Antibacterial agents of 2-pyrrolidinylphenylhydrazides (Machine-translation by Google Translate, not

专利摘要:
Agentes antibacterianos de 2-pyrrolidin phenylhydrazidas. The present invention relates to 2-pyrrolidin phenylhydrazide compounds of formula (I), which are selective antibacterials specifically against acinetobacter baumannii. The invention also relates to its therapeutic use as antibacterials, to a process for its preparation and to pharmaceutical compositions containing them. (Machine-translation by Google Translate, not legally binding)
公开号:ES2651943A1
申请号:ES201700452
申请日:2017-03-30
公开日:2018-01-30
发明作者:Albert Palomer Benet；Domingo Gargallo Viola
申请人:Abac Therapeutics S L；Abac Therapeutics SL；
IPC主号:

专利说明:

Antibacterial agents of 2-oirrolidin phenylhydrazides
The present invention relates to new antibacterial agents, particularly 2-pyrrotidine phenylhydrazide compounds that show selective antibacterial activity against the Gram-negative bacterium Acinetobacter baumannií.
STATUS OF THE TECHNIQUE Infections caused by bacteria Acinetobacter baumannii (A. baumannit) are increasingly being recognized as a serious health risk, especially in health care facilities, and are associated with increased morbidity, mortality and duration of the hospital stay, as well as with high health care costs (Giamarellou el al. Acinetobacler baumanníi: a universal threat lo public health Int. J. Antimicrob. Agents, 2008, 32 (2), 106-9; Howard el al. Acinetobacter baumannii. An emerging opporlunistic pathogen. Virulence 2012, 3 (3), 243-250).
A. baumannii is a Gram-negative rod-shaped bacillus that is aerobic and not mobile. It behaves like an opportunistic pathogen that primarily affects immunocompromised subjects, for example those who have an underlying disease, such as chronic lung disease or diabetes, and those hospitalized for long periods and undergoing multiple invasive procedures.
A. baumannii is frequently involved in in-hospital infections, so it has a high incidence among patients experiencing a 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 used in hospital settings, such as dialysis, mechanical ventilation, sutures or catheters, due to the known ability of A baumannii to survive for prolonged periods on environmental surfaces.
A baumannii can cause infections in virtually all human body organ systems, including pneumonia, surgical site infections, skin and soft tissue infections, urinary tract infections, postoperative meningitis and catheter-related infections.
Hospital acquired pneumonia is the most common life-threatening infection acquired in hospitals, and it 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.
Bloodstream infections (BSI) are also common hospital infections, which are also associated with increased morbidity, mortality and length of hospital stay. Infections caused by Acinetobacter correspond to 2% of total BSI cases, with a particularly high incidence of BSI acquired in the ICU.
Other infections acquired in indicated hospitals associated with A. baumanníi are, for example, surgical site infections (ISO) and urinary tract infections, such as urinary tract infections associated with catheters (lTUAC) or urinary tract infections acquired in hospitalization.
A. baumannii infections are currently treated with different broad-spectrum antibiotics or semi-broad spectrum or combinations, including, for example, carbapenemics imipenem, meropenem and doripenem, which are drugs of first choice. However, the treatment of A. baumannii infections is difficult as it has emerged as a highly drug-resistant pathogen, especially resistant to carbapenems, and therefore other alternative broad-spectrum antibacterials, such as polymyxins, are also used in therapy. colistin, polymyxin E and polymyxin B), tigecycline, tetracyclines (minocycline and doxycycline) or aminoglycosides (amicacin and tobramycin). None of the commonly used treatments are specific for A. baumannii.
The use of such broad-spectrum antibacterials implies significant disadvantages, since they have an important influence on normal flora, potentially decreasing the microbiota's immune function and potentially generating treatment-induced coinfections caused by resistant strains, as disclosed in Jernberg for example et al. Long ~ term impacts o (antibiotic exposure on the human intestinal microbiota, Microbiology, 2010, 156 (Pt 11), 3216-3223.
In addition, in a retrospective study conducted with 26,107 patients, it was concluded that the use of broad-spectrum antibiotics may be related to the development of irritable bowel syndrome (Sil), as disclosed in Villarreal
the al. Use o (broBd-spectrum antíbiotics and the deve / opment o (irritabfe bowef syndrome, WMJ, 2012, 111 (1), 17-20.
As previously mentioned, when broad-spectrum antibiotics are used, not only can the pathogenic organism develop resistance, but any other microorganism present in the treated subject (either human or animal) can develop it. The latter usually happens if the antibiotic is moderately active, but not lethal to the microorganism. It is also known in the state of the art that when a microorganism develops a resistance to a drug it is capable of transferring said resistance to other members of its species or even transferring said resistance to other species, this is known as Horizontal Gene Transfer (HGT acronym for Horizontal Gene Transfer), as disclosed in Wintersdorff, et al. Dissemination 01 Antimicrobial Resistance in Microbiaf Ecosystems through Horizontal Gene Transler, Front MicrobioL 2016, 7: 173. Therefore, it is an advantage of the specific treatment of pathogens that the generation of resistance in the pathogenic species cannot be carried out by this two-step process, that is, first that occurs in another microorganism and then transferred by HGT to the pathogenic spice.
On the contrary, treatments using pathogen-specific antibacterials that exclusively destroy infectious bacteria would minimize the impact on normal flora and prevent the selection of resistant strains of non-infectious microbiota bacteria, thereby minimizing any treatment-induced comorbidity and reducing the Horizontal transfer of genes between species.
The only selective antibacterial agents for Acinetobacter baumannii disclosed to date in the state of the art are a series of arylhydrazides containing a 2-pyridone moiety, as disclosed in the international patent application W02016 / 016291-A 1.
Therefore, it would be desirable to provide new compounds that are selective antibacterial agents against Bainmanni Acinelobacler bacteria, to thereby increase the number of currently available selective drugs. which are both effective for the treatment of life-threatening infections caused by A. baumannii and highly selective for these bacteria, to avoid the disadvantages associated with the non-selective broad-spectrum antibiotics currently used in therapy.
OBJECT OF THE INVENTION The object of the present invention is a compound of formula (1) as defined below.
A second aspect of the present invention relates to the compound of formula (1) for use as a medicament. A third aspect of the present invention relates to a compound of formula (1) for use as an antibacterial agent, particularly for the treatment or prevention of A baumannii infections.
A fourth aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (1) and at least one pharmaceutically acceptable excipient and / or vehicle.
A fifth aspect of the present invention relates to a process for preparing compounds of formula (1).
DETAILED DESCRIPTION OF THE INVENTION In a first aspect, the present invention relates to a compound of formula (1):
15 (1)
or a pharmaceutically acceptable salivate salt thereof,whereR, and R2 are independently selected from hydrogen, C alkyl, ..... haloalkyl C, "" 'and hydroxyalkyl e, ....;
R3, R ", Rs, Rs and R1 are independently selected from hydrogen, -OH, halogen. Alkoxy e, -s. Haloalkoxy e, ...., -O-cycloalkyl e3-6a1 alkyl and o..t, alkyl C, -EI. Cycloalkyl Clsalkyl CI) -4, haloalkyl C, -EI. Hydroxyalkyl C, -EI. Alkoxy C, .... alkyl C, -e, alkoxy C, .... alkoxy C, - <I . -OCORll, -OS (0 2) Rll • -NR "R'2, -NR" COR'2, -NRll C02R'2, -NRl1 S (02) R'2, -OCONR "R12, -CONR" R12, -S (02) NR I1 R'2. -S (02) R ". -eN and -e02Rl1: or two of R3 a
25 R7 attached to adjacent carbon atoms are connected to form a 5 or 6 membered cycloalkyl, where 1 6 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl may be optionally substituted with one or more C'-4 alkyl or haloalkyl C, ....; Rs is selected from -OH, C'-EI alkyl, C'-EI haloalkyl, C hydroxyalkyl, .., C, alkoxy.
30. CQ-4 alkyl, C3-6 cycloalkyl CQ-4 alkyl, C2 • S, -C (O) C3-6a1-C0-2 cycloalkyl, -CONR13R, •. -C (NR, s) NR "R,: AND -C02Rl1;
Rg is selected from hydrogen, Cl ..- alkyl and haloalkyl C, ..-:n is 0, 1, 2 6 3;each R, or, if present, is independently selected from -OH, halogen,
alkyl C, -6, haloalkyl C, -6, alkoxy C, -6, alkoxy C, ..- alkyl C1-6, -O-cycloalkyl alkylCQ- <I, -SRll, -NR "R12, -OCORn, -OS (02) R11, -NR" eOR'2, -NR1 e0 2RI2,-NR11 S (02) RI2, -oeONR'IRI2, -eN, phenyl, 5- or 6-membered heteroaryl ring thatit comprises 1 or 2 heteroatoms selected from N, O and S; where said phenyl andsaid heteroaryl ring may be optionally substituted with one or more alkyle l "" 'or haloalkyl e 1 -'1: or two R10 attached to a common carbon atom form an oxo;or two R10 attached to a common carbon atom form a cycloalkyl spiro CH, ortwo R10 attached to adjacent carbon atoms are connected to form a3 to 6-membered cycloalkyl, said cycloalkyl may be optionally substitutedwith one or more substituents independently selected from C1 alkyl ....,haloalkyl Cl -4 and halogen:each RlI and R12 is independently selected from hydrogen, Cl-4 alkyl,haloalkyl e 1-4 and cycloalkyl Cu; C ~ alkyl;each R13 and R, ~ is independently selected from hydrogen, Cl-4 alkyl,cycloalkyl e3-6alkyl CO.o and Hetu, where each C1-1 alkyl and cycloalkyl CHalkyl CO.o it may be optionally substituted with one or more R16, and where each alkyl the ""it may be optionally substituted with one or more HetH: or R13 and RH form, togetherwith the N atom to which they are attached, a saturated 4- to 6-membered heterocycle,which may optionally contain an additional heteroatom selected from N, SAnd 0, said heterocycle may be optionally substituted with one or moresubstituents independently selected from alkyl e, "", haloalkyl C, .... andC2-S acyl;R1S is selected from hydrogen, C alkyl, -6, haloalkyl C, -6, -CN, -CONR1 RI2,
-S (02) R11, -SOR1, and -S (02) NR11 RI2:each R16 is independently selected from alkyl, halogen, -CN, -e0 2Rll,-ORII, -SRl1, -NR17R '$, -CONR17RI8 and -OeOR11:Hetu is a 3 to 6-membered saturated monocyclic heterocyclic ring containing
a heteroatom selected from O, S and N, where said ring is linked to the restof the molecule through any available e atom and where said ring canbe optionally substituted with one or more selected substituentsindependently between alkyl the .... or haloalkyl e l ....: andeach R17 and R18 is independently selected from hydrogen, alkyl e, .... and
haloalkyl e '-4, or Rl1 and R, together with the N atom to which they are attached, form a 4 to 6 membered saturated heterocycle, which may optionally contain an additional heteroatom selected from N, 5 YO, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e, ... and haloalkyl e, ...: and where the following products are excluded: 1,2-pyrrolidinedicarboxylic acid, 1- (1,1-dimethylethyl ) ester, 2- (2-phenylhydrazide), (2S) -, 1,2-pyrrolidindicarboxylic acid, 1- (1,1-dimethylethyl) ester, 2- (1-methyl-2-phenylhydrazide), (2S) - , 1,2-pyrrolidindicarboxylic acid, 4-mercapto-, 1- (1,1-dimethylethyl) ester, 2- [2- [3 (aminosulfonyl) phenyl] hydrazide], (25,45) -, 1,2 acid -pyrrolidindicarboxylic, 4-mercapto-, 1- (1,1-dimethylethyl) ester, 2- [2- (3-carboxyphenyl) hydrazide), (25,45) -, 1,2-pyrrolidindicarboxylic acid, 4-mercapto-, 1 - (1,1-dimethylethyl) ester, 2- {2- [2 (trifluoromethyl) phenyl) hydrazide), (25,45) -, and 1,2-pyrrolidinedicarboxylic acid, 4-mercapto-, 1- (1,1-dimethylethyl) ester, 2- [2- [2-chloro-5 (trifluoromethyl) phenyl) hydrazide), (25,45) -.
The authors of the present invention have developed a group of phenylhydrazide compounds containing a 2-pyrrolidine moiety as depicted in formula (1) which, surprisingly, show antibacterial activity against Acinetobacter baumannii (A. baumannii) Gram-negative bacteria , thus providing a new and safer therapeutic tool to treat infections caused by this bacterium, while avoiding damage to the intestinal flora and multiple resistances involved with treatment with broad-spectrum antibacterials.
In addition, not only the compounds of formula (1) are highly active and the antibacterials selective against A. baumannii, as determined by in vitro tests, or not that are also highly stable in blood plasma, so they are expected to maintain its antibacterial activity in vivo, in the same way.
The following compounds are excluded from the first aspect of the present invention:
• 1,2-pyrrolidindicarboxylic acid, 1- (1,1-dimethylethyl) ester, 2- (2-phenylhydrazide), (25) - (CA5 474316-85-3)
• 1,2-pyrrolidindicarboxylic acid, 1- (1,1-dimethylethyl) ester, 2- (1-methyl-2
phenylhydrazide), (2S) - (CAS 1361235-82-6)
• 1,2-pyrrolidindicarboxylic acid, 4-mercapto-, 1- (1,1-dimethylethyl) ester, 2- (2- (3 (aminosulfonyl) phenylhydrazide), (2S, 4S) - (CAS 1188957-98-3)
• 1,2-pyrrolidindicarboxylic 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-pyrrolidindicarboxylic acid, 4-mercapto-, 1- (1,1-dimethylethyl) ester, 2- [2- [2
Chloro-5- (trifluoromethyl) phenyl] hydrazide1, (2S, 4S) - (CAS 1188958-04-4) These compounds have been described in the following prior art documents: Liu el 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 described only as reaction intermediates, but their medical use is not described or suggested in the prior art.
Definitions
Within the meaning of the present invention, the expression C, -a alkyl, as a group or part of a group, means a linear or branched alkyl chain containing from 1 to 6 carbon atoms and includes, among others, the groups methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tare-butyl, n-pentyl, isopentyl
or n-hexyl. Similarly, the expression alkyl e, ..., as a group or part of a group, means a linear or branched alkyl chain containing 1 to 4 carbon atoms and is a subgroup of alkyl e, -6 which includes methyl groups. ethyl, npropyl, isopropyl, n-butyl, isobutite, sec-butite and tere-butyl. Similarly, the term "alkyl" e, _2 means an alkyl chain containing 1 or 2 carbon atoms and includes the methyl and ethyl groups.
Halogen or its abbreviation halo means fluorine, chlorine, bromine or iodine.
A haloalquito group e'-6 means a group resulting from the replacement of one or more hydrogen atoms of a C, -6 alkyl group with one or more halogen atoms (i.e., fluorine, chlorine, bromine or iodine), which may Be the same or different. Examples include, among others, the fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoropropyl, 2-fluoropropyl , 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, undecafluoropenyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6yodohexyl. Similarly, the haloalkyl group C, .04 means a group resulting from the replacement of one or more hydrogen atoms of an alkyl group e, .... with one or more halogen atoms (ie, fluorine, chlorine, bromine or iodine), which can be the same
or different, and is a subgroup of haloalkyl C, -6. Examples include, among others, the fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl groups. chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-f1uoroethyl, 2chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-f1uoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 3-chloropropyl, 3-chloropropyl, 3-chloropropyl, 3-chloropropyl 3-dichloropropyl, 4-fluorobutyl. 4-chlorobutyl, 4-bromobutyl and nonafluorobutyl.
A C-6 hydroxyalkyl group means a group resulting from replacement.
'of one or more hydrogen atoms of a C-6 alkyl group by one or more groups'
hydroxy Examples include, among others, the hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl groups , 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 hydroxyalkyl group C, .... means a group resulting from the replacement of one or more hydrogen atoms of a C alkyl group, .04 by one or more hydroxy groups, and is a subgroup of the hydroxyalkyl group C , -6. Examples of the C.04 hydroxyalkyl group include, for example, hydroxymethyl, 1
'hydroxyethyl0, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 2-hydroxybutyl and 1-hydroxybutyl,
A C2 • S acyl group means a group of formula -C (O) C1.04 alkyl,
where the C alkyl moiety, .... has the same meaning as described above. Examples include, among others, acetyl, propanoyl, n-butanoyl, sec-butanoyl, tertbutanoyl, or n-pentanoyl. Similarly, a C2_3 acyl group means a group of formula -C (O) C2 alkyl, where the C'_2 alkyl moiety has the same meaning as described above. Examples include acetyl and propanollo,
A C-6 alkoxy group, as a group or part of a group, means a
'group of formula -O-C-6 alkyl, where the alkyl radical Cl-6 has the same meaning
'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, an alkoxy group e, ..... as a
group or part of a group, means a group of formula -Oalkyl C, ~, where the alkyl moiety e ,,,,,, has the same meaning as described above and is a subgroup of alkoxy C, -6 which includes , for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
An alco> cj C group, ... alkoxy e, ... means a group resulting from the replacement of a hydrogen atom of an alkoxy group e, ... with an alkoxy group e, ..., as has been 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.
A haloalkoxy group e, ... means a group resulting from the replacement of one or more hydrogen atoms of an alkoxy group e, ... with one or more halogen bonds (ie, fluorine, chlorine, bromine or iodine), They can be the same or different. Examples include. among others, the fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-bromoethoxy, 2-fluorophoxy , 2,3-difluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutmci.
An alkoxy group e, ... C, 06 alkyl means a group resulting from the replacement of one or more hydrogen atoms of an alkyl group '06 by one or more alkoxy groups e, ... as defined above, which They can be the same or different. Examples include, among others, the methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, tere-butoxymethyl, dimethoxymethyl, 1-methoxyethyl groups. 2-methoxyethyl, 2-ethoxyethyl, 1,2-diethoxyethyl, 1-butoxyethyl, 2-sec-butoxyethyl, 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-fere-butoxypropyl, 4-methoxybutyl, 5- methoxypentyl, 4-ethoxypentyl0 and 2-methoxy-3methylpenyl. Similarly, a C alkoxy group, ... alkyl the ... means a group resulting from the replacement of one or more hydrogen atoms of an alkyl group e, ... by one O more C alkoxy groups, .. As defined above, and is a subgroup of the C1 alkoxy group, alkyl and 1.fi. Examples of C-alkoxy, ... alkyl, etc. include, among others, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl, sec-butoxymethyl, ferc-butoxymethyl, dimethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 2- ethoxyethyl0, 1,2-diethoxyethyl. 1-butoxyethyl, 2-sec-butoxyietite. 3-methoxypropyl, 2-butoxypropyl, 1-methoxy-2-ethoxypropyl, 3-tert-butoxypropyl and 4-methoxybutyl.
A cycloalkyl group el.f, as a group or as part of a group, means a monocyclic saturated hydrocarbon ring group comprising from 3 to 6 carbon atoms, which may be optionally substituted with one or more substituents independently selected from C, ~ alkyl, C, alkoxy, and halogen, that is, one or more ring hydrogen atoms may be replaced by a C, ~ alkyl, a C alkoxy, ~ or a halogen. When there is more than one substitution, the substituents may be the same or different. Examples of cycloalkyl Cu groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
A cycloalkyl group Cu C, ~, as a group or as part of a group, means a group resulting from the replacement of a hydrogen atom of a C-alkyl group, ~ with a cycloalkyl group Cu, as defined above. Examples include, among others, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopentylpropyl and 4-cyclopentylbutan-2-yl. Similarly, a C'.2 cycloalkyl or C2 alkyl group, as a group or as part of a group, means a group resulting from the replacement of a hydrogen atom of a C'.2 alkyl group by a C3 cycloalkyl group -6, as defined above, is a subgroup of the cycloalkyl Cu C alkyl group, ~, including, among others, the following examples: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl0, cyclopentylethyl0, and cyclohexylethylJo. Thus, for example, the group -C (O) C3-6 cycloalkylJ C'.2 alkyl means a group resulting from the replacement of a hydrogen atom of a group -C (O) alkyl
C'.2 by a cycloalkyl group Cu. Similarly, the group -O-cycloalkyl CHalkyl C, ~ means a group resulting from the replacement of a hydrogen atom of a group -Oalkyl Cl "", by a cycloalkyl group CH.
The term "alkyl Co" indicates that the alkyl group is absent.
Thus, for example, the expression C3-6 cycloalkyl CQ-4 alkyl includes Cu cycloalkyl and C3-6 cycloalkyl C ,,,,,,, as defined above, and the expression cycloalkyl CH C0-2 alkyl includes CJ.tI cycloalkyl and cycloalkyl C) .tyalkyl C, _2. Similarly, the expression -C (O) C3-6a1 -C1 -alkyl alkyl includes C (O) Cu -Cycloalkyl and -C (O) C'2 -cycloalkyl Cu and the expression -O-C6 -C6 -alkyl-alkyl includes -O-C3-6 cycloalkyl and -O-C3-6 cycloalkyl C ,,,,,,.
Similarly, the expression C-alkoxy, Cn-6 alkyl includes CH alkoxy and C-alkoxy ,,,,,, C-alkyl, -8 as defined above.
A group "oxo ~ means = 0.
A group "methylene ~ means -CH; r.
The term "saturated ~" refers to groups that have no double or triple bond.
Any carbon atom, as well as any heteroatom with valences not satisfied in the formulas and schemes represented in the present description, is assumed to have a sufficient number of hydrogen atoms to satisfy the valences.
The term "optionally substituted with 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, with the condition that the group has sufficient available positions that can be substituted, that is, sufficient hydrogen atoms available for
10 replacement by a substituent. When more than one substituent is present, these may be the same or different and may be placed in any available position. In the compounds of formula (1), the variable junction point represented by the R substituents, or means that, if present, each R, or may be attached to any one of the three available positions of the ring of
Pyrrolidine capable of being substituted, that is, having hydrogen atoms available for replacement by an R, or, as shown by an asterisk (.) In the following figure. Each of the three labeled carbon atoms of the pyrrolidine ring has two hydrogens, whereby each of the labeled carbon atoms can have up to two substituents R, or, or two R, or attached to an atom of
Common carbon may form an oxo group, or two R's, or attached to a common carbon atom form a cycloalkyl Cu spiro. If more than one R, or is present, unless they form an oxo group or a cycloalkyl spiro, preferably they are not attached to the same carbon atom of the pyrrolidine ring. OR GO ,, ~
. (X 'R I ..- N '
. ,
R,
A 5 6 6 membered heteroaryl ring comprising 1 6 2 hetero atoms selected from N, OYS, as used in the present invention, includes, for example, pyridine, pyridazine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole rings and liazol. In the definition of the formula (1) above, two groups of R3 to Rr joined
30 adjacent carbon atoms of the phenyl ring can be connected to form a 5-6 membered cycloalkyl, where 1 or 2 cycloalkyl methylene groups can be replaced by O. Said cycloalkyl is, therefore, fused to the phenyl ring in the formula (one); Examples of said fused cycloalkyl rings include, but are not limited to, the following: / o /
one'"
IxX
R, Ro R, Ro R7 h R5 R, RoR, R,
'" / o /
or / * 0 R, l .ij
R, Ro R, Ro R7 R5 R, '"'" '"'"
R, R, R, or
or R, : *>: "': *)
R, R,
'"'"
In the definition of formula (1) above, two Rs, or attached to adjacent carbon atoms of the pyrrolidine ring may be connected to form a
5 cycloalkyl of 3 to 6 members. Said cycloalkyl is, therefore, condensed to the pyrrolidine ring in the formula (1); Examples of said fused cycloalkyl rings include the following:
In the definition of the formula (1) above, R'3 and R ,. can form together
10 with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heterocycly selected from N, SY 0, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e '- <4, haloalkyl e, - <4 and acyl e2_S, that is, one or more hydrogen atoms of the ring may be replaced by a Ct-4 alkyl, Ct-4 haloalkyl or C2_S acyl, the substitution may be in an atom of e or an atom of N, if present. Examples of such heterocycles include azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, among others.
Similarly, R17 and R18 may form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heleroatom selected from N, SY 0, said heterocycle may optionally be substituted with one O more substituents independently selected from Cl ~ alkyl and haloalkyl Cl ~, that is, one O more hydrogen atoms in the ring may be replaced by a C 1-4 alkyl or haloalkyl Cl ~, the substitution may be in an atom of C or an atom of N, if present. Examples of such heterocycles include azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, among others.
Throughout the description of the present invention, it is understood that when any variable (for example, C1-6 alkyl, CI-4 alkyl, Cl ~ alkoxy etc.) appears more than once in a compound of formula ( 1), its definition in each occurrence is independent of its definition in any other occurrence, so the variable may be the same or different on each occasion.
Similarly, when a variable group, such as Rto, R11 or R12, appears more than once in a compound of formula (1), its definition in each occurrence is independent of its definition in any other occurrence, so that Variable group is independently selected from their possible meanings at each occurrence, and may have the same or different meanings on each occasion. This can be indicated by the expression Mcada one independently selected from ~.
Similarly, the expression ~ independently selected from ~ applies to the definition of a group of different variable groups (for example, R3, R ~. R5, R6 and R7), means that the definition of each variable in that group It is independently selected from the definition of any other variable in the same group, and can have the same meaning or different meanings.
Compounds of the invention
Also included within the scope of the invention are pharmaceutically acceptable salts, solvates, isotopes, stereoisomers and polymorphs of compounds of formula (1). Therefore, any reference to a compound of formula
(1) throughout this specification includes a reference to any salt
Pharmaceutically acceptable, solvate, isotope or polymorph of such a compound of
Formula 1).
The compounds of formula (1) have one or more asymmetric centers or
chiral and therefore exist in different stereoisomeric forms. The intention is to
5 that all stereoisomeric forms of the compounds of formula (1), including
diastereomers, enantiomers, as well as mixtures thereof, such as mixtures
racemic, be part of the invention.
The compounds of the invention contain basic nitrogen atoms and
they can, therefore, form salts with organic or inorganic acids. The expression
1O ~ pharmaceutically acceptable salts as used herein, encompasses
any salt without any · Imitation on the type of salt that can be used, with the
condition that these are acceptable for administration to a patient, which
means that they do not induce excessive toxicity, irritation, allergic responses, or
Similar. Pharmaceutically acceptable salts are well known in the art.
fifteen For example, pharmaceutically acceptable salts suitable for
used in the present invention include those obtained from the following
acids: hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic acids. adipic
aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric,
glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1.5
twenty naphthalenedisulfonic, oxalic, pivotal, propionic, p.toluenesulfónico, succcfnico and
Tartaric, and the like. Hydrochloric acid is preferred.
The salts of a compound of formula (1) can be obtained, by
example, during the final isolation and purification of the compounds of the invention,
or they can be prepared by treating a compound of formula (1) with a sufficient amount
25 of the desired acid to give the salt in a conventional manner
The term ~ solvatosft as used herein, encompasses
a combination of a compound of formula (1) with solvent molecules,
linked by a non-covalent bond. Solvent molecules well
known that are capable of forming sotvates include water, alcohols and others
30 polar organic solvents. When the solvate is formed with water, it is also
known as a hydrate.
The term "isotopepos as used herein encompasses
any isotopically labeled form of the compounds of formmu la (1), where one
or more atoms are replaced by an atom that has the same atomic number,
35 but an atomic mass or mass number different from the atomic mass or number
mass that is normally found in nature. Examples of isotopes that
may be incorporated into the compounds of the invention include hydrogen isotopes, such as 2H and 3H, carbon, such as "c, 13C and '~ C, chlorine, such as 36CI. fluorine, such as 18F, iodine, such as 1231 and 1251 , nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, and sulfur, such as 35. Those isotopically labeled compounds are useful, for example, in metabolic or kinetic studies, particularly those marked with 2H, 3H, And HC In addition, substitution with heavier isotopes such as deuterium, 2H, can provide certain therapeutic advantages that result in increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
The isotopically labeled compounds of the invention can generally be prepared by methods analogous to those described herein, using a suitably labeled isotopic reagent instead of the unlabeled reagent that is otherwise employed.
The compounds of formula (1) may exist in different physical forms, that is, amorphous and crystalline forms. In addition, the compounds of the invention may have the ability to crystallize in more than one way, a feature 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 these physical forms of the compounds of formula (1), including all polymorphic polymorphic forms ~ ) are included within the scope of the invention.
In addition, any formula given herein is also intended to represent the corresponding tautomeric forms. ~ Tautomer "refers to alternative forms of a molecule that differ in the position of a proton. Examples include, among others, the amide · imic acid, ami na · imine and keto nol forms.
The first aspect of the invention is further defined by some specific and preferred embodiments as disclosed below. In one embodiment, the invention relates to a compound of formula (1)
or a pharmaceutically acceptable solvate salt thereof, where:R, and R2 are independently selected from hydrogen and C alkyl, "" ';R3, R ~, Rs, Rs and R7 are independently selected from hydrogen, -OH. halogen,C'-6 alkyl, cycloalkyl CH C0- <4 alkyl, -NRllR'2, C'-6 haloalkyl, C'-6 hydroxyalkyl,
Alkoxy CHalkyl CG-6, alkoxy C, ... alkoxy C, .... -CONR "R'2, -SOr NR1, R'2, and haloC,. ~ alkoxy, or two of R3 to R7 attached to atoms Adjacent carbon are connected to form a 5 or 6 membered cycloalkyl, where 1 or 2 meUlene groups of the
cycloalkyl may be replaced by 0, said cycloalkyl may beoptionally substituted with one or more alkyls e, ....;Ra is selected from -OH, C, -6 alkyl, haloalkyl and l-6, hydroxyalkyl ...., alkoxy e, _
C (I .- <II, cycloalkyl and 3-6C0-4alkyl, acyl e 2_S, -C (O) cycloalkyl and 3-6alkyl and o.2,-CONR13RH and -C (NR, s) NRllR'2:
Rg is selected from hydrogen and alkyl e, ....;n is 0, 1, 2 or 3;each R, or, if present, is independently selected from -OH, halogen.
C, -fi, alkoxy e, .... alkyl and o.fi, -SR "and -NR, IR, 2; or two R, or attached to an atom ofcommon carbon form an oxo; or two R, or attached to adjacent carbon atomsare connected to form a 3-6 membered cycloalkyl, said cycloalkylit may be optionally substituted with one or more selected substituentsindependently between alkyl and l .... and halogen;each R '1 and R12 are independently selected from hydrogen and alkyl e, ....;every R13 and R ,. are independently selected from hydrogen and alkyl e, ..... or R13and R14 together with the N atom to which they are attached, a saturated heterocycle of4 to 6 members. which may optionally contain an additional heteroatomselected from N and O, said heterocycle may be optionally substituted withone or more substituents independently selected from alkyl e, .... and acyl
e2_S; and R '5 is selected from hydrogen, C'-6 alkyl, haloalkyl e' -6, -eN, -CONR1, R, 2, -S02-RI1, -SO-R "and -SOr NR" R, 2.
In one embodiment, the invention relates to compounds of formula (1) wherein the phenyl ring has one, two or three substituents, that is, at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen .
In another embodiment, the invention relates to compounds of formula (1), wherein R1 and R2 are independently selected from hydrogen and methyl. In another embodiment, the invention relates to compounds of formula (1), wherein R, and R2 are hydrogen. In another embodiment, the invention relates to compounds of formmu (1), where one of R, and R2 is hydrogen and the other is alkyl e, ..... preferably is methyl.
In another embodiment, the invention relates to compounds of formula (1), wherein R, and R2 are alkyl e, ...., which are the same or different, preferably R, and R2 are the same C'-4 alkyl , and more preferably R, and R2 are both methyl.
In another embodiment, the invention relates to compounds of formula (1), wherein R 3, R 4, Rs, R 6 and R, are independently selected from hydrogen, -OH, halogen, C alkyl, -6, C 3-6 cycloalkyl alkyl) ...!, -NR "R'2. C'-6 haloalkyl, C-hydroxyalkyl, .3, C-alkoxy, ~ Cg alkyl ;, C-alkoxy, - <C-alkoxy C, ~, -CONR1 R'2, -SOrNR , R, 2 and haloalkoxy C, - <I; preferably are independently selected from hydrogen, -OH, halogen, C'.3 alkyl, haloalkyl C, -6, C'- 'alkoxyC0.6 alkyl, alkoxy C, "" alkoxy C, "", -S02-NR "R'2 and haloalkoxy C," "; more preferably it
independently selected from hydrogen, halogen, C alkyl, ~, haloalkyl C, ~, alkoxy C, "", -SOrNR "R'2 and haloalkoxy C, ~; and even more preferably R3, R4, Rs, Ra and R7 are selected independently of hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, triftuoromethyl, trifluoromethoxy and -S02-NH2.
In a preferred embodiment, the invention relates to compounds of formula (1), wherein R 5 is selected from -OH, halogen, C alkyl, -6, CJ cycloalkyl, CI alkyl) ...!, -NR 11 R, 2 haloalkyl C, ..., hydroxyalkyl C, ..., alkoxy C, "" alkyl Co.e, alkoxy C, .. alkoxy C, ~, -CONRl1 R'2, -SOrNRl1 R12 and haloalkoxy C, ~; preferably it is selected from -OH, halogen, C'-6 alkyl, C'-6 haloalkyl, C alkoxy, C0.6 alkyl, C alkoxy, "" C alkoxy, ~, -SOr NR "R'2 and haloalkoxyC, "" I; more preferably is selected from halogen, C alkyl, "", haloalkyl C, ~, alkoxy C, ~, -SOrNRllR'2 and haloalkoxy C, ",,; even more preferably it is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -S02-NH2: and even more preferably Rs is fluorine; R3 is selected from hydrogen, halogen and C'.3 alkyl: more preferably R3 is selected from hydrogen, halogen and C alkyl, ~ even more preferably R3 is selected from hydrogen, fluorine, chlorine, ethyl and methyl: and even more preferably R3 is hydrogen; and ~, ~ and R7 are hydrogen.
In another preferred embodiment, the invention relates to compounds of formula (1), wherein ~ and R6 are independently selected from -OH, halogen, C, -6 alkyl. C3-6 cycloalkylC1) alkyl! -NR "R12 • haloalkyl C, -6. Hydroxyalkyl C, .. fi,
C alkoxy, Co-e alkyl. C alkoxy, ~ C alkoxy, ~. -CONRlIR, 2, -SOrNR "R'2 and haloalkoxy C, ~; preferably selected from -OH, halogen, C-6 alkyl. C'-6 haloalkyl, C alkoxy," "CG.f alkyl; and haloalkoxy C, ""; more preferably selected from
halogen, C alkyl, ~, haloalkyl C, ~, alkoxy C, ~ and haloalkoxy C, ",, and even more preferably are selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy; and R3, Rs and R7 are hydrogen.
In another preferred embodiment. two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5 or 6 membered cycloalkyl, where 1 or 2 cycloalkyl methylene groups may be replaced by O, said cycloalkyl may be optionally substituted with one or more C alkyls, ... and preferably the other three from R3 to R7 are hydrogen; more preferably R. and Rs are connected to form a 5 or 6 membered cycloalkyl, where 1 or 2 cycloalkyl methylene groups may be replaced by O, said cycloalkyl may be optionally substituted with one or more C, - <I alkyls. and R3, R6 and R7 are hydrogen; more preferably R. and Rs are connected to form a 6-membered saturated cycloalkyl, where 1 or 2 methylene groups of the cycloalkyl may be replaced by O atoms. said cycloalkyl may be optionally substituted with one or more C '- <I alkyls, and R3. Rs and R7 are hydrogen; and even more preferably R. and Rs are connected to form a 1,4-dioxane. and R3, Rs and R7 are hydrogen.
In another embodiment, the invention relates to compounds of formula (1), wherein Ra is selected from -OH, C-alkyl, -ti, Cl-tyalkyl IC cycloalkyl) - <I, C2_S acyl, -CONR13R ,. and -C (NR, s) NR "R'2; where each R13 and R'4 are independently selected from hydrogen and alkyl C '- <I, or R13 and R,. form, together with the N atom to which they are attached, a 4 to 6 membered saturated heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, preferably selected from N and 0, said heterocycle may be optionally substituted with one or more substituents independently selected from C'- alkyl <I and C2_S acyl; more preferably Ra is selected from -OH, C '- <I alkyl, C'- <I cycloalkyl, C2_S acyl, -CONR13R,. And -C (NR' 5) NR "R '2; where each R'3 and R ,. are independently selected from hydrogen and C '- <I alkyl, or R'3 and R ,. they form, together with the atom of N to which they are attached. a 6-membered saturated heterocycle, containing an additional heteroatom selected from N and 0, preferably said heterocycle is piperazinyl or mor1olinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from C, - <I and C2_3 alkyl:
In another embodiment, the invention relates to compounds of formula (1), wherein Rg is C, - <I alkyl, preferably it is methyl. In another embodiment, the invention relates to compounds of formula (1), where Rg is hydrogen.
In another embodiment, the invention relates to compounds of formula (1), where n is 1, 2 or 3, preferably 1 or 2, and each R, or is independently selected from halogen, C, - <I and -NR alkyl "R'2; or two R, or attached to a common carbon atom form an oxo; or two R, or attached to adjacent carbon atoms are connected to form a 3-6 membered cycloalkyl, more preferably a 3-cycloalkyl 5-membered, and even more preferably a 3-membered cycloalkyl, said cycloalkyl may be optionally substituted with one or more substituents independently selected from CI-4 alkyl and halogen; more preferably, each R, or independently selected from chlorine, fluorine, methyl , ethyl, and -NH2 • or two Rlo attached to a common carbon atom form an oxo, or two Rlo attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl.
In another embodiment, the invention relates to compounds of formula (1), where n is O. In a preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and CI alkyl ....: preferably from hydrogen and methyl, and more preferably R, and R2 are hydrogen; R3, R., Rs, Rs and R7 are independently selected from hydrogen, -OH. halogen, C-alkyl, C-cycloalkyl 06) CQ-4 alkyl, -NRI, RI2, C 1- haloalkyl, C-hydroxyalkyl, -6, C-alkoxy, ... Co-e alkyl. C'-4alkoxy C, -4, -CONR "R12, -S02-NR" R12 and haloalkoxy C, -4; preferably they are independently selected from hydrogen, -OH, halogen. C, -6 alkyl, haloalkyl
C'-6, C'-4 alkoxy CQ.6 alkyl, C alkoxy, -4-alkoxy e, ...., -SO; r-NR "R'2 and haloalkoxy e,.; More preferably independently selected from hydrogen , halogen, alkyl e, -4, haloalkyl e '-4, alkoxy ""', -S02-NRl1R'2 and haloalkoxy Cl -4; and even more preferably R3, R.,., Rs, R6 and R, independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -S02-NH2; Rs is selected from -OH, C, -6 alkyl, haloalkyl and l-6, hydroxy-alkyl C1-4 C-alkoxy, .... CQ-I alkyl, C3-cycloalkyl-CQ.4 alkyl, C2 • 5, -C (O) cycloalkyl-C6-alkyl-Co-2, -eONR'3R,. and -C (NR, s ) NR "R'2: preferably selected from -OH, C-alkyl, fi, C-cycloalkylCalkyl. C2 • 5, -CONR13R14 and -C (NR1S) NR'lR12; where each R13 and R, ~ are independently selected from hydrogen and CI-4 alkyl. or R13 and R ,. form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, preferably selected from N and 0, said heterocycle may be optionally substituted with one or more selected substituents
independently between C '- <I alkyl and C2-6 acyl; more preferably R8 is
selects from -OH, C '- <I alkyl, C 1 -C 6 cycloalkyl, - <I, C 2 • 5 acyl,
- CONR'3R'4 and -C (NR, s) NR "R'2: where each R13 and RH are selected
independently between hydrogen and C '- <I alkyl, or R13 and R ,. form together
with the N atom to which they are attached, a saturated 6-membered heterocycle,
which contains an additional heteroatom selected from N and O,
preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle
may be optionally substituted with one or more substituents
independently selected from alkyl e '- <I and acyl e 2-3;
Rg is selected from hydrogen and C alkyl, - <I, preferably selected
between methyl and hydrogen, more preferably it is hydrogen; Y
n is 1, 2 or 3, preferably 1 6 2, and each R, or is selected
independently between -OH, halogen, C'-I alkyl: I, C'-alkoxy-<alkyl CG-6,
- SR'1 and -NRll R12; or two R, or attached to a common carbon atom form a
oxo; or two R, or attached to adjacent carbon atoms are connected to
form a 3-6 membered cycloalkyl, more preferably a cycloalkyl
3 to 5 members, and even more preferably a 3-member cycloalkyl,
said cycloalkyl may be optionally substituted with one or more
substituents independently selected from alkyl e, .... and halogen;
more preferably. each R, or is independently selected from
halogen, alkyl e, .. and -NR "R, 2 or two R, or attached to a carbon atom
common form an oxo; or two R'0 attached to adjacent carbon atoms
are connected to form a 3 to 5 member cycloalkyl,
preferably a 3-membered cycloalkyl, said cycloalkyl may be
optionally substituted with one or more selected substituents
independently between alkyl e, .. and halogen; and even more preferably,
each R, or is independently selected from chlorine, fluorine, methyl, ethyl, and
- NH2 • Or two R's, or attached to a common carbon atom form an oxo; or two
R, or attached to adjacent carbon atoms are connected to form a
3-member cycloalkyl;
and where:
preferably at least one of R3 to R7 is not hydrogen and at least two of R3 to R7
they are hydrogen;
each R "and R'2 are independently selected from hydrogen and alkyl e 1- <1, and
preferably they are selected from hydrogen and methyl; Y
R'5 is selected from hydrogen, C alkyl, -fi. haloalkyl e1-fi. -eN, -CONR "R, 2 •
- SOr R ". -SO-R" and -S02-NRllR'2; preferably it is selected from hydrogen, -eN and C, -4 alkyl; and more preferably R'5 is selected from hydrogen and alkyl
e, ....;
or a pharmaceutically acceptable salt or sotvate thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and C alkyl, -4: preferably from hydrogen and methyl, and more preferably R, and R2 are hydrogen; Rs is selected from -OH, halogen, C, -6 alkyl. cycloalkyl CH C0-4 alkyl, -NRllR'2, haloalkyl C'-6, hydroxyalkyl C'-6, alkoxy C'-4 to C1 alkyl) -6, alkoxy e, _ 4alkoxy e, ..., -CONRllR12, -SOr NRllR'2 yhaloalkoxy C, -4; preferably it is selected from -OH, halogen, C alkyl, .fi, haloalkyl CH, C'-4 alkoxy alkyl
CI) .f¡, C, -4 alkoxy C, -4, -SOr NR "R12 and haloC'-4I alkoxy; more preferably it is selected from halogen, C, -. 4 alkyl, C, -. 4 haloalkyl, and , -. 4, -S02-NRnR'2 and haloalkoxy e, ....; even more preferably it is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -S02-NH2; and even more preferably Rs is fluorine; RJ is selected from hydrogen, halogen and alkyl e, -6; more preferably R3 is selected from hydrogen, halogen and CH alkyl, even more preferably R3 is selected from hydrogen, fluorine, chlorine, ethyl and methyl; and even more preferably R3 is hydrogen; R ", Re and R7 are hydrogen; Ra is selected from -OH, C'-6 alkyl, C'-6 haloalkyl, C-hydroxyalkyl, -. 4, C'-4 to Cq.alkyl. 4, C3-6alkyl CI) .oI, CM, -C acyl (O) cycloalkyl Cl6alkyl e 0-2, -eONR1 ~ R'4 and -e (NR, s) NR "R, 2; preferably selected from -OH, C'-6 alkyl, cycloalkyl CHalkyl CI) .oI, aqueous C2-5, -CONR13R14 and -C (NR, s) NR "R12; where each R13 and R'4 are independently selected from hydrogen and alkyl and ,,,,,, or R13 and R ,,, form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SY O. preferably selected from N and O, said heterocycle may be optionally substituted with one or more substituents independently selected from C, -. 4 alkyl and C2-5 acyl; more preferably Rs is selected from -OH, C alkyl, -. 4, C3-6 cycloalkyl C, -. 4, C2_S acyl •
- eONR13R'4 and -C (NR, s) NR ll R'2: where each R'3 and R ,. are selected
independently between hydrogen and alkyl the ~, or R'3 and R'4 form, together
with the N atom to which they are attached, a saturated 6-membered heterocycle,
which contains an additional heteroetom selected from N and O,
preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle
may be optionally substituted with one or more substituents
independently selected from alkyl e, .. 04 and acyl e 2-3:
Rg is selected from hydrogen and C alkyl, ...., preferably it is selected
between methyl and hydrogen, more preferably it is hydrogen: and
n is 1, 2 6 3, preferably 1 or 2, and each R10 is selected
independently between -OH, halogen, alkyl e, ~, C 'alkoxy. 04 Co-s alkyl,
- SR "and -NR" R12: or two R, or attached to a common carbon atom form a
oxo; or two R, or attached to adjacent carbon atoms are connected to
form a 3-6 membered cycloalkyl, more preferably a cycloalkyl
3 to 5 members, and even more preferably a 3-member cycloalkyl,
said cycloalkyl may be optionally substituted with one or more
substituents independently selected from C, 04 alkyl and halogen;
more preferably, each R, or is independently selected from
halogen, alkyl e, .... and -NR "R12. or two R, or attached to a carbon atom
common form an oxo; or two R, or attached to adjacent carbon atoms
are connected to form a 3 to 5 member cycloalkyl,
preferably a 3-membered cycloalkyl, said cycloalkyl may be
optionally substituted with one or more selected substituents
independently between alkyl e, .... and halogen; and even more preferably,
each R, or is independently selected from chlorine, fluorine, methyl, ethyl, and
- NH2, or two Rs, or attached to a common carbon atom form an oxo; or two
R, or attached to adjacent carbon atoms are connected to form a
3-member cycloalkyl;
and where:
each R "and R'2 are independently selected from hydrogen and C'04 alkyl, and
preferably they are selected from hydrogen and methyl; YRu, is selected from hydrogen, C alkyl, ~, haloalkyl e, .. "-CN, -CONR" R'2,
- SO; rR ", -SO-R" Y -S02-NR "R'2: preferably selected from hydrogen,
- eN and C alkyl, .. 04; and more preferably R, s is selected from hydrogen and alkyl
C, .. 04:
or a pharmaceutically acceptable solvate salo thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and C, -4 alkyl; preferably between hydrogen and methyl, and more preferably R, and R2 are hydrogen; R4 and R6 are independently selected from -OH, halogen, C, -6 alkyl. C 3-6 cycloalkyl CQ-oI alkyl, -NRlIR'2, haloalkyl C, -4I. C'-6 hydroxyalkyl, C alkoxy, ..... CG-6 alkyl. C'-4alkoxy alkoxy e, ....., -CONRll R12, -S02-NR "R'2 and haloalkoxy e, -4; preferably selected from -OH, halogen, C-alkyl, -6. haloalkyl C, - 6. C'-4a1 alkoxy CD-6 alkyl and haloalkoxy e, .....; more preferably selected from halogen, C alkyl, "" ', C'-4 haloalkyl, C'-4 alkoxy and C, -4 haloalkoxy ; and even more preferably they are selected from fluorine: chloro, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy; R3. R5 and R1 are hydrogen; Re is selected from -OH, C alkyl, -8. haloalkyl C, -8 , C-4 hydroxyalkyl,
'C'-4 alkoxyC0- <4 alkyl, cycloalkyl Cu C0- <4 alkyl, C2_5 acyl, -C (O) C ~ cycloalkyl
6a1 alkyl CG-2, -CONR'3R ,. and -C (NR'5) NRllR'2: preferably selected from -OH, C alkyl, - &, cycloalkyl CH C0- <4 alkyl, C2_5 acyl -CONR'3R ,. and -C (NR, s) NRll R12: where each R'3 and R ,. are independently selected from hydrogen and C, -4, or R13 and R, alkyl. form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SY 0, preferably selected from N and O, said heterocycle may be optionally substituted with one or more substituents independently selected from C'-4 alkyl and C2-s acyl: more preferably Re is selected from -OH, C -4 alkyl, C-cycloalkyl; C -4 alkyl, C2_S acyl,
'
'-CONR13R'4 and -C (NR'5) NRll R, 2: where each R'3 and R ,. are selected
independently between hydrogen and alkyl e'-4, or R13 and R ,. form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, containing an additional heteroatom selected from N and 0, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from C'-4 alkyl and C2-3 acyl: R, is selected from hydrogen and C4 alkyl, preferably selected
'between methyl and hydrogen, more preferably it is hydrogen; Y
n is 1, 2 or 3, preferably 1 or 2, and each R10 is selected
independently between -OH, halogen, Cl-6 alkyl, C alkoxy, ... CQ.-6 alkyl,
- SR "and -NR" R'2; or two R, or attached to a common carbon atom form an oxo; or two R, or attached to adjacent carbon atoms are connected to form a 3 to 6 membered cycloalkyl, more preferably a 3 to 5 membered cycloalkyl, and even more preferably a 3 membered cycloalkyl, said cycloalkyl may be optionally substituted with one or more substituents independently selected from alkyl e, ... and halogen; more preferably, each R, or is independently selected from halogen, alkyl e, .. and -NR "R, 2. or two R, or attached to a common carbon atom forms an oxo; or two R, or attached to atoms Adjacent carbon are connected to form a 3 to 5 membered cycloalkyl, preferably a 3 membered cycloalkyl, said cycloalkyl may be optionally substituted with one or more substituents independently selected from e, .. and halogen alkyl; and even more preferably, each R, or is independently selected from chlorine, fluorine, methyl, ethyl, and -NH2 • or two R, or attached to a common carbon atom form an oxo; or two R, or attached to adjacent carbon atoms are connected to form a 3-membered cycloalkyl;
and where:
each Rl1 and R'2 are independently selected from hydrogen and C alkyl, ..., or
preferably they are selected from hydrogen and methyl; YR, s is selected from hydrogen, alkyl and l -6, haloalkyl C, -6, -eN, -CONRl1 R, 2,
- SO: z-R ", -SO-R" and -S02-NR "R, 2; preferably selected from hydrogen,
- eN and C alkyl, ...; and more preferably R'5 is selected from hydrogen and alkyl
and,..,;
or a pharmaceutically acceptable solvate salo thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and alkyl e, ...; preferably between hydrogen and methyl, and more preferably R, and R2 are hydrogen; two of R3 to R1 attached to adjacent carbon atoms are connected to form a 5 or 6 membered cycloalkyl, where 1 or 2 cycloalkyl methylene groups may be replaced by 0, said cycloalkyl may be optionally substituted with one or more alkyls e, .... and preferably the other three from R3 to R7 are hydrogen; more preferably, R4 and Rs are connected to form a 5 6 6 membered cycloalkyl, where 1 6 2 methylene groups of the cycloalkyl may be replaced by 0, said cycloalkyl may be optionally substituted with one or more alkyls ...., and preferably R3, R6 and R7 are hydrogen: even more preferably R. and Rs are connected to form a 6-membered saturated cycloalkyl, where 1 6 2 methylene groups of the cycloalkyl may be replaced by 0 atoms, said cycloalkyl may be optionally substituted with one or more rent e, ...., and R3. Rs and R7 are hydrogen; and even more preferably ~ and Rs are connected to form a 1,4-dioxane, and ~, R6 and R7 are hydrogen: Re is selected from -OH, C alkyl, -tl, haloalkyl C, -6, hydroxyalkyl C, - 4,
C'-4 alkoxy C (l-4, C3-{C-cycloalkyl) (C-4, C2-S acyl, -C (O) C0-2 cycloalkyl-C0-2 alkyl, -CONR'3R,. and -C ( NR, s) NRnR'2: preferably selected from -OH, C alkyl, -tl. C3 cycloalkyl-CQ-tlalkyl, t, CH acyl, -CONR '3RU and -C (NRI5) NR "R'2: where each R13 and R, are independently selected from hydrogen and C'-4 alkyl, or R13 and R,. Form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain a additional heteroatom selected from N, SYO, preferably selected from N and 0, said heterocycle may be
optionally substituted with one or more substituents independently selected from C alkyl, .. and C2-6 acyl: more preferably Re is selected from -OH, alkyl e, .., CJ cycloalkyl, C-5- alkyl, C2-5 acyl. -CONR13R, 4 and -C (NR, s) NRl1 R, 2: where each R13 and R ,. independently selected from hydrogen and alkyl e, .... "or R13 and R'4 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, containing an additional heteroatom selected from N and 0 , preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from C'-4 alkyl and C2-3 acyl: Rg is selected from hydrogen and C, -4 alkyl, preferably is selected from methyl and hydrogen, more preferably is hydrogen: and n is 1, 2 or 3, preferably 1 or 2, and each R, or is independently selected from -OH, halogen, C-alkyl, -tl, C'-4 alkoxy-CO-tl alkyl , -SR "and -NR" R12: or two R, or attached to a common carbon atom form a
oxo; or two R, or attached to adjacent carbon atoms are connected to
form a 3-6 membered cycloalkyl, more preferably a cycloalkyl
3 to 5 members, and even more preferably a 3-member cycloalkyl,
said cycloalkyl may be optionally substituted with one or more
substituents independently selected from alkyl e, .... and halogen;
more preferably, each R, or is independently selected from
halogen, C alkyl, .... and -NRllR12. or two R, or attached to a carbon atom
common form an oxo; or two R, or attached to adjacent carbon atoms
are connected to form a 3 to 5 member cycloalkyl,
preferably a 3-membered cycloalkyl, said cycloalkyl may be
optionally substituted with one or more selected substituents
independently between alkyl e, .... and halogen; and even more preferably,
each R10 is independently selected from chlorine, fluorine, methyl, ethyl, and
- NH2, or two Rs, or attached to a common carbon atom form an oxo; or two
R, or attached to adjacent carbon atoms are connected to form a
3-member cycloalkyl;
and where:
each R11 and R'2 are independently selected from hydrogen and C, -4 alkyl, or
preferably they are selected from hydrogen and methyl; Y
R'5 is selected from hydrogen, C, -6 alkyl, C, -6 haloalkyl. -CN, -eONR, IR12.
- SOrR'l, -SO-Rll and -S02-NRI1R'2; preferably selected from hydrogen,
- CN and C'-4 alkyl: and more preferably R'5 is selected from hydrogen and alkyl
Cl -4;
or a pharmaceutically acceptable solvate salt thereof. In a preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and C alkyl, ....: preferably from hydrogen and methyl, and more preferably R, and R2 are hydrogen; RJ, R4, Rs, R6 and R7 are independently selected from hydrogen, -OH.
halogen, C, -6 alkyl, C3-6 cycloalkyl CD- (, -NR, IR, 2. haloalkyl C, -6, hydroxyalkyl C, -6, C'-4 alkoxy C0-6 alkyl. alkoxy e, -4 -alkoxy C , -4. -CONR "R'2, -SOr NRllR12 and C'-4 haloalkoxy: preferably independently selected from hydrogen, -OH, halogen, C'-6 alkyl, Cl-6 haloalkyl. Cl-4alkoxy 6, C alkoxy, .... C alkoxy, -4. -SOrNR "R'2 and haloalkoxy e, _
. more preferably they are independently selected from hydrogen,
halogen, alkyl e ,,,,,,, haloalkyl e ,,,,,,, alkoxy e, "" ", -SO; rNRllR12 and haloalkoxy e, ... (; and even more preferably R3, R4, Rs, R6 and R7 are independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -SO; rNH2;
Re is selected from -OH, alkyl e -6, haloalkyl e, -6, hydroxyalkyl eH, 'alkoxy e, ... (alkyl) -' l, cycloalkyl e3-6alkyl el) - 'l, acyl e 2_S, -C (O) C3 cycloalkyl
6alkyl and o.2, -eONR13R'4 and -C (NR'S) NRll R'2; preferably selected
between -OH, alkyl e -6, cycloalkyl eualkyl Co ..., acyl e2.S, -CONR'3R'4 and '-C (NR15) NR, lR'2; where each R'3 and R'4 are independently selected from hydrogen and alkyl e, ... (, or Rl3 and Rl4 form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, preferably selected from N and 0, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e, "" "and acyl e 2-! i; more preferably Re is selected from -OH, alkyl e, "" ", cycloalkyl e3-6alkyl e, ... (, acyl e 2_S,
- eONR, 3R14 and -C (NR'S) NRllR'2; where each and R ,,. are selected
R'3 independently between hydrogen and C alkyl, ... (, or Rl3 and Rl4 form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, which contains an additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e, "" "and acyl e 2-3; Rg is selected from hydrogen and alkyl e, ... (, preferably is selected from methyl and hydrogen, more preferably it is hydrogen; and n is O; and where: preferably at least one of R3 to R7 is not hydrogen and at least two of R3 to R7 are hydrogen; each Rll and R'2 are independently selected between hydrogen and alkyl e, ... (, and preferably are selected from hydrogen and methyl; and R, S is selected from hydrogen, alkyl e -6, haloalkyl e, -6, -eN, -eONR "R, 2,
'-S0 2-Rll, -SO-R and -S02-NR11RI2; preferably it is selected from hydrogen, "-eN and alkyl e," ",,: and more preferably R'5 is selected from hydrogen and alkyl
and,,",,;
or a pharmaceutically acceptable solvate salt thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and alkyl and l ....; preferably between hydrogen and methyl, and more preferably R, and Rz are hydrogen; Rs is selected from -OH, halogen, C alkyl, -6, C3-6 cycloalkylC0-4 alkyl.
- NR "R'2, haloalkyl C, .6, hydroxyalkyl GI -6. Alkoxy C'-4alkyl CI) .6, alkoxy e,. .Alkoxy e, ...., -CONRllR'2, -SOr NRllR'2y haloalkoxy e, ....; is preferably selected from -OH, halogen, C'-6 alkyl, haloalkyl C, -6. C'-4a1alkyl CQ.ti, C'-4alkoxy alkoxy e, ..., - SOrNR "R'2 and haloalkoxyC'-4I; more preferably it is selected from halogen, alkyl e, ... haloalkyl the ../ "alkoxy e, .., -S02-NRl1R'2 and haloalkoxy e, ..; even more preferably it is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy and -S02-NH2: and even more preferably Rs is fluorine; R3 is selected from hydrogen, halogen and C alkyl, ~: more preferably R3 is selected from hydrogen, halogen and alkyl e,. .. even more preferably R3 is selected from hydrogen, fluorine, chlorine, ethyl and methyl; and even more preferably R3 is hydrogen; R ", Ra and R1 are hydrogen: Ra is selected from -OH, C, -6 alkyl, haloalkyl C l-6, hydroxyalkyl C, .. / "alkoxy C, .... alkyl ClJ ...!, Cycloalkyl CH alkyl ClJ ...!, Acyl C2-5 • -C (O) cycloalkyl Clsalkyl Co-2 • -CONR13R, ~ and -C (NR, s) NR'lR12: preferably selected from -OH. C alkyl, -6. C3-6 cycloalkyl ClJ ...!, C2 acyl • 5, -CONR13R, ~ and - e (NR, s) NR "R12: where each R13 and R'4 is selected independently act between hydrogen and C alkyl, ..... or R'3 and R'4 form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, preferably selected from N and 0, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e, .... and acyl e2.s: more preferably Ra is selected from -OH. alkyl e, ...., C3-6 cycloalkyl C1 ../ "acyl CM. -CONR'3R'4 and -C (NR1S) NR'IR12: where each R13 and R'4 are independently selected from hydrogen and alkyl G, .. / "or R'3 and R'4 form, together
with the N atom to which they are attached, a saturated 6-membered heterocycle,which contains an additional heteroatom selected from N and O,preferably said heterocycle is piperazinyl or morpholinyl, said heterocyclemay be optionally substituted with one or more substituentsindependently selected from C, ~ alkyl and C2 • 3 acyl:R9 is selected from hydrogen and C alkyl, ~, preferably selectedbetween methyl and hydrogen, more preferably it is hydrogen; Yn is O:
and where:each R "and R'2 are independently selected from hydrogen and alkyl e, ..." andpreferably they are selected from hydrogen and methyl; YR'5 is selected from hydrogen, alkyl e'-6, haloalkyl e'-6, -CN, -CONR "R'2,-SOr R ", -SO-R" and -S02-NR "R'2: preferably selected from hydrogen,-CN and alkyl e, ~; and more preferably R'5 is selected from hydrogen and alkyle, ~;
or a pharmaceutically acceptable solvate salt thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R, and R2 are independently selected from hydrogen and alkyl e, ...,: preferably from hydrogen and methyl, and more preferably R, and R2 are hydrogen: R "and R6 are independently selected from - OH, halogen, alkyl e, -6, cycloalkyl Cu C0.4 alkyl, -NR "R'2, haloalkyl e, .fI, hydroxyalkyl e, .fI, C alkoxy, ~ CO-f alkyl, C alkoxy, ~ C, ~, -CONRl1R'2, -S02-NR "R'2 and C-haloalkoxy, ..., preference is preferably selected from -OH, halogen, C'-6 alkyl, C'-6 haloalkyl, alkoxy C, C0-6 alkyl and haloalkoxy e, ..., are preferably selected from halogen. Alkyl e, ... "haloalkyl C, ~, C alkoxy, ..., and haloalkoxy C, ~; more preferably, it is selected from fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy: R3. Rs and R7 are hydrogen; Rs is selected from -OH, C alkyl, -6, haloalkyl C, -6, hydroxyalkyl e, ... "C alkoxy, C0.C4 alkyl, cycloalkyl and 0- <4 alkyl, C2 • S aeyl, -C (O) eieloalquil C: l
6 C0-2 alkyl, -CONRuR ,,, and -C (NR'5) NR "R12: preferably selected from -OH, alkyl e '-6, C3-tjalkyl alkyl) -4, acyl CN, -CONR13R ,, , and -C (NR15) NR "R12: where each R'3 and R ,. are independently selected
between hydrogen and alkyl e, -4, or R'3 and R ,. form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, preferably selected from N and O, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e'-4 and acyl e 2oÓ; more preferably Rs is selected from -OH, alkyl e, -4, cycloalkyl e3-6alkyl e, -4, acyl e 2.s, -CONR'3R ,. and -C (NR, s) NRllR12; where each R'3 and R ,. are selected
independently between hydrogen and alkyl e, -4, or R'3 and Rl. form, together with the N atom to which they are attached, a 6-membered saturated heterocycle, containing an additional heteroatom selected from N and O, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from -4 alkyl and e2_3 acyl; R9 is selected from hydrogen and alkyl and l ..., preferably it is selected from methyl and hydrogen, more preferably it is hydrogen; and n is O;
and where:each Rll and R'2 are independently selected from hydrogen and -4 alkyl, andpreferably hydrogen and methyl are selected: andR1S is selected from hydrogen, C,. {¡, Haloalkyl and, .6, -eN, -eONR "R'2,-SO; z-R ", -SO-R" and -S02-NR "R12; preferably selected from hydrogen,-eN and alkyl e, -4; and more preferably R, S is selected from hydrogen and alkyl
he ... :
or a pharmaceutically acceptable solvate salt thereof. In another preferred embodiment, the invention relates to compounds of
formula (1), where: R1 and R2 are independently selected from hydrogen and alkyl e, ...; preferably between hydrogen and methyl, and more preferably R, and R2 are hydrogen; two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5 6 6 membered cycloalkyl, where 1 6 2 methylene groups of the cycloalkyl may be replaced by 0, said cycloalkyl may be optionally substituted with one or more alkyls. ..; and preferably the other three from R3 to R7 are hydrogen; more preferably, R. and Rs are connected to form a 5 or 6 membered cycloalkyl, where 1 6 2 methylene groups of the cycloalkyl can be replaced by 0, said cycloalkyl
it can be optionally substituted with one or more C, -4 rents. Y
preferably RJ, Rs and R7 are hydrogen; even more preferably ~ and Rs
are connected to form a 6-member saturated cycloalkite, where 1
OR 2 methylene cycloalkyl groups may be replaced by atoms of
0, said cycloalkyl may be optionally substituted with one or more
you rent e, .... and R3. Rs and R7 are hydrogen; and even more preferably R ~ and Rs
they are connected to form a 1,4-dioxane, and ~, Re and R7 are hydrogen;
Re is selected from -OH. C-alkyl. (I. haloalkyl C, -6. hydroxyalkyl e, .... alkoxy Cl-4 to C 1 -alkyl; a. C0-4 cycloalkyl; C0-4 alkyl, C2_5 acyte, -C (O) cycloalkyl Cl6a1 alkyl CG-2, -CONR, 3R'4 and -C (NR, s) NR "R'2: preferably selected from -OH, C1- 'alkyl !, C-cycloalkyl: l-6alkyl ~, acyl e 2_s, - eONR, 3R'4 and -C (NR, s) NR "R12: where each R13 and R'4 are independently selected from hydrogen and alkyl e," ", or R'3 and R'4 form, together with the atom of N to which they are attached, a saturated 4 to 6 membered heterocycle, which may optionally contain an additional heteroatom selected from N, S YO, preferably selected from N and 0, said heterocycle may be optionally substituted with one or more independently selected substituents from alkyl e, "" and C2-6 acyl; more preferably Rs is selected from -OH, alkyl "" cycloalkyl e: l-6alkyl "", acyl e2-5,
- eONR13R'4 and -e (NR15) NR "R'2: where each R'3 and R'4 are independently selected from hydrogen and alkyl e," ", or R13 and R14 form, together with the N atom to which are linked, a 6-membered saturated heterocycle, containing an additional heteroatom selected from N and 0, preferably said heterocycle is piperazinyl or morpholinyl, said heterocycle may be optionally substituted with one or more substituents independently selected from alkyl e, "" and acyl e 2_3; R9 is selected from hydrogen and C1 "alkyl, preferably is selected from methyl and hydrogen, more preferably is hydrogen; and n is O;
and where:
each R "and R12: are independently selected from hydrogen and alkyl e," ", and
preferably they are selected from hydrogen and methyl; Y
R'5 is selected from hydrogen, C06 alkyl, haloalkyl e'-6, -eN, -CONR "R12 •
- SO; z-R ", -SO-R" and -S02-NR "R'2; preferably selected from hydrogen,
-CN and alkyl e ,,,,,,; and more preferably R15 is selected from hydrogen and alkyl
Cl -4;
or a pharmaceutically acceptable salt or solvate thereof.
In another preferred embodiment, the compound of formula el) is selected
5 Enter the following list of compounds:
-N '- (4-fluorophenyl) -1, 5-dimethylpyrrolidin-2-carbohydrazide
- {R) -2- {2- {4-fluorophenyl) hydrazylcarbonyl) pyrrolidin-1-carboxamide
- (8) -2- (2- (4-fluorophenyl) h idrazinocarbonyl) pyrrolidin-1-carboxam ida
-2- (2- (4-fluorophen iI} hid razinocarbonyl) pyrro1idin-1-carboxa measure
1 o -2- (2- (4-f1uoro-2-meti tphenyl) h idrazin-1-carbonyl) pyrrolidin-1-carboxamide
-2- (2- (3, 5-difluorophenyl) h idrazinocarboniI) pyrrolidin-1-ca rboxa mida
-2- (2- (4- (trifluoromethoxy) fen il) hydrazinoca rboni t) pyrrolid í n-1-carboxam ida
-2- (2- (4- (trifluoromethyl) phenyl) h idrazinoca rbon i 1) pyrrolidin-1-carboxamide
-2- (2- (4-chloro-2-fluorophenyl) h id razinoca rbon il) pi rrolidin-1-carboxamide
fifteen -2- (2- (4-methoxyphenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide
-2- (2- (2, 3-dih idrobenzo [b] [1, 4) dioxin-6-yl) hid razinoca rbonyl) pyrrolidin-1
carboxamide
-2- (2- (4-sulfa moilfen iI) hydrazi nocarbonyl) pyrrolidin-1-carboxa measure
- (2S, 4 S) -4-fluoro-2- (2 - (4-f1uorophenyl) hydrazinocarbonyl) pyrrolidin-1-ca rboxam ida
twenty - (R) -1-acetyl-N '- (4-fluorophenyl) pyrrolidin-2-carbohydrazide
_ N '- (4-fluorophenyl) -1-hydroxypyrrolidin-2-carbohydrazide
-N '- (4-fluorophenyl) -1, 2-dimethylpyrrolidin-2-carbohydrazide
-2- (2- (4-fluorophen il) hydrazi nocarbon il) -N, N-dimeUlpirrolidín-1-carboxam ida
-N '- (4-fl uorophen il} -1- (piperazin-1-carbon il) pyrrolidin-2-carbohydrazide
25 -1- (4-acetylpiperazin-1-carbonyl) -N '- (4-fluorofenll) pyrrolidin-2-carbohydrazide
-N '- (4-f! U orophen il) -1- (mo rfolin-4-ca rbon il) pyrrolidin-2 -carboh idrazida
-N '- (4-fI uorophen il) -1-methyl-5-oxopyrrole idin-2 -carbohydrazid a
-N '- (4-fluorophenyl) -1-methylpyrrolidin-2-carbohydrazide
-4-amino-N '- (4-fluorophenyl) -1-methylpyrrolidin-2-carboxyhydrazide
30 -4-f1uoro-N '- (4-fluorophenyl) -1-methylpyrrolidin-2-carbohydrazide
- (8) -1- (cyclopropyl methyl) -N '- {4-fluorophenyl) pyrrolidin-2-carboh idrazide
-N '- (4-fl uo rofen il) -3-methyl-3-aza bicyclo [3, 1, OJhexan0-2 -carbohydrazide
-N '- (4-fluorophenyl) -1, 4-dimethylpyrrolidin-2-carbohydrazide
-N '- (4-fluoropheniJ) -1 .3-dimethylpyrrolidin-2-carbohydrazide
35 -1-ethyl-N '- (4-fluorophenyl) pyrrolidin-2-carbohydrazide
-2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboximide measure -2- (2-phenylh idrazine-1-carbonyl) pyrrolidine-1-carboxamide -2- (1-methyl-2-phenylhydrazine-1 -carbonyl) pyrrolidine-1-carboxam ida -2- (2-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxam ida -2- (2 - (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine- 1-carboxamide -2- (2- (3-fluorophenyl) hydrazine-1-carbonylJ) pyrrolidine-1-carboxamide -2- (2- (2-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxam one way - 2- (2- (4-Chlorophen II) H Idrazine-1-Carbonyl) Pyrrolidine-1-Carboxam one way 2-- (2- (3-Chlorophen II) Hydrazine-1-Carbonyl) Pyrrolidine-1-Carboxam one way -2 - (2- (2-Chlorophenyl} hydrazine-1-carbonyl) pyrrolidine-1-carboxamide -2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidi na-1-carboxamide -2- (2 - ( 3-methoxyphenyl) hydrazin a-1-carbonyl) pyrrolidi na-1-carboxamide -2- (2- (2-methoxyphenyl) hydrazin a-1-carbonyl) pyrrolidi na-1-carboxamide -2- (2- (p- tolyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxamide -2- (2- (m-tolyl) hydrazine-1-carbonyl) pyr rolidine-1-carboxamide _ 2- (2- (o-tolyl) hydrazine-1-ca rbonyl) pyrrolid and na-1-ca rboxamide -2- (2- (4- (trifluoromethyl) phenyl) hyd razina-1- ca rbon il) pi rrolidine-1-carboxam ida -2- (2 - (3- (trifluoromethyl) phenyl) hid razina-1-ca rbon I) pl rrolidine-1-carboxam ida -2- (2- (2 - (trifluorometi I) phenyl) h id razina-1-ca rbon ¡I) pi rrolidine-1-carboxam ida -4- (2- (carbamoylprom) hydrazinyl) ethyl benzoate -3- (2- (carbamoylproliJ) hydrazinyl) ethyl benzoate -2- (2- (carbamoylprolyl) hydrazinyl) ethyl benzoate -2- (2- (4-cia nofen il} hydrazine-1-ca rboni l) pyrrolidine-1-carboxam ida -2- (2- (3-Cyanophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxamide -2- (2- (2-cyanophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxamide -Acid 4- (2- (carbamoylprolyl) hydrazinyl) benzoic acid 3- (2- (carbamoylprolyl) hydrazinyl) benzoic acid 2- (2- (carbamoylprolyl) hydrazinyl) benzoic acid -N-methi 2- 2- {2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxamide -N -meti ~ 2- (1-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxamide -N- Methyl ~ 2- (2-methyl-2-phenylhyd razina-1-ca rbonll) pl rrolidine-1-carboxamide -2 - (2- (4-f1uorophenyl) hydrazine-1-carbonyl) -N-methylpyrrolidine-1-ca rboxa mida -2- (2- (3-fluorophenyl) hydrazine-1-carbonyl) -N-methylpyrrolidine-1-ca rboxamide -2- (2- (2 -f1u orophen-yl) h idrazine-1-carbonyl) -N -met ilpirrolidine-1-ca rboxamide -2- (2- (4-chlorophenyl) hydrazine-1-carbonyl) -N-methylpyrrol idine-1-carboxamide -2- (2 - (3-chlorophenyl) hydrazine-1- carbonyl) -N-methylpyrrolidine-1-carboxam ida -2- (2- (2-chlorophenyl) hydrazine-l-carbonyl) -N-methylpyrrolidine-1-carboxam ida -2- (2 - (4-methoxyphenyl) hydrazine -1-carbonyl) -N-methylpyrrolidine-1-ca rboxa mida -2 - (2 - (3-methoxyphenyl) hydrazine-1-carbonyl) -N-methylpyrrolidine-1-ca rboxamide -2- (2 - (2 - methoxyphenyl) hydrazine-1-carbonyl) -N-methylpyrrolidine-1-ca rboxa mida -N-methyl-2 - (2 - (p-tolyl) hid razina-1-carbonyl) pi rrol idina-l-carboxamide -N -methyl-2 - (2 - (m-tol iI) hid razi na-1-ca rbonyl) pyrrolidine-1-ca rboxa mida -N-methyl-2 - (2 - (o-tol il) hydrazin a-1 -carbonyl) pi rrolid ina-l-carboxamide -N-methyl-2- (2- (4- (trifluoromethyl) phenyl) hydrazine-l-carbonyl) pyrrolidine-1
Carboxamide -N-methyl-2 - (2 - (3- (trifluoromethyl) phenyl) hid razina -'- carbonyl) pyrrolid and na-lcarboxamide -N-methyl-2- (2- (2- (trifluoromethyl) phenyl) hydrazine -l-carbonyl) pyrrolidine-1
Carboxamide -4- (2- «methylcarbamoyl) prolyl) hydrazinyl) ethyl benzoate -3- (2-« methylcarbamoyl) prolyl) hydrazinyl) ethyl benzoate -2- (2- «methylcarbamoll) prolyl) hydrazinyl) ethyl benzoate - 2- (2- (4-cia nofen i I) hydrazine-1-carbon iI) -N-methylpyrrolidi na-1-ca rboxa mida -2- (2 - (3-cia nofe n il) hydrazine-l-carbonyl ) -N-methylpyrrolidi na-1-ca rboxa mida -2 - (2- (2-cia nofen il) hydrazine-1-carbon il) -N-methylpyrrolid and na-1-ca rboxa mida -Acid 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 -l-carbonyl) pyrrolidine-l-carboxamide -N-cyclopropyl-2- (1-methyl-2-phenylhydrazine-l-carbonyl) pyrrolidine-1-carboxamide -N-cyclo pro pil-2 - (2 -meti 1- 2-phenylhydrazine-1-carbonyl) pyrrolidine-1-ca rboxa mida -N-cyclopropyl-2- (2 - (4-f1uo rofen il) hid razina-l-carbonyl) pyrrole idi na-1-ca rboxa mida -N -cyclopropyl-2 - (2 - (3-tI uorophenyl) h idrazine-1-carbo ni I) pyrrole idi na-1-ca rboxa mida -N-cyclopropyl-2- (2 - (2-fluorophenyl) h idrazine-1-carbon il) pyrrole idi na-1-carboxa mida -2- (2- ( 4-chlorophenyl) hydrazine-1-carbonyl) -N-cyclopropylpyrrolidine-l-carboxa mida -2 - (2- (3-chlorophenyl) hydrazine-1-carbonyl) -N-cyclopropyl rrolidine-l-carboxamide -2 - (2- (2-Chlorophenyl) hydrazine-l-carbonyl) -N-cyclopropyl rrolidine-l -carboxamide -N-cyclo pro pil-2 - (2 - (4-methoxyphenyl) hydrazine-1-ca rbonyl) pi rrolid and na-l-carboxamide -N-cyclopropyl-2 - (2 - (3-methoxyphenyl) h idrazine-l-carbonyl) pyrrolidine-l-carboxamide -N-cyclopropyl-2- (2- (2 ~ methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-l-carboxamide -N-cyclopropyl-2 - (2 - (p-toli1) hydrazine-1-carbon iI) pyrrolidi na-1-carboxamide -N-cyclopropyl-2 - (2 - (m-lolyl) hydrazi n a-1-carbonyl) pyrrolid i na-1-carboxa mida -N-cyclo propyl-2- (2 - (o-loliI) h idrazine-1-carbon i 1) pyrrolidi na-1 -carboxamide -N-cyclopropyl-2 - (2- (4- {trifluo romethyl) phenyl) hydrazine-1-carbonyl) pyrrolidine-1
carboxamide -N-cyclopro pi! -2 - (2 - (3- (trifluoromethyl) phenyl) hydrazine-1 - <; arbonyl) pyrrolidine -1
carboxamide -N-cyclopropyl-2 - (2 - (2- (trifluoromethyl) phenyl) hydrazine-1-carbonyl) pyrrolidine-1
carboxamide -4- (2- «cyclopropylcarbamoyl) prolyl) hydrazinyl) ethyl benzoate -3- (2-« cyclopropylcarbamoyl) prolyl} hydrazinyl) ethyl benzoate -2- (2 - {(cyclopropylcarbamoyl) prolyl) hydrazinyl) ethyl benzoate -2- (2- (4-cia nofenil) h idrazine-1-carbonyl) -N-cyclopropylpyrrolidine-1-ca rboxamide -2- (2 - (3-cia nophenyl) hydrazine-1-carbonyl) -N-cyclopropylpyrrolidine -1-ca rboxamide -2- (2- (2-cyanophenyl) hydrazine-1-carbonyl) -N-cyclopropylpyrrolidine-1-carboxamide -Acid 4- (2- «cyclopropylcarbamoyl) prolyl) hydrazinyl) benzoic acid -Acid or 3- (2- «cyclopro piIcarbamoi I) prol iI) hid razin iI) benzo ico -Acid 2- {2-« cyclopropylcarbamoyl) prolyl) hydrazinyl) benzoic - (2- {2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carbonyl ) ethyl alaninate - (2- (1-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1 - <; arbonyl) ethyl alaninate - (2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - {2- (2- {3-fluoropheni l) ethyl hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) alaninate - (2- (2- (2-f1uorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2 - (4-Chlorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2 - (3-chlorophenyl) hid razin-1-carbonyl) pyrrolidine-1-carbonyl) ethyl ninate - {2- (2- (2-Chlorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl ) ethyl alaninate - {2- (2- (3-methoxyphenyl) hydrazine-1 - <; arbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2- (2- (2-methoxyphenyl) hydrazine-1-carbonyl ) ethyl pyrrolidine-1-carbonyl alaninate - (2- (2- (p-tolyl) hydrazine-1-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2- (m-tolll) hydrazine -1-carbonyl) pyrrolidine-1-carboni1) ethyl alaninate - (2- (2- (0-tolyl) hydrazine-1-carbonyl) pyrrolidine-1-carboniI) ethyl alaninate - (2- (2- (4 - (lrifluoromethyl) fen i1) hydrazine-1-ca rbon il) pi rrolid ina-1-carbonyl) ala ninalo
of ethyl
- (2- (2 - (3- (trifl uoromethyl) phenyl) hydrazin a-1-carbon il) pyrro I idina-1-carbonyl) ethyl ninate - (2- (2- (2 - (tritluoromethyl) phenyl) hydrazi n a-1-ca rbon il) pyrro I idina-1-carbonyl) alaninate
Ethyl -4- (2 - «(1-ethoxy-1-oxopropan-2-yl) carbamoyl) prolyl) hydrazinyl) ethyl benzoate -3- (2 -« (1-ethoxy-l-oxopropan-2-yl ) carbamoyl) prolyl) hydrazinyl) ethyl benzoate -2- (2 - «(1-ethoxy-1-oxopropan-2-yl) carbamoyl) prolyl) hydrazinyl) ethyl benzoate - (2- (2- (4-cyanophenyl) ) hydrazine-1-carbonyl) pyrrolidine-l-carbonyl) ethyl alaninate - (2- (2- (3-cyanophenyl) hydrazine-l-carbonyl) pyrrolidine-1-carbonyl) ethyl alaninate - (2- (2- (2- (2-) (2-Cyanophenyl} hydrazine-1-carbonyl) pyrrolidine-l-carbonyl) ethyl alaninate -Acid 4- (2 - «(1-ethoxy-l-oxopropan-2-yl) carbamoyl) prolyl) hydrazinyl) benzoic acid- 3- (2 - «(l-ethoxy-l-oxopropan-2-yl) carbamoyl) prolyl) h idrazin i I) benzoic acid 2- (2 -« (1-ethoxy-l-oxopropan-2-yl) carbamoyl) prolyl) hydrazinyl) benzoic -2- (2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxylate methyl -2- (1-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxylate methyl - Methyl 2- (2-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxylate -2- (2- (4-fluorophenyl) hydrazine-1-carbon il) methyl pyrrolidine-1-carboxylate -2- (2- (3-fluorophenyl) hydrazine-1-carbonyl) methyl pyrrolidine-1-carboxylate -2- (2- (2-fluorophenyl) hydrazine-1-carbonyl) Methyl pyrrolidine-l-carboxylate -2- (2- (4-chlorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylic acid -2- (2- (3-chlorophenyl) hydrazine-1-carbonyl) pyrrolidine- Methyl 1-carboxylate -2- (2- (2-chlorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-methyl carboxylate -2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-1- methyl carboxylate -2- (2- (3-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-1-methyl carboxylate -2- (2- (2-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-l-carboxylate methyl -2- (2- (p-tolyl) hydrazine-l-carbonyl) pyrrolidine-1-carboxylate methyl -2- (2- (m-tolyl) hydrazine-l-carbonyl) pyrrolidine-1-carboxylate methyl - 2- (2- (o-Tolyl) hydrazine-l-carbonyl) pyrrolidine-l-carboxylate -2- (2- (4- (trifluoromethyl) phenyl) hydrazine-l-carbonll) pyrrolidine -'- carboxylate
methyl -2- (2- (3- (trifluoromethyl) fen i I) hydrazi na-l-carbonyl) pyrrolidine-1-carboxylate methyl -2- (2- (2 - (trifluoromethyl) phenyl) hydrazi na-l- carbonyl) pyrrolidine-1-methyl carboxylate -2- (2- (4- (ethoxycarbonyl) phenyl} hydrazi na-1-carbonll) pyrrolidine a-1-carboxylate
methyl
-2- (2- (3- (ethoxycarbon yl) phenyl) hydrazi na-1-ca rbonyl) pyrrolidine-1-ca methyl carboxylate -2- (2- (2- (ethoxycarbonyl) phenyl) hydrazine-1- carbonyl) pyrrolidine-1-carboxylate
5 methylMethyl -2- (2- (4-cyanophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylateMethyl -2- (2- (3-cyanophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylate-2- (2- (2-Cyanophenyl) hydrazine-1-carbonyl) pyrrolidine- '-carboxylate- 4- (2- «Methoxycarbonyl) prolyl) hydrazinyl) benzoic acid
1 O-3- (2- "Methoxycarbonyl) prolyl) hydrazinyl) benzoic acid-2- (2-" methoxycarbonyl) prolyl) hydrazinyl) benzoic acid -2- (2- (4-ftuorophen-yl) hydrazi na-1-carbonif ) pyrrolidine-1-ca rboxa mida -2- (2- (4-fluorophenyl) hydrazi na-1-carbonyl) -N-methylpyrrolidine-1-ca rboxamide -N-ethyl-2 - (2 - (4-f1uorophenyl ) h idrazine-1-carbonyl) pyrrolidine-1-ca rboxamide
1 5 -2- (2- (4-fluorophenyl) hydrazi na-1-carbonyl) -N-isopropyl pyrrolidine-1-ca rboxa mida -2- (2- (4-fIuorophen il) hydrazi na-1-carbonyl) -N- (2-h idroxyethyl) pyrrolidine-1-carboxamide -2- (2- (4-fl or orophenyl) hydrazi na-1-carbonyl) -N- (2-methoxyeti I) pyrrolidine-'carboxamide 20 -N- (2-aminoethyl) -2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxamide -N- (2 - (dimethylamino) ethyl) -2 - (2 - (4-fluorophenyl) hid razina-1-carbonyl) pyrrolidine-1-carboxamide -2- (2- (4-fl or orotine) hydro-a-1-carbonyl) -N- (2 - (piperazin-1-yl) ethyl) pyrrole idine- 1-carboxamide 25 -2- (2- (4-fl or orophenyl) h id razina-1-ca rbonyl) -N- (2 - (4-methylpiperazin-1-yl) ethyl) pyrrolid ina1-carboxamide -2- ( 2- (4-flu orophenyl) h idrazine -'- carboni1) -N- (2-morpholinoethyl) pyrrolidine-, carboxamide -N-cyclopropyl-2- (2 - (4-fluorophenyl) hyd razin-1-carbonyl) pyrrolidine -1-carboxamide
30 -N-cyclobutiI-2- (2- (4-fluorophenyl) hydrazine -'- carbonyl) pyrrolidine-1-carboxamide -N-cyclopepenti1-2- (2- (4-fluorophenyl) hydrazine ina-1-carbonyl) pyrrolidine -1-carboxamide -2- (2- (4-fluorophenyl) h idrazine -'- carbonyl) -N- (tetrahydro-2 H-pi ran-4-yl) pyrrolidine-1
carboxamide -2- (2- (4-tlu orothenyl) h idrazine -'- carbon i I) -N, N-dimethylpyrrolidine-1-carboxa measure 35 -N '- (4-fluorophenyl) -1 - (piperazine-1 -carbonyl) pyrrolidine-2-carbohydrazide
- N '- (4-f1uo rofen il} -1- (4-methylpiperazine-1-carbonyl) pyrrolid ina-2 -ca rboh idrazide -N' - (4-fluorophen il) -1- (morpholine-4-carbonH) pyrrolid ina-2 -ca rbohydrazid a -N- (2 -am i no-2 -oxoethyl) -2 - (2 - (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1
carboxamide -N- (1-ami no-1-oxopropan-2-yl) -2 - (2 - (4-fluorophenyl) hydrazi na-1-ca rbonyl) pyrrolidinal-carboxamide -N- (1-amino- 3-hydroxy -'- oxo butan-2 -yl) -2 - (2 - (4 -fl uorophenyl) h idrazine-1carbonyl) pyrrolidine-1-ca rboxa measure -N- (1-a-mino-3-methoxy) '-oxobutan-2-yl) -2 - (2- (4-fluorophenyl) h idrazin a-1-carbonyl) pyrrolidine-1-carboxamide-4-amino-3- {2- {2- (4-fluorophenyl) acetate hydrazine-1-carbonyl) pyrrolidine-1-carboxamido) -4-oxobutan-2-yl-N- (1-amino-3-hydroxy-l-oxopropan-2-yl) -2 - (2 - (4-fluorophenyl) h idrazine-1
carbon il) pyrrolid ina -1 -carboxamide -2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylate -2- (2- (4-fluoropheni1) hydrazine-l-carbonyl) pyrrolidine-l-carboxylate etho-2-- {2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-l-carboxylate isopropyl -2- {2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine- Cyclopentyl l-carboxylate -2- (2- (4-methoxyphenyl) hydrazine-l-carbonyl) pyrrolidine-l-carboxamide -2 - {2- (4-methoxyphenyl) hydrazine-1-carbonyl) -N-methylpyrrolidine-1 -ca rboxa mida -N-ethyl-2 - (2 - (4-methoxyphenyl) h idrazine-1-carbonyl) pyrrolidine-l-carboxa mida -N-isopropyl-2 - (2 - (4-methoxyphene) h idrazine -l-carbonyl) pyrrolidine -'- carboxamid a -N- (2-hydroxyethyl) -2 - (2 - (4-methoxyphenyl) h idrazine-l-carbonyl) pyrrolidine-1
carboxamide -N- (2-methoxyethyl) -2 - (2 - (4-methoxyphenyl) hydrazine-l-carbonyl) pyrrolidine-lcarboxamide -N- (2-aminoethyl) -2 - (2 - (4-methoxyphene) hydrazi na-1-ca rbon ¡I) pi rrol id in a-lcarboxamide -N- (2 - (dimethylamino) ethyl) -2 - (2 - (4-methoxyphenyl) hid razina-1-ca rbonyl) pyrrolidine- 1carboxamide -2- (2- (4-methoxyphene) hydrazine-1-carbonyl) -N- (2 - (piperazin-1-yl) ethyl) pi rrolidine-1carboxamide -2- (2- (4-methoxyphene) hydrazin a-1-carbonyl) -N- (2 - (4-methyl pi pe razin- 'il} ethyl) pyrrolidine-1-carboxamide -2- (2- (4-methoxyphenyl) hydrazi na-l-carbonyl) - N- (2-morphol ethyl) pyrrolidi na-l
carboxamide
-N-cyclopropyl-2 - (2 - (4-methoxyphene) hydrazine-l-carbonyl) pi rrolidine-l-carboxamide -N-cyclobutyl-2 - (2 - (4-methoxyphene) h id razine-1- ca rbonyl) pyrrolidine-1-ca rboxamide -N-cyclopentyl-2 - (2- (4-methoxyphenyl) hydrazine-l-carbonyl) pyrrolidine-l-carboxamide
5 -2- (2- (4-methoxyphenyl) hydrazin a-l-carbonyl) -N- (tetrah idro-2 H-piran-4-yl) pyrrolld ina-l
Carboxamide -2- (2- (4-methoxyphenyl) hid ration al-carbonyl) -N, N-dimethylpyrrolidine-l-carboxamide -N '- (4-methoxyphenyl) -1- (piperazine-1-ca rbonyl) pyrrole idi na-2 -ca rboh idrazide -N '- (4-methoxyphenyl) -1- (4-methylpiperazine-l-carbonyl) pi rrotid in a-2-carbohydrazide
1 O -N '- (4-methoxyphenyl) -1- (morpholine-4-ca rbonyl) pi rrolidine-2-carboxyhydrazide -N- (2 -a mino-2 -oxoethyl) -2 - (2- (4 -methoxyphene i) hydro razin a-1-carbonyl) pyrrolidine-1-carboxamide -N- (1-amino-1-oxopropan-2-yl) -2- (2- (4-methoxyphenyl) hydrazine-lcarbonyl) pyrrolidine-1- carboxa measure 15 -N- (1-amino-3-hydroxy-l-oxobutan-2-yl) -2- (2- (4-methoxyphenyl) hydrazine-1carbonyl) pyrrolidine-1-carboxa measure -N- (1- a mino-3-methoxy-1-oxobutan-2-yl) -2 - (2 - (4-methoxyphenyl) h idrazi na-lcarbonyl) pyrrolidine-l-carboxamide-4-amino-3- acetate (2- ( 2- (4-Methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-120 carboxamido) -4-oxobutan-2-iI-N- (1-amino-3-hydroxy-1-oxopropan-2-yl) -2- ( 2- (4-methoxyphenyl) hydrazine-1
carbonyl) pyrrolid ina-l-carboxamide -2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-l-carboxylate -2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) ethyl pyrrolidine-l-carboxylate
Isopropyl 2- (2- (4-methoxyphenyl} hydrazine-1-carbonyl} pyrrolidine-1-carboxylate -2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine-1-cyclopentyl carboxylate - 2- (2- (4-Fluoro rofenyl) hydrazine-l-carbonyl) pyrrolidine-1-ca rboxa mida -5- (2- (4-fluoro-phenyl) hydrazine-1-carbonyl) -2, 2-d imethylpyrrolidine -1-carboxa measure -2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) -4-methyl pyrrolidine-1-carboxamide
30 -2- (2- (4-f1uorophenyl) hydrazine-1-carbonyl) -4-isopropylpyrrolidine-1-ca rboxa mida -6- (2- (4-f1uorophenyl) hydrazine-1-carbonyl) -5-aza spiro [2.4] heptane-5-carboxamide -2- (2- (4-f1uorophenyl) hydrazine-1-carbonyl) -4-h idroxypyrrolidine-1-ca rboxa mid to -2- (2- (4-fluorophenyl) hydrazine -1-carbonyl) -4-methoxypyrrolidine-1-carboxamide-1-carbamoyl-5- (2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidin-3-yl acetate
35 -2- (2- (4-f1uorophenyl) hydrazine-1-carbon yl) -4-fluoropyrrolidine-1-carboxamide -4, 4 ... <fifluoro-2 - (2- (4-fluorophenyl) h idraz ina -1-ca rbon iI) pyrrole idin a-1-carboxamide -2- (2- (4-fl U orotenil) h idrazine-1-ca rbon il) -4- (trifl uoromethyl) pyrrolid i na-1
carboxamide -4-cia no-2 - (2 - (4-fluorophenyl) hydrazine-1-carbonyl) pi rrolidine-1-carboxamide -2- (2- (4-fl Uorofenll) h idrazine-1-ca carbonyl) -3-phenylpyrrolidine-1-carboxa mida -2- (2- (4-fl Uorotenil) h idrazine-1-ca rbonyl) -3-hydroxypyrrolidine-1-carboxamide -2- (2- (4-fl or orofenll) h idrazine-1-ca rbon i 1) -3-methoxy pyrrolidine-1-carboxamide-1-carbamoyl-2- (2- (4-f1uorophenyl) hydrazine-1-carbonyl) pyrrolidin-3-yl -2- (2- (4-fluorofenll) hydrazine-1-carbonyl) -3-azabicyclo (3.1.0] hexane-3
carboxamide -2- (2- (4-methoxyphenyl) h idrazine-1-carbon yl) pyrroJidi na-1-ca rboxa mida -S- (2- (4-methoxypheneJ) hydrazine-1-carboniJ} -2,2. .. <fimetiJpirroJidina-1-carboxamide -2- (2- (4-methoxypheneJ) hid razina-1-carbon il) -4-methylpyrrolidine-1-ca rboxamide -4-isopro pil-2 - (2 - (4- methoxyphenyl 1) hydrazine-1-carbon yl) pyrrolidine-1-carboxa mida -6- (2- (4-methoxyphenyl) hydrazine-1-carbonyl} -S-azaspiro [2.4) heptane-5-carboxamide -4-h idroxy- 2 - (2 - (4-methoxyphene) hydrazi n a-1-ca carbonyl) pyrrolidine-1-carboxamide -4-methoxy-2 - (2 - (4-methoxyphene) hydrazi na-1-ca rbonyl) pyrrolid ina-1-carboxamide-1-carbamoyl-S- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidin-3-yl -4-f1uoro-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) hyd razina-1-ca rbon il} -4- (trifluoromethyl) pyrrolidine-1
carboxamide -4-cia no-2 - (2 - (4-methoxyphene) hydrazi na-1-carbonyl) pyrrolid ina-1-ca rboxa mida -2- (2- (4-methoxyphenyl) hyd razina-1-carbon il} -3-phenylpyrrolidine-1-ca rboxa mida -3-h idroxy-2 - (2 - (4-methoxyphene 11) hydrazi na-1-ca rbonyl) pyrrolid ina-1-carboxamide -3-methoxy-2 - (2 - (4-methoxyphene I) hydraz I na-1-carbon II) pyrrolid ina-1-carboxamide-1-carbamoyl-2- (2- (4-methoxyphenyl) hydrazine-1-carbonyl) pyrrolidine- 3-yl -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-c1c1opropyl-5- (2 - (4-fluorophenyl) h idrazine-1-carbonyl) - 2.2 ... <fimethylpyrrolidine-1
carboxamide -N-cyclopropyl-2 - (2 - (4-fluorophenyl) h idrazine-1-carbonyl) -4-methylpyrrolidine-1carboxamide -N-cyclopropyl-2 - (2 - (4-fluorophenyl) h idrazin a-1- carbonyl) -4-isopropylpyrrolid and na-1
carboxamide
-N-cyclopropyl-6- (2 - (4-f1uorophen il) hydrazine-1-ca rbonyl) -5-azaspiro [2.4 Jheptane-5carboxamide
-N-cyclopropyl-2- (2- (4-t1uorophenyl) hydrazine-1-carbonyl) -4-hydroxypyrrolidine-lcarboxamide
-N-cyclopropyl-2- (2- (4-f1uorophen-yl) hydrazine-1-carbon-yl) -4-methoxy pyrrolid i na-l
carboxamide
- Acetatefrom1- (cyclopropylcarbamoyl) -5- (2 - (4-f1uorophen il) hydrazine-1 -
carbonyl) pyrrolidin-3-iI
- N-cyclopropyl-4-f1uoro-2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) pyrrolidine-1
carboxamide
N-cyclopropyl-4, 4-difluoro-2 - (2 - (4-fluoropheni I) hid razina-1-carbonyl) pi rrolidine-l
carboxamide
N-cyclopropyl-2 - (2 - (4-tluorophenyl) hydrazine-1-carbonyl) -4- (trifluoromethyl) pyrrolidine
1-carboxamide
-4-cia no-N-cyclopropyl-2 - (2 - (4-fluorophenyl) h idrazi na-1-carbonyl) pyrrolidi na-1carboxamide -N-cyclopropyl-2- (2 - (4-fluorophenyl) hydrazine- 1-carbon il) -3-fen ji pyrrolidine-1-carboxamide -N-cyclopropyl-2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) -3-hydroxypyrrolidine-1-carboxamide -N-cyclopropi 1-2- (2 - (4-fl uorophenyl) h idrazine-1-carbonyl) -3-methoxypyrrolidine-1-carboxamide-1- (cyclopropylcarba moil) acetate -2 - (2 - (4-fluorophenyl) h idrazine-1carbonyl) pyrrolidin-3-yl -N-cyclopropyl-2- (2- (4-fluorophenyl) hydrazine-1-carbonyl) -3-azabicyclo [3.1.0] hexane3-carboxamide -N-cyclopropyl-2 - (2 - (4-methoxyphene I) h idrazine-1-carbonyl) pi rrolidine-1-ca rboxa mid a and the pharmaceutically acceptable salts or solvates thereof.
In another embodiment, the invention relates to compounds of formula (1) having a minimum inhibitory concentration (Mle) against Acinetobacter baumannii of less than about 50 g / ml, preferably less than about 25 J.lg / ml, and more preferably less than about 10 J.lg / ml, in an assay as described in Example 31.
In another embodiment, the invention relates to compounds of formula (1) having (a) a MIC against Acinetobacter baumannii of less than about 50 Jg / ml, preferably less than about 25 Jglml, and more preferably less than approximately 10 Jg / ml; and (b) a MIC greater than about 100 IJg / 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 even more preferably against at least three of these bacteria in an assay such as that described in Example 31.
Use of compounds
As shown in Example 31, surprisingly, the compounds of the present invention showed high antimicrobial activity against bacterium A baumannii, with minimum inhibitory concentration (MIC) values equal to
or less than 25 Jg / ml, or even less, for sludge compounds tested, while they were inactive against the other bacteria tested, ie
Staphylococcus aureus (S. aureus), Streptococcus pneumoniae (S. pneumoniae), Enterococcus faecium (E. faecium), Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumonise (K. pneumoniae) and Eseheriehia eoli (E. eoll), MICs greater than 128 for almost all compounds.
Therefore, a second aspect of the present invention is a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.
A third aspect of the present invention is a compound of formula (1), or a pharmaceutically acceptable salt or solvate thereof, for use as an antibacterial agent, preferably for treating or preventing A. baumannii infections.
A preferred embodiment refers to any of the particular and preferred embodiments of compounds of formula (1) previously disclosed in relation to the first aspect of the present invention for use as antibacterial agents, preferably for treating or preventing A. baumannii infections.
This aspect of the present invention can be similarly reformulated in accordance with the following aspects.
Therefore, another aspect of the present invention relates to a method for treating bacterial infections in a subject in need thereof, which comprises administering an effective amount of a compound of formula (1) as defined above, or a salo a pharmaceutically acceptable solvate thereof, to the subject.
Another aspect of the present invention relates to the use of a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or solvate thereof, as an antibacterial agent.
Another aspect of the present invention relates to a method for treating an infection by A. baumannii in a subject in need thereof, which comprises administering an effective amount of a compound of formula (1) as defined above, or a salt or a pharmaceutically acceptable solvate thereof, to the subject.
A further aspect of the present invention relates to the use of a compound of formula (1) as defined above, or a pharmaceutically acceptable solva10 thereof, to treat A. baumannii infections.
The compounds of the present invention can be used without limitation for the treatment of all infections caused by A. baumannii. For example, they can be used to treat pneumonia, particularly ventilator-associated pneumonia; surgical site infections; wound infections; skin and soft tissue infections: urinary tract infections; postoperative meningitis; any type of catheter-related infection, for example urinary tract infection associated with catheter; or bloodstream infection.
As used herein, the terms "treatment ~ or ~ treat" refer to both prophylactic treatment and therapeutic treatment of A. baurnannii infections, that is, to prevent or inhibit infection in a subject that may be predisposed. to become infected but that has not yet been diagnosed as having the infection, and to reduce or eliminate the infection after its appearance in a subject, as well as to relieve and decrease its associated symptoms.
Particularly. the terms "prevention" or "prevent" refer more specifically to the prophylactic treatment of A. baumannii infections, that is to say to prevent or inhibit infection in a subject that may be predisposed to become infected but has not been diagnosed Still the infection.
As used herein the term "subject" refers to human beings.
As used herein, the expression "in a subject that needs it" refers to a subject that has not been infected but may be predisposed to acquire the infection as well as a subject that has been infected with A.
baumannii.
The compounds of the present invention are administered in a dose that is therapeutically active to treat infections, and the person skilled in the art will have no difficulty in adjusting the exact dose to be administered based on the type of patient, the specific infection to treat and its severity
Typically, the compounds of the invention are administered in an amount ranging from 1 to 20 mglkg of body weight.
In another embodiment, due to the high activity of the compounds of formula 1 against A. baumannii, these compounds can be used in therapy in combination with other antibacterials, typically with broad-spectrum antibacterials. that may have less activity or not be specifically active against
A. baumannii, to thereby reinforce the antibacterial efficacy of therapy. The compounds of formula (1) can be combined with any type of antibacterial agent used in therapy, for example, with Iactam antibiotics, such as penicillins, cephalosporins, monobactamics or carbapenems, among others.
The combination of the compound of formula (1) with an additional antibacterial agent can be performed by administering both substances as a fixed dose combination in the form of a single pharmaceutical dosage form or, alternatively, both drugs can be administered independently, according to a guideline. of therapeutic combination.
Alternatively, the compound of formula (1) may be combined with another antibacterial agent by chemical bonding of both compounds to form a single molecule. For example, a compound of formula (1) can be attached to a carbapenemic type antibacterial compound, to form a double compound, which has, for example, the following formula:
R (RX-O) * R3 R
R) ± (- ~ JlNR2.
. /, ('R: I I
/ l .- N, R, or
N // RII R1 R5
or
caOH Rs
Pharmaceutical compositions
A fourth aspect of the invention relates to a pharmaceutical composition comprising a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient and / or vehicle.
The pharmaceutical composition that is an aspect of the present invention can be adapted to any form of administration, for example for oral, parenteral, inhalation, rectal, transdermal or topical administration. Similarly, depending on the intended route, the composition may be in solid, liquid or semi-solid form, and all of them are encompassed by the scope of the present invention.
Suitable excipients for use in the pharmaceutical composition as well as its methods of preparation will vary depending on the intended form and route of administration,
Solid compositions for oral use include, for example, tablets, capsules and granules. They may contain excipients such as, for example, anti-caking agents, binders, diluents, disintegrating agents, emollients, lubricants, flavoring agents and sweetening agents. The tablets may be coated with various coating agents. The capsules may be hard capsules or soft capsules as is well known in the art.
Hybrid forms for oral administration include emulsions, solutions, suspensions and syrups and may incorporate various pharmaceutically acceptable carriers or excipients, such as a liquid vehicle, emulsifying agents, suspending agents, flavoring agents, coloring ages, buffering agents, preservatives and diluents. .
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.
Compositions for rectal administration may be in the form of suppositories, for example on an oily base. They may contain other excipients such as adsorbents, surfactants, antioxidants, preservatives and dyes.
Compositions for topical administration may be in the form of creams, gels, ointments or pastes, for example. They may contain excipients such as emulsifiers, viscosity increasing agents, preservatives, antioxidants and stabilizing agents.
In each case, the pharmaceutical compositions can be prepared using conventional methods that are well known to those skilled in the art such as those described in pharmaceutical technology manuals, for example the book Remington The Science and Practice of Pharmacy, 20 · edition, Lippincott, Williams & Wilkins, Philadelphia, 2000 [ISBN: 0-683-306472].
In addition, the excipients and the vehicles for use in said
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, 68 edition, Pharmaceutical Press, London, 2009 (ISBN: 978 or 85369 792 3). Said compositions typically contain from 1 to 40% by weight of the compound of formula (1) as active ingredient, the rest of the composition being pharmaceutical vehicles and / or excipients.
Optionally, the pharmaceutical composition may contain a
additional active substance in combination with the compound of formula (1).
preferably the pharmaceutical composition may contain another agent
10 antibacterial.
Process for preparing the compounds of the invention
A fifth aspect of the present invention relates to a process for the preparation of a compound of formula (1) as defined above, or a pharmaceutically acceptable salt or solvate thereof, which
comprises reacting a compound of formula (11)OR
(R "~
"
XOR "
~
R,
N,
R "
(eleven)
with a compound of formula (111) or a pharmaceutically acceptable salt or solvate thereof:
(111)
Where R16 is hydrogen or a C-alkyl, R17 is hydrogen or Rs, and where n and R1 to R1!, Have the same meaning as defined above in relation to the compounds of formula (1). The procedure can be represented according to Scheme 1: 25
(eleven)
SCHEME!
As is well known to the person skilled in the art, the use of conventional protecting groups may be necessary to prevent unwanted reactions of some reactive or labile groups. The choice of a suitable protecting group for a particular functional group, as well as the conditions suitable for protecting and deprotecting various functional groups are well known in the art. For example, numerous protective groups are described, and their introduction and withdrawal, in
T. W. Greene and G. M. Wuts, · Protecting Groups in Organic Synthesis ~. Third edition, Wiley, New York, 1999, and references cited therein.
For example, the processes may involve the reaction of a protected form of the compound of formula (11), or / and an amino protected form of the compound of formula (111), and the process can be followed, if necessary, by withdrawal of any of the protecting groups that may be present.
In one embodiment R17 is Re and the compound of formula 11 is a compound of formula (11.). According to this embodiment, the compound of formula
(1) can be obtained directly after the coupling reaction between the compound of formula (11.) and the compound of formula (111), followed, if necessary, by the removal of any of the conventional protecting groups that may be present (Method A).
In another embodiment R17 is hydrogen and the compound of formula (11) is a compound of formula (lit,). According to this embodiment, the compound of formula (! Lb), optionally in a protected form, is first coupled with the compound of formula (111), to form a compound of formula (IV), and the Re group can introduced after the coupling reaction (Method B), as shown below in Scheme 11.
or
(R ,, ~ Jl
«I'Ro 'OR"
.. NH g
(11.) ~ I I)
(B)
SCHEME 11
5 To protect the amine group of the pyrrolidine ring, as well as any other amine group that may need to be protected, any suitable protecting group can be used, for example, the tert-butoxycarbonyl protecting group can be used
(Boc) or the carboxybenzyl protecting group (Cbz or Z). In another embodiment, the compound of formula (1) obtained according to the procedure of Scheme I can be converted into another compound of formula
(1) converting one or more of the radicals R ,. R2, R3, ~, Rs. Rs. R7, Re. Rg and RlO (yes
is present) in other radicals R "R2, R3. R •. Rs, R6, R1 • Rg • Y R, or, respectively,
or by adding an R radical, or additional, or removing an R radical, or. using known procedures.
The coupling reaction between the compound of formula (11), both (11.) or (1 Ib), and the compound of formula (111), to form an amide bond, is preferably carried out in the presence of a coupling agent. , as is well known to the expert in organic chemistry. Among others. The following coupling agents can be used: ethyl- (N ', N'-dimethylamino) propylcarbodiimide hydrochloride
20 (also known as EDC.HCI), or 1 [bis (dimethylamino) methylene] -1 Hl, 2,3-triazolo [4,5-b] pyridinium-3-oxide) hexafluorophosphate (also known as HATU) . In addition, the coupling reaction can be performed using trimethylaluminum (AIMe3) as a coupling aid.
Compounds (11) and (111) are reacted suitably 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 (DI PEA), triethylamine
(TEA), 4-dimethylaminopyridine (DMAP), or mixtures thereof.
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, diethyl ether 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.
A preferred method of carrying out the coupling reaction of the compound (11) with the compound (111), as defined above, involves using the HATU coupling agent, more preferably in the presence of the DIPEA base. Preferably, the reaction is carried out using dimethylformamide as solvent, and at about room temperature.
Another preferred method for carrying out the coupling reaction of the compound (11) with the compound (111), as defined above. It involves using the EDC.HCI coupling agent, more preferably in the presence of the DMAP base, and optionally in the presence of hydroxybenzotriazole (HOSt). Preferably, the reaction is carried out using dichloromethane as solvent, and at about room temperature.
Another preferred method of carrying out the coupling reaction of the compound (lIb) with the compound (111), for example, when R16 is methyl or ethyl, involves using trimethylaluminum as a coupling aid. Preferably, the reaction can be carried out in the 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 of 50-130 oC. For example, the reaction can be carried out in a microwave reactor.
It will be appreciated that although some preferred conditions for performing the procedures, such as temperature, reagents, or solvents are described herein, for example, it will be a matter of course for the person skilled in the art to adjust such conditions to each particular case to achieve results. optimized
The compounds of formula (11) and formula (111) are commercially available or can be prepared using methods known to the person skilled in the art.
For example, a compound of formula (11.) can be obtained from a compound of formula (II ~) by attaching a group Re to the N atom of the pyrrolidine ring using known methods.
For example, when Re is a Cl-6 alkyl, the compound of formula (11) can be obtained by N-alkylation of pyrrolidine according to methods well known in the art, for example, using alkyl halides or alcohols as agents. alkylation, or by reductive alkylation by means of an aldehldo or ketone in the presence of a reducing agent.
When Re is a -CONH2 group, the compound of formula (11) can be obtained, for example, by reacting the corresponding compound of formula (1Ib) with potassium cyanate (KOCN).
When Re is a group -CONR13R104, the compound of formula (11.) can be obtained, for example, by reacting the corresponding compound of formula (H b) with CICONR13R14.
Alternatively, when RB is a group -CONR13R14, the compound of formula (H.) can be obtained, for example, by a transacylation reaction promoted by carbonyldiimidazole, as depicted in Scheme 111:
R "
one-
HN,
R "
Ao N ...- R13 I •
R1 •
SCHEME 111
x.e ""
// -N Ak-N: I
; ::::: J
The compounds of the invention, as well as the intermediates, can be prepared by the methods described herein, or small variations thereof, as well as using alternative methods, as will be a matter
25 routine for the expert in the field. The following examples are provided by way of illustration and should not be construed as limiting the present invention,
Examples
Abbreviations:
- Boc: tert-butoxycarbonyl
- (BochO or Boc anhydride: di · tert · butyl dicarbonate
- Cbz: carboxybenzyl
- DCM: dichloromethane
- DIPEA: N, N ~ iisopropylethylamine
- DMF: dimethylformamide
- EOC.HCI: eW · (N ', N' · dimethylamino) propylcarbodiimide hydrochloride
- EtOAc: ethyl acetate
- HATU: (1 · [bis (dimethylamino) methylene) hexafluorophosphate) · 1 H · 1, 2,3 · triazolo [4,5 ·
b] pyridinium · 3 · oxide)
- LiHMOS: lithium bis (trimethylsilyl) amide
- mCPBA: meta-chloroperoxybenzoic acid
- MeOH: methanol
- Pd / C: palladium on activated carbon
- ASD: triethylamine
- THF: tetrahydrofuran
General Methods:
Moisture and oxygen sensitive reactions were carried out in dry glass material (Schlenk flasks hermetically sealed with a rubber septum) in a nitrogen atmosphere.
Solvents
All solvents used were of an analytical grade quality and if not mentioned otherwise demineralized water was used.
Water-free solvents were distilled fresh before use in an atmosphere of N2 • -Tetrahydrofuran (THF) from sodium · benzophenone cetyl,
Methanol from magnesium methanolate, Oichloromethane (CH2Cb) from calcium hydride. The HPLC solvents had a gradient grade quality and doubly distilled water was used. All eluents were degassed by
ultrasound before use.
Thin layer chromatograph (TLC)
Thin layer chromatography was performed with TLC 5 60 F254 silica gel on aluminum sheets (Merck) in a saturated chamber at room temperature. The points were visualized under UV light (254 nm) and with reagents, such as iodine vapor with additional heating. Since the value of F strongly depends on the exact proportion of the eluent components and some of these components are highly volatile, the Fr values given simply represent approximate values.
Chromatograph in uftraffápid column (faith)
Flash column chromatography (fe) was performed with silica gel (100-200m 11m) (Spectrochem) as a stationary phase. Compressed air 15 was used to push the solvent through the column.
Method d. HPLC
Model: Waters 2695 separation module Column: Waters XTerrao MS C18 (5 ~ m) 20 2.1 x 250 mm column Solvent: A: acetonitrile with 0.05% formic acid (vlv).
B: water with 0.05% formic acid (vlv)Gradient:
time [minI solvent A ['lo]solvent B [minI
0, 0 5.095.0
3, 0 5.095.0
10.0 100.00.0
15.0 100.00.0
17.0 5.095.0
18.0 5.095.0
25 Flow rate: 0.30 ml / min Injection: volume: 2.0 jJl Wavelength: 210 -240 nm
Auto-zero baseline: 0.0 min
Calculation: use the white subtraction of the same series
Integration: manual
Calculation method:% of area
5 All HPLC methods were performed at room temperature.
Mass spectrometry
Mass spectra were recorded with a mass spectrometer.
Micromass Quatro micro ™ APio All samples were measured in ion mode
1O positive and negative, all specified fragments show ions or radicals
positively charged. Mass proportions are given at miz load and intensities
relative signal [%) of ions.
NMR spectroscopy
fifteen NMR spectra 'H (500 MHz) were recorded in a Brucker
UltraShiefd (500 MHz), operating at 23 oC. The chemical shifts 3 are
indicated in parts per million (ppm) against the reference compound tetramethylsilane and
they are calculated using the chemical shift of the solvent signal without deuterating.
Abbreviations for the multiplicities of the signals:
twenty s = singlet, d = doublet, t = triplet, c = quadruplet, quint. =
quintuplete, m = multiplet, dd = doublet of doublets, etc.
Intermediate 1: Methyl Oxopyrrolidin-2-carboxylate
To a stirred solution of 5-oxopyrrolidin-2-carboxylic acid (10 g,
25 77.4 mmol) in MeOH (100 mL) thionyl chloride (6.7 mL, 92.9 mmol) was added to
OoC and the reaction mixture was stirred at 70 ° C for 16 h. The progress of the reaction
It was controlled by TLC. The excess of MeOH was evaporated, the residue was diluted with
EtOAc (2 x 25 mL), the combined organic layer was stirred over K2C03 (3 g), washed with
water (20 ml) and brine (20 ml) and the organic layer was separated, dried over Na2S004
30 anhydrous and concentrated under reduced pressure. The crude compound was purified by
uttrarrápida column chromatography (silica gel, 100-200 mesh) to provide
the Utulo compound (4.3 g, 39% yield) in the form of a colored liquid
brown.
NMR 'H (500 MHz, CDCI,) b: 6.12 (s, 1H), 4.27 (e, J = 5.44 Hz, 1H),
35 3.79 (s, 3H), 2.51-2.41 (m, 1H), 2.43-2.37 (m, 2H), 2.34-2.24 (m, 1H).
54
Intennedium 2: S ... 1-tert-Butyl-2-methyl Qxopyrrolidin-1,2-dlcarboxylate
To a stirred solution of methyl 5-oxopyrrofidin-2-carboxylate (Intermediate t) (4.3 g, 30.06 mmol) in DCM (43 mL), DMAP (3.6 g, 29.50 mmol) was added ), followed by ASD (8.39 ml, 64.79 mmol) and Boe-anhydride (20.7 ml,
5 90.10 mmoi) at O oC 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 a 1 N aqueous solution of HC! (20 mi) followed by brine (20 mi). The organic layer was separated, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by chromatography on
10 ultrafast column (silica gel, 100-200 mesh) to provide the title compound (6.8 g, 93% yield) in the form of a brown liquid.
NMR 'H (400 MHz, CDCI,) 6 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)
Intennedium 3: methyl 1,5-Dimethylpyrrolidin-2-carboxylate
The title intermediate was prepared from intermediate 2 (-5-oxopyrrolidin-1, 2-methyl-butyl-2-methyl dicarboxylate) according to the procedure depicted in Scheme IV.
aoe ...... ~: c: oeH,
.
...... CH3 (Stage 2)
o o
or
o / eH,
N,
~ eH,
H, c
20 SCHEME IV
Step 1: Preparation of methyl 2- (tert-butoxycarbonifamino) -5-oxohexanoate To a stirred solution of 5-oxopyrrolidin-1, 2-dicarboxylate of 1-tert-25-butyl-2-methyl (6.8 g, 27.89 mmol) in THF (68 ml), CH3MgBr (3 M in ether) was added.
12.12 ml, 36.36 mmol) at 0 ° C in an 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 activated with an aqueous NH ~ CI solution and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (20 ml) and brine (20 ml), dried over anhydrous Na2S0 .. and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, 100-200 mesh) to provide the title compound (3.6 g,
5 yield of 49%) in the form of a yellow liquid.
NMR 'H (400 MHz, CDCI,) 6 5.10 (sa, 1 H), 4.25 (s, 1 H), 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-pyrroJ-2-carboxylate To a stirred solution of methyl 2- (teffi-butoxycarbonylamino) -5-oxohexanoate (6.8 g, 27 , 89 mmol) in DCM (36 ml), trifluoroacetic acid (5.3 ml. 40.9 mmol) was added to OoC and the reaction mixture was stirred for 2 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture is
15 concentrated under reduced pressure to provide the title compound (3.6 g, 28% yield) as a yellow liquid. The crude compound was used for the next step without purification.
Step 3: Preparation of methyl 5-methylpyrrolidin-2-carboxylate
To a stirred solution of methyl 5-methyl-3,4-dihydro-2H-pyrrol-2-carboxylate (3.6 g, 25.53 mmo1) in ethanol (36 mL), Pd / C was added ( 10% wet, 1 g) under a nitrogen atmosphere and the reaction mixture was stirred under a hydrogen atmosphere for 16 h at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a bed of ceJite and the filtrate was
25 concentrated under reduced pressure to provide the title compound (3.5 g, 95% yield) as a brown liquid. The crude compound was used for the next step without purification.
Step 4: Preparation of methyl 1,5-dimethylpyrrolidin-2-carboxylate
To a stirred solution of methyl 5-methylpyrrolidine-2-carboxylate (2.2 g, 13.99 mmol) in MeOH (15.4 mL) was added NaHCO, (1.29 g, 15.38mmol) to O · C. After stirring the reaction mixture for 5 min. Aqueous formaldehldo (37% p, 1.14 ml. 30.76 mmol) was added and stirring was continued for 2 h. followed by the addition of NaBH ~ (0.876 g, 23 mmo1) at the same temperature. The mixture of
The reaction was stirred for a further 1 h at room temperature. The progress of the reaction was monitored by TLC. The excess of MeOH was evaporated, the residue was diluted with water (20 ml), and extracted with EtOAc (2 x 20 ml). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over Na2S04 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, 100-200 mesh) to provide the title compound as a brown liquid.
NMR 'H (400 MHz, CDCI,) OR 3.75 (1, J = 9.08 Hz, 3H), 2.92 (1, 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 ~ arbamoylpyrrolidin-2-carboxylic acid
To a stirred solution of D-Proline (1 g, 8.69 mmol) in water (50 ml) was added concentrated HCI (pH -5), 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 (2 x 100 mL) and dried in vacuo to provide the compound of the Utulo (460 mg, 33% yield) in the form of a white solid.
Intermediate 5: (S) -1-carbamoylpyrrolidin-2-carboxylic acid
The Utulo compound (500 mg, 36% yield) was prepared following a procedure analogous to that of Intermediate 4, but using L-Proline (1 g, 8.69 mmol), as the starting material.
Intermediate 6: 1-carbamoylpyrrolldin-2-carboxylic acid
The title compound (500 mg, 14% yield) was prepared from DL-proline (2.5 g, 21.7 mmol), following a procedure analogous to that of Intermediate 4.
NMR 'H (400 MHz, DMSO-d,) OR 12.35 (s, 1 H), 5.85 (s, 2H), 4.15 (d, J = 8.44Hz, 1 H), 3, 25 (m, 1 H), 2.05 (m, 1 H), 1.8 (d, J = 5.2 Hz, 3H),
Intermediate 7: Acid (2S, 4S) -1-carbamoyl-4-fluoropyrrolidin-2-carboxillco
The title compound (260 mg, 79% yield) was prepared from (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid (260 mg, 1.87 mmol), following a procedure analogous to that of Intermediate 4 .
Intermediate 8: Methyl pyrrolidin-2-carboxylate
To a stirred solution of pyrrolidin-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 thionyl chloride was quenched with solid NaHC03, filtered, and the filtrate was concentrated under reduced pressure to provide the title compound (1, 1 g, yield 8%) in the form of a pale yellow solid.
Intermediate 9: 1-tert-butyl 2-methyl pyrrolidin-1,2-dicarboxylate
To a stirred solution of methyl pyrrolidine-2-carboxylate (Intermediate 8) (1 g, 7.74 mmol) in DCM (10 mL) was added TEA (2.7 mL), followed by di-tere dicarbonate. butyl (Boc anhydride, (BochO) (l, 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 mixture of The reaction was quenched with water (20 mL) and extracted with chloroform (2 x 20 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2S04 and concentrated under pressure. The crude compound was purified by column chromatography (silica gel, 100200 mesh) to provide the title compound (1.3 g, 73% yield) as a pale yellow liquid.
Intermediate 10: 2 · 1 · tert-Butyl-methyl-1,2-dicarboxylate
To a stirred solution of pyrrolidin-1,2-dicarboxylate of 1-tert-butyl 2-methyl (Intermediate 9) (2.75 g, 12.00 mmol) in THF (5.5 mL), LiHMDS (bis (trimethylsilyl) lithium amide) (1 M in n-hexane, 19.21 ml, 19.23 mmol) at -20 ° C. After stirring the reaction mixture for 1.5 h at the 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 a solution of NH4CI and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, 100-200 mesh) to provide the title compound (1.5 g, 51% yield) as a pale yellow liquid. CGEM miz: 243
Intermediate 11: 1 · Hydroxypyrrolidine · 2 - methyl carboxylate
The title compound was prepared from methyl pyrrolidine-2-carboxylate (Intermediate 8) according to the procedure depicted in Scheme V:
° .... CH,
ce o .... CH,
or • OR •
NH (Stage 1) N (Stage 2)
~ CN
SCHEME V
Stage 1: Preparation of 1- (2-cyanoethyl) pyrrolidin-2-carboxy / methyl ato
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 provide the title compound (200 mg, 56% yield) as a colorless liquid. The crude compound was used for the next step without purification.
NMR 'H (400 MHz, CDCI,) 6 3.75 (s, 3H), 3.35 (sa, 1 H), 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), 2.001.85 (m , 3H).
Stage 2: Preparation of 1-hydroxypyrrolidin-2-carboxy / methyl ato
To a stirred solution of methyl 1- (2-cyanoethyl) pyrrolidin-2-carboxylate
(1 g, 5.49 mmol) in DCM (15 mL), 6 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 flash column chromatography (silica gel, mana 100-200) to provide the title compound (150 mg, 18% yield) as a colorless liquid.
NMR 'H (400 MHz, DMSO-d,) 6 8.1 (s, 1H), 3.6 (s, 3H), 3.4 (1, J = 7.8 Hz, 1H), 3.03 -3.08 (m, 1H), 2.7 (e, J = 8.24 Hz, 1H), 2.05-1, 98 (m, 1H), 1.77-1, 71 (m, 3H ).
Intermediate 12: 1 .. (Oimethylcarbamoyl) methyl pyrrolidin-2-carboxylate
To a stirred solution of methyl pyrrolidine-2-carboxylate (200 mg, 1.74 mmol) in DCM (10 mL) was added TEA (0.72 mL, 5.27 mmol), followed by dimethylcarbamic chloride (0, 19 ml, 2.08 mmol) and the reaction mixture was stirred at temperature
ambient 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 (2 x 15 ml). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na2S0 ~ and concentrated under reduced pressure to provide the compound of the
5 title {180 mg, 51% yield} as an off-white solid.
Intermediate 13: 4 .. (2- (Methoxycarbonyl) pyrrolidin-1 <arbonyl) piperazin-1 <tert-butyl arboxylate The title compound was prepared according to the procedure 10 represented in Scheme VI:
E SAUEMA VI
Stage 1: Preparation of 4- (1H-imidazo / -1-carbonif) tere-15-butyl piperazin-1-carboxylate
To a stirred solution of carbonyldiimidazole (5 g, 30.84 mmol) in DCM (50 ml) TEA (4.33 mi, 30.83 mmol) and Boc-piperazine (5.74 g, 30.83 mmol) ) 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
20 water (50 ml) and extracted with OCM (2 x 50 ml). The combined organic layer was dried over anhydrous Na2S0 ~ and concentrated under reduced pressure to provide the title compound (3 g, crude) as an off-white solid. The crude compound was used for the next step without purification.
Step 2: Preparation of 1- (4- (tert-butoxycarboniJ) piperazin-1-carbonyl) -3-methyl-1 H-imidazol-3-io iodide To a stirred solution of 4- (1 H-imidazol-1- carbonyl) piperazin-1
le / thi-butyl carboxylate (3 g, 10.67 mmol) in acetonitrile (15 ml), iodomethane (2.64 ml, 42.70 mmo1) was added to OoC 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 provide the title compound.
5 (3 g, crude) in the form of an off-white solid. The crude compound was used for the next step without purification.
Stage 3: Proparation of 4- (2- (methoxycarbonyl) pyrrolidin-1-carbonyl) piperazin-1-carboxy / tert-butyl ato
10 To a stirred solution of 1- (4- (tert-butoxycarbonyl) piperazin-carbonyl) -3-methyl-1H-imidazol-3-io iodide (3 g, 10.16 mmol) in DCM (30 mL), TEA (1.42 mL, 50.84 mmol) and pyrrolidin-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 born with
15 water (50 ml), and extracted with DCM (2 x 50 ml). The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography to provide the title compound (1 g, 29% yield) as an off-white solid.
Intermediate 14: 1-methyl Morphol-4-carbonyl) pyrrolidin-2-carboxylate The Utulo compound was prepared according to the procedure depicted in Scheme VII:
SCHEME VII
Stage 1: Preparation of (1 H-imidazo / -1-yl) (morpholino) methanone To a stirred solution of carbonyldiimidazole (5 g, 30.83 mmol) in DCM (50 ml), ASD (4 , 3 ml, 30.83 mmol) and morpholine (2.5 g, 29.06 mmol) 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 (2 X 50 ml). The combined organic layer was washed with water (20 ml) and brine (20 ml), dried over Na2S0 ,. anhydrous and concentrated under reduced pressure to provide the title compound (3 g, crude) as an off-white solid. The crude compound was used for the next step without purification.
Stage 2: Preparation of (3-metif-1- (morphofin-4-carbonyl) -1H-imidazof-3-io iodide
To a stirred solution of (1 H -imidazol-1-yl) (morpholino) methanone (3 g, 16.55 mmol) in acetonilrile (15 mL) was added iodomethane (4.1 mL, 66.22 mmol) to OoC 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 provide the title compound (2 g, crude) as an off-white solid. The crude compound was used for the next step without purification.
Step 3: Preparation of methyl 1- (morpholin-4-carbonyl) pyrrolidin-2-carboxylate
To a stirred solution of (3-methyl-1- (morpholin-4-carbonyl) -1Himidazol-3-io (2 g, 10.16 mmol) iodide in DCM (30 ml) was added TEA (7.1 mi, 50.84 mmol) and pyrrolidin-2-carboxylic acid methyl ester (2.62 9, 20.35 mmol) 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 (2 x 25 ml) The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure The crude compound was purified by column chromatography to give the title compound (9, yield 41%) as an off-white solid.
Intermediate 15: 1-Methyl-6.oxypyrrolidin-2-carboxylate methyl
To a stirring solution of sodium hydride (2 equiv.) In anhydrous DMF (2 ml) under an ice-cooled condition under an argon atmosphere, a solution of ethyl 5-oxopyrrolidine-2-carboxylate was added dropwise (300 mg in 3 ml of DMF) for a period of 10 min, and the reaction mixture was stirred for 15 min at the same temperature. Then, iodomethane was added and allowed to stir for 3 h. To interrupt the reaction, a saturated solution of NH ~ CI (5 mL) was added and extracted with DCM (2 x 10 mL). The combined organic portion was dried over anhydrous sodium sulfate and removed by distillation under reduced pressure to obtain the title compound (175 mg).
LC-MS: 172.2 (M + H).
Intermediate 16: 1,2-dimethylpyrrolidin-2-carboxylic acid
The title compound was obtained by N-methylation of 2-methylpyrrolidin-2-carboxylic acid. Therefore, to a stirred solution of 2-methylpyrrolidin-2-carboxylic acid (300 mg) in anhydrous MeOH (10 ml), 1 ml of formaldehyde was added dropwise to O oC, followed by a catalytic amount of acetic acid , and the reaction mixture was stirred for 10 min at the same temperature. Then, 50 mg of 10% Pd / C was added and the reaction mixture was stirred at room temperature in the presence of a hydrogen atmosphere for 2 h. The progress of the reaction was monitored by TLC. After complete consumption of the starting materials, the reaction mixture was filtered through a bed of celite to remove the solid residue, which was washed several times with MeOH. 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-methylpyrrolidin-2-carboxylic acid
The title compound was obtained by N-methylation of 4-fluoropyrrolidine-2-carboxylic acid, following a procedure analogous to that previously disclosed for the preparation of Intermediate 16. 150 mg of 4-fluoropyrrolidine-2-carboxylic acid provided 120 mg of the title compound.
LC-MS: 148.2 (M + H).
Intermediate 18: 3-methyl-3-azabicyclo [3.1, O] hexane-2-carboxylic acid
The title compound was obtained by N-methylation of 3azabicyclo acid [3,1,0) hexane-2-carboxylic acid, following a procedure analogous to that previously disclosed for the preparation of Intermediate 16. 300 mg of 3azabicyclo acid [3.1, 0) hexane-2-carboxylic provided 300 mg of the title compound.
LC-MS: 144.18 (M + H).
Intermediate 19: 1,4-dimethylpyrrolidin-2-carboxylic acid The title compound was obtained by N-methylation of 4-methylpyrrolidin-2-carboxylic acid, following a procedure analogous to that disclosed.
previously for the preparation of Intermediate 16. 250 mg of 4 · methylpyrididine-2-carboxylic acid provided 250 mg of the title compound. LC-MS: 144.18 (M + H)
5 Intermediate 20: 1,3-dimethylpyrrolidine acid 2 - <: arboxylic
The title compound was obtained by N-methylation of 3-methylpyrrolidine-2-carboxylic acid, following a procedure analogous to that previously disclosed for the preparation of Intermediate 16. 250 mg of 3-methylpyrrolidine-2-carboxylic acid provided 250 mg of the title compound.
10 LC-MS: 144.18 (M + H)
Intermediate 21: 1-Ethylpyrrolidin-2-carboxylic acid The title compound was obtained by N-ethylation of pyrrolidin-2-carboxylic acid, following a procedure similar to that of N-methylation
15 previously disclosed for the preparation of Intermediate 16, but using acetaldehyde instead of formaldehyde. 1-9 of pyrrotidin-2-carboxylic acid provided 187 mg of the title compound. LC-MS: 144.18 (M + H)
20 Intermediate 22: 1 · (Benclloxlcarbonll) AcidJidln · 2-carboxylic acid A mixture of pyrrolidin · 2-carboxylic acid (2.5 g, 21.7 mmol), NaOH (2M 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 (2 x 50 mL). The
The combined organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide the title compound (1.5 g, 27% yield) as a colorless liquid.
Example 1: N'-i4-fluorofe n i 1) -1,5-d imeti I pi rro I id i n-2-ca rboh id razida
To a stirred solution of methyl 1,5-dimethylpyrrolidine-2-carboxylate (Intermediate 3) (0.3 g, 1.91 mmol) in toluene (6 mL) was added 4-fluorophenylhydrazine hydrochloride (0.31 g , 1.91 mmol), TEA (0.536 ml, 4.13 mmol) and trimethylaluminum (2 M solution in toluene, 0.96 ml, 1.91 mmol) at OoC and the reaction mixture was stirred at 70 ° C in a 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 (2 x 20 ml). The combined organic layer was washed with water (5 ml) and brine
5 (5 ml), dried over anhydrous Na2S0 .. and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, maUa 100200) to provide the Utulo compound (18 mg, 3% yield) as a pale brown solid. NMR 'H (400 MHz, DMSO-d,) OR 9.98 (s, 1H), 7.64 (s, 1H), 6.95 (1, J =
10 8.72 Hz, 2H), 6.7 (e, 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, 1 H), 1.40-1, 30 (m, 1 H), 0.93 (d, J = 6 Hz, 3H) LC-MS miz (M + H): 252.2 Purity (HPLC): 99.3%
Example 2: {R) -2- {2- {4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide
or
H2N - (O if ~~~ UF
To a stirred solution of (R) -1-carbamoylpyrrolidin-2-carboxylic acid (Intermediate 4) (500 mg, 3.16 mmol) in DMF (5 ml) OIPEA (1, 61 ml, 20 9) , 23 mmol), HATU (1.44 g, 3.79 mmol) and 4-fluorophenylhydrazine hydrochloride (563 mg, 3.48 mmol) at 0 ° C under a 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 (2 x 15 ml). The combined organic layer was washed with water (10 ml) and brine
25 (10 ml), dried over anhydrous Na ~ O .. and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, mana 100-200) to provide the title compound (28 mg) as an off-white solid.
NMR 'H (400 MHz, DMSO-d.) OR 9.61 (d, J = 2.6Hz, 1H), 7.59 (d, J = 30 2.4Hz, 1H), 6.91 (1, 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 miz (MH): 265.1 Purity (HPLC): 99.8% Example 3: (S) -2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide
or
H2N - (O
or,) l (~ UF The title compound was prepared following an analogous procedure.
5 to that of Example 2, but using (S) -1-carbamoylpyrrolidin-2-carboxylic acid (Intermediate 5) as starting material. 500 mg of Intermediate 5 provided 35 mg (4% yield) of the title compound as an off-white solid.
NMR 'H (400 MHz, DMSO-d,) OR 9.62 (s, lH), 7.60 (s, lH), 6.91 (1, J = 10 8.88 Hz, 2H), 6, 75-6.72 (m, 2H), 5.86 (s, 2H), 4.21-4.18 (m, lH), 3.38-3.31 (m, lH), 3.25- 3.19 (m, 1 H), 2.06-1, 91 (m, lH), 1.89-1.79 (m, 3H) LC-MS miz (MH): 265.0
Purity (HPLC): 99.6% 15 Examples 4-12
Examples 4-12 were prepared following procedures analogous to that disclosed for Example 2, using 1-carbamoylpyrrolidine-2-carboxylic acid (Intermediate 6) and suitable hydrazine as starting materials: Example 4: 2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide
or
H2N - (O
if ~~~~
~ F
NMR 'H (400 MHz, DMSO-d,) O 9.6 (s, lH), 7.6 (s, lH), 6.9 (1, 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, 1 H), 3.4-3.3 (m, lH), 3.3-3.2 (m, lH), 2.1-2.0 (m, lH), 1.90-1, 70 (m, 3H)
25 LC-MS miz (M-H): 265 Purity (HPLC): 99.0% Melting point: 140-144 oC
Example 5: 2- (2- (4-fluoro-2-methylphenyl) hydrazin-1-carbonyl) pyrrolidin-1-carboxamide
or
H2N- (or
if ~~~ n
H3C F
NMR 'H (400 MHz, DMSO-d,) fi 9.63 (d, J • 2.3Hz, 1 H), 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
5 3.20 (m, 1 H), 2.12 (s, 3H), 2.07-1.97 (m, 1 H), 1.96-1.83 (m, 3H)LC-MS miz (M-H): 279.2Purity (HPLC): 99.8%
Example 6: 2- (2 .. (3,5.c1lfluorofenll) hldraz¡nocarbonll) pyrrolidln ~ 1-carboxamide
H2N- (or o
if ~~~ yF
10 F NMR 'H (400 MHz, DMSO-d,) fi 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 miz (MH): 283.1
15 Purity (HPLC): 99.6%
Example 7: 2 .. (2 .. (4 .. (trlfluoromethoxy) phenyl) hydrazinocarbonll) pyrrolidin ~ 1 ~ carboxamide
or
H2N- (or H
, ~ J ~ Nl0-1 U ~ ~~ '~ VCF'
20 NMR 'H (400 MHz, DMSO-d,) fi 9.67 (d, J • 2, OHz, 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, 1 H), 3.29-3.20 (m, 1 H), 2.08-2.01 (m, 1 H), 1.92-1.78 (m, 3H )
LC-MS miz (M-H): 331.1
Purity (HPLC): 99.3%
Example 8: 2-i2-i4-itrlfluoromethyl) phenyl) hldrazlnocarbonyl) pyrrolidin-1carboxamlda
NMR 'H (400 MHz, DMSO-d,) 6 9.77 (s, 1H), 8.29 (s, 1H), 7.38 (d, J = 5 8.3Hz, 2H), 6.84 (d, J = 8.3Hz, 2H), 5.86 (s, 2H), 4.23-4.20 (m, 1 H), 3.39 (s, 1 H), 3,293.20 (m , 1 H), 2.12-2.03 (m, 1 H), 1.95-1, 81 (m, 3H) Cl-MS miz (MH): 315.2
Purity (HPLC): 99.8%
Example 9: 2-i2-i4 ~ loro-2-f1uorofenll) hydrazlnocarbonyl) plrrolldin-1 carboxamide
NMR 'H (400 MHz, DMSO-d,) 6 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),
15 3.29-3.20 (m, 1H), 2.07-2.00 (m, 1H), 1.95-1.79 (m, 3H) Cl-MS miz (MH): 299.1 Purity (HPlC): 99.9%
Example 10: 2-i2-i4-methoxyphenyl) hldrazlnocarbonll) plrrolldln-1-carboxamide
or
H ~ - (O
, ~ -Jl / ~~ U ~ V'VeH '
20 NMR 'H (400 MHz, DMSO- <l,) 6 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) Cl-MS miz (MH): 277.0 25 Purity (HPLC): 99, 7%
Example 11: 2- (2- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) hydrazinocarbonyl)
pyrrolidin-1-carboxamide
OR
H2N- {O
(r ~ '~ 1; ()
O NMR 'H (400 MHz, DMSO-d,) O 9.51 (s, 1H), 7.21-6.95 (m, 1H), 6.58 (d, 5 J = 8.2Hz, lH ), 6.25-6.23 (m, 2H), 5.82 (s, 2H), 4.21-4.10 (m, 5H), 3.37-3.25 (m, lH), 3.22-3.15 (m, 1H), 2.10-1.95 (m, 1H), 1.87-1.81 (m, 3H) LC-MS miz (M + H): 306, 2 Purity (HPLC): 99.7%
Example 12: 2- (2- (4-sulfamoylphenyl) hydrazylcarbonyl) pyrrolidln-1-carboxamlda
or
N
H2- {or H
H o
I
(rN '"' Q
fi ~ ....... NH2 1I
or NMR 'H (400 MHz, DMSO-d,) OR 9.77 (s, 1 H), 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), 3,413.36 (m, 1 H), 3.26-3.20 (m, 1 H), 2.09-2.02 (m, 1 H), 1.94-1.80 (m, 3H) 15 LC-MS miz ( MH): 326.1 Purity (HPLC): 98.2%
Example 13: (2S, 4S) -4-fl uoro-2 - (2 - (4-fluorophen i I) h id razi nocarbonil) pi rroli d i n-1
carboxamide
or
H2N- {o
or ,,) l ~ '~' QF
<20 f
The title compound (30 mg) was prepared following a procedure analogous to that of Example 2, but using (2S, 4S) -1-carbamoyl-4-f1uoropyrrolidin-2 acid
carboxylic (Intermediate 7) (260 mg, 1.47 mmol) as starting material.
NMR 'H (400 MHz, DMSO-d,) O9.58 (s, 1H), 7.57 (s, 1 H), 6.92-6.88 (m, 25 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 miz (M-H): 283.2 Purity (HPLC): 99.2% Example 14: (R) -1-acetyl-N '- (4-fluorofe n i1) pirro Iidin-2 -ca rbo h Idrazid a
To a stirred solution of (R) -1-acetylpyrrolidin-2-carboxylic acid
(50 mg, 0.31 mmol) in dry DMF (2 ml), DIPEA (82 mg, 0.63 mmol) was added,
HATU (181 mg, 0.47 mmol) and 4-ftuorophenylhydrazine hydrochloride (65 mg, 0.37 mmot) at OoC and then the reaction mixture was stirred for 1 h at room temperature.
10 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 in vacuo to give the title compound (30 mg, 35% yield) as an off-white solid.
NMR 'H (400 MHz, CD, OD) O6.95-6.84 (m, 4H), 4.45 (dd, J = 3.8Hz, J 15 = 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 miz (MH) : 266.2
Purity (HPLC): 98.8%
Example 15: N '- (4-fluorofenll) -1-hydroxypyrrolidin-2-carbohydrazide
(JY ~~
20 ~ F
To a stirred solution of methyl 1-hydroxypyrrolidine-2-carboxylate (Intermediate 11) (250 mg, 1,373 mmol) in dry toluene (5 mL), 4-f1-phenylpherazhydrazine hydrochloride (223 mg, 1.37 mmol) was added , TEA (0.355 mi, 2.74 mmol) and trimethylaluminum (2 M in toluene, 0.69 mi, 1.37 mmol) at OoC and the reaction mixture is
25 stirred at 70 ° C for 1.5 h in a 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 (2 x 15 mL). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na2S0 "and concentrated under reduced pressure. The crude compound was purified by column chromatography.
Ultrafast 30 (silica gel, 100-200 mesh) to provide the title compound (30
mg, 7% yield) as an off-white solid.
NMR 'H (400 MHz, DMSO-d,) OR 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, 1 H), 3.15 (s, 1 H), 2.7 (c, J = 8.76 Hz, 1 H ), 2.1 (c, J = 9.76 Hz, 1 H), 1.81-1, 65 (m, 3H)
5 LC-MS miz (M + H): 240.2
Purity (HPLC): 98.8%
Example 16: N '- (4-fluorofenll) -1, 2 ~ imetilplrrolidln · 2.Carbohldrazide
OR
~~ J ~
~ t: ~ F
Method A 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.HCI (1 , 5 equiv.) And DMA (1, 5 equiv.). After stirring for
At 10 min at 0 ° C, 4-fluorophenylhydrazine hydrochloride (1.5 equiv.) Was added under an argon atmosphere. After the addition was complete, 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 x 10 mL). The collected organic phase was dried over Na2S0. anhydrous and concentrated under reduced pressure
20 to obtain the title compound, which was purified by column chromatography
(DCM: MeOH = 9.5: 0.5) (42 mg, 12% yield).
NMR 'H (500 MHz, DMSO-d,) O1.12 (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, t H), 6.70-6.58 (m, 2H), 6.996.96 (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
The title compound was prepared by coupling 2-methylpyrrolidin-2
N-Boc-protected methyl carboxylate (Intermediate 10) with 4-fluorophenylhydrazine, followed by deprotection and methylation of the N atom of the pyrrolidine ring, according to the procedure depicted in Scheme VIII:
1: ~ '
or NH:
~
d'o / CH, _, ____.
N, Boc (Stage 1)
SCHEME VIII
Step 1: Preparation of tert-butyl 2- (2- (4-ffuorophenyl) hydrazinocarbonyl) -2-methyppinulidin-15 carboxylate
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 was added (2.4 g, 14.81 mmol), followed by TEA (3.1 g, 30.69 mmol) and trimethylaluminum (2 M in tatuene, 2.65 g, 36.80 mmol) at temperature
10 and the reaction mixture was stirred at 60 oC in microwave for 1 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with a solution of NH..CI and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (20 ml) and brine (20 ml), dried over anhydrous NalSO "and concentrated under reduced pressure. The crude compound was purified by
15 column chromatography (silica gel, 100-200 mesh) to provide the title compound (2.2 g, 53% yield) as an off-white solid.
NMR 'H (400 MHz, CDCI,) ~ 9.13 (s, 1H), 6.94-6.92 (m, 2H), 6.81 (s, 2H), 6.00 (s, 1H) , 3.51 (sa, 2H), 2.66 (s, 1H), 1.80 (s, 3H), 1.68 (s, 3H), 1.49 (s, 9H) 20 LC-MS miz (MH): 336.2
Stage 2: Preparation of N '- (4-fluorophenyl) -2-methylpyrrolidin-2-carbohydrazide
To a stirred solution of tert-butyl 2- (2- {4-f1uorophenyl) hydrazinocarbonyl) -2-methylpyrrolidin-1-carboxylate (2.2 g, 6.52 mmol) in DCM (4 mL), 25 af ' trifluoroacetic acid (4.4 ml) was added at OoC 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 OCM (3 x 10 mL). The crude compound was neutralized with a saturated solution of NaHC03 (3 mL) and was
extracted with 10% MeOH / chloroform (2 x 30 ml). The combined organic layer was washed with water (20 ml) and brine (20 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide the title compound (1 g, 64% yield) as a solid. brown
5Stage 3: Preparation of N '- (4-fluorophenyl) -1, 2-dimethypyrrolidin-2-carbohydrazide
To a stirred solution of N '- (4-fluorophenyl) -2-methylpyrrolidin-2carbohydrazide (1 g, 4.21 mmol) in acetonitrile (50 ml, K2C03 (1, 439, 10.51 mmol) was added, followed of iodomethane (0.313 ml, 5.07 mmol) at OoC and the mixture of
The reaction 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 (2 x 20 mL). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by column chromatography (silica gel, mana 100
15 200) to provide the title compound (350 mg, 33% yield) in the form of a brick-red solid. NMR 'H (400 MHz, CDCI,) O9.14 (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)
20 LC-MS miz (M + H): 252.2
Example 17: 2- (2 - (4-fluoropheniI) h idrazi n ocarboniI) -N, N -dim eti Ipi rrolidi n -1carboxamlda
o
/ No
(r (~~
~ F
The title compound was prepared following an ana lake procedure of 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 performed at 90 ° C for 60 min, and the reaction mixture was quenched with NH.CI. The crude compound was purified by preparative TLC to provide the
30 title compound (30 mg, 20% yield) as an off-white solid. NMR 'H (400 MHz, DMSO-d,) OR 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, 1 H), 4.62 (1, J = 7.9Hz, 1 H), 3, 50-3.40 (m, 2H), 2.90 (s, 6H), 2.32-2.24 (m, 1 H), 2.22-2.10 (m, 1 H), 2, 09-1.94 (m, 1 H), 1.86-1, 74
(m, 1H)LC-MS miz (M-H): 293.25 Purity (HPLC): 98.2%
Example 18: N '- (4-fluorophenyl) -1- (piperazin-1 ~ arbonyl) pyrrolidin-2 hydrochloride
carbohydrazide
HN ~ o
~ Ny O
, ~ J ~~~
U ~ ~ HCI
F
The title compound was prepared by coupling the corresponding pyrrolidine intermediate (Intermediate 13), which carries a Boc protecting group in the ring of
piperazine, with 4-fluorophenylhydrazine, and subsequent deprotection, according to the procedure represented in Scheme IX:
(Stage 2)
SCHEME IX
Stage 1: Preparation of tert-butyl 4- (2- (2- (4-fluorophenyl) hydrazinocarboniJ) pyrrolidin-1carbonyl) piperazin-1-carboxy
The coupling reaction was performed following a procedure analogous to that disclosed in Example 2, using tert-butyl 4- (2- (methoxycarbonyl) pyrrolidin-1-carbonyl) piperazin-1-carboxylate (Intermediate 13) (1 g, 2, 92 mmol) as starting material, to provide the Utulo compound (100 mg, yield of
8%) in the form of a yellow solid.
Stage 2: Preparation of N '- (4-fluorophenyl) -1- (piperazin-1carbonyl) piffOfidin-2-carbohydrazide hydrochloride
5 For deprotection, a mixture of tert-butyl 4- (2- (2- (4-noorophenyl) hydrazinocarbonyl) pyrrolidin-1-carbonyl) piperazin-1-carboxylate (100 mg, 0.22 mmol) in dioxane. HCI ( 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 provide the
10 title compound (30 mg, 36% yield) in the form of a pale yellow solid.
NMR 'H (400 MHz, DMSO-d,) ~ 9.68 (s, 1H), 8.91 (sa, 2H), 7.66 (s, 1H), 6.97-6.93 (m, 2H), 6.70-6.67 (m, 2H), 4.32 (t, J = 8.8 Hz, 1 H), 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)
15 LC-MS miz (M + H): 373.0 Purity (HPLC): 99.5%
Example 19: 1 ~ 4-acetllpiperazin-1-carbonyl) -N '~ 4 hydrochloride
fluorophenyl) pyrrolidin-2..c; arbohydrazide
or
} -N "
H, C ~ N- (O or
},) l / ~~
HC1
U ~ lA
A stirred solution of N '- (4-fluorophenyl) -1- (piperazin-1carbonyl) pyrrolidin-2-carbohydrazide hydrochloride (Example 18) (200 mg, 0.53 mmol) in pyridine (2 ml) is given Acetyl chloride (42 mg. 053 mmol) was added dropwise at OoC 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 (2 x 10 ml). The combined organic layer was washed with water (10 ml), brine (10 ml). dried over Na2So. "anhydrous and concentrated under reduced pressure. The crude compound was dissolved in dioxane, HCl (10 mL) at room temperature and stirred for 10 min, the
The solvent was evaporated and washed with EtOAc (5 mL) to give the title compound (50 mg, 22% yield) as a white solid.
NMR 'H (400 MHz, DMSO-d,) OR 9.63 (d, J = 2.4Hz, 1H), 7.64 (d, J = 2, OHz, 1H), 6.93 (1, J = 8.8Hz, 2H), 6.70-6.66 (m, 2H), 4.33 (1, J = 4.4Hz, 1H), 3,463.44 (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)
5 LC-MS miz (M + H): 415.1
Purity (HPLC): 99.8%
Example 20: N '- (4-f1uorophenyl) -1 .. (morpholin-4 <arbonyl) pyrrolidin-2 hydrochloride
carbohydrazide
eye
~ N - {o
6) tyH N
UHCI
10 F
The title compound was prepared following a procedure analogous to that of Example 15, using methyl 1- (morpholin-4-carbonyl) pyrrolidine-2-carboxylate
(Intermediate 14) (1 g, 4.12 mmol) as starting material. Raw compound
obtained was purified by column chromatography and the resulting compound was treated
15 with dioxane hydrochloride for 15 m at room temperature and the solvent was evaporated to give the title compound (30 mg) as an off-white solid.
NMR 'H (400 MHz, DMSO-d,) OR 9.62 (d, J = 2.5Hz, 1H), 7.65 (d, J =2.5Hz, lH), 6.96-6.92 (m, 2H), 6.70-6.67 (m, 2H), 4.32 (1, J = 7.9Hz, lH), 3, 61-3.51 (m,20 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, 1 H), 1.75-1, 68 (m, 2H)LC-MS miz (M-H): 374.0
Purity (HPlC): 99.7%
Example 21: N '· (4 ~ fluorofenll) · 1-methyl · 5.oxoplrrolidln · 2.carbohldrazide
H'C ~ o ~~ U
o ~ I
= <Jl
.or
F
To a solution of ethyl 1-methyl · 5 ~ oxopyrrolidin · 2-carboxylate (Intermediate 15) (500 mg in 5 ml of toluene), trimethylaluminum (3 equiv.) Was added under ice-cooling conditions and stirred in an argon atmosphere for
15 min Next, 4w fluorophenylhydrazine hydrochloride (1 equiv.) In 2 ml of toluene was added to the reaction mixture and refluxed at 120 ° C for 4 h. After completion of the reaction, the reaction mixture was quenched with a saturated NH ~CI solution and extracted with EtOAc (3 x 15 mL). The collected organic phase was dried over
5 Na2S0 ~ anhydrous and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM: MeOH = 9.7: 0.3) and recrystallized from DCM and diethyl ether to obtain the title compound (25 mg, 3.15% yield).
NMR 'H (500 MHz, DMSO-d,) 6 2.01 (s, lH), 2.21 (s, 2H), 2.37 (s, lH), 2.69 (s, 3H), 5 , 08 (d, J = 7.7 Hz, lH), 5.41 (s, 2H), 7.22 (sa, 2H), 7.60 (sa, 2H) ppm 10 LC-MS (M + H ): 252.2 Purity (HPLC): 95%
w
Example 22: N '- (4w fluorophenyl) -1-methylpyrrolidin2-carbohydrazide
The title compound was prepared using a procedure analogous to that disclosed for Example 16 (method A), using 1-methylpyrrolidine-2-carboxylic acid (400 mg) as the starting product. The crude product obtained in the reaction was purified by column chromatography (DCM: MeOH = 9.5: 0.5) to provide 27 mg of the title compound (3.7% yield).
20 NMR 'H (500 MHz, DMSO-d,) 61.79 -1.73 (m, 3H), 2.09 (s, lH). 2.272.25 (m, lH), 2.34 (s, 3H), 2.86-2.83 (m, lH), 3.03 (s, lH), 6.71-6.67 (m, 2H), 7,006.96 (m, 2H), 7.62 (s, lH), 9.61 (s, lH) ppm
LC-MS (M + H): 238.8 Purity (HPLC): 95.0% Example 23: 4-amino-N '- {4-fluorophenll) -1-methylplrrolidin-2-carbohydrazide
The title compound was obtained by coupling 4-fluorophenylhydrazine with 4 · amino-1 · methylpyrrolidin-2 · carboxylic acid, previously protecting the last 30 amine with a Boc protecting group, and deprotecting it after the reaction of
coupling, as depicted in Scheme X:
SCHEME X
5 Stage 1: Preparation of 4 · ((tert-butoxycarbonyl) amino acid) · 1 · methylpyrrolidine · 2-carboxylic acid
To a solution of 4 · amino-1 · methylpyrrolidin-2 · carboxylic acid (1 equiv.) In 60 ml of dioxane: H20 (2: 3), Na2C03 (3 equiv.) Was added and stirred for 10 min at O oC. Then, this reaction mixture was added dropwise anhydrous
10 of Boc (1, 1 equiv.) At the same temperature and allowed to stir at room temperature overnight. After the reaction was completed, the reaction mixture was acidified with 1 N HCI to bring the pH to 3 and extracted with 10% MeOH in DCM (60 mL). The organic layer was dried over anhydrous Na2S0. The organic solvent was distilled off under reduced pressure to obtain the compound of the
15 crude title, which was purified by column chromatography (DCM: MeOH = 9.6: 0.4) to provide the purified title compound (yield 9.8%). Cl-EN (M + H): 245.3
Stage 2: Preparation of tert-butyl (5- (2- (4-fluorophenyl) hydrazinocarbonyl) -1-methipyrrofidin-320 yl) carbamate
The title compound was prepared using a method analogous to that disclosed for Example 16 (method A), using 4 · "tert-butoxycarbonyl) amino) -1-methylpyrrolidine-2-carboxylic acid (100 mg) as the starting product. The crude product obtained in the reaction was purified by chromatography on
25 column (DCM: MeOH = 9.5: 0.5) to provide 50 mg of the title compound (yield 34.71%). Cl-MS (M + H): 353.4
Purity (HPLC): 92.14%
Stage 3: Preparation of 4-amino-N '- (4-fluoropheniJ) -1-methipyrrofidin-2-carbohydrazide
For deprotection, 5 ml of 5 N HCI was added dropwise at OoC
5 to a solution of (5- (2- (4-f1uorophenyl) hydrazinocarbonyl) -1-methylpyrrolidin-3-yl) lerc-butyl carbamate (1 equiv.) In 5 ml of DCM, and the mixture was allowed to stir for 4 h. After complete consumption of the starting material, the solvent was distilled off under reduced pressure to obtain a sticky solid, which was dissolved in 10% MeOH in DCM and washed with a saturated NaHC03 solution. Serving
The organic was collected and dried over Na2S04, the organic portion was distilled off under reduced pressure to obtain the title compound (25 mg, 69.4%). NMR 'H (500 MHz, DMSO-d,) 61, 65-1.4 (m, 1H), 2.37 (s, 3H), 2,472.41 (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, 1 H), 9.75 (sa, 1 H) ppm; NH protons,
15 remained undissolved.
Cl-MS (M + H): 253.4
Purity (HPLC): 95.0%
Example 24: 4-fluoro-N '~ 4-fluorophenyl) -1-metllplrro "dln-2-carbohldrazlda
The title compound was prepared using a procedure analogous to that disclosed for Example 21, using 4-fluoro-1-methylpyrrolidine-2-carboxylic acid (Intermediate 17) as the starting material. 90 mg of 4-f1uoro-l-methylpyrrolidine-2-carboxylic acid provided the title compound as a crude product. He
The crude product was purified by column chromatography using DCM as eluent to provide 20 mg of the title compound (13% yield). NMR 'H (500 MHz, DMSO- <1,) 6 2.35-2.25 (m, 1H), 2.57 (s, 3H), 2,642.62 (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, 1 H), 6.82-6.80 (m, 2H), 6.95-6.91 (m, 2H), 8.94 (s, 1 H) ppm
30 Cl-EN (M + H): 256.4
Purity (HPLC): 95.0%
Example 25: (S) -1- {cyclopropylmethyl) -N '- {4-fluorophenyl) pyrrolidin-2-carbohydrazide
The title compound was prepared using a procedure analogous to that disclosed for Example 16 (method A), using (R) -1 (cyclopropylmethyl) pyrrolidine-2-carboxylic acid (120 mg) as the starting material. The product
5 crude was purified by column chromatography using DCM as eluent to provide 30 mg of the title compound (12.2% yield).
NMR 'H (500 MHz, DMSO-d.) 6 0.11 (s, 1H), 0.49-0.44 (m, 2H), 0.9-1.1 (m, 1 H), 1 , 78-1, 76 (m, 3H), 1.99-2.05 (m, 1 H), 2.42-2.28 (m, 2H), 3.05 (s, 1 H), 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:
10 Cl-EN (M + H): 278.2
Purity (HPLC): 96.2%
Example 26: N '- (4-fluorophenyl) · 3 · metll · 3 · azabicyclo [3.1, O] hexane · 2 - carboh idrazide
o
if ~ / ~ UF
The title compound was prepared using a procedure analogous to that disclosed for Example 16 (method A), using 3-methyl-3azabicyclo acid [1, 0] hexane-2-carboxylic acid (Intermediate 18) (25 mg, 0 , 18 mmol) as a starting material, which provided 3 mg of the final product (7% yield).
NMR 'H (500 MHz, CDCI,) 6 0.52 (d, J = 5.4 Hz, 1 H), 0.78 (s, 1 H), 1.16 20 (d, J = 4.0 Hz, 1 H), 1.43 (t, J = 6.5 Hz, 1 H), 2.73 (5, 3H), 2.59 (d, J = 6.4 Hz, 1 H), 3,233 , 16 (m, 2H), 6.01 (s, 1 H), 6.83-6.80 (m, 2H), 6.95-6.92 (m, 2H), 8.38 (5, 1 H) ppm Cl-EN (M + H): 250.2
Purity (HPLC): 98.2%
Example 27: N '- (4-fluorophenyl) -1, 4-dimethylpyrrolidin-2-carbohydrazide
", C o
V ~ / ~ UF
H, C
column using 9.5: 0.5 (vlv) of MeOH: DCM as eluent to produce 30 mg of
title compound (17% yield).
NMR 'H (500 MHz, CDCI,) 6 1.17 (1, J; 7.2 Hz, 3H), 1.88-1, 85 (m, 2H), 1.96 (d, J; 4, 0 Hz, 1 H), 2.22-2.20 (m, 1 H), 2.45 (sa, 1 H), 2.62 (s, 1 H), 2.78 (1, J; 7, 3 5 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 (s at, 1H) ppmLC-MS (M + H): 252.5
Purity (HPLC): 96.45%
Example 30: 2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidine-1-carboxyximidamide hydrochloride
NH
H2 O H
N -f
R ~~ N ~ Hel
V-F
The title compound was prepared according to general method B (Scheme 11) by coupling N-Cbz protected pyrrolidin-2-carboxylic acid (Intermediate 15 22) with N-Boc protected 4-fluorophenylhydrazine. followed by deprotection of the N atom of pyrrolidine, introduction of the amidine group, and removal of the remaining protecting groups, according to the procedures represented in the
Scheme XI:
SCHEME XI
Stage 1: Preparation of 2- (2- (tert-butoxycarbonyl) -2- (4fluorophenyl) hydrazinocarbonyl) pyrrofidin-1-benzyl carboxylate
To a stirred solution of 1- (benzyloxycarbonyl) pyrrolidine-2-carboxylic acid (Intermediate 22) (1 g, 4.01 mmol) in DMF (15 ml) was added DI PEA (1.55 g, 12.01 mmol), HATU (1.9 g, 5.0 mmot) and 1- (4-fluorophenyl) tere-butyl hydrazinecarboxylate (1.15 g, 4.38 mmol) 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 (2 x 25 ml). The combined organic layer was washed with water (15 ml) and brine (15 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, 100-200 mesh) to provide the title compound (500 mg, 27% yield) as a pale yellow semi-solid. Step 2: Preparation of tert-butyl 1- (4-fluorophenyl) -2- (pyrrolidin-2-carbonyl) hydrazinecarboxylate
To a stirred solution of 2- (2- (tert-butoxycarbonyl) -2- (4f1uorophenyl) hydrazinocarbonyl) pyrrolidine-1-carboxylate (500 mg, 1.09 mmol) in MeOH (10 ml) was added PdlC (10% wet, 100 mg, 20% w / w) And the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through a bed of celite; and the filtrate was evaporated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, 100200 mesh) to provide the title compound (200 mg, yield 28/1: 1) as an off-white solid.
NMR 'H (400 MHz, DMSO-d,) 6 10.42 (s, 1 H), 7.34 (c, J = 3.8Hz, 2H), 7.16-7.11 (m, 2H) , 3.62 (c, J = 3.1Hz, 1H), 2.83 (1, J = 6.5Hz, 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 miz (M + H): 324.11
Stage 3: Preparation of 2- (1- (N, N'-bis (tert-butoxycarbonyl) carbamimidoyl) pyrrolidin-2-carbonyl) -1- (4-fluorophenyl) hydrazinecarboxy / tert-butyl ato
To a stirred solution of 1- (4-f1uorophenyl) -2- (pyrrolidin-2-carbonyl) tert-butyl hydrazinecarboxylate (300 mg, 0.928 mmol) in OMF (3 mL) was added 1,3-bis (tert) -butyloxycarbonyl) -2-methyl-2-thiopseudourea (294 mg, 1.01 mmol), TEA (234 mg, 2,314 mmol) and HgCI2 (251 mg, 0.926 mmol) at OoC 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 (2 x 10 ml). The combined organic layer was washed with water (5 ml) and brine (5 ml), dried over Na2S0. anhydrous and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel, 60-120 mesh) to provide the Utulo compound (200 mg, 38% yield) as a white solid.
LC-MS (M + H): 566.3
Stage 4: Preparation of 2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidine-1-carboxyximidamide hydrochloride
A solution of 2- (1- (N, N'-bis (tem-butoxycarbonyl) carbamimidoyl) pyrrolidin-2-carbonyl) -1- (4-fluorophenyl) hydrazinecarboxylate of tem-butyl (200 mg, 0.35 mmol) in 1,4-dioxane. HCI (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-ordinated with DCM to provide the title compound (25 mg, 26% yield) as a pale yellow liquid.
NMR 'H (400 MHz, DMSO-d,) ~ 9.92 (s, lH), 7.32 (s, 4H), 6.96 (1, J = 8.8Hz, 2H), 6.73 ( c, J = 4.2Hz, 2H), 4.62 (d, J = 6.2Hz, lH), 3.69-3.61 (m, 2H), 3,543.50 (m, 2H), 3, 42 (c, J = 7Hz, 2H)
LC-MS miz (M + H): 301, 75
Purity (HPLC): 94.0%
Example 31: Antimicrobial Activity
The products of the present invention were tested for their activity against Acinetobacter baumannii (A. baumannil) as; as against the following bacteria: Staphylococcus aureus (S. aureus), Streptococcus pneumoniae
(S. pneumoniae), Enterococcus fBecium (E. faecium). Pseudomonas aeruginosa (P. aeruginosa), Kfebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coll).
Minimal inhibitory concentrations (MIC) were determined using a conventional microtiter dilution method, in accordance with the procedures of the Institute of Laboratory and Clinical Standards (CLSI), in particular according to M07-A9: ~ Methods for Dilution Antimicrobial SusceptibiJity Tests for Bacteria That Grow Aerobically; Approved Standard - Ninth Edition ".
Briefly, the compounds were dissolved with dimethyl sulfoxide
(DMSO) at 12.8 mg / ml. Double serial dilutions of the compounds were made in DMSO and 1 ~ I of each dilution was transferred to microtiter culture plates, followed by 100 ~ I inoculated culture medium to provide a final microorganism concentration of 5x10s colony forming units /me. The plates were incubated at 37 DC for 24 hours and the MICs were determined as the lower compound concentration that inhibited growth. The media used in determinations were Mueller-Hinton culture broth with cations adjusted for all microorganisms except for S. pneumoniae and E. faeeíum whose culture media were supplemented with 2.5% of lysed horse blood. They were made
10 incubations in an air atmosphere except cultures of S. pneumoniae that were incubated with a 5% CO2 atmosphere. The MIC values found (in ~ g / ml) for the compounds tested are given in Table 1 below. TABLE 1
Ex. A. baumanni¡S. aureusS. pneumo níaeE. (aeeiumP. aerugino S8K. pneumo níaeE. coN
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 8128> 128> 128> 128> 128> 128
9 8> 128> 128> 128> 128> 128> 128
10 2> 128> 128> 128> 128> 128> 128
eleven 8> 128> 128> 128> 128> 128> 128
14 2> 128> 128> 128> 128> 128> 128
fifteen one> 128> 128> 128> 128> 128> 128
16 0.25> 128> 128> 128> 128> 128> 128
18 8128> 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
As shown in Table 1, the compounds of formula (1) according to the present invention are highly effective antibacterials against A. Baumannii. Particularly, the MIC values obtained in the assay were 8 IJg / ml or less for the compounds tested. Surprisingly, all the compounds showed great selectivity for A. baumannii, since they were practically inactive against the other bacteria tested.
Example 32: In vitro stability test in mouse plasma
Several compounds of the present invention were tested for stability in mouse plasma, by detection of LC-MS / MS. The concentration of the compounds tested in the test was 1 JM and the remaining% of each compound tested was calculated at the following time points: 0, 15, 30 and 60 minutes.
The frozen mouse plasma was thawed at room temperature, centrifuged at 1400 x RCF, at 4 oC, for 15 minutes. Approximately 90% of the clear supernatant fraction was transferred to a separate tube and used for the test.
A 1 mM reservoir of test compound in acetonitrile: water was prepared by diluting from a 10 mM reservoir (i.e. 10 µJ of a 10 mM reservoir solution was added to 90 µl of acetonitrile: water (50 : 50. ”A stock of test compound 25 j.JM in acetonitrile: water was prepared by diluting from a 1 mM reservoir (ie 2.5 µJ of 1 mM stock solution was added to 97.5 ! JI of acetonitrile: water (50:50 ».
For samples at 0 minutes, the plasma was heat inactivated at 56 oC. At 72! JI of heat-activated plasma 3! JI of test compound 25! JM were added. An aliquot of 50 JI of the mixture was taken and triturated with 200! JI of acetonltrile containing an internal standard and further processed together with other time points.
A final work review of 1 IJM was prepared by diluting in plasma (ie 10 J of acetonitrile reserve added: water 25 JM to 240 J J of plasma). 250 µL of plasma containing the test compound was incubated for 60 min at 37 ° C in a shaken water bath with gentle agitation. 50 1011 of sample HCl were precipitated at 15, 30 and 60 min immediately with 200 µL of acetonitrile containing internal standard and centrifuged at 4000x RCF, 4 ° C for 20 minutes. 150 JI of supernatant was diluted with 150 IJI of water and analyzed by LC-MS / MS.
The remaining percentage of the test substance was calculated as the ratio of peak area at each time point with respect to peak area ratio at zero minutes, multiplied by 100.
5 The CUEM / EM method used is defined by the following parameters: API4000 (MS), Shimadzu Prominance (Le), injection volume of 20 ~ I: column: Waters Xbridge, C18, 50 "4.6 mm, 3, 5! -1m; 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: 1 mi / m in.
The compounds of formula (1) were found to be highly stable in this assay, with percentages remaining in mouse plasma after 1 hour of 80% or more, in most cases of more than 90%. These data are highly relevant for the use of the compounds of the present invention as drugs, since long stability is desirable in
15 plasma to obtain good pharmacokinetic exposure of the drug and maintain activity in vivo and is therefore significant to achieve good therapeutic antibacterial efficacy.

权利要求:
Claims (15)
[1]
1.-A compound of formula (1):
(R'O ~ n ~ * R3
O R
X ~ RgN 'Re N ...... I R, R7I ~ ó4 R5
Rs
(one)
Or a pharmaceutically acceptable solvate salt thereof.whereR, and R2 are independently selected from hydrogen. C alkyl, -4. C'-4 haloalkyland hydroxyalkyl C, -4;R3 R4 R5 Rs and R7 are independently selected from hydrogen. -OH. halogen
C alkoxy, -6. haloalkoxy C, -4. -O-C3-6 cycloalkylC0-4alkyl. C alkyl, -s. C3 cycloalkyl C0-4 alkyl. haloalkyl C, -6. hydroxyalkyl C, -6. C'-4 alkoxy C, -6 alkyl. C'-4alkoxy alkoxyC, -4. -OCOR11 • -OS (02) R ". -NR" R12 • -NR "COR'2. -NR" C02R'2. -NR11S (02) R'2.-OCONR "R'2. -CONR" R'2. -S (Oú NR "R'2. -S (02) R". -CN and -C02R ,,; or two of R3 aR7 attached to adjacent carbon atoms are connected to form a5 or 6 member cycloalkyl. where 1 or 2 cycloalkyl methylene groups canbe replaced by O. said cycloalkyl may be optionally substituted withone or more C'-4 alkyl or haloalkyl CH;Re is selected from -OH. C alkyl, _s. haloalkyl C, _s. hydroxyalkyl C, -4. C alkoxy, _4 alkyl C0-4. C3-6 cycloalkylC0-4alkyl. C2-5 acyl. -C (O) C3-6 cycloalkyl C0-2 alkyl.-CONR, 3R'4. -C (NR'5) NR "R'2Y-C02R ,,;Rg is selected from hydrogen. C'-4 alkyl and haloalkyl C, -4;n is O. 1. 2 or 3;every R, or. if present independently selected from -OH. halogenC alkyl, _s. haloalkyl C, _s. C alkoxy, _s. C'-4 alkoxy C, -6 alkyl. -O-C3-6alkyl alkyl
C0-4. -SR ". -NR" R'2. -OCOR ". -OS (02) R". -NR "COR'2. -NR" C02R'2.-NR "S (02) R'2. -OCONR" R'2. -CN. phenyl. 5 or 6 membered heteroaryl ring thatit comprises 1 or 2 heteroatoms selected from N. O and S; where said phenyl andsaid heteroaryl ring may be optionally substituted with one or more alkylC'-4 or haloalkyl C, -4; or two Rs, or attached to a common carbon atom form an oxo;or two R, or attached to a common carbon atom form a C3-s cycloalkyl spiro. or
two Rl0 attached to adjacent carbon atoms are connected to form a 3-6 membered cycloalkyl, said cycloalkyl may be optionally substituted with one or more substituents independently selected from Cl-4 alkyl, Cl -4 haloalkyl and halogen: each R1 and R12 independently selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl and C3-cycloalkyl-CQ-4 alkyl: each R13 and R14 is independently selected from hydrogen, C1-4 alkyl, C3-6 cycloalkyl, CQ-4 alkyl and Het3-6 , where each Cl -4 alkyl and C3-cycloalkyl CQ-4 alkyl may be optionally substituted with one or more R1S, and where each Cl -4 alkyl may be optionally substituted with one or more Het3-6: or R13 and R14 form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, said heterocycle may be optionally substituted with one or more Substituents independently selected from Cl -4 alkyl, Cl -4 haloalkyl and C2-S acyl: R1S is selected from hydrogen, Cl -6 alkyl, Cl -6 haloalkyl, -CN, -CONR1 R12, -S (02) Rll, - SORll and -S (02) NRl1 R12: each R1S is independently selected from alkyl, halogen, -CN, -C02Rll, -ORl1, -SRl1, -NR17R18, -CONR17R18 and -OCORll: Het3-6 is a saturated monocyclic heterocyclic ring 3 to 6 members containing a heteroatom selected from O, SYN, where said ring is linked to the rest of the molecule through any available C atom and where said ring can be optionally substituted with one or more substituents independently selected from alkyl Cl -4 or haloalkyl Cl -4: and each R17 and R18 is independently selected from hydrogen, Cl -4 alkyl and haloalkyl Cl -4, or R17 and R18 form, together with the N atom to which they are attached, a saturated heterocycle 4 to 6 members, which may optionally contain an additional heteroatom selected from N, SYO, said heterocycle may be optionally substituted with one or more substituents independently selected from Cl -4 alkyl and Cl -4 haloalkyl: and where the following products are excluded: (S) -2- (2- tert-butyl phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxylate, (R) -2- (1-methyl-2-phenylhydrazine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester, (2S, 4S) -4-mercapto-2- (2 - (3-su Ifamoilfen il) h idrazi na-1-carbonyl) pi rrolidi na-1-carboxylate
of tert-butyl, 3- (2 - ((2 S, 4S) -1- (tert-butoxycarbonyl) -4-mercaptopyrrolidi na-2-carbonyl) h idrazinyl)
benzoic, (28,48) -4-mercapto-2- (2- (2- (trifluoromethyl) phenyl) hydrazine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester, and (28.48) -2- (2 - (2-Chloro-5- (trifluoromethyl) phenyl) hyd razina-1-carbon yl) -4-mercaptopi rrolidine-1-carboxylic acid tert-butyl ester.
[2]
2. A compound according to claim 1, wherein R1 and R2 are independently selected from hydrogen and C1-4 alkyl; R3, R4, Rs, R6 and R7 are independently selected from hydrogen, -OH, halogen, CH> alkyl, C3-6 cycloalkylC0-4 alkyl, -NR11R12, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-4alkoxyC0 alkyl -6, C1-4alkoxy C1-4alkoxy, -CONR11R12, -S02-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, where 1 or 2 methylene groups of the cycloalkyl may be replaced by O, said cycloalkyl may be optionally substituted with one or more C1-4 alkyls; Rs is selected from -OH, C1-6 alkyl, C1-6 haloalkyl, hydroxyalkyl CH, C14-4alkoxyC3-6alkylC0-4alkyl, C2-S acyl, -C (O) C3-6alkylC0-alkyl 2, -CONR13R14 and -C (NR1S) NR11R12; Rs is selected from hydrogen and C1-4 alkyl; n is O, 1, 2 or 3; each R10, if present, is independently selected from -OH, halogen, C1-6 alkyl, C1-4 alkoxyCalkyl, -SR11 and -NR11 R12; 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 may be optionally substituted with one or more substituents independently selected from C1-4 alkyl and halogen; each R11 and R12 is independently selected from hydrogen and C1-4 alkyl; each R13 and R14 is 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 may optionally contain an additional heteroatom selected from N, SYO, said heterocycle may be optionally substituted with one or more substituents independently selected from C1-4 alkyl and C2-S acyl; and R1S is selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, -CN, -CONR11R12, -S02-R11, -SO-R11 and -S02-NR11R12.
[3]
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]
4. A compound according to any one of claims 1 to 3, wherein R3, ~, Rs, Rs and R7 are independently selected from hydrogen, -OH, halogen, C1-S alkyl, C1-S haloalkyl, C1- alkoxy 4 C () -s alkyl, C1-4 alkoxy C1-4 alkoxy, -S02-NR11R12 and C1-4 haloalkoxy.
[5]
5. A compound according to claim 4, wherein R3, R4, Rs, Rs and R7 are independently selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -S02-NR11R12 and C1-4 haloalkoxy.
[6]
6. A compound according to claim 5, wherein Rs is selected from halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -S02-NR11R12 and C1-4 haloalkoxy; R3 is selected from hydrogen, halogen and C1-4 alkyl; and R4, Rs and R7 are hydrogen.
[7]
7. A compound according to claims 1 or 2, wherein R4 and Rs are connected to form a 5 or 6 membered cycloalkyl, where 1 or 2 methylene groups of the cycloalkyl can be replaced by O, said cycloalkyl can be optionally substituted with one or more C1-4 alkyls, and R3, Rs and R7 are hydrogen.
[8]
8. A compound according to any one of claims 1 to 7, wherein R1, R2Y Rg are hydrogen.
[9]
9. A compound according to any of claims 1 to 8, wherein Re is selected from -OH, C1-4 alkyl, C3 cycloalkyl-C1-4 salkyl, C2-S acyl, -CONR13R14 and -C (NR1S) NR11R12; where 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 an additional heteroatom selected from N and O , said heterocycle may be optionally substituted with one or more substituents independently selected from C1-4 alkyl and acyl
C2-3
[10]
10. A compound according to any one of claims 1 to 9, wherein n is 1 or 2 and each R10 is independently selected from halogen, C1-4 alkyl and -NR1, R12; or two Rs, or 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 may be optionally substituted with one or more substituents independently selected from C'-4 alkyl and halogen.
[11 ]
11. A compound according to any one of claims 1 to 9, wherein n is O.
[12]
12. A compound according to any of claim 1, which is
select from the group consisting of: -N '- (4-fluorophenyl) -1, 5-dimethylpyrrolidin-2-carbohydrazide _ (R) -2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide - (S) -2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide -2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide -2- (2- (4-fluoro- 2-methylphenyl) hydrazin-1-carbonyl) pyrrolidin-1-carboxamide -2 - (2- (3, 5-difluorophenyl) h idrazinocarbonyl) pyrrolidin-1-carboxyamide -2 - (2- (4- (trifluoromethoxy ) phenyl) hid razi nocarbonyl) pyrrolidin-1-carboxamide -2 - (2- (4- (trifluoromethyl) phenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide -2- (2- (4-chloro-2-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide -2- (2- (4-methoxyphenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide -2- (2- (2,3-dihydrobenzo [b] [1.41dioxin-6-yl) hydrazinocarbonyl) pyrrolidin- one
carboxamide -2- (2- (4-sulfamoylphenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide - (2S, 4S) -4-fluoro-2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboxamide - (R ) -1-acetyl-N '- (4-fluorophenyl) pyrrolidin-2-carbohydrazide
- N '- (4-fluorophenyl) -1-hydroxypyrrolidin-2-carbohydrazide
_ N '- (4-fluorophenyl) -1, 2-dimethylpyrrolidin-2-carbohydrazide
_ 2- (2_ (4-fluorophenyl) h idrazinocarbonyl) -N, N-d imethylpyrrolidin-1-carboxamide
- N '- (4-fluorophenyl) -1- (piperazin-1-carbonyl) pyrrolidin-2-carbohydrazide -1- (4-acetylpiperazi n-1-carbonyl) -N' - (4-fluorophenyl) pyrrolidin-2 - carboh idrazide -N '- (4-fluorophenyl) -1- (morpholin-4-ca rbonyl) pyrrolidin-2-carbohydrazide -N' - (4-fluorophenyl) -1-methyl-5-oxopi rrolidin-2-carbohydrazide - N '- (4-fluorophenyl) -1-methylpyrrolidin-2-carboh idrazide -4-amino-N' - (4-fluorophenyl) -1-methylpyrrolidin-2-carbohydrazide
-4-fluoro-N '- (4-fluorophenyl) -1-methylpyrrolidin-2-carbohydrazide - (S) -1- (cyclopropylmethyl) -N' - (4-fluorophenyl) pyrrolidin-2-carbohydrazide -N '- ( 4-fluorophenyl) -3-methyl-3-azabicyclo [3, 1) hexane-2-carbohydrazide -N '- (4-fluorophenyl) -1, 4-dimethylpyrrolidin-2-carbohydrazide
5-N '- (4-fluorophenyl) -1, 3-dimethylpyrrolidin-2-carbohydrazide-1-ethyl-N '- (4-fluorophenyl) pyrrolidin-2-carbohydrazide-2- (2- (4-fluorophenyl) hydrazinocarbonyl) pyrrolidin-1-carboximidamide
or a pharmaceutically acceptable solvate salt thereof.
13. A compound of formula (1):
(one)
or a pharmaceutically acceptable solvate salt thereof,where
R, and R2 are independently selected from hydrogen, C'-4 alkyl, C'-4 haloalkyl and C, -4 hydroxyalkyl; R3, R4, Rs, R6 and R7 are independently selected from hydrogen, -OH, halogen, C'-4 alkoxy, C'-4 haloalkoxy, C3-6 -cycloalkylC (C) alkyl. (4) C'-6 alkyl , C36 cycloalkyl C (). 4 alkyl, C'-6 haloalkyl, C'-6 hydroxyalkyl, C'-4 alkoxy CH alkyl, C1-4 alkoxy alkoxy
20 C'-4, -OCOR ", -OS (02) R", -NR "R'2, -NR" COR12, -NR "C02R'2, -NR" S (02) R'2, -OCONR11 R'2, -CONR "R12, -S (02) NR11R12, -S (02) R11, -CN and -C02R11; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a cycloalkyl of 5 or 6 members, where 1 or 2 cycloalkyl methylene groups may be replaced by O, said cycloalkyl may be optionally substituted with
One or more C'-4 alkyl or C1-4 haloalkyl; Re is selected from -OH, C'-6 alkyl, C'-6 haloalkyl, C'-4 hydroxyalkyl, C alkoxy, C4 alkyl (4), C3-6 cycloalkyl C () alkyl. 4, C2-S acyl , -C (O) C3-6 cycloalkyl C () '2, -CONR'3R14, -C (NR1S) NR "R'2 and -C02R ,,; Rg is selected from hydrogen, C'-4 alkyl and haloalkyl C, -4;
30 n is O, 1, 2 or 3; each R, or, if present, is independently selected from -OH, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, CH C1-6 alkyl alkoxy, -O-C3-6 cycloalkyl CQ-4 alkyl , -SR11, -NR11R12, -OCOR11, -OS (02) R11, -NR11COR12, -NR11C02R12, -NR11S (02) R12, -OCONR11R12, -CN, phenyl, 5- or 6-membered heteroaryl ring comprising 1 or 2 heteroatoms selected from N, OYS; wherein said phenyl and said heteroaryl ring may be optionally substituted with one or more C1-4 alkyl or C1-4 haloalkyl; or two R10 attached to a common carbon atom form an oxo;
or two R10 attached to a common carbon atom form a C3-6 cycloalkyl spiro, or two R10 attached to adjacent carbon atoms are connected to form a 3 to 6 membered cycloalkyl, said cycloalkyl may be optionally substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and halogen; each R11 and R12 is independently selected from hydrogen, C1-4 alkyl, C1-4 haloalkyl and C3-6 cycloalkyl CQ-4 alkyl; each R13 and R14 is independently selected from hydrogen, C1-4 alkyl, C3-6 cycloalkyl CQ-4 alkyl and Het3-6, where each C1-4 alkyl and C3-6 cycloalkyl CQ-4 alkyl may be optionally substituted with one or more R16 , and where each C1-4 alkyl may be optionally substituted with one or more Het3-6; or R13 and R14 form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may optionally contain an additional heteroatom selected from N, SYO, said heterocycle may be optionally substituted with one or more substituents independently selected from C1-4 alkyl, C1-4 haloalkyl and C2-5 acyl; R15 is selected from hydrogen, C1-6 alkyl, haloalkyl CH, -CN, -CONR11R12, -S (02) R11, -SOR11 AND -S (02) NR11R12; each R16 is independently selected from alkyl, halogen, -CN, -C02 R11, -OR11, -SR11. -NR17R18, -CONR17R18 Y-OCOR11; Het3-6 is a 3 to 6-membered saturated monocyclic heterocyclic ring containing a heteroatom selected from O, SYN, where said ring is linked to the rest of the molecule through any available C atom and where said ring can be optionally substituted with one or more substituents independently selected from C1-4 alkyl or C1-4 haloalkyl; and each R17 and R18 is independently selected from hydrogen, C1-4 alkyl and C1-4 haloalkyl, or R17 and R18 form, together with the N atom to which they are attached, a saturated 4- to 6-membered heterocycle, which may contain optionally an additional heteroatom selected from N, SYO, said heterocycle may be optionally substituted with one or more substituents independently selected from C'-4 alkyl and C, -4 haloalkyl;
For use as a medicine.
[14]
14. A compound according to any of claims 2 to 12 for use 5
as a medicine
[15]
15. A compound for use according to claims 13 or 14, for use as an antibacterial agent, preferably for treating or preventing infections by A.
baumannii.
16. A pharmaceutical composition comprising a compound of formula (1):
(one)
or a pharmaceutically acceptable solvate salt thereof,
Where R, and R2 are independently selected from hydrogen, C, -4 alkyl, C'-4 haloalkyl and C, -4 hydroxyalkyl; R3, R4, R5, R6 and R7 are independently selected from hydrogen, -OH, halogen,
C, -6 alkoxy, C'-4 haloalkoxy, -O-C3-6 cycloalkyl CQ-4 alkyl, C'-6 alkyl, C3 cycloalkyl
C 6 -C 6 alkyl, C'-6 haloalkyl, C'-6 hydroxyalkyl, C'-4 alkoxy C'-6 alkyl, C'-4 alkoxy C'-4 alkoxy, -OCOR ", -OS (02) R", -NR "R'2, -NR" COR'2, -NR "C02R'2, -NR" S (02) R'2, -OCONR "R'2, -CONR" R'2, -S (02 ) NR "R'2, -S (02) R", -CN and -C02R ,,; or two of R3 to R7 attached to adjacent carbon atoms are connected to form a 5- or 6-membered cycloalkyl, where 1 or 2 cycloalkyl methylene groups can
25 being replaced by O, said cycloalkyl may be optionally substituted with one or more C'-4 alkyl or C, -4 haloalkyl; Re is selected from -OH, C'-6 alkyl, C'_6 haloalkyl, C'-4 hydroxyalkyl, C alkoxy, 4CQ-4 alkyl, C3-6 cycloalkyl CQ-4 alkyl, C2-5 acyl, -C (O ) C3-6 cycloalkylC0-2 alkyl, -CONR13R'4, -C (NR'5) NR "R'2 and -C02R ,,;
Rs is selected from hydrogen, C'-4 alkyl and C, -4 haloalkyl; n is O, 1, 2 or 3; each R, or, if present, is independently selected from -OH, halogen,
C, -s alkyl, C'-6 haloalkyl, C'-6 alkoxy, C'-4 alkoxyC, _s, -O-C3-6alkyl alkyl alkylCQ-4, -SR ", -NR" R'2, -OCOR ", -OS (02) R", -NR "COR'2, -NR" C02R'2,-NR "S (02) R'2, -OCONR" R'2, -CN, phenyl, 5- or 6-membered heteroaryl ring whichit comprises 1 or 2 heteroatoms selected from N, O and S; where said phenyl andsaid heteroaryl ring may be optionally substituted with one or more alkylCH or haloalkyl C, -4; or two Rs, or attached to a common carbon atom form an oxo;or two R, or attached to a common carbon atom form a C3-S cycloalkyl spiro, ortwo R's, or attached to adjacent carbon atoms are connected to form a3 to 6-membered cycloalkyl, said cycloalkyl may be optionally substitutedwith one or more substituents independently selected from C'-4 alkyl,C'-4 haloalkyl and halogen;each R "and R'2 are independently selected from hydrogen, C'-4 alkyl,C'-4 haloalkyl and C3-cycloalkyl-CQ-4 alkyl;each R'3 and R'4 are independently selected from hydrogen, C'-4 alkyl,C3-6 cycloalkyl CQ-4 and Het3-6 alkyl, where each C'-4 alkyl and C3-cycloalkyl-CQ-4 alkylit may be optionally substituted with one or more R, s, Y where each C'-4 alkylit may be optionally substituted with one or more Het3-6; or R'3 and R'4 form, togetherwith the N atom to which they are attached, a saturated 4- to 6-membered heterocycle,which may optionally contain an additional heteroatom selected from N, SAnd O, said heterocycle may be optionally substituted with one or more
substituents independently selected from C'-4 alkyl, C'-4 haloalkyl andC2-5 acyl;R'5 is selected from hydrogen, C, -s alkyl, C'-6 haloalkyl, -CN, -CONR "R'2,-S (02) R ", -SORl1 Y-S (02) NR" R'2;
each R'6 is independently selected from alkyl, halogen, -CN, -C02R ",-OR ", -SR". -NR17R, 8, -CONR17R'8 Y-OCOR ,,;Het3-6 is a 3 to 6-membered saturated monocyclic heterocyclic ring containinga heteroatom selected from O, S and N, where said ring is linked to the restof the molecule through any available C atom and where said ring canbe optionally substituted with one or more selected substituentsindependently between C'-4 alkyl or haloalkyl C, -4; Yeach R'7 and R'8 is independently selected from hydrogen, C'-4 alkyl andhaloalkyl C'-4, or R17 and R'8 form, together with the N atom to which they are attached, a4 to 6 membered saturated heterocycle, which may optionally contain aadditional heteroatom selected from N, S and O, said heterocycle may beoptionally substituted with one or more selected substituents
independently between C'-4 alkyl and haloalkyl C, -4;and at least one pharmaceutically acceptable carrier and / or carrier.
[17]
17.-A process for the preparation of a compound of claim 1, which
comprises reacting a compound of formula (11)OR
(R'O ~
n
X ~ R9 OR'6
N,
R17
(eleven)
with a compound of formula (111) or a pharmaceutically acceptable solvate salt thereof
(111)
Wherein R, s is hydrogen or a C'-4 alkyl, R17 is hydrogen or Re, Y n Y R, at R'5 have the same meaning as described in claim 1.

类似技术:

---

公开号 | 公开日 | 专利标题

---

JP6577479B2|2019-09-18|Heterocyclic compounds and their use as NAV channel inhibitors

---

ES2838573T3|2021-07-02|Benzamide derivatives linked as potent ROCK inhibitors

---

US9738630B2|2017-08-22|Inhibitors of lysine methyl transferase

---

JP5475841B2|2014-04-16|Tri-, tetra-substituted-3-aminopyrrolidine derivatives

---

JP2018104463A|2018-07-05|3-TETRAZOLYL-BENZENE-1,2-DISULFONAMIDE DERIVATIVES AS METALLO-β-LACTAMASE INHIBITORS

---

CA2980395A1|2016-10-06|Heterocyclic compounds and their use in preventing or treating bacterial infections

---

ES2651943A1|2018-01-30|Antibacterial agents of 2-pyrrolidinylphenylhydrazides |

---

BRPI0819719B1|2020-09-24|DIPEPTIDIL PEPTIDASE-IV INHIBITION COMPOUNDS, METHODS OF PREPARATION OF THE SAME, AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME AS AN ACTIVE AGENT

---

CA2725572A1|2009-12-10|Heterocyclic urea derivatives and methods of use thereof

---

CN112341457A|2021-02-09|KRAS mutein inhibitors

---

ES2687826T3|2018-10-29|Arylhydrazides containing a fraction of 2-pyridone as selective antibacterial agents

---

CN112566916A|2021-03-26|Substituted thienopyrroles as PAD4 inhibitors

---

BR112020014516A2|2020-12-08|Aminopyrrolotriazines as kinase inhibitors

---

KR20180094042A|2018-08-22|Compound containing 7-oxo-6- | -1,6-diazabicyclo [3.2.1] octane-2-carboxamide and its use for the treatment of bacterial infections

---

WO2017081615A1|2017-05-18|7-oxo -6-|- 1,6-diazabicyclo [3.2.1] octane containing compounds and their use in treatment of bacterial infections

---

JPWO2019208797A1|2021-05-27|Oxo-substituted compound

---

CN112789087A|2021-05-11|Benzimidazole inhibitors of PAD enzymes

---

CN112805066A|2021-05-14|Substituted benzimidazoles as PAD4 inhibitors

---

JP2022502448A|2022-01-11|MDM2 Inhibitors, Methods of Preparation, Pharmaceutical Compositions and Applications

---

CN113754635A|2021-12-07|Fused ring compound and preparation method and application thereof

---

JP5063032B2|2012-10-31|Tri-, tetra-substituted-3-aminopyrrolidine derivatives

---

AU2018359413A1|2020-05-07|Kinase inhibitors for the treatment of central and peripheral nervous system disorders

---

AU2017335222A2|2019-05-09|Heterocyclic compounds and their use in preventing or treating bacterial infections

同族专利:

---

公开号 | 公开日

---

WO2018020004A1|2018-02-01|

---

TW201803848A|2018-02-01|

---

US20190177272A1|2019-06-13|

---

ES2651943B2|2018-08-14|

---

UY37348A|2018-01-31|

---

EP3490984B1|2020-09-09|

---

US10919851B2|2021-02-16|

---

PL3490984T3|2021-05-04|

---

EP3490984A1|2019-06-05|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

CN101525336A|2007-06-26|2009-09-09|山东轩竹医药科技有限公司|Carbapenem compound containing substituted formohydrazide group|

---

EP2100602A1|2008-03-12|2009-09-16|QuoNova Europe GmbH|Method and compositions suitable for treatment of wounds|

---

US20130018079A1|2011-07-11|2013-01-17|Weibel Douglas B|Antimicrobial compositions and methods of use thereof|

---

WO2016016291A1|2014-07-30|2016-02-04|Ferrer Internacional, S.A.|Arylhydrazides containing a 2-pyridone moiety as selective antibacterial agents|

---

GB769482A|1952-05-09|1957-03-06|Lepetit Spa|Thiazolecarboxylic acid hydrazide|

---

WO2012051708A1|2010-10-21|2012-04-26|The University Of British Columbia|Anti-bacterial pyruvate kinase modulator compounds, compositions, uses, and methods|

---

GB201206384D0|2012-04-11|2012-05-23|Redx Pharma Ltd|Antibacterial drug derivatives|

---

WO2016169291A1|2015-04-24|2016-10-27|日丰企业集团有限公司|Fast connection pipe|WO2020169682A1|2019-02-19|2020-08-27|Yncrea Hauts De France|Hydrazide derivatives and their specific use as antibacterial agents by controlling acinetobacter baumannii bacterium|

---

WO2020169683A1|2019-02-19|2020-08-27|Yncrea Hauts De France|Hydrazonopyrrolidine derivatives for use in preventing and/or treating disorders associated to acinetobacter baumannii|

---

WO2020228783A1|2019-05-14|2020-11-19|南京工业大学|Cyclic formyl and cyclic ketone compounds, preparation method therefor, and pharmaceutical use|

法律状态:
2018-08-14| FG2A| Definitive protection|Ref document number: 2651943 Country of ref document: ES Kind code of ref document: B2 Effective date: 20180814 |

优先权:

---

申请号 | 申请日 | 专利标题

---

EP16181965|2016-07-29|

---

EP16181965.1|2016-07-29|

---

EP17159942.6|2017-03-08|

---

EP17159942|2017-03-08|

---

EP17163270|2017-03-28|

---

EP17163270.6|2017-03-28|TW106125098A| TW201803848A|2016-07-29|2017-07-26|2-pyrrolidine phenylhydrazides antibacterial agents|

---

EP17754294.1A| EP3490984B1|2016-07-29|2017-07-28|2-pyrrolidine phenylhydrazides antibacterial agents|

---

UY0001037348A| UY37348A|2016-07-29|2017-07-28|ANTIBACTERIAL AGENTS OF 2-PIRROLIDIN PHENYL HYDRAZIDS|

---

US16/320,929| US10919851B2|2016-07-29|2017-07-28|2-pyrrolidine phenylhydrazides antibacterial agents|

---

PCT/EP2017/069179| WO2018020004A1|2016-07-29|2017-07-28|2-pyrrolidine phenylhydrazides antibacterial agents|

---

PL17754294T| PL3490984T3|2016-07-29|2017-07-28|2-pyrrolidine phenylhydrazides antibacterial agents|