TW201429972A - Antibacterial oxazolone derivatives - Google Patents

Abstract

The invention relates to antibacterial compounds of formula I wherein U represents CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents H, halogen, methyl, methoxy, cyano or ethynyl; either W represents a phenyl group substituted in para position with (C1-C3)alkyl, (C1-C3)alkoxy or (C1-C3)thioalkoxy and optionally in meta position with halogen, or W is a group having one of the formulae W1 and W2 below wherein Q is O or S and X is CH or N; and salts of such compounds.

Description

Antibacterial oxazolone derivatives

The present invention relates to antibacterial oxazolone derivatives, pharmaceutical compositions containing the same, and the use of such compounds in the manufacture of a medicament for the treatment of bacterial infections. These compounds are useful antimicrobial agents against a variety of human and veterinary pathogens, including, in particular, Gram-positive and Gram-negative aerobic and anaerobic bacteria and mycobacteria. .

The widespread use of antibiotics has exerted selective evolutionary pressure on microorganisms, resulting in genetically based resistance mechanisms. Modern medical and socio-economic behaviors exacerbate the problems of resistance due to the slow growth of pathogenic microorganisms in, for example, artificial joints and the support of, for example, long-term host storage in immunocompromised patients.

In the hospital environment, an increasing number of Staphylococcus aureus , Streptococcus pneumoniae , Enterococcus spp. , Enterobacteriacea , and Pseudomonas aeruginosa (the main source of infection) is becoming resistant to a variety of drugs and is therefore difficult, if not impossible, to treat: - S. aureus is resistant to beta-indoleamine, quinolinone and now even vancomycin (vancomycin -) is also resistant; - Streptococcus pneumoniae (S. pneumoniae) are becoming penicillin (pENICILLIN) -quinolinone or resistant to antibiotics and even to new macrocyclic lactones are also resistant ; - Enterococcus (enterococci) and resistant β- lactam antibiotics resistant strains such invalid -quinolinone and vancomycin; - Enterobacteriaceae cephalosporins (cephalosporin) -quinolinone and resistant ;- P. aeruginosa is resistant to β-endoamine and quinolinone.

In addition, the incidence of multi-drug resistant Gram-negative strains (eg, Enterobacteriaceae and Pseudomonas aeruginosa) is increasing, and new organisms (such as Acinetobacter) that have been selected for antibiotics currently in use during treatment (eg, Acinetobacter) Acinetobacter spp. or Clostridium difficile is becoming a real problem in the hospital environment. Therefore, there is an urgent need in the medical field for novel antibacterial agents that are resistant to such multi-drug resistant bacteria.

In addition, microorganisms that are causing persistent infections are increasingly being considered as causative factors or cofactors for severe chronic diseases such as peptic ulcers or heart diseases.

WO 2012/041194 describes antibacterial compounds of formula (A1)

Wherein "-----" is a (especially) bond; R ⁰ represents (especially) H; R ¹ represents (especially) halogen; when "-----" is a bond, U stands for CH or N; V represents (in particular) CH; R ² represents (especially) H; R ⁴ represents (especially) H; R ⁵ represents (especially) H; A represents (especially) - (CH ₂ ) _p -; G represents meta and/or a phenyl group substituted once or twice with a substituent independently selected from (C ₁ -C ₄ )alkyl, (C ₁ -C ₃ )alkoxy, and halogen, whereby (C ₁ -C ₃ ) The alkoxy substituent is preferably a linear (C ₁ -C ₃ ) alkoxy group and is in the para position, or the G system has a group of one of the following formulas G ¹ and G ² Wherein Q is O or S and X is CH or N; and Y ¹ , Y ² and Y ³ may each specifically represent CH; and when A represents -(CH ₂ ) _p -, n is 0, 1 or 2, p The system is 1, 2, 3 or 4, and the condition is the sum of n and p is 2, 3 or 4.

The present invention provides novel antibacterial compounds based on oxazolone moieties, i.e., compounds of formula I as set forth herein.

Various embodiments of the invention are presented below: 1) the invention relates to a compound of formula I

Wherein U represents CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents H, halogen, methyl, methoxy, cyano or ethynyl; Substituted by (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )thioalkoxy and optionally substituted by halogen (preferably fluorine) in the meta position a phenyl group, or a group of W having one of the following formulas W ¹ and W ²

Wherein Q is O or S and X is CH or N; and is a salt of a compound of formula I (specifically a pharmaceutically acceptable salt).

The following paragraphs provide definitions of the various chemical moieties in the compounds of the present invention, and are intended to be applied uniformly throughout the specification and claims, unless the definitions that are specifically set forth herein provide a broader or narrower definition.

The term "alkyl", when used alone or in combination, refers to a straight or branched alkyl group containing from 1 to 4 carbon atoms. The term "(C ₁ -C _x )alkyl" (x-based integer) means a straight-chain or branched alkyl group having 1 to x carbon atoms. For example, a (C ₁ -C ₃ )alkyl group contains from 1 to 3 carbon atoms. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second butyl, and tert-butyl. Preferred are methyl and ethyl. The best is methyl.

The term "alkoxy", when used alone or in combination, refers to a straight or branched alkoxy group containing from 1 to 4 carbon atoms. The term "(C _x -C _y ) alkoxy" (each of which is an integer of x and y) means an alkoxy group having from x to y carbon atoms as defined hereinbefore. For example, a (C ₁ -C ₃ ) alkoxy group contains from 1 to 3 carbon atoms. Representative examples of alkoxy include methoxy, ethoxy, n-propoxy and isopropoxy. Preferred are methoxy and ethoxy groups. The best is methoxy.

The term "thioalkoxy", when used alone or in combination, means an alkoxy group as defined above, wherein the oxygen atom is replaced by a sulfur atom. In addition to the sulfur atom, the thioalkoxy group thus includes a straight or branched alkyl group having one to four carbon atoms. The term "(C _x -C _y ) thioalkoxy" (each of which is an integer of x and y) means a thioalkoxy group having from x to y carbon atoms as defined hereinbefore. For example, (C ₁ -C ₃ )thioalkoxy contains 1 to 3 carbon atoms. Representative examples of alkoxy include methylthio, ethylthio, n-propylthio and isopropylthio. Preferred are methylthio and ethylthio. The best one is ethylthio.

The term "halogen" means fluoro, chloro, bromo or iodo, and preferably means fluoro or chloro.

The term "quinolinone resistance" as used herein refers to a bacterial strain that is the minimum inhibitory concentration of ciprofloxacin against the bacterial strain (this minimum inhibitory concentration is described in "Methods for Dilution Antimicrobial Susceptibility Tests". For Bacteria that Grow Aerobically", an approved standard, 7th edition, measured by the standard method of Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA, 2006) is at least 16 mg/l.

The term "methicillin-resistant" as used herein refers to a bacterial strain in which the minimum inhibitory concentration of methicillin against the bacterial strain is utilized (this minimum inhibitory concentration is described in "Methods" For Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Accredited Standards, 7th Edition, Clinical and Laboratory Standards Institute (CLSI) Document M7-A7, Wayne, PA, USA, 2006, measured by standard methods) is at least 16 mg / l.

The term "pharmaceutically acceptable salt" means a non-toxic, inorganic or organic acid and/or base addition salt. See "Salt selection for basic drugs", Int. J. Pharm. (1986), 33 , 201-217.

Herein, the bond broken by the wavy line shows the point at which the depicted group is attached to the rest of the molecule. For example, the groups shown below

3-terpoxy-3,4-dihydro- 2H -benzo[ b ][1,4]oxazin-6-yl.

Further, the term "room temperature" as used herein means a temperature of 25 °C.

Unless the temperature is used, the term "about" placed before the value "X" in this application refers to the range extending from X-10% X to X + 10% X, and preferably refers to X. -5% X extends to the X+5% X range. In the case of a particular temperature, the term "about" placed before the temperature "Y" means in the present application an interval extending from the temperature Y-10 ° C to Y + 10 ° C, and preferably from Y-5. °C extends to the interval of Y+5°C.

2) A second embodiment of the invention relates to a compound of formula I according to embodiment 1), which is also a compound of formula I _E1

The absolute configuration of the asymmetric carbon of the three rings is as shown in the formula I _E1 [ie the absolute configuration of the asymmetric carbon of the three rings ( S )].

3) A third embodiment of the invention relates to a compound of formula I according to embodiment 1), which is also a compound of formula I _E2

The absolute configuration of the asymmetric carbon of the three rings is as shown in the formula I _E2 [ie the absolute configuration of the asymmetric carbon of the three rings ( R )].

4) Preferably, the compound of formula I as defined in any one of embodiments 1) to 3) will be such that R represents H, fluoro, methyl, methoxy or cyano.

5) The invention relates in particular to a compound of formula I according to embodiment 1), which is also a compound of formula I _P

Wherein U represents CH or N; W represents a substitution at the para position by (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )thioalkoxy and optionally a phenyl group substituted by a halogen (preferably fluorine), or a group having a W group having one of the following formulas W ¹ and W ²

Wherein Q is O or S and X-based system CH or N; and based on a salt of a compound of formula I _P (a pharmaceutically acceptable salt thereof In particular).

6) A further embodiment of the present invention based on a compound in accordance with Example I _P 5) of the formula which compound is of formula I also _PE1

The absolute configuration of the asymmetric carbon of the three rings is as shown in the formula I _PE1 [ie the absolute configuration of the asymmetric carbon of the three rings ( S )].

7) A further embodiment of the present invention based on a compound in accordance with Example I _P 5) of the formula which compound is of formula I also _PE2

The absolute configuration of the asymmetric carbon of the three rings is as shown in the formula I _PE2 [ie the absolute configuration of the asymmetric carbon of the three rings ( R )].

8) According to a main embodiment of the invention, the compound of formula I as defined in any one of embodiments 1) to 7) will be such that U represents CH and V, if present, represents CH.

9) Example 8) One sub-embodiment as described based on the I compound of Formula 8) as defined in the embodiment, in which W 1 W-based formula) as defined in Example ¹ of the group.

10) Another sub-embodiment of embodiment 8) relates to a compound of formula I as defined in example 8), wherein W is a group of formula W ² as defined in example 1).

11) A further sub-embodiment of embodiment 8) is a compound of formula I as defined in example 8), wherein W represents (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ ) in the para position Alkoxy or (C ₁ -C ₃ )thioalkoxy and optionally substituted by halogen (preferably fluorine) in the meta position.

12) According to another principal embodiment of the invention, the compound of formula I as defined in any one of embodiments 1) to 4) will be such that each of U and V represents CH.

13) According to one variant of embodiment 12), the compound of formula I as defined in example 12) will be such that R represents fluorine.

14) According to another variant of embodiment 12), the compound of formula I as defined in example 12) will be such that R represents H.

15) According to a further variant of embodiment 12), the compound of formula I as defined in example 12) will be such that R represents methyl or methoxy.

16) According to a further variant of embodiment 12), the compound of formula I as defined in example 12) will be such that R represents a cyano group.

17) According to another principal embodiment of the invention, the compound of formula I as defined in any one of embodiments 1) to 4) will be such that U represents CH and V represents N.

18) According to one variant of embodiment 17), the compound of formula I as defined in example 17) will be such that R represents fluorine.

19) According to another variant of embodiment 17), the compound of formula I as defined in example 17) will be such that R represents H.

20) According to a further variant of embodiment 17), the compound of formula I as defined in example 17) will be such that R represents methyl or methoxy.

21) According to a further variant of embodiment 17), the formula I as defined in example 17) The substance will be such that R represents a cyano group.

22) According to still another principal embodiment of the invention, the compound of formula I as defined in any one of embodiments 1) to 7) will be such that U represents N.

23) Example 22) One sub-embodiment based on the compound as described in Example 22) as defined in the formula I, wherein W W-based formula as in Example 1) as defined in embodiment ¹ of the group.

24) Another sub-embodiment of embodiment 22) is a compound of formula I as defined in example 22), wherein W is a group of formula W ² as defined in example 1).

25) A further sub-embodiment of embodiment 22) is the compound of formula I as defined in example 22), wherein W represents (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ ) in the para position Alkoxy or (C ₁ -C ₃ )thioalkoxy and optionally substituted by halogen (preferably fluorine) in the meta position.

26) According to one of the variants of embodiment 22), the compound of formula I as defined in example 22) will be such that R represents fluorine.

27) According to another variant of embodiment 22), the compound of formula I as defined in example 22) will be such that R represents H.

28) According to a further variant of embodiment 22), the compound of formula I as defined in example 22) will be such that R represents methyl or methoxy.

29) According to yet another variant of embodiment 22), the compound of formula I as defined in example 22) will be such that R represents a cyano group.

30) According to a preferred main variant of the invention, the compound of formula I as defined in any one of embodiments 1) to 7) will be such that W is based on the formula W ¹ as defined in example 1) group.

31) According to another major variant of the invention, the compound of formula I as defined in any one of embodiments 1) to 7) will be such that W is a group of formula W ² as defined in example 1) .

32) According to still another major variant of the invention, the compound of formula I as defined in any one of embodiments 1) to 7) will be such that W represents (C ₁ -C ₃ )alkyl in the para position, C ₁ -C ₃ ) alkoxy or (C ₁ -C ₃ )thioalkoxy substituted and optionally substituted by halogen (preferably fluorine) in the meta position.

33) Preferably, the compound of formula I as defined in example 32) will be such that W represents (C ₁ -C ₃ )alkyl, (C ₁ -C ₂ )alkoxy or (C ₁ -C ₂ ) a phenyl group substituted by a thioalkoxy group and optionally substituted by fluorine at the meta position.

34) A preferred embodiment of the invention relates to a compound of formula I according to embodiment 1), wherein: U stands for CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents H, fluorine or cyano; W represents a phenyl group substituted at the para position by a (C ₁ -C ₃ )alkyl group, a (C ₁ -C 2 ) thioalkoxy group or a (C ₁ -C 2 ) alkoxy group, and optionally a fluorine group at the meta position. Or W is a group having one of the following formulas W ¹ and W ²

Wherein Q is O or S and X is CH or N.

35) A sub-embodiment of embodiment 34) is directed to a compound of formula I as defined in example 34), the absolute configuration of the asymmetric carbon of the tricyclic ring and as depicted in formula I _E1 as in Example 2) The same is true.

36) Another sub-embodiment of embodiment 34) is the compound of formula I as defined in example 34), the absolute configuration of the tricyclic asymmetric carbon and the formula I _E2 as in Example 3) The figures are the same.

37) In particular, the compounds of Examples 34) to 36) will be such that V represents CH and R represents fluorine.

38) An even preferred embodiment of the invention relates to a compound of formula I according to embodiment 1), wherein: U stands for CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents fluorine or cyano; The W system has a group of the following formula W ¹

Wherein Q is O or S and X is CH or N.

39) A sub-embodiment of embodiment 38) is directed to a compound of formula I as defined in embodiment 38), the absolute configuration of the asymmetric carbon of the tricyclic ring and as depicted in formula I _E1 as in Example 2) The same is true.

40) Another sub-embodiment of embodiment 38) is the compound of formula I as defined in example 38), the absolute configuration of the tricyclic asymmetric carbon and the formula I _E2 as in Example 3) The figures are the same.

41) In particular, the compounds of Examples 38) to 40) will be such that V represents CH and R represents fluorine.

42) A further embodiment of the invention is directed to a compound of formula I as defined in any one of embodiments 1) to 41) and as described in relation to isotope-labeled, in particular by ² H (氘) a compound of formula I as defined in any one of 41), which is the same as the compound of formula I as defined in any one of embodiments 1) to 41), except that one or more of the atoms have been Atom substitutions with the same atomic order but different atomic masses than those normally found in nature. Thus, isotopically labeled, especially ² H (indole) labeled compounds of formula I and salts thereof (particularly pharmaceutically acceptable salts) are within the scope of the invention. Substitution of hydrogen with the heavier isotope ² H (indole) may increase metabolic stability, such as, for example, prolonged in vivo half-life or reduced dosage requirements, or may result in reduced inhibition of cytochrome P450 enzymes, thereby making, for example, safe Improved characteristics. In one variation of the invention, the compound of formula I is not isotopically labeled or it is only labeled with one or more deuterium atoms. Isotopically labeled compounds of formula I can be prepared by methods analogous to those described hereinafter, but using suitable reagents or suitable isotopic variations of the starting materials.

43) Particularly preferred are the compounds of the formula I below as defined in Examples 1) to 5): -( S )-7-fluoro-6-{3-[3-(3-fluoro-4-methyl- Phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quina Porphyrin-3-one;-( R )-9-fluoro-1-{3-[3-(3-fluoro-4-methyl-phenyl)-2-oxo-2,3-dihydro -oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( R )-1-{3- [3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propylamino}}--fluoro-1,2-di Hydrogen-pyrrolo[3,2,1- ij ]quinolin-4-one;-( R )-6-{3-[3-(2,3-dihydro-benzo[1,4]dioxo Heterocyclohexene-6-yl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrole [1,2,3- de ]quinoxalin-3-one;-( S )-6-{3-[3-(4-ethoxy-phenyl)-2- oxo-2,3 -dihydro-oxazol-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;- R )-9-fluoro-1-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl]-propylamino }-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-7-fluoro-6-{3-[2- oxo-3- (4-propyl -phenyl)-2,3-dihydro-oxazole-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline-3- Ketone;-( S )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro-2 H -benzo[1,4]thiophene Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinoline-4 -ketone;-( R )-7-fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro-2 H -benzo[1,4] Thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline 3-ketone;-( S )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1, 4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quina Benzolin-4-one;-( R )-7-fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro-2 H -benzo[1] ,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ] Quinoxalin-3-one;-( S )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -pyridine [3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrole [3,2,1- ij ]quinolin-4-one;-( R )-7-fluoro- 6-{3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazine-6- -2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; - ( S )-7-Fluoro-6-{3-[2- oxo-3-(3- oxo-3,4-dihydro-2 H -pyrido[3,2- b ][ 1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de Quinoxalin-3-one;-( R )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro-2 H -pyridine And [3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrole And [3,2,1- ij ]quinolin-4-one;-( S )-9-fluoro-1-{3-[2-o-oxy-3-(3- oxo-3,4 -dihydro-2 H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}- 1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; and a salt thereof (particularly a pharmaceutically acceptable salt).

44) Also preferred are the compounds of formula I as defined in Example 1) or 5): -( R )-9-fluoro-1-{3-[2- oxo-3-(3- Sideoxy-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}- 1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-7-fluoro-6-{3-[2- oxo-3-(3) -Sideoxy-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino} -5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;-( R )-9-fluoro-1-{3-[2- oxo-3- (3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamine }}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-7-fluoro-6-{3-[2- oxo-3 -(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propyl Amino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;-( S )-1-{3-[3-(2,3-dihydrol) -benzo[1,4]dioxine-6-yl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamino}-9-fluoro -1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( R )-1-{3-[3-(2,3-dihydro-benzo[ 1,4]dioxane -6-yl)-2-yloxy-2,3-dihydro-oxazol-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2 , 1- ij ]quinolin-4-one;-( S )-6-{3-[3-(2,3-dihydro-benzo[1,4]dioxine-6-yl )-2-oxooxy-2,3-dihydro-oxazol-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de Quinoxaline-3-one;-( S )-9-fluoro-1-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-acean Zyrid-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( R )-7-fluoro-6-{ 3-[2-Sideoxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrole And [1,2,3- de ]quinoxalin-3-one;-( S )-1-{3-[3-(4-ethoxy-phenyl)-2- oxo-2, 3-dihydro-oxazol-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;- R )-6-{3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamino}-7 -fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;-( S )-9-fluoro-1-{3-[3-(3-fluoro -4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2 , 1- ij ]quinolin-4-one;- ( R )-7-fluoro-6-{3-[3-(3-fluoro-4-methyl-phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-prop Amino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;-( R )-9-fluoro-1-{3-[2- side oxygen 3-(3-oxo-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro- Oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-7-fluoro-6- {3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl) -2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;- R )-7-fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1, 4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quina Porphyrin-3-one; and a salt thereof (particularly a pharmaceutically acceptable salt).

45) Further, especially preferred are the compounds of the formula I as defined in Example 1): -( S )-1-{3-[2-Sideoxy-3-(3-Sideoxy-3) ,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino }-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-6-{3-[2-trioxy-3-(3-side Oxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]- Propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; -( R )-6-{3-[2-trioxy-3 -(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole- 5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one;-( S )-3-fluoro-4-{3 -[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2 ,3-dihydro-oxazol-5-yl]-propylamino}-4,5-dihydro-pyrrolo[3,2,1- de ][1,5]naphthyridin-7-one; - ( R )-3-fluoro-4-{3-[2-oxo-3-(3-oxo-3,4-dihydro- 2H -pyrido[3,2- b ][ 1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-4,5-dihydro-pyrrolo[3,2,1- de ][1,5]naphthyridine-7 -ketone;-( S )-9-methoxy-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3, 2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3, 2,1- ij ]quinolin-4-one;-( S )-9-methyl-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydrol -2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2 -dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one;-( S )-4-indolyl-1-{3-[2- oxo-3-(3- Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl] -propylamino}-1,2-dihydro- 4H -pyrrolo[3,2,1- ij ]quinoline-9-carbonitrile; and salts thereof (specifically, pharmaceutically acceptable salts) .

46) The invention further relates to a compound of formula I as defined in embodiment 1), which is selected from the group consisting of the compounds listed in Example 43), the compounds listed in Example 44) And the compounds listed in Example 45). In particular, the present invention is also directed to a group of compounds of formula I selected from the group consisting of the compounds listed in Example 43), the compounds listed in Example 44), and listed in Example 45. A compound of the formula, wherein the group of such compounds further corresponds to one of the examples 2) to 41); and is a salt of the compound (specifically a pharmaceutically acceptable salt). The invention is also related to selection Any of the individual compounds of the formula I: the compound listed in Example 43), the compound listed in Example 44), and the compound listed in Example 45), Salts of individual compounds (particularly pharmaceutically acceptable salts).

The compounds of the formula I according to the invention (ie any of the above Examples 1) to 46) are suitable for use as chemotherapeutic active compounds in human and veterinary medicine and are suitable for use in the preservation of inorganic and organic materials. (Specifically, all types of organic materials such as polymers, lubricants, coatings, fibers, leather, paper, and wood).

The compounds of formula I of the present invention are particularly active against bacterial and bacterial like organisms. Therefore, it is particularly suitable for the prevention and chemotherapeutic treatment of local and systemic infections caused by such pathogens and diseases associated with bacterial infections in human and veterinary medicine, including pneumonia, otitis media, sinuses associated with the following infections Inflammation, bronchitis, tonsillitis and mastoiditis: Streptococcus pneumoniae, Haemophilus influenzae , Moraxella catarrhalis , Staphylococcus aureus, Enterococcus faecalis Enterococcus faecium , Enterococcus casseliflavus , Staphylococcus epidermidis , Staphylococcus haemolyticus or Peptostreptococcus spp .; associated with the following infections Pharyngitis, rheumatic fever and glomerulonephritis: Streptococcus pyogenes , group C and streptococcus cocci (streptococci), Corynebacterium diphtheriae or Actinobacillus haemolyticum ; Infection-related respiratory infections: Human Mycoplasma pneumoniae (Mycoplasma pneumoniae), Legionella pneumophila bacteria veterans (Legionella pneumophila), Streptococcus pneumoniae, Haemophilus influenzae (H. influenzae), or Chlamydia pneumoniae (Chlamydia pneumoniae); caused by the blood of and tissue infections (including endocarditis and osteomyelitis): Staphylococcus aureus, Staphylococcus haemolyticus (S.haemolyticus), Enterococcus faecalis (E.faecalis), feces enterococci (E.faecium), durable enterococci ( Enterococcus durans ), including known antibacterial agents (such as (but not limited to) β-namidamide, vancomycin, aglycosides, quinolones, chloramphenicol, tetracycline, and macrolides Resistant strains; non-complex skin and soft tissue infections associated with infections and abscesses and puerperal fever: Staphylococcus aureus, coagulase-negative staphylococci (ie S. epidermidis , hemolysis) staphylococci, etc.), Streptococcus pyogenes (S.pyogenes), Streptococcus agalactiae (Streptococcus agalactiae), CF streptococci (Streptococcus small colonies), grass green streptococci (viridans streptoco Cci), Corynebacterium minutissimum , Clostridium spp. or Bartonella henselae ; non-concurrent acute urinary tract infection associated with infection: Staphylococcus aureus, Coagulase-negative staphylococci or enterococci; urethritis and cervicitis; sexually transmitted diseases associated with the following infections: Chlamydia trachomatis , Haemophilus ducreyi , Treponema pallidum , Ureaplasma urealyticum or Neiserria gonorrheae ; toxin diseases associated with infections: Staphylococcus aureus (food poisoning and toxic shock syndrome) or group A, group B and group C streptococci Ulcers associated with the following infections: Helicobacter pylori ; systemic febrile syndrome associated with infections: Borrelia recurrentis ; Lyme associated with Borrelia burgdorferi infection Lyme disease; conjunctivitis and keratitis associated with the following infections Dacryocystitis: Chlamydia trachomatis (C.trachomatis), Neisseria gonorrhoeae (N.gonorrhoeae), Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, or Listeria (Listeria spp .); disseminated Mycobacterium avium complex (MAC) disease associated with the following infections: Mycobacterium avium or Mycobacterium intracellulare ; infection caused by: tuberculosis Mycobacterium tuberculosis , Mycobacterium leprae , Mycobacterium paratuberculosis , Mycobacterium kansasii , or Mycobacterium chelonei ; and jejunum Gastroenteritis associated with Campylobacter jejuni infection; intestinal protozoa associated with Cryptosporidium spp. infection; odontogenic infection associated with S. cerevisiae infection; and Bordetella with Bordetella Pertussis ) persistent cough associated with infection; with Clostridium perfrin Gens) or the genus Bacteroides (Bacteroides spp) gas gangrene related to infection; The correlation of H. pylori and (of H.pylori) or Chlamydophila pneumoniae (C.pneumoniae) infection atherosclerosis or cardiovascular disease.

The previously listed infections and pathogens are to be understood as examples only and are in no way limiting.

The compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof can therefore be used for the preparation of a prophylactic or therapeutic bacterial infection (especially for the prevention or treatment of bacterial infections mediated by S. aureus or Acinetobacter baumanii , in particular prevention Or a medicament for treating a bacterial infection mediated by quinolinone resistance and methicillin-resistant Staphylococcus aureus or quinolinone-resistant Acinetobacter baumannii, and is suitable for the prevention or treatment.

Therefore, the compound of the formula I according to any one of the embodiments 1) to 46), or a pharmaceutically acceptable salt thereof, can be used for the preparation of a medicament for preventing or treating a bacterial infection selected from the group consisting of and suitable for the prevention or treatment: Respiratory infections, otitis media, meningitis, skin and soft tissue infections (concurrent or non-concurrent), pneumonia (including nosocomial pneumonia), bacteremia, endocarditis, intra-abdominal infection, gastrointestinal infection, refractory spores Bacterial infection, urinary tract infection, sexually transmitted infection, foreign body infection, osteomyelitis, Lyme disease, local infection, ophthalmic infection, tuberculosis and tropical diseases (such as malaria), and especially for preventing or treating bacteria selected from the group consisting of Infection: respiratory infections, otitis media, meningitis, skin and soft tissue infections (concurrent or non-concurrent), pneumonia (including nosocomial pneumonia) and bacteremia.

The compound of formula I according to any one of embodiments 1) to 46) (and in particular Example 1), wherein the W group W ¹ ) can be further used for the preparation of a medicament for the treatment of infections mediated by the following bacteria Medicine and suitable for this treatment: Gram-negative bacteria (eg Haemophilus influenzae, M. catarrhalis, Escherichia coli , Klebsiella pneumoniae and other enterobacteria ) Section Acinetobacter (Enterobacteriaceae, Acinetobacter spp)) (including Acinetobacter baumannii, Pseudomonas aeruginosa, Stenotrophomonas maltophilia Aeromonas (Stenotrophomonas maltophilia) and meningococcal (Neisseria meningitidis))), in particular selected from the group consisting of E. coli Gram-negative bacteria consisting of Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, M. catarrhalis, Stenotrophomonas maltophilia, and meningococcus. In particular, the compound of formula I according to any one of embodiments 1) to 46), in particular the compound of formula I of example 1) (wherein the W group W ¹ ), can be used for the preparation of a therapeutic Acinetobacter baumannii (especially quin A ketone-resistant Acinetobacter baumannii) or a M. catarrhalis-mediated bacterial infection, and suitable for this treatment.

The compound of formula I according to any one of embodiments 1) to 46) (and in particular Example 1), wherein the W group W ¹ ) can be further used for the preparation of a medicament for the treatment of infections mediated by the following bacteria Medicine and suitable for the treatment: Gram-positive bacteria, such as Staphylococcus aureus, Bacillus cereus , Bacillus anthracis , Clostridium faecalis, Corynebacterium spp. And Propionibacterium acnes , especially a Gram-positive bacterium selected from the group consisting of Bacillus cereus, Bacillus anthracis, Clostridium difficile, and Propionibacterium acnes. In particular, the compound of formula I according to any one of embodiments 1) to 46) (and in particular example 1), wherein the W group W ¹ ) can be used for the preparation of a treatment by Staphylococcus aureus (especially A quinolinone-resistant Staphylococcus aureus mediated drug for bacterial infection, and which is suitable for this treatment.

The compound of the formula I according to any one of embodiments 1) to 46) can be further used for the preparation of a medicament for treating a protozoal infection mediated by the following: suitable for the treatment: Plasmodium malaria , Plasmodium falciparum Plasmodium falciparum , Toxoplasma gondii , Pneumocystis carinii , Trypanosoma brucei and Leishmania spp .

The compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof can furthermore be used for the preparation of a medicament for the prophylaxis or treatment (and in particular treatment) of an infection caused by and suitable for the prevention or treatment: as by the US Centers for Disease Control (US Center) For Disease Control) lists the biohazardous bacterial pathogens (for a list of such biologically threatened bacterial pathogens, see http://www.selectagents.gov/Select%20Agents%20and%20Toxins%20List.html ), and in particular The pathogens of the following group are selected: Bacillus anthracis (anthrax), Clostridium botulinum , Yersinia pestis , Francisella tularensis ( Tularia ), sinus- like Burke Burkholderia pseudomallei and Burkholderia mallei .

Accordingly, one aspect of the invention relates to the use of a compound of formula I according to any one of embodiments 1) to 46), and in particular to a compound of formula I according to example 1 wherein the W group is Use of W ¹ ), or the use thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a bacterial infection (specifically one of the aforementioned infections mediated by Gram-negative bacteria or the aforementioned Medicine for the infection of Langer-positive bacteria). A further aspect of the invention relates to a compound of formula I according to any one of embodiments 1) to 46) (and in particular according to embodiment 1), wherein the W group W ¹ ) A pharmaceutically acceptable salt for use in preventing or treating a bacterial infection (particularly preventing or treating the aforementioned infection mediated by Gram-negative bacteria or the aforementioned infection mediated by Gram-positive bacteria).

A further aspect of the invention is the compound of formula I according to any one of embodiments 1) to 46) (and in particular according to embodiment 1), wherein the W group W ¹ ) A pharmaceutically acceptable salt, which is used as a medicine. A further aspect of the invention relates to a pharmaceutical composition comprising, as an active ingredient, a compound of formula I according to any one of embodiments 1) to 46) (and in particular according to example 1), Wherein W is a group W ¹ ) or a pharmaceutically acceptable salt thereof, and at least one medically inert excipient.

As in humans, it can also be found in other species (eg pigs, ruminants, horses, dogs, The compound of formula I (or a pharmaceutically acceptable salt thereof) is used in cats and poultry to treat bacterial infections.

The invention also relates to pharmaceutically acceptable salts and compositions and formulations of the compounds of formula I, I _E1 , I _E2 , I _P , I _PE1 or I _PE2 .

Where appropriate and convenient, any reference herein to a compound of formula I, I _E1 , I _E2 , I _P , I _PE1 or I _{PE2 is} understood to also refer to salts of such compounds (and especially pharmaceutically acceptable salts). ).

The pharmaceutical composition of the present invention contains at least one compound of the formula I (or a pharmaceutically acceptable salt thereof) as an active agent, and optionally a carrier and/or a diluent and/or an adjuvant, and may also contain other Know antibiotics.

The compounds of formula I and their pharmaceutically acceptable salts can be used in the form of pharmaceutical compositions for enteral or parenteral administration.

The pharmaceutical composition can be produced in any manner familiar to those skilled in the art (for example, see Remington, The Science and Practice of Pharmacy , 21st Ed. (2005), Part 5, "Pharmaceutical Manufacturing" [by Lippincott Williams & Wilkins publishes]) by combining the compound of formula I or a pharmaceutically acceptable salt thereof (as appropriate with other therapeutically valuable substances) together with suitable non-toxic, inert, therapeutically compatible solid or liquid carrier materials and (If necessary) a common pharmaceutical adjuvant is used to make a galenical administration form.

A further aspect of the invention relates to a method of preventing or treating a bacterial infection in a patient, comprising administering a compound of formula I according to any one of embodiments 1) to 46) to the pharmaceutically active amount of the patient (specifically Example 1) the compound of formula I, wherein group W ¹ W-based) or a pharmaceutically acceptable salt thereof. Accordingly, the present invention provides a method of preventing or treating a bacterial infection mediated by Gram-negative bacteria in a patient, in particular a bacterial infection mediated by Acinetobacter baumannii and especially by quinolinone-resistant Acinetobacter baumannii. a compound of formula I according to any one of embodiments 1) to 46) (specifically according to Example 1), wherein the W group is W ¹ ) or Its pharmaceutically acceptable salt. The present invention further provides a method of preventing or treating a bacterial infection mediated by Gram-positive bacteria in a patient, in particular a bacterial infection mediated by Staphylococcus aureus, in particular by quinolinone-resistant Staphylococcus aureus, It comprises a compound of formula I according to any one of embodiments 1) to 46) (specifically according to Example 1), wherein the W group is W ¹ ) or A pharmaceutically acceptable salt.

In addition, the compounds of formula I of the present invention may also be used for cleaning purposes, for example, removal of pathogenic microorganisms and bacteria from surgical instruments, catheters and artificial grafts or access to sterile rooms or areas. For these purposes, the compounds of formula I may be included in solution or spray formulations.

Accordingly, the present invention relates to a compound of formula I as defined in embodiment 1) or in view of its individual dependence further restricted by the characteristics of any of embodiments 2) to 46), and Accept the salt. Furthermore, the invention relates to the use of such compounds as medicines, in particular for the prevention or treatment of bacterial infections, in particular for the prevention or treatment of bacterial infections mediated by Gram-positive bacteria (specifically by golden yellow) Staphylococci, especially bacterial infections mediated by quinolinone-resistant Staphylococcus aureus), or for the prevention or treatment of bacterial infections mediated by Gram-negative bacteria (specifically by Acinetobacter baumannii and especially by Quinolinone resistant to Acinetobacter baumannii-mediated bacterial infection), and especially for the prevention or treatment of bacterial infections mediated by quinolinone-resistant Staphylococcus aureus or Acinetobacter baumannii. Thus, the following examples relating to the compounds of the formula I of the embodiment 1) are possible and intended and thus specifically disclosed in individualized form: 1, 2+1, 3+1, 4+1, 4+2 +1, 4+3+1, 5+1, 6+5+1, 7+5+1, 8+1, 8+2+1, 8+3+1, 8+4+1, 8+4 +2+1,8+4+3+1,8+5+1,8+6+5+1,8+7+5+1,9+8+1,9+8+2+1,9 +8+3+1, 9+8+4+1, 9+8+4+2+1, 9+8+4+3+1, 9+8+5+1, 9+8+6+5 +1,9+8+7+5+1, 10+8+1, 10+8+2+1, 10+8+3+1, 10+8+4+1, 10+8+4+2 +1, 10+8+4+3+1, 10+8+5+1, 10+8+6+5+1, 10+8+7+5+1, 11+8+1, 11+8 +2+1, 11+8+3+1, 11+8+4+1, 11+8+4+2+1, 11+8+4+3+1, 11+8+5+1, 11+8+6+5+1, 11+8+7+5+1, 12+1, 12+2+1, 12+3+1, 12+4+1, 12+4+2+1, 12+4+3+1, 13+12+1, 13+12+2+1, 13+12+3+1, 13+12+4+1, 13+12+ 4+2+1, 13+12+4+3+1, 14+12+1, 14+12+2+1, 14+12+3+1, 14+12+4+1, 14+12+ 4+2+1, 14+12+4+3+1, 15+12+1, 15+12+2+1, 15+12+3+1, 15+12+4+1, 15+12+ 4+2+1, 15+12+4+3+1, 16+12+1, 16+12+2+1, 16+12+3+1, 16+12+4+1, 16+12+ 4+2+1, 16+12+4+3+1, 17+1, 17+2+1, 17+3+1, 17+4+1, 17+4+2+1, 17+4+ 3+1, 18+17+1, 18+17+2+1, 18+17+3+1, 18+17+4+1, 18+17+4+2+1, 18+17+4+ 3+1, 19+17+1, 19+17+2+1, 19+17+3+1, 19+17+4+1, 19+17+4+2+1, 19+17+4+ 3+1, 20+17+1, 20+17+2+1, 20+17+3+1, 20+17+4+1, 20+17+4+2+1, 20+17+4+ 3+1, 21+17+1, 21+17+2+1, 21+17+3+1, 21+17+4+1, 21+17+4+2+1, 21+17+4+ 3+1, 22+1, 22+2+1, 22+3+1, 22+4+1, 22+4+2+1, 22+4+3+1, 22+5+1, 22+ 6+5+1, 22+7+5+1, 23+22+1, 23+22+2+1, 23+22+3+1, 23+22+4+1, 23+22+4+ 2+1, 23+22+4+3+1, 23+22+5+1, 23+22+6+5+1, 23+22+7+5+1, 24+22+1, 24+ 22+2+1, 24+22+3+1, 24+22+4+1, 24+22+4+2+1 24+22+4+3+1, 24+22+5+1, 24+22+6+5+1, 24+22+7+5+1, 25+22+1, 25+22+2+ 1, 25+22+3+1, 25+22+4+1, 25+22+4+2+1, 25+22+4+3+1, 25+22+5+1, 25+22+ 6+5+1, 25+22+7+5+1, 26+22+1, 26+22+2+1, 26+22+3+1, 26+22+4+1, 26+22+ 4+2+1, 26+22+4+3+1, 26+22+5+1, 26+22+6+5+1, 26+22+7+5+1, 27+22+1, 27+22+2+1, 27+22+3+1, 27+22+4+1, 27+22+4+2+1, 27+22+4+3+1, 27+22+5+ 1,27+22+6+5+1, 27+22+7+5+1, 28+22+1, 28+22+2+1, 28+22+3+1, 28+22+4+ 1, 28+22+4+2+1, 28+22+4+3+1, 28+22+5+1, 28+22+6+5+1, 28+22+7+5+1, 29+22+1, 29+22+2+1, 29+22+3+1, 29+22+4+1, 29+22+4+2+1 29+22+4+3+1, 29+22+5+1, 29+22+6+5+1, 29+22+7+5+1, 30+1, 30+2+1, 30+ 3+1, 30+4+1, 30+4+2+1, 30+4+3+1, 30+5+1, 30+6+5+1, 30+7+5+1, 31+ 1, 31+2+1, 31+3+1, 31+4+1, 31+4+2+1, 31+4+3+1, 31+5+1, 31+6+5+1, 31+7+5+1, 32+1, 32+2+1, 32+3+1, 32+4+1, 32+4+2+1, 32+4+3+1, 32+5+ 1, 32+6+5+1, 32+7+5+1, 33+32+1, 33+32+2+1, 33+32+3+1, 33+32+4+1, 33+ 32+4+2+1, 33+32+4+3+1, 33+32+5+1, 33+32+6+5+1, 33+32+7+5+1, 34+1, 35+34+1, 36+34+1, 37+34+1, 37+35+34+1, 37+36+34+1, 38+1, 39+38+1, 40+38+1, 41+38+1, 41+39+38+1, 41+40+38+1, 42+1, 42+2+1, 42+3+1, 42+4+1, 42+4+2+ 1, 42+4+3+1, 42+5+1, 42+6+5+1, 42+7+5+1, 42+8+1, 42+8+2+1, 42+8+ 3+1, 42+8+4+1, 42+8+4+2+1, 42+8+4+3+1, 42+8+5+1, 42+8+6+5+1, 42+8+7+5+1, 42+9+8+1, 42+9+8+2+1, 42+9+8+3+1, 42+9+8+4+1, 42+ 9+8+4+2+1, 42+9+8+4+3+1, 42+9+8+5+1, 42+9+8+6+5+1, 42+9+8+ 7+5+1, 42+10+8+1, 42+10+8+2+1, 42+10+8+3+1, 42+10+8+4+1, 42 +10+8+4+2+1, 42+10+8+4+3+1, 42+10+8+5+1, 42+10+8+6+5+1, 42+10+8 +7+5+1, 42+11+8+1, 42+11+8+2+1, 42+11+8+3+1, 42+11+8+4+1, 42+11+8 +4+2+1, 42+11+8+4+3+1, 42+11+8+5+1, 42+11+8+6+5+1, 42+11+8+7+5 +1, 42+12+1, 42+12+2+1, 42+12+3+1, 42+12+4+1, 42+12+4+2+1, 42+12+4+3 +1, 42+13+12+1, 42+13+12+2+1, 42+13+12+3+1, 42+13+12+4+1, 42+13+12+4+2 +1, 42+13+12+4+3+1, 42+14+12+1, 42+14+12+2+1, 42+14+12+3+1, 42+14+12+4 +1, 42+14+12+4+2+1, 42+14+12+4+3+1, 42+15+12+1, 42+15+12+2+1, 42+15+12 +3+1, 42+15+12+4+1, 42+15+12+4+2+1, 42+15+12+4+3+1, 42+16+12+1, 42+16+12+2+ 1, 42+16+12+3+1, 42+16+12+4+1, 42+16+12+4+2+1, 42+16+12+4+3+1, 42+17+ 1, 42+17+2+1, 42+17+3+1, 42+17+4+1, 42+17+4+2+1, 42+17+4+3+1, 42+18+ 17+1, 42+18+17+2+1, 42+18+17+3+1, 42+18+17+4+1, 42+18+17+4+2+1, 42+18+ 17+4+3+1, 42+19+17+1, 42+19+17+2+1, 42+19+17+3+1, 42+19+17+4+1, 42+19+ 17+4+2+1, 42+19+17+4+3+1, 42+20+17+1, 42+20+17+2+1, 42+20+17+3+1, 42+ 20+17+4+1, 42+20+17+4+2+1, 42+20+17+4+3+1, 42+21+17+1, 42+21+17+2+1 42+21+17+3+1, 42+21+17+4+1, 42+21+17+4+2+1, 42+21+17+4+3+1, 42+22+1, 42+22+2+1, 42+22+3+1, 42+22+4+1, 42+22+4+2+1, 42+22+4+3+1, 42+22+5+ 1, 42+22+6+5+1, 42+22+7+5+1, 42+23+22+1, 42+23+22+2+1, 42+23+22+3+1, 42+23+22+4+1, 42+23+22+4+2+1, 42+23+22+4+3+1, 42+23+22+5+1, 42+23+22+ 6+5+1, 42+23+22+7+5+1, 42+24+22+1, 42+24+22+2+1, 42+24+22+3+1, 42+24+ 22+4+1, 42+24+22+4+2+1, 42+24+22+4+3+1, 42+24+22+5+1, 42+24+22+6+5+ 1, 42+24+22+7+5+1, 42+25+22+1, 42+25+22 +2+1, 42+25+22+3+1, 42+25+22+4+1, 42+25+22+4+2+1, 42+25+22+4+3+1,42 +25+22+5+1, 42+25+22+6+5+1, 42+25+22+7+5+1, 42+26+22+1, 42+26+22+2+1 , 42+26+22+3+1, 42+26+22+4+1, 42+26+22+4+2+1, 42+26+22+4+3+1, 42+26+22 +5+1,42+26+22+6+5+1, 42+26+22+7+5+1, 42+27+22+1, 42+27+22+2+1, 42+27 +22+3+1, 42+27+22+4+1, 42+27+22+4+2+1, 42+27+22+4+3+1, 42+27+22+5+1 , 42+27+22+6+5+1, 42+27+22+7+5+1, 42+28+22+1, 42+28+22+2+1, 42+28+22+3 +1, 42+28+22+4+1, 42+28+22+4+2+1 42+28+22+4+3+1, 42+28+22+5+1, 42+28+22+6+5+1, 42+28+22+7+5+1, 42+29+ 22+1, 42+29+22+2+1, 42+29+22+3+1, 42+29+22+4+1, 42+29+22+4+2+1, 42+29+ 22+4+3+1, 42+29+22+5+1, 42+29+22+6+5+1, 42+29+22+7+5+1, 42+30+1, 42+ 30+2+1, 42+30+3+1, 42+30+4+1, 42+30+4+2+1, 42+30+4+3+1, 42+30+5+1, 42+30+6+5+1, 42+30+7+5+1, 42+31+1, 42+31+2+1, 42+31+3+1, 42+31+4+1, 42+31+4+2+1, 42+31+4+3+1, 42+31+5+1, 42+31+6+5+1, 42+31+7+5+1, 42+ 32+1, 42+32+2+1, 42+32+3+1, 42+32+4+1, 42+32+4+2+1, 42+32+4+3+1, 42+ 32+5+1, 42+32+6+5+1, 42+32+7+5+1, 42+33+32+1, 42+33+32+2+1, 42+33+32+ 3+1, 42+33+32+4+1, 42+33+32+4+2+1, 42+33+32+4+3+1, 42+33+32+5+1, 42+ 33+32+6+5+1, 42+33+32+7+5+1, 42+34+1, 42+35+34+1, 42+36+34+1, 42+37+34+ 1, 42+37+35+34+1, 42+37+36+34+1, 42+38+1, 42+39+38+1, 42+40+38+1, 42+41+38+ 1, 42+41+39+38+1, 42+41+40+38+1, 43+1, 43+2+1, 43+3+1, 43+4+1, 43+4+2+ 1, 43+4+3+1, 43+5+1, 43+6+5+1, 43+7+5+1, 43+8+1, 43+8+2+1, 43+8+ 3+1, 43+8+4+1, 43+8+4+2+1, 43+8+4 +3+1, 43+8+5+1, 43+8+6+5+1, 43+8+7+5+1, 43+9+8+1, 43+9+8+2+1 , 43+9+8+3+1, 43+9+8+4+1, 43+9+8+4+2+1, 43+9+8+4+3+1, 43+9+8 +5+1,43+9+8+6+5+1, 43+9+8+7+5+1, 43+10+8+1, 43+10+8+2+1, 43+10 +8+3+1, 43+10+8+4+1, 43+10+8+4+2+1, 43+10+8+4+3+1, 43+10+8+5+1 , 43+10+8+6+5+1, 43+10+8+7+5+1, 43+11+8+1, 43+11+8+2+1, 43+11+8+3 +1, 43+11+8+4+1, 43+11+8+4+2+1, 43+11+8+4+3+1, 43+11+8+5+1, 43+11 +8+6+5+1, 43+11+8+7+5+1, 43+12+1, 43+12+2+1 43+12+3+1, 43+12+4+1, 43+12+4+2+1, 43+12+4+3+1, 43+13+12+1, 43+13+12+ 2+1, 43+13+12+3+1, 43+13+12+4+1, 43+13+12+4+2+1, 43+13+12+4+3+1, 43+ 14+12+1, 43+14+12+2+1, 43+14+12+3+1, 43+14+12+4+1, 43+14+12+4+2+1, 43+ 14+12+4+3+1, 43+15+12+1, 43+15+12+2+1, 43+15+12+3+1, 43+15+12+4+1, 43+ 15+12+4+2+1, 43+15+12+4+3+1, 43+16+12+1, 43+16+12+2+1, 43+16+12+3+1, 43+16+12+4+1, 43+16+12+4+2+1, 43+16+12+4+3+1, 43+17+1, 43+17+2+1, 43+ 17+3+1, 43+17+4+1, 43+17+4+2+1, 43+17+4+3+1, 43+18+17+1, 43+18+17+2+ 1, 43+18+17+3+1, 43+18+17+4+1, 43+18+17+4+2+1, 43+18+17+4+3+1, 43+19+ 17+1, 43+19+17+2+1, 43+19+17+3+1, 43+19+17+4+1, 43+19+17+4+2+1, 43+19+ 17+4+3+1, 43+20+17+1, 43+20+17+2+1, 43+20+17+3+1, 43+20+17+4+1, 43+20+ 17+4+2+1, 43+20+17+4+3+1, 43+21+17+1, 43+21+17+2+1, 43+21+17+3+1, 43+ 21+17+4+1, 43+21+17+4+2+1, 43+21+17+4+3+1, 43+22+1, 43+22+2+1, 43+22+ 3+1, 43+22+4+1, 43+22+4+2+1, 43+22+4+3+1, 43+22+5+1, 43+22+6+5+1, 43+22+7+5+1, 43+23+22+1, 43+23+22+2+ 1, 43+23+22+3+1, 43+23+22+4+1, 43+23+22+4+2+1, 43+23+22+4+3+1, 43+23+ 22+5+1, 43+23+22+6+5+1, 43+23+22+7+5+1, 43+24+22+1, 43+24+22+2+1, 43+ 24+22+3+1, 43+24+22+4+1, 43+24+22+4+2+1, 43+24+22+4+3+1, 43+24+22+5+ 1, 43+24+22+6+5+1, 43+24+22+7+5+1, 43+25+22+1, 43+25+22+2+1, 43+25+22+ 3+1, 43+25+22+4+1, 43+25+22+4+2+1, 43+25+22+4+3+1, 43+25+22+5+1, 43+ 25+22+6+5+1, 43+25+22+7+5+1, 43+26+22+1, 43+26+22+2+1, 43+26+22+3+1, 43+26+22+4+1, 43+26+22+4+2+1 43+26+22+4+3+1, 43+26+22+5+1, 43+26+22+6+5+1, 43+26+22+7+5+1, 43+27+ 22+1, 43+27+22+2+1, 43+27+22+3+1, 43+27+22+4+1, 43+27+22+4+2+1, 43+27+ 22+4+3+1, 43+27+22+5+1, 43+27+22+6+5+1, 43+27+22+7+5+1, 43+28+22+1, 43+28+22+2+1, 43+28+22+3+1, 43+28+22+4+1, 43+28+22+4+2+1, 43+28+22+4+ 3+1, 43+28+22+5+1, 43+28+22+6+5+1, 43+28+22+7+5+1, 43+29+22+1, 43+29+ 22+2+1, 43+29+22+3+1, 43+29+22+4+1, 43+29+22+4+2+1, 43+29+22+4+3+1, 43+29+22+5+1, 43+29+22+6+5+1, 43+29+22+7+5+1, 43+30+1, 43+30+2+1, 43+ 30+3+1, 43+30+4+1, 43+30+4+2+1, 43+30+4+3+1, 43+30+5+1, 43+30+6+5+ 1, 43+30+7+5+1, 43+31+1, 43+31+2+1, 43+31+3+1, 43+31+4+1, 43+31+4+2+ 1, 43+31+4+3+1, 43+31+5+1, 43+31+6+5+1, 43+31+7+5+1, 43+32+1, 43+32+ 2+1, 43+32+3+1, 43+32+4+1, 43+32+4+2+1, 43+32+4+3+1, 43+32+5+1, 43+ 32+6+5+1, 43+32+7+5+1, 43+33+32+1, 43+33+32+2+1, 43+33+32+3+1, 43+33+ 32+4+1, 43+33+32+4+2+1, 43+33+32+4+3+1, 43+33+32+5+1, 43+33+32+6+5+ 1, 43+33+32+7+5+1, 43+34+1, 43+35+34+1, 43+36 +34+1, 43+37+34+1, 43+37+35+34+1, 43+37+36+34+1, 43+38+1, 43+39+38+1, 43+40 +38+1, 43+41+38+1, 43+41+39+38+1, 43+41+40+38+1, 44+1, 44+2+1, 44+3+1, 44 +4+1,44+4+2+1, 44+4+3+1, 44+5+1, 44+6+5+1, 44+7+5+1, 44+8+1, 44 +8+2+1, 44+8+3+1, 44+8+4+1, 44+8+4+2+1, 44+8+4+3+1, 44+8+5+1 , 44+8+6+5+1, 44+8+7+5+1, 44+9+8+1, 44+9+8+2+1, 44+9+8+3+1,44 +9+8+4+1, 44+9+8+4+2+1, 44+9+8+4+3+1, 44+9+8+5+1, 44+9+8+6 +5+1, 44+9+8+7+5+1, 44+10+8+1, 44+10+8+2+1, 44+10+8+3+1, 44+10+8+4+1, 44+10+8+4+2+1 44+10+8+4+3+1, 44+10+8+5+1, 44+10+8+6+5+1, 44+10+8+7+5+1, 44+11+ 8+1, 44+11+8+2+1, 44+11+8+3+1, 44+11+8+4+1, 44+11+8+4+2+1, 44+11+ 8+4+3+1, 44+11+8+5+1, 44+11+8+6+5+1, 44+11+8+7+5+1, 44+12+1, 44+ 12+2+1, 44+12+3+1, 44+12+4+1, 44+12+4+2+1, 44+12+4+3+1, 44+13+12+1, 44+13+12+2+1, 44+13+12+3+1, 44+13+12+4+1, 44+13+12+4+2+1, 44+13+12+4+ 3+1, 44+14+12+1, 44+14+12+2+1, 44+14+12+3+1, 44+14+12+4+1, 44+14+12+4+ 2+1, 44+14+12+4+3+1, 44+15+12+1, 44+15+12+2+1, 44+15+12+3+1, 44+15+12+ 4+1, 44+15+12+4+2+1, 44+15+12+4+3+1, 44+16+12+1, 44+16+12+2+1, 44+16+ 12+3+1, 44+16+12+4+1, 44+16+12+4+2+1, 44+16+12+4+3+1, 44+17+1, 44+17+ 2+1, 44+17+3+1, 44+17+4+1, 44+17+4+2+1, 44+17+4+3+1, 44+18+17+1, 44+ 18+17+2+1, 44+18+17+3+1, 44+18+17+4+1, 44+18+17+4+2+1, 44+18+17+4+3+ 1, 44+19+17+1, 44+19+17+2+1, 44+19+17+3+1, 44+19+17+4+1, 44+19+17+4+2+ 1, 44+19+17+4+3+1, 44+20+17+1, 44+20+17+2+1, 44+20+17 +3+1, 44+20+17+4+1, 44+20+17+4+2+1, 44+20+17+4+3+1, 44+21+17+1, 44+21 +17+2+1, 44+21+17+3+1, 44+21+17+4+1, 44+21+17+4+2+1, 44+21+17+4+3+1 , 44+22+1, 44+22+2+1, 44+22+3+1, 44+22+4+1, 44+22+4+2+1, 44+22+4+3+1 , 44+22+5+1, 44+22+6+5+1, 44+22+7+5+1, 44+23+22+1, 44+23+22+2+1, 44+23 +22+3+1, 44+23+22+4+1, 44+23+22+4+2+1, 44+23+22+4+3+1, 44+23+22+5+1 , 44+23+22+6+5+1, 44+23+22+7+5+1, 44+24+22+1, 44+24+22+2+1, 44+24+22+3 +1, 44+24+22+4+1, 44+24+22+4+2+1 44+24+22+4+3+1, 44+24+22+5+1, 44+24+22+6+5+1, 44+24+22+7+5+1, 44+25+ 22+1, 44+25+22+2+1, 44+25+22+3+1, 44+25+22+4+1, 44+25+22+4+2+1, 44+25+ 22+4+3+1, 44+25+22+5+1, 44+25+22+6+5+1, 44+25+22+7+5+1, 44+26+22+1, 44+26+22+2+1, 44+26+22+3+1, 44+26+22+4+1, 44+26+22+4+2+1, 44+26+22+4+ 3+1, 44+26+22+5+1, 44+26+22+6+5+1, 44+26+22+7+5+1, 44+27+22+1, 44+27+ 22+2+1, 44+27+22+3+1, 44+27+22+4+1, 44+27+22+4+2+1, 44+27+22+4+3+1, 44+27+22+5+1, 44+27+22+6+5+1, 44+27+22+7+5+1, 44+28+22+1, 44+28+22+2+ 1, 44+28+22+3+1, 44+28+22+4+1, 44+28+22+4+2+1, 44+28+22+4+3+1, 44+28+ 22+5+1, 44+28+22+6+5+1, 44+28+22+7+5+1, 44+29+22+1, 44+29+22+2+1, 44+ 29+22+3+1, 44+29+22+4+1, 44+29+22+4+2+1, 44+29+22+4+3+1, 44+29+22+5+ 1, 44+29+22+6+5+1, 44+29+22+7+5+1, 44+30+1, 44+30+2+1, 44+30+3+1, 44+ 30+4+1, 44+30+4+2+1, 44+30+4+3+1, 44+30+5+1, 44+30+6+5+1, 44+30+7+ 5+1, 44+31+1, 44+31+2+1, 44+31+3+1, 44+31+4+1, 44+31+4+2+1, 44+31+4+ 3+1, 44+31+5+1, 44+31+6+5+1, 44+31+7+5+1, 4 4+32+1, 44+32+2+1, 44+32+3+1, 44+32+4+1, 44+32+4+2+1, 44+32+4+3+1, 44+32+5+1, 44+32+6+5+1, 44+32+7+5+1, 44+33+32+1, 44+33+32+2+1, 44+33+ 32+3+1, 44+33+32+4+1, 44+33+32+4+2+1, 44+33+32+4+3+1, 44+33+32+5+1, 44+33+32+6+5+1, 44+33+32+7+5+1, 44+34+1, 44+35+34+1, 44+36+34+1, 44+37+ 34+1, 44+37+35+34+1, 44+37+36+34+1, 44+38+1, 44+39+38+1, 44+40+38+1, 44+41+ 38+1, 44+41+39+38+1, 44+41+40+38+1, 45+1, 45+2+1, 45+3+1, 45+4+1, 45+4+2+1, 45+4+3+1, 45+5+1, 45+6+5+1, 45+7+5+1, 45+8+1, 45+8+2+1, 45+8+3+1, 45+8+4+1, 45+8+4+2+1, 45+8+4+3+1, 45+8+5+ 1, 45+8+6+5+1, 45+8+7+5+1, 45+9+8+1, 45+9+8+2+1, 45+9+8+3+1, 45+9+8+4+1, 45+9+8+4+2+1, 45+9+8+4+3+1, 45+9+8+5+1, 45+9+8+ 6+5+1, 45+9+8+7+5+1, 45+10+8+1, 45+10+8+2+1, 45+10+8+3+1, 45+10+ 8+4+1, 45+10+8+4+2+1, 45+10+8+4+3+1, 45+10+8+5+1, 45+10+8+6+5+ 1, 45+10+8+7+5+1, 45+11+8+1, 45+11+8+2+1, 45+11+8+3+1, 45+11+8+4+ 1, 45+11+8+4+2+1, 45+11+8+4+3+1, 45+11+8+5+1, 45+11+8+6+5+1, 45+ 11+8+7+5+1, 45+12+1, 45+12+2+1, 45+12+3+1, 45+12+4+1, 45+12+4+2+1 45+12+4+3+1, 45+13+12+1, 45+13+12+2+1, 45+13+12+3+1, 45+13+12+4+1, 45+ 13+12+4+2+1, 45+13+12+4+3+1, 45+14+12+1, 45+14+12+2+1, 45+14+12+3+1, 45+14+12+4+1, 45+14+12+4+2+1, 45+14+12+4+3+1, 45+15+12+1, 45+15+12+2+ 1, 45+15+12+3+1, 45+15+12+4+1, 45+15+12+4+2+1, 45+15+12+4+3+1, 45+16+ 12+1, 45+16+12+2+1, 45+16+12+3+1, 45+16+12+4+1, 45+16+12+4+2+1, 45+16+ 12+4+3+1, 45+1 7+1, 45+17+2+1, 45+17+3+1, 45+17+4+1, 45+17+4+2+1, 45+17+4+3+1, 45+ 18+17+1, 45+18+17+2+1, 45+18+17+3+1, 45+18+17+4+1, 45+18+17+4+2+1, 45+ 18+17+4+3+1, 45+19+17+1, 45+19+17+2+1, 45+19+17+3+1, 45+19+17+4+1, 45+ 19+17+4+2+1, 45+19+17+4+3+1, 45+20+17+1, 45+20+17+2+1, 45+20+17+3+1, 45+20+17+4+1, 45+20+17+4+2+1, 45+20+17+4+3+1, 45+21+17+1, 45+21+17+2+ 1, 45+21+17+3+1, 45+21+17+4+1, 45+21+17+4+2+1, 45+21+17+4+3+1, 45+22+ 1, 45+22+2+1, 45+22+3+1, 45+22+4+1, 45+22+4+2+1 45+22+4+3+1, 45+22+5+1, 45+22+6+5+1, 45+22+7+5+1, 45+23+22+1, 45+23+ 22+2+1, 45+23+22+3+1, 45+23+22+4+1, 45+23+22+4+2+1, 45+23+22+4+3+1, 45+23+22+5+1, 45+23+22+6+5+1, 45+23+22+7+5+1, 45+24+22+1, 45+24+22+2+ 1, 45+24+22+3+1, 45+24+22+4+1, 45+24+22+4+2+1, 45+24+22+4+3+1, 45+24+ 22+5+1, 45+24+22+6+5+1, 45+24+22+7+5+1, 45+25+22+1, 45+25+22+2+1, 45+ 25+22+3+1, 45+25+22+4+1, 45+25+22+4+2+1, 45+25+22+4+3+1, 45+25+22+5+ 1, 45+25+22+6+5+1, 45+25+22+7+5+1, 45+26+22+1, 45+26+22+2+1, 45+26+22+ 3+1, 45+26+22+4+1, 45+26+22+4+2+1, 45+26+22+4+3+1, 45+26+22+5+1, 45+ 26+22+6+5+1, 45+26+22+7+5+1, 45+27+22+1, 45+27+22+2+1, 45+27+22+3+1, 45+27+22+4+1, 45+27+22+4+2+1, 45+27+22+4+3+1, 45+27+22+5+1, 45+27+22+ 6+5+1, 45+27+22+7+5+1, 45+28+22+1, 45+28+22+2+1, 45+28+22+3+1, 45+28+ 22+4+1, 45+28+22+4+2+1, 45+28+22+4+3+1, 45+28+22+5+1, 45+28+22+6+5+ 1, 45+28+22+7+5+1, 45+29+22+1, 45+29+22+2+1, 45+29+22+3+1, 45+29+22+4+ 1, 45+29+22+4+2+1, 45+29+22+4+3+1, 45+29+22 +5+1,45+29+22+6+5+1,45+29+22+7+5+1,45+30+1,45+30+2+1,45+30+3+1 45+30+4+1, 45+30+4+2+1, 45+30+4+3+1, 45+30+5+1, 45+30+6+5+1, 45+30 +7+5+1, 45+31+1, 45+31+2+1, 45+31+3+1, 45+31+4+1, 45+31+4+2+1, 45+31 +4+3+1, 45+31+5+1, 45+31+6+5+1, 45+31+7+5+1, 45+32+1, 45+32+2+1, 45 +32+3+1, 45+32+4+1, 45+32+4+2+1, 45+32+4+3+1, 45+32+5+1, 45+32+6+5 +1, 45+32+7+5+1, 45+33+32+1, 45+33+32+2+1, 45+33+32+3+1, 45+33+32+4+1 , 45+33+32+4+2+1, 45+33+32+4+3+1, 45+33+32+5+1, 45+33+32+6+5+1, 45+33+ 32+7+5+1, 45+34+1, 45+35+34+1, 45+36+34+1, 45+37+34+1, 45+37+35+34+1, 45+ 37+36+34+1, 45+38+1, 45+39+38+1, 45+40+38+1, 45+41+38+1, 45+41+39+38+1 and 45+ 41+40+38+1.

In the above list, the numbers refer to the embodiments according to the numbers provided above, and the "+" indicates the dependency with another embodiment. Different individualized embodiments are separated by a comma. In other words, for example, "4+3+1" refers to the embodiment 4) which depends on the embodiment 3) and depends on the embodiment 1), that is, the embodiment "4+3+1" corresponds to the further embodiment 3) And Example 1) of the feature limitation of 4). Similarly, "11+8+2+1" refers to embodiment 11) and 2) which rely on (as necessary to modify) and rely on embodiment 1), ie, the embodiment "11+8+2+ 1" corresponds to Example 1) further limited by the features of Example 11) and further limited by the features of Embodiments 2) and 8).

The compounds of formula I can be made according to the invention using the procedures described below.

Preparation of compounds of formula I abbreviation:

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

AcOH acetic acid

Aq.

Boc tert-butoxycarbonyl

Bs 4-bromobenzenesulfonate (brosylate)

Tube chromatography on CC silicone

Cipro ciprofloxacin

DAD diode array detection

DCE 1,2-dichloroethane

DCM dichloromethane

DIPEA N,N -diisopropylethylamine

DMAP 4-dimethylaminopyridine

DMF N , N - dimethylformamide

DMSO dimethyl hydrazine

EA ethyl acetate

ELSD Evaporative Light Scattering Detector

ESI electrospray ionization

Eq. equivalent

Et ethyl

EtOH ethanol

Hept heptane

Hex hexane

HPLC high performance liquid chromatography

HV high vacuum condition

LC liquid chromatography

Me methyl

MeCN acetonitrile

MeOH methanol

MS mass spectrometry

Ms methanesulfonyl (mesyl)

Nf nonafluorobutanesulfonyl

Ns 4-nitrophenylsulfonyl (nosylate)

Org. organic

Pd/C palladium on carbon

Ph phenyl

prep-HPLC preparative HPLC

Pyr pyridine

Rt room temperature

Sat. Saturated

TBAF tetra-n-butyl ammonium fluoride

TBDMS third butyl dimethyl decyl

TBDPS Tert-butyldiphenyldecyl

TBME third butyl methyl ether

tBu third butyl

TEA triethylamine

Tf trifluoromethanesulfonyl (triflyl)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

t _R retention time

Ts p-toluenesulfonyl

XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General reaction technology: General Reaction Technique 1 (Reductive Amination):

The reaction between the amine and the aldehyde-based or ketone via the allowable physical or chemical method (e.g., distillation of the solvent - water azeotrope or presence of drying agent (e.g. molecular sieves, MgSO ₄ or Na ₂ SO ₄₎₎ to remove the water formed Performed in a solvent system. The solvent is typically toluene, Hex, THF, DCM or DCE or a solvent mixture (eg DCE/MeOH). The reaction can be catalyzed by a trace of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (for example, NaBH ₄ , NaBH ₃ CN or NaBH(Oac) ₃ ) or via hydrogenation via a noble metal catalyst (for example Pd/C). The reaction is carried out between -10 ° C and 110 ° C, preferably between 0 ° C and 60 ° C. The reaction can also be carried out in a one-pot process. It can also be carried out in the presence of a pyridinium-borane complex in a protic solvent such as MeOH or water (Sato et al., Tetrahedron (2004), 60 , 7899-7906).

General Reaction Technique 2 (alkylation of an amine with mesylate or iodide):

Amine derivatives with desired iodine in the presence of an inorganic base (eg K ₂ CO ₃ ) or an organic base (eg TEA or DIPEA) between 0 ° C and +80 ° C in a solvent such as THF, DMF or DMSO The compound derivative or an alcohol derivative activated to be a sulfonate (OMs, ONf, ONs, OBs, OTf, OTs) is reacted. Further details can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, RC Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999) Section Amines, page 779.

General Reaction Technique 3 (Removal of Hydroxy Protecting Groups):

Use a source of fluoride anion (eg TBAF in THF between 0 °C and +40 °C, or HF between 0 °C and +40 °C in MeCN or water) or use acidic conditions (eg in THF/MeOH) Removal of the decyl ether group by AcOH or HCl in MeOH or TFA and trifluoromethanesulfonic acid in DCM (the latter method also removes the 4-methoxybenzyl protecting group on the indoleamine nitrogen) (if it exists)). Other methods for removing TBDMS and TBDPS groups are in TW Greene, PGM Wuts, Protecting Groups in Organic Synthesis , 3rd Edition (1999), 133-139 and 142-143, respectively (publisher: John Wiley and Sons, New York, NY) Given in ). Other general methods for removing alcohol protecting groups are set forth in TW Greene, PGM Wuts, Protecting Groups in Organic Synthesis , 3rd Edition (1999), 23-147 (publisher: John Wiley and Sons, Inc., New York, NY).

General Reaction Technique 4 (Alcohol Oxidation):

One of the allyl alcohol or benzyl alcohol dissolved in an organic solvent (for example, DCM or THF) is oxidized to the corresponding aldehyde with MnO ₂ . Other methods can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, RC Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999 ; Section aldehydes and ketones, page 1234 to 1236 pages.

General Reaction Technique 5 (Alcohol Activation):

The alcohol is reacted with MsCl, TfCl, BsCl, NfCl, NsCl or TsCl at -30 ° C and +50 ° C in an anhydrous aprotic solvent (eg Pyr, THF or DCM) in the presence of a base such as TEA. In the case of triflate or mesylate, Tf ₂ O or Ms ₂ O can also be used.

General Reaction Technique 6 (Formation of iodine, chlorine or bromine derivatives):

The sulfonate obtained by the general reaction technique 5 can be reacted with a sodium halide (for example, NaI or NaBr) at 40 ° C and 120 ° C in MeCN or DMF to obtain the corresponding iodide or bromide derivative. Alternatively, the corresponding bromide or chloride can also be obtained by reacting the corresponding alcohol derivative with PBr ₃ or PCl _{3 ,} respectively.

General preparation method: Preparation of a compound of formula I:

The compound of formula I can be produced by the methods given below, by the methods given in the examples or by analogous methods. Optimum reaction conditions can vary with the particular reactants or solvents employed, but such conditions can be determined by those skilled in the art by routine optimization procedures.

The general methods for preparing compounds of formula I are set forth in sections a) and b) below. Unless otherwise stated, the general groups U and W are as defined for Formula I. The general synthetic methods mentioned above in the section entitled "General Reaction Techniques" are mentioned and are explained below. In some cases, certain general groups may be incompatible with the assemblies illustrated in the following procedures and protocols, and thus will require the use of protecting groups. The use of protecting groups is well known in the art (see, for example, " Protective Groups in Organic Synthesis ", TW Greene, PGM Wuts, Wiley-Interscience, 1999).

Compounds of formula I are obtainable by the following:

a) using a general reaction technique 1 to make a compound of formula II

Wherein W has the same meaning as formula I and reacts with a compound of formula III

Wherein U, V and R have the same meaning as formula I; or

b) reacting a compound of formula III as defined in part a) with a compound of formula IV using general reaction technique 2

Wherein W has the same meaning as formula I, and A represents halogen (for example iodine) or the group OSO ₂ R ^A (wherein R ^A represents an alkyl group, a trifluoromethyl group or a tolyl group).

If desired, the compound of formula I so obtained can be converted to its salt using standard methods, and in particular converted to its pharmaceutically acceptable salt.

Preparation of synthetic intermediates: Compounds of formula II and IV:

Compounds of formula II and IV can be prepared as outlined in Scheme 1 below.

In Scheme 1, A represents a halogen (such as iodine) or a group OSO ₂ R ^A (wherein R ^A represents an alkyl group, a trifluoromethyl group or a tolyl group), and PG represents a hydroxy protecting group (for example, TBDMS or TBDPS), Has the same meaning as formula I, and W' represents a substitution at the para position by (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )thioalkoxy and a phenyl group substituted with a halogen group, a group W ² , an X system CH group W ¹ or a group W ¹ ' as appropriate

Wherein Q is O or S, and PG ² is 4-methoxybenzyl.

The bromoalkyne derivative of the formula I-1 can be reacted with the second aminooxycarbamic acid derivative of the formula I-2 under Cu(II) catalysis (Scheme 1) to give the formula I-3. a derivative which can be cycloisomerized by Au(I) catalysis (see Istrate et al, Org. Lett. (2008), 10, 925-928), followed by removal of the alcohol protecting group using general reaction technique 3 Conversion to the oxazolone derivative of formula I-4. In the particular case where W represents W ¹ ', when the alcohol protecting group is removed using a mixture of TFA and trifluoromethanesulfonic acid, 4-methoxybenzyl is removed simultaneously. The resulting alcohol derivative of formula I-4 can be oxidized to the aldehyde of formula II using general reaction technique 4, or by using the general reaction technique 5 with a compound of formula C1-SO ₂ R ^A (wherein R ^A represents an alkyl group, trifluoro Reaction with methyl or tolyl) followed by reaction of the resulting intermediate sulfonate with NaI or NaBr to a derivative of formula IV (wherein A is I or Br) using General Reaction Technique 6.

Compound of formula III:

Compounds of formula III can be prepared as described in WO 2010/041194.

Intermediates for the preparation of compounds of formula II, III and IV:

The compound of formula I-1 can be prepared as described or similar to that of Grandjean et al., Tetrahedron Lett. (1994), 35, 3529-30.

In the case where W' is a group W1' as defined above, the compound of formula ^1-2 can be prepared as outlined in Scheme 2 below. Alternatively, the compound of formula 1-2 can be prepared by reacting the corresponding commercially available aniline derivative W'-NH ₂ with (Boc) ₂ O.

In Scheme 2, Z represents halogen (e.g., Cl or Br), Q has the same meaning as Formula I, and PG ² represents 4-methoxybenzyl.

A derivative of formula III-1 (commercially available or according to Hamed et al, Synth. Commun. (2013), 43(24), 3315-3321) and 4-methoxybenzyl chloride in the presence of NaH can be used. Reaction (Scheme 2), followed by the presence of cesium carbonate, hydrazine (dibenzylideneacetone) dipalladium complex and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene carbamic acid tert-butyl ester (Buchwald reaction (Buchwald reaction)), to obtain a compound of formula I-2 wherein W 'line W ^1', and PG ² represents 4-methoxybenzyl.

The specific embodiments of the present invention are set forth in the following examples, which are intended to illustrate the invention in more detail and not to limit the scope of the invention.

Instance

All temperatures are expressed in °C. Unless otherwise stated, the reaction was carried out at room temperature.

Analytical TLC characterization was performed using a 0.2 mm plate: Merck, Silicone 60 F ₂₅₄ . Elution is carried out using EA, Hept, DCM, MeOH or a mixture thereof. Detection was carried out using UV or using a solution of subsequently heated KmnO ₄ (3 g), K ₂ CO ₃ (20 g), 5% NaOH (3 mL) and H ₂ O (300 mL).

The CC was carried out using Brunschwig 60A silicone (0.032-0.63 mm), and elution was carried out using EA, Hept, DCM, MeOH or a mixture thereof. When the compound contains an acid functional group, 1% AcOH is added to the eluent. NH ₄ OH for 25% aqueous solution of CC.

The compounds were characterized by ¹ H-NMR (300 MHz, Varian Oxford; 400 MHz, Bruker Avance 400 or 500 MHz, Bruker Avance 500 Cryoprobe). The chemical shift δ is expressed in ppm relative to the solvent used; multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, p = quintuple, hex = hexapole, hep = seven heavy peaks, m = multiple peaks, br. = broad peaks, and the coupling constant J is expressed in Hz. Alternatively, the compounds are characterized by LC-MS (Sciex API 2000 with Agilent 1100 binary pump and DAD and ELSD; or Agilent quadrupole MS 6140 with Agilent 1200 binary pump, DAD and ELSD); TLC (TLC plate from Merck, silicone 60 F ₂₅₄ ); or melting point.

Analytical LC-MS data has been obtained using the following individual conditions:

‧MS1 information:

○ column: Zorbax SB-Aq, 3.5μm, 4.6 × 50mm; ○ injection volume: 1μL; ○ column oven temperature: 40 ° C; ○ pump: Dionex HPG-3200RS; ○ supply pump: Dionex ISO-3100SD; ○ DAD: Dionex DAD-30000RS; ○ MS: Thermo MSQ Plus; ○ ELSD: Sedere Sedex 85; ○ detection: UV 210 nm, ELSD and MS; ○ MS ionization mode: ESI+; ○ eluent: A: H ₂ O +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).

‧MS2 information:

○ Column: Waters Atlantis T3, 5 μm, 4.6 × 30 mm; ○ Other parameters are the same as those used to obtain MS1 data.

‧MS3 information:

○ Column: Acquity UPLC BEH C18 from Waters 1.7 μm 2.1×50 mm, thermostated at 60 ° C in Acquity UPLC column manager; ○ pump: Waters Acquity binary solvent manager; ○ MS: Waters SQ detector ; ○ DAD: Acquity UPLC PDA detector; ○ ELSD: Acquity UPLC ELSD; ○ Eluent: A: H ₂ O + 0.05% TFA; B: MeCN + 0.045% TFA; ○ Elution method: Gradient: 2% B To 98% B over 2.0 min; ○ flow rate: 1.0 mL/min; ○ detection: UV 214 nm and ELSD.

‧MS4 information:

○ column: Zorbax SB-Aq, 3.5μm, 4.6×50mm; ○ injection volume: 1μL; ○ column oven temperature: 40°C; ○ pump: Agilent G4220A; ○ supply pump: Dionex HPG-3200SD; ○ DAD : Agilent G4212A; ○ MS: Thermo MSQ Plus; ○ ELSD: Sedere Sedex 90; ○ Detection: UV 210 nm, ELSD and MS; ○ MS ionization mode: ESI+; ○ Eluent: A: H ₂ O + 0.04% TFA And B: MeCN; ○ flow rate: 4.5 mL / min; ○ gradient: 5% B to 95% B (0.00 min - 1.07 min), 95% B (1.07 min - 1.57 min).

The number of decimal places given for the corresponding [M+H ⁺ ] peak for each test compound depends on the accuracy of the LC-MS device actually used.

Preparative HPLC purification was performed on a Gilson HPLC system using Gilson 215 autosampler, Gilson 333/334 pump, Dionex MSQ Plus detector system and Dionex UVD340U (or Dionex DAD-3000) UV. Detector:

‧method 1:

○ Column: Waters Atlantis T3 OBD, 10 μm, 30×75 mm; ○ Flow rate: 75 mL/min; ○ Eluent: A: H ₂ O + 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 μm, 30×75 mm; ○ Flow rate: 75 mL/min; ○ Eluent: A: H ₂ O + 0.1% HCOOH; B: MeCN + 0.1% HCOOH; ○ Gradient: 70% A To 5% A (0.0 min - 3.5 min), 5% A (3.5 min - 6.0 min).

‧ Method 3:

○ Column: Waters Atlantis T3 OBD, 10 μm, 30×75 mm; ○ Flow rate: 75 mL/min; ○ Eluent: A: H ₂ O + 0.1% HCOOH; B: MeCN + 0.1% HCOOH; ○ Gradient: 95% A to 50% A (0.0 min - 3.0 min), 50% A to 5% A (3.0 min - 4.0 min), 5% A (4.0 min - 6.0 min).

preparation: Preparation A: 3-[3-(3-Fluoro-4-methyl-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propanal:

Ai [5- (tert-butyl - dimethyl - Silicon alkoxy) - pent-1-ynyl] - (3-fluoro-4-methyl - phenyl) - carbamic acid butyl ester third: Treatment of (3-fluoro-4-methyl-phenyl)-carbamic acid tert-butyl ester with K ₃ PO ₄ (2.45 g), CuSO ₄ (213 mg) and phenanthroline monohydrate (528 mg) 1.0 g, prepared according to Lee et al, Bioorg. Med. Chem. Lett. (2005), 15 (18), 4136-4142) and [(5-bromo-4-pentyn-1-yl)oxy] ( A solution of the third butyl)dimethyl-decane (1.85 g; prepared according to Sabitha et al., Synlett (2003), 2699-2704) in toluene (13 mL). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. The resulting suspension was filtered and purified by EtOAc EtOAc (EtOAc)

A.ii. 5-[3-( Third butyl-dimethyl-decyloxy)-propyl]-3-(3-fluoro-4-methyl-phenyl)-3H-oxazole-2 - one: intermediate Ai (1.5g) in dry DCM (7.3mL) was treated in the AuPh ₃ PCl (35mg) and AgSbF ₆ (24mg) was suspended in MeCN (0.73 mL) in the. The mixture was stirred at 40 ° C. EtOAc (EtOAc m. ).

MS1 (ESI, m / z) : 366.1 [M + H +]; t R = 1.09min.

A.iii. 3-(3-Fluoro-4-methyl-phenyl)-5-(3-hydroxy-propyl)-3H-oxazol-2-one: TBAF (1 M at room temperature) A solution of the intermediate A. ii (1.09 g) in THF (45 mL). The mixture was stirred at room temperature for 1 h, diluted with EA, washed with water and brine, dried over MgSO _4, and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc) (EtOAc)

MS1 (ESI, m / z) : 252.1 [M + H +]; t R = 0.73min.

A.iv. 3-[3-(3-Fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5-yl]-propanal: intermediate a.iii (580mg) and DIPEA (1.6mL) in DCM (20mL) in the solution was cooled to 10 ℃, dropwise over 5min and with SO ₃ .Pyr complex (752 mg) in DMSO (6.5mL) in a solution of deal with. The reaction mixture was allowed to reach room temperature and further stirred at this temperature for 2 h. The reaction mixture was diluted with DCM and washed with 1 M HCl, water and brine, dried over MgSO _4, and concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc)

MS1 (ESI, m / z) : 250.1 [M + H +]; t R = 0.77min.

Preparation B: 3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propanal:

Bi [5- (tert-butyl - dimethyl - Silicon alkoxy) - pent-1-ynyl] - (4-ethoxy - phenyl) - carbamic acid butyl ester third: from (4 -Ethoxy-phenyl)-aminocarboxylic acid tert-butyl ester (1.0 g, prepared according to Zhang et al, J. Med. Chem. (1995), 38 , 1679-1688) and [(5-bromo- 4-pentyn-1-yl)oxy](t-butyl)dimethyl-nonane (1.17 g; prepared according to Sabitha et al, Synlett (2003), 2699-2704), and similar to the preparation A step The title compound (0.85 g, 46% yield).

MS1 (ESI, m / z) : 378.1 [M + H +] ( corresponding cyclized product); t _R = 1.15min.

B.ii. 5-[3-( Third butyl-dimethyl-decyloxy)-propyl]-3-(4-ethoxy-phenyl)-3H-oxazol-2-one: Starting from the intermediate Bi (0.85 g), mp.

MS1 (ESI, m / z) : 378.1 [M + H +]; t R = 1.07min.

B.iii. 3-(4-Ethoxy-phenyl)-5-(3-hydroxy-propyl)-3H-oxazol-2-one: starting from intermediate B.ii (0.60 g) and similar The title compound (0.42 g, 100% yield).

MS1 (ESI, m / z) : 264.2 [M + H +]; t R = 0.70min.

B.iv. 3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl] -propanal : from intermediate B.iii The title compound (0.33 g, 85% yield) was obtained as a brown oil.

MS1 (ESI, m / z) : 262.1 [M + H +]. T _R = 0.74 min.

Preparation C: 3-[2-Sideoxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl]-propanal:

Ci- (4-propyl-phenyl)-carbamic acid tert-butyl ester: 4-propylaniline (1.25 g) treated with guanidine hydrochloride (1.0 g) and dibutyl butyl carbonate (2.08 g) The solution in EtOH (30 mL) was stirred at 40 ° C for 1 h. The reaction mixture was allowed to reach room temperature, diluted with EA and extracted with water. The organic layer was dried over MgSO _4, filtered and concentrated under reduced pressure, and dried in the HV, so as to give a brown solid (2.17g; 100% yield).

C.ii. [5- (tert-butyl - dimethyl - Silicon alkoxy) - pent-1-ynyl] - (4-propylphenyl - phenyl) - carbamic acid butyl ester third: from Intermediate Ci (1.0 g) and [(5-bromo-4-pentyn-1-yl)oxy](t-butyl)dimethyl-decane (1.77 g; according to Sabitha et al, Synlett (2003) The title compound (1.9 g, 100% yield) was obtained as a yellow oil.

MS1 (ESI, m / z) : 376.1 [M + H +] ( corresponding cyclized product); t _R = 1.19min.

C.iii. 5-[3-( Third butyl-dimethyl-decyloxy)-propyl]-3-(4-propyl-phenyl)-3H-oxazol-2-one: from The title compound (0.56 g, 43% yield) was obtained as a white solid.

MS 1 (ESI, m/z): 376.1 [M+H ⁺ ]. T _R =1.12 min.

C.iv. 5-(3-Hydroxy-propyl)-3-(4-propyl-phenyl)-3H-oxazol-2-one: starting from intermediate C.iii (0.56 g) and similar The title compound (0.36 g, 92% yield).

MS1 (ESI, m/z): 262.2 [M+H+]. T _R =0.80 min.

Cv 3-[2- Sideoxy -3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl] -propanal : from intermediate C.iv (0.36 g) The title compound (0.26 g, 73% yield) was obtained from the title compound.

MS1 (ESI, m / z) : 260.2 [M + H +]. T _R =0.86 min.

Preparation D: 3-[3-(2,3-Dihydro-benzo[1,4]dioxine-6-yl)-2-oxo-2,3-dihydro-oxazole -5-yl]-propanal:

Di(5-(( t-butyldimethylmethylalkyl)oxy)pent-1-yn-1-yl)(2,3-dihydrobenzo[b][1,4]dioxole Benzene-6-yl)carbamic acid tert-butyl ester: from (2,3-dihydro-benzo[1,4]dioxine-6-yl)-carbamic acid tert-butyl a base ester (3.77 g, prepared according to WO 2004/009562) and [(5-bromo-4-pentyn-1-yl)oxy](t-butyl)dimethyl-decane (2.77 g; according to Sabitha et al. al, Synlett (2003), 2699-2704 preparation) starts, and similar to preparation A, step Ai proceeds to give the title compound as a yellow oil (2.1g, 47% yield).

D.ii. 5-(3-(( Tertiary butyldimethylmethyl)alkyl)oxy)propyl)-3-(2,3-dihydrobenzo[b][1,4]dioxa Cyclohexene-6-yl)oxazole-2(3H)-one: Starting from Intermediate Di (2.0 g), m. 80% yield).

D.iii. 3-(2,3-Dihydrobenzo[b][1,4]dioxine-6-yl)-5-(3-hydroxypropyl)oxazole-2 (3H The ketone: starting from the intermediate D. ii (1.30 g), and the title compound (0.92 g, 100% yield).

MS3 (ESI, m / z) : 287.2 [M + H +]; t R = 0.53min.

D.iv. 3-[3-(2,3-Dihydro-benzo[1,4]dioxan-6-yl)-2-oxo-2,3-dihydro-acean The azole-5-yl] -propanal : starting from the intermediate D. iii (0.90 g).

¹ H NMR (CDCl ₃ ) δ: 8.18 (s, 1H); 9.73 (s, 1H); 6.96 (d, J = 2.5 Hz, 1H); 6.82 (m, 2H); 6.47 (m, 1H); (s, 4H); 2.71 (m, 4H).

Preparation of E: 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4]-6-yl)-2,3-di Hydrogen-oxazole-5-yl]-propanal:

Ei 6-Amino-4-(4-methoxy-benzyl)-4H-benzo[1,4]thiazin-3-one: 6-Amino- 2H -1,4-benzoate A solution of thiazol-3( 4H )-one (5.63 g, prepared according to EP 415642) in DMF (100 mL) was cooled to EtOAc (EtOAc) The reaction mixture was cooled to 0<0>C, was taken <RTI ID=0.0>> The reaction mixture was treated with water and the resulting suspension was filtered. The solid was washed with water and EtOAc (EtOAc) elute

MS2 (ESI, m / z) : 301.3 [M + H +]; t R = 0.63min.

E.ii. [4-(4-Methoxy-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl]-amino third-carboxylic acid butyl ester:, DMAP (5mg) and di-tert-butyl ester (5.60 g) of intermediate Ei treated with TEA (2.2mL) (3.50g) in THF / DCM (110mL, 10: 1) The solution was stirred and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc andEtOAc. The aqueous layer was extracted with EA. The combined organic layers were dried over MgSO _4, filtered, and concentrated under reduced pressure by CC: Purification (Hept / EA 1 1), to thereby obtain a colorless solid (2.0g; 43% yield).

MS2 (ESI, m / z) : 401.2 [M + H +]; t R = 0.95min.

E.iii. [5-( Tertiary butyl-dimethyl-decyloxy)-pent-1-ynyl]-[4-(4-methoxy-benzyl)-3-oxo- -2H- 3,4-dihydro-benzo [1,4] thiazin-6-yl] - third amino acid butyl ester: Starting from intermediate E.ii (1.97g) and [(5-bromo - 4-pentyn-1-yl)oxy](t-butyl)dimethyl-nonane (1.17 g; prepared according to Sabitha et al, Synlett (2003), 2699-2704), and similar to the preparation A step The title compound (2.16 g, 77% yield).

MS2 (ESI, m / z) : 541.4 [M + H +] ( corresponding cyclized product); t _R = 1.33min.

E.iv. 6-{5-[3-( Third butyl-dimethyl-decyloxy)-propyl]-2-yloxy-oxazol-3-yl}-4-(4- Methoxy-benzyl)-4H-benzo[1,4]thiazin-3-one: starting from intermediate E.iii (2.14 g) and continuing similar to Preparation A Step A.ii, yielding a yellow solid The title compound (1.75 g, 90% yield).

MS2 (ESI, m / z) : 541.5 [M + H +]; t R = 1.18min.

Ev 6-[5-(3-hydroxy-propyl)-2-oxo-oxazol-3-yl]-4H-benzo[1,4]thiazin-3-one: using TFA (5.3 mL And a solution of the intermediate E.iv (750 mg) in DCM (50 mL). The reaction mixture was cooled to 0.degree. C. and EtOAc (EtOAc) The reaction mixture was diluted with water and DCM. The organic layer was separated and the aqueous layer was extracted with DCM. Washed successively with 0.1 N HCl, water, and combined organic layers were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The title compound (0.20 g; 47% yield).

MS2 (ESI, m / z) : 307.2 [M + H +]; t R = 0.54min.

E.vi. 3-[2-Alkyl-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-6-yl)-2,3- Dihydro-oxazol-5-yl]-propanal: Starting from Intermediate Ev (184 mg).

MS2 (ESI, m / z) : 346.2 [M + H +] (MeCN adduct); t _R = 0.57min.

Preparation F: 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2,3- Dihydro-oxazole-5-yl]-propanal:

Fi 6-Amino-4-(4-methoxy-benzyl)-4H-benzo[1,4]oxazin-3-one: from 6-amino- 2H -1,4-benzo Starting from the moxazin-3( 4H )-one (5.0 g), which was obtained from the title compound (5 g, m. 64% yield).

MS1 (ESI, m / z) : 326.3 [M + H +]; t R = 0.46min.

F.ii. [4-(4-Methoxy-benzyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-amino third-carboxylic acid butyl ester: Starting from intermediate Fi (3.5g) is started and step E was prepared similarly E.ii continues and by CC: after (EA / Hept 1 2) to afford protection comprising two -Boc A red oily mixture of the intermediate (1.4 g). The mixture was treated with water / dioxane (1-1, 6 mL) overnight at 100 °C. After cooling to room temperature, water was added and the mixture was extracted with DCM (3×). The combined organic layers were washed with water and brine, dried over MgSO _4, and concentrated by CC: Purification (EA / Hept 1 1), to give the title compound as a slightly yellow foam (0.84g, 18% yield).

MS1 (ESI, m / z) : 385.2 [M + H +]; t R = 0.84min.

F.iii. [5-( Tertiary butyl-dimethyl-decyloxy)-pent-1-ynyl]-[4-(4-methoxy-benzyl)-3-oxo- -2H- 3,4-dihydro-benzo [1,4] oxazin-6-yl] - third amino acid butyl ester: Starting from intermediate F.ii (602mg) and similar to preparation A, step starts Ai The title compound (627 mg, 69% yield).

MS1 (ESI, m / z) : 525.3 [M + H +] ( corresponding cyclized product); t _R = 1.16min.

F.iv. 6-{5-[3-( Third butyl-dimethyl-decyloxy)-propyl]-2-yloxy-oxazol-3-yl}-4-(4- Methoxy-benzyl)-4H-benzo[1,4]oxazin-3-one: starting from intermediate F.iii (600 mg) and continuing similar to Preparation A, step A.ii, with CC (EA/Hept 1:3).

MS1 (ESI, m / z) : 525.3 [M + H +]; t R = 1.08min.

Fv 6-[5-(3-hydroxy-propyl)-2-yloxy-oxazol-3-yl]-4H-benzo[1,4]oxazin-3-one: from intermediate F. The title compound (70 mg, 29% yield) was obtained as yd.

MS2 (ESI, m / z) : 291.1 [M + H +]; t R = 0.45min.

F.vi. 3-[2-Alkyl-3-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2,3- Dihydro-oxazol-5-yl]-propanal: Starting from Intermediate Fv (70 mg).

MS (ESI, m / z) : 330.0 [M + H +] (MeCN adduct); t _R = 0.58min.

Preparation G: 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazine-6- Base-2,3-dihydro-oxazole-5-yl]-propanal:

Gi 6-bromo-4-(4-methoxy-benzyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one: 6-bromo-2 H -pyridine And [3,2- b ][1,4]oxazin-3( 4H )-one (61.4g; prepared according to WO 02/056882), Cs ₂ CO ₃ (96.1 g) and 4-methoxybenzyl The suspension of the chloroform (44.1 g) in DMF (600 mL) was stirred at room temperature for 3 h. The reaction mixture was filtered and evaporated under reduced pressure. The residue was partitioned between EA and water. The aqueous layer was combined organic layers were washed with brine and extracted with EA and washed with water, dried over MgSO _4, concentrated under reduced pressure, and crystallized from Hept to give a colorless solid (87.7g; 94% yield).

MS1 (ESI, m / z) : 349.2 [M + H +]; t R = 0.92min.

G.ii. [4-(4-Methoxy-benzyl)-3-oxooxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine- 6-yl] - butyl amino acid third: and Cs ₂ CO ₃ (1.21g) treated with intermediate Gi-carbamic acid tert-butyl ester (369mg) (1.0g) in dioxane (25mL) Solution in the middle. The resulting solution was treated with hydrazine (dibenzylideneacetone) dipalladium (0) (39.3 mg) and XantPhos (49.7 mg) under Ar. The reaction mixture was stirred at 90 ° C for 4 days under Ar and filtered. The filtrate was concentrated under reduced pressure and purified with EtOAc (EtOAc)

MS1 (ESI, m / z) : 386.0 [M + H +]; t R = 0.94min

G.iii. [5-( Tertiary butyl-dimethyl-decyloxy)-pent-1-ynyl]-[4-(4-methoxy-benzyl)-3-oxo- -2H- 3,4-dihydro-pyrido [3,2-b] [1,4] oxazin-6-yl] - third amino acid butyl ester: Starting from intermediate G.ii (2.2g) And [(5-bromo-4-pentyn-1-yl)oxy](t-butyl)dimethyl-decane (2.37 g; prepared according to Sabitha et al, Synlett (2003), 2699-2704) The title compound (1.87 g, 56% yield) was obtained.

MS1 (ESI, m / z) : 581.8 [M + H +]; t R = 1.16min.

G.iv. 6-{5-[3-( Tertiary -butyl-dimethyl-decyloxy)-propyl]-2-yloxy-oxazol-3-yl}-4-(4- Methoxy-benzyl)-4H-pyrido[3,2-b][1,4]oxazin-3-one: starting from intermediate G.iii (1.87 g) and analogous to Preparation A Step A. The title compound (1.13 g, 67% yield) was obtained as a yellow solid.

MS1 (ESI, m / z) : 526.3 [M + H +]; t R = 1.11min.

Gv 6-[5-(3-hydroxy-propyl)-2-yloxy-oxazol-3-yl]-4H-pyrido[3,2-b][1,4]oxazole-3- The title compound (264 mg, 48% yield) was obtained from EtOAc EtOAc.

MS1 (ESI, m / z) : 292.1 [M + H +]; t R = 0.59min.

G.vi. 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6- -2,3-Dihydro-oxazol-5-yl] -propanal : starting from the intermediate Gv (590 mg), mp. , 68% yield).

MS1 (ESI, m / z) : 290.1 [M + H +]; t R = 0.61min.

Preparation of H: 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazine-6- Base-2,3-dihydro-oxazole-5-yl]-propanal:

Hi 6-chloro-4-(4-methoxy-benzyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one: from 6-chloro-2 H -pyridine And [3,2- b ]-1,4-thiazin-3( 4H )-one (4.2 g; prepared according to WO 2010/041194) was started and similar to the preparation G step Gi continued with TBME/EA The title compound (6.05 g, 90% yield)

MS1 (ESI, m / z) : 321.0 [M + H +]; t R = 0.93min.

H.ii. [4-(4-Methoxy-benzyl)-3-oxooxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine- 6-yl] - third amino acid butyl ester: Starting from intermediate Hi (5.3g) prepared analogously to start and continue G.ii step G, the title compound is obtained as an orange solid (4.76 g of; quantitative).

MS1 (ESI, m / z) : 401.9 [M + H +]; t R = 0.96min.

H.iii. [5-( Tertiary butyl-dimethyl-decyloxy)-pent-1-ynyl]-[4-(4-methoxy-benzyl)-3-oxo- -2H- 3,4-dihydro-pyrido [3,2-b] [1,4] thiazin-6-yl] - third amino acid butyl ester: Starting from intermediate H.ii (1.5g) The title compound (210 mg, 9% yield) was obtained as a yellow oil.

MS1 (ESI, m / z) : 598.3 [M + H +]; t R = 1.17min.

H.iv. 6-{5-[3-( Tertiary -butyl-dimethyl-decyloxy)-propyl]-2-yloxy-oxazol-3-yl}-4-(4- Methoxy-benzyl)-4H-pyrido[3,2-b][1,4]thiazin-3-one: starting from intermediate H.iii (180 mg) and analogous to Preparation A Step A.ii The title compound (83 mg, 51% yield) was obtained.

MS1 (ESI, m / z) : 542.2 [M + H +]; t R = 1.13min.

Hv 6-[5-(3-hydroxy-propyl)-2-yloxy-oxazol-3-yl]-4H-pyrido[3,2-b][1,4]thiazin-3- The title compound (31 mg, 74% yield).

MS1 (ESI, m / z) : 307.8 [M + H +]; t R = 0.64min.

H.vi. 3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6- -2,3-Dihydro-oxazol-5-yl]-propanal: starting from intermediate Hv (26 mg) and similar to Preparation A Step A.iv. , 51% yield).

MS1 (ESI, m / z) : 305.9 [M + H +]; t R = 0.66min.

Preparation of I:( S )-1-amino-9-methoxy-1 H -pyrrolo[3,2,1- ij ]quinolin-4(2 H )-one:

Ii (S)-t-butyl (9-methoxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-yl)amine Carbamate: ( S )-(9-fluoro-4-o-oxo-2,4-dihydro-1 H -pyrrolo[3,2,1- ij ]quinolin-1-yl)amine A solution of the tert-butyl formate (150 mg; similar to that prepared in WO 2010/041194) in THF / MeOH (1:1; 4 mL) was reacted with LiOH ( hydrate; 62 mg) at 60 ° C overnight. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EA, washed successively with water and brine, dried over MgSO ₄ and concentrated under reduced pressure to give a beige solid (142mg; 91% yield).

MS1 (ESI, m / z) : 316.94 [M + H +]; t R = 0.75min.

I.ii. (S)-1-Amino-9-methoxy-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one: treated with TFA (0.5 mL) A solution of <RTI ID=0.0># </RTI></RTI><RTIID=0.0> The solution was evaporated under reduced pressure, and the residue was dissolved in DCM and washed with concentrated aqueous NH ₄ OH. The aqueous layer was backwashed twice with DCM. The combined organic layers were dried over MgSO _4, filtered and concentrated under reduced pressure to give an off-white solid (63mg; 58% yield).

MS1 (ESI, m / z) : 217.12 [M + H +]; t R = 0.41min.

Preparation of J:( S )-1-amino-9-methyl-1 H -pyrrolo[3,2,1- ij ]quinolin-4(2 H )-one:

Ji (S)-(9-(Benzyloxy)-4-o-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin- 1-yl)amino Tert -butyl formate: A suspension of NaH (60% suspension in oil; 591 mg) in THF (20 mL). ( S )-(9-Fluoro-4-oxo-2,4-dihydro-1 H -pyrrolo[3,2,1- ij ]quinolin-1-yl)carbamic acid tert-butyl The resulting suspension was treated with a base (1000 mg; similar to that prepared in WO 2010/041194) and further stirred overnight at room temperature. The reaction mixture was cooled to 0 &lt;0&gt;C, taken with water andEtOAc &EtOAc. The organic layer was washed successively with water and brine, dried over MgSO ₄ and concentrated under reduced pressure. The oily material was purified by EtOAc (EtOAc:EtOAc:EtOAc

MS1 (ESI, m / z) : 392.95 [M + H +]; t R = 0.89min.

J.ii. (S)-(9-Hydroxy-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-yl)carbamic acid Tributyl ester: A suspension of the intermediate (1100 mg) in MeOH (20 mL) The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give a white solid (yield: 748 g, 88% yield).

MS1 (ESI, m / z) : 302.94 [M + H +]; t R = 0.72min.

J.iii. (S)-Trifluoromethanesulfonic acid 1-((t-butoxycarbonyl)amino)-4- oxo-2,4-dihydro-1H-pyrrolo[3,2, 1-ij]quinoline-9-yl ester: A suspension of intermediate J. ii (300 mg) in dry DCM (10 mL) was cooled to 0 &lt;0&gt;C and treated with 2,6-dimethylpyridine (159 mg). The reaction mixture was further stirred at this temperature for 15 min, cooled to -78.degree. C., and then was applied dropwise with trifluoromethanesulfonic acid (3mL). The reaction mixture was further stirred at this temperature for 2 h to 0&lt;0&gt;C and quenched with water. The reaction mixture was extracted using DCM / MeOH (9:1). Washed with M HCl, water, and the organic layer was washed with a brine, dried over MgSO ₄ and concentrated under reduced pressure to give a colorless solid (314mg, 73% yield).

MS1 (ESI, m / z) : 434.84 [M + H +]; t R = 0.87min.

J.iv. (S)-(9-Methyl-4-oxo-2,4-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-1-yl)carbamic acid Third butyl ester: intermediate J.iii (265 mg), potassium methyl trifluoroborate (112 mg), CsCO ₃ (608 mg) and [1,1 ' -bis(diphenylphosphino)ferrocene] A mixture of dichloropalladium(II) complex (149 mg) was placed in a sealed flask and degassed with nitrogen. The mixture was treated with THF/H ₂ O (10:1) and heated at 60 ° C for 4 days. The reaction mixture was quenched with water and extracted with EtOAc EtOAc. Successively with water and combined organic layers were washed with brine, dried over MgSO _4, filtered and concentrated under reduced pressure. The solid was purified by EtOAc (EtOAc:EtOAc:EtOAc

MS1 (ESI, m / z) : 301.00 [M + H +]; t R = 0.77min.

Jv (S)-1-Amino-9-methyl-1H-pyrrolo[3,2,1-ij]quinoline-4(2H)-one: Treatment of intermediate J.iv with TFA (0.75 mL) (114 mg) in DCM (3 mL). The solution was extracted with 1 M HCl and washed with DCM. The aqueous phase was treated with concentrated aqueous NaOH to adjust pH to 10 and aqueous phase was extracted twice with DCM/MeOH (9:1). Successively with water and combined organic layers were washed with brine, dried, and ₄ over MgS04 concentrated under reduced pressure, to give a beige solid (72mg, 95% yield).

MS1 (ESI, m / z) : 201.14 [M + H +]; t R = 0.41min.

Preparation of K:( S )-1-amino-4-oxo-1,2-dihydro- 4H -pyrrolo[3,2,1-ij]quinoline-9-carbonitrile:

Ki ((S) -9--cyano-4-oxo-1,2-dihydro -4H- pyrrolo [3,2,1-ij] quinolin-1-yl) - third amino acid Butyl ester: intermediate J.iii (250 mg), zinc cyanide (69 mg), hydrazine (dibenzylideneacetone) dipalladium (0) (158 mg) and 1,1 ' -bis(diphenylphosphino) A mixture of ferrocene (191 mg) was placed in a sealed flask and degassed with nitrogen. The mixture was treated with DMF (5 mL) and heated at EtOAc overnight. The reaction mixture was quenched with water and extracted twice with DCM / MeOH (9:1). Successively with water and combined organic layers were washed with brine, dried over MgSO _4, filtered and concentrated under reduced pressure. The solid was purified by EtOAc (EtOAc (EtOAc:EtOAc)

MS1 (ESI, m / z) : 311.96 [M + H +]; t R = 0.71min.

K.ii. (S)-1-Amino-4-oxo-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-9-carbonitrile: using TFA ( A solution of the intermediate EtOAc (5 mL) EtOAc m. The solution was evaporated to dryness. The residue was dissolved in DCM and washed with concentrated aqueous NH ₄ OH. The aqueous layer was extracted twice with DCM. Successively with water and combined organic layers were washed with brine, dried over MgSO ₄ and concentrated under reduced pressure to afford an off-white solid (17mg, 46% yield).

^{1 H NMR (500MHz, DMSO)} δ: 8.02 (d, J = 9.5Hz, 1H); 7.76 (d, J = 7.9Hz, 1H); 7.55 (d, J = 8.1Hz, 1H); 6.76 (d, J = 9.5 Hz, 1H); 4.94 (dd, J = 4.0, 8.3 Hz, 1H); 4.51 (dd, J = 8.5, 12.6 Hz, 1H); 3.92 (dd, J = 4.1, 12.6 Hz, 1H); 2.45 (m, 2H).

Examples of compounds of the invention: Example 1: ( S )-7-Fluoro-6-{3-[3-(3-fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5 -yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

Treatment of ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one with NaBH(Oac) ₃ (341 mg) (82.5 A solution of the compound (100 mg) in EtOAc (MeOH: EtOAc) The mixture was partitioned between saturated NaHCO ₃ and DCM, the phases were separated, the organic dried over MgSO _4, and concentrated under reduced pressure, and the (Method 1) was purified by preparative HPLC, to give a yellow solid (63mg; 36% yield ).

MS1 (ESI, m / z) : 439.0 [M + H +]; t R = 0.65min.

Example 2: ( R )-9-Fluoro-1-{3-[3-(3-fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5 -yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (82 mg; prepared according to WO 2010/041194) and preparation The title compound (102 mg; 58% yield) was obtained as a yellow solid.

MS1 (ESI, m / z) : 438.0 [M + H +]; t R = 0.66min.

Example 3: ( R )-1-{3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamine -9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (80 mg, prepared according to WO 2010/041194) and preparation The title compound (46 mg; 26% yield) was obtained as a yellow foam.

¹ H NMR (CDCl ₃ ) δ: 7.69 (d, J = 9.5 Hz, 1H); 7.44 (m, 3H); 6.93 (m, 3H); 6.64 (d, J = 9.5 Hz, 1H); , 1H); 5.00 (dd, J = 8.0, 3.2 Hz, 1H); 4.50 (m, 1H); 4.31 (dd, J = 13.4, 3.5 Hz, 1H); 4.04 (q, J = 7.0 Hz, 2H) ; 2.75 (m, 2H); 2.56 (m, 2H); 1.83 (m, 2H); 1.41 (t, J = 7.0 Hz, 3H).

MS1 (ESI, m / z) : 449.8 [M + H +]; t R = 0.65min.

Example 4: ( R )-6-{3-[3-(2,3-Dihydro-benzo[1,4]dioxine-6-yl)-2-oxo-2, 3-Dihydro-oxazol-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (70 mg; prepared according to WO 2010/041194) and preparation of compound D (94 mg) starts, and similar to example 1 to continue, by the CC: after purification (MeOH / EA 1 9 + 1 % NH 4 OH), to obtain the title compound as a beige foam (111mg; 69% Yield).

¹ H NMR (CDCl ₃ ) δ: 8.20 (s, 1H); 7.75 (dd, J = 8.9, 4.3 Hz, 1H); 6.98 (m, 4H); 6.47 (s, 1H); 5.00 (dd, J = 8.2, 3.7 Hz, 1H); 4.52 (dd, J = 13.6, 8.2 Hz, 1H); 4.26 (s, 5H); 2.66 (m, 4H); 1.83 (m, 2H).

MS3 (ESI, m / z) : 465.1 [M + H +]; t R = 0.49min.

Example 5: ( S )-6-{3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamine -7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (80 mg; prepared according to WO 2010/041194) and The title compound (50 mg; 28% yield) was obtained as the title compound.

¹ H NMR (CDCl ₃ ) δ: 8.21 (s, 1H); 7.75 (m, 1H); 7.40 (m, 2H); 7.01 (s, 1H); 6.93 (d, J = 9.0 Hz, 2H); (s, 1H); 5.00 (m, 1H); 4.52 (m, 1H); 4.27 (m, 1H); 4.03 (m, 2H); 2.76 (m, 2H); 2.56 (m, 2H); t, J = 7.1 Hz, 2H); 1.42 (t, J = 7.0 Hz, 3H).

MS1 (ESI, m / z) : 451.2 [M + H +]; t R = 0.63min.

Example 6: ( R )-9-fluoro-1-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl]- Propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (79 mg; prepared according to WO 2010/041194) and preparation The title compound (111 mg; 64% yield) was obtained as a yellow foam.

¹ H NMR (CDCl ₃ ) δ: 7.68 (d, J = 9.5 Hz, 1H); 7.43 (m, 3H); 7.23 (m, 2H); 6.91 (m, 1H); 6.63 (d, J = 9.5 Hz , 1H); 6.56 (s, 1H); 4.99 (m, 1H); 4.51 (dd, J = 13.3, 8.3 Hz, 1H); 4.30 (m, 1H); 2.77 (m, 2H); 2.58 (q, J = 7.1 Hz, 4H); 1.83 (m, 2H); 1.64 (m, 2H); 0.94 (t, J = 7.4 Hz, 3H).

MS1 (ESI, m / z) : 448.1 [M + H +]; t R = 0.72min.

Example 7: ( S )-7-Fluoro-6-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazole-5-yl]- Propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (76 mg; prepared according to WO 2010/041194) and The title compound (76 mg; 46% yield).

¹ H NMR (CDCl ₃ ) δ: 8.21 (s, 1 H); 7.75 (dd, J = 8.9, 4.3 Hz, 1H); 7.42 (m, 2H); 7.24 (m, 2H); 7.01 (t, J) = 9.0 Hz, 1H); 6.56 (s, 1H); 5.00 (m, 1H); 4.52 (m, 1H); 4.28 (dd, J = 13.6, 3.5 Hz, 1H); 2.76 (m, 2H); (m, 4H); 1.85 (d, J = 7.4 Hz, 2H); 1.64 (m, 2H); 0.94 (t, J = 7.3 Hz, 3H).

MS1 (ESI, m / z) : 448.9 [M + H +]; t R = 0.70min.

Example 8: ( S )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiophene Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinoline-4 -ketone:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (30 mg; prepared according to WO 2010/041194) and preparation The title compound (49 mg; 68% yield) was obtained from m.

¹ H NMR (CDCl ₃ ) δ: 7.70 (d, J = 9.4 Hz, 1H); 7.46 (m, 1H); 7.24 (m, 4H); 6.91 (t, J = 8.7 Hz, 1H); , 2H); 4.98 (dd, J = 8.2, 3.3 Hz, 1H); 4.49 (m, 1H); 4.27 (dd, J = 13.3, 3.5 Hz, 1H); 3.39 (s, 2H); 2.63 (m, 4H); 1.79 (m, 2H).

MS2 (ESI, m / z) : 493.3 [M + H +]; t R = 0.51min.

Example 9: ( R )-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiazepine Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline- 3-ketone:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (30 mg; prepared according to WO 2010/041194) and The title compound (49 mg; 67% yield) was obtained as a pale yellow solid.

MS2 (ESI, m / z) : 494.4 [M + H +]; t R = 0.50min.

Example 10: ( S )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4] Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinoline-4 -ketone:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (15 mg; prepared according to WO 2010/041194) and preparation The title compound (20 mg; 57% yield) was obtained as white crystals.

¹ H NMR (CDCl ₃ ) δ: 8.02 (s, 1H); 7.71 (d, J = 9.4 Hz, 1H); 7.48 (m, 1H); 7.15 (d, J = 2.3 Hz, 1H); 7.03 (m) , 1H); 6.92 (m, 2H); 6.58 (s, 1H); 4.99 (m, 1H); 4.57 (s, 2H); 4.48 (d, J = 8.3 Hz, 1H); 4.27 (m, 1H) ; 2.56 (m, 4H); 1.80 (m, 2H).

MS1 (ESI, m / z) : 477.2 [M + H +]; t R = 0.56min.

Example 11: ( R )-7-Fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4] Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline- 3-ketone:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (15 mg; prepared according to WO 2010/041194) and The title compound (20 mg; 57% yield) was obtained as a pale yellow solid.

MS1 (ESI, m / z) : 478.2 [M + H +]; t R = 0.55min.

Example 12: ( S )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyridine [3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrole [3,2,1- ij ]quinolin-4-one:

( S )-1-Amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (275 mg, prepared according to WO 2010/041194) and preparation the compound G (390 mg of) begins and proceeds similarly to example 1, in _{(DCM / MeOH / NH 4 OH} 1000: 25: 4 to 1000: 50: 8) CC by after purification, to obtain the title compound as a slightly yellow solid (428 mg; 66% yield).

¹ H NMR (CDCl ₃ ) δ: 9.41 (m, 1H); 7.73 (m, 2H); 7.48 (dd, J = 8.6, 4.6 Hz, 1H); 7.33 (d, J = 8.6 Hz, 1H); 7.18 (s, 1H); 6.92 (t, J = 8.9 Hz, 1H); 6.69 (d, J = 9.5 Hz, 1H); 5.01 (m, 1H); 4.67 (s, 2H); 4.52 (m, 1H) ; 4.33 (dd, J = 13.2, 3.5 Hz, 1H); 2.66 (m, 2H); 1.78 (m, 2H); 1.56 (m, 2H).

MS1 (ESI, m / z) : 478.3 [M + H +]; t R = 0.57min.

Example 13: ( R )-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3 - de ] quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (15 mg; prepared according to WO 2010/041194) and The title compound (21 mg; 60% yield) was obtained as a pale yellow solid.

MS1 (ESI, m / z) : 479.2 [M + H +]; t R = 0.56min.

Example 14: ( S )-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3 - de ] quinoxalin-3-one:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (11 mg; prepared according to WO 2010/041194) and The title compound (8 mg; 32% yield) was obtained as a pale yellow foam.

¹ H NMR (CDCl ₃ ) δ: 8.99 (m, 1H); 8.25 (s, 1H); 7.78 (m, 2H); 7.34 (d, J = 8.6 Hz, 1H); 7.12 (s, 1H); (t, J = 9.0 Hz, 1H); 5.03 (m, 1H); 4.67 (s, 2H); 4.54 (m, 1H); 4.33 (dd, J = 13.6, 3.4 Hz, 1H); 2.68 (m, 4H); 1.81 (m, 2H).

MS1 (ESI, m / z) : 479.2 [M + H +]; t R = 0.56min.

Example 15: ( R )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1 - ij ]quinoline-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (11 mg; prepared according to WO 2010/041194) and preparation The title compound (13 mg; 52% yield) was obtained as crystals.

¹ H NMR (CDCl ₃ ) δ: 7.72 (dd, J = 13.1, 8.6 Hz, 2H); 7.48 (dd, J = 8.6, 4.6 Hz, 1H); 7.29 (m, 2H); 6.92 (t, J = 9.0 Hz, 1H); 6.65 (d, J = 9.4 Hz, 1H); 4.99 (dd, J = 8.3, 3.2 Hz, 1H); 4.64 (s, 2H); 4.51 (m, 1H); 4.31 (dd, J = 13.3, 3.5 Hz, 1H); 2.64 (m, 4H); 1.78 (td, J = 6.6, 2.4 Hz, 2H).

MS1 (ESI, m / z) : 478.1 [M + H +]; t R = 0.57min.

Example 16: ( S )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1 - ij ]quinoline-4-one:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (4.3 mg, prepared according to WO 2010/041194) and The title compound (3 mg, 29% yield) was obtained as a colourless solid.

MS4 (ESI, m / z) : 494.1 [M + H +]; t R = 0.61min.

Example 17: ( R )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4] Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinoline-4 -ketone:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (8 mg, prepared according to WO 2010/041194) and preparation The title compound (2 mg, 11% yield) was obtained as a colourless powder.

MS4 (ESI, m / z) : 477.3 [M + H +]; t R = 0.57min.

Example 18: ( S )-7-Fluoro-6-{3-[2-oxo-3-(3-oxo-3,4-dihydro- 2H -benzo[1,4] Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline- 3-ketone:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (8 mg; prepared according to WO 2010/041194) and The title compound (2 mg; 11% yield) was obtained as a white powder.

MS4 (ESI, m / z) : 478.2 [M + H +]; t R = 0.55min.

Example 19: ( R )-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiazepine Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinoline-4 -ketone:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (8 mg, prepared according to WO 2010/041194) and preparation The title compound (7 mg, 38% yield) was obtained as a colourless powder.

MS4 (ESI, m / z) : 493.3 [M + H +]; t R = 0.60min.

Example 20: ( S )-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -benzo[1,4]thiazepine Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline- 3-ketone:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (8 mg; prepared according to WO 2010/041194) and The title compound (7 mg; 39% yield) was obtained as a pale yellow powder.

MS4 (ESI, m / z) : 494.3 [M + H +]; t R = 0.58min.

Example 21: ( S )-1-{3-[3-(2,3-Dihydro-benzo[1,4]dioxine-6-yl)-2-oxo-2, 3-Dihydro-oxazol-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (15 mg, prepared according to WO 2010/041194) and preparation The title compound (11 mg, 32% yield) was obtained as a pale yellow powder.

MS4 (ESI, m / z) : 464.3 [M + H +]; t R = 0.61min.

Example 22: ( R )-1-{3-[3-(2,3-Dihydro-benzo[1,4]dioxol-6-yl)-2-oxo-2, 3-Dihydro-oxazol-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (15 mg, prepared according to WO 2010/041194) and preparation The title compound (12 mg, 35% yield) was obtained as a pale yellow powder.

MS4 (ESI, m / z) : 464.3 [M + H +]; t R = 0.62min.

Example 23: ( S )-6-{3-[3-(2,3-Dihydro-benzo[1,4]dioxine-6-yl)-2-oxo-2, 3-dihydro-oxazole-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quina Porphyrin-3-one:

From ( S )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (15 mg; prepared according to WO 2010/041194) and The title compound (11 mg; 32% yield) was obtained as a brown powder.

MS4 (ESI, m / z) : 465.3 [M + H +]; t R = 0.60min.

Example 24: ( S )-9-Fluoro-1-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazole-5-yl]- Propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (9 mg, prepared according to WO 2010/041194) and preparation The title compound (13 mg, 66% yield) was obtained as a pale yellow oil.

MS4 (ESI, m / z) : 448.3 [M + H +]; t R = 0.70min.

Example 25: ( R )-7-Fluoro-6-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazol-5-yl]- Propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (9 mg; prepared according to WO 2010/041194) and The title compound (2 mg; 13% yield) was obtained as a yellow oil.

MS4 (ESI, m / z) : 449.3 [M + H +]; t R = 0.70min.

Example 26: ( S )-1-{3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamine -9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (8 mg, prepared according to WO 2010/041194) and preparation The title compound (8 mg, 45% yield) was obtained as a colorless oil.

MS4 (ESI, m / z) : 450.3 [M + H +]; t R = 0.64min.

Example 27: ( R )-6-{3-[3-(4-Ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamine -7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (8 mg; prepared according to WO 2010/041194) and The title compound (9 mg; 51% yield) was obtained as a pale yellow oil.

MS4 (ESI, m / z) : 451.3 [M + H +]; t R = 0.63min.

Example 28: ( S )-9-Fluoro-1-{3-[3-(3-fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5 -yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one:

From ( S )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (40 mg, prepared according to WO 2010/041194) and preparation The title compound (35 mg, 41% yield) was obtained as a yellow foam.

MS4 (ESI, m / z) : 438.2 [M + H +]; t R = 0.66min.

Example 29: (R)-7-Fluoro-6-{3-[3-(3-fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazole-5 -yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (40 mg); prepared according to WO 2010/041194) The title compound (38 mg; 44% yield) was obtained as a yellow foam.

MS4 (ESI, m / z) : 439.3 [M + H +]; t R = 0.65min.

Example 30: (R)-9-Fluoro-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1 - ij ]quinoline-4-one:

From ( R )-1-amino-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one (4 mg), prepared according to WO 2010/041194) and The title compound (4 mg, 38% yield) was obtained as a colourless powder.

MS4 (ESI, m / z) : 494.1 [M + H +]; t R = 0.61min.

Example 31: ( S )-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3 - de ] quinoxalin-3-one:

( S )-6-Amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (4 mg); prepared according to WO 2010/041194) The title compound (3 mg; 29% yield) was obtained as a pale brown powder (yield).

MS4 (ESI, m / z) : 495.1 [M + H +]; t R = 0.60min.

Example 32: (R)-7-Fluoro-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3 - de ] quinoxalin-3-one:

From ( R )-6-amino-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one (4 mg); prepared according to WO 2010/041194) The title compound (6 mg; 58% yield) was obtained as a brown solid.

MS4 (ESI, m / z) : 495.1 [M + H +]; t R = 0.60min.

Example 33: ( S )-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1, 4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quina Porphyrin-4-one:

From ( 1S )-1-amino-1,2-dihydro- 4H -pyrrolo[3,2,1- ij ]quinolin-4-one (6.5 mg; prepared according to WO 2010/041194) and preparation The title compound (3 mg; 21% yield) was obtained as a colorless crystals.

^{1 H NMR (500MHz, DMSO)} δ: 11.40 (m, 1H); 8.16 (s, 1H); 7.92 (d, J = 9.4Hz, 1H); 7.60 (m, 1H); 7.57 (m, 2H); 7.53 (m, 1H); 7.20 (m, 2H); 6.57 (d, J = 9.4 Hz, 1H); 4.73 (dd, J = 3.9, 8.3 Hz, 1H); 4.68 (s, 2H); 4.40 (dd , J = 8.4, 12.8 Hz, 1H); 4.03 (dd, J = 4.0, 12.8 Hz, 1H); 2.66 (m, 2H); 2.56 (m, 3H); 1.70 (p, J = 7.0 Hz, 2H) .

MS1 (ESI, m / z) : 495.96 [M + H +]; t R = 0.56min.

Example 34: ( S )-6-{3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1, 4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quina Porphyrin-3-one:

From ( 6S )-6-amino-5,6-dihydro- 3H -pyrrolo[1,2,3- de ]quinoxalin-3-one (6.4 mg; prepared according to WO 2010/041194) and The title compound (9 mg; 56% yield) was obtained as a white solid.

^{1 H NMR (500MHz, DMSO)} δ: 11.28 (m, 1H); 8.20 (s, 1H); 7.72 (s, 1H); 7.61 (s, 2H); 7.53 (s, 1H); 7.33 (s, 1H ); 7.20 (s, 1H); 4.75 (s, 1H); 4.68 (s, 2H); 4.48 (m, 1H); 4.07 (m, 1H); 2.64 (m, 4H); 1.70 (s, 2H) .

MS1 (ESI, m / z) : 460.97 [M + H +]; t R = 0.55min.

Example 35: (R)-6-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1, 4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quina Porphyrin-3-one:

From ( 6R )-6-amino-5,6-dihydro- 3H -pyrrolo[1,2,3- de ]quinoxalin-3-one (6.5 mg; prepared according to WO 2010/041194) and The title compound (10 mg; 61% yield) was obtained as a white solid.

^{1 H NMR (500MHz, DMSO)} δ: 11.36 (s, 1H); 8.20 (s, 1H); 7.72 (d, J = 7.9Hz, 1H); 7.61 (m, 2H); 7.52 (m, 1H); 7.33 (t, J = 7.5 Hz, 1H); 7.20 (s, 1H); 4.75 (d, J = 4.4 Hz, 1H); 4.68 (s, 2H); 4.47 (dd, J = 8.5, 12.8 Hz, 1H) 4.08 (m, 1H); 2.68 (m, 2H); 2.55 (m, 2H); 1.70 (m, 2H).

MS1 (ESI, m / z) : 460.98 [M + H +]; t R = 0.55min.

Example 36: ( S )-3-Fluoro-4-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-4,5-dihydro-pyrrolo[3,2,1 - de ][1,5]naphthyridin-7-one:

From ( S )-4-amino-3-fluoro-4 H -pyrrolo[3,2,1- de ][1,5]naphthyridin-7(5 H )-one (6.4 mg; according to WO 2010 The title compound (9 mg; 56% yield) was obtained as a colorless crystals.

1H NMR (500MHz, DMSO) δ: 11.34 (d, J = 0.7Hz, 1H); 8.46 (s, 1H); 7.99 (d, J = 9.7 Hz, 1H); 7.60 (d, 1H); 7.52 (m) , 1H); 7.20 (s, 1H); 6.78 (d, J = 9.7 Hz, 1H); 4.98 (d, J = 5.1 Hz, 1H); 4.68 (s, 2H); 4.47 (dd, J = 8.5, 12.6 Hz, 1H); 4.07 (dd, J = 3.5, 12.7 Hz, 1H); 2.69 (m, 2H); 2.55 (m, 2H); 1.70 (m, 2H).

MS1 (ESI, m / z) : 478.94 [M + H +]; t R = 0.54min.

Example 37: (R)-3-Fluoro-4-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-4,5-dihydro-pyrrolo[3,2,1 - de ][1,5]naphthyridin-7-one:

From ( R )-4-amino-3-fluoro-4 H -pyrrolo[3,2,1- de ][1,5]naphthyridin-7(5 H )-one (7 mg; according to WO 2010/ The title compound (4 mg; 27% yield) was obtained as a colorless crystal.

^{1 H NMR (500MHz, DMSO)} δ: 11.48 (s, 1H); 8.47 (s, 1H); 7.99 (m, 1H); 7.53 (dd, J = 0.6,1.4Hz, 1H); 7.31 (s, 1H ); 6.78 (m, 1H); 4.97 (m, 1H); 4.52 (m, 4H); 4.06 (m, 1H); 2.73 (d, J = 0.8 Hz, 4H); 1.80 (d, J = 0.4 Hz) , 2H).

MS1 (ESI, m / z) : 478.93 [M + H +]; t R = 0.54min.

Example 38: ( S )-9-Methoxy-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2 - b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2 , 1- ij ]quinolin-4-one:

Starting from the compound of Preparation I (7.5 mg) and the title compound (10 mg), and the title compound (9 mg; 54) %Yield).

MS1 (ESI, m / z) : 489.99 [M + H +]; t R = 0.58min.

Example 39: ( S )-9-Methyl-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2, 1- ij ]quinoline-4-one:

Starting from the preparation of the compound of J (7 mg) and the compound of compound (10 mg), and the title compound (5 mg; 33%) Yield).

^{1 H NMR (500MHz, DMSO)} δ: 11.37 (s, 1H); 8.18 (s, 1H); 7.86 (d, J = 9.4Hz, 1H); 7.59 (m, 1H); 7.52 (m, 1H); 7.48 (d, J = 8.0 Hz, 1H); 7.19 (s, 1H); 7.02 (d, J = 8.2 Hz, 1H); 6.48 (d, J = 9.4 Hz, 1H); 4.77 (dd, J = 3.1) , 8.0 Hz, 1H); 4.68 (s, 2H); 4.30 (m, 1H); 4.13 (dd, J = 3.3, 12.9 Hz, 1H); 2.56 (m, 4H); 2.47 (s, 3H); (p, J = 6.9 Hz, 2H).

MS1 (ESI, m / z) : 473.99 [M + H +]; t R = 0.58min.

Example 40: ( S )-4-Sideoxy-1-{3-[2-Sideoxy-3-(3-Sideoxy-3,4-Dihydro- 2H -pyridine And [3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-4 H -pyrrolo[3,2,1- ij ]quinoline-9-carbonitrile:

Starting from the preparation of the compound of K (7.3 mg) and the compound of compound (10 mg), and the title compound ( 7.4 mg; 44% yield).

^{1 H NMR (500MHz, DMSO)} δ: 11.31 (m, 1H); 8.01 (d, J = 9.5Hz, 1H); 7.77 (d, J = 8.1Hz, 1H); 7.60 (m, 1H); 7.57 ( d, J = 8.1 Hz, 1H); 7.52 (m, 1H); 7.20 (s, 1H); 6.76 (d, J = 9.5 Hz, 1H); 4.92 (dd, J = 3.4, 8.0 Hz, 1H); 4.68 (s, 2H); 4.41 (dd, J = 8.2, 12.7 Hz, 1H); 4.15 (dd, J = 3.7, 12.7 Hz, 1H); 3.17 (s, 1H); 2.65 (m, 5H); (m, 2H).

MS1 (ESI, m / z) : 484.93 [M + H +]; t R = 0.57min.

Pharmacological properties of the compounds of the invention In vitro analysis Minimum inhibitory concentration of bacterial growth: experimental method:

In the cation-adjusted Mueller-Hinton broth by microdilution method, according to "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically", Accreditation Standard, 7th Edition, Clinical and Laboratory Standards Institute (CLSI) Document M7- The instructions provided in A7, Wayne, PA, USA, 2006 determine the minimum inhibitory concentration (MIC; mg/l).

result:

All example compounds were tested against several Gram-positive and Gram-negative bacteria.

All example compounds were tested against several Gram-positive and Gram-negative bacteria. Typical antibacterial test results (MIC, expressed in mg/L) are given in Table 1 below. Staphylococcus aureus A798, Enterococcus faecium A949 and Acinetobacter baumannii T6474 are multi-resistant strains (specifically quinolinone-resistant), while M. catarrhalis A894 is a quinolinone-sensitive strain, And Staphylococcus aureus ATCC29213 is a methicillin-sensitive and quinolinone-sensitive strain.

Claims (16)

a compound of formula I, Wherein U represents CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents H, halogen, methyl, methoxy, cyano or ethynyl; a phenyl group substituted by (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )alkoxy and optionally substituted by halogen at the meta position, or W a group having one of the following formulas W ¹ and W ² Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I as claimed in claim 1, which is also a compound of formula I _P Wherein U represents CH or N; W represents a substitution at the para position by (C ₁ -C ₃ )alkyl, (C ₁ -C ₃ )alkoxy or (C ₁ -C ₃ )thioalkoxy and optionally a phenyl group substituted by a halogen at the meta position, or a group having a W group having one of the following formulas W ¹ and W ² Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I according to claim 1 or 2 wherein U represents CH; or a salt of such compounds. A compound of formula I according to claim 3, wherein the group of W is a group of W ¹ Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I according to claim 1 or 2, wherein U represents N; or a salt of such a compound. A compound of formula I according to claim 5, wherein the group of W is a group of W ¹ Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I according to claim 1, wherein W represents a substitution at the para position by (C ₁ -C ₃ )alkyl, (C ₁ -C ₂ )alkoxy or (C ₁ -C ₂ )thioalkoxy and a phenyl group substituted by fluorine in the meta position; or a salt of such a compound. A compound of formula I according to claim 1 or 2, wherein the group of W is a group of W ¹ Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I according to claim 1 or 2, wherein the group of W is a group of formula W ² A compound of formula I according to claim 1, wherein U represents CH or N; V represents CH or N, provided that at least one of U and V does not represent N; R represents H, fluoro or cyano; and W represents a phenyl group substituted by (C ₁ -C ₃ )alkyl, (C ₁ -C ₂ )thioalkoxy or (C ₁ -C ₂ )alkoxy and optionally substituted by fluorine at the meta position, or W a group having one of the following formulas W ¹ and W ² Wherein Q is O or S and X is CH or N; or a salt of such a compound. A compound of formula I according to claim 1 which is selected from the group consisting of: ( S )-7-fluoro-6-{3-[3-(3-fluoro-4-methyl-phenyl)-2-oxooxy -2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( R )-9-fluoro-1-{3-[3-(3-fluoro-4-methyl-phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propane Amino}},2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-1-{3-[3-(4-ethoxy-benzene 2-yloxy-2,3-dihydro-oxazole-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- Ij ]quinolin-4-one; ( R )-6-{3-[3-(2,3-dihydro-benzo[1,4]dioxan-6-yl)-2- Oxyloxy-2,3-dihydro-oxazol-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline 3-ketone; ( S )-6-{3-[3-(4-ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propane Amino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( R )-9-fluoro-1-{3-[2 -Sideoxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3, 2,1- ij ]quinolin-4-one; ( S )-7-fluoro-6-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-di Hydrogen-oxazole-5- ] - propylamino} -5,6-dihydro - pyrrolo [1,2,3- de] quinoxalin-3-one; (S) -9- fluoro-1- {3- [2- Oxalo-3-(3-oxo-3,4-dihydro- 2H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazole-5- ]]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-7-fluoro-6-{3-[2- Oxalo-3-(3-oxo-3,4-dihydro- 2H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazole-5- ]]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-9-fluoro-1-{3-[2 - oxo-3-(3-oxo-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5 -yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-7-fluoro-6-{3-[2 - oxo-3-(3-oxo-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5 -yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-9-fluoro-1-{3-[ 2-Phenoxy-3-(3-olyl-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3 -dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-7-fluoro -6-{3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro) -2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6 -dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-7-fluoro-6-{3-[2- oxo-3-(3-side oxygen) 3-,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propanyl胺amino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( R )-9-fluoro-1-{3-[2- oxy -3-(3-Sideoxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-acean Zyrid-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-9-fluoro-1-{3 -[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2 ,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-9 -fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2 ,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-7 -Fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -benzo[1,4]oxazin-6-yl)-2 ,3-dihydro-oxazole-5-yl]-propylamino}-5,6-dihydro-pyridyl And [1,2,3- de] quinoxalin-3-one; (R) -9- fluoro-l- {3- [2-oxo-3- (3-oxo-3,4 -dihydro-2 H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro- Pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-7-fluoro-6-{3-[2- oxo-3-(3- oxo-3,4) -dihydro-2 H -benzo[1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro- Pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-1-{3-[3-(2,3-dihydro-benzo[1,4]dioxole Hexene-6-yl)-2-oxo- 2,3-dihydro-oxazole-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3 , 2,1- ij ]quinolin-4-one; ( R )-1-{3-[3-(2,3-dihydro-benzo[1,4]dioxine-6- 2-yloxy-2,3-dihydro-oxazole-5-yl]-propylamino}-9-fluoro-1,2-dihydro-pyrrolo[3,2,1- Ij ]quinolin-4-one; ( S )-6-{3-[3-(2,3-dihydro-benzo[1,4]dioxan-6-yl)-2- Oxyloxy-2,3-dihydro-oxazol-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline 3-ketone; ( S )-9-fluoro-1-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro-oxazole-5-yl ]-propylamino}-1,2-dihydro-pyrrolo[3,2, 1- ij ]quinolin-4-one; ( R )-7-fluoro-6-{3-[2-o-oxy-3-(4-propyl-phenyl)-2,3-dihydro- Oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-1-{3-[ 3-(4-ethoxy-phenyl)-2-oxo-2,3-dihydro-oxazol-5-yl]-propylamino}-9-fluoro-1,2-dihydro -pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-6-{3-[3-(4-ethoxy-phenyl)-2- oxo-2, 3-dihydro-oxazole-5-yl]-propylamino}-7-fluoro-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; S )-9-fluoro-1-{3-[3-(3-fluoro-4-methyl-phenyl)-2-yloxy-2,3-dihydro-oxazol-5-yl]- Propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( R )-7-fluoro-6-{3-[3-(3- Fluoro-4-methyl-phenyl)-2-oxo-2,3-dihydro-oxazole-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1, 2,3- de ]quinoxalin-3-one; ( R )-9-fluoro-1-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2 H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-1,2- Dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-7-fluoro-6-{3-[2-o-oxy-3-(3-sideoxy- 3,4-dihydro-2 H -pyrido[3,2- b ][1,4]thio Pyrazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2,3- de ]quinoxaline- 3-ketone; ( R )-7-fluoro-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]thiazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-5,6-dihydro-pyrrolo[1,2, 3- de ]quinoxalin-3-one; ( S )-1-{3-[2- oxo-3-(3- oxo-3,4-dihydro-2 H -pyrido[ 3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-1,2-dihydro-pyrrolo[ 3,2,1- ij ]quinolin-4-one; ( S )-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro-2 H - Pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6-dihydro- Pyrrolo[1,2,3- de ]quinoxalin-3-one; ( R )-6-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro) -2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propylamino}-5,6 -dihydro-pyrrolo[1,2,3- de ]quinoxalin-3-one; ( S )-3-fluoro-4-{3-[2- oxo-3-(3-side oxygen 3-,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propanyl Amino}-4,5-dihydro-pyrrolo[3,2,1- de ][1, 5] naphthyridin-7-one; ( R )-3-fluoro-4-{3-[2-o-oxy-3-(3-o-oxy-3,4-dihydro- 2H -pyridine [3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazole-5-yl]-propylamino}-4,5-dihydro-pyrrole [3,2,1- de ][1,5]naphthyridin-7-one; ( S )-9-methoxy-1-{3-[2-trioxy-3-(3-side oxygen 3-,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-oxazol-5-yl]-propanyl (amino)}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-9-methyl-1-{3-[2-oxyl -3-(3-Sideoxy-3,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazin-6-yl)-2,3-dihydro-acean Oxazol-5-yl]-propylamino}-1,2-dihydro-pyrrolo[3,2,1- ij ]quinolin-4-one; ( S )-4-sideoxy-1- {3-[2-Sideoxy-3-(3-o-oxy-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazin-6-yl) -2,3-dihydro-oxazol-5-yl]-propylamino}-1,2-dihydro- 4H -pyrrolo[3,2,1- ij ]quinoline-9-carbonitrile Or a salt of such a compound. A compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11 for use as a medicament. A pharmaceutical composition comprising, as an active ingredient, a compound of formula I as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and at least one medically inert excipient. A compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 11 for use in the prevention or treatment of a bacterial infection. A compound according to claim 14 or a pharmaceutically acceptable salt for use in the prevention or treatment of a bacterial infection selected from the group consisting of respiratory tract infection, otitis media, meningitis, skin and soft tissue infections, pneumonia, bacteremia, Endocarditis, intra-abdominal infection, gastrointestinal infection, Clostridium difficile infection, urinary tract infection, sexually transmitted infection, foreign body infection, osteomyelitis, lyme disease, local infection, ophthalmic infection, Tuberculosis and tropical diseases. A compound according to claim 14 or a pharmaceutically acceptable salt for use in the prevention or treatment of a bacterial infection mediated by Staphylococcus aureus or Acinetobacter baumanii .