(19)
(11)EP 3 490 984 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
09.09.2020 Bulletin 2020/37

(21)Application number: 17754294.1

(22)Date of filing:  28.07.2017
(51)International Patent Classification (IPC): 
C07D 403/06(2006.01)
C07D 413/06(2006.01)
C07D 211/40(2006.01)
A61K 31/5375(2006.01)
A61K 31/40(2006.01)
A61P 31/04(2006.01)
C07D 405/12(2006.01)
C07D 211/36(2006.01)
C07D 211/94(2006.01)
A61K 31/4025(2006.01)
A61K 31/396(2006.01)
(86)International application number:
PCT/EP2017/069179
(87)International publication number:
WO 2018/020004 (01.02.2018 Gazette  2018/05)

(54)

2-PYRROLIDINE PHENYLHYDRAZIDES ANTIBACTERIAL AGENTS

2-PYRROLIDINE PHENYLHYDRAZIDE ANTIBAKTERIELLER WIRKSTOFF

AGENTS ANTIBACTERIAUX DE 2-PYRROLIDINE PHENYLHYDRAZIDE


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 29.07.2016 EP 16181965
08.03.2017 EP 17159942
28.03.2017 EP 17163270
30.03.2017 ES 201700452

(43)Date of publication of application:
05.06.2019 Bulletin 2019/23

(73)Proprietor: Abac Therapeutics, S.L
08950 Esplugues De LL (ES)

(72)Inventors:
  • PALOMER BENET, Albert
    08014 Barcelona (ES)
  • GARGALLO VIOLA, Domingo
    08940 Cornellà De Llobregat (ES)

(74)Representative: ZBM Patents - Zea, Barlocci & Markvardsen 
Rambla Catalunya, 123
08008 Barcelona
08008 Barcelona (ES)


(56)References cited: : 
WO-A1-2012/051708
WO-A1-2016/016291
GB-A- 769 482
WO-A1-2013/153394
CN-A- 101 525 336
  
  • LONGBIN LIU ET AL: "Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 5, 8 March 2012 (2012-03-08), pages 1868-1897, XP055407406, ISSN: 0022-2623, DOI: 10.1021/jm201331s
  • MARTIN VÖLKERT ET AL: "Phenylhydrazide as an Enzyme-Labile Protecting Group in Peptide Synthesis", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 67, no. 20, 1 October 2002 (2002-10-01), pages 6902-6910, XP055407404, ISSN: 0022-3263, DOI: 10.1021/jo0259966
  
Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


Description


[0001] This application claims the benefit of the European Patent Application EP16181965.1 filed on 29.07.2016, the European Patent Application EP17159942.6 filed on 08.03.2017, the European Patent Application EP17163270.6 filed on 28.03.2017 and the Spanish Patent Application ES 201700452 filed on 30.03.2017.

TECHNICAL FIELD



[0002] The present invention relates to new antibacterial agents, particularly to 2-pyrrolidine phenylhydrazide compounds that show selective antibacterial activity against the Gram-negative bacteria Acinetobacter baumannii.

BACKGROUND ART



[0003] Infections caused by Acinetobacter baumannii (A. baumannii) bacteria are increasingly recognized as a serious health threat, especially in healthcare facilities, and are associated with increased morbidity, mortality and duration of hospital stay, as well as with high healthcare costs (Giamarellou et al. Acinetobacter baumannii: a universal threat to public health? Int. J. Antimicrob. Agents, 2008, 32(2), 106-9; Howard et al. Acinetobacter baumannii. An emerging opportunistic pathogen. Virulence 2012, 3(3), 243-250).

[0004] A. baumannii is a rod-shaped Gram-negative bacillus that is aerobic, and non-motile. It behaves as an opportunistic pathogen mainly affecting immunocompromised subjects, for example those having an underlying disease, such as chronic lung disease or diabetes, and those hospitalized for long periods and subjected to multiple invasive procedures.

[0005] A baumannii is often implicated in nosocomial infections, so it has a high incidence among patients experiencing prolonged hospital stay, and is a particularly relevant source of infections in hospital intensive care units (ICUs). Among the main risk factors for acquiring A. baumannii is the use of artificial devices commonly employed in hospital settings, such as dialysis, mechanical ventilation, sutures or catheters, due to the notorious ability of A. baumannii to survive for extended periods on environmental surfaces.

[0006] A. baumannii can cause infections in virtually every organ system of the human body, including pneumonia, surgical site infections, skin and soft tissue infections, urinary tract infections, post-operative meningitis and catheter-related infections.

[0007] Hospital-acquired pneumonia is the most common life-threatening hospital-acquired infection, and is mainly associated with the use of mechanical ventilation, known as ventilator associated pneumonia (VAP). VAP infections caused by Acinetobacter are between 8% and 35% of total VAP cases.

[0008] Bloodstream infections (BSI) are also common nosocomial infections, which are also associated with increased morbidity, mortality and duration of hospital stay. Infections caused by Acinetobacter correspond to 2% of the total BSI cases, with a particular high incidence in ICU-acquired BSI.

[0009] Other reported hospital-acquired infections associated with A. baumannii are, for example, surgical site infections (SSI) and urinary tract infections, such as catheter-associated urinary tract infections (CAUTI) or hospitalized community-acquired urinary tract infections.

[0010] A. baumannii infections are currently treated with different broad- or semi-broad spectrum antibiotics or combinations, including, for example, the carbapenems imipenem, meropenem and doripenem, which are first choice drugs. However, treatment of A. baumannii infections is challenging since it has emerged as a highly drug-resistant pathogen, especially carbapenem-resistant, and therefore other alternative broad-spectrum antibacterials are also used in therapy, such as polymyxins (colistin, polymyxin E and polymyxin B), tigecycline, tetracyclines (minocycline and doxycycline) or aminoglycosides (amikacin and tobramycin). None of the currently used treatments are specific for A. baumannii.

[0011] The use of such broad-spectrum antibacterials entails important drawbacks, since they have a substantial impact on the normal flora, potentially diminishing the immunologic function of microbiota and potentially generating treatment-induced co-infections caused by resistant strains, as disclosed for example in Jernberg et al. Long-term impacts of antibiotic exposure on the human intestinal microbiota, Microbiology, 2010, 156(Pt 11), 3216-3223.

[0012] Moreover, in a retrospective study performed with 26,107 patients, it was concluded that the use of broad-spectrum antibiotics may have a relationship with the development of irritable bowel syndrome (IBS), as disclosed in Villarreal et al. Use of broad-spectrum antibiotics and the development of irritable bowel syndrome, WMJ, 2012, 111(1), 17-20.

[0013] As previously commented, when broad-spectrum antibiotics are used, not only the pathogenic microorganism, but any other microorganisms present in the treated subject (be either human or animal) may develop resistance. This latter may happen if antibiotic is moderately active but not lethal for it. Moreover, it is known in the art that when a microorganism develops a resistance to a drug is able to transfer such resistance to other members of its specie or even transfer this resistance to other species, this is known as Horizontal Gene Transfer (HGT), as disclosed in Wintersdorff, et al. Dissemination of Antimicrobial Resistance in Microbial Ecosystems through Horizontal Gene Transfer, Front Microbiol. 2016, 7:173. Consequently, it is an advantage of pathogen-specific treatment that generation of resistance in the pathogenic species does not happen by this two-stage process, namely, first producing in other microorganisms and then transfer by HGT to pathogenic species.

[0014] In contrast, treatments using pathogen-specific antibacterials that kill exclusively the infecting bacteria would minimize the impact on normal flora and would avoid the selection of resistant strains of non-infecting bacteria of microbiota, thus minimizing any treatment-induced co-morbidities and reducing the Horizontal Gene Transfer of resistance between species.

[0015] The only antibacterial agents selective for Acinetobacter baumannii disclosed so far in the state of the art are a series of arylhydrazides containing a 2-pyridone moiety, as disclosed in the international patent application WO2016/016291-A1.

[0016] GB769482A discloses thiazolecarboxylic acid hydrazide as an antibacterial.

[0017] WO2013/153394 discloses compounds which can be arylhydrazides substituted by quinolones, as antibacterials.

[0018] WO2012/051708 discloses antibiotic compounds being phenylhydrazides substituted by bicycle-methyl (including indolyl-methyl).

[0019] Therefore, it would be desirable to provide novel compounds which are selective antibacterial agents against Acinetobacter baumannii bacteria, to thus increase the number of selective drugs currently available, which are both effective for treating the life-threatening infections caused by A. baumannii and highly selective for this bacteria, in order to avoid the disadvantages associated to the non-selective broad-spectrum antibiotics currently used in therapy.

OBJECT OF THE INVENTION



[0020] The object of the present invention is a compound of formula (I) as defined below.

[0021] A second aspect of the present invention relates to the compound of formula (I) for use as a medicament.

[0022] A third aspect of the present invention relates to a compound of formula (I) for use as antibacterial agent, particularly for treating or preventing A. baumannii infections.

[0023] A fourth aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable excipient and/or carrier.

[0024] A fifth aspect of the present invention relates to a process for preparing compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION



[0025] In a first aspect, the present invention relates to a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,
wherein

R1 and R2 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and hydroxyC1-4alkyl;

R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkoxy, haloC1-4alkoxy, -OC3-6cycloalkylC0-4alkyl, C1-6alkyl, C3-6cycloalkylC0-4alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC1-6alkyl, C1-4alkoxyC1-4alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN and -CO2R11; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl;

R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14, -C(NR15)NR11R12 and -CO2R11;

R9 is selected from hydrogen, C1-4alkyl and haloC1-4alkyl;

n is 0, 1, 2 or 3;

each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, C1-4alkoxyC1-6alkyl, -OC3-6cycloalkylC0-4alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phenyl, 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, O and S; wherein said phenyl and said heteroaryl ring may be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to a common carbon atom form a spiro C3-6cycloalkyl, or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and halogen;

each R11 and R12 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and C3-6cycloalkylC0-4alkyl;

each R13 and R14 are independently selected from hydrogen, C1-4alkyl, C3-6cycloalkylC0-4alkyl and Het3-6, wherein each C1-4alkyl and C3-6cycloalkylC0-4alkyl may optionally be substituted by one or more R16, and wherein each C1-4alkyl may optionally be substituted by one or more Het3-6; or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and C2-5acyl;

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 and -S(O2)NR11R12;

each R16 is independently selected from alkyl, halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 and -OCOR11;

Het3-6 is a 3- to 6-membered saturated monocyclic heterocyclic ring containing one heteroatom selected from O, S and N, wherein said ring is bonded to the rest of the molecule through any available C atom and wherein said ring can be optionally substituted by one or more substituents independently selected from C1-4alkyl or haloC1-4alkyl; and

each R17 and R18 are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl, or R17 and R18 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and haloC1-4alkyl;

and wherein the following products are excluded:

1,2-pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, 2-(2-phenylhydrazide), (2S)-,

1,2-pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, 2-(1-methyl-2-phenylhydrazide), (2S)-,

1,2-pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[3-(aminosulfonyl)phenyl]hydrazide], (2S,4S)-,

1,2-pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-(3-carboxyphenyl)hydrazide], (2S,4S)-,

1,2-pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[2-(trifluoromethyl)phenyl]hydrazide], (2S,4S)-, and

1,2-pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[2-chloro-5-(trifluoromethyl)phenyl]hydrazide], (2S,4S)-.



[0026] The authors of the present invention have developed a group of phenylhydrazide compounds containing a 2-pyrrolidine moiety as depicted in formula (I) that, surprisingly, show selective antibacterial activity against the Gram-negative bacteria Acinetobacter baumannii (A. baumannii), providing therefore a new and safer therapeutic tool for treating the infections caused by this bacteria, while avoiding the damage to the intestinal flora and multiple resistances involved with the treatment with the broad-spectrum antibacterials.

[0027] Moreover, not only the compounds of formula (I) are highly active and selective antibacterials against A. baumannii, as determined in in vitro assays, but they are also highly stable in blood plasma, so they are expected to maintain their antibacterial activity in vivo, as well.

[0028] The following compounds are excluded from the first aspect of the present invention:
  • 1,2-pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, 2-(2-phenylhydrazide), (2S)- (CAS 474316-85-3)
  • 1,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, 2-(1-methyl-2-phenylhydrazide), (2S)- (CAS 1361235-82-6)
  • 1,2-Pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[3-(aminosulfonyl)phenyl]hydrazide], (2S,4S)- (CAS 1188957-98-3)
  • 1,2-Pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-(3-carboxyphenyl)hydrazide], (2S,4S)- (CAS 1188958-01-1)
  • 1,2-Pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[2-(trifluoromethyl)phenyl]hydrazide], (2S,4S)- (CAS 1188958-02-2)
  • 1,2-Pyrrolidinedicarboxylic acid, 4-mercapto-, 1-(1,1-dimethylethyl) ester, 2-[2-[2-chloro-5-(trifluoromethyl)phenyl]hydrazide], (2S,4S)- (CAS 1188958-04-4)
These compounds have been disclosed in the following prior art documents: Liu et al., J. Med. Chem., 2012, 55(5), 1868-1897 (compounds 474316-85-3 and 1361235-82-6) and CN101525336-A (compounds 1188957-98-3, 1188958-01-1, 1188958-02-2 and 1188958-04-4). These compounds are disclosed only as reaction intermediates, but their medical use is not disclosed or suggested in the prior art.

Definitions



[0029] Within the meaning of the present invention, the term C1-6alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 6 carbon atoms and includes, among others, the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl. Similarly, the term C1-4alkyl, as a group or part of a group, means a straight or branched alkyl chain which contains from 1 to 4 carbon atoms and is a subgroup of C1-6alkyl which includes the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Similarly, the term C1-2alkyl means an alkyl chain which contains 1 or 2 carbon atoms and includes the groups methyl and ethyl.

[0030] Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

[0031] A haloC1-6alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-6alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples include, among others, the groups fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl. Similarly, the haloC1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-4alkyl group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different, and is a subgroup of haloC1-6akyl. Examples include, among others, the groups fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl and nonafluorobutyl.

[0032] A hydroxyC1-6alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-6alkyl group with one or more hydroxy groups. Examples include, among others, the groups hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl, 1-hydroxybutyl, 5-hydroxypentyl, 4-hydroxypentyl, 3-hydroxypentyl, 2-hydroxypentyl, 1-hydroxypentyl, 6-hydroxyhexyl, 5-hydroxyhexyl, 4-hydroxyhexyl, 3-hydroxyhexyl, 2-hydroxyhexyl, and 1-hydroxyhexyl. Similarly, a hydroxyC1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-4alkyl group with one or more hydroxy groups, and is a subgroup of the hydroxyC1-6alkyl group. Examples of hydroxyC1-4alkyl group include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl.

[0033] A C2-5acyl group means a group of formula -C(O)C1-4alkyl, wherein the C1-4alkyl moiety has the same meaning as described above. Examples include, among other, acetyl, propanoyl, n-butanoyl, sec-butanoyl, tert-butanoyl, or n-pentanoyl. Similarly, a C2-3acyl group means a group of formula -C(O)C1-2alkyl, wherein the C1-2alkyl moiety has the same meaning as described above. Examples include acetyl and propanoyl.

[0034] A C1-6alkoxy group, as a group or part of a group, means a group of formula -OC1-6alkyl, wherein the C1-6alkyl moiety has the same meaning as described above. Examples include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, or n-hexoxy, among others. Similarly, a C1-4alkoxy group, as a group or part of a group, means a group of formula -OC1-4alkyl, wherein the C1-4alkyl moiety has the same meaning as described above and is a subgroup of the C1-6alkoxy which includes, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.

[0035] A C1-4alkoxyC1-4alkoxy group means a group resulting from the replacement of one hydrogen atom from a C1-4alkoxy group with one C1-4alkoxy group, as defined above. Examples include, among others, methoxymethoxy, methoxy-1-ethoxy, methoxy-2-ethoxy, ethoxymethoxy, ethoxy-1-ethoxy, ethoxy-2-ethoxy, methoxy-3-propoxy, ethoxy-3-propoxy, and propoxy-3-propoxy.

[0036] A haloC1-4alkoxy group means a group resulting from the replacement of one or more hydrogen atoms from a C1-4alkoxy group with one or more halogen atoms (i.e. fluoro, chloro, bromo or iodo), which can be the same or different. Examples include, among others, the groups fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy.

[0037] A C1-4alkoxyC1-6alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-6alkyl group with one or more C1-4alkoxy groups as defined above, which can be the same or different. Examples include, among others, the groups methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl, 4-methoxybutyl, 5-methoxypentyl, 4-ethoxypentyl and 2-methoxy-3-methylpenyl. Similarly, a C1-4alkoxyC1-4alkyl group means a group resulting from the replacement of one or more hydrogen atoms from a C1-4alkyl group with one or more C1-4alkoxy groups as defined above, and is a subgroup of the C1-4alkoxyC1-4alkyl group. Examples of C1-4alkoxyC1-4alkyl include, among others, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tert-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.

[0038] A C3-6cycloalkyl group, as a group or as a part of a group, means a saturated, monocyclic, hydrocarbon ring group comprising 3 to 6 carbon atoms, which can be optionally substituted by one or more substituents independently selected from C1-4alkyl, C1-4 alkoxy, haloC1-4alkyl and halogen, i.e., one or more hydrogen atoms of the ring can be replaced by a C1-4alkyl, a C1-4alcoxy or a halogen. When there is more than one substitution, the substituents can be the same or different. Examples of C3-6cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0039] A C3-6cycloalkylC1-4alkyl group, as a group or as a part of a group, means a group resulting from the replacement of one hydrogen atom from a C1-4alkyl group with one C3-6cycloalkyl group, as defined above. Examples include, among others, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopentylpropyl and 4-cyclopentylbutan-2-yl. Similarly, a C3-6cycloalkylC1-2alkyl group, as a group or as a part of a group, means a group resulting from the replacement of one hydrogen atom from a C1-2alkyl group with one C3-6cycloalkyl group, as defined above, and is a subgroup of the C3-6cycloalkylC1-4alkyl group, including among other the following examples: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, and cyclohexylethyl. Thus, for example, the -C(O)C3-6cycloalkylC1-2alkyl group means a group resulting from the replacement of one hydrogen atom from a -C(O)C1-2alkyl group with one C3-6cycloalkyl group. Analogously, the -OC3-6cycloalkylC1-4alkyl group means a group resulting from the replacement of one hydrogen atom from a -OC1-4alkyl group with one C3-6cycloalkyl group.

[0040] The term C0alkyl indicates that the alkyl group is absent.

[0041] Thus, for example, the term C3-6cycloalkylC0-4alkyl includes C3-6cycloalkyl and C3-6cycloalkylC1-4alkyl, as defined above, and the term C3-6cycloalkylC0-2alkyl includes C3-6cycloalkyl and C3-6cycloalkylC1-2alkyl. Analogously, the term-C(O)C3-6cycloalkylC0-2alkyl includes -C(O)C3-6cycloalkyl and -C(O)C3-6cycloalkylC1-2alkyl and the term -OC3-6cycloalkylC0-4alkyl includes -OC3-6cycloalkyl and -OC3-6cycloalkylC1-4alkyl.

[0042] Likewise, the term C1-4alkoxyC0-6alkyl includes C1-4alkoxy and C1-4alkoxyC1-6alkyl as defined above.

[0043] An "oxo" group means =O.

[0044] A "methylene" group means -CH2-.

[0045] The term "saturated" relates to groups that do not have any double or triple bonds.

[0046] Any carbon atom as well as any heteroatom with unsatisfied valences in the formulas and schemes depicted in the present description is assumed to have the sufficient number of hydrogen atoms to satisfy the valences.

[0047] The expression "optionally substituted by one or more" means that a group may be substituted with one or more substituents, preferably 1, 2, 3 or 4, more preferably 1, 2 or 3, and more preferably 1 or 2 substituents, provided that the group has enough positions available susceptible of being substituted, i.e., enough hydrogen atoms available for replacement by a substituent. When more than one substituent are present, they may be the same or different and may be located on any available position.

[0048] In the compounds of formula (I), the variable point of attachment depicted for the R10 substituents means that, if present, each R10 may be attached to any one of the three available positions of the pyrrolidine ring susceptible of being substituted, i.e., having hydrogen atoms available for replacement by a R10, as shown with an asterisk (*) in the figure below. Each of the three marked carbon atoms of the pyrrolidine ring has two hydrogens, so each of the marked carbon atoms can have up to two R10 substituents, or two R10 attached to a common carbon may form an oxo group, or two R10 attached to a common carbon atom form a spiro C3-6cycloalkyl. If more than one R10 is present, unless they form an oxo group or a spiro cycloalkyl, they are preferably not attached to the same carbon atom of the pyrrolidine ring.



[0049] A 5- or 6- membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, O and S, as used in the present invention, includes, for example, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole and thiazole rings.

[0050] In the definition of formula (I) above, two groups of R3 to R7 attached to adjacent carbon atoms of the phenyl ring may be connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O. Said cycloalkyl is, therefore, fused to the phenyl ring in formula (I); examples of said fused cycloalkyl rings include, among others, the following:







[0051] In the definition of formula (I) above two R10 attached to adjacent carbon atoms of the pyrrolidine ring may be connected to form a 3- to 6-membered cycloalkyl. Said cycloalkyl is, therefore, fused to the pyrrolidine ring in formula (I); examples of said fused cycloalkyl rings include the following:





[0052] In the definition of formula (I) above R13 and R14 may form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted with one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and C2-5acyl, i.e., one or more hydrogen atoms of the ring can be replaced by a C1-4alkyl, haloC1-4alkyl or C2-5acyl, the substitution may be on a C-atom or a N-atom, if present. Examples of such heterocycles include azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, among other.

[0053] Similarly, R17 and R18 may form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted with one or more substituents independently selected from C1-4alkyl and haloC1-4alkyl, i.e., one or more hydrogen atoms of the ring can be replaced by a C1-4alkyl or haloC1-4alkyl, the substitution may be on a C-atom or a N-atom, if present. Examples of such heterocycles include azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, among other.

[0054] Thorough the description of the current invention, it is understood that when any variable (e.g. C1-6alkyl, C1-4alkyl, C1-4alcoxy, etc.) occurs more than once in a compound of formula (I), its definition on each occurrence is independent of its definition at every each other occurrence, so that the variable may be the same or different on each occasion.

[0055] Likewise, when a variable group, such as R10, R11 or R12, occurs more than once in a compound of formula (I), its definition on each occurrence is independent of its definition at every each other occurrence, so that the variable group is independently selected from its possible meanings at each occurrence, and may have the same meaning or different meaning on each occasion. It may be indicated by the expression "each independently selected from".

[0056] Similarly, the term "independently selected from" applied to the definition of a group of different variable groups (e.g. R3, R4, R5, R6 and R7), means that the definition of each variable of that group is independently selected from the definition of the other variable of the same group, and may have the same meaning or different meanings.

Compounds of the invention



[0057] Also included within the scope of the invention are the pharmaceutically acceptable salts, solvates, isotopes, stereoisomers and polymorphs of compounds of formula (I). Thus, any reference to a compound of formula (I) throughout the present specification includes a reference to any pharmaceutically acceptable salt, solvate, isotope or polymorph of such compound of formula (I).

[0058] The compounds of formula (I) have one or more asymmetric or chiral centres and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formula (I), including diastereomers, enantiomers, as well as mixtures thereof such as racemic mixtures, form part of the invention.

[0059] The compounds of the present invention contain basic nitrogen atoms and may, therefore, form salts with organic or inorganic acids. The term "pharmaceutically acceptable salts" as used herein encompasses any salt with no limitation on the type of salt that can be used, provided that these are acceptable for administration to a patient, meaning that they do not induce undue toxicity, irritation, allergic responses, or the like. Pharmaceutically acceptable salts are well known in the art.

[0060] For example, the pharmaceutically acceptable salts suitable for being used in the present invention include those derived from the following acids: hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1,5-naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic and tartaric acids, and the like. Hydrochloric acid is preferred.

[0061] The salts of a compound of formula (I) can be obtained, for example, during the final isolation and purification of the compounds of the invention, or can be prepared by treating a compound of formula (I) with a sufficient amount of the desired acid to give the salt in the conventional manner.

[0062] The term "solvates" as used herein encompasses a combination of a compound of formula (I) with solvent molecules, bonded by a non-covalent bond. Well known solvent molecules which are able to form solvates include water, alcohols and other polar organic solvents. When the solvate is formed with water, it is also known as a hydrate.

[0063] The term "isotopes" as used herein encompasses any isotopically-labelled form of the compounds of formula (I), wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, and sulfur, such as 35S. Those isotopically-labelled compounds are useful, for example, in metabolic or kinetic studies, particularly those labelled with 2H, 3H, and 14C. Moreover, substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0064] Isotopically-labelled compounds of the invention can generally be prepared by processes analogous to those described herein, by using an appropriate isotopically-labelled reagent in place of the non-labelled reagent otherwise employed.

[0065] The compounds of formula (I) may exist in different physical forms, i.e. amorphous and crystalline forms. Moreover, the compounds of the invention may have the ability to crystallize in more than one form, a characteristic which is known as polymorphism. Polymorphic forms can be distinguished by various physical properties well known in the art such as X-ray diffraction pattern, melting point or solubility. All such physical forms of the compounds of formula (I), including all polymorphic forms ("polymorphs") are included within the scope of the invention.

[0066] Furthermore, any formula given herein is also intended to represent the corresponding tautomeric forms. "Tautomer" refers to alternate forms of a molecule that differ in the position of a proton. Examples include, among others, the amide-imidic acid, amine-imine and keto-enol forms.

[0067] The first aspect of the invention is further defined by some specific and preferred embodiments as disclosed below.

[0068] In one embodiment, the invention relates to a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein:

R1 and R2 are independently selected from hydrogen and C1-4alkyl;

R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12, and haloC1-4alkoxy, or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl;

R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12;

R9 is selected from hydrogen and C1-4alkyl;

n is 0, 1, 2 or 3;

each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen;

each R11 and R12 are independently selected from hydrogen and C1-4alkyl;

each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12.



[0069] In one embodiment, the invention relates to the compounds of formula (I) wherein the phenyl ring has one, two or three substituents, i.e., at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen.

[0070] In another embodiment, the invention relates to the compounds of formula (I) wherein R1 and R2 are independently selected from hydrogen and methyl.

[0071] In another embodiment, the invention relates to the compounds of formula (I) wherein R1 and R2 are hydrogen.

[0072] In another embodiment, the invention relates to the compounds of formula (I) wherein one of R1 and R2 is hydrogen and the other is C1-4alkyl, preferably is methyl.

[0073] In another embodiment, the invention relates to the compounds of formula (I) wherein R1 and R2 are C1-4alkyl, which are the same or different, preferably R1 and R2 are the same C1-4alkyl, and more preferably R1 and R2 are both methyl.

[0074] In another embodiment, the invention relates to the compounds of formula (I) wherein R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably are independently selected from hydrogen, -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; more preferably are independently selected from hydrogen, halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; and still more preferably R3, R4, R5, R6 and R7 are independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2.

[0075] In a preferred embodiment, the invention relates to the compounds of formula (I) wherein R5 is selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably is selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxyl; more preferably is selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; still more preferably is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2; and still more preferably R5 is fluoro; R3 is selected from hydrogen, halogen and C1-6alkyl; more preferably R3 is selected from hydrogen, halogen and C1-4alkyl, still more preferably R3 is selected from hydrogen, fluoro, chloro, ethyl and methyl; and still more preferably R3 is hydrogen; and R4, R6 and R7 are hydrogen.

[0076] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein R4 and R6 are independently selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably are selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl and haloC1-4alkoxy; more preferably are selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy; and still more preferably are selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy; and R3, R5 and R7 are hydrogen.

[0077] In another preferred embodiment two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl; and preferably the other three of R3 to R7 are hydrogen; more preferably R4 and R5 are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and R3, R6 and R7 are hydrogen; more preferably R4 and R5 are connected to form a saturated 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O atoms, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and R3, R6 and R7 are hydrogen; and still more preferably R4 and R5 are connected to form a 1,4-dioxane, and R3, R6 and R7 are hydrogen.

[0078] In another embodiment, the invention relates to the compounds of formula (I) wherein R8 is selected from selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;

[0079] In another embodiment, the invention relates to the compounds of formula (I) wherein R9 is C1-4alkyl, preferably is methyl.

[0080] In another embodiment, the invention relates to the compounds of formula (I) wherein R9 is hydrogen.

[0081] In another embodiment, the invention relates to the compounds of formula (I) wherein n is 1, 2 or 3, preferably is 1 or 2, and each R10 is independently selected from halogen, C1-4alkyl and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 6-membered cycloalkyl, more preferably a 3- to 5-membered cycloalkyl, and still more preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; more preferably, each R10 is independently selected from chloro, fluoro, methyl, ethyl, and -NH2, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl.

[0082] In another embodiment, the invention relates to the compounds of formula (I) wherein n is 0.

[0083] In a preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably are independently selected from hydrogen, -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; more preferably are independently selected from hydrogen, halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; and still more preferably R3, R4, R5, R6 and R7 are independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 1, 2 or 3, preferably is 1 or 2, and each R10 is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 6-membered cycloalkyl, more preferably a 3- to 5-membered cycloalkyl, and still more preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; more preferably, each R10 is independently selected from halogen, C1-4alkyl and -NR11R12, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a a 3- to 5-membered cycloalkyl, preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; and still more preferably, each R10 is independently selected from chloro, fluoro, methyl, ethyl, and -NH2, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl;
and wherein:

preferably at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen;

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0084] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R5 is selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably is selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxyl; more preferably is selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; still more preferably is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2; and still more preferably R5 is fluoro;
  • R3 is selected from hydrogen, halogen and C1-6alkyl; more preferably R3 is selected from hydrogen, halogen and C1-4alkyl, still more preferably R3 is selected from hydrogen, fluoro, chloro, ethyl and methyl; and still more preferably R3 is hydrogen;
  • R4, R6 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 1, 2 or 3, preferably is 1 or 2, and each R10 is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 6-membered cycloalkyl, more preferably a 3- to 5-membered cycloalkyl, and still more preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; more preferably, each R10 is independently selected from halogen, C1-4alkyl and -NR11R12, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a a 3- to 5-membered cycloalkyl, preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; and still more preferably, each R10 is independently selected from chloro, fluoro, methyl, ethyl, and -NH2, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0085] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R4 and R6 are independently selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably are selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl and haloC1-4alkoxy; more preferably are selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy; and still more preferably are selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy;
  • R3, R5 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 1, 2 or 3, preferably is 1 or 2, and each R10 is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 6-membered cycloalkyl, more preferably a 3- to 5-membered cycloalkyl, and still more preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; more preferably, each R10 is independently selected from halogen, C1-4alkyl and -NR11R12, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a a 3- to 5-membered cycloalkyl, preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; and still more preferably, each R10 is independently selected from chloro, fluoro, methyl, ethyl, and -NH2, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, or preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0086] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl; and preferably the other three of R3 to R7 are hydrogen; more preferably, R4 and R5 are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and preferably R3, R6 and R7 are hydrogen; still more preferably R4 and R5 are connected to form a saturated 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O atoms, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and R3, R6 and R7 are hydrogen; and still more preferably R4 and R5 are connected to form a 1,4-dioxane, and R3, R6 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 1, 2 or 3, preferably is 1 or 2, and each R10 is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 6-membered cycloalkyl, more preferably a 3- to 5-membered cycloalkyl, and still more preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; more preferably, each R10 is independently selected from halogen, C1-4alkyl and -NR11R12, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a a 3- to 5-membered cycloalkyl, preferably a 3-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen; and still more preferably, each R10 is independently selected from chloro, fluoro, methyl, ethyl, and -NH2, or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, or preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0087] In a preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12 and haloC1-4alkoxy; preferably are independently selected from hydrogen, -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy; more preferably are independently selected from hydrogen, halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2NR11R12 and haloC1-4alkoxy; and still more preferably R3, R4, R5, R6 and R7 are independently selected from hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6CycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 0;
and wherein:

preferably at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen;

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0088] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R5 is selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2NR11R12 and haloC1-4alkoxy; preferably is selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2NR11R12 and haloC1-4alkoxyl; more preferably is selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2NR11R12 and haloC1-4alkoxy; still more preferably is selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO2-NH2; and still more preferably R5 is fluoro;
  • R3 is selected from hydrogen, halogen and C1-6alkyl; more preferably R3 is selected from hydrogen, halogen and C1-4alkyl, still more preferably R3 is selected from hydrogen, fluoro, chloro, ethyl and methyl; and still more preferably R3 is hydrogen;
  • R4, R6 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkyl0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6CycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 0;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2R11, -SO-R11 and -SO2NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl; and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0089] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • R4 and R6 are independently selected from -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2NR11R12 and haloC1-4alkoxy; preferably are selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl and haloC1-4alkoxy; preferably are selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy and haloC1-4alkoxy; more preferably are selected from fluoro, chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy;
  • R3, R5 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 0;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2R11, -SO-R11 and -SO2NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0090] In another preferred embodiment, the invention relates to the compounds of formula (I) wherein:
  • R1 and R2 are independently selected from hydrogen and C1-4alkyl; preferably from hydrogen and methyl, and more preferably R1 and R2 are hydrogen;
  • two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl; and preferably the other three of R3 to R7 are hydrogen; more preferably, R4 and R5 are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and preferably R3, R6 and R7 are hydrogen; still more preferably R4 and R5 are connected to form a saturated 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O atoms, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and R3, R6 and R7 are hydrogen; and still more preferably R4 and R5 are connected to form a 1,4-dioxane, and R3, R6 and R7 are hydrogen;
  • R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12; preferably selected from -OH, C1-6alkyl, C3-6cycloalkylC0-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, preferably selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-5acyl; more preferably R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, C2-5acyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl;
  • R9 is selected from hydrogen and C1-4alky, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and
  • n is 0;
and wherein:

each R11 and R12 are independently selected from hydrogen and C1-4alkyl, and preferably are selected from hydrogen and methyl; and

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2R11, -SO-R11 and -SO2NR11R12; preferably is selected from hydrogen, -CN and C1-4alkyl;

and more preferably R15 is selected from hydrogen and C1-4alkyl;

or a pharmaceutically acceptable salt or solvate thereof.



[0091] In another preferred embodiment, compound of formula (I) is selected from the following list of compounds:
  • N'-(4-fluorophenyl)-1,5-dimethypyrrolidine-2-carbohydrazide
  • (R)-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • (S)-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluoro-2-methylphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3,5-difluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-(trifluoromethoxy)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-(trifluoromethyl)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-chloro-2-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-sulfamoylphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • (2S,4S)-4-fluoro-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide
  • (R)-1-acetyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-hydroxypyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1,2-dimethylpyrrolidine-2-carbohydrazide
  • 2-(2-(4-fluorophenyl)hydrazinecarbonyl)-N,N-dimethylpyrrolidine-1-carboxamide
  • N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide
  • 1-(4-acetylpiperazine-1-carbonyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-methyl-5-oxopyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide
  • 4-amino-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide
  • 4-fluoro-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide
  • (S)-1-(cyclopropylmethyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2-carbohydrazide
  • N'-(4-fluorophenyl)-1,4-dimethylpyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1,3-dimethylpyrrolidine-2-carbohydrazide
  • 1-ethyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide
  • 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboximidamide
  • 2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(p-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(m-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(o-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • ethyl 4-(2-(carbamoylprolyl)hydrazinyl)benzoate
  • ethyl 3-(2-(carbamoylprolyl)hydrazinyl)benzoate
  • ethyl 2-(2-(carbamoylprolyl)hydrazinyl)benzoate
  • 2-(2-(4-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(3-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(2-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 4-(2-(carbamoylprolyl)hydrazinyl)benzoic acid
  • 3-(2-(carbamoylprolyl)hydrazinyl)benzoic acid
  • 2-(2-(carbamoylprolyl)hydrazinyl)benzoic acid
  • N-methyl-2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(3-fluorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(2-fluorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(4-chlorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(3-chlorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(2-chlorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(3-methoxyphenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(2-methoxyphenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • N-methyl-2-(2-(p-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-(m-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-(o-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-methyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • ethyl 4-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 3-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 2-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoate
  • 2-(2-(4-cyanophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(3-cyanophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 2-(2-(2-cyanophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • 4-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • 3-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • 2-(2-((methylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • N-cyclopropyl-2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(3-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(2-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-chlorophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • 2-(2-(3-chlorophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • 2-(2-(2-chlorophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(3-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(2-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(p-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(m-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(o-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • ethyl 4-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 3-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 2-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoate
  • 2-(2-(4-cyanophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • 2-(2-(3-cyanophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • 2-(2-(2-cyanophenyl)hydrazine-1-carbonyl)-N-cyclopropylpyrrolidine-1-carboxamide
  • 4-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • 3-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • 2-(2-((cyclopropylcarbamoyl)prolyl)hydrazinyl)benzoic acid
  • ethyl (2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(3-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(2-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(4-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(3-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(2-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(3-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(2-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(p-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(m-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(o-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl 4-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 3-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl 2-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoate
  • ethyl (2-(2-(4-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(3-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • ethyl (2-(2-(2-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carbonyl)alaninate
  • 4-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoic acid
  • 3-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoic acid
  • 2-(2-(((1-ethoxy-1-oxopropan-2-yl)carbamoyl)prolyl)hydrazinyl)benzoic acid
  • methyl 2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-chlorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(p-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(m-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(o-tolyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-(ethoxycarbonyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-(ethoxycarbonyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-(ethoxycarbonyl)phenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(4-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(3-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • methyl 2-(2-(2-cyanophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • 4-(2-((methoxycarbonyl)prolyl)hydrazinyl)benzoic acid
  • 3-(2-((methoxycarbonyl)prolyl)hydrazinyl)benzoic acid
  • 2-(2-((methoxycarbonyl)prolyl)hydrazinyl)benzoic acid
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • N-ethyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-isopropylpyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(2-hydroxyethyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(2-methoxyethyl)pyrrolidine-1-carboxamide
  • N-(2-aminoethyl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(2-(dimethylamino)ethyl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(2-(piperazin-1-yl)ethyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(2-morpholinoethyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclobutyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopentyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-N,N-dimethylpyrrolidine-1-carboxamide
  • N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-(4-methylpiperazine-1-carbonyl)pyrrolidine-2-carbohydrazide
  • N'-(4-fluorophenyl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide
  • N-(2-amino-2-oxoethyl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-1-oxopropan-2-yl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-3-hydroxy-1-oxobutan-2-yl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-3-methoxy-1-oxobutan-2-yl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 4-amino-3-(2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamido)-4-oxobutan-2-yl acetate
  • N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(2-(4-fluorophenyl)hydrazine-1 - carbonyl)pyrrolidine-1-carboxamide
  • methyl 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • ethyl 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • isopropyl 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • cyclopentyl 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-methylpyrrolidine-1-carboxamide
  • N-ethyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-isopropyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(2-hydroxyethyl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(2-methoxyethyl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(2-aminoethyl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(2-(dimethylamino)ethyl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-(2-(piperazin-1-yl)ethyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-(2-(4-methylpiperazin-1-yl)ethyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-(2-morpholinoethyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclobutyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopentyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-N,N-dimethylpyrrolidine-1-carboxamide
  • N'-(4-methoxyphenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide
  • N'-(4-methoxyphenyl)-1-(4-methylpiperazine-1-carbonyl)pyrrolidine-2-carbohydrazide
  • N'-(4-methoxyphenyl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide
  • N-(2-amino-2-oxoethyl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-1-oxopropan-2-yl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-3-hydroxy-1-oxobutan-2-yl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-(1-amino-3-methoxy-1-oxobutan-2-yl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 4-amino-3-(2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamido)-4-oxobutan-2-yl acetate
  • N-(1-amino-3-hydroxy-1-oxopropan-2-yl)-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • methyl 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • ethyl 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • isopropyl 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • cyclopentyl 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 5-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-2,2-dimethylpyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-methylpyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-isopropylpyrrolidine-1-carboxamide
  • 6-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-5-azaspiro[2.4]heptane-5-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-methoxypyrrolidine-1-carboxamide
  • 1-carbamoyl-5-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-fluoropyrrolidine-1-carboxamide
  • 4,4-difluoro-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide
  • 4-cyano-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-phenylpyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxamide
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-methoxypyrrolidine-1-carboxamide
  • 1-carbamoyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • 2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 5-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-2,2-dimethylpyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-4-methylpyrrolidine-1-carboxamide
  • 4-isopropyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 6-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-5-azaspiro[2.4]heptane-5-carboxamide
  • 4-hydroxy-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 4-methoxy-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 1-carbamoyl-5-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • 4-fluoro-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 4,4-difluoro-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide
  • 4-cyano-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-3-phenylpyrrolidine-1-carboxamide
  • 3-hydroxy-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 3-methoxy-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • 1-carbamoyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • 2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-5-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-2,2-dimethylpyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-methylpyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-isopropylpyrrolidine-1-carboxamide
  • N-cyclopropyl-6-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-5-azaspiro[2.4]heptane-5-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-hydroxypyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-methoxypyrrolidine-1-carboxamide
  • 1-(cyclopropylcarbamoyl)-5-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • N-cyclopropyl-4-fluoro-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-4,4-difluoro-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-4-(trifluoromethyl)pyrrolidine-1-carboxamide
  • 4-cyano-N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-phenylpyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-hydroxypyrrolidine-1-carboxamide
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-methoxypyrrolidine-1-carboxamide
  • 1-(cyclopropylcarbamoyl)-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)pyrrolidin-3-yl acetate
  • N-cyclopropyl-2-(2-(4-fluorophenyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexane-3-carboxamide
  • N-cyclopropyl-2-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide
and the pharmaceutically acceptable salts or solvates thereof.

[0092] In another embodiment, the invention relates to compounds of formula (I) having a minimal inhibitory concentration (MIC) against Acinetobacter baumannii of less than about 50 µg/mL, preferably of less than about 25 µg/mL, and more preferably of less than about 10 µg/mL, in an assay as the one described in Example 31.

[0093] In another embodiment, the invention relates to compounds of formula (I) having (a) a MIC against Acinetobacter baumannii of less than about 50 µg/mL, preferably of less than about 25 µg/mL, and more preferably of less than about 10 µg/mL; and (b) a MIC greater than about 100 µg/mL against at least one of the following bacteria: Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli, preferably against at least two of these bacteria, and still more preferably against at least three of these bacteria; in an assay as the one described in Example 31.

Use of the compounds



[0094] As shown in Example 31, surprisingly, the compounds of the present invention showed high antimicrobial activity against the bacteria A. baumannii, with minimal inhibitory concentration (MIC) values equal to or less than 25 µg/mL , or even lower, for all the assayed compounds, while they were inactive against the other bacteria tested, i.e. Staphylococcus aureus (S. aureus), Streptococcus pneumoniae (S. pneumoniae), Enterococcus faecium (E. faecium), Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli), with MIC values greater than 128 for almost all the compounds.

[0095] Therefore, a second aspect of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

[0096] A third aspect of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as antibacterial agent, preferably for treating or preventing A. baumannii infections.

[0097] A preferred embodiment relates to any of the particular and preferred embodiments of compounds formula (I) above disclosed in relation with the first aspect of the present invention for use as antibacterial agents, preferably for treating or preventing A. baumannii infections.

[0098] This aspect of the present invention can be similarly reformulated as a compound of formula (I) for use in a method for treating bacterial infections in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, to the subject.

[0099] Another aspect of the present invention relates to the compound of formula (I) for use as defined above, or a pharmaceutically acceptable salt or solvate thereof, as antibacterial agent.

[0100] This aspect of the invention can particularly be reformulated as a compound of formula (I) for use in a method for treating a A. baumannii infection in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, to the subject.

[0101] Still another aspect of the present invention relates to the compound of formula (I) for use as defined above, or a pharmaceutically acceptable salt or solvate thereof, for treating A. baumannii infections.

[0102] The compounds of the present invention may be used without limitation for the treatment of all infections caused by A. baumannii. For example, they can be used for treating pneumonia, particularly ventilator-associated pneumonia; surgical site infections; wound infections; skin and soft tissue infections; urinary tract infections; post-operative meningitis; any kind of catheter-related infection, for example catheterassociated urinary tract infection; or bloodstream infection.

[0103] As used herein the terms "treatment" or "treating" refer to both prophylactic treatment and therapeutic treatment of A. baumannii infections i.e. to preventing or inhibiting the infection from occurring in a subject that may be predisposed to be infected but has not yet been diagnosed as having the infection, and to reducing or eliminating the infection after its onset in a subject, as well as to relieving and alleviating its associated symptoms.

[0104] Particularly, the terms "prevention" or "preventing" refer more specifically to prophylactic treatment of A. baumannii infections i.e. to preventing or inhibiting the infection from occurring in a subject that may be predisposed to be infected but has not yet been diagnosed as having the infection.

[0105] As used herein the term "subject" is referred to human beings.

[0106] As used herein the term "in a subject in need thereof" relates to both a subject who has not been infected but that may be predisposed to acquire the infection as well as to a subject who has been infected with A. baumannii.

[0107] The compounds of the present invention are administered in a dose which is therapeutically active for treating the infections, and the skilled in the art will have no difficulty for adjusting the exact dose to be administered based on the kind of patient, the specific infection to be treated and its severity.

[0108] Typically, the compounds of the invention are administered in an amount ranging from 1 to 20 mg/kg of body weight.

[0109] In another embodiment, due to the high activity of the compounds of formula (I) against A. Baumannii, these compounds can be used in therapy in combination with other antibacterials, typically with broad-spectrum antibacterials, which may have less activity or be not active specifically against A. Baumannii, to thus reinforce the antibacterial effectiveness of the therapy. The compounds of formula (I) may be combined with any kind of antibacterial agent used in therapy, for example, with β-lactam antibiotics, such as penicillins, cephalosporins, monobactams or carbapenems, among others.

[0110] The combination of the compound of formula (I) with an additional antibacterial agent may be performed by administering both substances as a fixeddose combination in the form of a single pharmaceutical dosage form or, alternatively, both drugs can be administered independently, according to a therapeutic combination schedule.

[0111] Also disclosed, but not forming part of the invention, is the fact that the compound of formula (I) may be combined with another antibacterial agent by chemically bonding both compounds to form a single molecule. For example a compound of formula (I) may be attached to a carbapenem-type antibacterial compound, to form a dual compound, having, for example, the following formula:


Pharmaceutical compositions



[0112] A fourth aspect of the invention relates to a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutical acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient and/or carrier.

[0113] The pharmaceutical composition that is an aspect of the present invention can be adapted to any form of administration, for example for oral, parenteral, by inhalation, rectal, transdermal or topical administration. Likewise, depending on the intended route, the composition may be in solid, liquid, or semi-solid form, and all of them are encompassed within the scope of the present invention.

[0114] The excipients suitable to be used in the pharmaceutical composition as well as their preparation methods will vary depending on the form and intended route of administration.

[0115] Solid compositions for oral use include, for example, tablets, capsules, and granulates. They may contain excipients such, for example, anticaking agents, binders, diluents, disintegrating agents, glidants, lubricants, flavoring agents and sweetening agents. Tablets can be coated with diverse coating agents. Capsules can be either hard capsules or soft capsules as are well known in the art.

[0116] Liquid forms for oral administration include emulsions, solutions, suspensions and syrups and can incorporate diverse pharmaceutically acceptable carriers or excipients, such as a liquid vehicle, emulsifying agents, suspending agents, flavoring agents, coloring agents, buffering agents, preservative agents, and diluents.

[0117] Injectable preparations comprise sterile solutions, suspensions or emulsions in aqueous or non-aqueous solvents such as propylene glycol, polyethylene glycol or vegetable oils, and can be administered intravenously, subcutaneously or intramuscularly.

[0118] Compositions for rectal administration can be in the form of suppositories, for example on an oily base. They may contain other excipients such adsorbents, surface-active agents, antioxidants, preservatives and colorants.

[0119] Compositions for topical administration can be in form of creams, gels, ointments or pastes, for example. They may contain excipients such emulsifiers, viscosity-increasing agents, preservatives, antioxidants, and stabilizing agents.

[0120] In each case, the pharmaceutical compositions can be prepared using standard methods that are well known to the skilled in the art such as those described in handbooks of pharmaceutical technology, for example the book Remington The Science and Practice of Pharmacy, 20th edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472].

[0121] Also the excipients and/or carriers to be used in such compositions are well known, as disclosed for example, in the book R.C.Rowe, P.J.Sheskey and M.E.Quinn, Handbook of Pharmaceutical Excipients, 6th edition, Pharmaceutical Press, London, 2009 [ISBN: 978 0 85369 792 3].

[0122] Such compositions typically contain from 1 to 40% by weight of compound of formula (I) as active ingredient, the remainder of the composition being pharmaceutical carriers and/or excipients.

[0123] Optionally, the pharmaceutical composition can contain an additional active ingredient, in combination with the compound of formula (I), preferably the pharmaceutical composition can contain another antibacterial agent.

Process for preparing the compounds of the invention



[0124] A fifth aspect of the present invention relates to a process for the preparation of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, which comprises reacting a compound of formula (II)

with a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof:

wherein R16 is hydrogen or a C1-4alkyl, R17 is hydrogen or R8, and wherein n and R1 to R15, have the same meaning as defined above in relation to compounds of formula (I).

[0125] The process can be represented according to the Scheme I:



[0126] As it is well known to the skilled in the art, the use of conventional protecting groups may be necessary to prevent undesired reactions of some reactive or labile groups. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protecting and deprotecting various functional groups are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, "Protecting Groups in Organic Synthesis", Third Edition, Wiley, New York, 1999, and the references cited therein.

[0127] For example, the process may involve the reaction of an amino-protected form of the compound of formula (II), or/and an amino-protected form of the compound of formula (III), and the process may be followed, if necessary, by the removal of any protective groups that may be present.

[0128] In one embodiment R17 is R8 and the compound of formula II is a compound of formula (IIa). According to this embodiment, the compound of formula (I) can be directly obtained after the coupling reaction between the compound of formula (IIa) and the compound of formula (III), followed, if necessary, by the removal of any protective groups that may be present (Method-A).

[0129] In another embodiment R17 is hydrogen and the compound of formula (II) is a compound of formula (IIb). According to this embodiment, the compound of formula (IIb), optionally in protected form, is first coupled with the compound of formula (III), to form a compound of formula (IV), and the group R8 can be introduced after the coupling reaction (Method-B), as represented below in Scheme II.



[0130] To protect the amine group of the pyrrolidine ring, as well as any other amine group which may need to be protected, any suitable protecting group may be used, for example, the tert-butoxycarbonyl protecting group (Boc) or the carboxybenzyl protecting group (Cbz, or Z) may be used.

[0131] In another embodiment, the compound of formula (I) obtained according to the process of Scheme I can be converted into another compound of formula (I) by converting one or more of the radicals R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 (if present) into other radicals R1, R2, R3, R4, R5, R6, R7, R9, and R10 respectively, or adding a further R10 radical, or removing an R10 radical, using known procedures.

[0132] The coupling reaction between the compound of formula (II), either (IIa) or (IIb), and the compound of formula (III), to form an amide bond, is preferably performed in the presence of a coupling agent, as are well known to the skilled in medicinal chemistry. Among others, the following coupling agents may be used: ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride (also known as EDC.HCl), or (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate) (also known as HATU). Also, the coupling reaction can be performed using trimethylaluminium (AlMe3) as coupling aid.

[0133] Compounds (II) and (III) are suitably reacted in the presence of a coupling agent and in the presence of a base. Suitable bases include, but are not limited to, N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), 4-dimethylaminopyridine (DMAP), or mixtures thereof.

[0134] The coupling reaction can take place in an inert organic solvent. Suitable organic solvents are, for example, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane; ethers, such as tetrahydrofuran (THF), dioxane, diethylether or diisopropyl ether; nitriles such as acetonitrile or propionitrile; ketones such as acetone, methyl ethyl ketone or diethyl ketone; alcohols, such as methanol, ethanol, n-propanol, isopropanol or n-butanol; and also dimethylformamide (DMF) or dimethylsulfoxide (DMSO), or mixtures thereof. Preferred solvents are dichloromethane, toluene, tetrahydrofuran and dimethylformamide.

[0135] A preferred method for carrying out the coupling reaction of compound (II) with compound (III), as defined above, involves using the coupling agent HATU, more preferably in the presence of the base DIPEA. Preferably, the reaction is carried out using dimethylformamide as solvent, and at about room temperature.

[0136] Another preferred method for carrying out the coupling reaction of compound (II) with compound (III), as defined above, involves using the coupling agent EDC.HCl, more preferably in the presence of the base DMAP, and optionally in the presence of hydroxybenzotriazole (HOBt). Preferably, the reaction is carried out using dichloromethane as solvent, and at about room temperature.

[0137] Another preferred method for carrying out the coupling reaction of compound (IIb) with compound (III), for example when R16 is methyl or ethyl, involves using trimethylaluminium as a coupling aid. Preferably, this reaction can be carried out in presence of triethylamine. The solvent is preferably selected from toluene, tetrahydrofuran or mixtures thereof. Preferably the solvent is toluene. The reaction is preferably carried out at a temperature in the range 50-130 °C. For example, the reaction can be carried out in a microwave reactor.

[0138] It will be appreciated that while some preferred conditions are herewith disclosed for carrying out the processes, such as temperature, reagents, or solvents, for example, it will be matter of routine for the skilled in the art to adjust such conditions to each particular case to achieve optimized results.

[0139] Compounds of formula (II) and formula (III) are either commercially available or can be prepared using methods known to the skilled in the art.

[0140] For example, a compound of formula (IIa) can be obtained from a compound of formula (IIb) by attaching a group R8 to the N atom of the pyrrolidine ring using known methods.

[0141] For example, when R8 is a C1-6alkyl the compound of formula (IIa) can be obtained by N-alkylation of pyrrolidine according to methods well known in the art, for example, using alkyl halides or alcohols as alkylating agents, or by reductive alkylation by means of an aldehyde or ketone in the presence of a reducing agent.

[0142] When R8 is a -CONH2 group, the compound of formula (IIa) can be obtained, for example, by reacting the corresponding compound of formula (IIb) with potassium cyanate (KOCN).

[0143] When R8 is a -CONR13R14 group, the compound of formula (IIa) can be obtained, for example, by reacting the corresponding compound of formula (IIb) with ClCONR13R14.

[0144] Alternatively, when R8 is a -CONR13R14 group, the compound of formula (IIa) can be obtained, for example, by a transacylation reaction promoted by carbonyldiimidazole, as represented in Scheme III:





[0145] The compounds of the invention, as well as the intermediate products, can be prepared by the methods described herein, or small variations thereof, as well as using alternative methods, as will be matter of routine to the skilled in the art.

[0146] The following examples are provided by way of illustration and should not be construed as limiting the present invention.

Examples


Abbreviations:



[0147] 
  • Boc: tert-butoxycarbonyl
  • (Boc)2O or Boc anhydride: di-tert-butyl dicarbonate
  • Cbz: carboxybenzyl
  • DCM: dichloromethane
  • DIPEA: N,N-diisopropylethylamine
  • DMF: dimethylformamide
  • EDC.HCl: ethyl-(N',N'-dimethylamino)propylcarbodiimide hydrochloride
  • EtOAc: ethyl acetate
  • HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid hexafluorophosphate)
  • LiHMDS: lithium bis(trimethylsilyl)amide
  • mCPBA: meta-chloroperoxybenzoic acid
  • MeOH: methanol
  • Pd/C: palladium on activated charcoal
  • TEA: triethylamine
  • THF: tetrahydrofuran

General methods:



[0148] Moisture and oxygen sensitive reactions were conducted in dry glassware (Schlenk flasks sealed with rubber septa) under nitrogen.

Solvents



[0149] All solvents used were of analytical-grade quality and if not otherwise mentioned demineralised water was used.

[0150] Water-free solvents were freshly distilled under N2 atmosphere prior to use.
  • Tetrahydrofuran (THF) from sodium-benzophenone ketyl,
  • Methanol form magnesium methanolate,
  • Dichloromethane (CH2Cl2) from calcium hydride.


[0151] HPLC solvents were of gradient-grade quality and double distilled water was used. All eluents were degassed by sonication prior to use.

Thin layer chromatography (TLC)



[0152] Thin layer chromatography was conducted with TLC silica gel 60 F254 on aluminium sheets (Merck) in a saturated chamber at room temperature.

[0153] The spots were visualized under UV light (254 nm) and with reagents such as iodine vapour with additional heating.

[0154] As the Rf-value strongly depends on the exact ratio of the components of the eluent and some of these components are highly volatile, the given Rf-values represent just approximate values.

Flash column chromatography (fc)



[0155] Flash column chromatography (fc) was conducted with silica gel (100 - 200 µm) (Spectrochem) as stationary phase. Compressed air was used to push the solvent through the column.

HPLC method



[0156] 
Model: Waters 2695 Separation Module
Column: Waters XTerra® MS C18 (5 µm)
  2.1 x 250 mm Column
Solvent: A: acetonitrile with 0.05% (v/v) formic acid.
  B: water with 0.05% (v/v) formic acid
Gradient:
 time [min]solvent A [%]solvent B [min]
  0.0 5.0 95.0
  3.0 5.0 95.0
  10.0 100.0 0.0
  15.0 100.0 0.0
  17.0 5.0 95.0
  18.0 5.0 95.0
Flow rate: 0.30 mL/min
Injection: volume: 2.0 µL
Wavelength: 210 - 240 nm
Baseline auto zero: 0.0 min
Calculation: use blank subtraction from same series
Integration: manual
Calculation method: area %


[0157] All HPLC methods were performed at room temperature.

Mass spectrometry



[0158] The mass spectra were recorded with a Micromass Quatro micro™ API mass spectrometer. As all samples were measured in the positive and negative ion mode, all specified fragments display positively charged ions or radicals. The mass-to-charge ratios m/z and the relative signal intensities [%] of the ions are given.

NMR spectroscopy



[0159] 1H NMR (500 MHz) spectra were recorded on a Brucker UltraShield (500 MHz), operating at 23 °C. Chemical shifts δ are reported in parts per million (ppm) against the reference compound tetramethylsilane and calculated using the chemical shift of the signal of the undeuterated solvent.

[0160] Abbreviations for the multiplicities of the signals:
s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, m=multiplet, dd=doublet of doublets etc.

Intermediate-1: Methyl 5-oxopyrrolidine-2-carboxylate



[0161] To a stirred solution of 5-oxopyrrolidine-2-carboxylic acid (10 g, 77.4 mmol) in MeOH (100 mL) thionyl chloride (6.7 mL, 92.9 mmol) was added at 0 °C and the reaction mixture was stirred at 70 °C for 16 h. The progress of the reaction was monitored by TLC. The excess of MeOH was evaporated, the residue was diluted with EtOAc (2x25 mL), the combined organic layer was stirred over K2CO3 (3 g), washed with water (20 mL) and brine (20 mL) and separated the organic layer, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (4.3 g, 39% yield) as brown liquid.
1H NMR (500 MHz, CDCl3) δ: 6.12 (s, 1H), 4.27 (q, J=5.44 Hz, 1H), 3.79 (s, 3H), 2.51-2.41 (m, 1H), 2.43-2.37 (m, 2H), 2.34-2.24 (m, 1H).

Intermediate-2: 1-tert-butyl-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate



[0162] To a stirred solution of methyl 5-oxopyrrolidine-2-carboxylate (Intermediate-1) (4.3 g, 30.06 mmol) in DCM (43 mL), DMAP (3.6 g 29.50 mmol) was added, followed by TEA (8.39 mL, 64.79 mmol) and Boc-anhydride (20.7 mL, 90.10 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with DCM (50 mL), washed with aqueous 1N HCI solution (20 mL) followed by brine (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (6.8 g, 93% yield) as brown liquid.
1H NMR (400 MHz, CDCl3) δ 4.62 (dd, J=9.32, 2.68 Hz, 1H), 3.77 (s, 3H), 2.70-2.60 (m, 1H), 2.58-2.44 (m, 1H), 2.35-2.28 (m, 1H), 2.06-1.99 (m, 1H), 1.5 (s, 9H).

Intermediate-3: Methyl 1,5-dimethylpyrrolidine-2-carboxylate



[0163] The title intermediate was prepared from Intermediate-2 (1-tert-butyl-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate) according to the procedure depicted in Scheme IV.




Step 1: Preparation of methyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate



[0164] To a stirred solution of 1-tert-butyl-2-methyl-5-oxopyrrolidine-1,2-dicarboxylate (6.8 g, 27.89 mmol) in THF (68 mL), CH3MgBr (3M in ether, 12.12 mL, 36.36 mmol) was added at 0 °C under inert atmosphere and the reaction mixture was stirred for 2 h at the same temperature. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NH4Cl solution and the aqueous layer was extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (3.6 g, 49% yield) as yellow liquid.
1H NMR (400 MHz, CDCl3) δ 5.10 (bs, 1H), 4.25 (s, 1H), 4.12 (d, J=7.04 Hz, 1H), 3.73 (s, 3H), 2.59-2.47 (m, 2H), 2.1 (s, 2H), 2.03 (s, 1H), 1.89-1.84 (m, 1H), 1.4 (s, 9H)

Step 2: Preparation of methyl 5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate



[0165] To a stirred solution of methyl 2-(tert-butoxycarbonylamino)-5-oxohexanoate (6.8 g, 27.89 mmol) in DCM (36 mL), trifluoroacetic acid (5.3 mL, 40.9 mmol) at 0 °C was added and the reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to afford the title compound (3.6 g, 28% yield) as yellow liquid. The crude compound was used in the next step without purification.

Step 3: Preparation of methyl 5-methylpyrrolidine-2-carboxylate



[0166] To a stirred solution of methyl 5-methyl-3,4-dihydro-2H-pyrrole-2-carboxylate (3.6 g, 25.53 mmol) in ethanol (36 mL), Pd/C (10% wet, 1 g) was added under nitrogen atmosphere and the reaction mixture was stirred under hydrogen atmosphere for 16 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to afford the title compound (3.5 g, 95% yield) as brown liquid. The crude compound was used in the next step without purification.

Step 4: Preparation of methyl 1,5-dimethylpyrrolidine-2-carboxylate



[0167] To a stirred solution of methyl 5-methylpyrrolidine-2-carboxylate (2.2 g, 13.99 mmol) in MeOH (15.4 mL) NaHCO3 (1.29 g, 15.38 mmol) was added at 0 °C. After stirring the reaction mixture for 5 min, aqueous formaldehyde (37%wt, 1.14 mL, 30.76 mmol) was added and stirring was continued for 2 h followed by the addition of NaBH4 (0.876 g, 23 mmol) at same temperature. The reaction mixture was stirred for another 1 h at room temperature. The progress of the reaction was monitored by TLC. Excess of MeOH was evaporated, the residue was diluted with water (20 mL), and extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound as pale brown liquid.
1H NMR (400 MHz, CDCl3) δ 3.75 (t, J=9.08 Hz, 3H), 2.92 (t, J=8.32 Hz, 1H), 2.32 (s, 3H), 2.04-1.92 (m, 1H), 1.87-1.85 (m, 3H), 1.28-1.25 (m, 1H), 1.15 (d, J=5.96 Hz, 3H)

Intermediate-4: (R)-1-carbamoylpyrrolidine-2-carboxylic acid



[0168] To a stirred solution of D-Proline (1 g, 8.69 mmol) in water (50 mL) concentrated HCI (pH∼5) was added, followed by KOCN (2.11 g, 26.01 mmol) and the reaction mixture was stirred at 60 °C for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, acidified with concentrated HCI (pH∼4), the solid formed was filtered, washed with ice-cold water (2x100 mL) and dried under vacuum to afford the title compound (460 mg, 33% yield) as white solid.

Intermediate-5: (S)-1-carbamoylpyrrolidine-2-carboxylic acid



[0169] The title compound (500 mg, 36% yield) was prepared following an analogous procedure as for Intermediate-4, but using L-Proline (1 g, 8.69 mmol), as starting material.

Intermediate-6: 1-carbamoylpyrrolidine-2-carboxylic acid



[0170] The title compound (500 mg, 14% yield) was prepared from DL-proline (2.5 g, 21.7 mmol), following an analogous procedure as for Intermediate-4.
1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 5.85 (s, 2H), 4.15 (d, J=8.44Hz, 1H), 3.25 (m, 1H), 2.05 (m, 1H), 1.8 (d, J=5.2 Hz, 3H).

Intermediate-7: (2S,4S)-1-carbamoyl-4-fluoropyrrolidine-2-carboxylic acid



[0171] The title compound (260 mg, 79% yield) was prepared from (2S,4S)-4-fluoropyrrolidine-2-carboxylic acid (260 mg, 1.87 mmol), following an analogous procedure as for Intermediate-4.

Intermediate-8: Methyl pyrrolidine-2-carboxylate



[0172] To a stirred solution of pyrrolidine-2-carboxylic acid (1 g, 8.69 mmol) in MeOH (10 mL) thionyl chloride (0.75 mL, 10.43 mmol) was added and the reaction mixture was stirred at reflux temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated, the residue was diluted with DCM (15 mL), the excess of thionyl chloride was quenched with solid NaHCO3, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound (1.1 g, 98% yield) as pale yellow solid.

Intermediate-9: 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate



[0173] To a stirred solution of methyl pyrrolidine-2-carboxylate (Intermediate-8) (1 g, 7.74 mmol) in DCM (10 mL) TEA (2.7 mL) was added, followed by di-tert-butyl dicarbonate (Boc anhydride, (Boc)2O) (1.86 g, 8.51 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with chloroform (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (1.3 g, 73% yield) as pale yellow liquid.

Intermediate-10: 1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate



[0174] To a stirred solution of 1-tert-butyl 2-methyl pyrrolidine-1,2-dicarboxylate (Intermediate-9) (2.75 g, 12.00 mmol) in THF (5.5 mL), LiHMDS (Lithium bis(trimethylsilyl)amide) (1 M in n-hexane, 19.21 mL, 19.23 mmol) was added at -20 °C. After stirring the reaction mixture for 1.5 h at same temperature, iodomethane (Mel) (2.72 g, 19.16 mmol) was added and stirring was continued at room temperature for 18 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (2x30 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (1.5 g, 51% yield) as pale yellow liquid.
GCMS m/z: 243

Intermediate-11: Methyl 1-hydroxypyrrolidine-2-carboxylate



[0175] The title compound was prepared from methyl pyrrolidine-2-carboxylate (Intermediate-8) according to the procedure depicted in Scheme V:


Step 1: Preparation methyl 1-(2-cyanoethyl)pyrrolidine-2-carboxylate



[0176] To a stirred solution of methyl pyrrolidine-2-carboxylate (Intermediate-8) (250 mg, 1.937 mmol) in MeOH (2 mL), acrylonitrile (0.15 mL, 2.264 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to afford the title compound (200 mg, 56% yield) as colourless liquid. The crude compound was used in the next step without purification.
1H NMR (400 MHz, CDCl3) δ 3.75 (s, 3H), 3.35 (bs, 1H), 3.22-3.20 (m, 1H), 3.19-3.10 (m, 1H), 2.86-2.81 (m, 1H), 2.58-2.55 (m, 3H), 2.15-2.13 (m, 1H), 2.00-1.85 (m, 3H).

Step 2: Preparation of methyl 1-hydroxypyrrolidine-2-carboxylate



[0177] To a stirred solution of methyl 1-(2-cyanoethyl)pyrrolidine-2-carboxylate (1 g, 5.49 mmol) in DCM (15 mL), mCPBA (1.9 g 8.715 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (150 mg, 18% yield) as colourless liquid.
1H NMR (400 MHz, DMSO-d6) δ 8.1 (s, 1H), 3.6 (s, 3H), 3.4 (t, J=7.8 Hz, 1H), 3.03-3.08 (m, 1H), 2.7 (q, J=8.24 Hz, 1H), 2.05-1.98 (m, 1H), 1.77-1.71 (m, 3H).

Intermediate-12: Methyl 1-(dimethylcarbamoyl)pyrrolidine-2-carboxylate



[0178] To a stirred solution of methyl pyrrolidine-2-carboxylate (200 mg, 1.74 mmol) in DCM (10 mL) TEA (0.72 mL, 5.27 mmol) was added, followed by dimethylcarbamic chloride (0.19 mL, 2.08 mmol) and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2x15 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (180 mg, 51% yield) as off-white solid.

Intermediate-13: tert-butyl 4-(2-(methoxycarbonyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate



[0179] The title compound was prepared according to the procedure depicted in Scheme VI:


Step 1: Preparation tert-butyl 4-(1H-imidazole-1-carbonyl)piperazine-1-carboxylate



[0180] To a stirred solution of carbonyldiimidazole (5 g, 30.84 mmol) in DCM (50 mL) TEA (4.33 mL, 30.83 mmol) and Boc-piperazine (5.74 g, 30.83 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2x50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (3 g, crude) as off-white solid. The crude compound was used in the next step without purification.

Step 2: Preparation of 1-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide



[0181] To a stirred solution of tert-butyl 4-(1H-imidazole-1-carbonyl)piperazine-1-carboxylate (3 g, 10.67 mmol) in acetonitrile (15 mL), iodomethane (2.64 mL, 42.70 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure to afford the title compound (3 g, crude) as off-white solid. The crude compound was used in the next step without purification.

Step 3: Preparation tert-butyl 4-(2-(methoxycarbonyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate



[0182] To a stirred solution of 1-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)-3-methyl-1H-imidazol-3-ium iodide (3 g, 10.16 mmol) in DCM (30 mL), TEA (1.42 mL, 50.84 mmol) and pyrrolidine-2-carboxylic acid methyl ester (2.62 g, 20.35 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (50 mL), and extracted with DCM (2x50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1 g, 29% yield) as off-white solid.

Intermediate-14: Methyl 1-(morpholine-4-carbonyl)pyrrolidine-2-carboxylate



[0183] The title compound was prepared according to the procedure depicted in Scheme VII:


Step 1: Preparation of (1H-imidazol-1-yl)(morpholino)methanone



[0184] To a stirred solution of carbonyldiimidazole (5 g, 30.83 mmol) in DCM (50 mL), TEA (4.3 mL, 30.83 mmol), and morpholine (2.5 g, 29.06 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2x50 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (3 g, crude) as off-white solid. The crude compound was used in the next step without purification.

Step 2: Preparation of (3-methyl-1-(morpholine-4-carbonyl)-1H-imidazol-3-ium iodide



[0185] To a stirred solution of (1H-imidazol-1-yl)(morpholino)methanone (3 g, 16.55 mmol) in acetonitrile (15 mL) iodomethane (4.1 mL, 66.22 mmol) was added at 0 °C and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure to afford the title compound (2 g, crude) as off-white solid. The crude compound was used in the next step without purification.

Step 3: Preparation of methyl 1-(morpholine-4-carbonyl)pyrrolidine-2-carboxylate



[0186] To a stirred solution of (3-methyl-1-(morpholine-4-carbonyl)-1H-imidazol-3-ium iodide (2 g, 10.16 mmol) in DCM (30 mL) TEA (7.1 mL, 50.84 mmol) and pyrrolidine-2-carboxylic acid methyl ester (2.62 g, 20.35 mmol) were added and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (20 mL) and extracted with DCM (2x25 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (1 g, 41% yield) as off-white solid.

Intermediate-15: Ethyl 1-methyl-5-oxopyrrolidine-2-carboxylate



[0187] To a stirring solution of sodium hydride (2 equiv) in anhydrous DMF (2 mL) at ice cooled condition under argon atmosphere, a solution of ethyl 5-oxopyrrolidine-2-carboxylate (300 mg in 3 mL DMF) was added dropwise over a time period of 10 min, and the reaction mixture was stirred for 15 min at the same temperature. Next, iodomethane was added and allowed to stirring for 3 h. To quench the reaction a saturated solution of NH4Cl (5 mL) was added and extracted with DCM (2 × 10 mL). The combined organic portion was dried over anhydrous sodium sulfate and distilled out under reduced pressure to obtain the title compound (175 mg).
LC-MS: 172.2 (M+H).

Intermediate-16: 1,2-dimethylpyrrolidine-2-carboxylic acid



[0188] The title compound was obtained by N-methylation of 2-methylpyrrolidine-2-carboxylic acid. Thus, to a stirred solution of 2-methylpyrrolidine-2-carboxylic acid (300 mg) in anhydrous MeOH (10 mL), 1 mL of formaldehyde was added dropwise at 0 °C, followed by a catalytic amount of acetic acid, and the reaction mixture was stirred for 10 min at the same temperature. Next, 50 mg of 10% Pd/C was added and the reaction mixture was stirred at room temperature in presence of hydrogen atmosphere for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of starting materials, the reaction mixture was filtered through a celite bed to remove the solid residue which was washed with MeOH for several times. The filtrate was collected and concentrated under reduced pressure to obtain the title compound (300 mg).
LC-MS: 144.18 (M+H)

Intermediate-17: 4-fluoro-1-methylpyrrolidine-2-carboxylic acid



[0189] The title compound was obtained by N-methylation of 4-fluoropyrrolidine-2-carboxylic acid, following an analogous procedure as disclosed above for the preparation of Intermediate-16. 150 mg of 4-fluoropyrrolidine-2-carboxylic acid afforded 120 mg of the title compound.
LC-MS: 148.2 (M+H).

Intermediate-18: 3-methyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid



[0190] The title compound was obtained by N-methylation of 3-azabicyclo[3.1.0]hexane-2-carboxylic acid, following an analogous procedure as disclosed above for the preparation of Intermediate-16. 300 mg of 3-azabicyclo[3.1.0]hexane-2-carboxylic acid afforded 300 mg of the title compound.
LC-MS: 144.18 (M+H).

Intermediate-19: 1,4-dimethylpyrrolidine-2-carboxylic acid



[0191] The title compound was obtained by N-methylation of 4-methylpyrrolidine-2-carboxylic acid, following an analogous procedure as disclosed above for the preparation of Intermediate-16. 250 mg of 4-methylpyrrolidine-2-carboxylic acid afforded 250 mg of the title compound.
LC-MS: 144.18 (M+H)

Intermediate-20: 1,3-dimethylpyrrolidine-2-carboxylic acid



[0192] The title compound was obtained by N-methylation of 3-methylpyrrolidine-2-carboxylic acid, following an analogous procedure as disclosed above for the preparation of Intermediate-16. 250 mg of 3-methylpyrrolidine-2-carboxylic acid afforded 250 mg of the title compound.
LC-MS: 144.18 (M+H)

Intermediate-21: 1-ethylpyrrolidine-2-carboxylic acid



[0193] The title compound was obtained by N-ethylation of pyrrolidine-2-carboxylic acid, following an analogous procedure as in the N-methylation disclosed above for the preparation of Intermediate-16, but using acetaldehyde instead of formaldehyde. 1 g of pyrrolidine-2-carboxylic acid afforded 187 mg of the title compound.
LC-MS: 144.18 (M+H)

Intermediate-22: 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid



[0194] A mixture of pyrrolidine-2-carboxylic acid (2.5 g, 21.7 mmol), NaOH (2 M solution, 10 mL) and carbobenzoxy chloride (3.7 g, 21.7 mmol) were stirred at room temperature for 6 h. The progress of the reaction was monitored by TLC. The reaction mixture was acidified with 2N HCI and extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (1.5 g, 27% yield) as colourless liquid.

Example 1: N'-(4-fluorophenyl)-1,5-dimethypyrrolidine-2-carbohydrazide



[0195] 



[0196] To a stirred solution of methyl 1,5-dimethylpyrrolidine-2-carboxylate (Intermediate-3) (0.3 g, 1.91 mmol) in toluene (6 mL) 4-fluorophenylhydrazine hydrochloride (0.31 g, 1.91 mmol), TEA (0.536 mL, 4.13 mmol) and trimethylaluminum (2M solution in toluene, 0.96 mL, 1.91 mmol) at 0 °C were added and the reaction mixture was stirred at 70 °C in microwave for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (5 mL), extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (18 mg, 3% yield) as pale brown solid.
1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.64 (s, 1H), 6.95 (t, J=8.72 Hz, 2H), 6.7 (q, 4.68 Hz, 2H), 3.4 (s, 1H), 3.1 (s, 1H), 2.3 (s, 3H), 2.05-2.00 (m, 2H), 1.68-1.65 (m, 1H),1.40-1.30 (m, 1H), 0.93 (d, J=6 Hz, 3H)
LC-MS m/z (M+H): 252.2
Purity (HPLC): 99.3%

Example 2: (R)-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0197] 



[0198] To a stirred solution of (R)-1-carbamoylpyrrolidine-2-carboxylic acid (Intermediate-4) (500 mg, 3.16 mmol) in DMF (5 mL) DIPEA (1.61 mL, 9.23 mmol), HATU (1.44 g 3.79 mmol) and 4-fluorophenylhydrazine hydrochloride (563 mg, 3.48 mmol) were added at 0 °C under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (28 mg) as off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 9.61 (d, J=2.6Hz, 1H), 7.59 (d, J=2.4Hz, 1H), 6.91 (t, J=8.8 Hz, 2H), 6.75-6.72 (m, 2H), 5.85 (s, 2H), 4.21-4.18 (m, 1H), 3.41-3.30 (m, 1H), 3.25-3.19 (m, 1 H), 2.09-1.97 (m, 1H), 1.94-1.78 (m, 3H)
LC-MS m/z (M-H): 265.1
Purity (HPLC): 99.8%

Example 3: (S)-2-(2-(4-fluorophenyl) hydrazinecarbonyl) pyrrolidine-1-carboxamide



[0199] 



[0200] The title compound was prepared following an analogous procedure as in Example 2, but using (S)-1-carbamoylpyrrolidine-2-carboxylic acid (Intermediate-5) as starting material. 500 mg of Intermediate-5 afforded 35 mg (4% yield) of the title compound as a off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.60 (s, 1H), 6.91 (t, J=8.88 Hz, 2H), 6.75-6.72 (m, 2H), 5.86 (s, 2H), 4.21-4.18 (m, 1H), 3.38-3.31 (m, 1H), 3.25-3.19 (m, 1 H), 2.06-1.91 (m, 1H), 1.89-1.79 (m, 3H)
LC-MS m/z (M-H): 265.0
Purity (HPLC): 99.6%

Examples 4-12



[0201] Examples 4-12 were prepared following analogous procedures as the one disclosed for Example 2, using 1-carbamoylpyrrolidine-2-carboxylic acid (Intermediate-6) and the suitable hydrazine as starting materials:

Example 4: 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0202] 



[0203] 1H NMR (400 MHz, DMSO-d6) δ 9.6 (s, 1H), 7.6 (s, 1H), 6.9 (t, J=8.88 Hz, 2H), 6.80-6.70 (m, 2H), 5.85 (s, 2H), 4.2 (dd, J=3.04 Hz, J=8.44 Hz, 1H), 3.4-3.3 (m, 1H), 3.3-3.2 (m, 1H), 2.1-2.0 (m, 1H), 1.90-1.70 (m, 3H)
LC-MS m/z (M-H): 265
Purity (HPLC): 99.0%
Melting point: 140-144°C

Example 5: 2-(2-(4-fluoro-2-methylphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide



[0204] 



[0205] 1H NMR (400 MHz, DMSO-d6) δ 9.63 (d, J=2.3Hz, 1H), 6.91(d, J=2.1Hz, 1H), 6.85-6.72 (m, 3H), 5.85 (s, 2H), 4.25-4.22 (m, 1H), 3.42-3.38 (m, 1H), 3.29-3.20 (m, 1H), 2.12 (s, 3H), 2.07-1.97 (m, 1H), 1.96-1.83 (m, 3H)
LC-MS m/z (M-H): 279.2
Purity (HPLC): 99.8%

Example 6: 2-(2-(3,5-difluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0206] 



[0207] 1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.22 (s, 1H), 6.40-6.33 (m, 3H), 5.90 (s, 2H), 4.19-4.16 (m, 1H), 3.41-3.36 (m, 1H), 3.24-3.20 (m, 1H), 2.09-2.02 (m, 1H), 1.95-1.80 (m, 3H)
LC-MS m/z (M-H): 283.1
Purity (HPLC): 99.6%

Example 7: 2-(2-(4-(trifluoromethoxy)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0208] 



[0209] 1H NMR (400 MHz, DMSO-d6) δ 9.67 (d, J=2.0Hz, 1H), 7.89 (d, J=1.9Hz, 1H), 7.06 (d, J=8.6Hz, 2H), 6.79 (d, J=8.9Hz, 2H), 5.86 (s, 2H), 4.22-4.19 (m, 1H), 3.41-3.36 (m, 1H), 3.29-3.20 (m, 1H), 2.08-2.01 (m, 1H), 1.92-1.78 (m, 3H)
LC-MS m/z (M-H): 331.1
Purity (HPLC): 99.3%

Example 8: 2-(2-(4-(trifluoromethyl)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0210] 



[0211] 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.29 (s, 1H), 7.38 (d, J=8.3Hz, 2H), 6.84 (d, J=8.3Hz, 2H), 5.86 (s, 2H), 4.23-4.20 (m, 1H), 3.39 (s, 1H), 3.29-3.20 (m, 1H), 2.12-2.03 (m, 1H), 1.95-1.81 (m, 3H)
LC-MS m/z (M-H): 315.2
Purity (HPLC): 99.8%

Example 9: 2-(2-(4-chloro-2-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0212] 



[0213] 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.75 (s, 1H), 7.21 (d, J=10.7Hz, 1H), 7.19-6.92 (m, 2H), 5.87 (s, 2H), 4.22-4.19 (m, 1H), 3.41-3.35 (m, 1H), 3.29-3.20 (m, 1H), 2.07-2.00 (m, 1H), 1.95-1.79 (m, 3H)
LC-MS m/z (M-H): 299.1
Purity (HPLC): 99.9%

Example 10: 2-(2-(4-methoxyphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0214] 



[0215] 1H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=2.7Hz, 1H), 7.28 (s, 1H), 6.77 (s, 4H), 5.84 (s, 2H), 4.21-4.19 (m, 1H), 3.65 (s, 3H), 3.38-3.31 (m, 1H), 3.24-3.18 (m, 1 H), 2.05-1.90 (m, 1H), 1.88-1.79 (m, 3H)
LC-MS m/z (M-H): 277.0
Purity (HPLC): 99.7%

Example 11: 2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) hydrazinecarbonyl) pyrrolidine-1-carboxamide



[0216] 



[0217] 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.21-6.95 (m, 1H), 6.58 (d, J=8.2Hz, 1H), 6.25-6.23 (m, 2H), 5.82 (s, 2H), 4.21-4.10 (m, 5H), 3.37-3.25 (m, 1H), 3.22-3.15 (m, 1H), 2.10-1.95 (m, 1H), 1.87-1.81 (m, 3H)
LC-MS m/z (M+H): 306.2
Purity (HPLC): 99.7%

Example 12: 2-(2-(4-sulfamoylphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0218] 



[0219] 1H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.29 (s, 1H), 7.51 (d, J=8.7Hz, 2H), 6.99 (s, 2H), 6.80 (d, J=8.6Hz, 2H), 5.88 (s, 2H), 4.23-4.20 (m, 1H), 3.41-3.36 (m, 1H), 3.26-3.20 (m, 1H), 2.09-2.02 (m, 1H), 1.94-1.80 (m, 3H)
LC-MS m/z (M-H): 326.1
Purity (HPLC): 98.2%

Example 13: (2S,4S)-4-fluoro-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide



[0220] 



[0221] The title compound (30 mg) was prepared following an analogous procedure as in Example 2, but using (2S,4S)-1-carbamoyl-4-fluoropyrrolidine-2-carboxylic acid (Intermediate-7) (260 mg, 1.47 mmol) as starting material.
1H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.57 (s, 1H), 6.92-6.88 (m, 2H), 6.70-6.75 (m, 2H), 5.99 (s, 2H), 5.38-5.24 (m, 1H), 4.36 (d, J=9.6Hz, 1H), 3.69-3.51 (m, 2H), 2.48-2.20 (m, 2H)
LC-MS m/z (M-H): 283.2
Purity (HPLC): 99.2%

Example 14: (R)-1-acetyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide



[0222] 



[0223] To a stirred solution of (R)-1-acetylpyrrolidine-2-carboxylic acid (50 mg, 0.31 mmol) in dry DMF (2 mL), DIPEA (82 mg, 0.63 mmol), HATU (181 mg, 0.47 mmol) and 4-fluorophenylhydrazine hydrochloride (65 mg, 0.37 mmol) were added at 0 °C and then the reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with ice-cold water (10 mL), the solid formed was filtered and dried under vacuum to afford the title compound (30 mg, 35% yield) as off-white solid.
1H NMR (400 MHz, CD3OD) δ 6.95-6.84 (m, 4H), 4.45 (dd, J=3.8Hz, J=8.6Hz, 1H), 3.70-3.60 (m, 2H), 2.2-2.16 (m, 2H), 2.10 (s, 3H), 2.07-2.00 (m, 4H)
LC-MS m/z (M-H): 266.2
Purity (HPLC): 98.8%

Example 15: N'-(4-fluorophenyl)-1-hydroxypyrrolidine-2-carbohydrazide



[0224] 



[0225] To a stirred solution of methyl 1-hydroxypyrrolidine-2-carboxylate (Intermediate-11) (250 mg, 1.373 mmol) in dry toluene (5 mL), 4-fluorophenylhydrazine hydrochloride (223 mg, 1.37 mmol), TEA (0.355 mL, 2.74 mmol) and trimethylaluminium (2 M in toluene, 0.69 mL, 1.37 mmol) were added at 0 °C and the reaction mixture was stirred at 70 °C for 1.5 h in microwave. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice-cold water (20 mL); the aqueous layer was extracted with EtOAc (2x15 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (30 mg, 7% yield) as off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 9.4 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 6.95 (t, J=8.84 Hz, 2H), 6.7 (m, 2H), 3.3 (s, 1H), 3.15 (s, 1H), 2.7 (q, J=8.76 Hz, 1H), 2.1 (q, J=9.76 Hz, 1H), 1.81-1.65 (m, 3H)
LC-MS m/z (M+H): 240.2
Purity (HPLC): 98.8%

Example 16: N'-(4-fluorophenyl)-1,2-dimethylpyrrolidine-2-carbohydrazide



[0226] 


Method A



[0227] 1,2-Dimethylpyrrolidine-2-carboxylic acid (Intermediate-16) (200 mg, 1.40 mmol) was dissolved in 7 mL of dry DCM, and subsequently TEA (3 equiv.), EDC.HCl (1.5 equiv.) and DMAP (1.5 equiv.) were added. After 10 min stirring at 0 °C, 4-fluorophenylhydrazine hydrochloride (1.5 equiv.) was added under argon atmosphere. After completion of the addition, the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved with 5% MeOH in DCM (20 mL) and washed with water (2 × 10 mL). The collected organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the title compound, which was purified by column chromatography (DCM: MeOH= 9.5:0.5) (42 mg, 12% yield).
1H NMR (500 MHz, DMSO-d6) δ 1.12 (s, 3H), 1.17-1.67 (m, 3H), 2.05 (s, 1H), 2.28 (s, 3H), 2.54-2.51 (m, 1H), 3.02 (d, J = 1.5 Hz, 1H), 6.70-6.58 (m, 2H), 6.99-6.96 (m, 2H), 7.51 (d, J = 2.9 Hz, 1H), 9.56 (d, J = 2.8 Hz, 1H) ppm
LC-MS: 252.4 (M+H)
Purity (HPLC): 96.0%

Method B



[0228] The title compound was prepared by coupling N-Boc protected methyl 2-methylpyrrolidine-2-carboxylate (Intermediate-10) with 4-fluorophenylhydrazine, followed by deprotection and methylation of the N-atom of the pyrrolidine ring, according to the process depicted in Scheme VIII:


Step 1: Preparation of tert-butyl 2-(2-(4-fluorophenyl)hydrazinecarbonyl)-2-methylpyrrolidine-1-carboxylate



[0229] To a stirred solution of 1-tert-butyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (Intermediate-10) (3 g, 12.34 mmol) in toluene (24 mL) 4-fluorophenylhydrazine hydrochloride (2.4 g, 14.81 mmol) was added, followed by TEA (3.1 g, 30.69 mmol) and trimethylaluminium (2 M in toluene, 2.65 g, 36.80 mmol) at room temperature and the reaction mixture was stirred at 60°C in microwave for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc (2x50 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (2.2 g, 53% yield) as off-white solid.
1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 6.94-6.92 (m, 2H), 6.81 (s, 2H), 6.00 (s, 1H), 3.51 (bs, 2H), 2.66 (s, 1H), 1.80 (s, 3H), 1.68 (s, 3H), 1.49 (s, 9H)
LC-MS m/z (M-H): 336.2

Step 2: Preparation of N'-(4-fluorophenyl)-2-methylpyrrolidine-2-carbohydrazide



[0230] To a stirred solution of tert-butyl 2-(2-(4-fluorophenyl)hydrazinecarbonyl)-2-methylpyrrolidine-1-carboxylate (2.2 g, 6.52 mmol) in DCM (4 mL), trifluoroacetic acid (4.4 mL) was added at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated, the residue was co-distilled with DCM (3x10 mL). The crude compound was neutralized with saturated NaHCO3 solution (3 mL) and extracted with 10% MeOH/chloroform (2x 30 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the title compound (1 g, 64% yield) as brown solid.

Step 3: Preparation of N'-(4-fluorophenyl)-1,2-dimethylpyrrolidine-2-carbohydrazide



[0231] To a stirred solution of N'-(4-fluorophenyl)-2-methylpyrrolidine-2-carbohydrazide (1 g, 4.21 mmol) in acetonitrile (50 mL), K2CO3 (1.43 g, 10.51 mmol) was added, followed by iodomethane (0.313 mL, 5.07 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2x20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel 100-200 mesh) to afford the title compound (350 mg, 33% yield) as brick red solid.
1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 6.95-6.920 (m, 2H), 6.79-6.76 (m, 2H), 5.97 (s, 1H), 3.19-3.08 (m, 1H), 2.59-2.53 (m, 1H), 2.37 (s, 3H), 2.20 (s, 1H), 1.85-1.77 (m, 3H), 1.23 (s, 3H)
LC-MS m/z (M+H): 252.2

Example 17: 2-(2-(4-fluorophenyl)hydrazinecarbonyl)-N,N-dimethylpyrrolidine-1-carboxamide



[0232] 



[0233] The title compound was prepared following an analogous procedure as in Example 15, using methyl 1-(dimethylcarbamoyl)pyrrolidine-2-carboxylate (Intermediate-12) (100 mg, 0.49 mmol) as starting material. In this case, the reaction was carried out at 90 °C for 60 min, and the reaction mixture was quenched with NH4Cl. The crude compound was purified by preparative TLC to afford the title compound (30 mg, 20% yield) as off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J=3.9 Hz, 1H), 6.97-6.90 (m, 2H), 6.88-6.75 (m, 2H), 5.97 (d, J=4.3Hz, 1H), 4.62 (t, J=7.9Hz, 1H), 3.50-3.40 (m, 2H), 2.90 (s, 6H), 2.32-2.24 (m, 1H), 2.22-2.10 (m, 1H), 2.09-1.94 (m, 1H), 1.86-1.74 (m, 1H)
LC- MS m/z (M-H): 293.2
Purity (HPLC): 98.2%

Example 18: N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide hydrochloride



[0234] 



[0235] The title compound was prepared by coupling the corresponding pyrrolidine intermediate (Intermediate-13), which carries a Boc protecting group on the piperazine ring, with 4-fluorophenylhydrazine, and subsequent deprotection, according to the process depicted in Scheme IX:


Step 1: Preparation of tert-butyl 4-(2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate



[0236] The coupling reaction was performed following an analogous procedure as disclosed in Example 2, using tert-butyl 4-(2-(methoxycarbonyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate (Intermediate-13) (1 g, 2.92 mmol) as starting material, to afford the title compound (100 mg, 8% yield) as yellow solid.

Step 2: Preparation of N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide hydrochloride



[0237] For the deprotection, a mixture of tert-butyl 4-(2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carbonyl)piperazine-1-carboxylate (100 mg, 0.22 mmol) in dioxane.HCl (1 mL) was stirred at room temperature for 5 h. The progress of the reaction was monitored by TLC. The solvent was evaporated under reduced pressure. The crude compound was washed with diethyl ether (5 mL) to afford the title compound (30 mg, 36% yield) as pale yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.91 (bs, 2H), 7.66 (s, 1H), 6.97-6.93 (m, 2H), 6.70-6.67 (m, 2H), 4.32 (t, J=8.8 Hz, 1H), 3.47-3.31 (m, 5H), 3.08-3.02 (m, 4H), 2.21 (s, 1H), 1.91 (s, 1H), 1.74-1.69 (m, 2H)
LC-MS m/z (M+H): 373.0
Purity (HPLC): 99.5%

Example 19: 1-(4-acetylpiperazine-1-carbonyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide hydrochloride



[0238] 



[0239] To a stirred solution of N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide hydrochloride (Example 18) (200 mg, 0.53 mmol) in pyridine (2 mL) acetyl chloride (42 mg, 053 mmol) was added at 0 °C dropwise and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was evaporated, the residue was quenched with ice cold-water (15 mL) and extracted with 10% MeOH/DCM (2x10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was dissolved in dioxane.HCl (10 mL) at room temperature and stirred for 10 min, the solvent was evaporated and washed with EtOAc (5 mL) to afford the title compound (50 mg, 22% yield) as white solid.
1H NMR (400 MHz, DMSO-d6) δ 9.63 (d, J=2.4Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 6.93 (t, J=8.8Hz, 2H), 6.70-6.66 (m, 2H), 4.33 (t, J=4.4Hz, 1H), 3.46-3.44 (m, 3H), 3.39-3.35 (m, 3H), 3.29-3.20 (m, 1H), 3.19-3.14 (m, 3H), 2.18 (s, 1H), 1.97 (s, 3H), 1.91 (s, 1H), 1.74-1.61 (m, 2H)
LC-MS m/z (M+H): 415.1
Purity (HPLC): 99.8%

Example 20: N'-(4-fluorophenyl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide hydrochloride



[0240] 



[0241] The title compound was prepared following an analogous procedure as in Example 15, using methyl 1-(morpholine-4-carbonyl)pyrrolidine-2-carboxylate (Intermediate-14) (1 g, 4.12 mmol) as starting material. The crude compound obtained was purified by column chromatography and the resulting compound was treated with dioxane hydrochloride for 15 min at room temperature and the solvent was evaporated to afford the title compound (30 mg) as off-white solid.
1H NMR (400 MHz, DMSO-d6) δ 9.62 (d, J=2.5Hz, 1H), 7.65 (d, J=2.5Hz, 1H), 6.96-6.92 (m, 2H), 6.70-6.67 (m, 2H), 4.32 (t, J=7.9Hz, 1H), 3.61-3.51 (m, 4H), 3.50-3.44 (m, 1H), 3.42-3.30 (m, 1H), 3.28-3.24 (m, 2H), 3.15-3.10 (m, 2H), 2.19-2.15 (m, 1H), 1.89 (s, 1H), 1.75-1.68 (m, 2H)
LC-MS m/z (M-H): 374.0
Purity (HPLC): 99.7%

Example 21: N'-(4-fluorophenyl)-1-methyl-5-oxopyrrolidine-2-carbohydrazide



[0242] 



[0243] To a solution of ethyl 1-methyl-5-oxopyrrolidine-2-carboxylate (Intermediate-15) (500 mg in 5 mL of toluene), trimethylaluminium (3 equiv.) was added at ice cold condition and stirred under argon atmosphere for 15 min. Then 4-fluorophenylhydrazine hydrochloride (1 equiv.) in 2 mL of toluene was added to the reaction mixture and refluxed at 120°C for 4h. After the completion of the reaction, the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (3 × 15 mL). The collected organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 9.7:0.3) and recrystallized with DCM and diethyl ether to obtain the title compound (25 mg, 3.15% yield).
1H NMR (500 MHz, DMSO-d6) δ 2.01 (s, 1H), 2.21 (s, 2H), 2.37 (s, 1H), 2.69 (s, 3H), 5.08 (d, J = 7.7 Hz, 1H), 5.41 (s, 2H), 7.22 (brs, 2H), 7.60 (brs, 2H) ppm
LC-MS (M+H): 252.2
Purity (HPLC): 95%

Example 22: N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide



[0244] 



[0245] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 1-methylpyrrolidine-2-carboxylic acid (400 mg) as starting product. The crude product obtained in the reaction was purified by column chromatography (DCM:MeOH= 9.5:0.5) to afford 27 mg of the title compound (3.7% yield).
1H NMR (500 MHz, DMSO-d6) δ 1.79 - 1.73 (m, 3H), 2.09 (s, 1H), 2.27-2.25 (m, 1H), 2.34 (s, 3H), 2.86-2.83 (m, 1H), 3.03 (s, 1H), 6.71 -6.67 (m, 2H), 7.00-6.96 (m, 2H), 7.62 (s, 1H), 9.61 (s, 1H) ppm
LC-MS (M+H): 238.8
Purity (HPLC): 95.0%

Example 23: 4-amino-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide



[0246] 



[0247] The title compound was obtained by coupling 4-fluorophenylhydrazine with 4-amino-1-methylpyrrolidine-2-carboxylic acid, previously protecting the amine of the latter with a Boc protecting group, and deprotecting it after the coupling reaction, as depicted in Scheme X:


Step 1: Preparation of 4-((tert-butoxycarbonyl)amino)-1-methylpyrrolidine-2-carboxylic acid



[0248] To solution of 4-amino-1-methylpyrrolidine-2-carboxylic acid (1 equiv.) in 60 mL dioxane:H2O (2:3), Na2CO3 (3 equiv.) was added and stirred for 10 min at 0 °C. Then, to this reaction mixture Boc anhydride (1.1 equiv.) was added dropwise at the same temperature and allowed for stirring at room temperature overnight. After completion of the reaction, the reaction mixture was acidified with 1 N HCl to bring the pH at 3 and it was extracted with 10% MeOH in DCM (60 mL). The organic layer was dried over anhydride Na2SO4. The organic solvent was distilled out at reduced pressure to obtain the crude title compound which was purified by column chromatography (DCM: MeOH = 9.6:0.4) to afford the purified title compound (9.8% yield).
LC-MS (M+H): 245.3

Step 2: Preparation of tert-butyl (5-(2-(4-fluorophenyl)hydrazinecarbonyl)-1-methylpyrrolidin-3-yl) carbamate



[0249] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 4-((tert-butoxycarbonyl)amino)-1-methylpyrrolidine-2-carboxylic acid (100 mg) as starting product. The crude product obtained in the reaction was purified by column chromatography (DCM:MeOH= 9.5:0.5) to afford 50 mg of the title compound (34.71% yield).
LC-MS (M+H): 353.4
Purity (HPLC): 92.14%

Step 3: Preparation of 4-amino-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide



[0250] For deprotection, 5 mL of 5 N HCL was added dropwise at 0 °C to a solution of tert-butyl (5-(2-(4-fluorophenyl)hydrazinecarbonyl)-1- methylpyrrolidin-3-yl)carbamate (1 equiv.) in 5 mL DCM, and the mixture was allowed to stirring for 4h. After complete consumption of starting material, the solvent was distilled out under reduced pressure to obtain a sticky solid which was dissolved in 10% MeOH in DCM and washed with saturated solution of NaHCO3. The organic portion was collected and dried over Na2SO4, the organic portion was distilled out under reduced pressure to obtain the title compound (25 mg, 69.4%).
1H NMR (500 MHz, DMSO-d6) δ 1.65-1.4 (m, 1H), 2.37 (s, 3H), 2.47-2.41 (m, 3H), 2.77 (d, J = 9.05 Hz, 1H), 2.82 (t, J = 6.35 Hz, 1H), 6.74 -6.71 (m, 2H), 6.99 - 6.96 (m, 2H), 7.62 (s, 1H), 9.75 (brs, 1H) ppm; The NH2 protons remain unsolved.
LC-MS (M+H): 253.4
Purity (HPLC): 95.0%

Example 24: 4-fluoro-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide



[0251] 



[0252] The title compound was prepared using an analogous procedure as disclosed for Example 21, employing 4-fluoro-1-methylpyrrolidine-2-carboxylic acid acid (Intermediate-17) as starting material. 90 mg of 4-fluoro-1-methylpyrrolidine-2-carboxylic acid afforded the title compound as crude product. The crude product was purified by column chromatography using DCM as eluent to afford 20 mg of the title compound (13% yield).
1H NMR (500 MHz, DMSO-d6) δ 2.35-2.25 (m, 1H), 2.57 (s, 3H), 2.64-2.62 (m, 1H), 3.21 (d, J = 7.5 Hz, 1H), 3.47-3.45 (m, 1H), 5.22 (m, 1H), 5.97 (d, J = 3.5 Hz, 1H), 6.82-6.80 (m, 2H), 6.95-6.91 (m, 2H), 8.94 (s, 1H) ppm
LC-MS (M+H): 256.4
Purity (HPLC): 95.0%

Example 25: (S)-1-(cyclopropylmethyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide



[0253] 



[0254] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing (R)-1-(cyclopropylmethyl)pyrrolidine-2-carboxylic acid (120 mg) as starting material. The crude product was purified by column chromatography using DCM as eluent to afford 30 mg of the title compound (12.2% yield).
1H NMR (500 MHz, DMSO-d6) δ 0.11 (s, 1H), 0.49-0.44 (m, 2H), 0.9-1.1 (m, 1H), 1.78-1.76 (m, 3H), 1.99-2.05 (m, 1H), 2.42-2.28 (m, 2H), 3.05 (s, 1H), 3.31 (s, 1H), 6.71-6.67 (m, 2H), 6.99-6.96 (m, 2H), 7.60 (s, 1H), 9.51 (s, 1H) ppm;
LC-MS (M+H): 278.2
Purity (HPLC): 96.2%

Example 26: N'-(4-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2-carbohydrazide



[0255] 



[0256] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 3-methyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (Intermediate-18) (25 mg, 0.18 mmol) as starting material, which afforded 3 mg of the final product (7% yield).
1H NMR (500 MHz, CDCl3) δ 0.52 (d, J = 5.4 Hz, 1H), 0.78 (s, 1H), 1.16 (d, J = 4.0 Hz, 1H), 1.43 (t, J = 6.5 Hz, 1H), 2.73 (s, 3H), 2.59 (d, J = 6.4 Hz, 1H), 3.23-3.16 (m, 2H), 6.01 (s, 1H), 6.83-6.80 (m, 2H), 6.95 - 6.92 (m, 2H), 8.38 (s, 1H) ppm
LC-MS (M+H): 250.2
Purity (HPLC): 98.2%

Example 27: N'-(4-fluorophenyl)-1,4-dimethylpyrrolidine-2-carbohydrazide



[0257] 



[0258] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 1,4-dimethylpyrrolidine-2-carboxylic acid (Intermediate-19) (100 mg, 0.70 mmol) as starting material, which afforded 14 mg of the final product (9% yield).
1H NMR (500 MHz, CDCl3) δ 1.13 (s, 3H), 1.63 (brs, 3H), 2.42 (s, 1H), 2.82 (s, 3H), 2.97 (s, 1H), 6.27 (s, 1H), 6.83-6.80 (m, 2H), 6.93 - 6.89 (m, 2H) ppm, one NH-proton remained unsolved
LC-MS (M+H): 252.4
Purity (HPLC): 95.1%

Example 28: N'-(4-fluorophenyl)-1,3-dimethylpyrrolidine-2-carbohydrazide



[0259] 



[0260] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 1,3-dimethylpyrrolidine-2-carboxylic acid (Intermediate-20) (200 mg, 1.4 mmol) as starting material, which afforded 48 mg of crude product which was purified by column chromatography using 2% MeOH in DCM as eluent to afford 29 mg of the title compound (8% yield).
1H NMR (500 MHz, DMSO-d6) δ 1.06 (s, 3H), 1.38 (s, 1H), 2.06-2.03 (m, 1H), 2.20 (s, 1H), 2.30 (s, 3H), 2.35 - 2.31 (m, 1H), 3.04 (t, J = 3.8 Hz, 1H), 6.71-6.58 (m, 2H), 7.00-6.96 (m, 2H), 7.63 (s, 1H), 9.63 (s, 1H) ppm;
LC-MS (M+H): 252.4
Purity (HPLC): 96.78%

Example 29: 1-ethyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide



[0261] 



[0262] The title compound was prepared using an analogous procedure as disclosed for Example 16 (method A), employing 1-ethylpyrrolidine-2-carboxylic acid (Intermediate-21) (100 mg, 0.70 mmol) as starting material, which afforded 30 mg of crude product which was purified by column chromatography using 9.5:0.5 (v/v) MeOH:DCM as eluent to yield 30 mg of the title compound (17% yield).
1H NMR (500 MHz, CDCl3) δ 1.17 (t, J = 7.2 Hz, 3H), 1.88-1.85 (m, 2H), 1.96 (d, J = 4.0 Hz, 1H), 2.22-2.20 (m, 1H), 2.45 (brs, 1H), 2.62 (s, 1H), 2.78 (t, J = 7.3 Hz, 1H), 3.24 (d, J = 6.5 Hz, 1H), 3.31 (s, 1H), 6.11 (s, 1H), 6.79-6.69 (m, 2H), 6.95 - 6.90 (m, 2H), 9.21 (brs, 1H) ppm
LC-MS (M+H): 252.5
Purity (HPLC): 96.45%

Example 30: 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboximidamide hydrochloride



[0263] 



[0264] The title compound was prepared according to the general method B (Scheme II) by coupling N-Cbz protected pyrrolidine-2-carboxylic acid (Intermediate-22) with N-Boc protected 4-fluorophenylhydrazine, followed by deprotection of the N-atom of the pyrrolidine, introduction of the amidine group, and removal of the remaining protecting groups, according to the process depicted in Scheme XI:


Step 1: Preparation of benzyl 2-(2-(tert-butoxycarbonyl)-2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate



[0265] To a stirred solution of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (Intermediate-22) (1 g, 4.01 mmol) in DMF (15 mL) DIPEA (1.55 g, 12.01 mmol), HATU (1.9 g, 5.0 mmol) and tert-butyl 1-(4-fluorophenyl)hydrazinecarboxylate (1.15 g, 4.38 mmol) were added at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into ice-cold water (25 mL) and extracted with EtOAc (2x25 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (500 mg, 27% yield) as pale yellow semi-solid.

Step 2: Preparation of tert-butyl 1-(4-fluorophenyl)-2-(pyrrolidine-2-carbonyl)hydrazinecarboxylate



[0266] To a stirred solution of 2-(2-(tert-butoxycarbonyl)-2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (500 mg, 1.09 mmol) in MeOH (10 mL) Pd/C (10% wet, 100 mg 20% wt/wt) was added and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a pad of celite; and the filtrate was evaporated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to afford the title compound (200 mg, 28% yield) as off white solid.
1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 7.34 (q, J=3.8Hz, 2H), 7.16-7.11 (m, 2H), 3.62 (q, J=3.1Hz, 1H), 2.83 (t, J=6.5 Hz, 2H), 1.98-1.94 (m, 1H), 1.76-1.70 (m, 2H), 1.67-1.57 (m, 2H), 1.38 (s, 9H)
LC-MS m/z (M+H): 324.11

Step 3: Preparation of tert-butyl 2-(1-(N,N'-bis(tert-butoxycarbonyl)carbamimidoyl) pyrrolidine-2-carbonyl)-1-(4-fluorophenyl) hydrazinecarboxylate



[0267] To a stirred solution of tert-butyl 1-(4-fluorophenyl)-2-(pyrrolidine-2-carbonyl) hydrazinecarboxylate (300 mg, 0.928 mmol) in DMF (3 mL) 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (294 mg, 1.01 mmol), TEA (234 mg, 2.314 mmol), and HgCl2 (251 mg, 0.926 mmol) were added at 0 °C and the reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was poured into water (20 mL), extracted with EtOAc (2x10 mL). The combined organic layer was washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 60-120 mesh) to afford the title compound (200 mg, 38% yield) as white solid.
LC-MS (M+H): 566.3

Step 4: Preparation of 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboximidamide hydrochloride



[0268] A solution of tert-butyl 2-(1-(N,N'-bis(tert-butoxycarbonyl)carbamimidoyl) pyrrolidine-2-carbonyl)-1-(4-fluorophenyl)hydrazinecarboxylate (200 mg, 0.35 mmol) in 1,4-dioxane.HCl (4 mL) was stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure; the residue was co-distilled with DCM to afford the title compound (25 mg, 26% yield) as pale yellow liquid.
1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.32 (s, 4H), 6.96 (t, J=8.8Hz, 2H), 6.73 (q, J=4.2Hz, 2H), 4.62 (d, J=6.2Hz, 1H), 3.69-3.61 (m, 2H), 3.54-3.50 (m, 2H), 3.42 (q, J=7Hz, 2H)
LC-MS m/z (M+H): 301.75
Purity (HPLC): 94.0%

Example 31: Antimicrobial activity



[0269] The products of the present invention were tested for their activity against Acinetobacter baumannii (A. baumannii) as well as against the following bacteria: Staphylococcus aureus (S. aureus), Streptococcus pneumoniae (S. pneumoniae), Enterococcus faecium (E. faecium), Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli).

[0270] Minimal inhibitory concentrations (MICs) were determined using a standard microtiter dilution method, according to the Clinical and Laboratory Standards Institute (CLSI) procedures, in particular according to M07-A9: "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Ninth Edition".

[0271] Briefly, compounds were dissolved with dimethyl sulfoxide (DMSO) at 12.8 mg/mL. Serial two-fold dilutions of compounds were performed in DMSO and 1 µl of each dilution were transferred into microtiter culture plates, followed by 100 µl of inoculated culture media to give a final microorganism concentration of 5×105 colony-forming units/mL. Plates were incubated at 37°C for 24 hours and MICs determined as the lowest compound concentration that inhibited growth. Media used in determinations were Cation adjusted Mueller-Hinton Broth for all the microorganisms except for S. pneumoniae and E. faecium whose culture media were supplemented with 2.5% of lysed horse blood. Incubations were performed at air atmosphere except S. pneumoniae cultures that were incubated with 5% CO2 atmosphere.

[0272] The MIC values found (in µg/mL) for the tested compounds are given in Table 1 below.
TABLE 1
Ex.A. baumanniiS. aureusS. pneumoniaeE. faeciumP. aerugino saK. pneumoniaeE. coli
2 4 >128 >128 >128 >128 >128 >128
3 4 >128 >128 >128 >128 >128 >128
4 2 >128 >128 >128 >128 >128 >128
7 8 128 >128 >128 >128 >128 >128
9 8 >128 >128 >128 >128 >128 >128
10 2 >128 >128 >128 >128 >128 >128
11 8 >128 >128 >128 >128 >128 >128
14 2 >128 >128 >128 >128 >128 >128
15 1 >128 >128 >128 >128 >128 >128
16 0,25 >128 >128 >128 >128 >128 >128
18 8 128 >128 >128 >128 >128 >128
25 0,25 >128 >128 >128 >128 >128 >128
26 0,25 >128 >128 >128 >128 >128 >128
30 2 >128 >128 >128 >128 >128 >128


[0273] As shown in Table 1, compounds of formula (I) according to the present invention are highly effective antibacterials against A. Baumannii. Particularly, the MIC values obtained in the assay were of 8 µg/mL or lower for the tested compounds. Surprisingly, all the compounds showed a great selectivity for A. baumannii, since they were virtually inactive against the other bacteria tested.

Example 32: In vitro stability assay in mouse plasma



[0274] Several compounds of the present invention were tested for their stability in mouse plasma, by LC-MS/MS detection. The concentration of the tested compounds in the assay was 1 µM and the % remaining of each tested compound was calculated at the following time points: 0, 15, 30 and 60 minutes.

[0275] The frozen mouse plasma was thawed at room temperature and centrifuged at 1400x RCF, at 4 °C, for 15 minutes. Approximately 90% of the clear supernatant fraction was transferred to a separate tube and was used for the assay.

[0276] 1 mM stock of test compound was prepared in acetonitrile:water by diluting from 10 mM stock (i.e. 10 µL of 10 mM stock solution was added to 90 µL of acetonitrile: water (50:50)). 25 µM stock of test compound was prepared in acetonitrile: water by diluting from 1mM stock (i.e. 2.5 µL of 1mM stock solution was added to 97.5 µL of acetonitrile: water (50:50)).

[0277] For 0 min samples, plasma was heat inactivated at 56 °C. To 72 µL of heat inactivated plasma 3 µL of 25 µM test compound was added. A 50 µL aliquot of the mixture was taken and crashed with 200 µL of acetonitrile containing internal standard and was further processed along with other time points.

[0278] Final working stock of 1 µM was prepared by diluting in plasma ((i.e. 10 µL of 25 µM acetonitrile:water stock was added to 240 µL of plasma). 250 µL of plasma containing the test compound was incubated for 60 min at 37 °C in shaker water bath with gentle shaking. 50 µL aliquot of sample at 15, 30 and 60 min was precipitated immediately with 200 µL of acetonitrile containing internal standard and centrifuged at 4000x RCF, 4 °C for 20 minutes. 150 µL of supernatant was diluted with 150 µL of water and analyzed by LC-MS/MS.

[0279] The percent remaining of the test substance was calculated as ratio of peak area at each time point to peak area ratio at zero min, multiplied by 100.

[0280] The LC/MS/MS method used is defined by the following parameters: API4000 (MS), Shimadzu Prominance (LC), 20 µL injection volume; Column: Waters Xbridge, C18, 50* 4.6 mm, 3.5 µm; eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: 0-0.80 min 95% A, 5% B; 0.08-1.6 min 5% A, 95% B; 1.6-2.5 min 95% A, 5% B; flow rate: 1mL ml/min.

[0281] The compounds of formula (I) were found highly stable in this assay, with percentages remaining in the mouse plasma after 1 hour of 80% or superior, in most cases of more than 90%.

[0282] This data is highly relevant for the use of the compounds of the present invention as drugs, since a long stability in plasma is desirable to obtain good pharmacokinetic exposure of the drug and to maintain the activity in-vivo and is therefore significant in order to achieve a good therapeutic antibacterial efficacy.


Claims

1. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,
wherein

R1 and R2 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and hydroxyC1-4alkyl;

R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkoxy, haloC1-4alkoxy, -OC3-6cycloalkylC0-4alkyl, C1-6alkyl, C3-6cycloalkylC0-4alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC1-6alkyl, C1-4alkoxyC1-4alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN and -CO2R11; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl;

R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, -C(O)C1-4alkyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14, -C(NR15)NR11R12 and -CO2R11;

R9 is selected from hydrogen, C1-4alkyl and haloC1-4alkyl;

n is 0, 1, 2 or 3;

each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, C1-4alkoxyC1-6alkyl, -OC3-6CYCloalkylC0-4alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phenyl, 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, O and S; wherein said phenyl and said heteroaryl ring may be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to a common carbon atom form a spiro C3-6cycloalkyl, or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl, C1-4alkoxy, haloC1-4alkyl and halogen;

each R11 and R12 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and C3-6cycloalkylC0-4alkyl;

each R13 and R14 are independently selected from hydrogen, C1-4alkyl, C3-6cycloalkylC0-4alkyl and Het3-6, wherein each C1-4alkyl and C3-6cycloalkylC0-4alkyl may optionally be substituted by one or more R16, and wherein each C1-4alkyl may optionally be substituted by one or more Het3-6; or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and -C(O)C1-4alkyl;

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 and -S(O2)NR11R12;

each R16 is independently selected from alkyl, halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 and -OCOR11;

Het3-6 is a 3- to 6-membered saturated monocyclic heterocyclic ring containing one heteroatom selected from O, S and N, wherein said ring is bonded to the rest of the molecule through any available C atom and wherein said ring can be optionally substituted by one or more substituents independently selected from C1-4alkyl or haloC1-4alkyl; and

each R17 and R18 are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl, or R17 and R18 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and haloC1-4alkyl;

and wherein the following products are excluded:

tert-butyl (S)-2-(2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate,

tert-butyl (R)-2-(1-methyl-2-phenylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate,

tert-butyl (2S,4S)-4-mercapto-2-(2-(3-sulfamoylphenyl)hydrazine-1-carbonyl) pyrrolidine-1-carboxylate,

3-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-mercaptopyrrolidine-2-carbonyl)hydrazinyl) benzoic acid,

tert-butyl (2S,4S)-4-mercapto-2-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl) pyrrolidine-1-carboxylate, and

tert-butyl (2S,4S)-2-(2-(2-chloro-5-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)-4-mercaptopyrrolidine-1-carboxylate.


 
2. A compound according to claim 1, wherein
R1 and R2 are independently selected from hydrogen and C1-4alkyl;
R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, C3-6cycloalkylC0-4alkyl, -NR11R12, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4aikoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -CONR11R12, -SO2-NR11R12, and haloC1-4alkoxy, or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl;
R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, -C(O)C1-4alkyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14 and -C(NR15)NR11R12;
R9 is selected from hydrogen and C1-4alkyl;
n is 0, 1, 2 or 3;
each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, C1-4alkoxyC0-6alkyl, -SR11 and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen;
each R11 and R12 are independently selected from hydrogen and C1-4alkyl;
each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and -C(O)C1-4alkyl; and
R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -SO2-R11, -SO-R11 and -SO2-NR11R12.
 
3. A compound according to claims 1 or 2, wherein at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen.
 
4. A compound according to any of claims 1 to 3, wherein R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-4alkoxyC0-6alkyl, C1-4alkoxyC1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy.
 
5. A compound according to claim 4, wherein R3, R4, R5, R6 and R7 are independently selected from hydrogen, halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2-NR11R12 and haloC1-4alkoxy.
 
6. A compound according to claim 5, wherein R5 is selected from halogen, C1-4alkyl, haloC1-4alkyl, C1-4alkoxy, -SO2NR11R12 and haloC1-4alkoxy; R3 is selected from hydrogen, halogen and C1-4alkyl; and R4, R6 and R7 are hydrogen.
 
7. A compound according to claims 1 or 2, wherein R4 and R5 are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl, and R3, R6 and R7 are hydrogen.
 
8. A compound according to any of claims 1 to 7, wherein R1, R2 and R9 are hydrogen.
 
9. A compound according to any of claims 1 to 8 wherein R8 is selected from -OH, C1-4alkyl, C3-6cycloalkylC1-4alkyl, -C(O)C1-4alkyl, -CONR13R14 and -C(NR15)NR11R12; wherein each R13 and R14 are independently selected from hydrogen and C1-4alkyl, or R13 and R14 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains one additional heteroatom selected from N and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and C2-3acyl.
 
10. A compound according to any of claims 1 to 9, wherein n is 1 or 2 and each R10 is independently selected from halogen, C1-4alkyl and -NR11R12; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to adjacent carbon atoms are connected to form a 3- to 5-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl and halogen.
 
11. A compound according to any of claims 1 to 9, wherein n is 0.
 
12. A compound according to claim 1, which is selected from the group consisting of:

- N'-(4-fluorophenyl)-1,5-dimethypyrrolidine-2-carbohydrazide

- (R)-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (S)-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-fluoro-2-methylphenyl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide

- 2-(2-(3,5-difluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-(trifluoromethoxy)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-(trifluoromethyl)phenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-chloro-2-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-methoxyphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-sulfamoylphenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (2S,4S)-4-fluoro-2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (R)-1-acetyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1-hydroxypyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1,2-dimethylpyrrolidine-2-carbohydrazide

- 2-(2-(4-fluorophenyl)hydrazinecarbonyl)-N,N-dimethylpyrrolidine-1-carboxamide

- N'-(4-fluorophenyl)-1-(piperazine-1-carbonyl)pyrrolidine-2-carbohydrazide

- 1-(4-acetylpiperazine-1-carbonyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1-methyl-5-oxopyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide

- 4-amino-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide

- 4-fluoro-N'-(4-fluorophenyl)-1-methylpyrrolidine-2-carbohydrazide

- (S)-1-(cyclopropylmethyl)-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

- N'-(4-fluorophenyl)-1,4-dimethylpyrrolidine-2-carbohydrazide

- N'-(4-fluorophenyl)-1,3-dimethylpyrrolidine-2-carbohydrazide

- 1-ethyl-N'-(4-fluorophenyl)pyrrolidine-2-carbohydrazide

- 2-(2-(4-fluorophenyl)hydrazinecarbonyl)pyrrolidine-1-carboximidamide

or a pharmaceutically acceptable salt, or solvate thereof.
 
13. A compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,
wherein

R1 and R2 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and hydroxyC1-4alkyl;

R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkoxy, haloC1-4alkoxy, -OC3-6cycloalkylC0-4alkyl, C1-6alkyl, C3-6cycloalkylC0-4alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC1-6alkyl, C1-4alkoxyC1-4alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN and -CO2R11; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl;

R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, -C(O)C1-4alkyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14, -C(NR15)NR11R12 and -CO2R11;

R9 is selected from hydrogen, C1-4alkyl and haloC1-4alkyl;

n is 0, 1, 2 or 3;

each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, C1-4alkoxyC1-6alkyl, -OC3-6CYCloalkylC0-4alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phenyl, 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, O and S; wherein said phenyl and said heteroaryl ring may be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to a common carbon atom form a spiro C3-6cycloalkyl, or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl, C1-4alkoxy, haloC1-4alkyl and halogen;

each R11 and R12 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and C3-6cycloalkylC0-4alkyl;

each R13 and R14 are independently selected from hydrogen, C1-4alkyl, C3-6cycloalkylC0-4alkyl and Het3-6, wherein each C1-4alkyl and C3-6cycloalkylC0-4alkyl may optionally be substituted by one or more R16, and wherein each C1-4alkyl may optionally be substituted by one or more Het3-6; or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and -C(O)C1-4alkyl;

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 and -S(O2)NR11R12;

each R16 is independently selected from alkyl, halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 and -OCOR11;

Het3-6 is a 3- to 6-membered saturated monocyclic heterocyclic ring containing one heteroatom selected from O, S and N, wherein said ring is bonded to the rest of the molecule through any available C atom and wherein said ring can be optionally substituted by one or more substituents independently selected from C1-4alkyl or haloC1-4alkyl; and

each R17 and R18 are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl, or R17 and R18 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and haloC1-4alkyl;

for use as a medicament.


 
14. A compound according to any of claims 2 to 12 for use as a medicament.
 
15. A compound for use according to claims 13 or 14, for use as antibacterial agent for treating or preventing A. baumannii infections.
 
16. A pharmaceutical composition comprising a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof,
wherein

R1 and R2 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and hydroxyC1-4alkyl;

R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen, C1-6alkoxy, haloC1-4alkoxy, -OC3-6cycloalkylC0-4alkyl, C1-6alkyl, C3-6cycloalkylC0-4alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-4alkoxyC1-6alkyl, C1-4alkoxyC1-4alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN and -CO2R11; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, wherein 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl can be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl;

R8 is selected from -OH, C1-6alkyl, haloC1-6alkyl, hydroxyC1-4alkyl, C1-4alkoxyC0-4alkyl, C3-6cycloalkylC0-4alkyl, -C(O)C1-4alkyl, -C(O)C3-6cycloalkylC0-2alkyl, -CONR13R14, -C(NR15)NR11R12 and -CO2R11;

R9 is selected from hydrogen, C1-4alkyl and haloC1-4alkyl;

n is 0, 1, 2 or 3;

each R10, if present, is independently selected from -OH, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, C1-4alkoxyC1-6alkyl, -OC3-6cycloalkylC0-4alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phenyl, 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, O and S; wherein said phenyl and said heteroaryl ring may be optionally substituted by one or more C1-4alkyl or haloC1-4alkyl; or two R10 attached to a common carbon atom form an oxo; or two R10 attached to a common carbon atom form a spiro C3-6cycloalkyl, or two R10 attached to adjacent carbon atoms are connected to form a 3-to 6-membered cycloalkyl, said cycloalkyl can be optionally substituted by one or more substituents independently selected from C1-4alkyl, C1-4alkoxy, haloC1-4alkyl and halogen;

each R11 and R12 are independently selected from hydrogen, C1-4alkyl, haloC1-4alkyl and C3-6cycloalkylC0-4alkyl;

each R13 and R14 are independently selected from hydrogen, C1-4alkyl, C3-6cycloalkylC0-4alkyl and Het3-6, wherein each C1-4alkyl and C3-6cycloalkylC0-4alkyl may optionally be substituted by one or more R16, and wherein each C1-4alkyl may optionally be substituted by one or more Het3-6; or R13 and R14 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl, haloC1-4alkyl and -C(O)C1-4alkyl;

R15 is selected from hydrogen, C1-6alkyl, haloC1-6alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 and -S(O2)NR11R12;

each R16 is independently selected from alkyl, halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 and -OCOR11;

Het3-6 is a 3- to 6-membered saturated monocyclic heterocyclic ring containing one heteroatom selected from O, S and N, wherein said ring is bonded to the rest of the molecule through any available C atom and wherein said ring can be optionally substituted by one or more substituents independently selected from C1-4alkyl or haloC1-4alkyl; and

each R17 and R18 are independently selected from hydrogen, C1-4alkyl and haloC1-4alkyl, or R17 and R18 form, together with the N atom to which they are attached, a 4- to 6-membered saturated heterocycle, which can optionally contain one additional heteroatom selected from N, S and O, said heterocycle can be optionally substituted by one or more substituents independently selected from C1-4alkyl and haloC1-4alkyl;

and at least one pharmaceutically acceptable excipient and/or carrier.


 
17. A process for the preparation of a compound of claim 1, comprising reacting a compound of formula (II)

with a compound of formula (III) or a pharmaceutically acceptable salt or solvate thereof

wherein R16 is hydrogen or a C1-4alkyl, R17 is hydrogen or R8, and n and R1 to R15 have the same meaning as described in claim 1.
 


Ansprüche

1. Eine Verbindung der Formel (I):

oder ein pharmazeutisch akzeptables Salz oder Solvat davon,
wobei

R1 und R2 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und Hydroxy(C1-4)-Alkyl;

R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, -OH, Halogen, (C1-6)-Alkoxy, Halogen(C1-4)-Alkoxy, -(OC3-6)-Cycloalkyl(C0-4)-Alkyl, (C1-6)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-4)-Alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN und -CO2R11; oder zwei von an angrenzende Kohlenstoffatome gebundenen R3 bis R7 verbunden sind, um ein 5- oder 6-gliedriges Cycloalkyl zu bilden, wobei 1 oder 2 Methylengruppen des Cycloalkyls durch O ersetzt sein können, wobei das Cycloalkyl wahlweise durch ein oder mehrere von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können;

R8 ausgewählt ist aus -OH, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-4)-Alkyl, (C1-4)-Alkoxy(C0-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, -C(O)(C1-4)-Alkyl, -C(O)(C3-6)-Cycloalkyl(C0-2)-Alkyl, -CONR13R14, -C(NR15)NR11R12 und -CO2R11;

R9 ausgewählt ist aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl;

n = 0, 1, 2, oder 3 ist;

jedes R10, wenn es darin vorhanden ist, unabhängig ausgewählt ist aus -OH, Halogen, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, (C1-6)-Alkoxy, (C1-4)-Alkoxy(C1-6)-Alkyl, -O(C3-6)-Cycloalkyl(C0-4)-Alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, Phenyl, 5- oder 6-gliedrigem Heteroarylring umfassend 1 oder 2 Heteroatome, die aus N, O und S ausgewählt sind;

wobei das Phenyl und der Heteroarylring wahlweise durch ein oder mehr von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 eine Oxogruppe bilden; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 ein Spiro-(C3-6)-Cycloalkyl bilden, oder zwei an angrenzende Kohlenstoffatome gebundene R10 verbunden sind, um ein 3- bis 6-gliedriges Cycloalkyl zu bilden, wobei das Cycloalkyl wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, (C1-4)-Alcoxy, Halogen(C1-4)-Alkyl und Halogen ausgewählt sind;

jedes R11 und R12 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl;

jedes R13 und R14 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl und Het3-6 ausgewählt ist, wobei jedes (C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl wahlweise durch ein oder mehr R16 substituiert sein kann, und wobei jedes (C1-4)-Alkyl wahlweise durch ein oder mehr Het3-6 substituiert sein kann; oder

R13 und R14, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und -C(O)(C1-4)-Alkyl ausgewählt sind;

R15 ausgewählt ist aus Wasserstoff, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 und -S(O2)NR11R12;

jedes R16 unabhängig voneinander ausgewählt ist aus Alkyl, Halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 und -OCOR11;

Het3-6 ein 3- bis 6-gliedriger gesättigter monocyclischer heterocyclischer Ring ist, der ein Heteroatom enthält, das aus O, S und N ausgewählt ist, wobei der Ring an den Rest des Moleküls durch ein verfügbares C-Atom gebunden ist und wobei der Ring wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl ausgewählt sind; und

jedes R17 und R18 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind, oder R17 und R18, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind;

und wobei die folgenden Produkte ausgeschlossen sind:

tert-Butyl (S)-2-(2-phenylhydrazin-1-carbonyl)pyrrolidin-1-carboxylat,

tert-Butyl (R)-2-(1-methyl-2-phenylhydrazin-1-carbonyl)pyrrolidin-1-carboxylat,

tert-Butyl (2S,4S)-4-mercapto-2-(2-(3-sulfamoylphenyl)hydrazin-1-carbonyl)pyrrolidin-1-carboxylat,

3-(2-((2S,4S)-1-(tert-Butoxycarbonyl)-4-mercaptopyrrolidin-2-carbonyl)hydrazinyl)benzoesäure,

tert-Butyl (2S,4S)-4-mercapto-2-(2-(2-(trifluoromethyl)phenyl)hydrazin-1-carbonyl)pyrrolidin-1-carboxylat, und

tert-Butyl (2S,4S)-2-(2-(2-chloro-5-(trifluoromethyl)phenyl)hydrazin-1-carbonyl)-4-mercaptopyrrolidin-1-carboxylat.


 
2. Eine Verbindung nach Anspruch 1, wobei
R1 und R2 unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Wasserstoff und (C1-C6)-Alkyl;
R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, -OH, Halogen, (C1-6)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, -NR11R12, Halogen(C1-6)-Alkyl, Hydroxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C0-6)-Alkyl, (C1-4)-Alkoxy(C1-4)-Alkoxy, -CONR11R12, -SO2-NR11R12, und Halogen(C1-4)-Alkoxy, oder zwei von an angrenzende Kohlenstoffatome gebundenen R3 bis R7 verbunden sind, um ein 5- oder 6-gliedriges Cycloalkyl zu bilden, wobei 1 oder 2 Methylengruppen des Cycloalkyls durch O ersetzt sein können, wobei das Cycloalkyl durch ein oder mehr von (C1-4)-Alkyl substituiert sein können;
R8 ausgewählt ist aus -OH, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-4)-Alkyl, (C1-4)-Alkoxy(C0-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, -C(O)(C1-4)-Alkyl, -C(O)(C3-6)-Cycloalkyl(C0-2)-Alkyl, -CONR13R14 und -C(NR15)NR11R12;
R9 ausgewählt ist aus Wasserstoff und (C1-4)-Alkyl;
n = 0, 1, 2, oder 3 ist;
jedes R10, wenn es darin vorhanden ist, unabhängig ausgewählt ist aus -OH, Halogen, (C1-6)-Alkyl, (C1-4)-Alkoxy(C0-6)-Alkyl, -SR11 und -NR11R12; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 eine Oxogruppe bilden; oder zwei an angrenzende Kohlenstoffatome gebundene R10 verbunden sind, um ein 3- bis 6-gliedriges Cycloalkyl zu bilden, wobei das Cycloalkyl wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und Halogen ausgewählt sind;
jedes R11 und R12 unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Wasserstoff und (C1-C6)-Alkyl;
jedes R13 und R14 unabhängig voneinander aus Wasserstoff und (C1-4)-Alkyl ausgewählt sind, oder R13 und R14, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4-bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und C(O)(C1-4)-Alkyl ausgewählt sind; und
R15 ausgewählt ist aus Wasserstoff, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, CN, -CONR11R12, -SO2-R11, -SO-R11 und -SO2-NR11R12.
 
3. Eine Verbindung nach den Ansprüchen 1 oder 2, wobei mindestens eines von R3 bis R7 kein Wasserstoff ist und mindestens zwei von R3 bis R7 Wasserstoff sind.
 
4. Eine Verbindung nach einem der Ansprüche 1 bis 3, wobei R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, -OH, Halogen, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, (C1-4)-Alkoxy(C0-6)-Alkyl, (C1-4)-Alkoxy(C1-4)-Alkoxy, -SO2-NR11R12 und Halogen(C1-4)-Alkoxy.
 
5. Eine Verbindung nach Anspruch 4, wobei R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, Halogen, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl, (C1-4)-Alkoxy, -SO2-NR11R12 und Halogen(C1-4)-Alkoxy.
 
6. Eine Verbindung nach Anspruch 5, wobei R5 ausgewählt ist aus Halogen, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl, (C1-4)-Alkoxy, -SO2-NR11R12 und Halogen(C1-4)-Alkoxy; wobei R3 ausgewählt ist aus Wasserstoff, Halogen und (C1-4)-Alkyl; und wobei R4, R6 und R7 Wasserstoff sind.
 
7. Eine Verbindung nach den Ansprüchen 1 oder 2, wobei R4 und R5 verbunden sind, um ein 5- oder 6-gliedriges Cycloalkyl zu bilden, wobei 1 oder 2 Methylengruppen des Cycloalkyls durch O ersetzt sein können, wobei das Cycloalkyl wahlweise durch ein oder mehr von (C1-4)-Alkyl substituiert sein können, und R3, R6 und R7 Wasserstoff sind.
 
8. Eine Verbindung nach einem der Ansprüche 1 bis 7, wobei R1, R2 und R9 Wasserstoff sind.
 
9. Eine Verbindung nach einem der Ansprüche 1 bis 8, wobei R8 ausgewählt ist aus -OH, (C1-4)-Alkyl, (C3-6)-Cycloalkyl(C1-4)-Alkyl, -C(O)(C1-4)-Alkyl, -CONR13R14 und -C(NR15)NR11R12; wobei jedes R13 und R14 unabhängig voneinander ausgewählt sind aus (C1-4)-Alkyl, oder R13 und R14, zusammen mit dem N-Atom, an das sie gebunden sind, einen 6-gliedrigen gesättigten Heterocyclus bilden, welcher ein zusätzliches Heteroatom enthält, das aus N und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und (C2-3)-Acyl ausgewählt sind.
 
10. Eine Verbindung nach einem der Ansprüche 1 bis 9, wobei n = 1 oder 2 ist und jedes R10 unabhängig voneinander ausgewählt ist aus Halogen, (C1-4)-Alkyl und -NR11R12; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 eine Oxogruppe bilden; oder zwei an angrenzende Kohlenstoffatome gebundene R10 verbunden sind, um ein 3-bis 5-gliedriges Cycloalkyl zu bilden, wobei das Cycloalkyl wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und Halogen ausgewählt sind.
 
11. Eine Verbindung nach einem der Ansprüche 1 bis 9, wobei n = 0 ist.
 
12. Eine Verbindung nach Anspruch 1, welche ausgewählt ist aus der Gruppe bestehend aus:

- N'-(4-Fluorophenyl)-1,5-dimethylpyrrolidin-2-carbohydrazid

- (R)-2-(2-(4-Fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- (S)-2-(2-(4-Fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-Fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-Fluoro-2-methylphenyl)hydrazin-1-carbonyl)pyrrolidin-1-carboxamid

- 2-(2-(3,5-Difluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-(Trifluoromethoxy)phenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-(Trifluoromethyl)phenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-Chloro-2-fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-Methoxyphenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- 2-(2-(4-Sulfamoylphenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- (2S,4S)-4-Fluoro-2-(2-(4-fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboxamid

- (R)-1-Acetyl-N'-(4-fluorophenyl)pyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1-hydroxypyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1,2-dimethylpyrrolidin-2-carbohydrazid

- 2-(2-(4-Fluorophenyl)hydrazincarbonyl)-N,N-dimethylpyrrolidin-1-carboxamid

- N'-(4-Fluorophenyl)-1-(piperazin-1-carbonyl)pyrrolidin-2-carbohydrazid

- 1-(4-Acetylpiperazin-1-carbonyl)-N'-(4-fluorophenyl)pyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1-(morpholin-4-carbonyl)pyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1-methyl-5-oxopyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1-methylpyrrolidin-2-carbohydrazid

- 4-Amino-N'-(4-fluorophenyl)-1-methylpyrrolidin-2-carbohydrazid

- 4-Fluoro-N'-(4-fluorophenyl)-1-methylpyrrolidin-2-carbohydrazid

- (S)-1-(Cyclopropylmethyl)-N'-(4-fluorophenyl)pyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-3-methyl-3-azabicyclo[3.1.0]hexan-2-carbohydrazid

- N'-(4-Fluorophenyl)-1,4-dimethylpyrrolidin-2-carbohydrazid

- N'-(4-Fluorophenyl)-1,3-dimethylpyrrolidin-2-carbohydrazid

- 1-Ethyl-N'-(4-fluorophenyl)pyrrolidin-2-carbohydrazid

- 2-(2-(4-Fluorophenyl)hydrazincarbonyl)pyrrolidin-1-carboximidamid

oder ein pharmazeutisch akzeptables Salz oder Solvat davon.
 
13. Eine Verbindung der Formel (I):

oder ein pharmazeutisch akzeptables Salz oder Solvat davon,
wobei

R1 und R2 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und Hydroxy(C1-4)-Alkyl;

R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, -OH, Halogen, (C1-6)-Alkoxy, Halogen(C1-4)-Alkoxy, -(OC3-6)-Cycloalkyl(C0-4)-Alkyl, (C1-6)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-4)-Alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN und -CO2R11; oder zwei von an angrenzende Kohlenstoffatome gebundenen R3 bis R7 verbunden sind, um ein 5- oder 6-gliedriges Cycloalkyl zu bilden, wobei 1 oder 2 Methylengruppen des Cycloalkyls durch O ersetzt sein können, wobei das Cycloalkyl wahlweise durch ein oder mehrere von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können;

R8 ausgewählt ist aus -OH, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-4)-Alkyl, (C1-4)-Alkoxy(C0-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, -C(O)(C1-4)-Alkyl, -C(O)(C3-6)-Cycloalkyl(C0-2)-Alkyl, -CONR13R14, -C(NR15)NR11R12 und -CO2R11;

R9 ausgewählt ist aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl;

n = 0, 1, 2, oder 3 ist;

jedes R10, wenn es darin vorhanden ist, unabhängig ausgewählt ist aus -OH, Halogen, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, (C1-6)-Alkoxy, (C1-4)-Alkoxy(C1-6)-Alkyl, -O(C3-6)-Cycloalkyl(C0-4)-Alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, Phenyl, 5- oder 6-gliedrigem Heteroarylring umfassend 1 oder 2 Heteroatome, die aus N, O und S ausgewählt sind;

wobei das Phenyl und der Heteroarylring wahlweise durch ein oder mehr von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 eine Oxogruppe bilden; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 ein Spiro-(C3-6)-Cycloalkyl bilden, oder zwei an angrenzende Kohlenstoffatome gebundene R10 verbunden sind, um ein 3- bis 6-gliedriges Cycloalkyl zu bilden, wobei das Cycloalkyl wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, (C1-4)-Alcoxy, Halogen(C1-4)-Alkyl und Halogen ausgewählt sind;

jedes R11 und R12 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl;

jedes R13 und R14 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl und Het3-6 ausgewählt ist, wobei jedes (C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl wahlweise durch ein oder mehr R16 substituiert sein kann, und wobei jedes (C1-4)-Alkyl wahlweise durch ein oder mehr Het3-6 substituiert sein kann; oder R13 und R14, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und -C(O)(C1-4)-Alkyl ausgewählt sind;

R15 ausgewählt ist aus Wasserstoff, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, -CN, -CONR11R12, -S(O2)R11, -SOR11 und -S(O2)NR11R12;

jedes R16 unabhängig voneinander ausgewählt ist aus Alkyl, Halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 und -OCOR11;

Het3-6 ein 3- bis 6-gliedriger gesättigter monocyclischer heterocyclischer Ring ist, der ein Heteroatom enthält, das aus O, S und N ausgewählt ist, wobei der Ring an den Rest des Moleküls durch ein verfügbares C-Atom gebunden ist und wobei der Ring wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl ausgewählt sind; und

jedes R17 und R18 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind, oder R17 und R18, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind;

zur Verwendung als Arzneimittel.


 
14. Eine Verbindung nach einem der Ansprüche 2 bis 12 zur Verwendung als Arzneimittel.
 
15. Eine Verbindung zur Verwendung nach den Ansprüchen 13 oder 14, zur Verwendung als antibakterielles Mittel zur Behandlung oder Prävention von durch A. baumannii verursachten Infektionen.
 
16. Eine pharmazeutische Zusammensetzung umfassend eine Verbindung der Formel (I):

oder ein pharmazeutisch akzeptables Salz oder Solvat davon,
wobei

R1 und R2 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und Hydroxy(C1-4)-Alkyl;

R3, R4, R5, R6 und R7 unabhängig voneinander ausgewählt sind aus Wasserstoff, -OH, Halogen, (C1-6)-Alkoxy, Halogen(C1-4)-Alkoxy, -(OC3-6)-Cycloalkyl(C0-4)-Alkyl, (C1-6)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-6)-Alkyl, (C1-4)-Alkoxy(C1-4)-Alkoxy, -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN und -CO2R11; oder zwei von an angrenzende Kohlenstoffatome gebundenen R3 bis R7 verbunden sind, um ein 5- oder 6-gliedriges Cycloalkyl zu bilden, wobei 1 oder 2 Methylengruppen des Cycloalkyls durch O ersetzt sein können, wobei das Cycloalkyl wahlweise durch ein oder mehrere von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können;

R8 ausgewählt ist aus -OH, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, Hydroxy(C1-4)-Alkyl, (C1-4)-Alkoxy(C0-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl, -C(O)(C1-4)-Alkyl, -C(O)(C3-6)-Cycloalkyl(C0-2)-Alkyl, -CONR13R14, -C(NR15)NR11R12 und -CO2R11;

R9 ausgewählt ist aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl;

n = 0, 1, 2, oder 3 ist;

jedes R10, wenn es darin vorhanden ist, unabhängig ausgewählt ist aus -OH, Halogen, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, (C1-6)-Alkoxy, (C1-4)-Alkoxy(C1-6)-Alkyl, -O(C3-6)-Cycloalkyl(C0-4)-Alkyl, -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, Phenyl, 5- oder 6-gliedrigem Heteroarylring umfassend 1 oder 2 Heteroatome, die aus N, O und S ausgewählt sind;

wobei das Phenyl und der Heteroarylring wahlweise durch ein oder mehr von (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl substituiert sein können; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 eine Oxogruppe bilden; oder zwei an ein gemeinsames Kohlenstoffatom gebundene R10 ein Spiro-(C3-6)-Cycloalkyl bilden, oder zwei an angrenzende Kohlenstoffatome gebundene R10 verbunden sind, um ein 3- bis 6-gliedriges Cycloalkyl zu bilden, wobei das Cycloalkyl wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, (C1-4)-Alcoxy, Halogen(C1-4)-Alkyl und Halogen ausgewählt sind;

jedes R11 und R12 unabhängig voneinander ausgewählt sind aus Wasserstoff, (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl;

jedes R13 und R14 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl, (C3-6)-Cycloalkyl(C0-4)-Alkyl und Het3-6 ausgewählt ist, wobei jedes (C1-4)-Alkyl und (C3-6)-Cycloalkyl(C0-4)-Alkyl wahlweise durch ein oder mehr R16 substituiert sein kann, und wobei jedes (C1-4)-Alkyl wahlweise durch ein oder mehr Het3-6 substituiert sein kann; oder R13 und R14, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl, Halogen(C1-4)-Alkyl und -C(O)(C1-4)-Alkyl ausgewählt sind;

R15 ausgewählt ist aus Wasserstoff, (C1-6)-Alkyl, Halogen(C1-6)-Alkyl, CN, -CONR11R12, -S(O2)R11, -SOR11 und -S(O2)NR11R12;

jedes R16 unabhängig voneinander ausgewählt ist aus Alkyl, Halogen, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 und -OCOR11;

Het3-6 ein 3- bis 6-gliedriger gesättigter monocyclischer heterocyclischer Ring ist, der ein Heteroatom enthält, das aus O, S und N ausgewählt ist, wobei der Ring an den Rest des Moleküls durch ein verfügbares C-Atom gebunden ist und wobei der Ring wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl oder Halogen(C1-4)-Alkyl ausgewählt sind; und

jedes R17 und R18 unabhängig voneinander aus Wasserstoff, (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind, oder R17 und R18, zusammen mit dem N-Atom, an das sie gebunden sind, einen 4- bis 6-gliedrigen gesättigten Heterocyclus bilden, der wahlweise ein zusätzliches Heteroatom enthalten kann, das aus N, S und O ausgewählt ist, wobei der Heterocyclus wahlweise durch einen oder mehr Substituenten substituiert sein kann, die unabhängig voneinander aus (C1-4)-Alkyl und Halogen(C1-4)-Alkyl ausgewählt sind;

und mindestens einen pharmazeutisch akzeptablen Hilfsstoff und/oder Trägerstoff.


 
17. Ein Verfahren zur Herstellung von einer Verbindung des Anspruchs 1, umfassend die Reaktion von einer Verbindung der Formel (II)

mit einer Verbindung der Formel (III) oder einem pharmazeutisch akzeptablen Salz oder Solvat davon,

wobei R16 Wasserstoff oder ein (C1-4)-Alkyl ist, R17 Wasserstoff oder R8 ist, und n und R1 bis R15 die gleiche Bedeutung, wie in Anspruch 1 definiert, haben.
 


Revendications

1. Un composé de formule (I) :

ou un sel ou un solvate pharmaceutiquement acceptable de celui-ci,

R1 et R2 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et hydroxyalkyle en C1-4 ;

R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, -OH, halogène, alcoxyle en C1-6, halogénoalcoxyle en C1-4, -cycloalkyle en (OC3-6)-(alkyle en C0-4), alkyle en C1-6, (cycloalkyle en C3-6)-(alkyle en C0-4), halogénoalkyle en C1-6, hydroxyalkyle en (C1-6), (alcoxyle en C1-4)-(alkyle en C1-6), (alcoxyle en C1-4)-(alcoxyle en C1-4), -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN et -CO2R11 ; ou deux de R3 à R7 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 5 ou 6 chaînons, où 1 ou 2 groupes méthylène du cycloalkyle peuvent être remplacés par O, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs groupes alkyle en (C1-4) ou halogénoalkyle en (C1-4) ;

R8 est choisi parmi -OH, alkyle en C1-6, halogénoalkyle en C1-6, hydroxyalkyle en C1-4, (alcoxyle en C1-4)-(alkyle en C0-4), (cycloalkyle en C3-6)-(alkyle en C0-4), -C(O)(alkyle en C1-4), -(C(O)cycloalkyle en C3-6)-(alkyle en C0-2), -CONR13R14, -C(NR15)NR11R12 et -CO2R11;

R9 est choisi parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4 ;

n est 0, 1, 2, ou 3 ;

chaque R10, s'il est présent, est indépendamment choisi parmi -OH, halogène, alkyle en C1-6, halogénoalkyle en C1-6, alcoxyle en C1-6, (alcoxyle en C1-4)-(alkyle en C1-6), -cycloalkyle en (OC3-6)-(alkyle en C0-4), -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phényle, anneau hétéroaryle à 5 ou 6 chaînons comprenant 1 ou 2 hétéroatomes choisis parmi N, O et S ; où ledit phényle et ledit anneau hétéroaryle peuvent être facultativement substitués par un ou plusieurs groupes alkyle en C1-4 ou halogénoalkyle en C1-4 ; ou deux R10 attachés à un atome de carbone commun forment un groupe oxo ; ou deux R10 attachés à un atome de carbone commun forment un spirocycloalkyle en C3-6, ou deux R10 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 3 à 6 chaînons, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, alcoxyle en C1-4, halogénoalkyle en C1-4 et halogène ;

chaque R11 et R12 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) ;

chaque R13 et R14 sont indépendamment choisis parmi l'hydrogène, alkyle en (C1-4), (cycloalkyle en C3-6)-(alkyle en C0-4) et Het3-6, où chaque alkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) peuvent être facultativement substitués par un ou plusieurs R16, et où chaque alkyle en C1-4 peut être facultativement substitué par un ou plusieurs Het3-6 ;

ou R13 et R14 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, halogénoalkyle en C1-4 et -C(O)-(alkyle en C1-4) ;

R15 est choisi parmi l'hydrogène, alkyle en C1-6, halogénoalkyle en C1-6, -CN, -CONR11R12, -S(O2)R11, -SOR11 et -S(O2)NR11R12 ;

chaque R16 est indépendamment choisi parmi alkyle, halogène, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 et -OCOR11 ;

Het3-6 est un anneau hétérocyclique monocyclique saturé à 3 à 6 chaînons contenant un hétéroatome choisi parmi O, S et N, où ledit anneau est lié au reste de la molécule à travers un atome C disponible quelconque et où ledit anneau peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 ou halogénoalkyle en C1-4 ; et

chaque R17 et R18 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4, ou R17 et R18 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, Set O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 et halogénoalkyle en C1-4 ;

et où les produits suivants sont exclus :

(S)-2-(2-phénylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate de tert-butyle,

(R)-2-(1-méthyl-2-phénylhydrazine-1-carbonyl)pyrrolidine-1-carboxylate de tert-butyle,

(2S,4S)-4-mercapto-2-(2-(3-sulfamoylphényl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate de tert-butyle,

acide 3-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-mercaptopyrrolidine-2-carbonyl)hydrazinyl)benzoïque,

(2S,4S)-4-mercapto-2-(2-(2-(trifluorométhyl)phényl)hydrazine-1-carbonyl)pyrrolidine-1-carboxylate de tert-butyle, et

(2S,4S)-2-(2-(2-chloro-5-(trifluorométhyl)phényl)hydrazine-1-carbonyl)-4-mercaptopyrrolidine-1-carboxylate de tert-butyle.


 
2. Un composé selon la revendication 1, dans lequel :

R1 et R2 sont indépendamment choisis parmi l'hydrogène et alkyle en C1-4 ;

R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, -OH, halogène, alkyle en C1-6, (cycloalkyle en C3-6)-(alkyle en C0-4), -NR11R12, halogénoalkyle en C1-6, hydroxyalkyle en C1-6, (alcoxyle en C1-4)-(alkyle en C0-6), (alcoxyle en C1-4)-(alcoxyle en C1-4), -CONR11R12, -SO2-NR11R12, et halogénoalcoxyle en C1-4, ou deux de R3 à R7 attachés à des atomes de carbone adjacents sont connectés pour former un cycloalkyle à 5 ou 6 chaînons, où 1 ou 2 groupes méthylène du cycloalkyle peuvent être remplacés par O, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs groupes alkyle en C1-4 ;

R8 est choisi parmi -OH, alkyle en C1-6, halogénoalkyle en C1-6, hydroxyalkyle en C1-4, (alcoxyle en C1-4)-(alkyle en C0-4), (cycloalkyle en C3-6)-(alkyle en C0-4), -C(O)(alkyle en C1-4), -(C(O)cycloalkyle en C3-6)-(alkyle en C0-2), -CONR13R14 et -C(NR15)NR11R12 ;

R9 est choisi parmi l'hydrogène et alkyle en C1-4 ;

n est 0, 1, 2, ou 3 ;

chaque R10, s'il est présent, est indépendamment choisi parmi -OH, halogène, alkyle en C1-6, (alcoxyle en C1-4)-(alkyle en C0-6), -SR11 et -NR11R12 ; ou deux R10 attachés à un atome de carbone commun forment un groupe oxo ; ou deux R10 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 3 à 6 chaînons, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi alkyle en C1-4 et halogène ;

chaque R11 et R12 sont indépendamment choisis parmi l'hydrogène et alkyle en C1-4 ;

chaque R13 et R14 sont indépendamment choisis parmi l'hydrogène et alkyle en C1-4, ou R13 et R14 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 et -C(O)-(alkyle en C1-4) ; et

R15 est choisi parmi l'hydrogène, alkyle en C1-6, halogénoalkyle en C1-6, -CN, -CONR11R12, -SO2-R11, -SO-R11 et -SO2-NR11R12.


 
3. Un composé selon les revendications 1 ou 2, dans lequel au moins un de R3 à R7 n'est pas l'hydrogène et au moins deux de R3 à R7 sont hydrogène.
 
4. Un composé selon l'une quelconque des revendications 1 à 3, dans lequel R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, -OH, halogène, alkyle en (C1-6), halogénoalkyle en (C1-6), (alcoxyle en C1-4)-(alkyle en C0-6), (alcoxyle en C1-4)-(alcoxyle en C1-4), -SO2-NR11R12 et halogénoalcoxyle en C1-4.
 
5. Un composé selon la revendication 4, dans lequel R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, halogène, alkyle en C1-4, halogénoalkyle en C1-4, alcoxyle en C1-4, -SO2-NR11R12 et halogénoalcoxyle en C1-4.
 
6. Un composé selon la revendication 5, dans lequel R5 est choisi parmi halogène, alkyle en C1-4, halogénoalkyle en C1-4, alcoxyle en C1-4, -SO2-NR11R12 et halogénoalcoxyle en C1-4 ; R3 est choisi parmi l'hydrogène, halogène et alkyle en C1-4 ; et R4, R6 et R7 sont hydrogène.
 
7. Un composé selon les revendications 1 ou 2, dans lequel R4 et R5 sont connectés en formant un cycloalkyle à 5 ou 6 chaînons, dans lequel 1 ou 2 groupes méthylène du cycloalkyle peuvent être remplacés avec O, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs groupes alkyle en C1-4, et R3, R6 et R7 sont hydrogène.
 
8. Un composé selon l'une quelconque des revendications 1 à 7, dans lequel R1, R2 et R9 sont hydrogène.
 
9. Un composé selon l'une quelconque des revendications 1 à 8 dans lequel R8 est choisi parmi -OH, alkyle en C1-4, (cycloalkyle en C3-6)-(alkyle en C1-4), -C(O)-alkyle en C1-4, -CONR13R14 et -C(NR15)NR11R12; dans lequel chaque R13 et R14 sont indépendamment choisis parmi l'hydrogène et alkyle en C1-4, ou R13 et R14 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 6 chaînons, qui contient un hétéroatome additionnel choisi parmi N et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi alkyle en C1-4 et acyle en C2-3.
 
10. Un composé selon l'une quelconque des revendications 1 à 9, dans lequel n est 1 ou 2 et chaque R10 est indépendamment choisi parmi halogène, alkyle en C1-4 et -NR11R12 ; ou deux R10 attachés à un atome de carbone commun forment un groupe oxo ; ou deux R10 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 3 à 5 chaînons, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi alkyle en C1-4 et halogène.
 
11. Un composé selon l'une quelconque des revendications 1 à 9, dans lequel n est 0.
 
12. Un composé selon la revendication 1, qui est choisi dans le groupe constitué de :

- N'-(4-fluorophényl)-1,5-diméthylpyrrolidine-2-carbohydrazide

- (R)-2-(2-(4-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (S)-2-(2-(4-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-fluoro-2-méthylphényl)hydrazine-1-carbonyl)pyrrolidine-1-carboxamide

- 2-(2-(3,5-difluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-(trifluorométhoxy)phényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-(trifluorométhyl)phényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-chloro-2-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-méthoxyphényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- 2-(2-(4-sulfamoylphényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (2S,4S)-4-fluoro-2-(2-(4-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboxamide

- (R)-1-acétyl-N'-(4-fluorophényl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1-hydroxypyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1,2-diméthylpyrrolidine-2-carbohydrazide

- 2-(2-(4-fluorophényl)hydrazinecarbonyl)-N,N-diméthylpyrrolidine-1-carboxamide

- N'-(4-fluorophényl)-1-(pipérazine-1-carbonyl)pyrrolidine-2-carbohydrazide

- 1-(4-acétylpipérazine-1-carbonyl)-N'-(4-fluorophényl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1-(morpholine-4-carbonyl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1-méthyl-5-oxopyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1-méthylpyrrolidine-2-carbohydrazide

- 4-amino-N'-(4-fluorophényl)-1-méthylpyrrolidine-2-carbohydrazide

- 4-fluoro-N'-(4-fluorophényl)-1-méthylpyrrolidine-2-carbohydrazide

- (S)-1-(cyclopropylméthyl)-N'-(4-fluorophényl)pyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-3-méthyl-3-azabicyclo[3.1.0]hexane-2-carbohydrazide

- N'-(4-fluorophényl)-1,4-diméthylpyrrolidine-2-carbohydrazide

- N'-(4-fluorophényl)-1,3-diméthylpyrrolidine-2-carbohydrazide

- 1-éthyl-N'-(4-fluorophényl)pyrrolidine-2-carbohydrazide

- 2-(2-(4-fluorophényl)hydrazinecarbonyl)pyrrolidine-1-carboximidamide ou un sel ou un solvate pharmaceutiquement acceptable de celui-ci.


 
13. Un composé de formule (I) :

ou un sel ou un solvate pharmaceutiquement acceptable de celui-ci,

R1 et R2 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et hydroxyalkyle en C1-4 ;

R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, -OH, halogène, alcoxyle en C1-6, halogénoalcoxyle en C1-4, -cycloalkyle en (OC3-6)-(alkyle en C0-4), alkyle en C1-6, (cycloalkyle en C3-6)-(alkyle en C0-4), halogénoalkyle en C1-6, hydroxyalkyle en (C1-6), (alcoxyle en C1-4)-(alkyle en C1-6), (alcoxyle en C1-4)-(alcoxyle en C1-4), -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, —NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN et -CO2R11 ; ou deux de R3 à R7 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 5 ou 6 chaînons, où 1 ou 2 groupes méthylène du cycloalkyle peuvent être remplacés par O, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs groupes alkyle en (C1-4) ou halogénoalkyle en (C1-4) ;

R8 est choisi parmi -OH, alkyle en C1-6, halogénoalkyle en C1-6, hydroxyalkyle en C1-4, (alcoxyle en C1-4)-(alkyle en C0-4), (cycloalkyle en C3-6)-(alkyle en C0-4), -C(O)(alkyle en C1-4), -(C(O)cycloalkyle en C3-6)-(alkyle en C0-2), -CONR13R14, -C(NR15)NR11R12 et -CO2R11 ;

Rg est choisi parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4 ;

n est 0, 1, 2, ou 3 ;

chaque R10, s'il est présent, est indépendamment choisi parmi -OH, halogène, alkyle en C1-6, halogénoalkyle en C1-6, alcoxyle en C1-6, (alcoxyle en C1-4)-(alkyle en C1-6), -cycloalkyle en (OC3-6)-(alkyle en C0-4), -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phényle, anneau hétéroaryle à 5 ou 6 chaînons comprenant 1 ou 2 hétéroatomes choisis parmi N, O et S ; où ledit phényle et ledit anneau hétéroaryle peuvent être facultativement substitués par un ou plusieurs groupes alkyle en C1-4 ou halogénoalkyle en C1-4 ; ou deux R10 attachés à un atome de carbone commun forment un groupe oxo ; ou deux R10 attachés à un atome de carbone commun forment un spirocycloalkyle en C3-6, ou deux R10 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 3 à 6 chaînons, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, alcoxyle en C1-4, halogénoalkyle en C1-4 et halogène ;

chaque R11 et R12 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) ;

chaque R13 et R14 sont indépendamment choisis parmi l'hydrogène, alkyle en (C1-4), (cycloalkyle en C3-6)-(alkyle en C0-4) et Het3-6, où chaque alkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) peuvent être facultativement substitués par un ou plusieurs R16, et où chaque (alkyle en C1-4) peut être facultativement substitué par un ou plusieurs Het3-6 ; ou R13 et R14 forment, conjointement avec l'atome de N atome auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, halogénoalkyle en C1-4 et -C(O)-(alkyle en C1-4) ;

R15 est choisi parmi l'hydrogène, alkyle en C1-6, halogénoalkyle en C1-6, -CN, -CONR11R12, -S(O2)R11, -SOR11 et -S(O2)NR11R12 ;

chaque R16 est indépendamment choisi parmi alkyle, halogène, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R18 et -OCOR11 ;

Het3-6 est un anneau hétérocyclique monocyclique saturé à 3 à 6 chaînons contenant un hétéroatome choisi parmi O, S et N, où ledit anneau est lié au reste de la molécule à travers un atome C disponible quelconque et où ledit anneau peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 ou halogénoalkyle en C1-4 ; et

chaque R17 et R18 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4, ou R17 et R18 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 et halogénoalkyle en C1-4 ;

pour l'utilisation comme un médicament.


 
14. Un composé selon l'une quelconque des revendications 2 à 12 pour l'utilisation comme médicament.
 
15. Un composé pour l'utilisation selon l'une quelconque des revendications 13 ou 14, pour l'utilisation comme agent antibactérien pour le traitement ou la prévention d'infections causées par A. baumannii.
 
16. Une composition pharmaceutique comprenant un composé de formule (I) :

ou un sel ou un solvate pharmaceutiquement acceptable de celui-ci,

R1 et R2 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et hydroxyalkyle en C1-4 ;

R3, R4, R5, R6 et R7 sont indépendamment choisis parmi l'hydrogène, -OH, halogène, alcoxyle en C1-6, halogénoalcoxyle en C1-4, -cycloalkyle en (OC3-6)-(alkyle en C0-4), alkyle en C1-6, (cycloalkyle en C3-6)-(alkyle en C0-4), halogénoalkyle en C1-6, hydroxyalkyle en (C1-6), (alcoxyle en C1-4)-(alkyle en C1-6), (alcoxyle en C1-4)-(alcoxyle en C1-4), -OCOR11, -OS(O2)R11, -NR11R12, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CONR11R12, -S(O2)NR11R12, -S(O2)R11, -CN et -CO2R11 ; ou deux de R3 à R7 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 5 ou 6 chaînons, où 1 ou 2 groupes méthylène du cycloalkyle peuvent être remplacés par O, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs groupes alkyle en (C1-4) ou halogénoalkyle en (C1-4) ;

R8 est choisi parmi -OH, alkyle en C1-6, halogénoalkyle en C1-6, hydroxyalkyle en C1-4, (alcoxyle en C1-4)-(alkyle en C0-4), (cycloalkyle en C3-6)-(alkyle en C0-4), -C(O)(alkyle en C1-4), -(C(O)cycloalkyle en C3-6)-(alkyle en C0-2), -CONR13R14, -C(NR15)NR11R12 et -CO2R11 ;

Rg est choisi parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4 ;

n est 0, 1, 2, ou 3 ;

chaque R10, s'il est présent, est indépendamment choisi parmi -OH, halogène, alkyle en C1-6, halogénoalkyle en C1-6, alcoxyle en C1-6, (alcoxyle en C1-4)-(alkyle en C1-6), -cycloalkyle en (OC3-6)-(alkyle en C0-4), -SR11, -NR11R12, -OCOR11, -OS(O2)R11, -NR11COR12, -NR11CO2R12, -NR11S(O2)R12, -OCONR11R12, -CN, phényle, anneau hétéroaryle à 5 ou 6 chaînons comprenant 1 ou 2 hétéroatomes choisis parmi N, O et S ; où ledit phényle et ledit anneau hétéroaryle peuvent être facultativement substitués par un ou plusieurs groupes alkyle en C1-4 ou halogénoalkyle en C1-4 ; ou deux R10 attachés à un atome de carbone commun forment un groupe oxo ; ou deux R10 attachés à un atome de carbone commun forment un spirocycloalkyle en C3-6, ou deux R10 attachés à des atomes de carbone adjacents sont connectés en formant un cycloalkyle à 3 à 6 chaînons, ledit cycloalkyle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, alcoxyle en C1-4, halogénoalkyle en C1-4 et halogène ;

chaque R11 et R12 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4, halogénoalkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) ;

chaque R13 et R14 sont indépendamment choisis parmi l'hydrogène, alkyle en (C1-4), (cycloalkyle en C3-6)-(alkyle en C0-4) et Het3-6, où chaque alkyle en C1-4 et (cycloalkyle en C3-6)-(alkyle en C0-4) peuvent être facultativement substitués par un ou plusieurs R16, et où chaque (alkyle en C1-4) peut être facultativement substitué par un ou plusieurs Het3-6 ; ou R13 et R14 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4, halogénoalkyle en C1-4 et -C(O)-(alkyle en C1-4) ;

R15 est choisi parmi l'hydrogène, alkyle en C1-6, halogénoalkyle en C1-6, -CN, -CONR11R12, -S(O2)R11, -SOR11 et -S(O2)NR11R12 ;

chaque R16 est indépendamment choisi parmi alkyle, halogène, -CN, -CO2R11, -OR11, -SR11, -NR17R18, -CONR17R8 et -OCOR11;

Het3-6 est un anneau hétérocyclique monocyclique saturé à 3 à 6 chaînons contenant un hétéroatome choisi parmi O, S et N, où ledit anneau est lié au reste de la molécule à travers un atome C disponible quelconque et où ledit anneau peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 ou halogénoalkyle en C1-4 ; et

chaque R17 et R18 sont indépendamment choisis parmi l'hydrogène, alkyle en C1-4 et halogénoalkyle en C1-4, ou R17 et R18 forment, conjointement avec l'atome de N auquel ils sont attachés, un hétérocycle saturé à 4 à 6 chaînons, qui peut contenir facultativement un hétéroatome additionnel choisi parmi N, S et O, ledit hétérocycle peut être facultativement substitué par un ou plusieurs substituants indépendamment choisis parmi un alkyle en C1-4 et halogénoalkyle en C1-4 ;

et au moins un excipient et/ou véhicule pharmaceutiquement acceptable.


 
17. Un procédé de préparation d'un composé de la revendication 1, comprenant faire réagir un composé de formule (II)

avec un composé de formule (III) ou un sel ou solvate pharmaceutiquement acceptable de celui-ci,

où R16 es hydrogène ou un alkyle en C1-4, R17 est hydrogène ou R8, et n et R1 à R15 ont la signification décrite dans la revendication 1.
 






Cited references

REFERENCES CITED IN THE DESCRIPTION



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Patent documents cited in the description




Non-patent literature cited in the description