹ and D ² do not represent each H by treatment with aqueous sodium periodate followed by an acidic treatment with diluted hydrochloric acid.

IV-4

Scheme 4b

In Scheme 4b, A ^cp has the same meaning as in formula I. The derivatives of formula Villa wherein R ² = Me, D ¹ and D ² represent each (Ci-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 can be obtained (Scheme 4) from the methylcyclopropene derivatives of formula IV-4 by addition of boranes of formula IV-2 wherein D ¹ and D ² have the same meanings as in compounds of formula Villa. The reaction can be catalysed by rhodium complexes such as the Wilkinson's catalyst ((PPh ₃ )2RhCI) in a solvent such as THF.

The potassium trifluoroborate salt of formula VII lb wherein A and R ² 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-C2)alkyl or when taken together represent CH2C(Me)2CH2, C(Me)2C(Me)2 or 1 ,2-phenyl by treatment with an aqueous solution of potassium fluoride.

Compounds of formulae IX: The compounds of formula IX can be prepared as summarised in Scheme 5 hereafter.

Scheme 5

In Scheme 5, M is as defined in formula I, 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 V-1 wherein Y = Br (Scheme 3) can be transformed to the compounds of formula V-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 V-1 can be transformed to the compounds of formula V-2 using general reaction technique 5. The compounds of formula V-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.

Compounds of formulae X: The compounds of formula X can be prepared as summarised in Scheme 6 hereafter.

VI-1

Scheme 6

In Scheme 6, A ^CB is as defined in formula I.

The compounds of formula X (Scheme 6) can be obtained from the compounds of formula VI-1 by first transforming the alcohol in to a suitable leaving group using general reaction technique 7 and subsequent reaction with a bromide source such as lithium bromide in a solvent such as DMF. Alternatively, the compound of formula X can be obtained by reacting the compounds of formula VI-1 with carbon tetrabormide in presence of triphenyl phosphine in a solvent such as DCM or THF.

Other synthesisj^^

The compounds of formula II-5 and II-6 can be prepared by standard methods known to one skilled in the art. 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 7 hereafter.

Scheme 7

In Scheme 7, Y ^b represents iodine or bromine and A ^cp and R ² have the same respective meanings than in formula I.

The derivatives of formula 1-1 can be obtained (Scheme 7) by reaction of the pyrrole aldehydes of formula VII- 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 11-1 can be prepared as summarised in Scheme 8 hereafter.

Scheme 8

In Scheme 8, Y represents iodine or bromine and A ^cp and R ² have the same respective meanings than in formula I. R represents (Ci-C4)alkyl.

The derivative of formula VIII-2 can be obtained (Scheme 8) by reaction of the compound of formula VI 11-1 wherein Yb represents bromine or iodine by reaction with compounds of formula Villa or VI I lb following general reaction technique 3. The compound of formula 11-1 can then be obtained using general reaction technique 6.

The compounds of formula V-1 wherein Y represents bromine or iodine, R represents tBu and M represents M1 can be prepared as summarised in Scheme 9 hereafter.

Scheme 9

In Scheme 9, Y represents bromine or iodine.

The derivative of formula IX-1 can be obtained (Scheme 9) by reaction of the pyrrole aldehyde of formula VI 1-1 with the amine of formula I-2 using general reaction technique 5. The derivative of formula V-1 can then be obtained from the derivatives of formula IX-1 by treatment with CDI 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. The reaction 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 V-1 wherein Y represents bromine or iodine, R represents ethyl and M represents M1 can be prepared as summarised in Scheme 10 hereafter.

V-1 (M = M1, R = Et)

Scheme 10

In Scheme 10, Y represents bromine or iodine.

The oxime of formula X-1 can be obtained (Scheme 10) by reaction of the pyrrole aldehydes of formula VI-1 with hydroxylamine in AcOH in the presence of NaOAc. The oxime derivatives of formula X-1 can be reduced to the amine derivative of formula X-2 by treatment with Zn in a solvent such as AcOH. The derivative of formula X-3 can be obtained from the derivative of formula X-2 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 to 50°C, and ideally at rt. The compound of formula V-5 can then be transformed into the compounds of formula VI-1 by treatment with the bromide of formula X-4 in the presence of a base such as NaH and in a solvent such as THF or DMF. The reaction 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 V-1 wherein Y ^b represents Br and M represents M2 can be prepared as summarised in Scheme 11 hereafter.

V-1 (R = tBu, M = M2) XI-3

Scheme 11

In Scheme 1 1 , Y represents bromine or iodine.

The compounds of formula Xl-I can be transformed (Scheme 1 1 ) to the amide derivatives of formula XI-2 by reaction with the amine of formula I-2 using general reaction technique 2. The resulting derivatives of formula XI-2 can be transformed to the derivatives of formula X-3 by treatment with NBS in a solvent such as CCU in the presence of a radical initiator such as AIBN; this reaction is usually performed at reflux. The resulting bromo derivatives of formula XI-3 is subsequently transformed to the compounds of formula V-1 by treatment with a base such as LDA or LiHMDS in a solvent such as THF. The reaction can also be performed with racemic material and the (R)-enantiomer can be obtained by chiral HPLC separation at any step when suitable.

Alternatively, the compounds of formula V-1 wherein Y ^b represents Br and M represents M2 can be prepared as summarised in Scheme 12 hereafter.

Scheme 12

In Scheme 12, Y represents bromine or iodine.

The compounds of formula V-1 can be obtained (Scheme 12) by reaction of the compounds of formula XI 1-1 with the amine of formula I-2 in DCM in presence of acetic acid at a temperature ranging between rt and 40°C, and ideally at rt. The reaction 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 VII- 1 wherein Y 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 IV- 1 , IV-2, X-4, VI-1 , VI 11-1 XI-1 and XI 1-1 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

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 : Column: Zorbax SB-Aq, 30.5 μιη, 4.6 x 50 mm; Injection volume: 1 μί; Column oven temperature: 40°C; Detection: UV 210 nm, ELSD and MS; MS ionization mode: ESI+; Eluents: A: H ₂ 0 + 0.04% TFA; and B: MeCN; Flow rate: 4.5 mL/min; Gradient: 5% B to 95% B (0.0 min - 1.0 min), 95% B (1.0 min - 1.45 min). MS 2: Column: Zorbax RRHD, 1.8 μιη, 3.0 x 50 mm; Injection volume: 0.15 μί; Column oven temperature: 40°C; Detection: UV 210 nm, ELSD and MS; MS ionization mode: ESI+; Eluents: A: H ₂ 0; and B: MeCN; Flow rate: 0.8 mL/min; Gradient: 5% B to 95% B (0.0 min - 1.2 min), 95% B (1.2 min - 1.9 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 : Column: Waters Atlantis T3 OBD, 10 μιτι, 30 75 mm; Flow rate: 75 mL/min; Eluents: A: H ₂ 0 + 0.1 % HCOOH; B: MeCN + 0.1 % HCOOH; Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min). Method 2: Column: Waters XBridge C18, 10 μιη, 30x75 mm; Flow rate: 75 mL/min; Eluents: A: H ₂ 0 + 0.5% NH ₄ OH solution (25%); B: MeCN; Gradient: 90% A to 5% A (0.0 min - 4.0 min), 5% A (4.0 min - 6.0 min). Method 3: Column: Agilent Zorbax SB-AQ, 5 μιη, 30 ^χ 75 mm; Flow rate: 75 mL/min; Eluents: A: H ₂ 0 + 0.5% HCOOH; B: MeCN; 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.

Semi-preparative chiral HPLC Method D: The semi-preparative chiral HPLC is performed on a Daicel ChiralCel IB 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 ChiralCel IB 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 E: The semi-preparative chiral HPLC is performed on a Daicel ChiralCel OZ-H 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 ChiralCel OZ-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:. A mixture of the bromo derivative (0.49 mmol), the boronic acid or boronate ester derivative (0.59 mmol), K ₂ C0 ₃ (0.175 g; 1.26 mmol) and Pd(PPh ₃ ) ₄ (0.116 g; 0.1 mmol) is flushed with nitrogen for 15 min. Dioxane (2.4 mL) and water (0.71 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 MgS04 and concentrated to dryness. The residue is then purified by CC using an appropriate eluent.

PrQcedure.B; To the THP-protected hydroxamic acid derivative (0.156 mmol) in EtOH (2.6 mL) is added PPTS (0.023 g; 0.09 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.

Pr.Qcedure.C: The potassium trifluoroborate salt (0.53mmol), the halo-derivative (0.44mmol), PdCl2(dppf).DCM (0.02g; 0.02 mmol), Cs ₂ C0 ₃ (0.49 g; 1.5 mmol) are dissolved in THF (4.31 mL) and water (0.89 mL). The reaction mixture is stirred overnight under reflux. The reaction mixture is partitioned between EA (15mL) and H ₂ 0 (10mL). The evaporation residue is purified by CC using an appropriate solvent.

Procedure _. P: To a solution of the THP-protected hydroxamic acid derivative (0.11 mmol) in MeOH (0.6 mL) is added 2M HCI (0.6 mL; 1.2 mmol). The reaction mixture is stirred until completion. The reaction mixture, after neutralization with sat. NaHC0 ₃ solution, is extracted with DCM-MeOH (9-1 , 3 x 20 mL). The evaporation residue is then purified by CC (DCM-MeOH gradient) or by prep-HPLC using a suitable method.

Procedure.. E:. The boronate ester (0.6mmol), the halo-derivative (0.5mmol), PdCl2(dppf).DCM (0.037g; 0.045 mmol), Cs2C0 ₃ (0.35 g; 1.1 mmol) and silver oxide (0.18 g; 0.77 mmol) are dissolved in dioxane (1.35 mL) and water (0.02 mL). The reaction mixture is stirred for 3h under reflux. The reaction mixture is partitioned between EA (15mL) and H2O (10mL). The evaporation residue is purified by CC using an appropriate solvent.

Procedure.F: Cul (0.036 g; 0.189 mmol), PdCI ₂ (PPh ₃ ) ₂ (0.072 g; 0.102 mmol), (trimethylsilyl)ethynyl acetylene (12.1 mmol) and the halo derivative (0.581 mmol) are introduced in a two-necked round flask. The atmosphere is flushed with nitrogen during 30 min, then degassed THF (21 mL) and degassed TEA (2.5 mL; 18.1 mmol) are added. The suspension is stirred under nitrogen atmosphere at 50°C for 2 h. After concentration to dryness, the residue is then purified by CC using an appropriate solvent.

Procedure G: Vial A: A 20 mL screw-cap vial is charged with lr[dF(CF ₃ )ppy]2(dtbbpy)PF ₆ (0.01 g, 0.009 mmol), aryl bromide (0.9 mmol), alkyl bromide (1.34 mmol), Na2CC>3 (0.19 g, 1.8 mmol) and tris(trimethylsilyl)silane (0.28 mL, 0.9 mmol). The vial ias sealed, evacuated and backfilled with N2. Degassed DME (7 mL) was added to the mixture. Vial B: A separate 5 mL screw-cap vial is charged with NiCfe-glyme (0.0028 g, 0.012 mmol) and 4,4-di-tert-butyl-2,2-bipyridine (0.0034 g, 0.012 mmol). The vial is sealed, evacuated and backfilled with N2. Degassed DME (1 mL) is added and the mixture is stirred for exactly 5 min to obtain a stock solution of Ni- precatalyst. 0.36 mL of this solution is transferred via cannula into vial A.The suspension in vial A is again degassed by bubbling N2 through the mixture for 10 min. The vial is carefully sealed and irradiated with a 24 W blue LED stripe until full consumption of the starting material. The mixture was filtered and the filtrate was concentrated under reduced pressure.The residue is purified by CC or by prep-HPLC using an appropriate eluent.

PREPARATIONS:

Preparation A: (2R)-iert-Butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate:

A.i. (RS)-tert-Butyl 2-(methylsulfonyl)propanoate: To a suspension of sodium methanesulfinate (100 g; 929 mmol) in tBuOH (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 as a white yellow solid (175 g; 96% yield). 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).

AM. (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) for 1.5 h, keeping the temperature below 7°C. The mixture was stirred at 0°C for 1.5 h, allowed to reach rt and stirred 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 the temperature below 22°C. The reaction mixture was stirred for 2 h. The mixture was poured into cold water (1 L) and Et20 (1 L) and the aq. layer was extracted with Et ₂ 0 (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 as a pale yellowish oil (116.8 g; 59% yield). 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).

AM. (2RS)-tert-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 sodium azide (54.6 g; 831 mmol). The reaction was stirred at 80°C overnight. The mixture was cooled to rt and 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 as a white solid (59.6 g; 96% yield). ¹ H NMR (DMSO-cie) δ: 3.66-3.60 (m, 1 H); 3.35-3.29 (overlapped m, 1 H); 3.11 (s, 3H); 2.49-2.43 (m, 1 H); 2.04-1.96 (m, 1 H); 1.46 (s, 9H); 1.44 (s, 3H). MS (ESI, m/z): 278.95 [M+H ⁺ ] for CioHi ₉ N ₃ 04S; tR = 0.80 min.

A.iv. (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, identified as the second eluting compound, was obtained as a light orange oil (90.7 g). 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).

A. v. (2R)-tert-Butyl 4-amino-2-methyl-2-(methylsulfonyl)butanoate: A solution of intermediate A.iv (45 g; 162 mmol) in a mixture of iBuOH/EA (1/1 , 900 mL) was treated with 10% Pd/C (2.3 g). The suspension was stirred 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 which crystallized on standing (grey solid; 40.6 g; 99% yield). ¹ H NMR (DMSO-cie) <5: 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). MS (ESI, m/z): 252.03 [M+H ⁺ ] for C10H21NO4S; t _R = 0.45 min.

Preparation B: ferf-butyl ( ?)-4-(2-bromo-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl) -2-methyl-2- (methylsulfonyl)butanoate

B.i. tert-Butyl (2R)-2-methyl-2-(methylsulfonyl)-4-(6-oxo-4 -d^ To a solution of thiophenedicarboxaldehyde (1.05 g; 7.24 mmol) and the compound of Preparation A (1.89 g; 7.53 mmol) in DCM (65 mL), cooled at 0°C, was added AcOH (1.8 mL; 31.2 mmol). The reaction solution was stirred at rt for 4h. The reaction mixture was concentrated in vacuo. The residual oil was co-evaporated with cyclohexane (2 x 20 mL). The residue was purified by CC (Hept-EA-MeOH gradient) to afford the title compound as a dark solid (2.27 g; 84% yield). ¹ H NMR (DMSO-cie) δ: 7.97 (d, J = 4.8 Hz, 1 H); 7.24 (d, J = 4.8 Hz, 1 H); 4.47-4.36 (m, 2H); 3.63 (m, 1 H); 3.51 (m, 1 H); 3.12 (s, 3H); 2.43 (m, 1 H); 2.04 (m, 1 H); 1.53 (s, 3H); 1.34 (s, 9H).MS (ESI, m/z): 373.8 [M+H ⁺ ] for C16H23NO5S2; t _R = 0.76 min.

B. ii. tert-Butyl (R)-4-(2-bromo-6-oxo-4 -dihydro-5H-thieno[2,3-c^

(methylsulfonyl)butanoate: To solution of intermediate B.i (7.74 g, 20.7 mmol) in AcOH (50 mL) and water (20 mL), cooled at 0°C was added dropwise bromine (1.4 mL, 27.2 mmol), keeping the internal temperature below 5°C. The resulting solution was stirred overnight, letting the temperature settle to rt during the course of the reaction. The reaction was cooled to 0°C and additional bromine (0.44 mL, 8.56 mmol) was added. The reaction mixture was allowed to warm to rt overnight. Water (50mL) was added and the mixture was extracted with EA (2 x 75 mL). The combined extracts were washed with 10% aq. NaHS03 (50 mL), sat. aq. NaHC03 (50 mL) and brine (50 mL), dried over MgSC>4, filtered and evaporated under reduced pressure. The evaporation residue was purified by CC (Hept-EA-MeOH 9 gradient) to afford the title compound as a light brown solid (7.21g; 77% yield). ¹ H NMR (DMSO-cie) δ: 7.48 (s, 1 H); 4.46-4.37 (m, 2H); 3.60 (m, 1 H); 3.50 (m, 1 H); 3.10 (s, 3H); 2.53-2.44 (overlapped m, 1 H); 2.03 (m, 1 H); 1.51 (s, 3H); 1.35 (m, 9H). MS (ESI, m/z): 453.9 [M+H ⁺ ] for t _R = 0.83 min.

Preparation C: Potassium trifluoro((1S*,2S*)-2-(2-fluorophenyl)cyclopropyl)borate

C.i. (E)-2-(2-Fluorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborola ne: To a mixture of 2-fluorophenyl acetylene (commercial, 2 g; 16.1 mmol) and TEA (0.23 mL, 1.65 mmol) were added pinacolborane (3.6 mL; 24.1 mmol) and Cp2ZrHCI (0.45 g; 1.65 mmol). The suspension was heated at 50°C overnight. The reaction mixture was diluted with EA and filtered. The filtrate was concentrated to dryness and the evaporation residue was purified by CC (Hept.-EA gradient) to afford the title compound (3.06 g; 76% yield) as a yellow oil. ¹ H NMR (DMSO-cie) δ: 7.77 (m, 1 H); 7.38-7.44 (m, 2H); 7.22-7.26 (m, 2H); 6.25 (d, J = 18.6 Hz, 1 H); 1.26 (s, 12H).

C.ii. 2-((1R*,2R*)-2-(2-Fluorophenyl)cyclopiOpyl)-4,4,5,5-tetram (1 M in hex,

12.1 mL, 12.1 mmol) was added to DCM (20 mL) under. The solution was cooled to 0°C and a solution of TFA (0.93 mL, 12.1 mmol) in DCM (40 mL) was added drop wise over 80 min. After 45 min stirring at 0°C, a solution of CH2I2 (1 mL, 12.2 mmol) in DCM (20 mL) was added drop wise. After an additional 45 min stirring, a solution of intermediate C.i (1.5 g; 6.05 mmol) in DCM (20mL) was added dropwise over 15 min. The resulting solution was stirred overnight at rt. The reaction mixture was quenched with NH4CI (30 mL) and extracted with DCM (2 x 20 mL). The combined org. layers were washed with NaHCC>3 (1 M, 20 mL) then brine (10mL). The evaporation residue afforded the title compound (2.2 g; >95% yield) as a yellow oil. ¹ H NMR {d6- DMSO) δ: 7.19 (m, 1 H); 7.08-7.14 (m, 2H); 7.01 (td, J = 1.7, 7.8 Hz, 1 H); 2.13 (dt, J = 5.5, 8.0 Hz, 1 H); 1.20 (d, J = 2.5 Hz, 12H); 1.10 (m, 1 H); 1.05 (m, 1 H); 0.20 (m, 1 H).

C. iii. Potassium trifluoro((1S* _: 2S*)-2-(2-fluorophenyl)cyclopropyl)borate: Intermediate C.ii (1.59 g; 6.05 mmol) was dissolved in a mixture of MeOH (18 mL) and H ₂ 0 (4.5 mL). KHF ₂ (2.36g; 30.2 mmol) was added and the reaction was stirred overnight at rt. The reaction mixture was filtered, washed with MeCN. The filtrate was concentrated to dryness. The resulting solid was taken up in MeCN (20 mL) and refluxed for 15 min. The solids were filtered off. The filtrate was evaporated to afford title compound (1.1 g; 75% yield) as a white solid. ¹ H NMR (DMSO-cie) δ: 6.98-7.03 (m, 3H); 6.77 (m, 1 H); 1.68 (m, 1 H); 0.65 (td, J = 2.3, 7.4 Hz, 1 H); 0.39 (m, 1 H); -0.22 (m, 1 H). MS (ESI, m/z): 242.2 [M+K ⁺ ] for C ₉ H ₈ BF ₄ ; t _R = 0.67 min.

Preparation D: ((1 ?*,2 ?*)-2-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclopropyl)methyl benzoate

D. i. ((1R* _: 2R*)-2-(4 _: 4 _: 5 _: 5-Tetramethyl-1 _: 3 _: 2-dioxaborolan-2-yl)cyclopropyl)metanol:To a solution of iert- 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 6h. 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. ¹ H NMR (CDC ) δ: 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).

DM. ((1R*,2R*)-2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cy clopro^ benzoate: To a solution of intermediate D.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 3h30. 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. ¹ H NMR (CDCb) 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, 11.4 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 E : Potassium ((1S*,2S*)-2-((benzoyloxy)methyl)cyclopropyl)trifluoroborate

Starting from the compound of Preparation D (2.17 g; 7.18mmol) and proceeding in analogy to Preparation C, step C.iii (1.22 g) was prepared as a white solid. ¹ H NMR (acetone-cie) δ: 8.07-8.03 (m, 2H); 7.62 (m, 1 H); 7.54-7.49 (m, 2H); 4.35 (dd, J = 5.9, 1 1.1 Hz, 1 H); 3.84 (dd, J = 8.7, 1 1.0 Hz, 1 H); 1.00 (m, 1 H); 0.35 (m, 1 H); 0.1 1 (m, 1 H); -0.52 (m, 1 H).

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

To a mixture of (2R)-4-(6-bromo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2- (methylsulfonyl)butanoic acid (prepared as described in Chapoux, G. and al. WO2015132228, 5.0 g; 13.2 mmol) in DCM (90 mL) and MeOH (90 mL), cooled at 0°C, was added dropwise TMS-diazomethane (2M in hexanes, 16 mL) over 15min. The reaction mixture was stirred at rt for 4h. AcOH (2.4 mL) was added. After 30 min stirring, the solution was concentrated to dryness. The residue was co-evaporated with cyclohexane (2x50mL) to afford the title compound as a yellow solid (5.18 g; 100% yield).

¹ H NMR (DMSO-cie) δ: 7.35 (d, J = 0.8 Hz, 1 H); 6.22 (m, 1 H); 4.39 (s, 2H); 3.61 (m, 1 H); 3.51 (s, 3H); 3.47 (m, 1 H); 3.12 (s, 3H); 2.61 (m, 1 H); 2.06 (m, 1 H); 1.58 (s, 3H). MS (ESI, m/z): 395.0 [M+H ⁺ ] for Ci ₃ Hi ₇ N ₂ BrS; t _R = 0.82 min.

Preparation G: 4-((1S*,2S*)-2-(4,4,5 _! 5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)cyclopropyl)phenethyl benzoate

Starting from 2-(4-ethynylphenyl)ethanol (commercial, 1.77 g; 12.2 mmol) and proceeding successively in analogy to Preparation D, step D.ii (52% yield), Preparation, steps C.i (45% yield) and C.ii (90% yield) the title compound (1.0 g) was prepared, after final purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.96-7.98 (m, 2H); 7.66 (m, 1 H); 7.50-7.56 (m, 2H); 7.26 (d, J = 8.1 Hz, 2H); 6.96 (d, J = 8.2 Hz, 2H); 5.26 (s, 2 H); 1.46 (m, 1 H); 0.63 (td, J = 2.5, 7.3 Hz, 1 H); 0.37 (dd, J = 2.9, 7.3 Hz, 1 H); -0.27 (m, 1 H).MS2 (ESI, m/z): 393.2 [M+H ⁺ ] for C ₂ 4H ₂ 90 _a B; t _R = 1.21 min.

Preparation H: 4,4,5 _! 5-Tetramethyl-2-((1 S* _! 2S*)-2-(4-(oxetan-3-yl)phenyl)cyclopropyl)-1 _! 3,2- dioxaborolan

Hi 3-(4-lodophenyl)oxetane:Ua\ (3.63 g, 24.2 mmol) and Cul (0.39 g; 2.04 mmol) were added a solution of 3- (4-bromophenyl)oxetane, 2.16 g; 10.1 mmol) in dioxane (16.5 mL) and trans-N,N'-dimethylcyclohexane-1 ,2- diamine (0.65mL; 4.06mmol). The green reaction mixure was then heated at 125°C for 20 h. The reaction mixure was filtered over celite and the solids were washed with EA. The filtrate was evaporated under reduced pressure. The evaporation residue was purified by CC (Hex-TBME gradient) to afford the title compound (2.34 g, 89% yield) as bright white neediest NMR (CDCb) δ: 7.72 (d, J = 8.4 Hz, 2H); 7.18 (d, J = 8.1 Hz, 2H); 5.09 (dd, J = 6.1 , 8.4 Hz, 2H); 4.74 (t, J = 6.4 Hz, 2H); 4.19 (m, 1 H).Hi. Trimethyl((4-(oxetan- 3-yl)phenyl)ethynyl)silane:Siartinq from intermediate H.i (2.33 g; 8.96 mmol), and proceeding in analogy to Procedure F (97% yield), the title conpound (2.0 g) was obtained after purification by CC (Hept-EA gradient) as a dark yellow oil. ¹ H NMR (CDC ) δ: 7.49 (d, J = 8.3 Hz, 2H); 7.35 (d, J = 8.1 Hz, 2H); 5.09 (dd, J = 6.1 , 8.4 Hz, 2H); 4.78-4.74 (m, 2H); 4.23 (m, 1 H); 0.27 (s, 9H).

H.iii. 3-(4-Ethynylphenyl)oxetane:To a solution of intermediate H.ii (2.01 g; 8.71 mmol) in MeOH (28 mL) was added K2CO3 (1.56 g; 1 1.3 mmol). The reaction mixture was stirred at rt for 2h. DCM (120 mL) and water (50 mL) were added. The two layers were separated and the aq. layer was extracted with DCM-MeOH (9-1 , 2 x 80 mL).The evaporation residue afforded the title compound (1.38g, >95% yield) as a brown oil which cristallized on standing. ¹ H NMR (CDCb) δ: 7.54-7.51 (m, 2H); 7.38 (d, J = 8.1 Hz, 2H); 5.10 (dd, J = 6.1 , 8.4 Hz, 2H); 4.79-4.75 (m, 2H); 4.25 (m, 1 H); 3.10 (s, 1 H).

H.iv. 4A5,5-Tetramethyl-2-((1S*,2S*)-2-(4-(oxetan-3-yl)phenyl)cy ^ Starting from intermediate H.ii (1.37 g; 8.66 mmol), and proceeding in analogy to Preparation C, steps C.i (42% yield) and C.ii (58% yield), the title compound (0.287 g) was obtained after purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.27 (d, J = 8.1 Hz, 2H); 7.09 (d, J = 8.2 Hz, 2H); 4.91 (dd, J = 5.9 Hz, 8.4 Hz, 2H); 4.54-4.59 (m, 2H); 4.19 (m, 1 H); 1.99 (m, 1 H); 1.19 (d, J = 5.3 Hz, 12H); 0.99-1.04 (m, 2H); 0.15 (m, 1 H).

Preparation I : Potassium ((1 S,2S)-2-(4-((benzoyloxy)methyl)phenyl)cyclopropyl)trifluorob orateStarting from 2-(4-ethynylphenyl)metanol (commercial, 2.1 g; 15.9 mmol) and proceeding successively in analogy to Preparation D, step D.ii (>95% yield), Preparation, steps C.i (56% yield), C.ii (59% yield) and C.iii (65% yield), the title compound (0.207 g) was prepared, after final purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.91 -7.93 (m, 2H); 7.66 (m, 1 H); 7.53 (t, J = 7.9 Hz, 2H); 7.19 (d, J = 8.1 Hz, 2H); 7.03 (d, J = 8.1 Hz, 2H); 4.44 (t, J = 6.7 Hz, 2H); 2.98 (t, J = 6.7 Hz, 2H); 1.97 (m, 1 H); 1.18 (d, J = 5.2 Hz, 12H); 1.02-0.96 (m, 2H); 0.14 (m, 1 H). Preparation J: 4,4,5,5-tetramethyl-2-((1 S,2S)-2-(4-((((2 ?S)-tetrahydro-2H-pyran-2- yl)oxy)methyl)phenyl)cyclopropyl)-1 ,3,2-dioxaborolane

J.i. (4-((1S,2S)-2-(4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)phe Starting from (4- ethynylphenyl)methanol (2.0 g; 14.7 mmol) and proceeding successively in analogy to Preparation C, steps C.i (49% yield) and C.ii (75% yield), the title compound (1.2 g) was prepared, after purification by CC (Hept- EA gradient) as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.18 (m, 2H); 7.03 (d, J = 8.1 Hz, 2H); 5.08 (t, J = 5.7 Hz, 1 H); 4.43 (d, J = 5.7 Hz, 2H); 1.96-1.99 (m, 1 H); 1.19 (d, J = 5.1 Hz, 12H); 0.97-1.03 (m, 2H); 0.15 (m, 1 H).

J.ii. 4AA5-Tetramethyl-2-((1S,2S)-2-(4-((((2RS)4etrahydro-2H^

1,3,2-dioxaborolane: To a solution of intermediate J.i (0.5 g; 1.82 mmol) in DCM (5 mL) were added PPTS

(0.045 g; 0.182 mmol) and 3 ,4-d i hyd ro-2 - -py ra n (0.41 mL; 4.4 mmol). The reaction was stirred at rt overnight.

The reaction mixture was evaporated and the residue was partitioned between water (25 mL) and diethyl ether (50 mL). The evaporation residue was purified by CC (Hept-EA gradient) to afford the title compound

(0.57 g; 87% yield), as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.18-7.21 (m, 2H); 7.07 (d, J = 8.1 Hz, 2H); 4.64 (t, J = 3.2 Hz, 1 H); 4.61 (d, J = 1 1.9 Hz, 1 H); 4.39 (d, J = 11.9 Hz, 1 H); 3.76-3.80 (m, 1 H); 3.44-3.48 (m, 1 H);

1.97-2.01 (m, 1 H); 1.70-1.75 (m, 1 H); 1.60-1.66 (m, 1 H); 1.43-1.53 (m, 4H); 1.19 (d, J = 5.2 Hz, 12H); 0.99-

1.05 (m, 2H); 0.16 (m, 1 H).

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

Starting from (2R)-4-(6-iodo-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid (prepared as described in Chapoux, G. and al. WO2015132228, 3.8 g; 9.09 mmol) as proceeding in analogy to Preparation F (>95% yield), the title compound (4.15 g) was prepared 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): 441.0 [M+H ⁺ ] for Ci ₃ Hi ₇ N ₂ IS; t _R = 0.85 min.

Preparation L: 4,4,5,5-tetramethyl-2-((1 S*,2S*)-2-(thiophen-2-yl)cyclopropyl)-1 ,3,2-dioxaborolane

Starting from 2-ethynylthiophene (commercial, 0.42 g; 3.9 mmol) and proceeding successively in analogy to Preparation C, steps C.i and C.ii (86% yield, two steps), the title compound (0.63 g) was prepared, after purification by CC (Hept-EA gradient) as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.02 (dd, J = 1.1 , 5.1 Hz, 1 H); 6.86 (dd, J = 3.5, 5.1 Hz, 1 H); 6.78 (d, J = 3.4 Hz, 1 H); 2.31 (m, 1 H); 1.24 (s, 6H); 1.23 (s, 6H); 1.17 (m, 1 H); 1.02 (m, 1 H); 0.34 (ddd, J = 5.6, 6.8, 9.9 Hz, 1 H). MS2 (ESI, m/z): 251.1 [M+H ⁺ ] for C13H19O2BS; t _R = 1.06 min. Preparation M: ferf-Butyl 4-(((1-phenyl-1 H-tetrazol-5-yl)sulfonyl)methyl)piperidine-1-carboxylate

Ml tert-Butyl 4-(((1-phenyl-1H-tetrazol-5-yl)thio)methyl)piperidine-1-^^^ To a solution of phenyltetrazole thiol (1.83 g; "lOmmol) in EtOH (28 mL) was added KOH (0.681 g; 12.1 mmol). The reaction mixture was heated at 80°C for 2h. A solution of iert-butyl 4-(iodomethyl)piperidine-1 -carboxylate (3.06 g; 9.41 mmol) in EtOH (5 mL) was added. The reaction proceeded overnight. Water (5m L) was added. The white precipitate that formed was filtered and thoroughly washed with water and dried to a constant weight to afford the title compound was obtained as a white solid (3.27 g, 93% yield). ¹ H NMR (DMSO-cie) δ: 7.60-7.53 (m, 5H); 4.174.09 (m, 2H); 3.36-3.33 (m, 2H); 2.72-2.67 (m, 2H); 1.96 (m, 1 H); 1.89-1.83 (m, 2H); 1.45 (s, 9H); 1.21 (qd, J = 4.5, 12.3 Hz, 2H). MS2 (ESI, m/z): 376.1 [M+H ⁺ ] for C18H25N5O2S; t _R = 1.06 min.

Ml tert-Butyl 4-fff^pheny/-W-ieirazo/-5-y/Jsu/fony/Jme /Jp/ er/ ^' ci/ne- ^' /-cari)oxy/aie ylate: To a suspension of intermediate M.i (3.27 g; 8.72 mmol) in EtOH (60 mL) was added ammonium molybdate (2.19 g; 1.75mmol) and H2O2 (35% aq., 1.5 mL; 17.4 mmol). The reaction mixture was stirred at 65°C for 3h. The reaction mixture was stirred at 65°C for 5h. After cooling to rt, water (50 mL) was added and the volatiles were removed in vacuo. The solid that formed was filtered off, washed with water and dried to a constant weight to afford the title sulfone as a greenish solid (3.57g, 100% yield). ¹ H NMR (DMSO-cie) δ: 7.71 -7.67 (m, 2H); 7.66-7.59 (m, 3H); 4.20-4.00 (m, 2H); 3.72 (d, J = 6.3 Hz, 2H); 2.80-2.69 (m, 2H); 2.34 (m, 1 H); 1.96-1.91 (m, 2H); 1.45 (s, 9H); 1.42-1.32 (m, 2H). MS2 (ESI, m/z): 408.1 [M+H ⁺ ] for C18H25N5O4S; t _R = 1.04 min.

Preparation N: (3-Bromocyclobutyl)benzene

To a solution of 3-phenylcyclobutan-1-ol (commercial, 3.940 g; 26.6 mmol) in DCM (200 mL) was added PP i3 on polymer (loading 3mmol/g, 17.73 g) and CB^ (17.631 g; 53.2 mmol). The mixture was stirred at rt for 16h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography using hexane as an eluent to afford the title compound ( 2.30 g, 40 % yield) as a colorless oil. ¹ H NMR (CDCb) δ: 7.37-7.34 (m, 2 H), 7.26-7.23 (m, 3 H), 4.70 (m, 1 H), 4.04 (quint, J = 8.2 Hz, 1 H), 2.89- 2.86 (m, 4 H).

Preparation O: ((3-Bromocyclobutyl)methoxy)(tert-butyl)diphenylsilane

Starting from 3-(((iert-butyldiphenylsilyl)oxy)methyl)cyclobutan-1-ol (5 g; 14.7 mmol) and proceeding in analogy to Preparation N, the title compound (2.3 g, 39% yield) was obtained, after purification by CC (hexane) as a colorless oil. ¹ H NMR (CDCb) δ: 7.67 (d, J = 6.6 Hz, 4 H), 7.39-7.46 (m, 6 H), 4.60 (m, 1 H), 3.66 (d, J = 5.5 Hz, 2 H), 2.77 (m, 1 H), 2.67-2.55 (m, 4 H), 1.09 (s, 9 H).

Preparation P: 4-(3-Bromocyclobutyl)phenethyl benzoate

PI (3-Bromocyclobutoxy)(tert-butyl)diphenylsilane: To a solution of 3-bromocyclobutan-1 -ol (3.750 g, 24.8 mmol) in DCM (70 mL) was added imidazole (2.029 g, 29.8 mmol), TBDPS-CI (7.75 mL; 29.8 mmol) and DMAP (0.303 g, 2.48 mmol) The reaction proceeded at rt for 16h. Water ( 20 mL) was added and the two layers were separated . The evaporation residue was purified by CC ( EA-Hept gradient) to afford the title compound as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.64-7.55 (m, 4 H), 7.50-7.41 (m, 6 H), 4.18-3.99 (m, 2 H), 2.93-2.83 ( m, 2 H), 2.48-2.39 (m, 2 H), 0.98 (m, 9H).

P.ii. 4-(3-((tert-Butyldiphenylsilyl)oxy)cyclobutyl)phenethyl benzoate: Starting from 4-bromophenethyl benzoate (prepared as described by Ritter, T. and al. in WO2014/052622, 0.915 g, 3 mmol) and intermediate P.i (1.75 g; 4.5 mmol), and proceeding in analogy to Procedure G, the title compound (3.4 g, 71 % yield) was obtained, after purification by CC using an EA-Hept gradient, as a colorless oil. MS2 (ESI, m/z): 534.7 [M+H ⁺ ] for C35H38O3S1; t _R = 1.41 min.

P.iii. 4-(3-Hydroxycyclobutyl)phenethyl benzoate: To a solution of intermediate P.ii (3.67 g; 6.8 mmol) in THF (17 mL) was added TBAF (1 M in THF, 28 mL). The reaction mixture was stirred at rt for 2h. Water (15 mL) was added (15 mL) and the volatiles were removed in vacuo. The residue was extracted with EA (3x50 mL). the evaporation residue was purified by CC (EA-Hept) to afford the title compound (1.60 g, 80 % yield) as a white solid. ¹ H NMR (DMSO-cie) δ: 7.27-7.24 (m, 2 H), 7.94-7.92 (m, 2 H), 7.66 (m, 1 H), 7.54-7.49 (m, 2 H), 7.19 (m, 2 H), 5.06 (m, 1 H), 4.494.41 (m, 2 H), 4.28-4.32 (m, 0.5 H), 4.00 (m, 0.5 H), 3.40-3.48 (m, 0.5 H), 3.02-2.96 (m, 2 H), 2.82 (m, 0.5 H), 2.57 (m, 1 H), 2.30-2.25 (m, 2 H), 1.85 (m, 1 H). MS2 (ESI, m/z): 297.1 [M+H ⁺ ] for C19H20O3; t _R = 0.98 min.

P.iv. 4-(3-((Methylsulfonyl)oxy)cyclobutyl)phenethyl benzoate: To an ice-chilled solution of intermediate P.iii. (1.09 g; 3.68 mmol) in DCM (7.2 mL) was added TEA (0.614 mL; 4.41 mmol) and MsCI (0.313 mL; 4.05 mmol). The reaction proceeded at 0°C for 30 min. Water (5 mL) was added and the 2 layers were separated. The evaporation residue was purified by CC (EA-Hept gradient) to afford the title compound (0.344g, >95% yield) as a white solid. MS2 (ESI, m/z): 297.1 [M+H ⁺ ] for C19H20O3; t _R = 0.98 min.

P.v 4-(3-bromocyclobutyl)phenethyl benzoate: A mixture of intermediate P.iv. (1.130 g; 3.02 mmol) and lithium bromide (0.39 g; 4.5 mmol) in DMF (20 mL) was stirred at 90°c for 16h. The reaction minxture was partitioned between water (1 mL)and diethyl ether (5 mL). The evaporation residue was purified by CC (EA-Hept gradient) to afford the title compound (0.614 g; 56% yield) as a white solid. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 7.94-7.92 (m, 2H), 7.66 (m, 1 H), 7.53 (t, J = 7.8 Hz, 2H), 7.29-7.19 (m, 4H), 4.774.83 (m, 0.5H), 4.65 (m, 0.5H), 4.46 (t, J = 6.7 Hz, 2H), 3.92 (m, 0.5 H), 3.34 (m, 0.5H), 3.06-2.99 (m, 3H), 2.78-2.71 (m, 2H), 2.50 overlaid m, 1 H).

Preparation Q: (1S)-1-(4-(3-Bromocyclobutyl)phenyl)ethane-1 ,2-diyl dibenzoate

Q.i. (S)-1-(4-Bromophenyl)ethane-1 _: 2-diyl dibenzoate: To a solution of (1 S)-1-(4-bromophenyl)ethane-1 ,2-diol (commercial, 4.8 g; 22.1 mmol) in DCM (60 mL) were added TEA (12.3 mL; 88.5 mmol) and benzoyl chloride (7.7 mL; 66.3 mmol). The reaction proceeded overnight at rt. The reaction mixture was concentrated to dryness and the residue was directly subjected to CC (EA-Hept gradient) to afford the title compound (9.0 g; 96% yield) as a colorless oil. ¹ H NMR (CDCI3) δ: 8.21 -8.18 (m, 1 H); 8.17-8.14 (m, 1 H); 8.12-8.09 (m, 1 H); 8.02-7.99 (m, 1 H); 7.73-7.68 (m, 1 H); 7.62-7.68 (m, 5H); 7.49-7.41 (m, 4H); 6.37 (dd, J = 3.9, 7.8 Hz, 1 H), 4.74 (dd, J= 7.8, 1 1.9 Hz, 1 H), 4.67 (dd, J= 3.9, 1 1.9 Hz, 1 H).

Q i.(1S)-1-(4-(3-((tert-Butyldiphenylsilyl)oxy)cyclobutyl)phen yl)eth^ dibenzoate: Starting from intermediate Q.i (1.27 g, 3 mmol) and intermediate P.i (1.75 g; 4.5 mmol), and proceeding in analogy to Procedure G (4 more repetitions), the title compound (6.0 g, 61 % yield) was obtained, after purification of all pooled batches by CC using an EA-Hept gradient, as a yellowish oil (86% purity). MS2 (ESI, m/z): 534.1 [M+H ⁺ -C ₇ H ₅ 0] for C42H42O5S1; t _R = 1.41 min.

Q.iii. (1S)-1-(4-(3-Bromocyclobutyl)phenyl)ethane-1,2-diyl dibenzoate: Starting from intermediate Q.ii (6.0 g, 9.16 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (65% yield), P.iv (98% yield) and P.v (69% yield), the title compound (1.90 g) was obtained, after purification by CC using an EA-Hept gradient, as a yellowish oil (86% purity). ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 8.04-8.02 (m, 2 H), 7.92-7.90 (m, 2 H), 7.70-7.68 (m, 2 H), 7.56-7.50 (m, 6 H), 7.39-7.29 (m, 2 H), 6.36 (dd, J = 3.5, 7.7 Hz, 1 H), 4.83-4.63 (m, 3 H), 3.38 (m, 1.5 H), 3.02 (m, 1.5 H), 2.80 (m, 1 H), 2.50 (overlapped m, 1 H). MS2 (ESI, m/z): 359.0 [M+H ⁺ -C ₇ H ₅ 0] for C ₂ 6H ₂ 30 ₄ Br; t _R = 1.22 min.

Preparation R: (1-(4-(3-Bromocyclobutyl)phenyl)cyclopropyl)methyl benzoate

R.i.(1-(4-Bromophenyl)cyclopropyl)methyl benzoate: Starting from (1-(4-bromophenyl)cyclopropyl)metanol (4.92 g; 21.7 mmol) and proceeding in analogy to Preparation Q, step Q.i, the title compound (6.18 g; 86% yield), was obtained, after purification by CC using an EA-Hept gradient, as a white solid. ¹ H NMR (DMSO-de) δ: 7.91 -7.89 (m, 2 H), 7.65 (m, 1 H), 7.54-7.48 (m, 4 H), 7.36-7.32 (m, 2 H), 4.41 (s, 2 H), 1.09-1.05 (m, 2 H), 0.97-0.95 (m, 2 H).

R.H. (^( -(3-((ίert-buί / hen /s/7 /Jo Jc c/obuί /J hen /Jc c/o ro /Jme / benzoate: Starting from intermediate R.i (1 g, 3 mmol) and intermediate P.i (1.75 g; 4.5 mmol), and proceeding in analogy to Procedure G (repeated 5 more times), the title compound (6.68 g, 65% yield) was obtained, after purification of all pooled batches by CC using an EA-Hept gradient, as a colorless oil. MS2 (ESI, m/z): 439.1 [M+H ⁺ - C7H5O] for C37H40O3S1; t _R = 1.41 min.

R.iii. (1-(4-(3-Bromocyclobutyl)phenyl)cyclopropyl)methyl benzoate: Starting from intermediate R.ii (6.66 g, 11.9 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (78% yield), P.iv (92% yield) and P.v (76% yield), the title compound (3.14 g, 69% yield) was obtained, after purification by CC using an EA-Hept gradient, as a yellowish oil. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 8.04-8.02 (m, 2 H), 7.92-7.90 (m, 2 H), 7.70-7.68 (m, 2 H), 7.56-7.50 (m, 6 H), 7.39-7.29 (m, 2 H), 6.36 (dd, J = 3.5, 7.7 Hz, 1 H), 4.83-4.63 (m, 3 H), 3.38 (m, 1.5 H), 3.02 (m, 1.5 H), 2.80 (m, 1 H), 2.50 (overlapped m, 1 H). MS2 (ESI, m/z): 339.9 [M+H ⁺ ] for C ₂ i H ₂ i0 ₂ Br; t _R = 1.20 min.

Preparation S: 4-(3-Bromocyclobutyl)benzyl benzoate

S.i. 4-Bromobenzyl benzoate: Starting from 4-bromobenzyl alcohol (2 g; 10.7 mmol) and proceeding in analogy to Preparation Q, step Q.i, the title compound (2.79 g; 90% yield), was obtained, after purification by CC using an EA-Hept gradient, as a white solid. ¹ H NMR (DMSO-cie) δ: 8.10-8.07 (m, 2H); 7.59 (m, 1 H); 7.56- 7.52 (m, 2H); 7.48-7.45 (m, 2H); 7.37-7.33 (m, 2H); 5.33 (s, 2H).

S.ii. (^( -(3-((ίert-βuί / hen /s/7 /Jo Jc c/obuί /J hen /Jc c/o ro /Jme / benzoate: Starting from intermediate S.i (0.87 g, 3 mmol) and intermediate P.i (1.75 g; 4.5 mmol), and proceeding in analogy to Procedure G (repeated 6 more times), the title compound (7.48 g, 68% yield) was obtained, after purification of all pooled batches by CC using an EA-Hept gradient, as a colorless oil. MS2 (ESI, m/z): 400.1 [M+H ⁺ - C7H5O2] for C34H36O3S1; t _R = 1.39 min.

S.iii. 4-(3-Bromocyclobutyl)benzyl benzoate: Starting from intermediate S.ii (7.48 g, 14.4 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (76% yield), P.iv (87% yield) and P.v (73% yield), the title compound (2.33 g) was obtained, after purification by CC using an EA-Hept gradient, as a colorless oil. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 8.00-7.98 (m, 2H); 7.67 (m, 1 H); 7.56-7.52 (m, 2H); 7.45-7.42 (m, 2H); 7.34 (d, J = 8.0 Hz, 0.5H); 7.29 (d, J = 8.0 Hz, 1.5H); 5.33 (s, 2H); 4.67 (m, 0.5H); 3.39 (m, 0.5H); 3.07-3.01 (m, 2H), 2.82 (m, 1 H); 2.55-2.46 (overlapped m, 2H). MS2 (ESI, m/z): 225.2 [M+H ⁺ ] for C ₂ iH ₂ i0 ₂ Br; t _R = 1.20 min.

Preparation T: Benzyl (1-(4-(3-bromocyclobutyl)phenyl)cyclopropyl)carbamate

T.i. Benzyl (^( -(3-((ίert-buίy/ heny/s/7y/Jo yJcyc/obuίy/J heny/Jcyc/o ro y/Jcarbamaίe.· Starting from benzyl (1-(4-bromophenyl)cyclopropyl)carbamate (1 g, 3 mmol) and intermediate P.i (1.75 g; 4.5 mmol), and proceeding in analogy to Procedure G (repeated 5 more times), the title compound (6.94 g, 67% yield) was obtained, after purification of all pooled batches by CC using an EA-Hept gradient, as a yellowish oil of about 90% purity. MS2 (ESI, m/z): 576.3 [M+H ⁺ ] for C37H41 NO3S1; t _R = 1.35 min.

T.ii. Benzyl (1-(4-(3-bromocyclobutyl)phenyl)cyclopropyl)carbamate: Starting from intermediate T.i (6.94 g, 10.5 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (92% yield), P.iv (93% yield) and P.v (65% yield), the title compound (2.95 g) was obtained, after purification by CC using an EA-Hept gradient, as a white solid. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 8.15 (s, 1 H), 7.40-7.10 (m, 9H), 5.00 (s, 2H), 4.80 (s, 0.3 H), 4.65 (m, 0.7 H), 3.33 (overlapped m, 1 H), 3.0 (m, 1.4 H), 2.75-2.79 (m, 0.6 H), 2.49-2.45 (overlapped m, 2 H), 1.15-1.12 (m, 4 H). MS2 (ESI, m/z): 414.0 [M+H ⁺ ] for C ₂ iH ₂₂ N0 ₂ Br; tR = 1.11 min. Preparation U: 3-(4-(3-Bromocyclobutyl)phenyl)oxetane

ill tert-Butyl(3-(4-(oxetan-3-yl)phenyl)cyclobutoxy)diphenylsila ne: Starting from 3-(4-bromophenyl)oxetane (0.78 g, 3.66 mmol) and intermediate P.i (2.14 g; 5.49 mmol), and proceeding in analogy to Procedure G (repeated 3 more times), the title compound (combined yield 4.61 g, 60% yield) was obtained, after purification of all pooled batches by CC using an EA-Hept gradient, as a colorless oil. MS2 (ESI, m/z): 443.3 [M+H ⁺ ] for C29H34O2S1; t _R = 1.35 min.

U.ii. 3-(4-(3-Bromocyclobutyl)phenyl)oxetane: Starting from intermediate U.i (4.61 g, 10.4 mmol) and proceeding successively in analogy to Preparation P, steps P.iii (81 % yield), P.iv (92% yield) and P.v (65% yield), the title compound (1.35 g) was obtained, after purification by CC using an EA-Hept gradient, as a white solid. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 7.39 (d, J = 8.1 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 5.09 (dd, J = 6.0, 8.4 Hz, 2 H), 4.79 (t, J = 6.2 Hz, 2 H), 4.66 ( m, 0.22 H), 4.51 (m, 0.78 H), 4.24 (m, 1 H), 4.03 (m, 0.22 H), 3.37 (m, 0.78 H), 3.12-3.04 (m,1.56 H), 2.85-2.89 (m, 0.78 H), 2.62-2.69 (m,1.56 H).

Preparation V: 3-((1s*,3r*)-3-Bromocyclobutyl)propyl benzoate

V.i. Ethyl (E)-3-((1s _: 3s)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)acrylat e: To an ice-chilled suspension of NaH (60% in mineral oil, 0.578 g; 14.4 mmol) in -DME (40 mL), was added triethylphosphonoacetate (2.92 mL; 14.4 mmol). The reaction mixture was stirred for 30 min at rt and (1 s*,3s*)-3-((iert- butyldiphenylsilyl)oxy)cyclobutane-1-carbaldehyde (prepared as described by Fu, J. and al. in WO2015/0664134, 4.6 g; 13.6 mmol) was added. The reaction proceeded at 0°C for 30 min. The reaction mixture was partitioned between water (50 mL) and Et20 (100 mL). The aq. layer was extracted once with Et20 (100 mL). The evaporation residue was purified by CC (EA-Hept gradient) to afford the title compound (4.86 g, 86% yield) as a colorless oil. MS2 (ESI, m/z): 409.2 [M+H ⁺ ] for C ₂ 5H ₃ 20 ₃ Si; t _R = 1.31 min.

V.ii. Ethyl 3-((1s* _: 3r*)-3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)propan oate: To a solution of intermediate V.i (4.8 g; 11.7 mmol) in EtOH (50 mL) under inert atmosphere was added 10% Pd/C (0.5 g). The reaction was stirred at rt under hydrogen atmosphere for 1 h. The catalyst was removed by filtration and the filtrate was concentrated to dryness to afford the title crude product (4.8 g; >95% yield) as a colorless oil. MS2 (ESI, m/z): 41 1.2 [M+H ⁺ ] for C ₂ 5H ₃ 40 ₃ Si; t _R = 1.29 min.

V.iii. 3-((1s* _: 3r*)-3-((tert-Butyldiphenylsilyl)oxy)cyclobutyl)propan -1-ol: To an ice-chilled solution of intermediate V.ii (4.8 g, 9.74 mmol) in THF (50 mL) was slowly added a LiAIH ₄ solution (2M in THF) (4.9 mL; 9.74 mmol). The reaction was allowed to warm to rt over 30 min. After cooling to 0°C, water (1 mL), EA (100 mL) and 1 M NaOH (2 mL) were carefully added and the reaction mixture was stirred for 5 min. MgSC>4 (25 g) was added and the suspension was filtered. The filtrate was concentrated to get the crude title product (4.3 g; >95% yield) as a colorless oil. MS2 (ESI, m/z): 369.1 [M+H ⁺ ] for C ₂ 2H ₃₂ 0 ₂ Si; t _R = 1.24 min.

V.iv. 3-((1s*,3r*)-3-Bromocyclobutyl)propyl benzoate: Starting from intermediate V.iii (4.61 g, 10.4 mmol) and proceeding successively in analogy to Preparation Q, step Q.i, (76% yield), Preparation P, steps P.iii (80% yield), P.iv (86% yield) and P.v (62% yield), the title compound (1.09 g) was obtained, after purification by CC using an EA-Hept gradient, as a white solid. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 7.98-7.96 (m, 2 H), 7.67 (t, J = 7.4 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 2 H), 4.74 (t, J = 6.7 Hz, 0.3 H), 4.51 (m, 0.7 H), 4.26-4.22 (m, 2 H), 2.78-2.73 (m, 1.4 H), 2.62-2.57 (m, 0.3 H), 2.50 (overlapped m, 0.6 H) 2.38 (m, 0.6 H), 2.14 (m,0.7 H), 2.06 (m, 1.4 H), 1.67-1.56 (m, 4 H)

Preparation W: 4-((1s,3r)-3-Bromocyclobutyl)butyl benzoate

W.i. 4-(3-Oxocyclobutyl)butyl benzoate:To a stirred solution of DMA (0.267 mL, 2.87 mmol) in DCE (12 mL) cooled at -15°C, was added trifluoromethanesulfonic anhydride (0.584 mL, 3.47 mmol). A solution of hex-5- en-1-yl benzoate (prepared as described in Schleicher, K.D. Org. Lett. 2007, 9, 875-878, 1.173 g, 5.74 mmol) in 2,4,6-collidine (0.459 mL, 3.46 mmol) and DCE (3 mL) was added drop wise over a 20 min period. The resulting mixture was microwaved at 130°C for 3h. After three more repetitions, all batches were pooled and diluted with water (50 mL). the resulting mixture was stirred at 80°C overnight. After cooling, DCM (20 mL) was added. The aq. layer was extracted once with DCM (20 mL). The evaporation residue was purified by CC (DCM-Hept gradient) to afford the title compound (1.90 g; 67% yield) as a yellowish solid. MS2 (ESI, m/z): 247.2 [M+H ⁺ ] for Ci ₅ Hi ₈ 0 ₂ ; t _R = 0.97 min.

W.ii. 4-(3-Hydroxycyclobutyl)butyl benzoate: To a solution of intermediate W.i (2 g, 8.12 mmol) in THF (20 mL) was added NaBH4 (0.614 g, 16.2 mmol) . After stirring 15 min at rt , water (0.1 mL) was added. The reaction proceeded at the temperature for 1 h. The reaction mixture was partitioned between Et20 (50 mL) and water (5 mL). The two layers were separated and the ethereal layer was dried over MgSC The evaporation residue was purified by CC(EA-Hept gradient) to afford the title compound (1.55 g; 77 % yield) as a yellowish oil. MS2 (ESI, m/z): 249.2 [M+H ⁺ ] for Ci ₅ H ₂ o0 ₂ ; t _R = 0.94 min.

W.iii. 4-((1s,3r)-3-Bromocyclobutyl)butyl benzoate: Starting from intermediate W.ii (1.55 g, 6.24 mmol) and proceeding successively in analogy to Preparation P, steps P.iv (93% yield) and P.v (44% yield), the title compound (0.8 g) was obtained, after purification by CC using an EA-Hept gradient, as a colorless oil. ¹ H NMR (DMSO-cie) mixture of diastereomers δ: 7.99-7.95 (m, 2H), 7.66 (m, 1 H), 7.57-7.52 (m, 2H), 4.73 (m, 0.26 H), 4.449 (m, 0.74 H), 4.304.23 (m, 2H), 2.76-2.70 (m, 1.48H), 2.44-2.51 (overlapped m, 0.52H), 2.36 (m, 0.74 H), 2.20-1.96 (m, 2.26H), 1.72-1.63 (m, 2H), 1.53-1.48 (m, 2H), 1.35-1.27 (m, 2H).

EXAMPLES OF COMPOUNDS ACCORDING TO THE INVENTION:

Example 1 and Example 2: (2/?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1 S,2S)-2- phenylcyclopropyl)-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)b utanamide and (2/?)-A/-hydroxy-2-methyl- 2-(methylsulfonyl)-4-(6-oxo-2-((1 /?,2/?)-2-phenylcyclopropyl)-4,6-dihydro-5H-thieno[2,3-c]pyr rol-5- yl)butanamide:

1/21 tert-Butyl (R)-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1 S*, 2S*)-2-phenylcyclopropyl)-4, 6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)butanoate Starting from the compound of Preparation B (0.221 g; 0.49 mmol) and irans-2-phenylcyclopropylboronic acid pinacol ester (commercial, 0.145 g; 0.59 mmol), and proceeding in analogy to Procedure A, the title compound was obtained, after purification by CC (Hept-EA-MeOH gradient), as a yellow foam (0.214 g; 89% yield). MS (ESI, m/z): 490.1 [M+H ⁺ ] for C25H31 NO5S2; t _R = 0.94 min.

1/2.H. (R)-2-Methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1S^2S*)^hen

c]pyrrol-5-yl)butanoic acid: To a mixture of intermediate 1/2.i (0.202 g; 0.41 mmol) in 4N HCI in dioxane (3.8 mL) was added H2O (0.104 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated to dryness then co-evaporated with diethyl ether (2 x 10 mL) to give the title acid as a yellow gum (0.177 g, 99% yield). MS (ESI, m/z): 434.0 [M+H ⁺ ] for C21 H23NO5S2; t _R = 0.79 min.

1/2.HL (2R)-2-Methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1*,2S*)^

c]pyrrol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamid e: To a solution of intermediate M2.W (0.177 g; 0.41 mmol) in DMF (2 mL) were added successively HOBT (0.123 g, 0.88 mmol), TEA (0.171 mL, 1.23 mmol), THPONH2 (0.195 g; 1.58 mmol) and EDC.HCI (0.172 g, 0.86 mmol). The reaction mixture was stirred at rt for 24h.The reaction mixture was partitioned between water (10 mL) and EA (20 mL). The org. layer was washed with aq. 15% aq. NaHSC>4 (10mL), sat. NaHCC>3 (10 mL) and brine (10 mL). The org. layer was dried over MgSC>4, filtered and concentrated to dryness.The evaporation residue was purified by CC using (Hept-EA-MeOH gradient) to afford the title compound as a yellow foam (0.083g, 38% yield). ¹ H NMR (DMSO-c¼) δ: (mixture of diasteroisomers) 1 1.36 (s, 0.5H); 1 1.32 (s, 0.5H); 7.31-7.28 (m, 2H); 7.20-7.17 (m, 3H); 7.05 (m, 1 H); 4.87 (m, 0.5H); 4.57 (m, 0.5H); 4.41-4.30 (m, 2H); 4.03 (m, 0.5H); 3.96 (m, 0.5H); 3.60-3.48 (m, 2H); 3.46-3.35 (m, 2H); 3.06 (s, 1.5H); 3.03 (s, 1.5H); 2.65-2.47 (overlapped m, 1 H); 2.30 (m, 1 H); 1.95 (m, 1 H); 1.65-1.59 (m, 3H); 1.56 (s, 1.5H); 1.54 (s, 1.5H); 1.54-1.44 (m, 5H). MS (ESI, m/z): 533.1 [M+H ⁺ ] for C26H32N2O6S2; t _R = 0.86 min.

1/2.IV. (2R)-M-Hydroxy-2-methyl-2-(methylsulfonyl)4-(6-oxo

5H-thieno[2,3-c]pyrrol-5-yl)butanamide: Starting from intermediate 1/2.iii (0.083 g; 0.16 mmol), and proceeding in analogy Procedure B, the title compound was obtained, after purification by prep-HPLC (Method 1 ), as a yellow solid (0.05 g; 71 % yield). ¹ H NMR (DMSO-cie) δ: 10.94 (s, 1 H); 9.18 (s, 1 H); 7.31 -7.27 (m, 2H); 7.20-7.17 (m, 3H); 7.04 (s, 1 H); 4.424.31 (m, 2H); 3.54 (m, 1 H); 3.41-3.30 (overlapped m, 1 H); 3.06 (s, 3H); 2.59-2.46 (overlapped m, 2H); 2.31 (m, 1 H); 1.94 (m, 1 H); 1.61 (m, 1 H); 1.52 (s, 3H); 1.54-1.49 (overlapped m, 1 H). MS (ESI, m/z): 449.0 [M+H ⁺ ] for C21H24N2O5S2; t _R = 0.75 min.

1/2.V. (2R)-N ydroxy-2-methyl-2-(methylsulfonyl)-4-(6-oxo-2-((1^

thieno[2,3-c]pyrrol-5-yl)butanamide and (RJ-W-hyciroxy-2-meihy/-2-(meihy/su/fony/J-4-(6-oxo-2-((iR _; 2RJ-2- pheny/cyc/opropy/J-4,6-d/hydro-5H-ih/ ^' eno 2,3-c]pyrro/-5-y/Jbuianam/ ^' cie: Intermediate 1/2. iv (0.022 g) was separated by semi-preparative chiral HPLC Method B (EtOH-MeCN (containing 0.5% DEA) 3-2; flow rate: 16 mL/min, UV detection at 284 nm); the respective retention times of the enantiomers (flow rate: 0.8 mL/min) were 4.9 and 7.1 min. The title enantiomers, first-eluting enantiomer (0.010 g) and second-eluting enantiomer (0.01 g) respectively, were obtained as white solids. The respective absolute configurations of the two diastereomeric compounds have not been determined. Example 1 and Example 2 refer to the first-eluting enantiomer and the second-eluting enantiomer respectively. Both isomers displayed identical NMR, MS and t _R . ¹ H NMR (DMSO-cie) δ: 10.94 (s, 1 H); 9.15 (m, 1 H); 7.28-7.32 (m, 2H); 7.18-7.22 (m, 3H); 7.05 (s, 1 H); 4.30-4.44 (m, 2H); 3.54 (m, 1 H); 3.38 (m, 1 H); 3.07 (s, 3H); 2.46-2.58 (overlapped m, 2H); 2.32 (m, 1 H); 1.95 (m, 1 H); 1.62 (m, 1 H); 1.53 (s, 3H); 1.51 -1.55 (overlapped m, 1 H). MS (ESI, m/z): 449.0 [M+H ⁺ ] for C ₂ iH24N ₂ O5S2; tR = 0.75 min.

Example 3 and Example 4: (2 ?)-4-(2-((1 S,2S)-2-(2-Fluorophenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H- thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2-(methylsulfo nyl)butanamide and (2 ?)-4-(2-((1 ?,2 ?)-2-(2- fluorophenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c] pyrrol-5-yl)-A/-hydroxy-2-methyl-2- (methylsulfonyl)butanamide

3/41 (2R)-4-(2-((1S*,2S*)-2-(2^uorophenyl)cyclopropyl)-6-oxo^

hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from the compound of Preparation B (0.1 g; 0.44 mmol) and the compound of Preparation C (0.128 g; 0.53 mmol), and proceeding successively in analogy to Procedure C (34% yield), Example 1 , steps 1.ii to 1.iii (83% yield, two steps) and Procedure D (56% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white solid (0.214 g; 89% yield). MS (ESI, m/z): 467.3 [M+H ⁺ ] for C21 H23N2O5FS; t _R = 0.76 min.

3/4.H. (2R)-4-(2-((1 S, 2S)-2-(2-Fluorophenyl)cyclopropyl)-6-oxo-4, 6-dihydro-5H-thieno[2, 3-c]pyrrol-5-yl)-N- hydroxy-2-methyl-2-(methylsulfonyl)butanamide and (2R)-4-(2-((1R,2R)-2-(2-fluorophenyl)cyclopropyl)-6-oxo- 4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-N-hydroxy-2-methyl^ Intermediate 3/4. i (0.02 g) was separated by semi-preparative chiral HPLC Method B (EtOH-MeCN (containing 0.5% TFA) 1-1 ; flow rate: 16 mL/min, UV detection at 282 nm); the respective retention times of the enantiomers (flow rate: 0.8 mL/min) were 4.6 and 5.7 min. The title enantiomers, first-eluting enantiomer (0.010 g) and second- eluting enantiomer (0.01 g) respectively, were obtained as white solids. The respective absolute configurations of the two diastereomeric compounds have not been determined. Example 3 and Example 4 refer to the first-eluting enantiomer and the second-eluting enantiomer respectively. Both isomers displayed identical NMR, MS and t _R . ¹ H NMR (DMSO-cie) δ: 10.95 (s, 1 H); 9.20 (s, 1 H); 7.26 (m, 1 H); 7.16-7.20 (m, 3H); 7.08 (s, 1 H); 4.37-4.42 (m, 2H); 3.37-3.58 (overlapped m, 2H); 3.07 (s, 3H); 2.50-2.58 (overlapped m, 2H); 2.37-2.41 (m, 1 H); 1.95 (m, 1 H); 1.70 (m, 1 H); 1.53-1.58 (overlapped m, 1 H); 1.53 (s, 3H). MS (ESI, m/z): 467.2 [M+H ⁺ ] for C21 H23N2O5FS2; t _R = 0.76 min.

Example 5 and Example 6 : (2 ?)-4-(2-((1 S,2 ?)-2-((£)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4,6- dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-A/-hydroxy-2-methyl-2-( methylsulfonyl)butanamide and (2 ?)-4-(2-

((1 ?,2S)-2-((£)-2 yclopropylvinyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3 -c]pyrrol-5-yl)-A/- hydroxy-2-methyl-2-(methylsulfonyl)butanamide

5/6.1 ((1S^2S^2-(5-((2R)-4-(tert-Butoxy)-3-methyl-3-(methy^^ thieno[2,3-c]pyrrol-2-yl)cyclopropyl)methyl benzoate: Starting from the compound of Preparation B (0.76 g; 1.68 mmol) and the compound of Preparation E (0.51 g; 1.82 mmol), and proceeding in analogy to Procedure C, the title compound was obtained, after purification by CC (DCM-MeOH gradient), as a yellow foam (0.53 g; 58% yield). MS2 (ESI, m/z): 548.2 [M+H ⁺ ] for C27H33NO7S2; t _R = 1.06 min.

5/6.H. (2R)-4-(2-((1 S*, 2S*)-2-((Benzoyloxy)methyl)cyclopropyl)-6-oxo-4, 6-dihydro-5H-thieno[2, 3-c]pyrrol-5-yl)- 2-methyl-2-(methylsulfonyl)butanoic acid: Starting from the intermediate 5/6.i (0.53 g; 0.98 mmol) and proceeding in analogy to Example 1 , step 1.ii (> 95% yield), the title compound (0.55 g) was obtained as a crude beige solid. MS2 (ESI, m/z): 492.1 [M+H ⁺ ] for C23H25NO7S2; t _R = 0.87 min.

5/6.iii. ((1 S*, 2S*J-2-(5-((2RJ-4-iWeihoxy-3-me /-3-(meihy/su/fony/J-4-oxobuiy/J-6-oxo-5, 6-dihydro-4H- thieno[2,3-c]pyrrol-2-yl)cyclopropyl)methyl benzoate: To a solution of intermediate 5/6. ii (0.430 g; 0.87 mmol) in DCM (6 mL) and MeOH (6 mL), cooled at 0°C, was added drop wise TMS-diazomethane (2M in hexanes, 1.1 mL) over 5min. The reaction mixture was stirred at rt for 1 h40. AcOH (0.12 mL) was added. After 20 min stirring, the solution was concentrated to dryness. The residue was co-evaporated with cyclohexane (15 mL). The evaporation residue was purified by CC (DCM-MeOH gradient) to afford the title compound (0.319 g, 72% yield) as a yellowish foam. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 7.99-7.97 (m, 2H); 7.67 (m, 1 H); 7.56-7.53 (m, 2H); 6.98 (d, J = 4.2 Hz, 1 H); 4.37-4.23 (m, 4H); 3.65 (m, 1 H); 3.49 (s, 3H); 3.54-3.42 (overlapped m, 1 H); 3.1 1 (s, 3H); 2.57 (m, 1 H); 2.38 (m, 1 H); 2.02 (m, 1 H); 1.71 -1.55 (overlapped m, 1 H); 1.58 (s, 3H); 1.24 (m, 1 H); 1.15 (m, 1 H). MS2 (ESI, m/z): 506.1 [M+H ⁺ ] for C24H27NO7S2; t _R = 0.96 min.

5/6./V. Methyl (2R)-4-(2-((1 S*, 2S*)-2-(hydroxymethyl)cyclopropyl)-6-oxo-4, 6-dihydro-5H-thieno[2, 3-c]pyrrol-5- yl)-2-methyl-2-(methylsulfonyl)butanoate: To a solution of intermediate 5/6. iii (0.319 g, 0.63 mmol) in MeOH (3.4 mL) was added K2CO3 (0.164 g; 1.19 mmol) . The reaction mixture was stirred at rt for 45min. The reaction mixture was diluted with DCM (30mL) and washed with aq. 15% NaHS04 solution (15mL). The aq. layer was extracted with DCM-MeOH 9-1 (3x15mL). The evaporation residue was purified by CC (DCM- MeOH gradient) gradient to afford the title compound (0.132g, 52% yield) as a yellowish gum. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 6.92 (s, 1 H); 4.69 (t, J = 5.7 Hz, 1 H); 4.26 (s, 2H); 3.66 (m, 1 H); 3.51-3.42 (overlapped m, 2H); 3.49 (s, 3H); 3.37-3.30 (overlapped m, 1 H); 3.1 1 (s, 3H); 2.58 (m, 1 H); 2.1 1 (m, 1 H); 2.02 (m, 1 H); 1.58 (s, 3H); 1.37 (m, 1 H); 1.04 (m, 1 H); 0.92 (m, 1 H). MS2 (ESI, m/z): 402.1 [M+H ⁺ ] for C17H23NO6S2; t _R = 0.64 min.

5/6.V. Methyl (R)-4-(2-((1S,2S)-2-formylcyclopropyl)-6-oxo-4 ^

(methylsulfonyl)butanoate: To a solution of intermediate 5/6. iv (0.129 g; 0.32 mmol) in DCM (2 mL), cooled at -10°C, was added DIPEA (0.22 mL; 1.25 mmol). Pyr.S0 ₃ complex (45% S0 ₃ basis, 0.137 g; 0.39 mmol) in DMSO (0.3 mL) was then added drop wise over 5 min. The reaction mixture was stirred for 2h45 at 0°C. The reaction mixture was partitioned between water (10mL) and DCM (10mL). The 2 layers were decanted and the aq. layer was extracted with DCM (10mL). The evaporation residue was dissolved in toluene (10mL) and evaporated again to afford the title crude aldehyde (0.137 g) as a yellow-brown gum (0.137g, >95% yield). MS2 (ESI, m/z): 400.1 [M+H ⁺ ] for Ci ₇ H ₂ i N06S ₂ ; t _R = 0.80 min.

5/6. vi. Methyl (2R)-4-(2-((1 S*, 2R*)-2-((E)-2-cyclopropylvinyl)cyclopropyl)-6-oxo-4, 6-dihydro-5H-thieno[2, 3- c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanoate: To a solution of intermediate 5/6.v (0.137 g, crude) and 5- (((cyclopropyl)methyl)sulfonyl)-1-phenyl-1 H-tetrazole (prepared as described by Ghosh, A.K. and al. in J.Org.Chem. 2009, 74, 8531 , 0.137 g; 0.52 mmol) in 1 ,2-DME (3.9mL), cooled to -78°C, was added drop wise a solution of KHMDS (0.46 mL, 1 M in THF) over 5 minutes. The reaction was warmed gradually warming to rt over 1 h. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (2x1 OmL). The evaporation residue was purified by CC (Hept-EA-MeOH gradient ) to afford the title compound (0.082g; 59% yield)as a yellowish gum. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 6.93 (s, 0.5H); 6.92 (s, 0.5H); 5.22 (m, 1 H); 5.13 (m, 1 H); 4.26 (s, 2H); 3.66 (m, 1 H); 3.52-3.42 (overlapped m, 1 H); 3.49 (s, 1.5H); 3.48 (s, 1.5H); 3.1 1 (s, 3H); 2.58 (m, 1 H); 2.22 (m, 1 H); 2.01 (m, 1 H); 1.70 (m, 1 H); 1.58 (s, 3H); 1.34 (m, 1 H); 1.21- 1.17 (m, 2H); 0.66-0.62 (m, 2H); 0.33-0.29 (m, 2H). MS2 (ESI, m/z): 437.8 [M+H ⁺ ] for C21 H27NO5S2; t _R = 0.97 min.

5/6. vii. (2R)-4-(2-((1 S*, 2R*)-2-((E)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4 _: 6-dihydro-5H-thieno[2, 3-c]pyrrol-5- yl)-2-methyl-2-(methylsulfonyl)butanoic acid: To a solution of intermediate 5/6.vi (0.077 g, 0.18 mmol) in THF (1.1 mL) and water (0.693 mL) was added LiOH (0.030 g; 0.4 mmol). The reaction mixture was stirred at rt for 2h. The solvent was removed in vacuo and the residue was acidified to pH=3 adding 15% aq. NaHSC>4 (30 drops). EA-MeOH (9-1 , 5 mL) was added. The two layers were separated and the aq. layer was extracted with EA-MeOH (9-1 , 3 x 5 mL).The evaporation residue afforded the title compound (0.075g, >95 % yield) as a yellowish solid. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 13.60 (br.s, 1 H); 6.92 (m, 1 H); 5.22 (m, 1 H); 5.13 (m, 1 H); 4.36-4.26 (m, 2H); 3.61 (m, 1 H); 3.49 (m, 1 H); 3.1 1 (s, 3H); 2.65-2.35 (overlapped m, 1 H); 2.22 (m, 1 H); 1.99 (m, 1 H); 1.70 (m, 1 H); 1.51 (s, 3H); 1.35 (m, 1 H); 1.21-1.18 (m, 2H); 0.67-0.62 (m, 2H); 0.33- 0.29 (m, 2H). MS2 (ESI, m/z): 424.1 [M+H ⁺ ] for C20H25NO5S2; t _R = 0.89 min.

5/6. viii. (2R)-4-(2-((1 S*, 2R*)-2-((E)-2-Cyclopropylvinyl)cyclopropyl)-6-oxo-4 _: 6-dihydro-5H-thieno[2, 3-c]pyrrol-5- yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 5/6.vii (0.075 g; 0.17 mmol) and proceeding successively in analogy to Example 1 , step 1/2.iii (> 95% yield) and Procedure B (62% yield), the title compound (0.041 g) was obtained after purification by prep-HPLC (Method 3) as a off-white solid. MS2 (ESI, m/z): 439.2 [M+H ⁺ ] for C20H26N2O5S2; t _R = 0.83 min.

5/6.IX. (2R)-4-(2-((1S,2R)-2-((E)-2-Cyclopropylvinyl)cyclop^^

yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide and (2R)-4-(2-((1R,2S)-2-((E)-2- cyclopropylvinyl)cyclopropyl)-6-oxo-4,6-dihydro -thieno^^^

(methylsulfonyl)butanamide: Intermediate 5/6.viii (0.04 g) was separated by semi-preparative chiral HPLC Method B (EtOH-Heptane (containing 0.5% TFA) 7-3; flow rate: 19 mL/min, UV detection at 210 nm); the respective retention times of the enantiomers (flow rate: 1 mL/min) were 10.3 and 13.1 min. The title enantiomers, first-eluting enantiomer (0.020 g) and second-eluting enantiomer (0.019 g) respectively, were obtained as yellowish solids. The respective absolute configurations of the two diastereomeric compounds have not been determined. Example 5 and Example 6 refer to the first-eluting enantiomer and the second- eluting enantiomer respectively. Both isomers displayed identical NMR, MS and tR. ¹ H NMR (DMSO-cie) δ: 10.92 (br.s, 1 H); 8.18 (br.s, 1 H); 6.92 (s, 1 H); 5.21 (m, 1 H); 5.13 (m, 1 H); 4.37-4.29 (m, 2H); 3.52 (m, 1 H); 3.36 (m, 1 H); 3.05 (s, 3H); 2.93 (m, 1 H); 2.21 (m, 1 H); 1.93 (m, 1 H); 1.70 (m, 1 H); 1.51 (s, 3H); 1.34 (m, 1 H); 1.20-1.17 (m, 2H); 0.66-0.62 (m, 2H); 0.33-0.29 (m, 2H). MS2 (ESI, m/z): 439.2 [M+H ⁺ ] for C20H26N2O5S2; t _R = 0.83 min.

Example 7: (2 ?)-A/-Hydroxy-4-(6-((1S*,2S*)-2-(4-(2-hydroxyethyl)phenyl)cy clopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e amide

Starting from the compound of Preparation G (0.23 g; 0.6mmol) and the compound of Preparation F (0.2 g; 0.5 mmol) and proceeding successively in analogy to Procedure F (39% yield), Example 5, steps 5/6.iv (82% yield) and 5/6.vii (>95% yield), Example 1 , step 1/2.iii (67% yield) and Procedure D (64% yield), the title compound (0.049 g) was obtained after purification by prep-HPLC (Method 2) as a off-white solid. ¹ H NMR (DMSO-cie) δ: 10.92 (br.s, 1 H); 8.18 (br.s, 1 H); 6.92 (s, 1 H); 5.21 (m, 1 H); 5.13 (m, 1 H); 4.37-4.29 (m, 2H); 3.52 (m, 1 H); 3.36 (m, 1 H); 3.05 (s, 3H); 2.93 (m, 1 H); 2.21 (m, 1 H); 1.93 (m, 1 H); 1.70 (m, 1 H); 1.51 (s, 3H); 1.34 (m, 1 H); 1.20-1.17 (m, 2H); 0.66-0.62 (m, 2H); 0.33-0.29 (m, 2H). MS2 (ESI, m/z): 439.2 [M+H ⁺ ] for C20H26N2O5S2; t _R = 0.83 min.

Example 8: (2 ?)-4-(6-((1S*,2S*)-2-(2-Fluorophenyl)cyclopropyl)-3-oxo-1H-p yrrolo[1 ,2-c]imidazol-2(3H)- yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)butanamide

81 tert-Butyl (2R)-4-(6-((1S^2S^-2-(2-fluorophenyl)cyclopropyl)^

methyl-2-(methylsulfonyl)butanoate: Starting from iert-butyl (2R)-4-(6-iodo-3-oxo-1 /-/-pyrrolo[1 ,2-c]imidazol- 2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described in Chapoux, G. and al. WO2015132228, 0.26 g; 0.54 mmol) and the compound of Preparation C (0.21 g; 0.82 mmol) and proceeding in analogy to Procedure E (84% yield), the title compound (0.221 g) was obtained after purification by CC (DCM-MeOH gradient) as a brownish solid. MS (ESI, m/z): 491.2 [M+H ⁺ ] for C23H29N3O6S; t _R = 1.09 min.

8./Ϊ. (2R)-2-Methyl-2-(methylsulfonyl) -(3-oxo-6-((1S*,2S*)^h

2(3H)-yl)butanoic acid: To an ice-chilled solution of intermediate 8.i (0.17 g; 0.284 mmol) in DCM (1 mL) was added triethylsilane (0.05 mL; 0.31 mmol) followed by TFA (0.7 mL; 9.14 mmol). The solution was stirred at rt for 3h. The solvent was removed in vacuo and the residue was coevaporated with diethyl ether (2 x 10 mL) to afford the title compound (0.25 g, >95% yield) as a brown residue. MS (ESI, m/z): 435.1 [M+H ⁺ ] for C23H29N3O6S; t _R = 0.92 min.

8.iii. (2R) -(6-((1S*,2S 2-(2-Ruo phenyl)cyclop pyl)-3-oxo-1H^

2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 8.ii (0.25 g; 0.58mmol) and proceeding successively in analogy to Example 1 , step 1/2.iii (51 % yield) and Procedure D (18% yield), the title compound (0.012 g) was obtained after purification by prep-HPLC (Method 2) as a beige solid. ¹ H NMR (DMSO-cie) δ: 9.21 (m, 1 H); 7.49 (t, J = 6.0 Hz, 1 H); 7.20 (m, 1 H); 7.15-7.09 (m, 3H); 7.01 (s, 1 H); 5.99 (s, 1 H); 4.39 (s, 2H); 3.47 (m, 1 H); 3.40 (m, 1 H); 3.07 (s, 3H); 2.15 (m, 1 H); 2.06 (m, 1 H); 1.96 (m, 1 H); 1.53 (s, 3H); 1.49-1.40 (m, 2H). MS2 (ESI, m/z): 449.2 [M+H ⁺ ] for C21 H24N3O5FS2; t _R = 0.84 min.

Example 9: (2 ?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1S*,2S*)-2- (4-(oxetan-3- yl)phenyl)cyclopropyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from (2R)-4-(6-iodo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-A/- ((tetrahydro-2/-/-pyran-2-yl)oxy)butanamide (prepared as described in Chapoux, G. and al. WO2015132228, 0.1 g; 0.19 mmol) and the compound of Preparation H (0.07 g; 0.23 mmol) and proceeding in analogy to Procedure E (but using THF instead of dioxane as a solvent, 48% yield) and Procedure D (7% yield), the title compound (0.003 g) was obtained after purification by prep-HPLC (Method 2) as a white solid. MS (ESI, m/z): 488.2 [M+H ⁺ ] for C24H29N3O6S; t _R = 0.80 min.

Example 10: (2 ?)-4-(6-((1 ?*,2S*)-2-((£)-2-Cyclopropylvinyl)cyclopropyl)-3-oxo-1H-pyr rolo[1 _! 2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

Starting from the compound of Preparation F (0.4 g; 1.0 mmol) and the compound of Preparation E (0.35 g; 1.17 mmol), and proceeding successively in analogy to Procedure E, Example 5, steps 5/6. iv, 5/6.v (30% yield, 2 steps), 5/6.vi (60% yield), 5/6.vii (74% yield), 5/6.vii (> 95% yield), Example 1 , step 1/2.iii (94% yield) and Procedure B (47% yield), the title compound (0.036 g) was obtained after purification by CC (DCM-MeOH gradient), as a yellow solid. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 10.93 (s, 1 H); 9.19 (s, 1 H); 6.87 (s, 1 H); 5.84 (s, 1 H); 5.15 (dd, J = 8.4, 15.3 Hz, 1 H); 5.04 (dd, J = 8.5, 15.3 Hz, 1 H); 4.34 (s, 2H); 3.45 (m, 1 H); 3.36-3.27 (overlapped m, 1 H); 3.05 (s, 3H); 2.60-2.41 (overlapped m, 1 H); 1.94 (m, 1 H); 1.69 (m, 1 H); 1.51 (s, 3H); 1.44 (m, 1 H); 1.32 (m, 1 H); 0.95 (m, 1 H); 0.88 (m, 1 H); 0.63-0.60 (m, 2H); 0.29-0.26 (m, 2H). MS2 (ESI, m/z): 422.3 [M+H ⁺ ] for C20H27N3O5S; t _R = 0.85 min.

Example 11 : (2 ?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((1 S*,2S*)-2-phenylcyclopropyl)- 1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from (2R)-4-(6-iodo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)-A/- ((tetrahydro-2/-/-pyran-2-yl)oxy)butanamide (prepared as described in Chapoux, G. and al. WO2015132228, 0.15 g; 0.29 mmol) and 4,4,5,5-tetramethyl-2-((1 S*,2S*)-2-phenylcyclopropyl)-1 ,3,2-dioxaborolane (commercial, 0.07 g; 0.23 mmol) and proceeding in analogy to Procedure E (but using THF instead of dioxane as a solvent, 28% yield) and Procedure D (18% yield), the title compound (0.006 g) was obtained after purification by prep-HPLC (Method 2) as a white solid. ¹ H NMR (DMSO-cie) δ: (mixture of diastereomers) 10.08-11.41 (m, 1 H); 8.49-9.65 (m, 1 H); 7.26 (t, J = 7.5 Hz, 2H); 7.1 1 -7.16 (m, 3H); 6.98 (s, 1 H); 5.96 (d, J = 1.2 Hz, 1 H); 4.38 (s, 2H); 3.45-3.48 (m, 1 H); 3.07 (s, 3H); 2.54-2.59 (m, 1 H); 1.99-2.07 (m, 2H); 1.93-1.98 (m, 1 H); 1.52 (s, 3H); 1.28-1.35 (m, 2H). MS (ESI, m/z): 432.3 [M+H ⁺ ] for C21 H25N3O5S; t _R = 0.76 min. Example 12: (2 ?)-A/-Hydroxy-2-methyl-4-(6-((1 S*,2S*)-2-methyl-2-phenylcyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-(methylsulfonyl)butanamide

Starting from the compound of Preparation F (0.3 g; 0.75 mmol) and 4,4,5,5-tetramethyl-2-((1 S*,2S*)-2- methyl-2-phenylcyclopropyl)-1 ,3,2-dioxaborolane (prepared as described in Rubina, M. and al. J.Am.Chem.Soc. 2003, 125, 7198-7199, 0.59 g; 2.2 mmol), and proceeding successively in analogy to Procedure E (18% yield), Example 5, step 5/6.vi (85% yield), Example 1 , step 1/2.iii (73% yield) and Procedure B (21 % yield), the title compound (0.01 g) was obtained after purification by Prep-HPLC (Method 2), as a yellow solid. ¹ H NMR (DMSO-cie) δ: 9.50-8.93 (m, 1 H); 7.31 (d, J = 4.0 Hz, 4H); 7.20-7.16 (m, 1 H); 7.00 (s, 1 H); 6.07 (s, 1 H); 4.45-4.35 (m, 2H); 3.52-3.43 (m, 1 H); 3.08 (s, 3H); 2.08-2.01 (m, 1 H); 2.01 -1.89 (m, 1 H); 1.57-1.47 (m, 3H); 1.39 (m, 1 H); 1.21 -1.15 (m, 3H). MS2 (ESI, m/z): 446.2 [M+H ⁺ ] for C ₂₂ H ₂₇ N3O ₅ S; t _R = 0.88 min.

Example 13 and Example 14 : (2 ?)-A/-Hydroxy-4-(2-((1 S,2S)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6- oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2-methyl-2-(met hylsulfonyl)butanamide and (2R)-N- hydroxy-4-(2-((1 ?,2 ?)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-6-oxo-4,6-dihydro -5H-thieno[2,3- c]pyrrol-5-yl)-2-methyl-2-(methylsulfonyl)butanamide

13/141 (2R)^ydroxy-4-(2-((1S^2S*)-2-(4-(hydroxymethyl)phenyl)cyclop m

ih/ ^' eno 2,3-c]pyrro/-5-y/J-2-meihy/-2-(me /su/fony/Jbuianam/ ^' cie:Starting from the compound of Preparation B (0.08 g; 0.177 mmol) and the compound of Preparation I (0.08 g; 0.2 mmol), and proceeding successively in analogy to Procedure C (44% yield), Example 1 , steps 1.ii to 1.iii (96% yield; two steps), Example 5, step 5/6 and Procedure D (66% yield), the title compound was obtained, after purification by prep-HPLC (Method 2), as a white amorphous solid (0.02 g). MS (ESI, m/z): 479.2 [M+H ⁺ ] for C27H34N2O7S2; t _R = 0.64 min.

13/14.H. (2R)-N-Hydroxy-4-(2-((1S,2S)-2-(4-(hydroxymethyl)phenyl)cyc^

ίΛ/βηο 2,3-φγΓΓθ/-5-γ/;-2^β /-2-^β /δυ/¾η>'^υί3η3/77/οίβ and (2R)-N-hydroxy-4-(2-((1R,2R)-2-(4- (hydroxymethyl)phenyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thie n

(methylsulfonyl)butanamide: Intermediate 13/14.1 (0.015 g) was separated by semi-preparative chiral HPLC Method B (MeCN-EtOH (containing 0.1 % TFA) 50-50; flow rate: 16 mL/min, UV detection at 284 nm); the respective retention times of the enantiomers (flow rate: 0.8 mL/min) were 4.6 and 5.9 min. The title enantiomers, first-eluting enantiomer (0.0047 g) and second-eluting enantiomer (0.005 g) respectively, were obtained as off-white solids. The respective absolute configurations of the two diastereomeric compounds have not been determined. Example 13 and Example 14 refer to the first-eluting enantiomer and the second- eluting enantiomer respectively. Both isomers displayed identical NMR, MS and tR. ¹ H NMR (DMSO-cie) δ: 10.94 (s, 1 H); 9.18 (m, 1 H); 7.23 (d, J = 8.2 Hz, 2H); 7.14 (d, J = 8.2 Hz, 2H); 7.04 (s, 1 H); 4.46 (s, 2H); 4.42- 4.32 (m, 2H); 3.54 (m, 1 H); 3.47-3.24 (overlapped m, 1 H); 3.07 (s, 3H); 2.57-2.48 (overlapped m, 2H); 2.30 (m, 1 H); 1.94 (m, 1 H); 1.60 (m, 1 H); 1.53 (s, 3H); 1.51 (overlapped m, 1 H). MS (ESI, m/z): 479.2 [M+H ⁺ ] for C27H34N2O7S2; t _R = 0.64 min.

Example 15: (2 ?)-A/-Hydroxy-4-(6-((1 S*,2S*)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from the compound of Preparation F (0.3 g; 0.75 mmol) and the compound of Preparation J (0.3 g; 0.82 mmol), and proceeding successively in analogy to Procedure E (34% yield), Example 5, step 5/6.vi (92% yield), Example 1 , step 1/2.iii (90% yield) and Procedure B (10% yield), the title compound (0.003 g) was obtained after purification by prep-HPLC (Method 2), as a white amorphous solid. ¹ H NMR (DMSO-cie) δ: 9.23- 9.17 (m, 1 H); 7.20 (d, J = 7.8 Hz, 2H); 7.07 (d, J = 8.0 Hz, 2H); 6.97 (s, 1 H); 5.96 (d, J = 0.3 Hz, 1 H); 5.08 (m, 1 H); 4.44 (d, J = 5.6 Hz, 2H); 4.39-4.36 (m, 2H); 3.48 (m, 1 H); 3.07 (s, 3H); 2.04 (m, 1 H); 2.00-1.91 (m, 2H); 1.53-1.51 (m, 3H); 1.46-1.40 (m, 1 H); 1.33-1.27 (m, 2H); 1.24 (m, 1 H). MS2 (ESI, m/z): 462.9 [M+H ⁺ ] for C27H34N2O7S2; t _R = 0.70 min.

Example 16: (2 ?)-A/-Hydroxy-4-(6-((1 S*,2S*)-2-(4-(hydroxymethyl)phenyl)cyclopropyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

Starting from the compound of Preparation K (0.138 g; 0.31 mmol) and the compound of Preparation L (0.093 g; 0.37 mmol), and proceeding successively in analogy to Procedure E (26% yield), 5/6.vii (86% yield), Example 1 , step 1/2.iii (>95% yield) and Procedure D (34% yield), the title compound (0.003 g) was obtained after purification by prep-HPLC (Method 2), as a yellowish amorphous solid. ¹ H NMR (DMSO-cie) δ: 10.93 (br.s, 1 H); 9.19 (br.s, 1 H); 7.25 (dd, J = 1.1 , 5.1 Hz, 1 H); 6.99 (s, 1 H); 6.92 (dd, J = 3.5, 5.1 Hz, 1 H); 6.85 (m, 1 H); 5.96 (m, 1 H); 4.37 (s, 2H); 3.47 (m, 1 H); 3.40-3.28 (overlapped m, 1 H); 3.06 (s, 3H); 2.60-2.47 (overlapped m, 1 H); 2.27 (m, 1 H); 2.02 (m, 1 H); 1.95 (m, 1 H); 1.52 (s, 3H); 1.34 (m, 1 H); 1.28 (m, 1 H). MS2 (ESI, m/z): 438.1 [M+H ⁺ ] for C19H23N3O5S2; t _R = 0.82 min. Example 17: (2 ?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(2-((1S*,2 ?*)-2-((-E)-2-(1-(oxetan-3- yl)piperidin -yl)vinyl)cyclopropyl)-6-oxo ,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)butanami

171 tert-Butyl 4-((E)-2-((1R,2S)-2-(5-((R)-4-methoxy-3-methyl-3-(me^

dihydro-4H-thieno[2,3-c]pyrrol-2-yl)cyclopropyl)vinyl)pip eridm^^ Starting from intermediate 5/6.v (0.2 g; 0.5 mmol) and the compound of Preparation M (0.310 g; 0.75 mmol), and proceeding successively in analogy to Example 5, steps 5/6.vi ( (27% yield), 5/6.vii (86% yield), Example 1 , step 1/2.iii (>9%% yield) and Procedure D (34% yield), the title compound (0.003 g) was obtained after purification by prep-HPLC (Method 2), as a yellowish amorphous solid. ¹ H NMR (DMSO-cie) δ: 6.94 (m, 1 H); 5.55 (dd, J = 6.7, 15.5 Hz, 1 H); 5.14 (dd, J = 8.7, 15.6 Hz, 1 H); 4.26 (s, 2H); 3.94-3.86 (m, 2H); 3.66 (m, 1 H); 3.51 -3.42 (overlapped m, 1 H); 3.49 (s, 3H); 3.1 1 (s, 3H); 2.80-2.65 (m, 2H); 2.58 (m, 1 H); 2.24 (m, 1 H); 2.09 (m, 1 H); 2.02 (m, 1 H); 1.74 (m, 1 H); 1.63-1.56 (overlapped m, 2H); 1.58 (s, 3H); 1.38 (s, 9H); 1.31 -1.19 (m, 2H); 1.15-1.07 (m, 2H). MS2 (ESI, m/z): 581.4 [M+H ⁺ ] for C28H40N2O7S2; t _R = 1.07 min.

171 Methyl (R)-2-methyl-2-(methylsulfonyl) -(6-oxo-2-((1S,2R)^

dihydro-5H-thieno[2,3-c]pyrrol-5-yl)butanoate hydrochloride: To a solution of intermediate 17.i (0.073 g; 0.13 mmol) in dioxane (0.26 mL) was added 4N HCI in dioxane (0.29 mL). The solution was stirred at rt for 3h30. The reaction mixture was concentrated to dryness then the residue was co-evaporated with diethyl ether (2 mL) to give the title compound (0.072g, >95% yield) as a a yellow gum. ¹ H NMR (DMSO-cie) δ: 8.54 (m, 1 H); 8.27 (m, 1 H); 6.95 (s, 1 H); 5.56 (dd, J = 6.4, 15.6 Hz, 1 H); 5.18 (m, 1 H); 4.27 (s, 2H); 3.73-3.63 (m, 2H); 3.51 -3.44 (overlapped m, 2H); 3.49 (s, 3H); 3.24 (m, 1 H); 3.11 (s, 3H); 2.88 (m, 1 H); 2.59 (m, 1 H); 2.25 (m, 2H); 2.02 (m, 1 H); 1.79-1.76 (m, 3H); 1.58 (s, 3H); 1.39-1.44 (m, 2H); 1.25-1.21 (m, 2H). MS2 (ESI, m/z): 481.1 [M+H ⁺ ] for C23H32N2O5S2; t _R = 0.62 min.

17 M. Methyl (RJ-2-me /-2-(meίh /su// ^: on /J- -(2-((ίS _; 2RJ-2-((EJ-2-( (o eίan-3- /J / erid/n- - y/J y/Jcyc/opropy/J-6-oxo-4,6-d/hydro-5H-ih/ ^' eno 2,3-c]pyrro/-5-y/Ji)uianoaie: To a solution of intermediate 17.ii (0.075 g) in DCM (1.6 mL) and MeOH (0.05 mL), cooled at 0°C, were added oxetanone (0.032 g; 0.44 mmol) and NaBH(OAc)3 (0.1 12 g; 0.51 mmol). The reaction mixture was stirred at rt for 8h. Sat. aq. NaHCOs (5 mL) and DCM/MeOH 9/1 (8 mL) were added. The aq. layer was extracted with DCM-MeOH mixture (9-1 ; 3 x 6 mL). The evaporation residue was purified by CC (DCM-MeOH containing 1 % aq. NH4OH) 4-1 ) to afford the title compound (0.030g; 44% yield) as a yellowish gum. ¹ H NMR (DMSO-cie) (mixture of diastereomers) δ: 6.95 (s, 1 H); 5.56 (dd, J = 6.7, 15.4 Hz, 1 H); 5.14 (dd, J = 8.4, 15.4 Hz, 1 H); 4.51 (t, J = 6.4 Hz, 2H); 4.40 (t, J = 6.1 Hz, 2H); 4.27 (s, 2H); 3.67 (m, 1 H); 3.53-3.43 (overlapped m, 2H); 3.50 (s, 3H); 3.12 (s, 3H); 2.59 (m, 1 H); 2.24 (m, 1 H); 2.03 (m, 1 H); 1.92 (m, 1 H); 1.79-1.72 (m, 3H); 1.64-1.57 (overlapped m, 3H); 1.59 (s, 3 H); 1.32-1.24 (m, 3H); 1.23-1.18 (m, 2H). MS2 (ESI, m/z): 537.2 [M+H ⁺ ] for C26H36N2O6S2; t _R = 0.62 min.

17 (2R)-N-Hydroxy-2- ethyl-2-( ethylsulfonyl)-4-(2-((1S 2R 2-((E)^^^

yl)vinyl)cyclopropyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]p yrrol-5-y^^ Starting from intermediate 17.iii (0.029 g; 0.054 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (>95% yield), Example 1 , step 1/2. iii (79% yield, two steps) and Procedure B (61 % yield), the title compound (0.013 g) was obtained after purification by CC (DCM-MeOH gradient), as a yellowish foam. ¹ H NMR (DMSO-cie) δ: 10.94 (s, 1 H); 9.17 (s, 1 H); 6.95 (s, 1 H); 5.56 (dd, J = 6.7, 15.5 Hz, 1 H); 5.14 (dd, J = 8.5, 15.5 Hz, 1 H); 4.51 (t, J = 6.4 Hz, 2H); 4.40 (t, J = 6.1 Hz, 2H); 4.38-4.30 (m, 2H); 3.53 (m, 1 H); 3.40-3.29 (overlapped m, 2H); 3.06 (s, 3H); 2.69-2.62 (m, 2H); 2.24 (m, 1 H); 1.96-1.88 (m, 2H); 1.76-1.72 (m, 3H); 1.63-1.60 (m, 2H); 1.53 (s, 3H); 1.32-1.24 (m, 3H); 1.23-1.19 (m, 2H). MS2 (ESI, m/z): 538.3 [M+H ⁺ ] for C25H35N3O6S2; t _R = 0.54 min.

Example 18: (2 ?)-A/-hydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((1r,3 ?)-3-phenylcyclobutyl)-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

18.i Methyl (2R)-2-methyl-2-(methylsulfonyl)-4-(3-oxo-6-((1r,3R^

c]imidazol-2(3H)-yl)butanoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)- yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.2 g, 0.509 mmol) and the compound of Preparation N (0.161 g; 0.763 mmol), and proceeding in analogy to Procedure G (4 repetitions), the intermediate mixture of cisltrans isomers (0.338 g) was obtained after purification of the pulled reaction mixtures by CC (Hept-EA gradient) as a colorless oil: The latter (0.338 g) was separated by semi-preparative chiral HPLC Method C (EtOH-carbon dioxide 3-7; flow rate: 160 mL/min, UV detection at 210 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.3 and 4.0 min. The title trans diasteroemer, first-eluting enantiomer (0.126 g) was obtained as a white solid. MS2 (ESI, m/z): 446.2 [M+H ⁺ ] for C23H28N2O5S; t _R = 1.04 min.

18.H (2R)^ydroxy-2-methyl-2-(methylsulfonyl)-4-(3-oxo

c]imidazol-2(3H)-yl)butanamide: Starting from intermediate 18. i (0.126 g; 0.28 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii 93% yield), Example 1 , step 1/2.iii (88% yield,) and Procedure B (73% yield), the title compound (0.074 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.21 (m, 1 H),7.35-7.31 (m, 4 H), 7.19 (m, 1 H),7.09 (m, 1 H), 6.13 (m, 1 H), 4.42 (s, 2 H), 3.66 (m, 1 H), 3.54-3.33(m, 3 H), 3.08 (s, 3 H), 2.63-2.55 (m, 2 H), 2.47 (m, 1 H), 2.45-2.38 (m, 2 H), 1.97 (m, 1 H), 1.53 (s, 3 H). MS2 (ESI, m/z): 446.2 [M+H ⁺ ] for C22H27N3O5S; t _R = 0.89 min.

Example 19: (2 ?)-4-(6-((1r,3 ?)-3-ethynylcyclobutyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H )-yl)-A/- hydroxy-2-methyl-2-(methylsulfonyl)butanamide

191 Methyl (2R)-4-(6-((1r,3R)-3-(((tert-butyldiphenylsi^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanoate : Starting from methyl (2R)-4-(6-bromo-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and al. in WO2017/037221 , 0.2 g, 0.509 mmol) and the compound of Preparation O (0.126 g; 0.28 mmol) and proceeding in analogy to Procedure G (4 repetitions) afforded an intermediate mixture of cisltrans isomers (0.348 g). The latter was separated by chiral prep-HPLC (Method D) (EtOH-carbon dioxide 1-4; flow rate: 160 mL/min, UV detection at 210 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.0 and 3.4 min. The title trans diastereomer, second-eluting diastereomer (0.348 g) was obtained as a yellowish foam. ¹ H NMR (DMSO-cie) δ: 7.64-7.63 (m, 4 H), 7.50-7.44 (m, 6 H), 6.91 (s, 1 H), 6.03 (s, 1 H), 4.32 (s, 2 H), 3.83-3.69 (m, 2 H), 3.59 (m, 1 H), 3.50 (s, 3 H), 3.45(m, 2 H), 3.34 (m, 1 H), 3.13 ( s, 3H), 2.62 (m, 1 H), 2.16-2.08 (m, 2 H), 2.007-2.01 (m, 3 H), 1.59 (s, 3 H), 1.02 (s,9H). MS2 (ESI, m/z): 637.2 [M+H ⁺ ] for CaHwtoOeSSi; t _R = 1.27 min.

19.H. (2R)-4-(6-((1r,3R)-3-Formylcyclobutyl)-3-oxo-1H yrroW

(methylsulfonyl)-N-(((R)-tetrahydro-2H-pyran-2-yl)oxy)butana mide: Starting from intermediate 19.i (0.348 g; 0.54 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (>95% yield), Example 1 , step 1/2.iii (91 % yield), Preparation D, step D.i (84% yield) and Example 5, step 5/6.v (50% yield), the title compound (0.106 g) was obtained after purification by CC (EA-Hept gradient), as a white solid. MS2 (ESI, m/z): 482.2 [M+H ⁺ ] for C ₂ 3H ₃ i N0 ₆ S; t _R = 0.78 min.

19.iii (2R)-4-(6-((1r,3R)-3^thynylcyclobutyl)-3-oxo-1H^yrrolo[1,2^

(methylsulfonyl)-N-(((R)-tetrahydro-2H-pyran-2-yl)oxy)but anamide:To a suspension of intermediate 19.ii (0.106 g; 0.22 mmol) and K ₂ C0 ₃ (0.061 1 g; 0.442 mmol) in MeOH (1.72 mL; 42.5 mmol) was added dimethyl (1-diazo-2-oxopropyl) phosphonate (0.0432 mL; 0.288 mmol) .The reaction proceeded at rt for 24 h. The solvent was evaporated and the residue was partitioned between DCM (20 mL) and water (10 mL). The evaporation residue was purified by CC (EA-MeOH gradient) to afford the title compound (0.074 g, 71 % yield), as a white foam. MS2 (ESI, m/z): 478.2 [M+H ⁺ ] for C ₂ 3H ₃ iN0 ₆ S; t _R = 0.89 min.

19 (2R) -(6-((1r,3R)-3^thynylcyclobutyl)-3-oxo-1H yrrolo[1^^^

(methylsulfonyl)butanamide: Starting from intermediate 19.iii (0.074 g; 0.15 mmol) and proceeding in analogy to Procedure B (73% yield), the title compound (0.043 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.90 (m, 1 H), 9.18 (m, 1 H), 6.98 (s, 1 H), 6.05 (d, J = 1.2 Hz, 1 H), 4.39 (s, 2 H), 3.45-3.55 (m, 3 H), 3.07 (m, 3H), 3.05 (d, J = 2.4 Hz, 1 H), 2.55-2.56 (m, 2 H), 2.50 (overlaid m, 1 H), 2.29-2.35 (m, 3 H), 1.92-1.98 (m, 1 H), 1.52 (s, 3 H). MS2 (ESI, m/z): 394.2 [M+H ⁺ ] for C18H23N3O5S; tR = 0.75 min.

Example 20: (2 ?)-A/-hydroxy-4-(6-((1r,3 ?)-3-(4-(2-hydroxyethyl)phenyl)cyclobutyl)-3-oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

201 4-((1R,3r)-3-(2-((2R)-4-Methoxy-3-methyl-3-(methy^

pyrrolo[1,2-c]imidazol-6-yl)cyclobutyl)phenethyl benzoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1 /-/- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.25 g, 0.636 mmol) and the compound of Preparation P (0.3 g; 0.835 mmol) and proceeding in analogy to Procedure G (repeated twice) afforded an intermediate mixture of cisltrans isomers (0.4 g). The latter was separated by chiral prep-HPLC (Method A) (EtOH-MeOH-Hexane 9-9-2; flow rate: 16 mL/min, UV detection at 227 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 12.5 and 14.7 min. The title trans diastereomer, first-eluting diastereomer (0.188 g) was obtained as a white foam. ¹ H NMR (DMSO-cie) δ: 7.95-7.93(m, 2 H), 7.66 (m, 1 H), 7.55-7.51 (m, 2 H), 7.29- 7.24 (m, 4 H), 7.05 (s, 1 H), 6.13 (d, J = 1.2 Hz, 1 H), 4.47 (t, J = 6.8 Hz, 2 H), 4.35-4.33 (m, 2 H), 3.66-3.58 (m, 2 H), 3.51 (s, 3 H), 3.48-3.39 (m, 2 H), 3.14 (s, 3 H), 3.02 (t, J = 6.7 Hz, 2 H), 2.62 (m, 1 H), 2.48-2.42 (m, 2 H), 2.41-2.36 (m, 2 H), 2.06 (m, 1 H), 1.60 (s, 3 H). MS2 (ESI, m/z): 593.2 [M+H ⁺ ] for C32H ₃ 6N20 ₇ SSi; t _R = 1.16 min.

20.H. (2R)^ydroxy-4-(6-((1r,3R)-3-(4-(2-hydroxyethyl)phen

2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 20.i (0.188 g; 0.31 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (>98% yield), Example 1 , step 1/2. iii (38% yield) and Procedure B (82% yield), the title compound (0.047 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.95 (br s., 1 H),9.22 (br s., 1 H) 7.23-7.14 (m,4 H), 7.04 (s, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.63 (t, J = 5.2 Hz, 1 H), 4.42 (s, 2 H), 3.65-3.55 (m, 3 H), 3.50 (m, 1 H), 3.40 (m, 1 H), 3.30 ( overlapped m, 1 H ), 3.08 (s, 3 H), 2.69 (t, J = 7.2 Hz, 2 H), 2.50-2.35 (m, 4H), 1.97 (m, 1 H), 1.53 (s, 3 H). MS2 (ESI, m/z): 490.2 [M+H ⁺ ] for C24H31N3O6S; t _R = 0.79 min.

Example 21 : (2 ?)-4-(6-((1 S,3 ?)-3-(4-((1S)-1 ,2-dihydroxyethyl)phenyl)cyclobutyl)-3-oxo-1H-pyrrolo[1,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

211 (1S)-1-(4-((1R,3S)-3-(2-((2R)-4-Methoxy-3-methyl-3-^

pyrrolo[1 _: 2-c]imidazol-6-yl)cyclobutyl)phenyl)ethane-1 _: 2-diyl dibenzoate: Starting from methyl (2R)-4-(6- bromo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.2 g, 0.509 mmol) and the compound of Preparation Q (0.366 g; 0.764 mmol) and proceeding in analogy to Procedure G (repeated four more times) afforded an intermediate mixture of cisltrans isomers (0.36 g). The latter was separated by chiral prep-HPLC (Method E) (C0 ₂ -MeCN-EtOH 70-15-15; flow rate: 160 mL/min, UV detection at 228 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.6 and 4.4 min. The title trans diastereomer, second-eluting diastereomer (0.18 g) was obtained as a colorless oil. ¹ H NMR (DMSO-cie) δ: 8.05-8.01 (m, 2 H), 7.93-7.90 (m, 2 H), 7.70-7.63 (m, 2 H), 7.57-7.49 (m, 6 H), 7.39-7.36 (m, 2 H), 7.05 ( m, 1 H) , 6.37 (dd, J = 3.5, 7.7 Hz, 1 H), 6.13 ( m, 1 H), 4.75 (dd, J = 7.9, 11.9 Hz, 1 H),4.68 (dd, J = 3.5, 1 1.9 Hz, 1 H) , 4.35 (s, 2 H), 3.69-3.59 (m, 2 H), 3.47-3.30 (m, 5 H), 3.14 (s, 3 H), 2.60 (m, 1 H), 2.50-2.44 (overlapped m, 2H), 2.42 -2.39 (m, 2 H), 2.05 (m, 1 H), 1.60 (s, 3 H). MS2 (ESI, m/z): 713.3 [M+H ⁺ ] for C39H40N2O9S; to = 1.16 min.

21.il (2R)-4-(6-((1S _: 3R)-3-(4-((1S)-1 _: 2-Dihydroxyethyl)phenyl)cyc^

2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 21. i (0.18 g; 0.25 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (88% yield), Example 1 , step 1/2.iii (70% yield), Example 5, step 5/6.iv (83% yield) and Procedure B (66% yield), the title compound (0.044 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.9 (br s. , 1 H), 9.21 (br s, 1 H), 7.30-7.22 (m, 4 H), 7.05 (s, 1 H), 6.13 (d, J = 1.2 Hz, 1 H), 5.16 (d, J = 4.2 Hz, 1 H), 4.70 (t, J = 5.9 Hz, 1 H), 4.51 (m, 1 H), 4.45-4.39 (m, 2 H), 3.63 (m, 1 H), 3.50 (m, 1 H), 3.44-3.38 (m, 3 H), 3.07 (s, 3 H), 2.57 (m, 2 H), 2.50-2.36 (m, 4 H), 1.97 (m, 1 H), 1.53 ( s, 3H). MS2 (ESI, m/z): 506.2 [M+H ⁺ ] for C24H31N3O7S; t _R = 0.69 min.

Example 22: (2 ?)-N-Hydroxy-4-(6-((1r,3 ?)-3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3- oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

221 (1-(4-((1R,3r)-3-(2-((R)-4-Methoxy-3-methyl-3-(me^

pyrrolo[1 _: 2-c]imidazol-6-yl)cyclobutyl)phenyl)cyclopropyl)methyl benzoate: Starting from methyl (2R)-4-(6- bromo-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.2 g, 0.509 mmol) and the compound of Preparation R (0.294 g; 0.763 mmol) and proceeding in analogy to Procedure G (repeated five more times) afforded an intermediate mixture of cisltrans isomers (0.358 g). The latter was separated by chiral prep-HPLC (Method E) (C0 ₂ -MeCN-EtOH 70-15-15; flow rate: 160 mL/min, UV detection at 228 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.5 and 4.2 min. The title trans diastereomer, second-eluting diastereomer (0.175 g) was obtained as a colorless oil. ¹ H NMR (DMSO-cie) δ: 7.93 (d, J = 1.2 Hz, 2 H), 7.65 (m, 1 H), 7.53 (m, 2 H), 7.32 (m, 2 H), 7.22 (m, 2 H), 7.04 (s, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.40 (s, 2 H), 4.34 (s, 2 H), 3.61 (m, 2 H), 3.50 (s, 3 H), 3.44 (m, 1 H), 3.40 (m, 1 H), 3.14 (s, 3 H), 2.60 (m, 1 H), 2.48-2.42 (m, 2 H), 2.39-2.34(m, 2 H), 2.04-2.07 (m, 1 H), 1.60 (s, 3 H), 1.03-1.05 (m, 2H), 0.93 (m, 2 H). MS2 (ESI, m/z): 619.3 [M+H ⁺ ] for C39H40N2O9S; t _R = 1.18 min.

22.// (2R)-4-(6-((1r,3R)-3-(4-(1-(Hydroxymethyl)cyclopropy^

c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)^ Starting from intermediate 22. i (0.175 g; 0.28 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (96% yield), Example 1 , step 1/2.iii (79% yield), Example 5, step 5/6.iv (79% yield), the title compound (0.101 g) was obtained after purification by CC (DCM-MeOH), as a white solid. MS2 (ESI, m/z): 600.3 [M+H ⁺ ] for C31 H41 N3O7S; t _R = 0.97 min.

22.iii. (2R)-4-(6-((1S _: 3R)-3-(4-((1S)-1 _: 2-Dihydroxyethyl)phenyl)cyc^

2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 22.ii (0.03 g; 0.05 mmol) and proceeding in analogy to Procedure D (78% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.92 (br s. , 1 H), 9.22 (br s., 1 H), 7.25-7.20 (m, 4 H), 7.04 (m, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.63 (t, J = 5.7 Hz, 1 H), 4.45-4.38 (m, 2 H), 3.61 (m, 1 H), 3.53-3.47 (m, 3 H), 3.40 (m, 1 H), 3.08 (s, 3 H), 2.58 (m, 1 H), 2.50-2.35 (overlapped m, 5 H), 1.97 (m, 1 H), 1.53 (s, 3 H), 0.83-0.80 (m, 2 H), 0.69-0.66 (m, 2 H). MS2 (ESI, m/z): 516.2 [M+H ⁺ ] for C26H33N3O6S; t _R = 0.69 min. Example 23: (2 ?)-N-Hydroxy-4-(6-((1r,3 ?)-3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3- oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

231. (2R)-4-(6-((1r _: 3R)-3-(4-(1-Formylcyclopropyl)phenyl)cyclob^

yl)-2-methyl-2-(methylsulfonyl)-N-(((2RS)-tetrahydro-2H yrafr from intermediate 22. ii (0.068 g; 0.11 mmol) and proceeding in analogy to Example 5/6, step5/6.v (81 % yield), the title compound (0.055 g) was obtained after purification by CC (Hept-EA), as a white foam. MS2 (ESI, m/z): 598.0 [M+H ⁺ ] for C31 H39N3O7S; t _R = 1.02 min.

23.» (2R)-4-(6-((1r,3R)-3-(4-(1-((3-Fluoroazetidin-1-yl^

pyrivlo[1,2 ]imidazol-2(3H)-yl)-2-methyl-2-(methylsd

yl)oxy)butanamide: To a solution of intermediate 23.i (0.055 g; 0.092 mmol) in DCM-MeOH (9:1 , 1 mL) were added TEA (0.0282 mL; 0.202 mmol) and 3-fluoroazetidine hydrochloride (0.0226 g; 0.202 mmol). After stirring for 5 min., sodium tris(acetoxy)borohydride (0.0546 g; 0.258 mmol) was added . The reaction proceeded for 1 h. DCM-MeOH (9-1 , 10 mL) and a sat. solution of NaHC03 (3 mL) were added. The 2 layers were separated and the aq layer was extracted with EA (10 mL). The evaporation residue was purified by CC (Hept-EA-MeOH ) to afford the title compound(0.035 g, 57 % yield), as a white solid. MS2 (ESI, m/z): 633.2 [M+H ⁺ ] for C30H37N4O6FS; tR = 0.74 min.

23./// ^' (2R)^ydroxy-4-(6-((1r,3R)-3-(4-(1-(hydroxymethyl)cyclopro

pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfon Starting from intermediate 23. ii

(0.033 g; 0.05 mmol) and proceeding in analogy to Procedure D (35% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 2), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.96 (br s. , 1 H), 9.22 (br s, 1 H), 7.22-7.17 (m, 4 H), 7.04 (s, 1 H), 6.12 (d, J = 1.1 Hz, 1 H), 5.16-4.97 (m, 1 H), 4.45-4.38 (m, 2 H), 3.61 (m, 1 H), 3.56-3.46 (m, 3 H), 3.43-3.38 (m, 2 H), 3.08 (s, 3 H), 3.03 (m, 1 H), 2.98 (m, 1 H), 2.60-2.55 (m, 3H), 2.46-2.36 (m, 4 H),1.96 (m, 1 H), 1.53 (s, 3 H), 0.65-0.74 (m, 4 H). MS2 (ESI, m/z): 573.2 [M+H ⁺ ] for C29H37N4O5S; t _R = 0.70 min.

Example 24: (2 ?)-N-Hydroxy-4-(6-((1r,3 ?)-3-(4-(1-(hydroxymethyl)cyclopropyl)phenyl)cyclobutyl)-3- oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamid e

241 4-((1R,3r)-3-(2-((2R)-4-Methoxy-3-methyl-3-(methylsul^

pyrrolo[1,2-c]imidazol-6-yl)cyclobutyl)benzyl benzoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.21 g, 0.54 mmol) and the compound of Preparation S (0.280 g; 0.812 mmol) and proceeding in analogy to Procedure G (repeated six more times) afforded an intermediate mixture of cisltrans isomers (0.505 g). The latter was separated by chiral prep-HPLC (Method E) (C02-MeCN- EtOH 70-15-15; flow rate: 160 mL/min, UV detection at 228 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.2 and 3.8 min. The title trans diastereomer, second-eluting diastereomer (0.224 g) was obtained as a colorless oil. ¹ H NMR (DMSO-cie) δ: 8.01-7.99 (m, 2H); 7.68 (m, 1 H); 7.56-7.53 (m, 2H); 7.45-7.42 (m, 2H); 7.37-7.34 (m, 2H); 7.06 (s, 1 H); 6.14 (d, J = 1.2 Hz, 1 H); 5.33 (s, 2H); 4.35 (s, 2H); 3.71 -3.60 (m, 2H); 3.51 (s, 3H); 3.48-3.42 (m, 4H); 3.14 (s, 3H); 2.62 (m, 1 H); 2.45-2.39 (m, 2H); 2.06 (m, 1 H); 1.60 (s, 3H). MS2 (ESI, m/z): 579.2 [M+H ⁺ ] for C31 H34N2O7S; to = 1.14 min.

24.H (2R)-4-(6-((1r,3R)-3-(4-(Hydroxymethyl)phenyl)cyM^

me /-2-(me /su/fony/J-W-(((2RSJ-ieirahydro-2H-pyran-2-y/JoxyJbuianam/ ^' cie: Starting from intermediate 24.i (0.224 g; 0.38 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (78% yield), Example 1 , step 1/2.iii (66% yield), Example 5, step 5/6. iv (81 % yield), the title compound (0.083 g) was obtained after purification by CC (DCM-MeOH), as a white solid. MS2 (ESI, m/z): 560.2 [M+H ⁺ ] for C28H37N3O7S; t _R = 0.89 min.

24.iii. (2R)-4-(6-((1S,3R)-3-(4-((1S)-1,2-Dihydroxye1 yl)phenyl)cyclob

2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 24.ii (0.05 g; 0.09 mmol) and proceeding in analogy to Procedure B (35% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.96 (br, s, 1 H), 9.22 (br, s, 1 H), 7.26 (s, 4H), 7.05 (s, 1 H), 6.13 (s, 1 H), 5.11 (t, J = 5.8 Hz, 1 H), 4.47 (d, J = 5.7 Hz, 2H), 4.42 (s, 2H), 3.67-3.60 (m, 1 H), 3.52-3.47 (m, 1 H), 3.44-3.33 (m, 2H), 3.07 (s, 3H), 2.61-2.55 (m, 2H), 2.48-2.45 (m, 1 H), 2.43-2.38 (m, 1 H), 1.99-1.93 (m, 1 H), 1.53 (s, 1 H). MS2 (ESI, m/z): 476.2 [M+H ⁺ ] for C23H29N3O6S; tR = 0.75 min.

Example 25: (2 ?)-4-(6-((1r,3 ?)-3-(4-((3-fluoroazetidin-1-yl)methyl)phenyl)cyclobutyl)-3- oxo-1H- pyrrolo[1 ,2-c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfony l)butanamide

251 (2R)-4-(6-((1r,3R)-3-(4-Formylphenyl)cyclobutyl)-3-oxo-1^

(methylsulfonyl)-N-(((2R)-tetrahydro-2H-pyran-2-yl)oxy)butan amide: A mixture of intermediate 24.ii (0.030 g; 0.053 mmol) and Mn0 ₂ (0.0699 g; 0.804 mmol) in DCM (0.27 mL) was refluxed for 1 h. After cooling, the reaction mixture was filtered through a pad of celite. The filtrate was evaporated to dryness. The same procedure was repeated twice from the evaporation residue to eventually afford the title compound (0.03 g, 100% yield) as a white foam. MS2 (ESI, m/z): 558.2 [M+H ⁺ ] for C28H35N3O7S; t _R = 0.98 min.

25.H (2R)-4-(6-((1r,3R)-3-(4-((3-Fluoroazetidin-1-yl)meth^hen

2(3H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 25.i (0.03 g; 0.054 mmol) and proceeding in analogy to Example 23, step 23. ii (51 % yield) and Procedure B (35% yield), the title compound (0.020 g) was obtained after purification by prep-HPLC (Method 3), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.98 (br.s., 1 H); 9.24 (br.s., 1 H); 7.25 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H); 7.04 (s, 1 H); 6.13 (d, J = 1.2 Hz, 1 H); 5.16 (m, 1 H); 4.42 (s, 2H); 3.65 (m, 1 H); 3.58 (s, 2H); 3.55-3.47 (m, 4H); 3.4 (overlapped m, 1 H); 3.13 (m, 1 H); 3.08 (s, 3H), 3.08 (overlapped m, 1 H); 2.58 (m, 1 H); 2.48-2.45 (m, 2H); 2.42-2.38 (m, 2H); 1.97 (m, 1 H); 1.53 (s, 3H. MS2 (ESI, m/z): 533.2 [M+H ⁺ ] for C26H33N4O5FS; t _R = 0.62 min. Example 26: (2 ?)-4-(6-((1r,3 ?)-3-(4-(1-aminocyclopropyl)phenyl)cyclobutyl)-3-oxo-1H-pyrr olo[1,2- c]imidazol-2(3H)-yl)-A/-hydroxy-2-methyl-2-(methylsulfonyl)b utanamide

261. Methyl (2R)-4-(6-((1r,3R)-3-(4-(1-(((benzyloxy)carbonyl)a ino)cyclopropy^

pyrrolo[1,2-c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfon Starting from methyl (2R)-4-(6-bromo- 3-oxo-1/-/-pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and al. in WO2017/037221 , 0.310 g, 0.79 mmol) and the compound of Preparation T (0.473 g; 1.18 mmol) and proceeding in analogy to Procedure G (5 more repetitions) afforded an intermediate mixture of cisltrans isomers (1.06 g). The latter was separated by chiral prep-HPLC (Method B) (carbon dioxide-EtOH-MeCN 55-22.5-22.5; flow rate: 4 mL/min, UV detection at 210 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.0 and 3.9 min. The title trans diastereomer, second- eluting diastereomer (0.494 g) was obtained as a yellowish foam. ¹ H NMR (DIVISOR) δ: 8.14 (m, 1 H), 7.40- 7.30 (m, 4H), 7.24 ( m, 1 H), 7.21 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.2 Hz, 2H), 7.05 (s, 1 H), 6.13 (d, J = 0.9 Hz, 1 H), 5.01 (s, 2H), 4.35 (s, 2H), 3.66-3.59 (m, 2H), 3.51 ( m, 3H), 3.49-3.39 (m, 2H), 3.14 (s, 3H), 2.61 (m, 1 H), 2.48-2.41 (m, 2H), 2.41 -2.37 (m, 2H), 2.06 (m, 1 H), 1.60 (s, 3H), 1.15-1.12 (m, 4H). MS2 (ESI, m/z): 501.1 [M+H ⁺ ] for C26H32N2O6S; t _R = 1.01 min.

26.H. Benzyl (1-(4-((1R,3r)-3-(2-((3R)-3-methyl-3-(methylsulfonyl^

yl)oxy)amino)butyl)-3 )xo-2,3-dihydro-1H yrrolo[1,2-c]^

Starting from intermediate 26. i (0.494 g; 0.78 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (99% yield), Example 1 , step 1/2.iii (74% yield), and Procedure B, the title compound (0.408 g) was obtained after purification by CC (EA-Hept-MeoH gradient), as a yellowish foam. MS2 (ESI, m/z): 719.38 [M+H ⁺ ] for C38H46N4O8S; t _R = 1.08 min.

26.iii. (2R)-4-(6-((1r,3R)-3-(4-(1-Aminocyclopropyl)phenyl)cyc^

yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide: To a solution of intermediate 26.ii (0.276 g; 0.38 mmol) in DCM (5.5 mL) was added at -10°C, a 1 M solution of BBr ₃ in DCM (0.768 mL, 0.768 mmol). The reaction porcceded at the same temperature for 45 min. Aq. NH4OH was added until pH=7 was reached. The resulting mixture was concentrated to dryness and the residue was dissolved in DMFand directly purified by prep HPLC (Method 3) to afford the title compound ( 0.0071 g, 4 % yield), as a white solid. ¹ H NMR (DMSO-cie) δ: 7.26- 7.18 (m, 4H), 7.04 (m, 1 H), 6.12 (d, J = 1.2 Hz, 1 H), 4.464.37 (m, 2H), 3.61 (m, 1 H), 3.49 (m, 2H), 3.41 (m, 2H), 3.07 (s, 3H), 2.61 -2.53 (m, 2H), 2.47-2.36 (m, 4H), 1.96 (m, 1 H), 1.53 (s, 3H), 0.94-0.86 (m, 4H). MS2 (ESI, m/z): 501.2 [M+H ⁺ ] for C25H32N4O5S; t _R = 0.63 min.

Example 27: (2 ?)-N-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1r,3 ?)-3-(4-(oxetan-3- yl)phenyl)cyclobutyl)-3-oxo-1 H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

271 Methyl (2R)-2-methyl-2-(methylsulfonyl) -(6-((1r,3R)-3-(4-(oxeta^^

pyrrolo[1 _: 2-c]imidazol-2(3H)-yl)butanoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1 /-/-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.433 g, 1.1 mmol) and the compound of Preparation U (0.441 g; 1.65 mmol) and proceeding in analogy to Procedure G (2 more repetitions) afforded an intermediate mixture of cisltrans isomers (0.75 g). The latter was separated by chiral prep-HPLC (Method C) (EtOH-carbon dioxide 7-13; flow rate: 160 mL/min, UV detection at 224 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 3.1 and 4.1 min. The title trans diastereomer, first-eluting diastereomer (0.356 g) was obtained as a white foam. ¹ H NMR (DMSO-cie) δ: 7.37-7.29 (m, 4H), 7.06 (s, 1 H), 6.14 (d, J = 1.2 Hz, 1 H), 4.93 (dd, J = 5.9, 8.4 Hz, 2H), 4.61 (dd, J = 5.9, 6.8 Hz, 2H), 4.35 (s, 2H), 4.23 (m, 1 H), 3.68-3.60 (m, 2H), 3.51 (s, 3H), 3.49-3.40 (m, 2H), 3.14 (s, 3H), 2.61 (m, 1 H), 2.48-2.44 (m, 2H), 2.42-2.37 (m, 2H), 2.06 (m, 1 H), 1.60 (s, 3H). MS2 (ESI, m/z): 501.1 [M+H ⁺ ] for C26H32N2O6S; t _R = 1.01 min.

27. H. (2R)^ydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1^

pyrrolo[1,2-c]imidazol-2(3H)-yl)butanamide: Starting from intermediate 27.i (0.336 g; 0.67 mmol) and proceeding successively in analogy to Example 5, step 5/6-vii (80% yield), Example 1 , step 1/2. iii (90% yield), and Procedure B (62% yield), the title compound (0.057 g) was obtained after purification by prep-HPLC (Method 3), as a white solid. ¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.23 (m, 1 H), 7.38-7.29 (m, 4H), 7.05 (s, 1 H), 6.13 (d, J = 1.2 Hz, 1 H), 4.93 (dd, J = 5.9, 8.4 Hz, 2H), 4.63-4.58 (m, 2H), 4.45-4.39 (m, 2H), 4.22 (m, 1 H), 3.65 (m, 1 H), 3.50 (m, 1 H), 3.44-3.39 (m, 2H), 3.07 (s, 3H), 2.58 (m, 1 H), 2.36-2.50 (m, 4H), 1.97 (m, 1 H), 1.54 (s, 3H). MS2 (ESI, m/z): 501.98 [M+H ⁺ ] for C25H31N3O6S; t _R = 0.85 min.

Example 28: ((2 ?)-A/-Hydroxy-4-(6-((1s,3 ?)-3-(3-hydroxypropyl)cyclobutyl)-3-oxo-1H-pyrrolo[1,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

281 3-((1R _: 3s)-3-(2-((2R)-4-Methoxy-3-methyl-3-(methylsulfony^

pyrrolo[1,2-c]imidazol-6-yl)cyclobutyl)propyl benzoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1 H- pyrrolo[1 ,2-c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoa te (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.433 g, 1.1 mmol) and the compound of Preparation V (0.491 g; 1.65 mmol) and proceeding in analogy to Procedure G (1 more repetitions) afforded an intermediate mixture of cisltrans isomers (0.322 g). The latter was separated by chiral prep-HPLC (Method C) (MeOH-carbon dioxide 3-7; flow rate: 160 mL/min, UV detection at 230 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 2.3 and 2.77 min. The title trans diastereomer, second-eluting diastereomer (0.137 g) was obtained as a yellowish foam. MS2 (ESI, m/z): 531.2 [M+H ⁺ ] for C27H34N2O7S; t _R = 1.10 min.

28. H. ((2R)-N^ydroxy-4-(6-((1s,3R)-3-(3-hydroxypropyl)cyclob^

2-methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 28.i (0.137 g; 0.258 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (88% yield), Example 1 , step 1/2.iii (71 % yield), Example 5, step 5/6 (80% yield) and Procedure B (82% yield), the title compound (0.046 g) was obtained after purification by prep-HPLC (Method 3), as a white solid. ¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.22 (m, 1 H), 6.91 (s, 1 H), 6.03 (d, J = 1.2 Hz, 1 H), 4.36-4.38 (m, 3H), 3.48 (m, 1 H), 3.40-3.34 (m, 3H), 3.30 (m, 1 H), 3.07 (s, 3H), 2.56 (m, 1 H), 2.25 (m, 1 H), 2.08 (m, 2H), 1.94 (m, 3H), 1.52 (s, 3H), 1.50-1.47 (m, 2H), 1.40-1.34 (m, 2H). MS2 (ESI, m/z): 428.21 [M+H ⁺ ] for C19H29N3O6S; t _R = 0.68 min.

Example 29: (2 ?)-A/-Hydroxy-4-(6-((1s,3 ?)-3-(4-hydroxybutyl)cyclobutyl)-3-oxo-1H-pyrrolo[1 ,2- c]imidazol-2(3H)-yl)-2-methyl-2-(methylsulfonyl)butanamide

291 4-((1R,3s)-3-(2-((R)-4-Methoxy-3-methyl-3-(methylsulfonyl)-4 -oxobu^

c]imidazol-6-yl)cyclobutyl)butyl benzoate: Starting from methyl (2R)-4-(6-bromo-3-oxo-1 /-/-pyrrolo[1 ,2- c]imidazol-2(3/-/)-yl)-2-methyl-2-(methylsulfonyl)butanoate (prepared as described by Blumstein, A.C. and a/, in WO2017/037221 , 0.335 g, 0.85 mmol) and the compound of Preparation W (0.398 g; 1.28 mmol) and proceeding in analogy to Procedure G (1 more repetitions) afforded an intermediate mixture of cisltrans isomers (0.327 g). The latter was separated by chiral prep-HPLC (Method C) (MeCN-EtOH-carbon dioxide 7- 7-36; flow rate: 160 mL/min, UV detection at 226 nm); the respective retention times of the diastereomers (flow rate: 4 mL/min) were 2.55 and 3.07 min. The title trans diastereomer, second-eluting diastereomer (0.145 g) was obtained as a colorless oil. MS2 (ESI, m/z): 545.1 [M+H ⁺ ] for C28H36N2O7S; t _R = 1.14 min.

29.il (2R)^ydroxy-4-(6-((1s,3R)-3-(4-hydroxybutyl)cyc^

methyl-2-(methylsulfonyl)butanamide: Starting from intermediate 28.i (0.145 g; 0.266 mmol) and proceeding successively in analogy to Example 5, step 5/6.vii (79% yield), Example 1 , step 1/2.iii (71 % yield), Example 5, step 5/6.IV (83% yield) and Procedure B (61 % yield), the title compound (0.035 g) was obtained after purification by prep-HPLC (Method 3), as a white solidJ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.21 (m, 1 H), 6.90(m, 1 H), 6.03 (d, J = 1.2 Hz, 1 H), 4.40-4.37 (m, 2H), 4.35 (t, J = 5.2 Hz, 1 H), 3.48 (m, 1 H), 3.37 (m, 2H), 3.31 (m, 1 H), 3.06 (s, 3H), 2.56 (overlapped m, 2H), 2.25 (m, 1 H), 2.08 (m, 2H), 1.95 (m, 3H), 1.52 (s, 3H), 1.49-1.42 (m, 2H), 1.44-1.38 (m, 2H), 1.28-1.19 (m, 2H). MS2 (ESI, m/z): 442.21 [M+H ⁺ ] for C20H31 N3O6S; t _R = 0.74 min.

Example 30: (2 ?)-A/-Hydroxy-2-methyl-2-(methylsulfonyl)-4-(6-((1r,3 ?)-3-(4- (morpholinomethyl)phenyl)cyclobutyl)-3-oxo-1H-pyrrolo[1 ,2-c]imidazol-2(3H)-yl)butanamide

Starting from intermediate 25. i (0.06 g; 0.108 mmol) and morpholine (0.02 g; 0.23 mmol) and proceeding in analogy to Example 23, step 23.ii (74% yield) and Procedure D (60% yield), the title compound (0.026 g) was obtained after purification by prep-HPLC (Method 2), as a white foam. ¹ H NMR (DMSO-cie) δ: 10.9 (m, 1 H), 9.20 (m, 1 H), 7.26 (m, 4H), 7.05 (s, 1 H), 6.13 (d, J = 1.1 Hz, 1 H), 4.42 (s, 2H), 3.64 (m, 1 H), 3.56 (t, J = 4.5 Hz, 4H), 3.50 (m, 1 H), 3.42-3.40 (m, 3H), 3.08 (s, 3H), 2.57(m, 1 H), 2.43-2.33 (m, 9H), 1.96 (m, 1 H), 1.53 (s, 3H).MS2 (ESI, m/z): 545.2 [M+H ⁺ ] for C27H36N4O6S; t _R = 0.82 min.

Bacterial growth minimal inhibitory concentrations:

E p nentaJ. 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 Aerobicallf, Approved standard, 7 ^th ed., Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA (2006). Results:. All Example compounds were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results are given in Table 1 hereafter (MICs in mg/L). 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.

MIC for 14 4 8 4

MIC for MIC for

Exam P.

E. coli K. 15 0.5 8 4 pie aeruginosa

ATCC2 Pneumoniae

No. ATCC2785 16 0.125 2 0.5

5922 A-651

3

17 1 8 2

1 0.25 8 2 18 0.125 4 0.5

2 0.25 8 2 19 1 2 4

3 0.5 8 2 20 <0.06 1 0.125

4 0.25 4 1 21 1 2 2

5 0.5 8 4 22 0.25 4 1

6 0.25 8 2 23 2 8 4

7 0.25 2 0.5 24 0.25 2 1

8 0.125 8 0.125 25 0.25 1 0.125

9 0.125 4 0.25 26 1 4 2

10 <0.06 2 <0.06 27 <0.06 4 0.25

11 0.25 4 1 28 2 4 8

12 0.25 4 0.125 29 0.25 2 0.5

13 4 16 16 30 0.25 4 0.5