WO2019243971A1 - Novel compounds and their methods of use thereof - Google Patents

Novel compounds and their methods of use thereof Download PDF

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Publication number
WO2019243971A1
WO2019243971A1 PCT/IB2019/054978 IB2019054978W WO2019243971A1 WO 2019243971 A1 WO2019243971 A1 WO 2019243971A1 IB 2019054978 W IB2019054978 W IB 2019054978W WO 2019243971 A1 WO2019243971 A1 WO 2019243971A1
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Prior art keywords
piperazin
methyl
quinolin
oxadiazole
arh
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PCT/IB2019/054978
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French (fr)
Inventor
Shruthi Thimlapura GANGADHARAIAH
Ganesh Sambasivam
Sumesh ESWARAN
Shridhar Narayanan
Rk SHANDIL
Parvinder Kaur
Vijay Potluri
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Foundation For Neglected Disease Research
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Publication of WO2019243971A1 publication Critical patent/WO2019243971A1/en

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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention is related to novel quinoline compounds or their pharmaceutically acceptable salts for the treatment of Tuberculosis and other mycobacterial infections.
  • Tuberculosis continues to be a serious and potentially fatal infection with a world wide distribution.
  • World Health Organization estimates that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide. If these trends continue, tuberculosis incidence will increase by 410% in the next twenty years.
  • the present invention relates to novel compounds and their use as a pharmaceutical for the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis and other mycobacterium infections.
  • the invention provides, a compound of formula (I):
  • Ri is selected from hydrogen, fluorine, chlorine, bromine, Iodine optionally substituted Cl- C10 alkyl, optionally substituted C1-C10 alkoxyl, optionally substituted phenyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl, morhpholine, -OH, -OCF , -CHF 2 , -CH(F)CH , -OCH 2 CF , -N(CH ) 2 , -CN;
  • R 2 is selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Cl- C10 alkoxyl, optionally substituted phenyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl, -CHF 2 , -CH(F)CH 3 , -OCH 2 CF 3 , or pharmaceutically acceptable salt thereof.
  • Rl is selected from but not limited to
  • R2 is selected from but not limited to
  • the invention includes but not restricted to the following compounds or a pharmaceutically acceptable salt thereof:
  • the invention provides, a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluents.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or any Mycobacterium infection.
  • the invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of tuberculosis or a Mycobacterium infection.
  • the invention provides a method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or other Mycobacterial infections.
  • the invention provides a quinoline compounds of formula (I) or a
  • the invention provides a compound of formula (I) in the manufacture of a medicament for use in the treatment of tuberculosis or a Mycobacterium infection.
  • the invention provides a method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the language“therapeutically effective amount” includes an amount of the co-crystals described herein that will elicit the biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a Mycobacterium infection or tuberculosis, amelioration of symptoms of a Mycobacterium infection or tuberculosis, or the slowing or delaying of progression of a Mycobacterium infection or tuberculosis.
  • the language“therapeutically effective amount” includes the amount of a co-crystal described herein, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a Mycobacterium infection or tuberculosis, and/or reduce or inhibit the bacterial growth, replication or bacterial load of Mycobacterium in a subject.
  • the term“subject” includes warm blooded mammals, for example, primates, cows, sheep, dogs, cats, rabbits, rats, voles, seals and mice.
  • the subject is a primate, for example, a human.
  • the subject is suffering from a Mycobacterium infection or tuberculosis.
  • the subject is in need of treatment (e.g., the subject would benefit biologically or medically from treatment).
  • the language“inhibit,”“inhibition” or“inhibiting” includes a decrease in the baseline activity of a biological activity or process.
  • the language“treat,”“treating” and“treatment” includes the reduction or inhibition of enzyme or protein activity related to a Mycobacterium infection or tuberculosis in a subject, amelioration of one or more symptoms of a Mycobacterium infection or tuberculosis in a subject, or the slowing or delaying of progression of a Mycobacterium infection or tuberculosis in a subject.
  • the language“treat,”“treating” and“treatment” also includes the reduction or inhibition of the bacterial growth, replication or a reduction or inhibition of the bacterial load of Mycobacterium in a subject.
  • the language“other Mycobacterium infection” includes infections caused by one or more of the species of the Mycobacterium tuberculosis complex, e.g., Mycobacterium tuberculosis,
  • Mycobacterium bovis Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti or Mycobacterium pinnipedii.
  • the Mycobacterium infection is a Mycobacterium tuberculosis infection.
  • the term“tuberculosis” refers to the disease caused by an infection in a subject of one or more species of the Mycobacterium tuberculosis complex.
  • the term“tuberculosis” includes latent tuberculosis (LTBI), non-drug resistant tuberculosis, multiple drug resistant tuberculosis (MDR- TB) and extensively drug resistant tuberculosis (XRD-TB).
  • latent tuberculosis includes an infection of a subject caused by one or more species of Mycobacterium tuberculosis complex but where the subject does not necessarily exhibit symptoms a tuberculosis disease.
  • non-drug resistant tuberculosis includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that exhibits no antibacterial resistance to standard tuberculosis therapy.
  • the language“multiple drug resistant tuberculosis (MDR-TB)” includes tuberculosis caused by an infection by of one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid.
  • tuberculosis includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid, as well as any member of the quinolone family, and is also resistant to at least one of kanamycin, capreomycin and amikacin.
  • the tuberculosis infection is acute. In some embodiments, the tuberculosis infection is chronic.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for in treating mycobacterium tuberculosis infection.
  • the invention provides a compound of formula (I) in the manufacture of a medicament for use in treating mycobacterium tuberculosis infection.
  • the invention provides a method of inhibiting DprEl comprising contacting a cell with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • 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.
  • the compounds described herein may be applied as a sole therapy or may involve one or more other substances and/or treatments. Such co-treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
  • Suitable classes and substances include one or more antibacterial agents useful in the treatment of Mycobacterium infections and/or tuberculosis, such as, for example, rifampicin, isoniazid, pyrizinamide, ethambutol, quinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin), aminoglycosides (e.g., streptomycin, kanamycin, and amikacin), polypeptides (e.g., capreomycin, viomycin and enviomycin), rifabutin, clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D and R207910.
  • antibacterial agents useful in the treatment of Mycobacterium infections and/or tuberculosis such as, for example, rifampicin, isoniazid, pyrizinamide, etham
  • “Pharmaceutically acceptable salts” forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine,
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn
  • salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine,
  • phenylethylamine dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D- isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts.
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates and the liks thereof.
  • Compounds of the invention or “present invention” refers to the compounds of the present invention represented by general Formula (I) as here in defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them.
  • the compounds of the present invention are useful as antibacterial agents particularly in the treatment of mycobacterial infections, and more particularly tuberculosis.
  • the present invention also provides pharmaceutical compositions containing the compounds of invention as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosters, polymorphs, enantiomers, diastereomers, their pharmaceutically acceptable salts or solvates in combination with suitable pharmaceutically acceptable carriers, and/or diluents.
  • the pharmaceutical compositions according to the present invention are useful antibacterial agents.
  • the pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays and the likes thereof and may contain flavorants, sweeteners etc., in a suitable solid or liquid carriers or diluents or in a suitable sterile media to form injectable solutions or suspensions. It is understood that in any of the above schemes, any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art. Suitable protecting groups comprise N-Boc, N-Cbz, N-Fmoc, alkyl,
  • the invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of compounds of invention, which are readily convertible in vivo into compounds of the invention.
  • the invention also encompasses the active metabolites of the compounds of the present invention of general Formula (I).
  • DMSO Dimethylsuf oxide
  • ACN Acetonitrile
  • NMP N-methyl Pyrrolidine
  • HC1 hydrochloric acid
  • DMF N,N-dimethylformamide
  • NaH sodium hydride.
  • El electrospray ionization
  • HRMS high resolution mass spectrometry.
  • Reagents and conditions (a) Diethyl ethoxymethylenemalonate, 110 °C; (b) Dowtherm medium, 240 °C; (c) POCb, reflux; (d) Piperazine, IPA, 95 °C; (e) Chloroacetonitrile, Et 3 N, ACN, DMF, RT; (f) Aromatic boronic acids, Pd 2 (dba)3, s-Phos, K3PO4, l,4-dioxane, water, 100 °C; (g) Hydroxylamine hydrochloride, NaHC0 3 / Et 3 N, methanol, 70 °C; (h) Aromatic/aliphatic acid, EDCI, HOBT, DIPEA, RT (i) DBU, DMF, 90 °C.
  • a Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCCh (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum.
  • reaction mixture was purged with argon for 30 min, to this Pd 2 (dba) 3 (6.38 g, 0.007 mol) was added and further purged argon for 15 min.
  • the reaction mixture was heated at 100 °C for 16 h under argon
  • the reaction mixture was heated at 100 °C for 16 h under argon atmosphere.
  • the reaction mixture was cooled to room temperature and filtered through celite bed and washed with 1 ,4-dioxane.
  • the filtrate was concentrated and the resultant aqueous layer was added 100 mL water, extracted with ethyl acetate (2 x 200 mL).
  • the combined organic layers were washed with water (200 mL), saturated brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated.
  • the crude was purified by column chromatography on silica gel using 3 % methanol in dichloromethane to get pale yellow solid.
  • the resulted solid was converted into HC1 salt using l,4-dioxane-HCl (3 M).
  • N-Hydroxy-2-[4-(7-pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl]-acetamidine (8a) (1 g, 2.759 mmol) was added at 0 °C.
  • the reaction mixture was gradually warmed to room temperature and stirred for 12 h.
  • the reaction mixture was quenched with ice cold water.
  • the aqueous layer was extracted with dichloromethane (20 mL X2).
  • the combined organic layer was washed with saturated brine solution and dried over sodium sulphate, filtered and concentrated under vacuum.
  • the crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichloromethane.
  • Cyclopentanecarboxylic acid ⁇ !-[ (Z)-hydroxyimino] -2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )- piperazin-l-yl] -ethyl ⁇ -amide ( lnt-9e):T ⁇ s compound was prepared by coupling of compound Int-8a with cyclopentanecarboxylic acid in presence ofEDC.HCl. It was obtained as anoff white solid Yield: 0.759 g (60 %)
  • This compound was prepared by coupling of compound Int-8b with 4-isopropyl-benzoic acid in the presence of EDC.HC1. It is obtained as a pale yellow solid Yield: 0.820 g (60 %)
  • the aqueous layer was extracted with dichloromethane (20 mL X2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate filtered and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichlorome thane.
  • Cyclopentanecarboxylic acid [2-[ 4-( 7-chloro-quinolin-4-yl )-piperazin-l -yl]-l -hydroxyamino- eth-(Z)-ylidene] -amide (Int-lle):This compound was prepared by coupling of compound Int-8c with cyclopentanecarboxylic acidin the presence of EDC.HC1. It is obtained as an off white solid Yield: 0.884 g (68 %).
  • This compound was prepared by coupling of compound Int-8c with 4-isopropyl-benzoic acid in presence of EDC.HC1. It is obtained as a pale yellow solid Yield: 0.874 g (60 %) pale brown solid
  • This compound was prepared by coupling of compoundInt-8d with cyclopentanecarboxylic acid in presence of EDC.HC1. It was obtained as an off white solid. Yield: 0.759 g (63.2 %)
  • This compound was prepared by coupling of compound Int-8d with 4-isopropyl-benzoic acid in presence of EDC.HC1. It was obtained as a pale yellow solid Yield: 0.9 g (64.15 %)
  • Example 2 4- ⁇ 4-[5-(3 ,5-Difluoro-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin- l-yl ⁇ -7 -pyridin-4-yl- quinoline (Example 2): This compound was prepared by cyclization of compound Int-9b using DBU. It was obtained as a white solid. Yield: 0.265 g (55 %)
  • Example 3 3- ⁇ 3-[4-(7 -Pyridin-4-yl-quinolin-4-yl)-piperazin-l -ylmethyl] -[ 1,2,4] oxadiazol-5-yl ⁇ -benzonitrile (Example 3):This compound was prepared by cyclization of compound Int-9c using DBU. It was obtained as a white solid. Yield: 0.337 g (70 %)
  • Example 6 4- ⁇ 4-[5-(4-Isopropyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-l-yl ⁇ -7 -pyridin-4-yl- quinoline (Example 6): This compound was prepared by cyclization of compound Int-9f with DBU. It was obtained as an off white solid. Yield: 0.360 g (75 %)
  • Example 9 3-(3- ⁇ 4-[7-(2, 5-Difluoro-phenyl)-quinolin-4-yl] -piperazin-1 -ylmethyl ⁇ -[ 1,2,4] oxadiazol-5-yl)- benzonitrile (Example 9): This compound was prepared by cyclization of compound Int-lOc with DBU. It was obtained as a white solid. Yield: 0.361 g (75 %)
  • Example- 11 4-[4-(5-Cyclopentyl-[ 1,2,4] oxadiazol-3-ylmethyl)-piperazin-l -yl]-7-(2, 5-difluoro-phenyl)- quinoline (Example- 11): This compound was prepared by cyclization of compound Int-lOe with DBU. It was obtained as a Pale yellow solid. Yield: 0.33 g (69 %)
  • Example l4 7-Chloro-4- ⁇ 4-[ 5-( 3,5-difluoro-phenyl)-[ 1,2,4 ]oxadiazol-3-ylmethyl] -piperazin- 1 -yl ⁇ - quinoline (Example l4):This compound was prepared by cyclization of compound Int-l lb using DBU. It was obtained as a white solid. Yield: 0.365 g (76 %)
  • Example 23 4- ⁇ 4-[5-(2,3-Dimethyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-1 -yl ⁇ -7 -pyridin-3-yl- quinoline (Example 23): This compound was prepared by cyclization of compound Int-l2d using DBU. It was obtained as a beige color solid. Yield: 0.284 g (59 %)
  • Example 24 This compound was prepared by cyclization of compound Int-l2e with DBU. It was obtained as a beige color solid. Yield: 0.278 g (58 %)
  • Example 25 4- ⁇ 4-[5-(4-Isopropyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-l-yl ⁇ -7 -pyridin-3-yl- quinoline (Example 25): This compound was prepared by cyclization of compound Int-l2f with DBU. It was obtained as an off white solid. Yield: 0.360 g (75 %)
  • test compounds were dissolved in DMSO, double-diluted in a 10-concentration dose response (10-DR) and the culture was added at an inoculum of 3-7X105 cfu/ml.
  • the QC includes: media controls, growth controls, and the reference drug inhibitors (Rifampicin and Isoniazid).
  • the assay plates were incubated at 37 °C for 15 days. The growth appears as turbidity or as a deposit of cells at the bottom of the well. The results were enumerated and a
  • Metabolic stability was carried out using human liver microsomes.
  • the final composition of the assay included 1 mM of test items and control item (Diclofenac or Imipramine) prepared from DMSO stock, so that the final concentration of DMSO was 0.1 %, microsomal protein 0.125 mg/mL and cofactors (5.0 mM G-6-P, 0.06 U/mLG-6-PDH, 2.0 mM MgCk, 1.0 mM NADP+).
  • Test item/ Control items were incubated with human liver microsomes with cofactors and without cofactors.
  • the reaction mixture (100 pL) was removed at specified time period and the reaction was stopped by addition of stop solution.
  • the samples were extracted in presence of internal standard and were analyzed using LC-MS/MS. The percent of the test/control item remaining after specified incubation period was calculated with respect to the peak area ratio at time 0 min. Results are presented in Table 4.
  • Example 3 Oral PK study: About 15 mg of compound was weighed and transferred to graduated tube. Exactly 250 m L of N,NDimethylacetamide (5 % v/v) was added, vortex mixed thoroughly and sonicated till test item gets completely dissolved. Then 250 pF of Tween 80 (5 % v/v) was added and vortex mixed, then 250 pF of propylene glycol (5 % v/v) was added and vortex mixed, finally the sterile water for injection was added in small increments and vortex mixed thoroughly. The final volume was made up to 5 mL with sterile water for injection (85 % v/v) to obtain the final strength of 3 mg/mL. The pH of the formulation was measured and was found to be 6.01. Formulation was freshly prepared before administration to the animals.
  • mice All the experimental protocols involving animals and the use of animals were approved by the Institutional Animal Ethics Committee, registered with the Government of India. BALB/c mice used for these studies are aged between 6 to 8 weeks with an average body weight of 20-30grams. Animals were housed in Individually ventilated cages (IVC’s) in BSL3 conditions. They were randomly assigned to cages and allowed to acclimatize for 1 week prior to experiments. Feed and water weregiven ad libitum.
  • IVC Individually ventilated cages
  • mice For the enumeration of lung CFU at the onset (early control) and 48 h after the completion of treatment, groups of mice were euthanized by exposure to C02. Infected lungs were aseptically removed and homogenized in a final volume of 3.0 ml with tissue grinders (W012576;
  • test compound was administered from day 3 by oral gavage or any other suitable route, 7 days a week, for a period of 4 weeks. Isoniazid was used as a positive control at a dose of 30mg/kg orally once daily. Blood samples were collected during 2 nd or 4 th weeks post-onset of treatment if PK need to be generated in parallel in infected mice.

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Abstract

The present invention provides novel quinoline compounds or their pharmaceutically acceptable salts. The compounds of the invention efficacious in the treatment of Tuberculosis and other mycobacterial infections.

Description

Novel Compounds and their Methods of Use thereof
Related Application
This application is related to and takes priority from the Provisional Application
201741045313 filed June 17, 2018 and is herein incorporated in its entirety.
Field of Invention
The present invention is related to novel quinoline compounds or their pharmaceutically acceptable salts for the treatment of Tuberculosis and other mycobacterial infections. Background
Tuberculosis continues to be a serious and potentially fatal infection with a world wide distribution. World Health Organization estimates that more than 8 million people contract TB each year, and 2 million people die from tuberculosis yearly. In the last decade, TB cases have grown 20% worldwide. If these trends continue, tuberculosis incidence will increase by 410% in the next twenty years.
The present invention relates to novel compounds and their use as a pharmaceutical for the treatment of bacterial diseases, including diseases caused by pathogenic mycobacteria such as Mycobacterium tuberculosis and other mycobacterium infections.
Brief Description of Drawings
Figure 1. Time & concentration dependent killing kinetics of Example 25.
Figure 2. Efficacy of Example 25 in Acute and chronic mouse TB model.
Description of the Invention
In some aspects, the invention provides, a compound of formula (I):
Figure imgf000002_0001
Wherein, Ri is selected from hydrogen, fluorine, chlorine, bromine, Iodine optionally substituted Cl- C10 alkyl, optionally substituted C1-C10 alkoxyl, optionally substituted phenyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl, morhpholine, -OH, -OCF , -CHF2, -CH(F)CH , -OCH2CF , -N(CH )2, -CN;
R2 is selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Cl- C10 alkoxyl, optionally substituted phenyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl, -CHF2, -CH(F)CH3, -OCH2CF3, or pharmaceutically acceptable salt thereof.
Furthermore, Rl is selected from but not limited to
Figure imgf000003_0001
R2 is selected from but not limited to
Figure imgf000003_0002
Furthermore, the invention includes but not restricted to the following compounds or a pharmaceutically acceptable salt thereof:
Table 1. Examples 1-76: Compounds of the invention.
Figure imgf000004_0002
Figure imgf000004_0001
Figure imgf000005_0001
Figure imgf000005_0002
Figure imgf000006_0002
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000009_0001
Figure imgf000009_0002
Figure imgf000010_0001
Figure imgf000010_0002
In some aspects, the invention provides, a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluents.
In some aspects, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or any Mycobacterium infection.
In some aspects, the invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of tuberculosis or a Mycobacterium infection.
In some aspects, the invention provides a method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In some aspects, the invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or other Mycobacterial infections.
Methods of Use
In some aspects, the invention provides a quinoline compounds of formula (I) or a
pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis or a
Mycobacterium infection.
In some aspects, the invention provides a compound of formula (I) in the manufacture of a medicament for use in the treatment of tuberculosis or a Mycobacterium infection.
In some aspects, the invention provides a method of treating tuberculosis or a Mycobacterium infection comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
The language“therapeutically effective amount” includes an amount of the co-crystals described herein that will elicit the biological or medical response of a subject, for example, the reduction or inhibition of enzyme or protein activity related to a Mycobacterium infection or tuberculosis, amelioration of symptoms of a Mycobacterium infection or tuberculosis, or the slowing or delaying of progression of a Mycobacterium infection or tuberculosis. In some embodiments, the language“therapeutically effective amount” includes the amount of a co-crystal described herein, that when administered to a subject, is effective to at least partially alleviate, inhibit, and/or ameliorate a Mycobacterium infection or tuberculosis, and/or reduce or inhibit the bacterial growth, replication or bacterial load of Mycobacterium in a subject. The term“subject” includes warm blooded mammals, for example, primates, cows, sheep, dogs, cats, rabbits, rats, voles, seals and mice. In some embodiments, the subject is a primate, for example, a human. In some embodiments, the subject is suffering from a Mycobacterium infection or tuberculosis. In some embodiments, the subject is in need of treatment (e.g., the subject would benefit biologically or medically from treatment).
The language“inhibit,”“inhibition” or“inhibiting” includes a decrease in the baseline activity of a biological activity or process.
The language“treat,”“treating” and“treatment” includes the reduction or inhibition of enzyme or protein activity related to a Mycobacterium infection or tuberculosis in a subject, amelioration of one or more symptoms of a Mycobacterium infection or tuberculosis in a subject, or the slowing or delaying of progression of a Mycobacterium infection or tuberculosis in a subject.
The language“treat,”“treating” and“treatment” also includes the reduction or inhibition of the bacterial growth, replication or a reduction or inhibition of the bacterial load of Mycobacterium in a subject.
The language“other Mycobacterium infection” includes infections caused by one or more of the species of the Mycobacterium tuberculosis complex, e.g., Mycobacterium tuberculosis,
Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, Mycobacterium caprae, Mycobacterium microti or Mycobacterium pinnipedii. In some embodiments, the Mycobacterium infection is a Mycobacterium tuberculosis infection.
The term“tuberculosis” refers to the disease caused by an infection in a subject of one or more species of the Mycobacterium tuberculosis complex. The term“tuberculosis” includes latent tuberculosis (LTBI), non-drug resistant tuberculosis, multiple drug resistant tuberculosis (MDR- TB) and extensively drug resistant tuberculosis (XRD-TB). The language“latent tuberculosis” includes an infection of a subject caused by one or more species of Mycobacterium tuberculosis complex but where the subject does not necessarily exhibit symptoms a tuberculosis disease.
The language“non-drug resistant tuberculosis” includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that exhibits no antibacterial resistance to standard tuberculosis therapy. The language“multiple drug resistant tuberculosis (MDR-TB)” includes tuberculosis caused by an infection by of one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid. The language “extensively drug resistant tuberculosis (XRD-TB)” includes tuberculosis caused by an infection by one or more species of the Mycobacterium tuberculosis complex that is resistant to rifampicin and isoniazid, as well as any member of the quinolone family, and is also resistant to at least one of kanamycin, capreomycin and amikacin. In some embodiments, the tuberculosis infection is acute. In some embodiments, the tuberculosis infection is chronic.
In some aspects, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for in treating mycobacterium tuberculosis infection.
In some aspects, the invention provides a compound of formula (I) in the manufacture of a medicament for use in treating mycobacterium tuberculosis infection.
In some aspects, the invention provides a method of inhibiting DprEl comprising contacting a cell with a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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.
Combinations
The compounds described herein may be applied as a sole therapy or may involve one or more other substances and/or treatments. Such co-treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.
Suitable classes and substances include one or more antibacterial agents useful in the treatment of Mycobacterium infections and/or tuberculosis, such as, for example, rifampicin, isoniazid, pyrizinamide, ethambutol, quinolones (e.g., ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin), aminoglycosides (e.g., streptomycin, kanamycin, and amikacin), polypeptides (e.g., capreomycin, viomycin and enviomycin), rifabutin, clarithromycin, linezolid, thioacetazone, thioridazine, arginine, vitamin D and R207910.
Definitions
Unless otherwise specified, the term "substituted" as used herein refers to mono, bi, tri or tetra substitution with any one or combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine, - COOR2, -C(0)R2, - C(S)R2, -C(0)NR2R3, - C(0)0NR3R4, -NR2CONR3R4, - N(R2)SOR3, -N(R2)S02R3, -(=N- N(R2)R3), - NR2C(0)0R3, -NR2R3, -NR2C(0)R3, - NR2C(S)R3, -NR2C(S)NR3R4, -SONR2R3, - S02NR2R3, -OR2, -0R2C(0)NR3R4, - 0R2C(0)0R3, -0C(0)R2, -0C(0)NR2R3, - R2NR3C(0)R4, -R2OR3, -R2C(0)0R3, - R2C(0)NR3R4, -R2C(0)R3, -R20C(0)R2, -SR2, - SOR2, -S02R2, and - 0N02, wherein R2, R3 and R4 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or
unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. Alternately R3 and R4 together along with the nitrogen they are attached with, form a 4 to 8 membered ring which can be substituted or unsubstituted. According to one embodiment, the substituents in the
aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl" the substituent on "substituted aryl" cannot be "substituted alkenyl"
"Pharmaceutically acceptable salts" forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Al, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, 2- dimethylaminoethanol, isopropylamine, morpholine, piperazine, piperidine, procaine, diethylamine, triethylamine, trimethylamine, tripropylamine, tromethamine, choline hydroxide, dicyclohexylamine, metformin, benzylamine,
phenylethylamine, dialkylamine, trialkylamine, thiamine, aminopyrimidine, aminopyridine, purine, pyrimidine, spermidine, and the like; chiral bases like alkylphenylamine, glycinol, phenyl glycinol and the like, salts of natural amino acids such as glycine, alanine, valine, leucine, isoleucine, lysine, arginine, serine, threonine, phenylalanine; unnatural amino acids such as D- isomers or substituted amino acids; salts of acidic amino acids such as aspartic acid, glutamic acid; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts. Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, methanesulfonates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates and the liks thereof.
"Compounds of the invention" or "present invention" refers to the compounds of the present invention represented by general Formula (I) as here in defined, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their bioisosters, their diastereomers, their polymorphs, their enantiomers, their appropriate N-oxides, their pharmaceutically acceptable salts, their pharmaceutically acceptable hydrates, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions containing them. The compounds of the present invention are useful as antibacterial agents particularly in the treatment of mycobacterial infections, and more particularly tuberculosis.
The present invention also provides pharmaceutical compositions containing the compounds of invention as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, bioisosters, polymorphs, enantiomers, diastereomers, their pharmaceutically acceptable salts or solvates in combination with suitable pharmaceutically acceptable carriers, and/or diluents.
The pharmaceutical compositions according to the present invention are useful antibacterial agents. The pharmaceutical composition may be tablets, capsules, powders, syrups, solutions, suspensions, sprays and the likes thereof and may contain flavorants, sweeteners etc., in a suitable solid or liquid carriers or diluents or in a suitable sterile media to form injectable solutions or suspensions. It is understood that in any of the above schemes, any reactive group in the substrate molecule may be protected according to any conventional procedure known in the prior art. Suitable protecting groups comprise N-Boc, N-Cbz, N-Fmoc, alkyl,
benzophenoneimine for protection of amino group, acetal protection for aldehyde, ketal protection for ketone. The invention also encompasses prodrugs of compounds of the invention, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of compounds of invention, which are readily convertible in vivo into compounds of the invention. The invention also encompasses the active metabolites of the compounds of the present invention of general Formula (I).
Synthesis
All anhydrous solvents, reagent grade solvents for chromatography and starting materials were purchased from either Sigma Aldrich Chemical Co. or Fisher Scientific. Water was distilled and purified through a Milli-Q water system (Millipore Corp., Bedford, MA). General methods of purification of compounds involved the use of silica cartridges purchased from Grace
Purification systems. The reactions were monitored by TLC on precoated Merck 60 F254 silica gel plates and visualized using UV light (254 nm). All compounds were analyzed for purity by HPLC and characterized by 1H NMR using Bruker 300 MHz NMR and/or Bruker 400 MHz NMR spectrometers. Chemical shifts are reported in ppm (d) relative to the residual solvent peak in the corresponding spectra; chloroform d 7.26, methanol d 3.31, DMSO-d6 d 3.33 and coupling constants (J) are reported in hertz (Hz) (where s = singlet, bs = broad singlet, d = doublet, dd = double doublet, bd = broad doublet, ddd = double doublet of doublet, t = triplet, tt - triple triplet, q = quartet, m = multiplet) and analyzed using ACD NMR data processing software. Mass spectra values are reported as m/z.
All reactions were conducted under Nitrogen unless otherwise noted. Solvents were removed in vacuo on a rotary evaporator.
Abbreviations: DMSO = Dimethylsuf oxide; ACN = Acetonitrile; NMP = N-methyl Pyrrolidine; HC1 = hydrochloric acid; DMF = N,N-dimethylformamide; NaH = sodium hydride. El = electrospray ionization; HRMS = high resolution mass spectrometry.
The synthesis of benzimidazole analogues is outlined in Scheme 1. Synthesis can be initiated with the commercially available starting materials. 3-Chloroaniline (Int-1) was converted to 2- [(3-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (Int-2) by reacting with diethyl ethoxymethylenemalonate at 110 °C and subsequent cyclisation in dowtherm medium at 240 °C afforded 7-chloro-4-hydroxyquinoline (Int-3). The chlorination of intermediate using POC13 at reflux temperature resulted 4,7-Dichloro-quinoline (Int-4) and condensation of 4,7-Dichloro- quinoline and piperazine in IPA at 95 °C resulted 7-Chloro-4piperazin-l-yl-quinoline (Int-5) with excellent yield. The common intermediate, [4-(7-Chloroquinolin-4-yl)-piperazin-l-yl]- acetonitrile (Int-6) was synthesized by coupling of chloroacetonitrile with 7-Chloro-4-piperazin- l-yl-quinoline (Int-5). Intermediates (Int-7a-c) were prepared via suzuki coupling of respective boronic acids with intermediate Int-6 using Pd2(dba)3 catalyst and s-Phos. The intermediate, Int-6 and Int-7a-c were readily converted into corresponding hydroxy-acetamidine Int-8(a-d) by treating with hydroxylamine in presence of suitable base. The quinoline amide derivativeslnt- Int-9(a-f), Int-lO(a-f), Int-ll(a-f) and Int-12(d-f) were obtained by acid amine coupling of Int- 8(a-d) with carboxylic acids in presence EDCI and HOBt with good yield. Examples 1 to 76 were synthesized in good yield from their precursors by heating them with DBU at 90 °C. The structures of all the newly synthesized compounds were confirmed by FTIR, 1 H and 13C NMR and LC-MS studies.
Figure imgf000017_0001
Scheme 1. Scheme for synthesis of Examples 1-76 as provided in Table 1. Examples 1-76 herein indicate the compounds of the invention.
Reagents and conditions: (a) Diethyl ethoxymethylenemalonate, 110 °C; (b) Dowtherm medium, 240 °C; (c) POCb, reflux; (d) Piperazine, IPA, 95 °C; (e) Chloroacetonitrile, Et3N, ACN, DMF, RT; (f) Aromatic boronic acids, Pd2(dba)3, s-Phos, K3PO4, l,4-dioxane, water, 100 °C; (g) Hydroxylamine hydrochloride, NaHC03/ Et3N, methanol, 70 °C; (h) Aromatic/aliphatic acid, EDCI, HOBT, DIPEA, RT (i) DBU, DMF, 90 °C.
Experimental protocol:
Preparation of 2-[(3-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (Int-2):
A suspension of 3-Chloro-phenylamine (Int-l) 50 g (0.391 mol) in diethyl ethoxymethylene malonate 119 mL (0.587 mol) was heated tol 10 °C for 4 h. The reaction mixture was cooled to room temperature, the solid thus formed was taken in hexane (10 vol), stirred for 15 min and filtered to get compound 2 as a Pale yellow solid. The isolated compound was taken for next step without further purification. Yield: 70 g (63 %)
Preparation of 7-chloro-4-hydroxyquinoline (Int-3):
A solution of 2-[(3-Chloro-phenylamino)-methylene]-malonic acid diethyl ester (2) 50 g (0.168 mol) in dowtherm (100 mL, 2 vol) medium was heated at 250 °C for 4 h. The reaction mixture was cooled to room temperature. To the above mixturewas added hexane and stirred for 15 min, the solid thus precipitated was filtered and dried to get compound 3 as an off white solid. Yield: 15 g (49.7 %)
Preparation of 4,7-Dichloro-quinoline (Int-4):
A Phosphorus oxychloride (10 mL, 1 vol) was added to 7-chloro-4-hydroxyquinoline (3) (10 g, 0.055 mol) in a round bottom flask equipped with a reflux condenser. The mixture was heated to reflux for 6 h, then allowed to cool to room temperature. The solution was concentrated under high vacuum to a thick oil, then dumped over cracked ice. The resulting solution was neutralized with saturated NaHCCh (aq), solid precipitated was filtered and washed with water. The solids were dried under vacuum. The crude compound was purifiedby column chromatography over silica gel using eluent 30 % ethyl acetate in hexane to afford 4,7-dichloroquinoline as a white solid Yield: 8 g (81.6 %) (analytical data reference of step-2, 3 and 4: Synthesis and Antitumor Activity of Halogen-Substituted 4-(3,3-Dimethyl-l-triazeno)quinolones, Journal q Medicinal Chemistry, 1978, Vol. 2i, No. 3)
Preparation of 7-Chloro-4-piperazin-l-yl-quinoline (Int-5):
To a suspension of 4,7-Dichloro-quinoline (4) (50 g, 0.252 mol) in isopropyl alcohol (150 mL, 3 vol) was added piperazine (65.2 g, 0.757 mol) at ambient temperature. The reaction mixture was stirred under nitrogen at 90 °C for 16 h. The reaction mass was turned into clear solution at the beginning and the solid precipitation was observed slowly. The progress of the reaction was monitored by TLC. The reaction mass was cooled to room temperature and diluted with ethyl acetate (1L, 20 vol). The unreacted piperazine was precipitated, it was removed by filtration. The filtrated solid was washed with ethyl acetate (500 mL). The filtrate was washed with water (500 mL X 2), dried over solid sulphate, concentrated under reduced pressure to give crude desired compound. The crude compound was purified by column chromatography using silica gel (60- 120), eluent 5 % methanol in dichloromethane to get desired compound as a pale yellow solid. Yield: 50 g (80.6 %)
(analytical data reference: An Efficient, Green Chemical Synthesis of the Malaria drug,
Piperaquine Tropical Journal of Pharmaceutical Research, October 20l3;l2(5):79l-798, doi.org/l0.43l4/tjpr. vl2i5.20)
Preparation of [4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-acetonitrile(Int-6):A solution of 7-Chloro-4-piperazin-l-yl-quinoline (5) (50 g, 0.201 mol) in acetonitrile and N,N-dimethyl form amide (1: l)(lL, 20 vol) was cooled at 0°C for 15 min and was added triethyl amine (85 mL, 0.603 mol) followed by chloroacetonitrile (25.6 mL, 0.403 mol) and gradually warmed to ambient temperature. The reaction mixture was stirred for 16 h at ambient temperature. A white suspension was cooled to 0 °C and diluted with water (2L), stirred for 15 min, the solid precipitated was filtered and dried to afford desired compound as a off white solid. Yield: 47 g (83 %)
NMR (CDCls 400 MHz) d (ppm): 2.91 (t, 4H, -CH2), 3.28 (s, 4H, -€¾), 3.67 (s, 2H, -CH2), 6.86 (d, 7=5.2 Hz, 1H, ArH), 7.46 (dd,/= 9.2, 2.4 Hz, IH,AGH), 7.95 (d, /= 9.2 Hz, 1H, ArH)
8.05 (d, /= 2 Hz, 1H, ArH), 8.74 (d, / = 5.2 Hz, 1H, ArH);13C NMR (CDCI3-IOO MHz) 46.01, 51.61, 51.66, 109.20, 114.58, 114.58, 121.82, 125.03, 126.39, 128.88, 134.98, 150.08, 151.93, 156.48; LC/MS (ESI-MS) m/z 287.1 (M+l)
Preparation of[4-(7-Pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl]-acetonitrile (Int-7a):To a solution of [4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-acetonitrile(6) (20 g, 0.069 mol) in mixture of l,4-dioxane (200 mL) and water (50 mL) was added pyridine-4-boronic acid (9.43 g, 0.076 mol), S-Phos (7.15 g, 0.017 mol), K3PO4 (29.3 g, 0.138 mol). The reaction mixture was purged with argon for 30 min, to this Pd2(dba)3 (6.38 g, 0.007 mol) was added and further purged argon for 15 min. The reaction mixture was heated at 100 °C for 16 h under argon
atmosphere.The reaction mixture was cooled to room temperature and filtered through celite bed and washed with 1 ,4-dioxane. The filtrate was concentrated and the resultant aqueous layer was added 100 mL water, extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (200 mL), saturated brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by column chromatography on silica gel (60-120) using 3 % methanol in ethyl acetate in hexane to get pale yellow solid. Yield: 18 g (78.3 %)
lH NMR (DMSO-de 400 MHz) d (ppm): 2.95 (t, 4H, / = 4.8, -CH2), 3.35 (brs, 4H, -€¾), 3.69 (s, 2H, -CH2), 6.91 (d, / = 4.8 Hz, 1H, ArH), 7.67 (dd, / = 4.8, 1.6 Hz, 2H, ArH) 7.79 (dd, / = 8.8, 2 Hz, 1H, ArH), 8.14 (d, / = 8.8 Hz, 1H, ArH), 8.37 (d, J = 2 Hz, 1H), 8.74 (dd, 2H, / = 4.8, 1.6 Hz), 8.8 (d, lH, / = 4.8);13C NMR (CDCL-100 MHz); 46.01, 51.63, 109.47, 114.58, 121.77, 123.49, 124.06, 124.76, 128.21, 138.60, 147.30, 149.63, 150.46, 151.63, 156.36 LC/MS (ESI- MS) m/z 330.2 (M+l)
Preparation of {4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-acetonitrile (Int-
7b):To a solution of [4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-acetonitrile (6) (20 g, 0.069 mol) in mixture of l,4-dioxane (200 mL) was added 2,5-difluorophenylboronic acid (12.1 g, 0.076 mol), S-Phos (7.15 g, 0.017 mol), DIPEA (70 mL, 0.244 mol). The reaction mixture was purged with argon for 30 min, to this Pd2 (dba)3 (2.74 g, 0.003 mol) was added and further purged argon for 15 min. The reaction mixture was heated at 100 °C for 16 h under argon atmosphere. The reaction mixture was cooled to room temperature and filtered through celite bed and washed with 1 ,4-dioxane. The filtrate was concentrated and the resultant aqueous layer was added 100 mL water, extracted with ethyl acetate (2 x 200 mL). The combined organic layers were washed with water (200 mL), saturated brine solution (200 mL), dried over anhydrous sodium sulphate, filtered and concentrated. The crude was purified by column chromatography on silica gel using 3 % methanol in dichloromethane to get pale yellow solid. The resulted solid was converted into HC1 salt using l,4-dioxane-HCl (3 M).
Preparation of HC1 salt: The solid (22 g) from column was dissolved in dichloromethane (220 mL,l0 vol) cooled to 0 °C, was added l,4-dioxane-HCl (3 M) dropwise and stirred for 30 min. The solid precipitated was filtered and dried to afford desired compound as an off white solid. Yield: 21 g (75 %)
lH NMR (CDsOD 400 MHz) d (ppm): 3.39 (t, 4H, / = 4 .4, -CH2), 4.12 (t, 4H, 7 - 4.8, -CH2), 4.28 (s, 2H, -CH2), 7.40-7.28 (m, 3H, ArH), 7.54-7.49 (m, 1H, ArH), 8.00 (dt, / = 8.8, 1.6 Hz,
1H, ArH), 8.21 (s, 1H, ArH), 8.36 (d, / = 9.2 Hz, 1H), 8.71 (d, 1H, / = 6.8 Hz);13C NMR (DMSO de-lOO MHz); 43.52, 49.76, 50.99, 107.47, 114.36, 117.41 (dd, J= 25, 3 Hz), 118.10 (dd, 7 = 26,9 Hz), 119.23, 120.68 (d, / = 4), 127.18, 127.56 (dd, J = 15, 8 Hz), 138.71, 139.65,
143.06, 154.57 (d, J = 1), 157.32 (dd, J = 63,1 Hz), 160.04, 160.74 LC/MS (ESI-MS) m/z 365.2 (M+l)
Preparation of [4-(7-Pyridin-3-yl-quinolin-4-yl)-piperazin-l-yl]-acetonitrile (Int-7c):This compound was synthesized by coupling [4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl] -acetonitrile (6) with pyridine-3-boronic acid following (7a) protocol pale yellow solid. Yield: 15 g (65.25
%)
NMR (CDCls 400 MHz) d (ppm): 2.95 (t, 4H, / = 4 .8, -CH2), 3.36 (brs, 4H, -CH2), 3.69 (s, 2H, -CH2), 6.90 (d, / = 4.8 Hz, 1H, ArH), 7.45 (ddd, / = 12.8, 8, 4.8 Hz, 1H, ArH) 7.77 (dd, / = 8.8, 2 Hz, 1H, ArH), 8.05 (dt, / = 8, 2 Hz, 1H, ArH), 8.14 (d, J = 8.8 Hz, 1H, ArH), 8.32 (d,/ = 1.6 Hz, IH,AGH), 8.67 (dd,/ = 4.8, 1.6 Hz, IH,AGH), 8.79 (d, / = 5.2Hz, 1H, ArH), 9.02 (dd, / = 2.4, 0.8 Hz,lH);13C NMR (CDCE-lOO MHz); 45.92, 51.55, 109.12, 114.51, 122.76, 123.68, 124.38, 124.59, 127.89, 134.45, 135.53, 138.29, 148.39,148.93, 149.12, 151.50, 156.23 LC/MS (ESI-MS) m/z 330.2 (M+l)
Preparation of N-Hydroxy-2-[4-(7-pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl]-acetamidine (Int-8a):To a solution of [4-(7-Pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl]-acetonitrile(7a) (10 g, 0.030 mol) in methanol (100 mL, 10 vol) was added hydroxylamine hydrochloride (4.21 g, 0.06 mol) and sodium bicarbonate (7.56 g, 0.090mol). Then the reaction mixture was refluxed at 70 °C for 18 h. The resultant solution was cooled to room temperature, diluted with water, the solid precipitated was filtered and dried to afford compound (8a) as an off white solid. Yield: 8 g (72.7 %)
' H NMR (DMSO-de 400 MHz) d (ppm): 2.69 (brs, 4H, -CH2), 2.98 (s, 2H, -CI-I2), 3.24 (brs, 4H, -CH2), 5.30 (brs, 2H, -NH2), 7.03 (d, / = 5.2 Hz, 1H, ArH), 7.89 (dd, / = 4.4, 1.6 Hz, 2H, ArH) 7.96 (d, / = 8.8, 1H, ArH), 8.13 (d, / = 8.8 Hz, 1H, ArH), 8.37 (d, J = 1.6 Hz, 1H, ArH), 8.70 (dd, /= 4.4, 1.6 Hz, 2H), 8.75 (d, / = 4.8, 1H, ArH), 9.04 (s, 1H, -OH);13C NMR (DMSO-d6-lOO MHz) 52.18, 52.83, 58.29, 109.99, 121.99, 123.43, 124.18, 125.50, 128.03, 137.97, 146.62, 149.79, 150.44, 150.89, 152.19, 156.49. LC/MS (ESI-MS) m/z 363.6 (M+l)
Preparation of 2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-N-hydroxy- acetamidine (Int-8b): To a solution of {4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-acetonitrile (7b) (10 g, 0.027 mol) in ethanol (100 mL, 10 vol) was added hydroxylamine hydrochloride (3.81 g, 0.054 mol) and triethylamine (13.3 mL, 0.094 mol). Then the reaction mixture was refluxed at 80°C for 18 h. The reaction was monitored by TLC. The resultant solution was cooled to room temperature, diluted with water and the solid precipitated was filtered, dried to afford compound(8b) as a off white solid.Yield: 8 g (73.4 %)
lH NMR (DMSO d6 400 MHz) d (ppm): 2.68 (brs, 4H, ~CH2), 2.98 (s, 2H, -CH2), 3.23 (brs, 4H, -C¾), 5.30 (brs, 2H, -NH2) 7.03 (d, J = 5.2, IH,AGH), 7.36-7.04 (m, 1H, ArH), 7.44 (td, / = 9.2,
4.8 Hz, 1H, ArH), 7.61-7.56 (m, 1H, ArH), 7.74 (d, / = 8.8 Hz, 1H, ArH), 8.09 (d, / = 8.8 Hz, IH,AGH), 8.14 (s, 1H, ArH), 8.73 (d, / = 4.8, 1H, ArH), 9.04 (s, 1H, -OH) LC/MS (ESI-MS) m/z 398.6 (M+l)
Preparation of 2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-N-hydroxy-acetamidine (Int- 8c): This compound was prepared using [4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl] -acetonitrile (6)(l0 g, 0.034 mol) by following(8b) syntheticprocedure. Yield: 7.2 g (64.5 %)
lH NMR (DMSO-de 400 MHz) d (ppm): 2.65(brs, 4H, -CH2), 2.99 (brs, 4H, -C¾), 3.20 (s, 2H, -CH2), 5.29 (brs, 2H, -NH2), 7.01 (d, /= 5.2 Hz, 1H, ArH), 7.55 (dd, /= 8.8, 2 Hz, 1H, ArH) 7.97 (d, /= 2.4, 1H, ArH), 8.01 (d, / = 9.2 Hz, 1H, ArH), 8.70 (d, /= 5.2 Hz, 1H, ArH), 9.03 (s, 1H, - OH);13C NMR (DMSO-d6-lOO MHz) 52.17, 52.77, 58.27, 109.84, 121.82, 126.20, 126.51,
128.52, 134.01, 150.09, 150.42, 152.63, 156.75 LC/MS (ESI-MS) m/z 320.7 (M+l)
Preparation of N-Hydroxy-2-[4-(7-pyridin-3-yl-quinolin-4-yl)-piperazin-l-yl]-acetamidine (Int-8d) :This compound was prepared using [4-(7-Pyridin-3-yl-quinolin-4-yl)-piperazin-l-yl]- acetonitrile (7c)(l0 g, 0.030 mol) by following(8a) synthetic procedure. Yield: 7.5 g (67.18 %) lH NMR (DMSO-de 400 MHz) d (ppm): 2.69 (brs, 4H, -CH2), 2.98 (s, 2H, -CTI2), 3.24 (brs, 4H, -CH2), 5.30 (brs, 2H, -NH2), 7.01 (d, / = 5.2 Hz, 1H, ArH), 7.55 (ddd, / = 8, 4.4, 0.8 Hz, 1H,
ArH) 7.92 (dd, / = 8.8, 1.6 Hz, 1H, ArH), 8.11 (d, / = 8.8 Hz, 1H, ArH), 8.26 (dt, J = 8, 1.6 Hz,
1H, ArH), 8.28 (dd, /= 5.2, 2 Hz, 1H, ArH), 8.64 (dd, / = 4.8, 1.6 Hz, 1H, ArH), 8.73 (d, / = 5.2, 1H, ArH) 9.04 (s, 1H, -OH), 9.06 (dd, / = 2.4, 0.8 Hz, 1H) ;13C NMR (DMSO-de-lOO MHz):
51.71, 52.37, 57.82, 109.23, 122.25, 124.04, 124.14, 124.89, 127.20, 134.53, 134.74, 137.47, 147.96, 148.99, 149.41, 149.97, 151.57, 156.03 LC/MS (ESI-MS) m/z 363.6 (M+l)
General procedure for preparation of N-{l-[(Z)-Hydroxyimino]-2-[4-(7-pyridin-4-yl-quinolin- 4-yl)-piperazin-l-yl]-ethyl}-amide (Int-9a-f): To a solution of acid derivative (a-f)(l.2 eq) in DMF (20 mL, 20 vol) was added EDC.HC1 (1.054 g, 5.518 mol), HOBt (0.557 g, 4.125 mmol) and DIPEA (1.4 mL, 8.277 mmol) at 0 °C. To the above mixture N-Hydroxy-2-[4-(7-pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl]-acetamidine (8a) (1 g, 2.759 mmol) was added at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h.The reaction mixture was quenched with ice cold water. The aqueous layer was extracted with dichloromethane (20 mL X2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate, filtered and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichloromethane.
N-{l-[ (Z)-Hydroxyimino ]-2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )-piperazin-l -yl] -ethyl }-3,5- dimethoxy-benzamide (Int-9a :This compound was prepared by coupling of compound Int-8a with 3,5-dimethoxy-benzoic acid in the presence of EDC.HC1. It was obtained as a pale yellow solid Yield: 0.9 g (62 %)
¾ NMR (CDC13 400 MHz) d (ppm): 2.92 (brs, 4H, -CH2), 3.4 (brs, 6H, -C¾), 3.86 (s, 6H, - OCHs), 5.42 (brs, 2H, -NH-OH), 6.68 (t, / = 2.4 Hz,/ = 2.4, 1H, ArH), 6.92 (d, / = 5.2 Hz, 1H, ArH), 7.19 (d, / = 2.4 Hz, 2H, ArH) 7.68 (dd, / = 4.4, 1.6 Hz, 2H, ArH), 7.80 (d, / = 8.8 Hz,
1H, ArH), 8.12 (d, / = 8.8 Hz, 1H, ArH), 8.46 (s, 1H, ArH), 8.75 (d, J =6 Hz, 2H, ArH), 8.78 (d, / = 5.2 Hz, 1H, ArH) ;13C NMR (CDC13-100 MHz) ; 52.09, 52.94, 55.67, 56.9, 105.23, 107.29, 109.29, 121.8, 123.5, 124.05, 124.85, 128.14, 131.35, 138.69, 147.35, 149.58, 150.44, 151.53, 156.53, 156.64, 160.72, 163.91, LC/MS (ESI-MS) m/z 527.6 (M+l)
3.5-Difluoro-N-{l-[(Z)-hydroxyimino]-2-[4-(7-pyridin-4-yl-quinolin-4-yl)-piperazin-l-yl ]- ethyl} -benzamide ( lnt-9b):T \s compound was prepared by coupling of compound Int-8a with
3.5-diflouro-benzoic acid in the presence of EDC.HC1. It was obtained as a pale brown solid. Yield: 0.873 g (63 %).
¾ NMR (CDC13 400 MHz) d (ppm): 2.91 (brs, 4H, -CH2), 3.25 (brs, 4H, ·('! ! ). 3.35 (s, 2H),
5.31 (brs, 2H, -NH-OH), 6.91 (d, / = 5.2 Hz, 1H, ArH), 7.05 (tt, / = 8.4, 2.4 Hz, 1H, ArH), 7.58 (dd, 7 =7.2, 2.4 Hz, 2H, ArH) 7.67 (dd, / = 4.4, 1.6 Hz, 2H, ArH), 7.80 (dd, / = 8.8, 2 Hz, 1H, ArH), 8.12 (d, / = 8Hz, 1H, ArH), 8.40 (s, 1H, ArH), 8.73 (d, / =4.8, 2 Hz, 2H, ArH), 8.78 (d,
1H, / = 5.2, ArH) ;13C NMR (CDCI3-IOO MHz) ; 52.09, 52.98, 56.80, 108.53 (t, / = 25), 109.34, 112.55 (q, / = 12), 121.80, 123.54, 124.06, 124.79, 128.29, 132.68, 138.69, 147.37, 149.74,
150.47, 151.65, 156.67, 161.56 (d, / = 12), 161.94, 163.55 (d, 7 =12) LC/MS (ESI-MS) m/z 503.2 (M+l)
3-Cyano-N-{ 1 -[ (Z)-hydroxyimino] -2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )-piperazin-l -yl]-ethyl}- benzamide ( lnr-9c):T \s compound was prepared by coupling of compound Int-8a with 3-cyano- benzoic acid in the presence of EDC.HC1. It was obtained as a pale brown solid. Yield: 0.881 g (65 %)
lH NMR (DMSO d6 400 MHz) d (ppm): 2.99 (brs, 4H, CH2), 3.37 (brs, 4H, -CS l ). 3.97 (s, 2H, -CH2), 6.50 (brs, 2H, -NH-OH), 6.90 (d, / = 5.2 Hz, 1H, ArH), 7.77-7.66 (m, 4H, ArH), 7.91 (dt, / = 6.4, 1.6 Hz, 1H, ArH) 8.13 (d, / = 8.8 Hz, 1H, ArH), 8.35 (d, 1H, / = 1.6 ArH), 8.43 (dt, / = 8, 1.6, 2H, ArH) 8.51 (s, 1H, ArH), 8.73 (d, / = 6 Hz, 2H, ArH), 8.79 (d, / = 4.8 Hz, 1H) ;13C NMR (CDCb-lOO MHz) ; 52.91, 52.80, 52.95, 109.38, 113.83, 117.42, 121.76, 123.54, 124.84, 125.32, 128.25, 130.25, 131.69, 135.86, 138.48, 147.34, 149.66, 150.41, 151.71, 156.61, 168.05, 173.98 LC/MS (ESI-MS) m/z 474.5 (M+l)
N-{l-[ (Z)-Hydroxyimino ]-2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )-piperazin-l -yl] -ethyl }-2,3- dimethyl-benzamide ( lnt-9d):T \s compound was prepared by coupling of compound Int-8a with 2,3-dimethyl-benzoic acid in the presence of EDC.HC1. It was obtained as an off white solid. Yield: 0.887 g (65 %)
NMR (CDCE 400 MHz) d (ppm): 2.34 (s, 3H, -CH3), 2.47 (s, 3H, -CH3), 2.90 (brs, 4H, - €¾), 3.32 (s, 2H, -CH2),3.39 (brs, 4H, -CH2), 5.38 (brs, 2H, -NH-OH), 6.9 (d, / = 5.2 Hz, 1H, ArH), 7.16 (t, / = 7.6 Hz, 1H, ArH), 7.31 (d, / = 7.6 Hz, 1H, ArH) 7.55 (d, / = 7.6 Hz, 1H, ArH) 7.67 (dd, / = 4.4, 1.6 Hz, 2H, ArH), 7.78(dd, J = 8.8, 2 Hz, 2H,ArH), 8.13 (d, / = 8.8 Hz, 1H, ArH), 8.36(d, / = 2 Hz, IH,AGH), 8.74 (dd, J = 4.8, 1.6 Hz, 2H, ArH), 8.79 (d,/ = 4.8, 1H, ArH) ;13C NMR (CDCb-lOO MHz) ; 16.75, 20.51, 29.72,52.10, 52.97, 56.94, 109.34, 121.84, 123.57, 124.04, 124.85, 125.30, 126.99, 128.23, 130.74, 132.94, 136.98, 138.17, 138.64, 147.44, 149.68, 150.37, 151.65, 156.11, 156.62, 166.32, LC/MS (ESI-MS) m/z 495.1 (M+l)
Cyclopentanecarboxylic acid {!-[ (Z)-hydroxyimino] -2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )- piperazin-l-yl] -ethyl} -amide ( lnt-9e):T \s compound was prepared by coupling of compound Int-8a with cyclopentanecarboxylic acid in presence ofEDC.HCl. It was obtained as anoff white solid Yield: 0.759 g (60 %)
¾ NMR (DMSO d6 400 MHz) d (ppm): 1.72-1.54 (6H, m), 1.89-1.86 (2H, m), 2.74 (brs, 4H, - CH2), 2.89-2.83 (m, 1H, -CH), 3.09 (s, 2H, -CH2), 3.25 (brs, 4H, -CH2), 6.33 (brs, 2H, -NH-OH), 7.039 (d, / = 4.8 Hz, 1H, ArH), 7.88 (dd, / = 8.4, 1.6 Hz, 2H, ArH), 7.95 (dd, / = 8.4 1.6 Hz, 1H, ArH) 8.14 (d, / = 8.8 Hz, 1H, ArH), 8.37 (d, / = 1.6 Hz, 1H, ArH), 8.70 (dd, / = 4.4, 1.6 Hz,
2H, ArH), 8.75 (d, / = 4.8, IH,AGH) ;13C NMR (CDC13-100 MHz) ; 25.88, 30.34, 42.70, 52.12, 52.95, 56.95, 109.32, 121.80, 123.57, 124.04, 124.82, 128.33, 138.69, 147.39, 149.78, 150.50, 157.69, 155.51, 156.59, 173.90 LC/MS (ESI-MS) m/z 459.6 (M+l)
N-{l-[ (Z)-Hydroxyimino ]-2-[ 4-( 7-pyridin-4-yl-quinolin-4-yl )-piperazin-l -yl] -ethyl }-4-isopropyl- benzamide(Int-9f):This compound was prepared by coupling of compound Int-8a with 4- isopropyl-benzoic acid in presence of EDC.HC1. It was obtained as a pale yellow solid. Yield: 0.954 g (68 %)
NMR (CDCI3 400 MHz) d (ppm): 1.28 (d, 6H,/ = 6.8), 2.91 (brs, 4H, -CH2), 2.98 (sept, 1H,/
= 6.8, -CH), 3.36 (brs, 4H, -CH2), 3.40(s, 2H, -CH2), 5.41 (brs, 2H, -NH-OH), 6.90 (d, / = 5.2 Hz, 1H, ArH), 7.33 (d, / = 8.4 Hz, 2H, ArH), 7.68 (dd, / = 4.8, 1.6 Hz, 2H, ArH), 7.79 (dd, / =
8.8, 1.6 Hz, 1H, ArH), 8.00 (dd, / = 6.8, 1.6 Hz, 2H, ArH), 8.13 (d, / = 8.8 Hz, 1H, ArH), 8.40 (d, / = 1.6, 1H, ArH), 8.74 (d, / = 5.2, 2H, ArH), 8.79 (d, / = 5.2, 1H, ArH);13C NMR (CDCI3- 100 MHz) ; 23.69, 32.24, 52.07, 52.92, 56.98, 109.31, 121.78, 123.53, 123.98, 124.86, 126.61, 127.04, 128.19, 129.62, 138.57, 147.35, 149.66, 150.39, 151.61, 154.52, 156.38, 156.59, 164.18 LC/MS (ESI-MS) m/z 509.2 (M+l)
General procedure for preparation N-[2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin- l-yl}-l-hydroxyamino-ethylidene]-amide (Int-lOa-f):
To a solution of acid derivative (a-f) in DMF (20 mL, 20 vol) was added EDC.HC1 (0.962 g,
5.023 mol), HOBt (0.509 g, 3.774 mmol) and DIPEA (1.3 mL, 7.548 mmol) at 0 °C. To the above mixture 2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-N-hydroxy- acetamidine(Int-8b) (1 g, 2.516 mmol) was added at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for 12 h. The reaction mixture was quenched with ice cold water and the phases were separated. The aqueous layer was extracted with
dichloromethane (20 mL X2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate filtered and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichloromethane.
N-[2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-l-hydroxyamino-ethylidene]- 3,5-dimethoxy-benzamide (\x\t-l()a ):This compound was prepared by coupling of compound Int- 8b with 3,5-dimethoxy-benzoic acid in the presence of EDC.HC1. It is obtained as a white solid. Yield: 0.989 g
¾ NMR (CDC13 400 MHz) d (ppm): 2.89 (brs, 4H, -CH2), 3.33 (brs, 4H, -CH2), 3.35 (s, 2H, - CH2), 3.85 (s, 6H, -OCHs), 5.43 (brs, 2H, -NH-OH), 6.67 (t, / = 2 Hz, 1H, ArH), 6.89 (d, / = 4.8 Hz, 1H, ArH), 7.09-7.04 (m, 1H, ArH), 7.20-7.14 (m, 3H, ArH), 7.31-7.27 (m, 1H, ArH), 7.69 (td, / = 8.8, 2 Hz, 1H, ArH), 8.07 (d, / = 8.8, 1H, ArH), 8.24 (s, 1H, ArH), 8.77 (d, 1H, / = 4.8, ArH) ; LC/MS (ESI-MS) m/z 562.2 (M+l)
N-[2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-l-hydroxyamino-ethylidene]- 3,5-difluoro-benzamide (Int-lOb): This compound was prepared by coupling of compoundInt-8b with 3,5-diflouro-benzoic acid in the presence of EDC.HC1. It is obtained as a brown solid Yield: 0.743 g (55 %)
¾ NMR (CDC13 400 MHz) d (ppm): 2.90 (brs, 4H, -CH2), 3.34 (brs, 4H, ·('! ! ). 3.39 (s, 2H, - CH2), 5.45 (brs, 2H, -NH-OH), 6.89 (d, / = 5.2 Hz, 1H, ArH), 7.10-7.03 (m, 1H, ArH), 7.18 (td, 1H, / = 9.2, 4.4 Hz, ArH), 7.32-7.27 (m, 1H, ArH), 7.61-7.56 (m, 2H, ArH), 7.70 (dt, / = 8.8, 2 Hz, 1H, ArH), 8.08 (d, / = 8.8, 1H, ArH), 8.26 (s, 1H, ArH), 8.78 (d, 1H, / = 4.8, ArH) ; LC/MS (ESI-MS) m/z538.1 (M+l)
3-Cyano-N-[2-{4-[7-(2,5-difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-l-hydroxyamino- ethylidene] -benzamide ( l nt- 10c ):T \s compound was prepared by coupling of compound Int-8b with 3-cyano-benzoic acid in the presence of EDC.HC1. It is obtained as a pale brown solid. Yield: 0.98 g (74 %)
lH NMR (DMSOde 400 MHz) d (ppm): 2.79 (brs, 4H, -CH ), 3.18 (s, 2H, -C! fc), 3.34 (brs, 4H, - CH2), 6.97-6.59 (brs, 2H, -NH-OH), 7.05 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.33 (m, 1H, ArH), 7.45 (td, / = 9.2, 4.8 Hz, 1H, ArH), 7.77-7.72 (m, 2H, ArH), 8.11 (s, 1H, ArH), 8.14 (d, / = 5.2 Hz, 2H, ArH), 8.38 (dt, / = 8.4, 1.2 Hz, 1H, ArH), 8.69 (t, / = 1.4 Hz, 1H, ArH), 8.74 (d, 1H, / = 4.8, ArH) ; LC/MS (ESI-MS) m/Z527.l (M+l)
N-[2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-l-hydroxyamino-ethylidene]- 2,3-dimethyl-benzamide (Int-i0<i):This compound was prepared by coupling of compound Int- 8b with 2,3-dimethyl-benzoic acid in the presence of EDC.HC1. It is obtained as a off white solid. Yield: 0.807 g (65 %)
lH NMR (DMSO d6 400 MHz) d (ppm): 2.27 (s, 3H, -CHs), 2.35 (s, 3H, -CHs), 2.78 (brs, 4H, - CEE), 3.16 (s, 2H, -CH2), 3.27 (brs, 4H, -CH2), 6.40 (brs, 2H, -NH-OH), 7.044 (d, / = 5.2 Hz, 1H, ArH), 7.18 (t, / = 7.6 Hz, 1H, ArH), 7.37-7.31 (m, 2H, ArH), 7.45 (td, / = 9.2, 4.8 Hz, 1H, ArH), 7.62-7.57 (m, 2H, ArH), 7.75 (dt, / = 8.8, 2 Hz, 1H, ArH), 8.12 (d, / = 8.8 Hz, ArH), 8.14 (s, 1H, ArH), 8.74 (d, 1H, J = 5.2, ArH) ; LC/MS (ESI-MS) m/Z530.2 (M+l)
Cyclopentanecarboxylic acid [2-{4-[7-( 2,5-difluoro-phenyl )-quinolin-4-yl ]-piperazin-l -yl}-l- hydroxyamino-ethylidene] -amide (Int-10e):This compound was prepared by coupling of compound Int-8b with cyclopentanecarboxylic acidin the presence of EDC.HC1. It is obtained as an off white solidYield: 0.807 g (65 %)
Figure imgf000027_0001
(ppm): 1.55-1.52 (m, 2H, -CH2) 1.72-1.55 (m, 4H, -CH2), 1.89-1.84 (m, 2H, -CH2), 2.74 (brs, 4H, -CH?.), 2.85 (quint, 1H, / = 8.4 Hz, -CH), 3.08 (s, 2H, - C¾), 3.25 (brs, 4H, -CH2), 6.32 (brs, 2H, -NH-OH), 7.34 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.30 (m, 1H, ArH), 7.44 (td, / = 9.2, 2 Hz, 1H, ArH), 7.61-7.56 (m, 1H, ArH), 7.75 (dt, / = 8.8, 1.6 Hz, 1H, ArH), 8.10 (d, 1H, / = 8.8 Hz, ArH), 8.14 (s, 1H, ArH), 8.74 (d, 1H, / = 4.8, ArH) ;
LC/MS (ESI-MS) m/z 494.2 (M+l)
N-[2-{4-[7-(2,5-Difluoro-phenyl)-quinolin-4-yl]-piperazin-l-yl}-l-hydroxyamino-eth-(Z)- ylidene] -4-isopropyl-benzamide ( Int-1 Of):
This compound was prepared by coupling of compound Int-8b with 4-isopropyl-benzoic acid in the presence of EDC.HC1. It is obtained as a pale yellow solid Yield: 0.820 g (60 %)
NMR (DMSOde 400 MHz) d (ppm): 1.23 (d, 6H, / = 6.8 Hz, ArH), 2.79 (brs, 4H, -CH?), 2.97 (sept, 1H, -CH), 3.17 (s, 2H, -CTI2), 3.27 (brs, 4H, -CH2), 6.50 (brs, 2H, -NH-OH), 7.05 (d, / =
4.8 Hz, 1H, ArH), 7.38 (d, / = 8 Hz, 2H, ArH), 7.36-7.31 (m, 1H, ArH), 7.45 (td, / = 9.2, 4.4 Hz, 1H, ArH) 7.62-7.57 (m, 1H, ArH), 7.76 (dt, / = 8.8, 1.6 Hz, 1H, ArH), 8.05 (dd, / = 6.8, 2 Hz,
2H, ArH), 8.12 (d, / = 4.4 Hz, 1H, ArH), 8.14 (t, 1H, / = 1.6, ArH), 8.74 (d, / = 5.2 Hz, 1H,
ArH) ; LC/MS (ESI-MS) m/z 544.2 (M+l)
General procedure for preparation N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l- hydroxyamino-ethylidene]-amide (Int-lla-f):
To a solution of acid derivative (a-f) in DMF (20 mL, 20 vol) was added EDC.HC1 (1.2 g, 6.32 mol), HOBt (0.633 g, 4.690 mmol) and DIPEA (1.6 mL, 9.360 mmol) at 0 °C. To the above mixture 2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-N-hydroxy-acetamidine (8c)(l g, 3.126 mmol) was added at 0 °C. The reaction mixture was gradually warmed to room temperature and stirred for l2h.The reaction mixture was quenched with ice cold water and the phases were separated. The aqueous layer was extracted with dichloromethane (20 mL X2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate filtered and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichlorome thane.
N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l-hydroxyamino-eth-(Z)-ylidene]-3,5- dimethoxy-benzamide (Int-lla): This compound was prepared by coupling of compound Int-8c with 3,5-dimethoxy-benzoic acid in presence of EDC.HC1. It is obtained as a off white solid. Yield: 1.08 g (72 %)
NMR (CDCls 300 MHz) d (ppm): 2.87 (brs, 4H, -C! l· ). 3.28 (brs, 4H, -Cf i ). 3.37 (s, 2H, - CH2), 3.85 (s, 6H, -OCHs), 5.41 (brs, 2H, -NH-OH) 6.66 (t, 7=2.1 Hz, 1H, ArH), 6.84 (d, J= 5.1 Hz, 1H, ArH), 7.18 (d, 7=2.4 Hz, 2H, ArH) 7.45 (dd, 7= 8.7, 1.8 Hz, 1H, ArH), 7.93 (d, 7 = 9 Hz, 1H, ArH), 8.07 (d, 7=1.8 Hz, 1H, ArH), 8.73 (d, 7=5.1 Hz, 1H, ArH) ;13C NMR (CDC13-75 MHz) 52.08, 52.88, 56.87, 105.19, 107.28, 109.00, 121.83, 125.15, 126.31, 128.81, 131.38, 134.96, 150.09, 151.85, 156.70, 160.70, 163.88; LC/MS (ESI-MS) m/z 485.1 (M+l)
N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l-hydroxyamino-eth-(Z)-ylidene]-3,5-difluoro- benzamide (Int-llb): This compound was prepared by coupling of compound Int-8c with 3,5- diflouro-benzoic acid in presence of EDC.HC1. It is obtained as a pale brown solid. Yield: 1.0 g (70 %)
NMR (DMSO-d6400 MHz) d (ppm): 2.75 (brs, 4H, -CH2), 3.15 (s, 2H, -CH2), 3.24 (brs, 4H, -CH2), 6.56 (brs, 2H, -NH-OH) 7.03 (d, 7= 4.8 Hz, 1H, ArH), 7.61-7.54 (m, 2H, ArH) 7.86 (dd, 7= 8, 2 Hz, 1H, ArH), 7.98 (d, 7 = 2 Hz, 1H, ArH), 8.04 (d, 7=8.8 Hz, 1H, ArH), 8.71 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDC13-75 MHz) 51.95, 52.77, 56.61, 108.33 (t, 7 = 25.2),
108.88, 112.36 (q, J=l7.7, 8.6 Hz), 121.7, 124.94, 126.22, 128.72, 132.54, 134.89, 149.97, 151.70, 156.54, 156.64, 160.97 (d, J=l 1.9), 161.77, 164.29 (d, J =11.9)·, LC/MS (ESI-MS) m/z 460.0 (M+l)
N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l-hydroxyamino-eth-(Z)-ylidene]-3-cyano- benzamide (Int-llc):
This compound was prepared by coupling of compound Int-8c with 3-cyano-benzoic acid in presence of EDC.HC1. It is obtained as a pale brown solid. Yield: 1.05 g (75 %)
NMR (CDCls 400 MHz) d (ppm): 2.88 (brs, 4H, -CH2), 3.30 (brs, 4H, -CH2), 3.39 (s, 2H, - CH2), 5.47 (brs, 2H, -NH-OH) 6.86 (d, 7= 5.2 Hz, 1H, ArH), 7.46 (dd, lH,7 =9.2 Hz, 2 ArH) 7.64 (t, 7 =8 Hz, 1H, ArH), 7.88 (dt, 7= 8 Hz, 1.2 Hz, 1H, ArH), 7.94 (d, 7=9.2 Hz, 1H, ArH), 8.08 (s, 1H, ArH), 8.34-8.30 (m, 2H, ArH), 8.75 (d, 7=5.2 Hz, 1H) ;13C NMR (CDC13-75 MHz) 52.02, 52.85, 56.74, 109.0, 112.81,117.79, 121.77, 124.94, 125.12, 126.26, 128.71, 129.55,
130.84, 132.91, 133.62, 134.92, 1135.92, 149.99, 151.78, 156.65, 156.89, 162.17; LC/MS (ESI- MS) m/z 449.6 (M+l)
N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l-hydroxyamino-eth-(Z)-ylidene]-2,3- dimethyl-benzamide ( Inr- 11 d):T \s compound was prepared by coupling of compound Int-8c with 2,3-dimethyl-benzoic acid in presence of EDC.HC1. It is obtained as an off white
solid.Yield: 0.989 g (70 %)
NMR (CDCls -400 MHz) d (ppm): 2.34 (s, 3H, -CH3), 2.47 (s, 3H, -CH3) 2.87 (t, 4H, 7=4.4,- Ce2), 3.29 (brs, 4H, -CH2), 3.38 (s, 2H, -CH2), 5.37 (brs, 2H, -NH-OH) 6.85 (d, 7= 5.2 Hz, 1H, ArH), 7.16 (t, 1H, 7= 7.6Hz, ArH) 7.31 (d, 7= 7.6 Hz, 1H, ArH), 7.46 (dd, 7 = 8.8, 2 Hz, 1H, ArH), 7.55 (d, 7=7.6 Hz, 1H, ArH), 7.94 (d, 7=8.8 Hz, 1H, ArH), 8.08 (d, 7=2.4 Hz, 1H),
8.73(d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDCI3- 100 MHz): 16.73, 20.48, 52.07, 52.88, 56.88, 109.01, 121.82, 125.19, 125.26, 126.26, 128.78, 130.76, 132.87, 134.91, 136.88, 138.07, 150.05,
151.85, 156.16, 156.70, 166.30; LC/MS (ESI-MS) m/z 452.6 (M+l)
Cyclopentanecarboxylic acid [2-[ 4-( 7-chloro-quinolin-4-yl )-piperazin-l -yl]-l -hydroxyamino- eth-(Z)-ylidene] -amide (Int-lle):This compound was prepared by coupling of compound Int-8c with cyclopentanecarboxylic acidin the presence of EDC.HC1. It is obtained as an off white solid Yield: 0.884 g (68 %).
NMR (CDCl3 -400 MHz) d (ppm): 1.77-1.82 (m, 2H, -CH2), 1.86-1.91 (m, 3H, -CH2), 1.98- 1.93 (m, 3H, -CI-I2), 2.87-2.79 (m, 5H, -CH2, -CH), 3.26 (brs, 4H, -CH2), 3.3 (s, 2H, -CH2), 5.30 (brs, 2H, -NH-OH) 6.84 (d, 7= 5.2 Hz, IH,AGH), 7.44 (dd, 7=8.8, 2 Hz, lHArH), 7.93 (d, 7=9.2 Hz, 1H, ArH), 8.05 (d, 7 = 1.6 Hz, 1H, ArH), 8.73 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDCI3- 75 MHz): 25.69, 30.15, 42.51, 51.94, 52.70, 56.75, 108.85, 121.69, 124.99, 126.14, 128.67, 134.81, 149.95, 151.69, 155.36, 156.57, 173.72; LC/MS (ESI-MS) m/z 416.6 (M+l)
N-[2-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-yl]-l-hydroxyamino-eth-(Z)-ylidene] -4-isopropyl- benzamide (Int-llf):
This compound was prepared by coupling of compound Int-8c with 4-isopropyl-benzoic acid in presence of EDC.HC1. It is obtained as a pale yellow solid Yield: 0.874 g (60 %) pale brown solid
lH NMR (DMSO d6 -400 MHz) d (ppm): 1.22 (d, 6H, 7=6.8 Hz, -CH3), 2.67 (brs, 4H, -CH2), 3.24 (brs, 4H, -CH2), 3.15 (s, 2H, -CH2), 2.99 (sept, 1H, -CH), 7.03 (d, J= 4.8 Hz, 1H, ArH),
7.38 (d,7= 8.4 Hz, 2H,ArH), 7.56 (dd, 7=8.8, 2 Hz, 1H, ArH), 7.98 (d, 7 = 2 Hz, 1H, ArH), 8.04 (d, 7=8.4 Hz, 3H, ArH), 8.71 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDC13- 100 MHz): 23.73, 34.28, 52.13, 52.91, 56.93, 109.03, 121.86, 125.17, 126.36, 126.64, 127.07, 128.87, 129.63, 135.03, 150.11, 151.88, 154.55, 156.32, 156.75, 164.13; LC/MS (ESI-MS) m/z 466.6 (M+l) N-{l-[ (Z)-Hydroxyimino ]-2-[ 4-( 7-pyridin-3-yl-quinolin-4-yl )-piperazin-l -yl] -ethyl }-2,3- dimethyl-benzamide ( Int- 12d):T \s compound was prepared by coupling of compound Int-8d with 2,3-dimethyl-benzoic acid in presence of EDC.HC1. It was obtained as a pale yellow solid. Yield: 0.85 g (62.3 %)
NMR (CDCb 400 MHz) d (ppm): 2.34 (s, 3H, -CH3), 2.47 (s, 3H, -CH3), 2.90 (brs, 4H, - CH2), 3.33 (brs, 4H, -CEE), 3.40 (s, 2H, -CH2), 5.30 (brs, 2H, -NH-OH), 6.88 (d, 7 = 4.8 Hz, 1H, ArH), 7.15 (t, 7 = 7.6 Hz, 1H, ArH), 7.3 (d, 7 = 7.2 Hz, 1H, ArH) 7.44 (dd, 7 = 8, 4.8 Hz, 1H, ArH), 7.55(d, J = 7.6 Hz, 1H, ArH), 7.75 (dd, J = 8.4, 1.6 Hz, 1H, ArH), 8.04 (dt, J =6, 2 Hz, 1H ArH), 8.12 (d, J = 8.8 Hz, 1H, ArH), 8.30 (d, 1H, 7 = 1.6 Hz), 8.66 (dd, 7 = 4.8, 1.2 Hz, 1H),
8.78 (d, 7 = 5.2, 1H), 9.02 (s, 1H) ;13C NMR (CDCb-lOO MHz) ; 16.72, 20.47, 52.09, 52.97, 56.92, 109.05, 122.88, 123.79, 124.44, 124.77, 125.27, 126.97, 127.89, 130.77, 132.89, 134.59, 135.68, 136.93, 138.11, 138.43, 148.47, 148.98, 149.74, 151,40, 156.14, 156.62, 166.29 LC/MS (ESI-MS) m/z 495.1 (M+l)
Cyclopentanecarboxylic acid {!-[ (Z)-hydroxyimino] -2-[ 4-( 7-pyridin-3-yl-quinolin-4-yl )- piperazin- 1 -yl] -ethyl} -amide (Int-12e) :
This compound was prepared by coupling of compoundInt-8d with cyclopentanecarboxylic acid in presence of EDC.HC1. It was obtained as an off white solid. Yield: 0.759 g (63.2 %)
¾ NMR (DMSO d6 400 MHz) d (ppm): 1.72-1.53 (6H, m), 1.89-1.84 (2H, m), 2.74 (brs, 4H, - CH2), 2.83 (quint, 1H, -CH), 3.09 (s, 2H, -CH2), 3.25 (s, 4H), 6.33 (brs, 2H, -NH-OH), 7.02 (d, 7 = 4.8 Hz, 1H, ArH), 7.55 (dd, 7 = 8, 4.8 Hz, 1H, ArH), 7.93 (d, 7 = 8.4 1.6 Hz, 1H, ArH) 8.12 (d, 7 = 8.8 Hz, 1H, ArH), 8.26 (dt, 7 = 8, 1.6 Hz, 1H, ArH), 8.29 (d, 7 = 1.6 Hz, 1H, ArH), 8.63 (dd, 7 = 4.8, 1.6 1H, ArH), 8.73 (d, 1H, 7 = 4.8), 9.06 (s, 1H, ArH) ;13C NMR (DMSO d6-l00 MHz); 25.38, 29.72, 41.93, 51.62, 52.36, 56.92, 109.18, 122.20, 124.00, 124.10, 124.86, 127.17, 134.48, 134.71, 137.45, 147.94, 148.96, 149.39, 151.52, 155.87, 155.96, 173.44 LC/MS (ESI- MS) m/z 459.6 (M+l) N-(l-[ (Z)-Hydroxyimino ]-2-[ 4-( 7-pyridin-3-yl-quinolin-4-yl )-piperazin-l -yl] -ethyl }-4-isopropyl- benzamide (Int-12f):
This compound was prepared by coupling of compound Int-8d with 4-isopropyl-benzoic acid in presence of EDC.HC1. It was obtained as a pale yellow solid Yield: 0.9 g (64.15 %)
NMR (CDCls 400 MHz) d (ppm): 1.28 (d, 6H, = 6.8), 2.90 (brs, 4H, -€¾), 2.98 (sept, 1H, J = 6.8, -CH), 3.34 (brs, 4H, -CH2), 3.39 (s, 2H, CH2), 5.41 (brs, 2H, -NH-OH), 6.90 (d, / = 5.2 Hz, 1H, ArH), 7.32 (d, / = 8.0 Hz, 2H, ArH), 7.44 (dd, / = 8, 4.8 Hz, 1H, ArH), 7.76 (dd, / =
8.8, 1.6 Hz, 1H, ArH), 7.99 (d, / = 8 Hz, 2H, ArH), 8.05 (dt, / = 8, 2 Hz, 1H, ArH), 8.12 (d, / = 8.8 Hz, 1H, ArH), 8.31 (1H, s), 8.66 (dd, / = 4.4, 1.2, 1H, ArH), 8.78 (d, / = 4.8, 1H, ArH), 9.05 (s,lH, ArH);13C NMR (CDC13-100 MHz) ; 23.67, 34.21, 52.06, 52.92, 56.93, 109.04, 122.87, 123.76, 124.74, 126.57, 127.04, 127.93, 129.59, 134.54, 135.66, 138.34, 148.46, 149.96, 151.54, 154.46, 156.36, 156.54, 164.12 LC/MS (ESI-MS) m/z 509.2 (M+l)
General procedure for preparation of 4-[4-(5-substituted-[l,2,4] oxadiazol-2-ylmethyl)- piperazin-l-yl]-quinoline:
To a solution of Int-9 (a-f), Int-lO (a-f), Int-l 1 (a-f) and Int-l2(d-f) (1 mmol) in DMF (10 mL, 20 vol) was added 1, 8-Diazabicycloundec-7-ene (2 mmol) was added at ambient temperature. The reaction mixture was stirred at 90 °C for 6-18 h.The complete consumption of starting material was observed by TLC.The reaction mixture was cooled room temperature and diluted with ice cold water. The aqueous layer was extracted with dichloromethane (20 mL X2). The combined organic layer was washed with saturated brine solution and dried over sodium sulphate filtered and concentrated under vacuum. The crude compound was purified by column chromatography over silica gel using lto3 % methanol in dichloromethane.
4-{4-[5-(3 ,5-Dimethoxy-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-1 -yl}-7-pyridin-4-yl- quinoline( Example 1): This compound was prepared by cyclization of compound Int-9a using DBU. It was obtained as a white solid. Yield: 0.3 l3 g (65 %)
NMR (DMSO d6 400 MHz) d (ppm): 2.87 (brs, 4H, -CH2), 3.26 (brs, 4H, -CH2), 3.86 (s, 6H, -OCH3), 3.90 (s, 2H, -CH2), 6.84 (t, / = 2.4 Hz, 1H, ArH), 7.04 (d, / = 4.8 Hz, 1H, ArH), 7.23 (d, / = 2 Hz, 2H, ArH) 7.88 (dd, / = 4.4, 1.6 Hz, 2H, ArH), 7.96 (dd, / = 8.8, 2 Hz, 1H, ArH), 8.13 (d, / = 8.8 Hz, 1H, ArH), 8.36 (d, 1H, / = 1.6 Hz, ArH), 8.70 (d, / = 5.6 Hz, 2H), 8.75 (d, / = 4.8, 1H) ;13C NMR (CDCI3-IOO MHz) ; 51.92, 52.98, 55.75, 105.65, 105.90, 109.36, 121.79, 123.57, 123.85, 124.88, 125.44, 128.25, 138.53, 147.41, 149.67, 150.43, 157.70, 156.7, 161.21, 167.69, 176.03; LC/MS (ESI-MS) m/z 509.3 (M+l). Purity: 97%.
4-{4-[5-(3 ,5-Difluoro-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin- l-yl}-7 -pyridin-4-yl- quinoline (Example 2): This compound was prepared by cyclization of compound Int-9b using DBU. It was obtained as a white solid. Yield: 0.265 g (55 %)
NMR (DMSO d6 400 MHz) d (ppm): 2.88 (brs, 4H, -CH2), 3.25 (brs, 4H, -CH2), 3.92 (s, 2H),7.04 (d, 7 = 4.8 Hz, 1H, ArH), 7.70 (tt, 7 = 8.4, 2.4 Hz, 1H, ArH), 7.89-7.85 (m, 4H, ArH) 7.96 (dd, 7 = 8.8, 2 Hz, 1H, ArH), 8.13 (d, 7 = 8.8 Hz, 1H, ArH), 8.37 (d, 7 = 1.6 Hz, 1H, ArH), 8.70 (dd, 2H,7 = 4.4, 1.6 Hz, ArH), 8.75 (d, 7 = 5.2 Hz, 1H) ;13C NMR (CDC13-100 MHz) ; 51.94, 52.84, 52.97, 108.47 (t, 7 = 25 Hz), 109.34, 111.47 (q, 7 = 8.2 Hz), 121.82, 123.54,
123.93, 124.86, 126.61 (t, 7 = 10.6), 128.21, 138.67, 147.40, 149.60, 150.47, 151.61, 156.74, 161.99 (d, 7 = 12.3 Hz), 164.50 (d, 7 = 12.3 Hz), 168.04, 174.07 LC/MS (ESI-MS) m/z 485.5 (M+l). Purity: 98.57 %
3-{ 3-[4-(7 -Pyridin-4-yl-quinolin-4-yl)-piperazin-l -ylmethyl] -[ 1,2,4] oxadiazol-5-yl}-benzonitrile (Example 3):This compound was prepared by cyclization of compound Int-9c using DBU. It was obtained as a white solid. Yield: 0.337 g (70 %)
' H NMR (DMSOde 400 MHz) d (ppm): 2.79 (brs, 4H, -CH2), 3.18 (s, 2H, -CH2), 3.28 (brs, 4H, - CH2), 6.5 (brs, 2H, -NH-OH), 7.05 (d, 7 = 4.8 Hz, 1H, ArH), 7.74 (t, 7 = 8 Hz, 1H, ArH), 7.89 (dd, 7 = 4.8, 1.6 Hz, 2H, ArH) 7.98 (dd, 7 = 8.4, 1.6 Hz, 1H, ArH), 8.16 - 8.11 (m, 2H, ArH), 8.38 (dd, 7 = 4.8, 1.2, 2H, ArH) 8.71- 8.39 (m, 3 H, ArH), 8.75 (d, 1H, 7 = 4.8) ;13C NMR (DMSO de-lOO MHz) ; 52.11, 52.87, 57.46, 109.99, 112.37, 118.63, 121.99, 123.42, 124.19, 125.50, 128.04, 130.41, 131.07, 133.54, 134.43, 136.85, 137.98, 146.62, 149.80, 150.88, 152.18, 156.44, 157.01, 162.36. LC/MS (ESI-MS) m/z 474.5 (M+l). Purity: 98.85 %
4-{4-[5-(2,3-Dimethyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin- 1 -yl}-7 -pyridin-4-yl- quinolinel Ex am pie 4): This compound was prepared by cyclization of compound Int-9d using DBU. It was obtained as a Beige color solid. Yield: 0.284 g (59 %)
Figure imgf000032_0001
(ppm): 2.40 (s, 3H, -CH3), 2.61 (s, 3H, -CH3), 3.01 (t, 4H, 7 =4.4, -C¾), 3.41 (brs, 4H, -CH2), 3.98 (s, 2H, -CH2),6.9l (d, 7 = 5.2 Hz,IH, ArH), 7.25 (t, 7 = 7.6 Hz, 1H, ArH), 7.39 (d, 7 = 7.6 Hz, 1H, ArH), 7.67 (dd, 7 = 4.4, 1.6 Hz, 2H, ArH) 7.77 (dd, 7 = 8.8, 2 Hz, 1H, ArH), 7.78 (d, J = 7.6, 1 Hz, 1H, ArH), 8.13 (d, J = 8.8 Hz, 1H, ArH), 8.39 (s, 1H ArH), 8.74 (dd, J = 4.4, 1.6 Hz, 2H, ArH), 8.77 (d, 1H, 7 = 5.2) ;13C NMR (CDCb-lOO MHz) ; 17.11, 20.75, 51.99, 52.89, 52.98, 109.38, 121.80, 123.59, 123.79, 124.90 125.88, 128.25, 128.37, 133.86, 137.39, 138.49, 147.43, 149.69, 150.38, 151.72, 156.71, 167.18, 177.36 LC/MS (ESI-MS) m/z 477.4 (M+l). Purity: 99.1 %
4-[4-(5-Cyclopentyl-[J2,4]oxadiazol-3-ylmethyl)-piperazin-l-yl]-7-pyridin-4-yl-quinoline (Example 5): This compound was prepared by cyclization of compound Int-9e using DBU. It was obtained as a beige color solid. Yield: 0.278 g (58 %)
1H NMR (DMSO d6 400 MHz) d (ppm): 1.75-1.69 (2H, m, -CH2), 1.86-1.81 (4H, m, -CH2), 2.12-2.09 (m, 2H, -CH), 2.81 (brs, 4H, -CH2), 3.23 (brs, 4H, -CH2), 3.44 (quint, 1H, -CH, J = 7.6 Hz), 3.78 (s, 2H), 7.03 (d, 7 = 4.8 Hz, 1H, ArH), 7.88 (d, J = 6 Hz, 2H, ArH), 7.96 (dd, J = 8.8, 2 Hz, 1H, ArH) 8.12 (d, J = 8.8 Hz, 1H, ArH), 8.37 (d, J = 1.6 Hz, 1H, ArH), 8.70 (dd, 7 = 6 Hz, 2H, ArH), 8.74 (d, 7 = 4.8, 1H, ArH) ;13C NMR (CDC13-100 MHz) ; 25.65, 31.56, 37.12, 51.91, 52.98, 109.34, 121.82, 123.56, 123.85, 124.89, 128.22, 138.56, 147.44, 149.64, 150.42, 151.67, 156.75, 166.87, 183.85LC/MS (ESI-MS) m/z 441.5 (M+l). Purity: 99.58 %
4-{4-[5-(4-Isopropyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-l-yl}-7 -pyridin-4-yl- quinoline (Example 6): This compound was prepared by cyclization of compound Int-9f with DBU. It was obtained as an off white solid. Yield: 0.360 g (75 %)
lH NMR (CDCI3 400 MHz) d (ppm): 1.24 (d, 6H, 7 = 6.8), 2.87 (brs, 4H, -CH2), 3.00 (sept, 1H, 7 = 6.8, -CH), 3.25 (brs, 4H, -CH2), 3.89 (s, 2H, -CH2), 7.03 (d, 7 = 5.2 Hz, 1H, ArH), 7.52 (d, 7 = 8.4 Hz, 2H, ArH), 7.88 (dd, 7 = 4.4, 1.6 Hz, 2H, ArH), 7.95 (dd, 7 = 8.8, 2 Hz, 1H, ArH), 8.06 (dd, 7 = 6.4, 1.6 Hz, 2H, ArH), 8.09 (d, 7 = 8.8 Hz, 1H, ArH), 8.36 (d, 7 = 1.6, 1H, ArH), 8.69 (d, 7 = 4.4, l.2Hz, 2H, ArH), 8.74 (d, 7 = 5.2, 1H, ArH);13C NMR (CDC13-75 MHz) ; 23.64, 34.32, 51.94, 52.92, 109.32, 121.62, 121.75, 123.57, 123.79, 124.86, 127.25, 128.20, 128.35, 138.52, 147.39, 149.73, 150.49, 154.49, 156.69, 167.57, 176.15 ;LC/MS (ESI-MS) m/z 491.2 (M+l). Purity: 98.8 %
7-(2, 5-Difluoro-phenyl)-4-{4-[5-(3, 5-dimethoxy-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin- 1 -yl } -quinoline] Ex am pie 7): This compound was prepared by cyclization of compound Int-lOa with DBU. It was obtained as a white solid. Yield: 0.348 g (72 %)
NMR (DMSO d6 400 MHz) d (ppm): 2.86 (brs, 4H, -CTI2), 3.24 (brs, 4H, -Cl¾), 3.85 (s, 6H, -OCH3), 3.88 (s, 2H, -CH2), 6.83 (s, 1H, ArH), 7.025 (d, 7 = 4.8 Hz, 1H, ArH), 7.22 (d, 7 = 1.2 Hz, 2H, ArH), 7.35-7.29 (m, 1H, ArH), 7.4369 (td, 7 = 9.2, 4.8 Hz, 1H, ArH), 7.59-7.55 (m, 1H, ArH), 7.73 (d, 7 = 8.8 Hz, 1H, ArH), 8.09 (d, 7 = 8.8, 1H, ArH), 8.13 (s, 1H, ArH), 8.73 (d, 1H, 7 = 4.8, ArH); LC/MS (ESI-MS) m/z 544.7 (M+l). Purity: 99.9 % 7-(2,5-Difluoro-phenyl)-4-{4-[5-(3,5-difluoro-phenyl)-[J2,4]oxadiazol-3-ylmethyl]-piperazin-l- yl}-quinoline( Example 8):This compound was prepared by cyclization of compound Int-lOb with DBU. It was obtained as a white solid. Yield: 0.241 g (50 %)
NMR (DMSO d6 400 MHz) d (ppm): 2.87 (brs, 4H, CH2), 3.25 (brs, 4H, -CS l ). 3.92 (s, 2H, -CH2), 7.03 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.30 (m, 1H, ArH), 7.44 (td, 1H, / = 9.6, 4.8 Hz,
ArH), 7.60-7.56 (m, 1H, ArH), 7.69 (dt, / = 9.6, 2.4 Hz, 1H, ArH), 7.74 (d, / = 8.8, 1H, ArH), 7.89-7.83 (m, 2H, ArH), 8.01 (d,/= 8.2, 1H, ArH), 8.13 (s, IH,AGH), 8.73 (d, / = 4.8, 1H, ArH) ; LC/MS (ESI-MS) m/z520.6 (M+l). Purity: 98.0 %
3-(3-{4-[7-(2, 5-Difluoro-phenyl)-quinolin-4-yl] -piperazin-1 -ylmethyl}-[ 1,2,4] oxadiazol-5-yl)- benzonitrile (Example 9): This compound was prepared by cyclization of compound Int-lOc with DBU. It was obtained as a white solid. Yield: 0.361 g (75 %)
NMR (DMSOde 400 MHz) d (ppm): 2.88 (brs, 4H, -CJfe), 3.25 (brs, 4H, -CH2), 3.93 (s, 2H, - CH2), 7.04 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.30 (m, 1H, ArH), 7.44 (td, / = 9.6, 4.8 Hz, 1H,
ArH), 7.61-7.56 (m, 1H, ArH), 7.74 (d, J = 8.8 Hz, 1H, ArH), 7.86 (t, / = 7.6 Hz, 1H, ArH), 8.10 (d, / = 8.8 Hz, 1H, ArH), 8.13 (s, 1H, ArH), 8.19 (d, / = 8 Hz, 1H, ArH), 8.57 (s, 1H, ArH), 8.73 (d, / = 5.2 Hz, 1H) ; LC/MS (ESI-MS) m/z 509.6 (M+l). Purity: 99.42 %
7-(2, 5-Difluoro-phenyl)-4-{4-[5-(2, 3 -dimethyl-phenyl)-] 1,2,4] oxadiazol-3-ylmethyl] -piperazin- 1-yl] -quinoline (Example 10): This compound was prepared by cyclization of compound Int-lOd with DBU. It was obtained as a brown solid. Yield: 0.289 g (60 %)
NMR (DMSO d6 400 MHz) d (ppm): 2.36 (s, 3H, -CH3), 2.52 (s, 3H, -CH3), 2.89 (brs, 4H, - Cl-h), 3.26 (s, 4H, -CH2), 3.92 (brs, 2H, -CH2), 7.04 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.31 (m, 1H, ArH), 7.49-7.41 (m, 2H, ArH), 7.60-7.56 (m, 2H, ArH), 7.74 (d, / = 8.8 Hz, 1H, ArH), 7.79 (d, / = 7.6 Hz, ArH), 8.10 (d, / = 8.4 Hz, 1H, ArH), 8.14 (s, IH,AGH), 8.73 (lH,d, / = 4.8 Hz, ArH) ; LC/MS (ESI-MS) m/z 512.2 (M+l). Purity: 97.04 %
4-[4-(5-Cyclopentyl-[ 1,2,4] oxadiazol-3-ylmethyl)-piperazin-l -yl]-7-(2, 5-difluoro-phenyl)- quinoline (Example- 11): This compound was prepared by cyclization of compound Int-lOe with DBU. It was obtained as a Pale yellow solid. Yield: 0.33 g (69 %)
Figure imgf000034_0001
400 MHz) d (ppm): 1.75-1.65 (m, 4H, -CH2) 1.86-1.81 (m, 4H, -CH2), 2.12-2.07 (m, 2H, -CH2), 2.81 (brs, 4H, -Cl¾), 3.23 (brs, 4H, -CH2), 3.44 (quint, 1H, / = 7.6 Hz, -CH), 3.77 (s, 2H, -CH2), 7.028 (d, / = 5.2 Hz, 1H, ArH), 7.36-7.33 (m, 1H, ArH), 7.44 (td, / = 9.2, 2 Hz, 1H, ArH), 7.61-7.56 (m, 1H, ArH), 7.74 (dt, / = 8.8, 1.6 Hz, 1H, ArH), 8.09 (d, 1H, / = 8.8 Hz, ArH), 8.14 (s, 1H, ArH), 8.73 (d, 1H, 7 = 4.8, ArH) ; LC/MS (ESI-MS) m/z476.5 (M+l). Purity: 98.47 %
7-(2,5-Difluoro-phenyl )-4- { 4- j 5 -(4-isopropyl -phenyl )-j 1 ,2,4 joxadiaz.ol- 3 -ylmethy l j -piperazin- 1 - yl}-quinoline (Example 12): This compound was prepared by cyclization of compound lOf with DBU. It was obtained as a green solid. Yield: 0.279 g (58 %)
lH NMR (DMSOde 400 MHz) d (ppm): 1.24 (d, 6H, 7 = 6.8 Hz, ArH), 2.87 (brs, 4H, -CH2), 3.01 (sept, 1H, 7 = 13.6, 6.8 Hz, -CH), 3.25 (s, 4H, -CH2), 3.89 (s, 2H, -CH2), 7.03 (d, J = 4.8 Hz, 1H, ArH), 7.35-7.31 (m, 1H, ArH), 7.44 (td, 7 = 9.6, 4.4 Hz, 1H, ArH), 7.52 (d, 2H,7 = 8, ArH), 7.58- 7.57 (m, 1H, ArH), 7.73 (d, 7 = 8.4 Hz, 1H, ArH), 8.1-8.05 (m, 4H, ArH), 8.73 (d, 1H, 7 = 4.8, ArH); LC/MS (ESI-MS) m/z 526.8(M+l). Purity: 98.08 %
7-Chloro-4-{4-[5-(3,5-dimethoxy-phenyl)-[J2,4]oxadiazol-3-ylmethyl]-piperazin-l-yl}- quinoline (Example l3):This compound was prepared by cyclization of compound Int-l la with DBU. It was obtained as a pale brown solid. Yield: 0.361 g (75 %)
lH NMR (DMSO-de 400 MHz) d (ppm): 2.84 (brs, 4H, -CH2), 3.21 (brs, 4H, -CH2), , 3.85 (s, 6H, -OCHs), 3.88 (s, 2H, -CH2), 6.83 (s, 1H, ArH), 7.01 (d, J= 4.8 Hz, 1H, ArH), 7.22 (d, 7=2 Hz, 2H, ArH) 7.54 (dd, J= 8.8, l.6Hz, 1H, ArH), 7.97 (d, J = 1.6 Hz, 1H, ArH), 8.02 (d, 7=9.2 Hz, 1H, ArH), 8.70 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDC13-100 MHz) 51.96, 52.95, 55.75, 105.65, 105.89, 109.06, 121.88, 125.19, 125.46, 126.18, 128.89, 134.90, 150.11, 151.94, 156.84, 161.21, 167.69, 176.02; LC/MS (ESI-MS) m/z 466.6 (M+l). Purity: 99.43 %
7-Chloro-4-{4-[ 5-( 3,5-difluoro-phenyl)-[ 1,2,4 ]oxadiazol-3-ylmethyl] -piperazin- 1 -yl}- quinoline (Example l4):This compound was prepared by cyclization of compound Int-l lb using DBU. It was obtained as a white solid. Yield: 0.365 g (76 %)
NMR (DMSO-de 400 MHz) d (ppm): 2.84 (brs, 4H, -C¾), 3.21 (brs, 4H, -CH2), 3.90 (s, 2H, -CH2), 7.01 (d, 7= 5.2 Hz, 1H, ArH), 7.54 (dd, 7=8.8, 2 Hz, 1H, ArH) 7.70 (tt, 7=9.2, 2.4 Hz, 1H, ArH), 7.85 (d, 7 = 5.2 Hz, 2H, ArH), 7.97 (d, 7=2 Hz, 1H, ArH), 8.02 (d, 7=9.2 Hz, 1H, ArH), 8.70 (d, 7=5.2 Hz, 1H, ArH) ;13C NMR (CDCI3-IOO MHz) 51.96, 52.81, 52.93, 108.43 (t, 7=25 Hz), 109.08, 111.45 (q, J=l2, 8 Hz), 121.88, 125.14, 126.22, 126.61 (t, 7=11), 128.90, 134.94, 150.11, 151.94, 156.81, 161.97 (d, J=l2), 164.47 (d, J=i2 , 168.04, 174.03; LC/MS (ESI-MS) m/z 442.7 (M+l). Purity: 99.51 % 3-{3-[4-(7-Chloro-quinolin-4-yl)-piperazin-l-ylmethyl]-[ 1,2,4] oxadiazol-5-yl}-benzonitrile (Example 15): This compound was prepared by cyclization of compound Int-l lc using DBU. It was obtained as a pale brown solid. Yield: 0.351 g (73 %)
NMR (DMSO-d6400 MHz) d (ppm): 2.86 (brs, 4H, -€¾), 3.21 (brs, 4H, -CH2), 3.91 (s, 2H, -CH2), 7.02 (d, 7= 5.2 Hz, 1H, ArH), 7.55 (dd, 1H, 7= 8, 2 Hz, ArH) 7.87 (t, 7= 8 Hz, 1H, ArH), 7.97 (d, 7 =2.4 Hz, 1H, ArH), 8.02 (d, 7=8.8 Hz, 1H, ArH), 8.19 (dt, lH,7=8, 1.2 Hz, ArH), 8.44 (dt, 7=8, 1.2 Hz, 1H), 8.56 (t, 7= 1.6, 1H), 8.70 (d, 7=5.2, 1H) ;13C NMR (CDC13-75 MHz) 51.78, 52.62, 52.74, 108.9, 113.66, 117.24, 121.67, 125.01, 125.17, 126.00, 128.64, 130.08, 131.50, 131.83, 134.71, 135.68, 149.86, 151.73, 156.63, 167.88, 173.80; LC/MS (ESI-MS) m/z 431.5 (M+l). Purity: 98.46 %
7-Chloro-4-{4-[5-(2,3-dimethyl-phenyl)-[J2,4]oxadiazol-3-ylmethyl]-piperazin-l-yl}-quinoline (Example 16): This compound was prepared by cyclization of compound Int-l ld using DBU. It was obtained as a yellow solid. Yield: 0.327 g (68 %)
NMR (DMSOde-400 MHz) d (ppm): 2.36 (s, 3H, -CH3), 2.53 (s, 3H, -CH3) 2.87 (brs, 4H, - CEE), 3.22 (brs, 4H, -CH2), 3.92 (s, 2H, -CH2), 7.02 (d, 7= 4.8 Hz, 1H, ArH), 7.32 (t, 1H, 7= 8 Hz, ArH), 7.48 (d, 7= 7.6, 1H, ArH), 7.55 (dd, 7 = 8.8, 2.4 Hz, 1H, ArH), 7.79 (d, 7=7.6, 1H, ArH), 7.97 (d, 7=2.4, 1H, ArH), 8.02 (d, 7= 8.8 Hz, 1H), 8.70 (d, 7=5.2, 1H) ;13C NMR (CDC13- 100 MHz): 17.12, 20.77, 52.05, 52.86, 52.98, 109.06, 121.90, 123.83, 125.22, 125.88, 126.18, 128.39, 128.49, 133.85, 134.91, 137.40, 138.49, 150.11, 151.93, 156.89, 167.20, 177.56; LC/MS (ESI-MS) m/z 434.7 (M+l). Purity: 96.88 %
7-Chloro-4- [4-(5-cyclopentyl-[ 1,2, 4] oxadiazol-3-ylmethyl)-piperazin-l-yl] -quinoline (Example 17): This compound was prepared by cyclization of compound Int-l le using DBU. It was obtained as a brown gummy solid. Yield: 0.336 g (70 %)
Figure imgf000036_0001
(ppm): 1.85-1.74 (m, 6H, -CH2), 2.12-2.06 (m, 2H, -CH2), 2.79 (brs, 4H, -CH2), 3.19 (brs, 4H, -CH2), 3.43 (pent, 1H, -CH), 3.76 (s, 2H, -CH2) 7.01 (d, 7= 4.8 Hz, 1H, ArH), 7.55 (dd, 7=9.2, 2.4 Hz, 1H, ArH), 7.97 (d, 7=2.4 Hz, 1H, ArH), 8.01 (d, 7=9.2 Hz, 1H, ArH), 8.70 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDCI3- 75 MHz): 25.68, 31.60, 37.17, 52.00, 52.98, 109.08, 121.94, 125.23, 126.19, 128.93, 134.94, 150.18, 151.97, 156.91, 166.93, 183.84; LC/MS (ESI-MS) m/z 398.6 (M+l). Purity: 98.32 % 7-Chloro-4-{4-[5-(4-isopropyl-phenyl)-[J2,4]oxadiazol-3-ylmethyl]-piperazin-l-yl}-quinoline (Example 18): This compound was prepared by cyclization of compound Int-l lf using DBU. It was obtained as a brownsolid. Yield: 0.360 g (75 %)
NMR (DMSO d6 -400 MHz) d (ppm): 1.24 (d, 6H, 7=6.8, -CH3), 2.84 (brs, 4H, -CH2), 3.01 (sept, 1H, -CH), 3.21 (brs, 4H, -CH2), 3.87 (s, 2H, -CH2), 7.01 (d, 7= 5.2 Hz, 1H, ArH), 7.55- 7.50 (m, 3H, ArH), 7.97 (d, 7=2.4 Hz, 1H, ArH), 8.01 (d, 7 =8.8 Hz, 1H, ArH), 8.05 (dd, 7=6.8, 2 Hz, 2H, ArH), 8.71 (d, 7=4.8 Hz, 1H, ArH) ;13C NMR (CDCI3- 75 MHz): 23.50, 34.17, 51.81, 52.72, 52.77, 108.87, 121.48, 121.72, 125.05, 125.98, 127.10, 128.68, 134.73, 149.94, 151.73, 154.31, 156.71, 167.41, 175.98; LC/MS (ESI-MS) m/z 448.6 (M+l). Purity: 99.72 %
4-{4-[5-(2,3-Dimethyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-1 -yl}-7 -pyridin-3-yl- quinoline (Example 23): This compound was prepared by cyclization of compound Int-l2d using DBU. It was obtained as a beige color solid. Yield: 0.284 g (59 %)
lH NMR (CDCI3 400 MHz) d (ppm): 2.35 (s, 3H, -CH3), 2.53 (s, 3H, -CH3), 2.89 (brs, 4H, - CH2), 3.25 (brs, 4H, -CH2), 3.92 (s, 2H, -CH2), 7.01 (d, 7 = 5.2 Hz, 1H, ArH), 7.32 (t, 7 = 7.6 Hz, 1H, ArH), 7.48 (d, 7 = 7.2 Hz, 1H, ArH) 7.54 (dd, 7 = 7.6, 4.8 Hz, 1H, ArH), 7.80 (d, J = 7.6, 1 Hz, IH,AGH), 7.89 (dd, J = 8.4, 1.6 Hz, 1H, ArH), 8.11 (d,7 = 8.4, IH,AGH), 8.25 (dt, J = 8.4, 1.6 Hz, 1H, ArH), 8.28 (d, 1H, 7 = 1.6 Hz, ArH), 8.63 (dd, 1H, 7 = 4.8, 1.2 Hz, ArH), 8.73 (1H, d, 7 = 4.8 Hz, ArH), 9.05 (d, 7 = 2 Hz, 1H) ;13C NMR (CDCb-lOO MHz) ; 17.00, 20.63, 51.89,
52.79, 52.87, 108.99, 122.83, 123.65, 123.68, 124.11, 124.72, 125.75, 127.85, 128.25,
133.72, 134.45, 135.60, 137.26, 138.13, 138.35, 148.36, 148.82, 149.69, 151.51, 156.59, 167.09, 177.19. LC/MS (ESI-MS) m/z 477.' 7 (M+l). Purity: 97.6 %
4-[4-(5-Cyclopentyl-[J2,4]oxadiazol-3-ylmethyl)-piperazin-l-yl]-7-pyridin-3-yl-quinoline (Example 24): This compound was prepared by cyclization of compound Int-l2e with DBU. It was obtained as a beige color solid. Yield: 0.278 g (58 %)
Figure imgf000037_0001
(ppm): 1.75-1.65 (m, 4H), 1.86-1.81 (m, 2H), 2.l2-2.07(m, 2H), 2.81 (brs, 4H, -CH?.), 3.23 (brs, 4H, -CH2), 3.44 (quint, 7 = 8, 1H, -CH), 3.78 (s, 2H, -CH2), 7.01 (d, 7 = 4.8 Hz, 1H, ArH), 7.55 (dd, 7 = 8, 4.8 Hz, 1H, ArH), 7.92 (dd, 7 = 8.8, 2 Hz, 1H, ArH) 8.11 (d, 7 = 8.8 Hz, 1H, ArH), 8.26 (dt, 7 = 8, 1.6 Hz, 1H, ArH), 8.64 (dd, 7 = 4.8, 1.6 Hz, 1H, ArH), 8.73 (d, 7 = 5.2, 1H, ArH), 9.05 (s, 1H) ;13C NMR (CDCI3-IOO MHz) ;25.6l, 31.52, 37.07, 51.87, 52.92, 52.96, 109.07, 122.91, 123.75, 124.22, 124.78, 127.92, 134.60, 135.72, 138.25, 148.42, 148.88, 149.73, 151.58, 156.70, 166.84, 183.79LC/MS (ESI-MS) m/z 441.6 (M+l). Purity: 99.62 %
4-{4-[5-(4-Isopropyl-phenyl)-[ 1,2,4] oxadiazol-3-ylmethyl] -piperazin-l-yl}-7 -pyridin-3-yl- quinoline (Example 25): This compound was prepared by cyclization of compound Int-l2f with DBU. It was obtained as an off white solid. Yield: 0.360 g (75 %)
lH NMR (DMSO 400 MHz) d (ppm): 1.23 (d, 6H, / = 6.8), 2.86 (brs, 4H, -CH2), 2.99 (sept,
1H, J = 6.8, -CH), 3.24 (brs, 4H, -CH2), 3.88 (s, 2H, -CH2), 7.00 (d, / = 5.2 Hz, 1H, ArH), 7.50 (d, / = 8.4 Hz, 2H, ArH), 7.54 (dd, / = 7.6, 4.8 Hz, 1H, ArH), 7.90 (dd, / = 8.8, 1.6 Hz, 1H, ArH), 8.05 (d, / = 8.4 Hz, 2H, ArH), 8.1 (d, / = 8.8 Hz, 1H, ArH), 8.24 (dt, / = 8, 2 Hz, 1H, ArH), 8.27 (d, / = 1.6 Hz, 1H, ArH), 8.63 (dd, / = 4.4, 1.2 Hz, 1H, ArH), 8.72 (d, 1H, / = 5.2), 9.05 (s, lH);13C NMR (CDC13-75 MHz) ; 14.16, 34.33, 51.94, 52.95, 109.09, 121.60, 122.93, 123.77, 124.26, 124.83, 127.28, 127.92, 128.36, 134.60, 135.74, 138.31, 148.48, 148.93, 149.73, 151.57, 154.50, 156.75, 167.58, 176.16LC/MS (ESI-MS) m/z 491.7 (M+l). Purity: 99.8 % Compounds in examples 19 to 22 and 49 to 76 were synthesized employing general procedures used in the synthesis of examples 13-18 using the appropriate starting materials. Compounds in examples 24-41 were synthesized employing general procedures used in the synthesis of examples 23-25.
Examples
Example 1. MIC Assay protocol (turbidometric)
The test compounds were dissolved in DMSO, double-diluted in a 10-concentration dose response (10-DR) and the culture was added at an inoculum of 3-7X105 cfu/ml. The QC includes: media controls, growth controls, and the reference drug inhibitors (Rifampicin and Isoniazid). The assay plates were incubated at 37 °C for 15 days. The growth appears as turbidity or as a deposit of cells at the bottom of the well. The results were enumerated and a
turbidometric reading was noted. The first dilution that shows growth inhibition, was recorded as MIC (Minimum Inhibitory Concentration) and are provided in Table 2 against Mtb strains and Table 3 in other bacterial infections. Figure 1 provides the killing kinetics of Example 25.
Table 2. Anti-Mtb activity of against H37Rv Mtb stains
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000039_0003
Figure imgf000039_0002
Table 3. Antimicrobial activity of against ESKAPE panel of bacterial stains
Figure imgf000040_0001
Example 2. In Vitro Metabolic Stability in human liver microsomes
Metabolic stability was carried out using human liver microsomes. The final composition of the assay included 1 mM of test items and control item (Diclofenac or Imipramine) prepared from DMSO stock, so that the final concentration of DMSO was 0.1 %, microsomal protein 0.125 mg/mL and cofactors (5.0 mM G-6-P, 0.06 U/mLG-6-PDH, 2.0 mM MgCk, 1.0 mM NADP+). Test item/ Control items were incubated with human liver microsomes with cofactors and without cofactors. The reaction mixture (100 pL) was removed at specified time period and the reaction was stopped by addition of stop solution. The samples were extracted in presence of internal standard and were analyzed using LC-MS/MS. The percent of the test/control item remaining after specified incubation period was calculated with respect to the peak area ratio at time 0 min. Results are presented in Table 4.
Figure imgf000040_0002
Figure imgf000041_0002
Example 3. Oral PK study: About 15 mg of compound was weighed and transferred to graduated tube. Exactly 250 m L of N,NDimethylacetamide (5 % v/v) was added, vortex mixed thoroughly and sonicated till test item gets completely dissolved. Then 250 pF of Tween 80 (5 % v/v) was added and vortex mixed, then 250 pF of propylene glycol (5 % v/v) was added and vortex mixed, finally the sterile water for injection was added in small increments and vortex mixed thoroughly. The final volume was made up to 5 mL with sterile water for injection (85 % v/v) to obtain the final strength of 3 mg/mL. The pH of the formulation was measured and was found to be 6.01. Formulation was freshly prepared before administration to the animals.
Dose Administration: Adult healthy male BALB/c mice aged 8-10 weeks were used for experimentation after a minimum 3 days of acclimation. Fasted animals were administered with test compound in recommended vehicle (5 % (v/v) N,N-Dimethylacetamide + 5 % (v/v) Tween 80 + 5 % (v/v) propylene glycol + 85 % (v/v) sterile water for injection) by oral route with a dose of 30 mg/kg body weight and at dose volume of 10 mF/kg body weight. Under mild isoflurane anesthesia, blood specimens were collected into pre-labeled tubes containing anticoagulant (K2EDTA - 2 mg/mF blood) during the next 24 hours of post-dose. Collected blood specimens were centrifuged at 4000 rpm, 4 °C for 10 minutes and plasma was separated and stored at -80 °C until analysis.
Table 5: Single Dose Oral Pharmacokinetics Studies in Male BALB/c Mice
Figure imgf000041_0001
Example 4. Animal Efficacy Studies:
Animals: All the experimental protocols involving animals and the use of animals were approved by the Institutional Animal Ethics Committee, registered with the Government of India. BALB/c mice used for these studies are aged between 6 to 8 weeks with an average body weight of 20-30grams. Animals were housed in Individually ventilated cages (IVC’s) in BSL3 conditions. They were randomly assigned to cages and allowed to acclimatize for 1 week prior to experiments. Feed and water weregiven ad libitum.
Dose response studies in the chronic infection model: (Figure 2) Mice were infected with 100 CFU of M. tuberculosis H37Rv per mouse via inhalation in an aerosol infection chamber. Treatment was initiated after 4 weeks post infection. Mice were treated PO by oral gavage or any other suitable route, with compound alone and in combination with first line TB drugs (HREZ) in appropriate formulation with once daily dosing for 4 weeks. Rifampicin 10 mg/kg wasused as reference drug control.
For the enumeration of lung CFU at the onset (early control) and 48 h after the completion of treatment, groups of mice were euthanized by exposure to C02. Infected lungs were aseptically removed and homogenized in a final volume of 3.0 ml with tissue grinders (W012576;
Wheaton). Each suspension was serially diluted in 10-fold steps, and at least three dilutions were plated on Middlebrook 7H11 agar supplemented with 10% albumin-dextrose catalase. Plates were incubated at 37°C with 5% C02 for 3 weeks. Blood samples (6-8 time points) were be collected during 2nd or 4th weeks post-onset of treatment at steady state if PK data need to be generated in parallel in infected mice.
Dose response studies in the Acute infection model: (Figure 2) Mice were infected with 104 °CFU of M. tuberculosis H37Rv per mouse via the inhalation route in an aerosol infection chamber as described earlier, and treatment initiated after 3 days of infection while bacteria ai the lungs are in a logarithmic phase. For the enumeration of lung CFU at the onset (early control) and 48 h after the completion of treatment, groups of mice were euthanized by exposure to C02. Infected lungs were aseptically removed and homogenized in a final volume of 3.0 ml with tissue grinders. Each suspension was serially diluted in 10-fold steps, and at least three dilutions were plated on Middlebrook 7H11 agar supplemented with 10% albumin-dextrose catalase. Plates were incubated at 37°C with 5% C02 for 3 weeks. For dose-responses studies in Acute infection model, test compound was administered from day 3 by oral gavage or any other suitable route, 7 days a week, for a period of 4 weeks. Isoniazid was used as a positive control at a dose of 30mg/kg orally once daily. Blood samples were collected during 2nd or 4th weeks post-onset of treatment if PK need to be generated in parallel in infected mice.

Claims

Claims We Claim:
1. A compound of formula (I):
Figure imgf000043_0001
Wherein, Ri is selected from hydrogen, fluorine, chlorine, bromine, Iodine optionally substituted C1-C10 alkyl, optionally substituted C1-C10 alkoxyl, optionally substituted phenyl, optionally substituted 2-pyridyl, optionally substituted 3-pyridyl, optionally substituted 4-pyridyl,-OH, -OCF3, -CHF2, -CH(F)CH3, -OCH2CF3, -N(CH3)2, -CN;
R2 is selected from hydrogen, optionally substituted C1-C10 alkyl, optionally substituted Cl- C10 cycloalkyl, optionally substituted C1-C10 alkoxyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted 2-pyridyl, optionally substituted 3- pyridyl, optionally substituted 4-pyridyl, -CHF2, -CH(F)CH3, -OCH2CF3, or their pharmaceutically acceptable salts
2. The compound as claimed in claim 1, wherein the said Rl is selected from the group consisting of
Figure imgf000043_0002
3. The compound as claimed in claim 1, wherein the said R2 is selected from the group consisting of
Figure imgf000044_0001
4. The compound of claim 1 , wherein the compound is selected from
5-(3,5-dimethoxyphenyl)-3-((4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-l-yl)methyl)- l,2,4-oxadiazole,
5-(3,5-difluorophenyl)-3-((4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-(3-((4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5- yl)benzonitrile,
5-(2,3-dimethylphenyl)-3-((4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-cyclopentyl-3-((4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole, 3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(4-isopropylphenyl)- l,2,4-oxadiazole,
3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(3,5- dimethoxyphenyl)- 1 ,2,4-oxadiazole,
5-(3,5-difluorophenyl)-3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)- l,2,4-oxadiazole,
3-(3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5- yl)benzonitrile,
3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(2,3- dimethylphenyl)- 1 ,2,4-oxadiazole,
5-cyclopentyl-3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-((4-(7-(2,5-difluorophenyl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(4-isopropylphenyl)- l,2,4-oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin- l-yl)methyl)-5-(3,5-dimethoxyphenyl)- 1,2,4- oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin- l-yl)methyl)-5-(3,5-difluorophenyl)- 1,2,4- oxadiazole,
3-(3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)benzonitrile,
3-((4-(7-chloroquinolin-4-yl)piperazin- l-yl)methyl)-5-(2,3-dimethylphenyl)- 1,2,4- oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-5-cyclopentyl-l,2,4-oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin- l-yl)methyl)-5-(4-isopropylphenyl)- 1,2,4- oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-5-(m-tolyl)-l,2,4-oxadiazole, 3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-5-(pyridin-4-yl)-l,2,4-oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-5-(3-(trifluoromethyl)phenyl)-l,2,4- oxadiazole,
3-((4-(7-chloroquinolin-4-yl)piperazin-l-yl)methyl)-5-(pyridin-3-yl)-l,2,4-oxadiazole,
5-(2,3-dimethylphenyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-cyclopentyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-(4-isopropylphenyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(m-tolyl)-l,2,4-oxadiazole,
5-(3,5-dimethoxyphenyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- l,2,4-oxadiazole,
5-(4-methoxyphenyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(pyridin-4-yl)- 1,2,4- oxadiazole,
5-(l-methyl-lH-pyrrol-2-yl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- l,2,4-oxadiazole,
5-(pyridin-3-yl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-pentyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(methoxymethyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(tetrahydro-2H-pyran-4-yl)- l,2,4-oxadiazole,
5-methyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-phenyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-isopropyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(piperidin-4-yl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-cyclohexyl-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
5-(3-chlorophenyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-5-(3-(trifluoromethyl)phenyl)- l,2,4-oxadiazole,
5-(4-isopropylphenyl)-3-((4-(7-(2-methoxyethoxy)quinolin-4-yl)piperazin-l-yl)methyl)- l,2,4-oxadiazole,
5-(4-isopropylphenyl)-3-((4-(7-methoxyquinolin-4-yl)piperazin- l-yl)methyl)- 1,2,4- oxadiazole,
5-(4-isopropylphenyl)-3-((4-(7 -phenoxyquinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4- oxadiazole,
5-(3-chlorophenyl)-3-((4-(7-phenoxyquinolin-4-yl)piperazin-l-yl)methyl)- 1,2,4- oxadiazole,
4-(4-(4-((5-(4-isopropylphenyl)- 1 ,2,4-oxadiazol-3-yl)methyl)piperazin- 1 -yl)quinolin-7- yl)morpholine,
4-(4-(4-((5-(m-tolyl)-l,2,4-oxadiazol-3-yl)methyl)piperazin-l-yl)quinolin-7- yl)morpholine,
4-(4-(4-((5-(3-chlorophenyl)-l,2,4-oxadiazol-3-yl)methyl)piperazin-l-yl)quinolin-7- yl)morpholine,
5-(4-isopropylphenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(pyridin-3-yl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(3,5-dimethoxyphenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(4-methoxyphenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-5-(m-tolyl)-l,2,4-oxadiazole,
5-(methoxymethyl)-3-((4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4- oxadiazole,
5-( 1 -methyl- 1 H-pyrrol-2-yl)-3-((4-(quinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4- oxadiazole,
3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-5-(3-(trifluoromethyl)phenyl)- 1,2,4- oxadiazole,
5-pentyl-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-5-(p-tolyl)-l,2,4-oxadiazole,
5-phenyl-3-((4-(quinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4-oxadiazole,
5-(2,3-dimethylphenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-cyclopentyl-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(pyrrolidin-2-yl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole, methyl 4-(3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)benzoate,
(4-(3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)phenyl)methanol,
N-(4-(3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)phenyl)acetamide,
5-(4-chlorophenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
5-(lH-pyrazol-3-yl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole, 4-(3-((4-(quinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4-oxadiazol-5-yl)benzoic acid,
5 -methyl-3 -((4-(quinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4-oxadiazole,
5-(pyrimidin-4-yl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
4-(3-((4-(quinolin-4-yl)piperazin- 1 -yl)methyl)- 1 ,2,4-oxadiazol-5-yl)phenol,
5-(4-butoxyphenyl)-3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazole,
4-((3-((4-(quinolin-4-yl)piperazin-l-yl)methyl)-l,2,4-oxadiazol-5-yl)methyl)benzonitrile,
3-((4-(7-fluoroquinolin-4-yl)piperazin-l-yl)methyl)-5-(4-isopropylphenyl)-l,2,4- oxadiazole,
3-((4-(7-fluoroquinolin-4-yl)piperazin-l-yl)methyl)-5-(pyridin-3-yl)-l,2,4-oxadiazole and 3-((4-(7-fluoroquinolin-4-yl)piperazin-l-yl)methyl)-5-pentyl-l,2,4-oxadiazole, or their pharmaceutically acceptable salt.
5. The pharmaceutical composition comprising a compound of claim 1 or 4, or their pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent.
6. The compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, for use in the treatment of tuberculosis and other Mycobacterial infections.
7. The compound of claim 1 or 4, for use in the manufacture of a medicament for the treatment of tuberculosis and other Mycobacterial infections.
8. A method of treating tuberculosis andother Mycobacterial infections comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or 4, or their pharmaceutically acceptable salt.
9. A pharmaceutical composition comprising a compound of claim 1 or 4 or their pharmaceutically acceptable salt, for use in the treatment of tuberculosis and other Mycobacterial infections.
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