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WO2018172925A1 - Inhibitors of dna gyrase for treatment of bacterial infections - Google Patents

Inhibitors of dna gyrase for treatment of bacterial infections Download PDF

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Publication number
WO2018172925A1
WO2018172925A1 PCT/IB2018/051848 IB2018051848W WO2018172925A1 WO 2018172925 A1 WO2018172925 A1 WO 2018172925A1 IB 2018051848 W IB2018051848 W IB 2018051848W WO 2018172925 A1 WO2018172925 A1 WO 2018172925A1
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Prior art keywords
ethyl
piperidin
methyl
reaction
nitrobenzylamino
Prior art date
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PCT/IB2018/051848
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French (fr)
Inventor
Chandrasekhar ALAPATI
Ankita BANERJEE
Radha RANGARAJAN
Rajinder Kumar
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Vitas Pharma Research Pvt Ltd
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Priority claimed from US15/467,820 external-priority patent/US20170197935A1/en
Application filed by Vitas Pharma Research Pvt Ltd filed Critical Vitas Pharma Research Pvt Ltd
Publication of WO2018172925A1 publication Critical patent/WO2018172925A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention is related to compounds which specifically inhibit bacterial DNA Gyrase for the treatment of bacterial infections.
  • Antibacterial drug resistance is a worldwide problem; new mechanisms of resistance emerge periodically and spread rapidly across the globe.
  • the growing rate of antimicrobial resistance in clinical and non clinical settings poses significant threat to human health and animals, not only in India but also globally (Lancet Infectious Diseases, 9, 228-36, 2009).
  • Each mechanism of resistance renders yet another class of antibiotics ineffective, ultimately resulting in fewer and fewer therapeutic options for patients.
  • WHO now recognizes antimicrobial resistance as one of three greatest threats to human health (Clinical Infectious Diseases 50, 1081-1083, 2010).
  • To address the issue of drug resistance new chemotypes that target critical pathways in bacteria must be developed.
  • DNA Topioisomerases are involved in the transient breaking and rejoining of DNA during replication, transcription and recombination. They are well conserved across the bacterial species and essential for viability. There are two classes of Topoisomerases, depending on whether they introduce single stranded (type 1) or double stranded breaks (type 2). DNA Gyrase and Topo IV are Type 2 Topoisomerases. Gyrase is responsible for the introduction of negative supercoils into DNA to allow fork progression during replication. It is a heterodimer consisting of two subunits of GyrA and two subunits of GyrB (Reviewed in Infectious Disorders - Drug Targets7, 3-9, 2007).
  • Gyrase is a clinically validated target. Inhibitors of this target, the fluoroquinolones have been in use since the 1960s but suffer widespread drug resistance. Despite extensive research, newer generations of fluorquinolones have not overcome resistance effectively. Recently two non-fluoroquinolone inhibitors of Gyrase have been described. One of them is NXL101 and the other is GSK299423. NXL101 belongs to a novel quinoline class with potent activity against gram-positive bacteria, including methicillin-and fluoroquinolone-resistant strains
  • GSK299423 shows potent antibacterial activity against MRSA, fluoroquinolone resistant strains of S. aureus and Gram negatives such as E. coli, H. influenzae, M. catarrhalis and Klebsiella, pneumoniae (Nature, 466, 935-942, 2010;. While the compound potently inhibits DNA Gyrase, it has serious hERG binding liability (BMCL, 21 , 7489-7495, 2011). Similarly, NXL-101 causes QT prolongation, which led to its discontinuation from clinical development (North American Journal of Medical Science, 4, 537-47, 2012). Nevertheless, the target continues to be attractive and novel chemotypes directed against the target will have significant clinical benefits, once proven to be efficacious and safe.
  • Figure 1 discloses time kill kinetics of VT-03 -00061 against MRSA 33591.
  • Figure 2 discloses time kill kinetics of VT-03-00061 against E. coli 25922.
  • Zi, Z 2 , Z 3 are each independently CRi ;
  • Z 4 , Z 5 , Z 6 are each independently selected from a group consisting of N or CRi ;
  • Z 2 and Z 3 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
  • Z5 and Z 6 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
  • Z 4 and Z 6 directly form a bond in absence of Z5 where its substitution together form an optionally substituted saturated or unsaturated 5-6 membered cyclic ring containing at least one heteroatom at bridging or any other position of the ring;
  • Ri are each independently selected from a group consisting of hydrogen, oxo, cyano, halogen, hydroxyl and Ci-6 alkyl optionally substituted with one or two Ci-6 alkoxy.
  • Ai is selected from a group consisting of -(CR2R3) m -CH 2 - , -CH 2 -(CR 2 R3) m - , -NH- (CR 2 R 3 ) m -CH 2 ,-(CR 2 R 3 ) m -CH 2 -0- and
  • m is 1 or 2;
  • R 2 is selected from a group consisting of hydrogen, halogen, hydroxyl, acyloxy, Ci- 6 alkyl optionally substituted with one or two Ci-6 alkoxy and Ci-6 alkoxy optionally substituted with C 1-6 alky 1
  • R3 is hydrogen
  • G is selected from a group of formulae consisting of Gl, G2, G3, G4, G5, G6, G7, G8, G9 and Gl 0 as provided below
  • a 2 is CR 4 R 5 or is absent; wherein R 4 and R5 are each independently hydrogen or
  • monocyclic aryl and hetero-aryl can be five or six membered ring bearing one or two hetero atom (N, O, S)
  • aryl or hetero aryl ring substituted independently with halogen F, CI, Br
  • the monocyclic or bicyclic aryl or heteroaryl is fused to saturated or unsaturated cyclic ring containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulphur which is optionally substituted with halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkyl substituted with Ci-6 alkoxy, Ci-6 alkoxy optionally substituted with Ci-6 alkyl, Ci-4 haloalkoxy, C 1 -4 haloalkyl, C 1 -4 thioalkyl, nitro, cyano, carboxy, C 1 -4 alkylsulfonyl, aminosulfonyl, hydroxyl, amino, aminoalkyl, oxo, hydroxyalkyl, alkynyl, alkylcarbonyl and carbonyl.
  • Zi and Z 3 are each independently selected from a group consisting of CH or N ;
  • Ai is selected from the group consisting of -(CR 2 R 3 ) m -CH 2 - , -CH 2 -(CR 2 R 3 ) m - -NH- (CR 2 R 3 ) m -CH 2 ,-(CR 2 R 3 ) m -CH 2 -0- and
  • m is lor 2
  • R 2 is selected from the group consisting of hydrogen, halogen, acyloxy, Ci- 6 alkyl optionally substituted with one or two Ci_6alkoxy and Ci_6alkoxy optionally substituted with Ci-6 alkyl;
  • R3 is hydrogen
  • a 2 is CR4R5 or is absent; wherein R4 and R5 are each independently hydrogen or
  • VT-03 compounds of the invention show minimal (insignificant) hERG binding activity indicating the advantage of these compounds as against the known compounds in the art (BMCL, 21 , 7489-7495, 2011).
  • VT-03 compounds of formula I of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species,
  • Enterococcus species Streptococcus species, Moraxella species, E.coli, Klebsiella species, Pseudomonas species and Acinetobacter species.
  • the invention also provides compounds of formula (II) or pharmaceutically acceptable salts thereof:
  • Zi and Z 3 are each independently selected from a group consisting of CH or N ;
  • Ri is independently selected from the group consisting of hydrogen, methoxy, cyano, halogen, hydroxyl, Ci- 6 alkoxy and Ci- 6 alkyl optionally substituted with one or two Ci_6 alkoxy, alkyne, carboxyl, carboxamide;
  • G is Gl, G2 or G3
  • R 2 is selected from the group consisting of
  • VT-03 compounds of Formula II of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species, Enterococcus species, Streptococcus species, Moraxella species, E.coli, Mycobacterium species, Neisseria meningitidis, Neisseria
  • the instant invention provides preferred VT-03 compounds of formula I in Table I
  • the instant invention provides preferred VT-03 compounds of formula II II -03 Compounds of the Invention
  • the invention further consists of the following
  • VT-03-00014 Synthesis ofVT-03-00014, VT-03-00017, VT-03-00021, VT-03-00021a, VT-03-00022, VT-03- 00024, VT-03-00026, VT-03-00026a, VT-03-00027, VT-03-00028, VT-03-00030, VT-03- 00031, VT-03-00032, VT-03-00042, VT-03-00043, VT-03-00045, VT-03-00046, VT-03-00048, VT-03-00049, VT-03-00050, VT-03-00051, VT-03-00052, VT-03-00053, VT-03-00054, VT-03- 00055, VT-03-00056, VT-03-00057, VT-03-00058, VT-03-00059, VT-03-00060, VT-
  • a sealed tube was charged with (7-bromoquinoxalin-2(lH)-one (2.2g, 9.82mmol), Zn(CN) 2 (1.72g, 14.73mmol), Pd 2 (dba) 3 (0.896g,0.98mmol), dppf(0.542mg, 0.98mmol), Zn powder(0.126g, 1.96mmol) and DMF(20mL). It was degassed for lOmin with Nitrogen and heated at 90°C for 0.5h. Upon completion, the reaction was diluted with EtOAc and filtered through a celite bed. The filtrate was concentrated.
  • VT-03-00110 (71a) Tert-butyl l-(2-(7-ethynyl-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate :-
  • VT-03-00124 - Compound-83c (30mg) was taken in MeOH(6ml) and triturated with 10% Pd-C(50mg) under Hydrogen atmosphere. Upon completion the reaction was filtered through celite bed and concentrated. The crude was triturated with EtOAc to give the required compound VT-03-00124 as a brown solid (7mg).
  • the compounds of the invention are useful for the treatment of infections in subjects, mammals in particular, including humans.
  • the compounds may be used for the treatment of infections of soft tissues, blood, skin, mouth, lungs, respiratory tract, urinary tract and reproductive tract.
  • the compounds of the invention are useful for the treatment of infections caused by microorganisms, such as but not limited to Staphylococcus species such as
  • Staphylococcus aureus Staphylococcus epidermidis, Staphylococcus haemolyticus,
  • Enterococcus species such as Enterococcus faecalis, Enterococcus faecium, Streptococcus species like Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella species, for example Moraxella catarrhalis, E. coli, Mycobacterium species,
  • Neisseria meningitidis Neisseria gonorrhoeae
  • Klebsiella species such as Klebsiella
  • pneumoniae Klebsiella oxytoca
  • Pseudomonas species such as Pseudomonas aeruginosa
  • Acinetobacter species such as Acinetobacter baumannii.
  • the compounds of the present invention are delivered to the subjects by forms suitable for each administration route.
  • the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository.
  • the route of administration is oral, parenteral or topical.
  • Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.
  • composition of the present invention is presented in unit dosage form generally in an amount that produces a therapeutic effect in the subject.
  • the compounds of the present invention are administered at a daily dose that is the lowest dose effective to produce a therapeutic effect.
  • the dosage will effect from about 0.0001 to about lOOmg per kg body weight per day.
  • the dosage will range from about 0.001 to 75mg per kg body weight per day and more preferably, the dosage will range from about 0.1 to about 50mg per kg body weight per day.
  • Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention.
  • the effective daily dose of the compound is administered as two, three, four or more sub- doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms.
  • the antibacterial compositions of the present invention may be administered by any method known in the art.
  • suitable modes of administration include oral, intravenous, intramuscular topical or any other parenteral mode of administration.
  • the present invention is directed to a method of formulating compounds of the present invention in a pharmaceutically acceptable carrier or excipient and may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like.
  • a pharmaceutically acceptable carrier or excipient may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like.
  • Such carriers may include one or more of solid diluents or fillers, sterile aqueous media, and various nontoxic organic solvents, etc.
  • tablets may contain various excipients such as one or more of microcrystalline cellulose, sodium citrate, calcium carbonate and the like, along with various disintegrants such as starch and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose and the like.
  • solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluents or solvent e.g. as solution in 1, 3 butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils are conventionally employed including synthetic mono or diglycerides.
  • fatty acids such as oleic acid find in the preparation of injectables.
  • aqueous solutions may be suitable for intravenous injection purposes.
  • the oily solutions may be suitable for intra articular, intramuscular, and/or subcutaneous injection purposes.
  • the compounds of the present invention may be administered topically that include transdermal, buccal, or sublingual application.
  • therapeutic compounds may be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion, and/or a cream.
  • topical carriers may include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, and/or mineral oils.
  • the timing of the administration of the pharmaceutical composition may also be regulated.
  • the compounds may be administered intermittently or by controlled release.
  • an "independently" selected substituent refers to a group of substituents, wherein the substituents may be different.
  • variable "A 2 " for a formula (I) compound indicates that in the absence of the said variable, the adjacent variables on both sides of the absent variable are connected directly together and is synonymous to a single covalent bond For example, in the chain -G-A2-NH-A3-R 6j if A 2 is "absent", then the chain becomes -G-NH-A 3 -R 6 .
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups; wherein the term “cycloalkyl” refers to a saturated or unsaturated monocyclic alkyl ring consisting of 3-8 carbon atoms or a saturated or partially unsaturated bicyclic ring consisting of 9 or 10 carbon atoms.
  • aryl refers to a mono- or bicylic aromatic ring containing optionally substituted carbon atoms.
  • the said term"aryl” can be fused to saturated or unsaturated cyclic ring containing minimum one heteroatom selected from oxygen, nitrogen and sulphur which is optionally substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • heteroaryl refers to an optionally substituted 5- or 6-membered monocyclic hetero aromatic ring or a 9- or 10-membered bicyclic hetero aromatic ring containing minimum one heteroatom which are independently selected from nitrogen, sulphur or oxygen.
  • heteroaryl can be fused to saturated or unsaturated cyclic ring containing minimum one of the said heteroatom which is optionally substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • alkoxy refers to alkyl ether radical, wherein the term “alkyl” is as defined above.
  • amino refers to -NH 2 group.
  • aminoalkyl refers to -NH(alkyl) or -N(alkyl)(alkyl) group wherein the term “alkyl” is as defined above.
  • halogen refers to F, CI, Br or I.
  • haloalkyl refers to an "alkyl” group substituted with one or more halogen wherein the terms “alkyl” and “halogen” are as defined above.
  • haloalkoxy refers to an "alkoxy” group substituted with at least one "halogen” wherein the terms “alkoxy” and “halogen” are as defined above.
  • hydroxyl refers to -OH group.
  • hydroxyalkyl refers to an alkyl group which is substituted with one or more, preferably one
  • nitro refers to -N0 2 group.
  • cyano refers to -CN group.
  • thiol or "thio” refers to -SH group.
  • alkyl sulfonyloxy refers to -OS0 2 — alkyl group wherein the term “alkyl” is as defined above.
  • aryloxy refers to aryl ether radical, wherein the term “aryl” is as defined above.
  • thioalkyl or "alkylthio” refers to -S-alkyl radical wherein the term “alkyl” is as defined above.
  • arylthio refers to -S-aryl radical wherein the term “aryl” is as defined above.
  • acylthio refers to -S-acyl radical wherein the term “acyl” is as defined above.
  • heterocyclylthio refers to -S-heterocyclyl radical wherein the term “heterocyclyl” is as defined herein.
  • heterocyclyloxy refers to -O-heterocyclyl radical wherein the term “heterocyclyl” is as defined herein.
  • heterocyclic or “heterocyclyl” as used above includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing minimum one heteroatom selected from oxygen, nitrogen and sulphur, which rings may be optionally C- substituted.
  • the preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
  • containing at least one heteroatom refers to at least one carbon atom of the ring being replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
  • the compounds of present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention is inclusive of all possible enantiomers and diastereomers in pure or substantially pure form and mixtures of two or more stereoisomers in ratios that are effective. This means that the compounds of present invention may exist both as levorotatory and as dextrorotatory, in the form of racemates and in the form of two enantiomers.
  • the compounds of present invention are capable of forming both pharmaceutically acceptable salts. Examples of salts include but not restricted to metals or amines such as alkali and alkaline earth metals or organic amines.
  • acids for salt formation include but is not limited to hydrochloric, sulphuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic and the likes thereof.
  • the compound of the present invention can exist as unsolvated or solvated forms including hydrated forms.
  • the compounds detailed in the present disclosure are capable of forming pharmaceutically acceptable prodrugs.
  • Prodrugs are covalently bonded carriers that release the active compound internally after administration to the subject.
  • the present invention provides pharmaceutical compositions comprising an effective amount of compound of Formula (I), prodrugs, tautomeric forms, stereoisomers, optical isomers, pharmaceutically acceptable salts, solvates, polymorphs, analogs or derivatives thereof with pharmaceutically acceptable carriers.
  • Example 2 MICs against Fluoroquinolone resistant strains
  • the activity of compounds was evaluated in an in vitro Gyrase assay using recombinant Gyrase protein as per the instructions of the assay kit (Inspiralis).
  • the assay measures the ability of E.coli Gyrase to convert relaxed plasmid DNA into the supercoiled form.
  • the enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours. The gel is then stained with Ethidium bromide and DNA in the different forms is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
  • Example 8 In vivo activity in the systemic infection model against S.aureus (MRSA ATCC 33591)
  • the activity of compounds was evaluated in an in vitro Gyrase supercoiling assay using ciprofloxacin resistant recombinant Gyrase protein (with mutation S83L) as per the instructions of the assay kit (Inspiralis).
  • the enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours.
  • the amount of supercoiled DNA is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
  • VT-03 compounds (of Formula II) to bind the hERG channel
  • membranes expressing the hERGchannel were incubated with radiolabeled Astemizole and displacement of the labeled ligand in the presence of compounds was measured.
  • the table below shows IC 50 concentrations. The compounds show no significant hERG binding activity up to the highest concentration tested.

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Abstract

The present invention relates to compounds which specifically inhibit bacterial DNA Gyrase and can be used for the treatment of respiratory tract infections.

Description

Inhibitors of DNA Gyrase for treatment of bacterial infections
CROSS-REFERENCE TO RELATED APPLICATIONS
The present PCT application is related to and takes priority from US Patent Application 15/467,820 filed 23 March 2017 which is a continuation-in-part of US National Phase
Application 14/434,870 which is entitled to the benefit under 35 U.S.C. § 120 and 365(c) of International Patent Application PCT/IB2013/059192, entitled, "Inhibitors of DNA Gyrase for treatment of bacterial infections", filed, 8 October 2013, which claims priority to Indian Patent Application 2795/CHE/2012, filed, 10 October 2012, all of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
This invention is related to compounds which specifically inhibit bacterial DNA Gyrase for the treatment of bacterial infections.
BACKGROUND OF THE INVENTION
Antibacterial drug resistance is a worldwide problem; new mechanisms of resistance emerge periodically and spread rapidly across the globe. The growing rate of antimicrobial resistance in clinical and non clinical settings poses significant threat to human health and animals, not only in India but also globally (Lancet Infectious Diseases, 9, 228-36, 2009). Each mechanism of resistance renders yet another class of antibiotics ineffective, ultimately resulting in fewer and fewer therapeutic options for patients. In fact, WHO now recognizes antimicrobial resistance as one of three greatest threats to human health (Clinical Infectious Diseases 50, 1081-1083, 2010). To address the issue of drug resistance, new chemotypes that target critical pathways in bacteria must be developed. We have identified a novel series of compounds that inhibit DNA Gyrase, a member of the DNA Topoisomerase family, and have broad spectrum antimicrobial activity.
DNA Topioisomerases are involved in the transient breaking and rejoining of DNA during replication, transcription and recombination. They are well conserved across the bacterial species and essential for viability. There are two classes of Topoisomerases, depending on whether they introduce single stranded (type 1) or double stranded breaks (type 2). DNA Gyrase and Topo IV are Type 2 Topoisomerases. Gyrase is responsible for the introduction of negative supercoils into DNA to allow fork progression during replication. It is a heterodimer consisting of two subunits of GyrA and two subunits of GyrB (Reviewed in Infectious Disorders - Drug Targets7, 3-9, 2007).
Gyrase is a clinically validated target. Inhibitors of this target, the fluoroquinolones have been in use since the 1960s but suffer widespread drug resistance. Despite extensive research, newer generations of fluorquinolones have not overcome resistance effectively. Recently two non-fluoroquinolone inhibitors of Gyrase have been described. One of them is NXL101 and the other is GSK299423. NXL101 belongs to a novel quinoline class with potent activity against gram-positive bacteria, including methicillin-and fluoroquinolone-resistant strains
(Antimicrobial Agents and Chemotherapy, 52, 3339-3349, 2008). GSK299423 shows potent antibacterial activity against MRSA, fluoroquinolone resistant strains of S. aureus and Gram negatives such as E. coli, H. influenzae, M. catarrhalis and Klebsiella, pneumoniae (Nature, 466, 935-942, 2010;. While the compound potently inhibits DNA Gyrase, it has serious hERG binding liability (BMCL, 21 , 7489-7495, 2011). Similarly, NXL-101 causes QT prolongation, which led to its discontinuation from clinical development (North American Journal of Medical Science, 4, 537-47, 2012). Nevertheless, the target continues to be attractive and novel chemotypes directed against the target will have significant clinical benefits, once proven to be efficacious and safe.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1 discloses time kill kinetics of VT-03 -00061 against MRSA 33591.
Figure 2 discloses time kill kinetics of VT-03-00061 against E. coli 25922.
DETAILED DESCRIPTION OF THE INVENTION
[1] The present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof:
Figure imgf000004_0001
wherein,
Zi, Z2, Z3 are each independently CRi;
Z4, Z5, Z6 are each independently selected from a group consisting of N or CRi;
Z2 and Z3 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
Z5 and Z6 together form an optionally substituted saturated or unsaturated 5-6 member ed cyclic ring which contains minimum one heteroatom at bridging or any other position of the ring;
Z4 and Z6 directly form a bond in absence of Z5 where its substitution together form an optionally substituted saturated or unsaturated 5-6 membered cyclic ring containing at least one heteroatom at bridging or any other position of the ring;
Ri are each independently selected from a group consisting of hydrogen, oxo, cyano, halogen, hydroxyl and Ci-6 alkyl optionally substituted with one or two Ci-6 alkoxy.
Ai is selected from a group consisting of -(CR2R3)m-CH2- , -CH2-(CR2R3)m- , -NH- (CR2R3)m-CH2 ,-(CR2R3)m-CH2-0- and
Figure imgf000004_0002
wherein, m is 1 or 2;
is connectivity to G;
R2 is selected from a group consisting of hydrogen, halogen, hydroxyl, acyloxy, Ci-6 alkyl optionally substituted with one or two Ci-6 alkoxy and Ci-6 alkoxy optionally substituted with C 1-6 alky 1
R3 is hydrogen;
G is selected from a group of formulae consisting of Gl, G2, G3, G4, G5, G6, G7, G8, G9 and Gl 0 as provided below
A l -A2-NH-A3-R6 A^N^^— A2— N H- A3— R6 Α -Ν^- 2
G1 G2 G3
Figure imgf000005_0001
G7 G8 G9 G10
A2 is CR4R5 or is absent; wherein R4 and R5 are each independently hydrogen or
Ci-6 alkyl; A3 is -CH2-, C(=0) or S02; wherein, Re is selected from a group consisting of i) substituted or unsubstituted monocylic or bicyclic aryl;
ii) substituted or unsubstituted monocylic or bicyclic heteroaryl;
iii) monocyclic aryl and hetero-aryl can be five or six membered ring bearing one or two hetero atom (N, O, S)
iv) aryl or hetero aryl ring substituted independently with halogen (F, CI, Br), N02, CN, OMe, Me, CF3, OCF3, Ethyl, Butyl, isobutyl, small alkyl chain substituted with halogen, amino, NMe2 alkoxy, carbonyl or sulfonyl.
v) the monocyclic or bicyclic aryl or heteroaryl is fused to saturated or unsaturated cyclic ring containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulphur which is optionally substituted with halogen, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkyl substituted with Ci-6 alkoxy, Ci-6 alkoxy optionally substituted with Ci-6 alkyl, Ci-4 haloalkoxy, C1-4 haloalkyl, C1-4 thioalkyl, nitro, cyano, carboxy, C1-4 alkylsulfonyl, aminosulfonyl, hydroxyl, amino, aminoalkyl, oxo, hydroxyalkyl, alkynyl, alkylcarbonyl and carbonyl.
A compound of Formula (I) selected from the group consisting of
Figure imgf000006_0001
or a pharmaceutically acceptable salt thereof, wherein,
Zi and Z3 are each independently selected from a group consisting of CH or N;
Z6 is independently selected from group consisting of CH, C-CN, C=0, wherein the bold line is an optional double bond;
gen, G5,
Figure imgf000006_0002
G1 G2 G3
Figure imgf000006_0003
G7 G8 G9 G10 wherein, Ai is selected from the group consisting of -(CR2R3)m-CH2- , -CH2-(CR2R3)m- -NH- (CR2R3)m-CH2 ,-(CR2R3)m-CH2-0- and
w
Figure imgf000007_0001
herein when Z6 is C-CN and A1-G-A2-NH-A3-R6 is G2, Al is
m is lor 2;
is connectivity to G;
R2 is selected from the group consisting of hydrogen, halogen, acyloxy, Ci-6 alkyl optionally substituted with one or two Ci_6alkoxy and Ci_6alkoxy optionally substituted with Ci-6 alkyl;
R3 is hydrogen;
A2 is CR4R5 or is absent; wherein R4 and R5 are each independently hydrogen or
Ci-6 alkyl;
A3 is -CH2-, C(=0) or S02; and
wherein, Rsis selected from the group consisting of
(i) a substituted or unsubstituted monocylic or substituted or unsubstituted bicyclic aryl; and
(ii) a substituted or unsubstituted monocylic or substituted or
unsubstitutedbicyclic heteroaryl.
In one aspect, VT-03 compounds of the invention show minimal (insignificant) hERG binding activity indicating the advantage of these compounds as against the known compounds in the art (BMCL, 21 , 7489-7495, 2011). VT-03 compounds of formula I of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species,
Enterococcus species, Streptococcus species, Moraxella species, E.coli, Klebsiella species, Pseudomonas species and Acinetobacter species.
In another aspect, the invention also provides compounds of formula (II) or pharmaceutically acceptable salts thereof:
Figure imgf000008_0001
Formula II
wherein, Zi and Z3 are each independently selected from a group consisting of CH or N;
Z2 is independently selected from group consisting of C=0 and C=S;
Ri is independently selected from the group consisting of hydrogen, methoxy, cyano, halogen, hydroxyl, Ci-6 alkoxy and Ci-6 alkyl optionally substituted with one or two Ci_6 alkoxy, alkyne, carboxyl, carboxamide;
G is Gl, G2 or G3
Figure imgf000008_0002
G1 G2 G3 wherein, R2 is selected from the group consisting of
(i) a substituted or unsubstituted monocylic aryl; and
(ii) a substituted or unsubstituted monocylic heteroaryl.
VT-03 compounds of Formula II of the invention are useful in the treatment of patients suffering from infections caused by Staphylococcus species, Enterococcus species, Streptococcus species, Moraxella species, E.coli, Mycobacterium species, Neisseria meningitidis, Neisseria
gonorrhoeae, Klebsiella species, Pseudomonas species and Acinetobacter species. [2] In an embodiment the instant invention provides preferred VT-03 compounds of formula I in Table I
Table I: VT-03 Compounds of the Invention
Figure imgf000009_0001
VT-03-00014 VT-03-00017 VT-03-00021
Figure imgf000009_0002
VT-03-00021a VT-03-00022 VT-03-00024
Figure imgf000009_0003
VT-03-00026 VT-03-00026a VT-03-00027
Figure imgf000009_0004
VT-03-00028 VT-03-00030 VT-03-00031
Figure imgf000009_0005
VT-03-00032 VT-03-00042 VT-03-00043
Figure imgf000009_0006
VT-03-00045 VT-03-00046 VT-03-00048
Figure imgf000010_0001
Figure imgf000010_0002
VT-03-00052 VT-03-00053 VT-03-00054
Figure imgf000010_0003
Figure imgf000010_0004
Figure imgf000010_0005
VT-03-00063 VT-03-00064 VT-03-00065
Figure imgf000011_0001
VT-03-00066 VT-03-00067 VT-03-00068
Figure imgf000011_0002
Figure imgf000011_0003
VT-03-00072 VT-03-00074 VT-03-00075
Figure imgf000011_0004
VT-03-00076 VT-03-00077 VT-03-00078
Figure imgf000011_0005
Figure imgf000012_0001
Figure imgf000012_0002
Figure imgf000012_0003
VT-03-00092 VT-03-00093 VT-03-00094
Figure imgf000012_0004
VT-03-00095
embodiment the instant invention provides preferred VT-03 compounds of formula II II -03 Compounds of the Invention
Figure imgf000013_0001
Figure imgf000014_0001
The invention further consists of the following
[3] General Synthesis of VT-03 Compounds of the Invention
Figure imgf000015_0001
Figure imgf000015_0002
8
STEP-?
Preparation of 6-Methoxy-4-vinyl-quinoline-3-carbonitrile (compound of step 8);- a) 2-r(4-Methoxy-phenylamino)-methylenel-malonic acid diethyl ester:
To a solution of 4-aminoanisole (40g, 324.8 mmol) in ethanol was added diethyl
ethoxymethylenemalonate (70.23 g, 324.8 mmol). The reaction was refluxed at 85°C for 4h. The ethanol in the reaction mixture was distilled out under reduced pressure. The residue was chromatographed on silicagel eluting with 5% ethylacetate in hexane to afford the product as oil 2 (61g).
b) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester:
Compound 2 (61 g) was taken up in dowtherm( 400ml) and heated at 250°C for 3h. The reaction mixture was cooled to (RT) and treated with pentane (300 mL) and filtered under suction. The resulting solids were washed thoroughly with excess of pentane and dried under vacuum to give 3 (23 g).
c) 4-Bromo-6-methoxy-quinoline-3-carboxylic acid ethyl ester:
To a stirred solution of compound 3 (23 g, 93 mmol) in DMF (91 rriL) was added PBr3 (8.8mL, 93 mmol)dropwise at RT. The reaction mixture was stirred at ambient temperature for lh after which 200ml ice cold water was added. The reaction was neutralized with aq. NaHCC solution. The obtained solids were collected by filtration, washed with water and dried under vacuum to give the required product 4 (32 g).
d) 4-Bromo-6-methoxy-quinoline-3-carboxylic acid:
To a stirred solution of compound 4(20 g) in THF was added 2N NaOH solution (71 mL) dropwise at 0 °C. The reaction mixture was brought to RT and stirred for 24h after which it was concentrated to remove the THF. The aqueous layer was washed with ethyl acetate to remove the insoluble impurities. The resulting aqueous layer was acidified to pH 2. The product was collected by filtration then codistilled with Toluene and dried under vacuum to afford the required compound 5 (15.5 g).
e) 4-Chloro-6-methoxy-quinoline-3-carboxylic acid amide:
To a stirred solution of compound 5 (15 g, 53.4 mmol) in anhydrous dichloromethane(200ml) was added oxalyl chloride (9.2mL, 106.7 mmol) dropwise at 0°c followed by the addition of a catalytic amount of dry DMF. The reaction mixture was gradually brought to RT and stirred for lh. The CH2CI2 and oxalyl chloride in the reaction mass were removed by distillation. The residue obtained was redissolved in CH2CI2, and conc.NH4OH solution (5ml) was added dropwise very slowly to this solution at 0°C (highly exothermic). The reaction was stirred for an additional 2 h. The observed solids were isolated via filtration, codistilled with Toluene and dried under vacuum to give the required compound 6 (22 g).
f) 4-Chloro-6-methoxy-quinoline-3-carbonitrile:
To a stirred solution of compound 6 (26.5 g, 112.05 mmol) in CH2Cl2, was added triethylamine (104ml) at 0°C followed by dropwise addition of trifluoroacetic anhydride (59.6 mL, 425.9 mmol) at the same temperature. The reaction was stirred at RT for 3 h and quenched by adding water (150 mL). The organic layer was separated, dried over Na2S04 and concentrated under reduced pressure. The obtained residue was treated with cold hexanes and filtered under suction to afford the required compound 7 (7.5 g). g) 6-Methoxy-4-vinyl-quinoline-3-carbonitrile:-
To a stirred solution of compound 7(3 g,13.7mmol)in 1 ,2-dimethoxyethane(90 mL) and water(30 mL) was added K2C03 (14.9 mmol), Pd(PPh3)4(0.274 mmol) and finally 2,4,6-tnvinyl cycloborane-pyridine complex (14.9mmol). The reaction was stirred at 80°C for 6h. The reaction mass was diluted with Ethyl acetate and filtered under celite. The filtrate was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The obtained residue was chromatographed on silicagel eluting with 25% ethylacetate in hexanes to afford the product as a solid 8 (2.1 g). [4] Synthesis of Specific Compounds of the Invention
Synthesis ofVT-03-00014, VT-03-00017, VT-03-00021, VT-03-00021a, VT-03-00022, VT-03- 00024, VT-03-00026, VT-03-00026a, VT-03-00027, VT-03-00028, VT-03-00030, VT-03- 00031, VT-03-00032, VT-03-00042, VT-03-00043, VT-03-00045, VT-03-00046, VT-03-00048, VT-03-00049, VT-03-00050, VT-03-00051, VT-03-00052, VT-03-00053, VT-03-00054, VT-03- 00055, VT-03-00056, VT-03-00057, VT-03-00058, VT-03-00059, VT-03-00060, VT-03-00061, VT-03-00062, VT-03-00062A, VT-03-00063, VT-03-00064, VT-03-00065, VT-03-00066, VT- 03-00067, VT-03-00068, VT-03-00069, VT-03-00070, VT-03-00071, VT-03-00072, VT-03- 00074, VT-03-00075, VT-03-00076, VT-03-00077, VT-03-00078, VT-03-00079, VT-03-00080, VT-03-00081, VT-03-00083, VT-03-00084, VT-03-00085, VT-03-00086, VT-03-00087, VT-03- 00088, VT-03-00089, VT-03-00090, VT-03-00091, VT-03-00092, VT-03-00093, VT-03-00094, VT-03-00095 are provided in detail in the parent US application no. 14/434,870 which is incorporated herein in its entirety by reference.
It should be noted that the intermediates referred in the foregoing are described in the US application no. 14/434,870 and PCT/IB2013/059192 both of which are incorporated herein by reference.
(65) Synthesis of VT-03-00101
Figure imgf000018_0001
VT-01 -00101
(65a) 2,6-dichloro-3-nitropyridine :-
To an ice cold solution of 2,6-Dichloropyridine(25g) in cone H2SO4(60 mL), was added fuming HNO3(30mL) dropwise at 0°C. This mixture was heated at 110°C for 6h. Upon completion the reaction was cooled to ambient temperature and poured into ice. Solids precipitated which were washed with excess water. These solids were dried to give the required compound 65a (30g).
(65b) 6-chloro-3-nitropyridin-2-amine:-
To a stirred solution of compound 65a (12g) in MeOH(50mL) in a sealed tube was added 2M NH3in MeOH at 0°C. The reaction was gradually brought to ambient temperature and stirred for 16h. Upon completion, the reaction was diluted with water and filtered under suction. The precipitate was dried to afford the required compound 65b (3.1g)
(65c) 6-methoxy-3-nitropyridin-2-amine:-
To an ice cold solution of MeOH(102mL) under Nitrogen atmosphere was added Sodium(1.9g) metal. After the complete solubilization of the Sodium, compound-65b(6.0g) was added. The reaction was heated at 90°C for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and EtOAc. The EtOAc layers were dried over Na2S04and concentrated under reduced pressure to afford the required compound-65c (6.5g).
(65d) 6-methoxypyridine-2,3-diamine:-
To a stirred solution of compound-65c (4.5g) in EtOH(80mL) was added 10% Pd-C(2.13g) under stirred under latm hydrogen pressure for 16h. Upon completion the reaction was diluted with EtOAc and filtered through celite bed. The filtrate was concentrated under reduced pressure to afford Compound-65d (3.65g) as a black solid.
(65e) 6-methoxypyrido[3,2-b]pyrazin-3(4H)-one:-
To a chilled solution of compound-65d (3.25g) in MeOH(30mL) was added ethylglyoxalate(50% in toluene) at 0°C. The reaction was gradually brought to ambient temperature and stirred for 16h. Upon completion, the reaction was diluted with MeOH and filtered under suction. The obtained filtrate was concentrated. The resulting crude was purified by flash column chromatography eluting the required compound with 4% MeOH-CH2Cl2. Compound-65e (0.53g) was thus obtained.
(65f)Tert-butyl l-(2-(6-methoxy-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)piperidin-4- ylcarbamate:-
To a stirred solution of compound-65e (0.53g) in DMF(5mL) at 0°C, was added NaH(0.23g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e(1.15g)synthetic methods for which, are provided in detail in the parent US application no. 14/434,870 dissolved in DMF(5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH- CH2C12. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-65f with 6% MeOH-CH2Cl2 as a brown solid.(0.35g).
(65g) 4-(2-(4-aminopiperidin-l-yl)ethyl)-6-methoxypyrido[3,2-b]pyrazin-3(4H)-one:- To a chilled solution of compound-65f(0.35g, 0.868mmol) in CH2C12, was added TFA(2.8ml) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-65g (0.27g crude).
(65h) VT-03-00101 :-
To a chilled solution of compound-65g(0.27g, 0.88mmol) and 3-Fluoro-4-methyl benzaldehyde (0.122g, 0.88mmol)in EtOH(5mL) was added Titanium isopropoxide(0.25ml). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.33g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00101 with 6% MeOH-CH2Cl2 as a pale brown solid(0.012g).
'HNMR (400 MHz, CDC13) δ 8.56 (S, 1H) ,8.05 ( d, 1H), 7.19-7.21 (m , 2H ) ,7.0-7.1 (m, 3H), 4.60( t, 2H) , 4.12 (s, 3H) , 3.75 (s, 2H ) , 3.01 ( d, 2H ) ,2.85 ( t, 2H ) ,2.55-2.65 (m , 1H) , 2.25 ( s, 3H) , 2.20 ( t, 2H) , 1.90 ( d, 3H) , 1.48 ( q, 2H ) , Mass spectra [M+H]+ m/z 426.00.
(66) Synthesis of VT-03-00102 :-
Figure imgf000020_0001
VT-03-00102
(66a) Tert-butyl l-(2-(7-bromo-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate :-
To a stirred solution of 7-bromoquinoxalin-2(lH)-one (0.4g) in DMF(5mL) at 0°C, was added
NaH(0.085g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e (0.86g) dissolved in DMF(5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-66a with 4% MeOH-CH2Cl2 as a pale brown solid.(0.22g).
(66b) l-(2-(4-aminopiperidin-l-yl)ethyl)-7-bromoquinoxalin-2(lH)-one :-
To a chilled solution of compound-66a(0.22g, 0.488mmol) in CH2Cl2(10mlL), was added TFA(lml) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04 and concentrated under reduced pressure to afford the required compound-66b (0.1 lg crude).
(66c)VT-03-00102
To a chilled solution of compound-66b (0.1 lg, 0.285mmol) and 3-Fluoro-4-methyl benzaldehyde
(0.047g, 0.342mmol)in EtOH(4mL) was added Titanium isopropoxide(0.34mL, 1.14mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.021g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2SC>4and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00102 with 8% MeOH-CH2Cl2 as a green viscous(0.020g).
'HNMR (400 MHz, CDC13): δ 8.22(s,lH), 7.72(d,lH), 7.65(s,lH), 7.45(d,2H), 7.12(t,lH), 7.0- 7.1(m,2H), 4.32(t,2H), 3.79(s,2H), 2.97(d,2H), 2.65(t, 2H), 2.56-2.66(m,lH), 2.25(s,3H), 2.20(t,2H), 1.86(d,2H), 1.46(q,2H) Mass spectra [M+H]+ m/z 475.2
(67) nthesis of VT-03-00103:
Figure imgf000021_0001
VT-03-00103
(67a) 3-Oxo-3,4-dihydroquinoxaline-6-carbonitrile:-
A sealed tube was charged with (7-bromoquinoxalin-2(lH)-one (2.2g, 9.82mmol), Zn(CN)2 (1.72g, 14.73mmol), Pd2(dba)3(0.896g,0.98mmol), dppf(0.542mg, 0.98mmol), Zn powder(0.126g, 1.96mmol) and DMF(20mL). It was degassed for lOmin with Nitrogen and heated at 90°C for 0.5h. Upon completion, the reaction was diluted with EtOAc and filtered through a celite bed. The filtrate was concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound -67a with 50% EtOAc-Hexanes as a pale brown solid 67a(0.650g). (67b) tert-butyl l-(2-(7-cyano-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate:-
To a stirred solution of compound-67a (0.45g) in DMF(7.5ml) at 0°C, was added NaH(0.126g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e(l g) dissolved in
DMF(7.5ml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and
10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-67b with 5% MeOH-CH2Cl2 as off white solid(0.32g).
(67c) 4-(2-(4-aminopiperidin-l-yl)ethyl)-3-oxo-3,4-dihydroquinoxaline-6-carbonitrile:- To a chilled solution of compound-67b(0.3g, 0.755mmol) in CH2Cl2(10mL), was added TFA(1.5mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-67c (0.15g crude).
(67d) VT-03-00103 :-
To a chilled solution of compound-67c(0.1g, 0.336mmol) and 3-Fluoro-4-methyl benzaldehyde (0.055g, 0.403mmol)in EtOH(5mL) was added Titanium isopropoxide(0.4mL, 1.34mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.025g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00103 with 8% MeOH-CH2Cl2 as a pale yellow solid(0.010g). 'HNMR (400 MHz, CDC13) δ 8.23(s,lH), 7.82(d,lH), 7.78(s,lH), 7.42(d,lH), 7.15( t,lH), 7.05(t,2H), 4.36(t,2H), 3.79(s,2H), 2.96(d,2H), 2.65(t,2H), 2.54-2.60(m,lH), 2.21(s,3H), 2.21(t,2H), 1.92(d,2H), 1.45(q,2H) Mass spectra [M+H]+ m/z 420.1
(68) Synthesis of VT-03-00104 :-
Figure imgf000022_0001
To a chilled solution of compound-67c (O. lg, 0.336mmol) and 3-Nitro-4-methyl benzaldehyde (0.066g, 0.403 mmol)in EtOH(5mL) was added Titanium isopropoxide(0.4mL, 1.34mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH (0.025g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04 and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00104 with 7% MeOH-CH2Cl2 as a pale brown solid(0.012g). 'HNMR (400 MHz, CDC13) δ 8.29(s,lH), 8.0(s,lH), 7.71(d,lH), 7.56(d,lH), 7.45(d, 1H), 7.18(d,lH), 7.05(d,lH), 4.31(t, 2H), 3.75(s,2H), 2.96(d,2H), 2.65(t,2H), 2.51-2.60(m,lH), 2.21(s,3H),2.19(t,2H), 1.89(d,2H), 1.46(q,2H) Mass spectra [M+H]+ m/z 447.1
(69)
Figure imgf000023_0001
VT-03-00108
(69a) Jert-butyl l-(2-(7-(methylcarbamoyl)-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4- ylcarbamate:-
To a stirred solution of N-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxamide (0.8g) in DMF (10ml) at 0°C, was added NaH(0.190g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e (1.52 g) dissolved in DMF(lOml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-69a with 4% MeOH-CH2Cl2 as an Pale brown solid(0.44g).
(69b) 4-(2-(4-aminopiperidin-l-yl)ethyl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-6-carboxamide:- To a chilled solution of compound-69a(0.21g, 0.489mmol) in CH2Cl2(10mL), was added TFA(1.2mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-69b (0.15g crude). (69c) VT-03-00108 :-
To a chilled solution of compound-69b (0.15g, 0.455mmol) and 3-Nitro-4-methyl benzaldehyde (0.091g, 0.546 mmol)in EtOH(4mL) was added Titanium isopropoxide(0.5ml, 1.82mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.033g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00108 with 2% MeOH-CH2Cl2 as a green viscous(0.015g).
'HNMR (400 MHz, CDC13) δ 8.36(s,lH), 7.92(d,2H), 7.80-7.89(m,lH), 7.52(d,lH), 7.30-7.42(m,lH), 4.52(t, 2H), 3.81(s,2H), 3.51(s,lH), 3.18-3.24(m,2H), 3.05(s,3H), 2.81-2.91(m,2H), 2.62(s,3H), 2.41- 2.50(m,2H), 2.11-2.21(m, 3H), 1.57-1.67(m,2H), Mass spectra [M+H]+ m/z 479.1
(70) Synthesis of VT-03-00109 :-
Figure imgf000024_0001
To a chilled solution of compound-69b (0.15g, 0.455mmol) and 3-Fluoro-4-methyl benzaldehyde (0.075g, 0.546 mmol)in EtOH(4mL) was added Titanium isopropoxide(0.5mL, 1.82mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.033g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00109 with 2% MeOH-CH2Cl2 as a green viscous(0.019g).
!HNMR (400 MHz, CDC13) δ 8.36(s,lH), 8.10(s,lH), 7.92(d,lH), 7.75(d,lH), 7.16(t,lH), 6.92- 6.98(m,3H), 4.46(t, 2H), 3.76( s,2H), 3.09(s,6H), 2.79(t,2H), 2.61-2.71(m,lH), 2.22(s,3H), 1.96(d,3H), 1.54(d,2H), 1.36(s,2H) Mass spectra [M+H]+ m/z 452.1
(71) Synthesis of VT-03-00110 :-
Figure imgf000024_0002
VT-03-00110 (71a) Tert-butyl l-(2-(7-ethynyl-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate :-
To a stirred solution of 7-ethynylquinoxalin-2(lH)-one (0.2g) in DMF (4ml) at 0"C, was added
NaH(0.056g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e(0.451 g) dissolved in DMF(4ml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-71a with 2% MeOH-CH2Cl2 as an Pale yellow viscous(0.13g).
(71b)l-(2-(4-aminopiperidin-l-yl)ethyl)-7-ethynylquinoxalin-2(lH)-one :-
To a chilled solution of compound-71a (0.14g, 0.35mmol) in CH2Cl2(10mL), was added TFA(0.6mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-71b (0.1 lg crude).
(71c) VT-03-00110 :-
To a chilled solution of compound-71b (O. lg, 0.337mmol) and 3-Fluoro-4-methyl benzaldehyde (0.055g, 0.404 mmol)in EtOH(5mL) was added Titanium isopropoxide(0.4mL, 1.34mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.025g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00110 with 8% MeOH-CH2Cl2 as a green viscous(0.012g).
'HNMR (400 MHz, CDC13) δ 8.45(s,lH), 7.96(d,2H), 7.61(d,2H), 7.15(t, 1H), 7.05-7.10(m,2H),
4.65(t,2H), 3.50(s,lH), 3.15(d,2H), 2.96(t,2H), 2.75-2.83(m,lH), 2.36-2.46(m,2H), 2.21(s,3H), 2.15- 2.20(m,2H)1.98-2.1(m,2H), 1.67(q,2H), 1.41(s,2H). Mass spectra [M+H]+ m/z 419.1
(72)
Figure imgf000025_0001
VT-03-001 11 (72a)Tert-butyl l-(2-(6-chloro-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)piperidin-4-ylcarbamate :-
To a stirred solution of 6-chloropyrido[3,2-b]pyrazin-3(4H)-one (0.2g,l. l lmmol) in DMF (5mL) at 0"C, was added NaH(0.043g, 60%in oil). The reaction was stirred at this temperature for lh. Then compound 26e(0.43 g) dissolved in DMF(5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by silica gel (100-200 mesh) Flash column chromatography eluting the required compound-72a with 70% EtOAc-Hexanes as a golden yellow viscous(0.3 lg).
(72b)4-(2-(4-aminopiperidin-l-yl)ethyl)-6-chloropyrido[3,2-b]pyrazin-3(4H)-one :- To a chilled solution of compound-72a(0.2g) in CH2Cl2(2.8mL), was added TFA(1.2mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHCC^ solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-72b (0.103g crude).
(72c) VT-03-00111 :-
To a chilled solution of compound-72b(0.1g, 0.334mmol) and 3-Fluoro-4-methyl benzaldehyde (0.046g, 0.335 mmol)in EtOH(4mL) was added Titanium isopropoxide(0.4ml). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.019g) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2 . The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00111 with 10% MeOH-CH2Cl2 as a green viscous(0.009g).
'HNMR (400 MHz, CDC13) δ 8.30(s,lH),8.11(d,lH), 7.29(s,lH), 7.15(t,lH), 6.96-7. l(m,2H), 4.56(t, 2H), 3.78(s,2H), 3.05(d,2H), 2.76(t,2H), 2.51-2.61(m,lH), 2.26(s,3H), 2.15(t,2H), 1.83(d,2H), 1.25(d, 3H). Mass spectra [M+H]+ m/z 430.1
(73)
Figure imgf000026_0001
VT-03-00112 (73a)7-ethylquinoxalin-2(lH)-one:-
To a stirred solution of 7-ethynylquinoxalin-2(lH)-one (0.460g, 2.70mmol) in MeOH(20mL) was added 10% Pd-C(0.3g). The reaction was stirred under latm Hydrogen pressure for 18h. Upon completion, the reaction was passed through a celite bed and the filtrate was concentrated. The crude was triturated with n-Pentane to afford the required compound-73a as brown solid(0.350g).
(73b)Tert-butyl l-(2-(7-ethyl-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate:- To a stirred solution of compound-73a (0.35g, 2.01mmol) in DMF (5mL) at 0°C, was added NaH(0.096g, 60%in oil, 4.02mmol). The reaction was stirred at this temperature for lh. Then compound 26e(0.776g, 2.41mmol) dissolved in DMF(5ml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) flash column chromatography eluting the required compound-73b with 80% EtOAc-Hexanes as yellow semisolid (0.18g).
(73c)l-(2-(4-aminopiperidin-l-yl)ethyl)-7-ethylquinoxalin-2(lH)-one:-
To a chilled solution of compound-73b (0.180g) in CH2Cl2(8mL), was added TFA(lmL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHCC^ solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-73c (0.120g crude).
(73d) VT-03-00112 :-
To a chilled solution of compound-73c (0.12g, 0.4mmol) and 3-Fluoro-4-methyl benzaldehyde (0.066g, 0.48 mmol)in EtOH(4mL) was added Titanium isopropoxide(0.5mLl, 1.6mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.030g, 0.8mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00112 with 8% MeOH-CH2Cl2 as a green liquid(0.015g).
'HNMR (400 MHz, CDC13) δ 8.22(s,lH), 7.80(d,lH), 7.23-7.33(m.2H), 7.18(t,lH), 7.01(t,2H),
4.40(t,2H), 3.80(s,2H), 3.01(d,2H), 2.82(q,2H), 2.70(t,2H), 2.56-2.66(m,lH), 2.32(s,3H), 2.20(t,2H), 1.91(d,2H), 1.52(q,2H), 1.32(t, 3H). Mass spectra [M+H]+ m/z 423.25
(74) Synthesis of VT-03-00113 :-
Figure imgf000028_0001
VT-03-001 13
(74a) tert-butyl l-(2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate:-
To a stirred solution of 7-fluoroquinoxalin-2(lH)-one (0.5g, 3.048mmol) in DMF (7.5mL) at 0°C, was added NaH(0.146g, 60%in oil, 6.1mmol). The reaction was stirred at this temperature for lh. Then compound 26e (1.17g, 3.658mmol) dissolved in DMF(7.5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-74a with 80% EtOAc-Hexanes as a semisolid (0.35g).
(74b) l-(2-(4-aminopiperidin-l-yl)ethyl)-7-fluoroquinoxalin-2(lH)-one:-
To a chilled solution of compound-74a(0.35g) in CH2Cl2(9mL), was added TFA(1.6mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2SC>4and concentrated under reduced pressure to afford the required compound-74b (0.240g crude).
(74c) VT-03-00113 :-
To a chilled solution of compound-74b(0.15g, 0.515mmol) and 3-Nitro-4-methyl benzaldehyde (0.102g, 0.618 mmol)in EtOH(5mL) was added Titanium isopropoxide(0.61mL, 2.06mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.038g, 1.03mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00113 with 2% MeOH-CH2Cl2 as a green liquid(0.030g). 'HNMR (400 MHz, CDCI3) δ 8.21(s,lH), 7.91(s,lH), 7.82(q,lH), 7.51(d,lH), 7.3(q,lH), 7.15- 7.23(m,2H), 4.31(t,2H), 3.82(s,2H), 2.92(d,2H), 2.65(t, 2H), 2.60(s,3H), 2.51-2.61(m,lH), 2.22(t, 2H), 1.91(d, 2H), 1.41(q,2H) Mass spectra [M+H]+ m/z 440.1
Figure imgf000029_0001
(75a) Tert-butyl l-(2-(2-oxo-7-(trifluoromethoxy)quinoxalin-l(2H)-yl)ethyl)piperidin-4- ylcarbamate
To a stirred solution of 7-(trifluoromethoxy)quinoxalin-2(lH)-one (0.5g, 2.173mmol) in DMF (7.5mL) at 0°C, was added NaH(0.104g, 60%in oil, 4.36mmol). The reaction was stirred at this temperature for lh. Then compound 26e (0.840g, 2.607mmol) dissolved in DMF(7.5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-75a with 80% EtOAc- Hexanes as a golden yellow viscous(0.35g).
(75b)l-(2-(4-aminopiperidin-l-yl)ethyl)-7-(trifluoromethoxy)quinoxalin-2(lH)-one :-
To a chilled solution of compound-75a (0.35g, 0.767mmol) in CH2C12 (9ml), was added TFA(1.8mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-75b (0.220g crude).
(75c) VT-03-00114 :-
To a chilled solution of compound-75b(0.15g, 0.421mmol) and 3-Nitro-4-methyl benzaldehyde (0.083g, 0.505 mmol)in EtOH(5mL) was added Titanium isopropoxide(0.5mL, 1.684mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.031g, 0.842mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2SC>4and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00114 with 2% MeOH-CH2Cl2 as a green
viscous(0.030g).
'HNMR (400 MHz, CDC13) δ 8.92(s,lH), 7.92(s,lH), 7.51(d,lH), 7.29(d,2H), 7.20(d,lH), 4.30(t,2H), 3.85(s,2H), 2.95(d,2H), 2.65(t,2H), 2.60(s,3H), 2.50-2.56(m,lH), 2.20(t, 2H), 1.95(d,2H), 1.45(q,2H) Mass spectra [M+H]+ m/z 506.1
(76) Synthesis of VT-03-00116 : -
Figure imgf000030_0001
To a stirred solution of compound-74b (0.422g, 1.45mmol) and 4-Chloro-3-nitrobenzaldehyde(0.27g, 1.45mmol) in CHCl3(14ml) was added Sodium Triacetoxyborohydride (0.368g, 1.74mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2SC>4and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00116 with 6% MeOH-CH2Cl2 as a pale brown viscous(0.132g).
'HNMR (400 MHz, CDCI3) δ 8.19(s,lH), 8.01(s,lH),7.85(t,lH), 7.65(t,2H), 7.55(d,lH), 7.21(t,lH), 4.22(t,2H), 3.76(s,2H), 2.91(d,2H), 2.52(t,2H), 2.31(s,lH), 2.01(t,2H), 1.75(d,2H), 1.21(d,3H);Mass spectra [M+H]+ m/z 460.1
(77) Synthesis of VT-03-00117:-
Figure imgf000030_0002
To a stirred solution of compound-74b (0.6g, 2.06mmol) and 5-Formyl-2-methylbenzonitrile(0.3g, 2.06mmol) in CHCl3(16mL) was added Sodium Triacetoxyborohydride (0.52g, 2.47mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel (100-200mesh) flash column chromatography of the crude eluted the required compound VT- 03-00117 with 6% MeOH-CH2Cl2 as a pale brown viscous(0.167g).
'HNMR (400 MHz, DMSO-d6) δ 8.19( s, 1H), 7.85-7.95(m, 1H), 7.65(s, 1H), 7.54-7.60(m, 2H), 7.38(d, 1H), 7.21(t, 1H), 4.22(t, 2H), 3.75(s, 2H), 2.85(d, 2H), 2.57(t, 2H), 2.41(s, 3H), 2.30-2.36(m, 1H), 2.0( s, 2H), 1.78(d, 2H), 1.20(m ,2H), Mass spectra [M+H]+ m/z 420.1
(78) Synthesis of VT-03-00118 :-
Figure imgf000031_0001
To a stirred solution of compound-72b (0.45g, 1.46mmol) and 4-methyl-3-nitrobenzaldehyde(0.214g, 1.461mmol) in l,2-Dichloroethane(5mL) was added Sodium Triacetoxyborohydride (0.40 lg, 1.89mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00118 with 11% MeOH-CH2Cl2 as a pale brown viscous(0.142g).
'HNMR (400 MHz, DMSO-d6) δ 8.31(t, 2H), 7.91( s, 1H), 7.58( d, 1H), 7.52(d, 1H), 7.40( d,lH), 4.34( t, 2H) , 3.78 (s, 2H) , 2.85( d, 2H) , 2.56( t, 2H), 2.42( s,3H), 2.28-2.35( m, 1H), 1.98 ( t, 2H) , 1.75 (d, 2H) , 1.5 (q, 2H), Mass spectra [M+H]+ m/z 457.00.
(79 Synthesis of VT-03-00119 :-
Figure imgf000031_0002
(79a) 7-bromopyrido[2,3-b]pyrazin-2(lH)-one :-
To a stirred solution of 2,3-Diamino-5-bromopyridine(5g, 26.8mmol) in MeOH(70ml) was added Ethyl glyoxalate(50% in toluene,25ml) dropwise and stirred at ambient temperature for 18h. Upon completion, the reaction mass was filtered through a celite bed and the filtrate was concentrated. Silicagel(100- 200mesh) flash column chromatography of the crude eluted the required compound-79awith 50% EtOAc- Hexanes as a pale brown solid (2.2g).
(79b)2-oxo-l,2-dihydropyrido[2,3-b]pyrazine-7-carbonitrile
A sealed tube was charged with compound-79a(2.0g, 8.88mmol), Zn(CN)2(1.55g, 13.32mmol),
Pd2(dba)3(0.805g ,0.88mmol), dppf(0.476g,0.86mmol), Zn powder(0.115g, 1.77mmol) and
DMF(16ml)was added. The reaction was heated at 90°C for 30 min. Upon completion, the reaction was filtered through celite bed and the filtrate concentrated to dryness. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-79b with 50% EtOAc-Hexanes as a dark brown solid(0.65g).
(79c)tert-butyl l-(2-(7-cyano-2-oxopyrido[2,3-b]pyrazin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate:- To a stirred solution of compound-79b (0.55g, 3.197mmol) in DMF (7.5mL) at 0°C, was added
NaH(0.153g, 60%in oil, 6.394mmol). The reaction was stirred at this temperature for lh. Then compound 26e(1.23g, 3.836 mmol) dissolved in DMF(7.5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2 . The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-79c with 100% EtOAc as a golden yellow viscous(0.31g).
(79d) l-(2-(4-aminopiperidin-l-yl)ethyl)-2-oxo-l,2-dihydropyrido[2,3-b]pyrazine-7-carbonitrile :-
To a chilled solution of compound-79c(0.3g, 0.75mmol) in CH2Cl2(10mL), was added TFA(2mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHCC solution. The organic layer was dried over Na2SC>4and concentrated under reduced pressure to afford the required compound-79d (0.140g crude).
(79e) VT-03-00119 :-
To a chilled solution of compound-79d(0.1g, 0.336mmol) and 3-Nitro-4-methyl benzaldehyde (0.066g, 0.403 mmol)in EtOH(5mL) was added Titanium isopropoxide(0.4mL, 1.344mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.025g, 0.672mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2 . The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00119 with 6% MeOH-CH2Cl2 as a yellow
viscous(0.007g). 'HNMR (400 MHz, CDCI3) δ 8.22(s,lH), 7.92(s,lH),7.91(d,lH), 7.50(d,lH), 7.25(d,lH), 7.20(d,lH),4.30(t,2H), 3.82(s,2H), 2.92(d.2H), 2.76(t,2H), 2.61(s,3H), 2.31 -2.40(m,lH), 2.20(t,2H), 1.92(d,2H), 1.56(t,2H) Mass spectra [M+H]+ m/z 448.2
(80) Synthesis of VT-03-00120 :-
Figure imgf000033_0001
VT-03-00120
(80a)Pyrido[2,3-b]pyrazin-2(lH)-one:-
To a stirred solution of 7-bromopyrido[2,3-b]pyrazin-2(lH)-one (2.2g, 9.77mmol) in EtOH(30mL) was added Et3N (2mL) followed by 10% Pd-C (lg). The reaction was stirred under latm Hydrogen pressure for 16h. The reaction mass was filtered through a celite bed and concentrated under reduced pressure. . The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-80a with 90% EtOAcin Hexanes as a brown solid(0.725g).
(80b)tert-butyl l-(2-(2-oxopyrido[2,3-b]pyrazin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate:- To a stirred solution of compound-80a (0.4g, 2.74mmol) in DMF (7.5mL) at 0°C, was added
NaH(0.13 lg, 60%in oil, 5.48mmol). The reaction was stirred at this temperature for lh. Then compound 26e(1.05g, 3.28 mmol) dissolved in DMF(7.5mL) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-80b with 100% EtOAc as a golden yellow viscous (0.3g).
(80c)l-(2-(4-aminopiperidin-l-yl)ethyl)-2-oxo-l,2-dihydropyrido[2,3-b]pyrazine-7-carbonitrile:-
To a chilled solution of compound-80b(0.3g, 0.804mmol) in CH2Cl2(10mL), was added TFA(1.5mLl) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-80c (0.150g crude).
(80d) VT-03-00120 :- To a chilled solution of compound-80c(0.150g, 0.551mmol) and 3-Nitro-4-methyl benzaldehyde (O. l lOg, 0.661 mmol)in EtOH(lOmL) was added Titanium isopropoxide(0.65ml, 2.204 mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.040g, 1.102mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00120 with 4% MeOH-CH2Cl2 as a green
viscous(0.008g).
1HNMR (400 MHz, CDC13) δ 8.21(s,lH), 7.92(s,lH), 7.82(q,lH), 7.51(d, 1H), 7.23(d,lH), 7.11- 7.20(m,2H), 4.31(t, 2H), 3.83(s,2H), 2.92(d,2H), 2.65(t,2H), 2.58(s,3H), 2.51-2.55(m,lH), 2.20(t,2H), 1.91(d,2H), 1.42(q,2H) Mass spectra [M+H]+ m/z 423.2
(81)
Figure imgf000034_0001
VT-03-00121
(81a)4-((l,3-dioxolan-2-yl)methyl)-6-chloropyrido[3,2-b]pyrazin-3(4H)-one :-
To a stirred solution of 6-chloropyrido[3,2-b]pyrazin-3(4H)-one (4.0g, 22.01mmol) in DMF(50mL) was added NaH(1.32g) and heated at 50°C for 40 min. Then 2-Bromomethyl-l,3-dioxolane (6.8ml, 66.1ml) was added dropwise and heated at 100°C for 2h. Upon completion the DMF in the reaction was distilled out. The crude was partitioned between water and EtOAc. The organic layers were dried over Na2S04 and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-81a with 30% EtOAc-Hexanes as a brown solid(0.613g).
(81b) 4-((l,3-dioxolan-2-yl)methyl)-6-fluoropyrido[3,2-b]pyrazin-3(4H)-one:- To a stirred solution of compound-81a(0.613g, 2.28mmol) in DMF(42mL) was added CsF(3.46g, 22.8mmol) and heated at 100°C for lh. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and EtOAc. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-81b with 40% EtOAc-Petether as a brown solid(0.380g).
(81c) 2-(6-fluoro-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)acetaldehyde:- A stirred solution of compound-81b(0.38g) in 80% TFA(15ml) was heated at 65°C for lh. Upon completion, the solvent in the reaction was distilled out. The crude was basified (pH=8) with IN NaOH solution and extracted with EtOAc. The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-81c with 50% EtOAc-Hexanes as a brown solid(0.2g).
(81d) tert-butyl l-(2-(6-fluoro-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)piperidin-4-ylcarbamate:- To a stirred solution of compound-81c (0.2g, 0.964mmol) and 4-(N-Boc-amino)piperidine (0.186g, 0.964mmol) in l,2-DCE(12mL) was added Sodium triacetoxyborohydride(0.244g, 1.45mmol) and stirred at ambient temperature for 4h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure to afford the required compound-81d as a green viscous (0.225g crude).
(81e) 4-(2-(4-aminopiperidin-l-yl)ethyl)-6-fluoropyrido[3,2-b]pyrazin-3(4H)-one:-
To a chilled solution of compound-81d(0.32g) in CH2Cl2(5ml), was added TFA(1.5ml) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-81e (0.220g crude).
(81f) VT-03-00121 :-
To a stirred solution of compound-81e (0.16g) and 4-methyl-3-nitrobenzaldehyde(0.09g, 0.556mmol) in l,2-Dichloroethane(5ml) was added Sodium Triacetoxyborohydride (0.140g, 0.667mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00121 with 4% MeOH-CH2Cl2 as a pale brown solid(0.035g). 'HNMR (400 MHz, CDC13) δ 8.25-8.31(m,2H), 7.92(s,lH), 7.54(d,lH), 7.21(s,lH), 6.90(d,lH), 4.52(t,2H), 3.82(s,2H), 3.05(d,2H), 2.76(t,2H), 2.62(s,3H), 2.56-2.60(m,lH), 2.22-2.35(m,2H),
1.92(t,3H), 1.35(q,2H) Mass spectra [M+H]+ m/z 441.3
(82) Synthesis of VT-03-00122 :-
Figure imgf000036_0001
To a stirred solution of compound-74b (0.21g, 0.723mmol) and 4-methyl-3-fluorobenzaldehyde (0.12g, 0.723mmol) in CHCl3(7mL) was added Sodium Triacetoxyborohydride (0.18g, 0.867mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00122 with 6% MeOH-CH2Cl2 as a pale brown solid(0.067g).
'HNMR (400 MHz, DMSO-d6) δ 8.19( s, 1H), 7.82( q, 1H), 7.50( dd, 1H), 7.15-7.26( m, 2H), 7.01- 7.09(m , 2H), 4.25-4.35( m, 2H), 3.65(s, 2H), 2.85(d, 2H), 2.59(t, 2H), 2.39-2.42(m, 1H), 2.19(s, 3H), 2.01(t, 2H), 1.90(s, 2H), 1.75(d,2H), 1.21-1.31(m ,2H), Mass spectra [M+H]+ m/z 413.00.
(83) Synthesis of VT-03-00124 :-
Figure imgf000036_0002
(83a)benzyl 4-(2-(4-(tert-butoxycarbonylamino)piperidin-l-yl)ethyl)-3-oxo-3,4-dihydroquinoxaline -6- carboxylate :- To a stirred solution of benzyl 3-oxo-3,4-dihydroquinoxaline-6-carboxylate (0.5g, 1.78mmol) in DMF (7.5mlml) at 0°C, was added NaH(0.085g, 60%in oil, 3.57mmol). The reaction was stirred at this temperature for lh. Then compound 26e(0.690g, 2.142mmol) dissolved in DMF(7.5ml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-83a with 90% EtOAc-Hexanes as a brown viscous(0.29g).
(83b) benzyl 4-(2-(4-aminopiperidin-l-yl)ethyl)-3-oxo-3,4-dihydroquinoxaline-6-carboxylate:- To a chilled solution of compound-83a(0.29g, 0.573mmol) in CH2Cl2(10mL), was added TFA(1.5mL) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-83b (0.150g crude).
(83c) benzyl 4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)-3-oxo-3,4- dihydroquinoxaline-6- carboxylate:-
To a chilled solution of compound-83b(0.15g, 0.369mmol) and 3-Nitro-4-methyl benzaldehyde (0.073g, 0.442mmol)in EtOH(5ml) was added Titanium isopropoxide(0.4ml, 1.476mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.028g, 0.738mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2 . The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-83c with 5% MeOH-CH2Cl2 as a green viscous(0.030g).
(83d) VT-03-00124:- Compound-83c (30mg) was taken in MeOH(6ml) and triturated with 10% Pd-C(50mg) under Hydrogen atmosphere. Upon completion the reaction was filtered through celite bed and concentrated. The crude was triturated with EtOAc to give the required compound VT-03-00124 as a brown solid (7mg).
'HNMR (400 MHz, CDC13) δ 8.30(s,lH), 7.92(s, 1H), 7.89(d, 1H), 7.51(d,lH), 7.32(s,2H), 7.20(d,lH), 4.32(t,2H), 3.90(s,2H), 2.95(d,2H), 2.80(s,3H), 2.72(t,2H), 2.56-2.61(m,2H), 2.21(t,2H), 1.91(d,2H), 1.20-1.25(m,3H) Mass spectra [M+H]+ m/z 420.3 (84) Synthesis of VT-03-00125 :-
Figure imgf000038_0001
To a chilled solution of compound-65g(0.42g, 1.40mmol) and 3-Nitro-4-methyl benzaldehyde (0.277g, 1.68 mmol)in EtOH(lOml) was added Titanium isopropoxide(0.6ml, 2.1mmol). The reaction was stirred at ambient temperature for 16h. Then NaBH4 (0.05g, 1.54mmol) followed by two drops of AcOH were added and stirred for 3h. Upon completion, the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2 . The organic layers were dried over Na2S04and concentrated under reduced pressure. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00125 with 8% MeOH-CH2Cl2 as a brown solid(0.121g).
'HNMR (400 MHz, CDC13) δ 8.55( s,lH), 8.05( d, 1H), 7.93( s, 1H) , 7.51( d, 1H), 7.25(d, 1H) , 7.15(d, 1H), 4.55( t, 2H), 4.15( s, 3H), 3.85( s, 2H), 3.01( d, 2H), 2.61( s, 3H), 2.55( s, 1H), 2.20-2.26( m, 2H), 1.95( d ,3H), 1.27-1.37( m, 2H), Mass spectra [M+H]+ m/z 453.3.
(85) Synthesis of VT-03-00126 :-
Figure imgf000038_0002
VT-03-00126
(85a)7-methoxyquinoxaline-2(lH)-thione:-
To a stirred solution of compound-26c(0.6g, 3.40mmol) in Pyridine(lOml) was added P2S5(2.7g, 6.16mmol) and heated at 130°C for 6h. Upon completion, the Pyridine in the reaction was distilled out. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound-85a with 11% EtOAc-Petether as a brown solid(0.65g).
(85b)tert-butyl l-(2-(7-methoxy-2-thioxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylcarbamate To a stirred solution of compound-85a (0.45g, 2.38mmol) in DMF (13.5mLl) at 0 C, was added NaH(0.104g, 60% in oil, 2.6mmol). The reaction was stirred at this temperature for lh. Then compound 26e(0.92g, 2.86mmol) dissolved in DMF(7.5ml) was added dropwise at 0°C. The reaction was stirred at ambient temperature for 16h. Upon completion the solvent in the reaction was distilled out. The crude was partitioned between water and 10% MeOH-CH2Cl2. The organic layers were dried over Na2S04and concentrated under reduced pressure. The obtained crude was purified by Silica gel (100-200 mesh) Flash column chromatography eluting the required compound-85b with 90% EtOAc-Hexanes as a brown viscous(0.44g).
(85c) l-(2-(4-aminopiperidin-l-yl)ethyl)-7-methoxyquinoxaline-2(lH)-thione:- To a chilled solution of compound-85b (0.44g, 1.05mmol) in CH2Cl2(5ml), was added TFA(0.97ml) dropwise at 0°C . The reaction was stirred at ambient temperature for 2h. Upon completion, the solvent in the reaction was distilled out. The crude was diluted with 10% MeOH-CH2Cl2and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04and concentrated under reduced pressure to afford the required compound-85c (0.210g crude).
(85d) VT-03-00126 :-
To a stirred solution of compound-85c(0.1g, 0.313mmol) and 4-methyl-3-fluorobenzaldehyde (0.05g, 0.313mmol) in CHCl3(5mL) was added Sodium Triacetoxyborohydride (0.079g, 0.376mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00126 with 7% MeOH-CH2Cl2 as a dark green solid(0.010g).
'HNMR (400 MHz, CDC13) δ 8.41(s,lH), 7.90(d,lH), 7.21-7.31(m,5H), 3.96(s,3H), 3.91(s,2H), 3.51(t, 2H), 3.21(d,2H), 2.85-2.95(m,3H), 2.75-2.80(m,2H), 2.21(s,3H), 1.9-2.0(m,2H), 1.25-1.3 l(m,3H), Mass spectra [M+H]+ m/z 441.2
(86) Synthesis of VT-03-00127 : -
Figure imgf000039_0001
To a stirred solution of compound-85c(0.21g, 0.659mmol) and 4-methyl-3-nitrobenzaldehyde (O. lg, 0.659mmol) in CHCl3(5ml) was added Sodium Triacetoxyborohydride (0.16g, 0.79mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00127 with 7% MeOH-CH2Cl2 as a pale brown viscous(0.015g).
'HNMR (400 MHz, CDC13) δ 8.41(s,lH), 7.92(s,lH), 7.82(d,lH), 7.50(d,lH),7.31(d,lH), 7.22(d,2H), 3.96(s,3H), 3.85(s,2H), 3.54-3.64(m,2H), 3.15(m,2H), 2.85-2.95(m,2H), 2.58(s,3H), 3.35-3.45(m,2H), 2.05-3.15(m,2H), 0.91(t,2H) Mass spectra [M+H]+ m/z 468.1
(87) Synthesis of VT-03-00128 :-
Figure imgf000040_0001
To a stirred solution of compound-26g (0.4g, 1.32mmol) synthetic methods for which, are provided in detail in the parent US application no. 14/434,870 and 4-Chloro-3-nitrobenzaldehyde (0.24g, 1.32 mmol) in CHCi3(14mL) was added Sodium Triacetoxyborohydride (0.325g, 1.58mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH- CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00128 with 6% MeOH-CH2Cl2 as a yellow solid(0.063g).
'HNMR (400 MHz, DMSO-d6) δ 8.01(s, 2H), 7.65-7.72( m, 3H), 7.01( s, 2H), 4.30( t, 2H), 3.91( s, 3H), 3.75( s, 2H), 2.91( d, 2H), 2.52( t, 2H),2.35-2.44( m, 1H), 2.01(t, 2H),1.75 ( d, 2H) , 1.21( t, 2H), Mass
Figure imgf000040_0002
0.65mmol) in CHCl3(6mL) was added Sodium Triacetoxyborohydride (0.178g, 1.3mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00131 with 6% MeOH-CH2Cl2 as a brownsolid(0.059g).
!HNMR (400 MHz, DMSO-d6) δ 8.35( t, 2H), 7.65( s, 1H), 7.52( t, 2H), 7.38( d, 1H), 4.35( t, 2H), 3.65(s, 2H), 2.85( d,2H), 2.78( t, 3H), 2.40( s, 3H), 2.25-2.35( m, 1H), 1.98-2.05( m ,2H), 1.75(d, 2H), 1.15(q ,2H), Mass spectra [M+H]+ m/z 437.20.
Figure imgf000041_0001
To a stirred solution of compound-85c (0.21g, 0.659mmol) and 5-Formyl-2-methylbenzonitrile (0.094g, 0.659 mmol) in CHCl3(10mLl) was added Sodium Triacetoxyborohydride (0.16g, 0.79mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00132 with 8% MeOH-CH2Cl2 as a brown viscous(0.017g).
'HNMR (400 MHz, CDC13) δ 8.41(s,lH), 7.90(d,lH), 7.21-7.33(m,5H), 3.96(s,3H), 3.91(s,2H), 3.5 l(t, 2H), 3.21(d,2H), 2.85-2.90(m,3H), 2.75-2.80(m,2H), 2.21(s,3H), 1.9-2.05(m,2H), 1.25-1.35(m,3H), Mass spectra [M+H]+ m/z 448.2
(90) Synthesis of VT-03-00133 :-
Figure imgf000041_0002
To a stirred solution of compound-26g(0.3g, 0.993mmol) and 5-Formyl-2-methylbenzonitrile (0.158g, 0.993 mmol) in CHCi3(10mL) was added Sodium Triacetoxyborohydride (0.251g, 1.19mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03- 00133 with 6% MeOH-CH2Cl2 as a yellow solid(0.067g).
'HNMR (400 MHz, DMSO-d6) δ 8.01( s, 1H) , 7.75 ( t, 2H ) , 7.45( d, 1H) , 7.38(d, 1H) , 6.98 ( d , 2H) , 4.30 ( t , 2H) , 3.91 (s, 3H) , 3.70 ( d , 2H) , 2.90 ( d, 2H), 2.52 ( t ,2H) ,2.41 (t, 2H) , 2.35-2.39( m, 1H) , 2.0( t, 2H), 1.75( d, 2H), 1.18( s, 4H),Mass spectra [M+H]+ m/z 432.30 (91) Synthesis of VT-03-00134 :-
Figure imgf000042_0001
To a stirred solution of l-(2-((3R,4S)-4-amino-3-fluoropiperidin-l-yl)ethyl)-7-methoxyquinoxalin-2(lH)- one (O. lg, 0.312mmol) and 4-methyl-3-nitrobenzaldehyde(0.057g, 0.343mmol) in CHCl3(5ml) was added Sodium Triacetoxyborohydride (0.098g, 0.468mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00134 with 7% MeOH- CH2C12 as a pale green solid(0.022g).
'HNMR (400 MHz, CDC13) δ 8.15 (s, 1H ) , 7.98 ( s, 1H) , 7.79 ( d, 1H) , 7.51 ( d, 1H) , 7.25 ( d, 1H) , 6.92( d, 2H) , 6.85( s, 1H ) , 5.80 ( d, 1H) , 5.35 ( m, 2H) , 4.92 ( s, 3H ) , 4.89 ( s, 2H ), 3.25-3.46 ( m, 1H) , 3.05 ( d, 1H) , 2.78-2.85 ( m ,2H) , 2.59 ( s , 3H) , 2.35-2.45( m, 2H) , 1.80( m , 3H), Mass spectra [M+H]+ m/z 470.20.
(95)Svnthesis of VT-03-00135 :-
Figure imgf000042_0002
To a stirred solution of l-(2-((3S,4S)-4-amino-3-hydroxypiperidin-l-yl)ethyl)-7-methoxyquinoxalin- 2(lH)-one (0.25g, 0.760mmol) and 4-methyl-3-nitrobenzaldehyde (0.128g, 0.760 mmol) in CHCl3(6ml) was added Sodium Triacetoxyborohydride (0.190g, 0.930mmol) at 0°C. The reaction was stirred at ambient temperature for 3h. Upon completion, the reaction mass was diluted with 10% MeOH-CH2Cl2and washed with water. The organic layers were dried over Na2S04and concentrated. Silicagel(100-200mesh) flash column chromatography of the crude eluted the required compound VT-03-00135 with 8% MeOH- CH2C12 as a pale brown solid(0.17g).
'HNMR (400 MHz, DMSO-d6) δ 8.40(s, 1H), 8.19(s,lH), 7.86(d,lH), 7.75(d,lH), 7.54(d,lH), 7.24- 7.34(m,2H), 5.51(s,lH), 4.55(t,2H), 4.20(t,2H), 3.90(s,3H), 3.61-3.70( m,lH), 3.16(p,lH), 3.01(q,lH), 2.83(q,2H), 2.61-2.72(m,lH), 2.45(s,3H), 2.05(d,2H), 2.0(p,lH), 1.56(d,lH) Mass spectra [M+H]+ m/z 468.30. [5] Uses
The compounds of the invention are useful for the treatment of infections in subjects, mammals in particular, including humans. In one embodiment, the compounds may be used for the treatment of infections of soft tissues, blood, skin, mouth, lungs, respiratory tract, urinary tract and reproductive tract.
In another embodiment, the compounds of the invention are useful for the treatment of infections caused by microorganisms, such as but not limited to Staphylococcus species such as
Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus,
Enterococcus species such as Enterococcus faecalis, Enterococcus faecium, Streptococcus species like Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella species, for example Moraxella catarrhalis, E. coli, Mycobacterium species,
Neisseria meningitidis, Neisseria gonorrhoeae, Klebsiella species such as Klebsiella
pneumoniae, Klebsiella oxytoca, Pseudomonas species such as Pseudomonas aeruginosa, Acinetobacter species such as Acinetobacter baumannii.
[6] Route of Administration
The compounds of the present invention are delivered to the subjects by forms suitable for each administration route. For example, the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository. In a preferred embodiment, the route of administration is oral, parenteral or topical. Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.
[7] Dosage Forms
The composition of the present invention is presented in unit dosage form generally in an amount that produces a therapeutic effect in the subject.
The compounds of the present invention are administered at a daily dose that is the lowest dose effective to produce a therapeutic effect. Generally, the dosage will effect from about 0.0001 to about lOOmg per kg body weight per day. Preferably, the dosage will range from about 0.001 to 75mg per kg body weight per day and more preferably, the dosage will range from about 0.1 to about 50mg per kg body weight per day. Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200 or 250 mg of the compound of the invention. As per the requirement of the subject, the effective daily dose of the compound is administered as two, three, four or more sub- doses administered separately at appropriate intervals throughout the day, optionally in unit dosage forms. [8] Formulation
The antibacterial compositions of the present invention may be administered by any method known in the art. Some examples of suitable modes of administration include oral, intravenous, intramuscular topical or any other parenteral mode of administration.
In certain embodiments, the present invention is directed to a method of formulating compounds of the present invention in a pharmaceutically acceptable carrier or excipient and may be administered in a wide variety of different dosage forms e.g. tablets, capsules, sprays, creams, lotions, ointments, aqueous suspensions syrups, and the like. Such carriers may include one or more of solid diluents or fillers, sterile aqueous media, and various nontoxic organic solvents, etc.
For oral administration, tablets may contain various excipients such as one or more of microcrystalline cellulose, sodium citrate, calcium carbonate and the like, along with various disintegrants such as starch and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose and the like. Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluents or solvent e.g. as solution in 1, 3 butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed including synthetic mono or diglycerides. In addition, fatty acids such as oleic acid find in the preparation of injectables. These aqueous solutions may be suitable for intravenous injection purposes. The oily solutions may be suitable for intra articular, intramuscular, and/or subcutaneous injection purposes. In another embodiment, the compounds of the present invention may be administered topically that include transdermal, buccal, or sublingual application. For topical applications, therapeutic compounds may be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion, and/or a cream. Such topical carriers may include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, and/or mineral oils.
The timing of the administration of the pharmaceutical composition may also be regulated. For example the compounds may be administered intermittently or by controlled release. [9] Definitions
As used herein, an "independently" selected substituent refers to a group of substituents, wherein the substituents may be different.
The term "optionally substituted" indicates that the said substituent can be unsubstituted or substituted. The term "absent" is used to designate the lacking of a group or describe the structural value of a variable. For example in some embodiments, A2 and A3 may be null or does not exist. In some other embodiments variable "A2" for a formula (I) compound, indicates that in the absence of the said variable, the adjacent variables on both sides of the absent variable are connected directly together and is synonymous to a single covalent bond For example, in the chain -G-A2-NH-A3-R6j if A2 is "absent", then the chain becomes -G-NH-A3-R6.
The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups and cycloalkyl substituted alkyl groups; wherein the term "cycloalkyl" refers to a saturated or unsaturated monocyclic alkyl ring consisting of 3-8 carbon atoms or a saturated or partially unsaturated bicyclic ring consisting of 9 or 10 carbon atoms.
The term "aryl" refers to a mono- or bicylic aromatic ring containing optionally substituted carbon atoms. The said term"aryl" can be fused to saturated or unsaturated cyclic ring containing minimum one heteroatom selected from oxygen, nitrogen and sulphur which is optionally substituted. The preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy. The term "heteroaryl" refers to an optionally substituted 5- or 6-membered monocyclic hetero aromatic ring or a 9- or 10-membered bicyclic hetero aromatic ring containing minimum one heteroatom which are independently selected from nitrogen, sulphur or oxygen. The said term"heteroaryl" can be fused to saturated or unsaturated cyclic ring containing minimum one of the said heteroatom which is optionally substituted. The preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
The term "alkoxy" refers to alkyl ether radical, wherein the term "alkyl" is as defined above.
The term "amino" refers to -NH2 group.
The term "aminoalkyl" refers to -NH(alkyl) or -N(alkyl)(alkyl) group wherein the term "alkyl" is as defined above.
The term "aminosulfonyl" refers to— S(=0)2— NR'2 radical, wherein each R' independently represent "alkyl" as defined above or hydrogen.
The term "halogen" refers to F, CI, Br or I.
The term "haloalkyl" refers to an "alkyl" group substituted with one or more halogen wherein the terms "alkyl" and "halogen" are as defined above.
The term "haloalkoxy" refers to an "alkoxy" group substituted with at least one "halogen" wherein the terms "alkoxy" and "halogen" are as defined above.
The term "hydroxyl" refers to -OH group.
The term "hydroxyalkyl" refers to an alkyl group which is substituted with one or more, preferably one
"hydroxyl" group and, wherein the terms "hydroxyl" and "alkyl" are as defined above.
The term "carbomyl" refers to -C(0)NH2 group.
The term "carbonyl" refers to -C=0 group.
The term "oxo" refers to double bonded oxygen atom (=0).
The term "nitro" refers to -N02 group.
The term "cyano" refers to -CN group.
The term "carboxy" refers to -C(=0)OH group.
The term "thiol" or "thio" refers to -SH group.
The term "sulfonyl" refers to -S(=0)2 group.
The term "alkylsulfonyl" refers to -S(=0)2-alkyl group wherein the term "alkyl" is as defined above. The term "arylsulfonyl" refers to -S(=0)2-aryl group wherein the term "aryl" is as defined above. The term "alkyl sulfonyloxy" refers to -OS02— alkyl group wherein the term "alkyl" is as defined above. The term "aryloxy" refers to aryl ether radical, wherein the term "aryl" is as defined above.
The term "acyloxy" refers to alkyl-C(=0)-0-alkyl where alkyl-C(=0) is the "acyl" group and the term "alkyl" is as defined above.
The term "alkylcarbonyl" refers to -C(=0)(alkyl)- group wherein the term "alkyl" is as defined above.
The term "alkenylcarbonyl" refers to -C(=0)(alkenyl)- group wherein the term "alkenyl" is as defined above.
The term "alkoxycarbonyl" refers to -C(=0)(alkoxy)- group wherein the term "alkoxy" is as defined above.
The term "thioalkyl" or "alkylthio" refers to -S-alkyl radical wherein the term "alkyl" is as defined above.
The term "arylthio" refers to -S-aryl radical wherein the term "aryl" is as defined above.
The term "acylthio" refers to -S-acyl radical wherein the term "acyl" is as defined above.
The term "heterocyclylthio" refers to -S-heterocyclyl radical wherein the term "heterocyclyl" is as defined herein.
The term "heterocyclyloxy" refers to -O-heterocyclyl radical wherein the term "heterocyclyl" is as defined herein.
Unless otherwise defined, the term "heterocyclic" or "heterocyclyl" as used above includes optionally substituted aromatic and non-aromatic, single and fused, mono- or bicyclic rings suitably containing minimum one heteroatom selected from oxygen, nitrogen and sulphur, which rings may be optionally C- substituted. The preferred substituents are alkyl, alkoxy, alkyl optionally substituted with alkoxy, alkoxy optionally substituted with alkyl, carboxy, hydroxyalkyl, hydroxyl, halogen, haloalkyl, alkylthio, alkylsulfonyl, cyano, nitro, alkynyl, amino, aminoalkyl, alkylcarbonyl, aminosulfonyl, oxo, carbomyl, carbonyl, haloalkoxy.
The term "containing at least one heteroatom" refers to at least one carbon atom of the ring being replaced by a heteroatom selected from oxygen, nitrogen and sulphur.
The compounds of present invention may exist in specific geometric or stereoisomeric forms. The present invention is inclusive of all possible enantiomers and diastereomers in pure or substantially pure form and mixtures of two or more stereoisomers in ratios that are effective. This means that the compounds of present invention may exist both as levorotatory and as dextrorotatory, in the form of racemates and in the form of two enantiomers. The compounds of present invention are capable of forming both pharmaceutically acceptable salts. Examples of salts include but not restricted to metals or amines such as alkali and alkaline earth metals or organic amines. Examples of suitable acids for salt formation include but is not limited to hydrochloric, sulphuric, phosphoric, acetic, citric, oxalic, malonic, salicyclic, malic, fumaric, succinic, ascorbic and the likes thereof.
The compound of the present invention can exist as unsolvated or solvated forms including hydrated forms.
The compounds detailed in the present disclosure are capable of forming pharmaceutically acceptable prodrugs. Prodrugs are covalently bonded carriers that release the active compound internally after administration to the subject.
The present invention provides pharmaceutical compositions comprising an effective amount of compound of Formula (I), prodrugs, tautomeric forms, stereoisomers, optical isomers, pharmaceutically acceptable salts, solvates, polymorphs, analogs or derivatives thereof with pharmaceutically acceptable carriers.
The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be noted that many variations and modifications may be made while remaining within the scope of the invention.
Example 1
Analysis of microbiological activity of compounds
Shown below are the microbiological activities of representative compounds of Formula I of the invention. The compounds were tested by the microbroth dilution method (National committee for Clinical Laboratory Standards, 2011, M07-08) and the Minimum Inhibitory Concentration (MIC) was determined.
Figure imgf000048_0001
00021a
VT-03- I 2 2 4 4 >64 ND 00022
VT-03- 1 2 2 8 8 >32 ND 00024
VT-03- 2 4 1 8 2 32 64 00026
VT-03- 1 2 2 8 4 16 ND 00026a
VT-03- 2 4 2 4 8 >32 ND 00027
VT-03- 0.25 0.5 0.25 1 4 >32 >32 00028
VT-03- 2 4 4 4 1 8 >32 00030
VT-03- 1 2 1 2 4 16 >32 00031
VT-03- 2 4 4 8 8 >32 >32 00032
VT-03- >16 >16 ND ND ND >32 ND 00042
VT-03- 16 >16 ND ND ND >32 ND 00043
VT-03- 0.06 0.12 0.5 4 2 32 ND 00045
VT-03- 16 >16 ND ND ND >32 ND 00046
VT-03- 0.12 0.5 0.5 4 1 8 >32 00048
VT-03- 0.12 0.5 0.5 2 8 32 >32 00049
VT-03- 0.25 0.5 4 4 4 16 >16 00050
VT-03- 2 4 >4 4 2 >32 >16 00051
VT-03- 0.125 0.25 1 4 16
00052
VT-03- 0.25 0.25 1 2 0.5 4 >32 00053
VT-03- 0.03 0.12 0.5 2 1 8 32 00054
VT-03- 1 4 0.03 0.25 >32 >32 >32 00055
VT-03- 0.25 0.5 0.25 8 1 4 >32 00056
VT-03- 0.12 0.25 0.5 2 0.5 2 >32 00057
VT-03- 0.015 0.06 0.03 0.25 0.5 1 16 00058
VT-03- 0.25 1 2 8 8 >32 >32 00059
VT-03- >4 >4 ND ND >32 >32 ND 00060
VT-03- 0.015 0.015 0.015 0.25 0.12 1 8 00061 VT-03- <0.0075 0.015 0.015 0.12 <0.06 0.5 8 00062
VT-03- 0.5 1 0.5 4 2 4 >32 00062a
VT-03- 0.25 0.5 0.25 2 0.25 4 >32 00063
VT-03- 0.12 0.25 0.12 2 0.25 4 >32 00064
VT-03- 0.25 1 4 >32 >32 >32 >32 00065
VT-03- 0.5 1 1 4 4 16 >32 00066
VT-03- 0.12 0.5 0.25 ND 2 16 32 00067
VT-03- >4 >4 ND ND ND >4 ND 00069
VT-03- >4 >4 ND ND ND >4 ND 00070
VT-03- ND ND ND ND ND ND ND 00071
VT-03- >4 >4 ND ND ND >4 ND 00072
VT-03- 1 2 2 8 2 32 ND 00074
VT-03- 0.12 0.12 0.06 0.5 0.5 4 >16 00075
VT-03- 0.015 0.03 0.03 0.25 0.25 2 >16 00076
VT-03- 0.06 0.12 0.12 1 0.25 2 >16 00077
VT-03- >4 ND ND ND ND >32 ND 00078
VT-03- 2 2 2 32 4 32 ND 00079
VT-03- 0.25 1 2 4 >4 32 ND 00080
VT-03- ND 1 ND ND ND >32 ND 00081
VT-03- 0.06 0.12 ND ND ND 4 ND 00083
VT-03- 0.5 0.5 0.25 2 2 8 ND 00084
ND = not done
Example 2: MICs against Fluoroquinolone resistant strains
To test if compounds are able to overcome fluoroquinolone resistance, we have determined the
MICS against Fluoroquinolone (FQ) resistant clinical strains of MRS A and E. coli.
Figure imgf000050_0001
VT-03-00062 <0.0075 0.015
Compound name MIC in μρ,/ml against FQ resistant strains
£. co// El 851 £.co/z U1306 £.co/z U5690 E.coli 86
VT-03-00057 2 16 8 16
VT-03-00061 0.5 2 2 2
Ciprofloxacin >4 >4 >4 >4
Example 3: Analysis of Target Specificity of compounds
To test for target specificity, the activity of compounds was evaluated in an in vitro Gyrase assay using recombinant Gyrase protein as per the instructions of the assay kit (Inspiralis). The assay measures the ability of E.coli Gyrase to convert relaxed plasmid DNA into the supercoiled form. The enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours. The gel is then stained with Ethidium bromide and DNA in the different forms is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
Figure imgf000051_0001
Example 4: Mutation prevention concentration studies
The mutation prevention concentration or the concentration above which mutants are unlikely to be selected, was determined based on published protocols (Antimicrobial Agents and
Chemotherapy, 45, 433-438, 2001 ). Table 2: Mutation prevention concentration for VT-03-00061 against MRSA 33591
Figure imgf000052_0001
Example 5: Time kill kinetics
To understand the kinetics of growth in the presence of the VT-03 compounds, we undertook time kill assays (National committee for Clinical Laboratory Standards, M07-A8, Volume 29, 2009). Data for VT-03-00061 against 33591 (Figure 1 : time kill kinetics of VT-03-00061 against MRSA) and E. coli 25922 (Figure 2: time kill kinetics of VT-03-00061 against E. coli); GC = Growth control.
Example 6: hERG binding studies
Inhibition of the inward rectifying voltage gated potassium channel encoded by the human ether- a-go-go related gene (hERG) current causes QT interval prolongation which may lead to cardiac arrhythmia (Current Topics in Ion Channels, 2008, 2, 87-93). To test the ability of the VT-03 compounds to bind the hERG channel, membranes expressing the hERG channel were incubated with radiolabeled Astemizole and displacement of the labeled ligand in the presence of compounds was measured. These data were used to derive the concentration at which 50% of the radioligand is displaced (IC50). The compounds show no significant hERG binding activity up to the highest concentration tested indicating the advantage of VT-03 compounds over the known prior art antibacterial compounds (ref: BMCL, 21, 7489-7495, 2011).
Figure imgf000052_0002
Example 7: Pharmacokinetic profiles
Compounds were dosed to male Swiss albino mice to determine the pharmacokinetic profiles. Data for VT-03-00061 are shown below. The compound is orally bioavailable.
Table 5: Pharmacokinetic profiles of select compounds
Figure imgf000053_0001
Example 8: In vivo activity in the systemic infection model against S.aureus (MRSA ATCC 33591)
In order to evaluate the in vivo efficacy of the scaffold, we tested representative compounds for activity in the systemic infection model in mice (Antimicrobial Agents and Chemotherapy, 47, 2507-2512, 2003). In this model, a 15X medial lethal dose of the bacteria (MRSA ATCC33591) is administered to mice intraperiotoneally. An hour later, the compound is administered i.v. and again 4 hours later. VT-03-00061, was efficacious with a 50% survival at a dose of 10 mg/kg in this model.
Example 9
Analysis of microbiological activity of compounds
Shown below are the microbiological activities of representative compounds of Formula II of the invention. The compounds were tested by the microbroth dilution method as per the reference in Example 1.
To test for target specificity, the activity of compounds was evaluated in an in vitro Gyrase supercoiling assay using ciprofloxacin resistant recombinant Gyrase protein (with mutation S83L) as per the instructions of the assay kit (Inspiralis). The enzyme is incubated with the substrate (relaxed DNA) in the presence and absence of compounds for 1 hour at 37 ° C and the DNA is run on a gel at low voltage for several hours. The amount of supercoiled DNA is quantified using DNA imaging and quantification software (Image Lab). The activity of the enzyme is proportional to the amount of supercoiled form detected.
Figure imgf000053_0002
00101
VT-03- <0.0075 0.5 8 >16 NT NT 95.3 96.5 00102
VT-03- 0.03 0.25 0.5 8 1 32 87.48 55.8 00103
VT-03- 0.06 0.5 1 8 NT NT NT NT 00107
VT-03- 0.25 2 8 >32 NT NT NT NT 00108
VT-03- 1 2 16 >32 NT NT NT NT 00109
VT-03- 0.125 0.5 1 >16 NT NT 87.64 90.42 00111
VT-03- 0.125 NT 2 32 NT NT NT NT 00112
VT-03- 0.03 0.25 0.125 8 0.25 8 93.97 89.95 00113
VT-03- 0.06 0.5 2 32 NT NT NT NT 00114
VT-03- 0.03 0.25 0.25 8 0.25 16 94.28 96.91 00116
VT-03- 0.125 0.25 0.5 8 0.25 16 97.55 88.2 00117
VT-03- 0.015 0.125 0.25 8 0.25 8 88.97 91.46 00118
VT-03- 4 16 8 >32 8 >32 NT NT 00119
VT-03- 0.06 0.5 0.25 8 0.25 16 97.08 95.45 00122
VT-03- NT NT 2 32 NT NT NT NT 00124
VT-03- >4 NT 32 NT NT NT No No 00125 inhibition inhibition
VT-03- 0.5 NT 2 32 8 >32 NT NT 00126
VT-03- 0.125 1 1 8 1 8 72% 39% 00127
VT-03- 0.015 0.25 0.5-1 16 0.25 8 51% 34% 00128
VT-03- NT NT 4 >32 4 >32 NT NT 00129
VT-03- 0.25 0.25 0.25- 8 0.25 16 NT NT 00131 1
VT-03- 1 1 2 NT 2 32 NT NT 00132
VT-03- 0.015 0.25 2 32 0.5 32 NT NT 00134
VT-03- NT NT 8 NT NT NT NT NT 00135
Example 10
Mutation prevention concentration studies The mutation prevention concentration and mutation frequencies were determined based on published protocols, the reference of which is provided in Example 4.
Figure imgf000055_0001
Example 11
hERG binding studies
To test the ability of the VT-03 compounds (of Formula II) to bind the hERG channel, membranes expressing the hERGchannel were incubated with radiolabeled Astemizole and displacement of the labeled ligand in the presence of compounds was measured. The table below shows IC50 concentrations. The compounds show no significant hERG binding activity up to the highest concentration tested.
Figure imgf000055_0002
Example 12
Pharmacokinetic profiles
Compounds were dosed to male Swiss albino mice to determine the pharmacokinetic profiles. Results suggest that the compounds are orally bioavailable
Figure imgf000055_0003

Claims

Claims We Claim:
1. A com ound of Formula (II) or a pharmaceutically acceptable salt thereof,
Figure imgf000056_0001
Formula (II)
wherein, Zi and Z3 are each independently selected from a group consisting of CH or N;
Z2 is independently selected from group consisting of C=0 and C=S;
Ri is independently selected from the group consisting of hydrogen, methoxy, cyano, halogen, hydroxyl, Ci-6 alkoxy and Ci-6 alkyl optionally substituted with one or two Ci_6 alkoxy, alkyne, carboxyl, carboxamide;
G is Gl, G2 or G3;
Figure imgf000056_0002
G1 G2 G3 and wherein, R2 is selected from the group consisting of
(i) a substituted or unsubstituted monocylic aryl; and
(ii) a substituted or unsubstituted monocylic heteroaryl.
2. A compound selected from the group consisting of:
VT-03-000100: 1 -(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l -yl)ethyl)-7-methoxy quinoxalin-2( 1 H)-one;
VT-03-000101:4-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l-yl)ethyl)-6-methoxy pyrido[3,2-b]pyrazin-3(4H)-one; VT-03-000102:7-bromo-l-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l- yl)ethyl)quinoxalin-2(lH)-one;
VT-03-000103: 4-(2-(4-(3-fluoro-4-methylbenzylamino)pipendin-l-yl)ethyl)-3-oxo-3,4- dihydroquinoxaline-6-carbonitrile;
VT-03-000104:4-(2-(4-(4-methyl-3-nitrobenzylamino)pipendin-l-yl)ethyl)-3-oxo-3,4- dihydroquinoxaline-6-carbonitrile;
VT-03-000106: 6-methoxy-4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l- yl)ethyl)pyrido[3,2-b]pyrazin-3(4H)-one;
VT-03-000107: 6-chloro-4-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l-yl)ethyl)-l,2- dihydropyrido[3,2-b]pyrazin-3(4H)-one
VT-03-000108: N-methyl-4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)-3-oxo- 3,4-dihydroquinoxaline-6-carboxamide;
VT-03-000109: 4-(2-(4-(3-fluoro-4-methylbenzylamino)pipendin-l-yl)ethyl)-N-methyl-3-oxo- 3,4-dihydroquinoxaline-6-carboxamide;
VT-03-000110: 7-ethynyl-l-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l-yl)ethyl) quinoxalin-2( 1 H)-one;
VT-03-000111 : 6-chloro-4-(2-(4-(3 -fluoro-4-methy Ibenzy lamino)piperidin- 1 - yl)ethyl)pyrido[3,2-b]pyrazin-3(4H)-one;
VT-03-000112: 7-ethyl- 1 -(2-(4-(3-fluoro-4-methy Ibenzy lamino)pipendin- 1 -yl)ethy 1) quinoxalin-2( 1 H)-one;
VT-03-000113: 7-fluoro-l-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl) quinoxalin- 2(lH)-one;
VT-03-000114: l-(2-(4-(4-methyl-3-nitrobenzylamino)pipendin-l-yl)ethyl)-7- (trifluoromethoxy)quinoxalin-2( 1 H)-one;
VT-03-000115: l-(2-(4-(4-methyl-3-nitrobenzylamino)pipendin-l-yl)ethyl)quinoxalin-2(lH)- one;
VT-03-000116: l-(2-(4-(4-chloro-3-nitrobenzylamino)piperidin-l-yl)ethyl)-7-fluoroquinoxalin- 2(lH)-one;
VT-03-000117: 5-((l-(2-(7-fluoro-2-oxoquinoxalin-l(2H)-yl)ethyl)piperidin-4-ylamino) methyl)-2-methylbenzonitrile; VT-03-000118: 6-chloro-4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)pyrido[3,2- b]pyrazin-3(4H)-one;
VT-03-000119: l-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)-2-oxo-l,2- dihydropyrido[2,3-b]pyrazine-7-carbonitrile;
VT-03-000120: l -(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)pyrido[2,3- b]pyrazin-2(lH)-one;
VT-03-000121: 6-fluoro-4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)pyrido[3,2- b]pyrazin-3(4H)-one;
VT-03-000122: 7-fluoro- 1 -(2-(4-(3 -fluoro-4-methy lbenzylamino)pipendin- 1 - y l)ethyl)quinoxalin-2( 1 H)-one;
VT-03-000123: 4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)-3-oxo-3,4- dihydroquinoxaline-6-carboxylic acid;
VT-03-000124: 4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)-3-oxo-3,4- dihydroquinoxaline-6-carboxylic acid;
VT-03-000125: 6-methoxy-4-(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l- yl)ethyl)pyrido[3,2-b]pyrazin-3(4H)-one;
VT-03-000126: l-(2-(4-(3-fluoro-4-methylbenzylamino)piperidin-l-yl)ethyl)-7- methoxyquinoxaline-2( 1 H)-thione;
VT-03-000127: 7-methoxy-l -(2-(4-(4-methyl-3-nitrobenzylamino)piperidin-l - yl)ethyl)quinoxaline-2(lH)-thione;
VT-03-000128: l-(2-(4-(4-chloro-3-nitrobenzylamino)piperidin-l-yl)ethyl)-7- methoxyquinoxalin-2(lH)-on;
VT-03-000131: 5-((l-(2-(6-chloro-3-oxopyrido[3,2-b]pyrazin-4(3H)-yl)ethyl)pipendin-4- ylamino)methyl)-2-methylbenzonitrile;
VT-03-000132: 5-((l-(2-(7-methoxy-2-thioxoquinoxalin-l(2H)-yl)ethyl)piperidin-4- ylamino)methyl)-2-methylbenzonitrile;
VT-03-000133: 5-((l-(2-(7-methoxy-2-oxoquinoxalin-l(2H)-yl)ethyl)pipendin-4- ylamino)methyl)-2-methylbenzonitrile;
VT-03-000134: l-(2-((3R,4S)-3-fluoro-4-(4-methyl-3-nitrobenzylamino)pipendin-l-yl)ethyl)-7- methoxyquinoxalin-2(lH)-one; and VT-03-000135: l-(2-((3S,4S)-3-hydroxy-4-(4-methyl-3-nitrobenzylamino)piperidin-l-yl)ethyl)- 7-methoxyquinoxalin-2( 1 H)-one.
3. A method of treating a patient suffering from an infection comprising administering an effective amount of a compound of claim 1 , wherein the infection is caused by at least one oiStaphylococcus species, Enterococcus species, Streptococcus species, Moraxella species, E. coli, Mycobacterium species, Neisseria meningitidis, Neisseria gonorrhoeae, Klebsiella species, Pseudomonas species, or Acinetobacter species.
4. A method of treating a patient suffering from an infection comprising administering an effective amount of a compound of claim 2, wherein the infection is caused by at least one of Staphylococcus species, Enterococcus species, Streptococcus species, Moraxella species, E.coli, Mycobacterium species, Neisseria meningitidis, Neisseria gonorrhoeae, Klebsiella species, Pseudomonas species, or Acinetobacter species.
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WO2019145919A1 (en) 2018-01-29 2019-08-01 Cadila Healthcare Limited Heterocyclic compounds useful as antibacterial agents
JP2023551272A (en) * 2020-11-26 2023-12-07 エルジー・ケム・リミテッド Heterocyclic compounds and their uses as diacylglycerol kinase inhibitors
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