WO2021260722A1 - Design, synthesis of novel oxyindole inhibitors of denv rna dependent rna polymerase - Google Patents

Design, synthesis of novel oxyindole inhibitors of denv rna dependent rna polymerase Download PDF

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WO2021260722A1
WO2021260722A1 PCT/IN2021/050596 IN2021050596W WO2021260722A1 WO 2021260722 A1 WO2021260722 A1 WO 2021260722A1 IN 2021050596 W IN2021050596 W IN 2021050596W WO 2021260722 A1 WO2021260722 A1 WO 2021260722A1
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sulfonamide
ylmethylene
thiazol
oxo
indoline
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PCT/IN2021/050596
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French (fr)
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Rambabu GUNDLA
Shailendra ASTHANA
Sankar BHATTACHARYYA
Venkatanarayana Chowdary MADDIPATI
Lovika MITTAL
Jaskaran KAUR
Yogita RAWAT
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Translational Health Science And Technology Institute
Gandhi Institute Of Technology And Management
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Publication of WO2021260722A1 publication Critical patent/WO2021260722A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention pertains to the field of pharmaceuticals, particularly to novel Oxyindole compounds, their process of synthesis, compositions comprising the said compounds and use of the compounds for inhibition of DENV RNA-dependent RNA polymerase (RdRp).
  • DF Dengue fever
  • DHF Dengue hemorrhagic fever
  • I, II, III and IV increasingly hazardous grades
  • DSS Dengue shock syndrome
  • peripheral blood contains moderate to high level of infectious DENV, and a greater probability of developing DHF and DSS is associated with higher virus titer at this stage.
  • naive mosquitoes feed on the blood of individuals with high viral load, these get infected leading to further spread of the virus.
  • DENV is endemic to more than 100 countries and is estimated to cause close to 400 million infections each year, causing widespread hospitalization and death among children and the elderly in Latin as well as Asian countries.
  • DENV belongs to the group of Flaviviruses and the global DENV population can be grouped into either of four distinct serological groups (termed serotype DEN-1, DEN-2, DEN-3 and DEN-4) all of which are capable of causing severe illness. Therefore, an effective drug should be equally capable of inhibiting all four serotypes.
  • the viral non-structural protein 5 (NS5) is catalyzes replication of the RNA genome and is a suitable target for anti-viral drug design.
  • RNA-dependent RNA polymerases polymerization by Dengue virus RdRp is prone to high rate of error in incorporation of nucleotides, which generates diversity in the progeny viruses.
  • a random error can be positively selected for subsequent propagation if it provides resistance to a drug that is being used to inhibit the viral multiplication. Once the drug develops resistance, it is not possible to use this drug for resistance.
  • the RdRp domain of dengue virus is similar to that found in other such enzymes, containing 3 major sub-domains namely, thumb, palm and fingers.
  • the palm sub-domain houses the active site.
  • RdRp inhibition can be achieved using either nucleoside/nucleotide inhibitor (NI) drugs which mimic ribonucleotide monomers and target the active site or non- nucleoside inhibitors (NNI) drugs which bind to allosteric sites on the protein and prohibit enzyme function.
  • NI nucleoside/nucleotide inhibitor
  • NNI non- nucleoside inhibitors
  • An NI hinders polymerization through either chain termination or by steric hindrance to incorporation of endogenous ribonucleotides.
  • NNIs on the other hand are designed to interact with allosteric sites on the enzyme and prevent enzyme activity by steric interference in structural movements.
  • DENV RNA-dependent RNA polymerase is an enzyme that utilizes RNA as a template to polymerize a complementary RNA. This polymerase is different from other types of polymerases like DNA-dependent RNA polymerases, DNA-dependent DNA polymerases and RNA-dependent DNA polymerases and can be a suitable target for inhibition of DENV.. However, there are no effective inhibitors of DENV RNA-dependent RNA polymerase.
  • An object of the invention is to provide compounds for inhibition of DENV RNA dependent and RNA polymerase, process of synthesis of the compounds, compositions comprising the said compounds and use of the compounds and treatment of dengue comprising administration of the compounds of the present invention.
  • Figure 1 depicts the structural architecture of Dengue RdRp and its Binding site:
  • Panel A Schematic Ribbon diagram of Dengue virus (serotype 3, PDB-ID 5F3T) RNA-dependent RNA polymerase (RdRp) showing different domains (thumb, finger, palm, active site etc.) that are important for catalysis.
  • Panel B Ribbon diagram of RdRp showing the possible binding site of compound 1015.
  • Panel C Schematic interaction diagram of ligands into the binding site indicating the amino acids potentially interacting with functional groups on 1038 (1), 1039 (2) and UNK-586 (3) from the most stable molecular dynamics simulation pose.
  • Figure 2 depicts the stability of the complex of Compound 1039 of the present invention throughout 300ns through molecular dynamics simulations confirming the identified I- pocket through root mean square deviation (RMSD) analysis (left panel) and covariance analysis (right panel).
  • RMSD root mean square deviation
  • Figure 3 depicts the method for ex vivo screening of inhibitors of Dengue virus replication in K562 cells.
  • Panel A Schematic representation of experiments to screen for experimental compounds that can inhibit virus replication
  • Panel B Detection of intracellular Dengue virus antigen by immunofluorescence. K562 cells either mock infected or Dengue virus infected were fixed, permeabilized and immune stained using anti-Dengue primary antibody and Alexa-488 conjugated secondary antibody. The number of Dengue antigen positive cells was quantified by flow cytometry
  • Panel C Dynamic range of template detection in real time PCR.
  • Figure 4 depicts the efficacy of active molecules in inhibition of DENV2 growth.
  • Panel A K562 cells either mock-infected of DENV2-infected were incubated in growth media supplemented with either 0.1% DMSO (vehicle) or 20mg/ml of the indicated compounds for 48 hours post-infection. At the end of incubation, the cells were fixed using paraformaldehyde, permeabilized and immune-stained using anti-Flavivirus primary antibody (4G2) followed by anti-mouse Alexa-488 conjugated secondary antibody. The percentage of cells positive for viral antigen was quantified in a flow cytometer and plotted. The error bars represent standard deviation.
  • Panel B K562 cells either mock-infected of DENV2-infected were incubated in growth media supplemented with either 0.1% DMSO (vehicle) or 20mg/ml of the indicated compounds for 48 hours post-infection. At the end of incubation, the cells were fixed using paraformaldehyde,
  • FIG. 5 depicts the inhibition of Dengue vims production from infected cells by.
  • Panel A K562 cells infected with Dengue vims 2 were incubated in growth media supplemented with either appropriate concentration of DMSO or 10 ug/ml of either 1038 or compound 1039.
  • Panel B K562 cells infected with Dengue vims 2 were incubated in growth media supplemented with either appropriate concentration of DMSO or 10 ug/ml of either 1038 or compound 1039.
  • Figure 6 depicts the toxicity of compound 1039 in K562 and primary cells.
  • Panel A The total ATP content as a direct correlate of relative luciferase activity was quantified in increasing number of exponentially growing K562 cells. The coefficient of correlation is shown as R 2 .
  • Panel B Peripheral blood mononuclear cells were isolated and incubated in growth media. At 24 or 72 hours post isolation the total ATP content in increasing number of PBMCs was quantified. The coefficient of correlation is shown as R 2 .
  • Panel C Panel C.
  • K562 cells were incubated at a density of 0.3xl0 6 cells/ml in growth media supplemented with either increasing quantity of DMSO (in % corresponding to compound 1039 solution in DMSO) or compoundl039 or 200mg/ml of Etoposide. After 48 hours of incubation 5x 10 3 cells from the culture was used for analysis of ATP content. A known cytotoxic agent, Etoposide was used as positive control. Panel D. PBMCs were incubated in growth media either un-supplemented or supplemented with indicated concentration of DMSO (in % corresponding to compound 1039 solution in DMSO) or compound 1039 or Etoposide. After 24 or 48 hours of incubation the total ATP content was estimated as direct correlate of relative luciferase activity.
  • Figure 7 depicts the pan-serotype efficacy of 1038 or 1039 compared to NITD.
  • K562 cells infected with either DENV 1 or DENV2 or DENV3 or DENV4 was incubated for 48 hours in growth media supplemented with either DMSO or NITD (10 uM) or 1038 (20 ug/ml) or 1039 (20 ug/ml).
  • the culture supernatant was collected, serially diluted by 10-folds and the dilutions used for Focus-forming unit (Ffu) assay using Indirect Immunofluorescence (IF).
  • the Ffu/ml for each culture supernatant was calculated, transformed to logarithmic value to the base of 10 and plotted.
  • the error bars represent standard deviation.
  • Figure 8 depicts the inhibition of DENV replication by 1038 or 1039 and 1040-1181.
  • Panel A and Panel B K562 cells were infected with DENV2 and incubated for 48 hours in growth media supplemented with either DMSO (0.2%) of NITD8 (lOuM) or 20ug/ml of the indicated compounds. The culture supernatant was collected, serially diluted by 10-folds and the dilutions used for Focus-forming unit (Ffu) assay using Indirect Immunofluorescence (IF). The Ffu/ml for each culture supernatant was calculated, transformed to logarithmic value to the base of 10 and plotted. The error bars represent standard deviation.
  • R 1 is H, Ci-Ce straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which is optionally substituted with R6, carbocyclyl which is optionally substituted with R6, (CH2)n(heterocyclyl)n, which is optionally substituted with R6; (CH2)n(carbocyclyl)nwhich is optionally substituted with R6;
  • R 2 is H, Ci-C 6 alkyl
  • R 3 is H, 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
  • R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6
  • R 4 , R 5 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6or R5 can be C1-C6 alkyl which is substituted with one or more 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S, wherein the ring system is optionally substituted with R6; or R 4 and R 5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; or R 4 and R 5 may
  • R 6 is H, halo, CN, CF3,OCHF2 , hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C 6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR 7 , CONHOH, CON(CI-C 6 alkyl)n, CON(CI-C 6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CFh)n(OCFl2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group compris
  • R 7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
  • the present invention includes compounds of Formula II and Formula III and illustrative compounds of the present invention.
  • the present invention also discloses a process for preparing the compounds as set out herein and use of these compounds in inhibition of DENV RNA dependent RNA polymerase.
  • the present invention discloses compounds of formula (I), including any conformational isomeric form, salts and solvates thereof:
  • R 1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which is optionally substituted with R6, carbocyclyl which is optionally substituted with R6, (CH2)n(heterocyclyl)n, which is optionally substituted with R6; (CH2)n(carbocyclyl)nwhich is optionally substituted with R6;
  • R 2 is H, Ci-C 6 alkyl
  • R 3 is H, 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
  • R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6
  • R 4 , R 5 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6or R5 can be C1-C6 alkyl which is substituted with one or more 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S, wherein the ring system is optionally substituted with R6; or R 4 and R 5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; or R 4 and R 5 may
  • R 7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
  • the compounds of the present application may be represented by the Formula II, for inhibition of DENV RNA-dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof:
  • R 1 is H, C 1 -C 6 straight chain or branched chain alkyl; C 2 -C 6 straight chain or branched chain alkenyl; C2-Cr, straight chain or branched chain alkynyl; C2-Cr, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)nwhich may be optionally substituted with R6 R 2 is H, Ci-C 6 alkyl;
  • R 3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
  • R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
  • R 4 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6, 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R 6 ;
  • R 6 is H, halo, CN, CF3,OCHF2 , hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C 6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR 7 , CONHOH, CON(CI-C 6 alkyl)n, CON(CI-C 6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CFh)n(OCF[2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group compris
  • R 7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
  • the compounds of the present invention may be represented by Formula III, for inhibition of DENV RNA-dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof:
  • R 1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)nwhich may be optionally substituted with R6 R 2 is H, Ci-C 6 alkyl;
  • R 3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
  • R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
  • R 4 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6, 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R 6 ;;
  • R 6 is H, halo, CN, CF3,OCHF2 , hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C 6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR 7 , CONHOH, CON(C I -C 6 alkyl)n, CON(C I -C 6 branched chain alkyl)n, CON(C 3 -C 6 cyclic alkyl)n, CON(CH 2 )n(OCH 2 )n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 hetero
  • R 7 is H, OH, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
  • the compounds of the present invention include: i. (E/Z)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; ii. (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)benzoic acid; iii. (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; iv.
  • the compounds of the present invention may be i. 1061- (E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; ii. 1089 - (E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; iii.
  • the present invention provides for pharmaceutically acceptable acid addition salts of compounds of formula (I) as well as pharmaceutically acceptable bass addition salts.
  • the non- toxic acids which are used to prepare the pharmaceutically acceptable acid addition salts of above-mentioned base compounds of this invention.
  • Appropriate acids comprise, for example, the inorganic acids such as theHydrochloride, Hydrobromide, Hydroiodide, Phosphorates, Nitric acid and Sulfuric acid; or organic acids such as Methanesulfonate, Acetate, Fumarate, Saccharate, p-toluenesulfonate, Benzenesulfonate, Lactate, Succinate, Citrate, Tartrate, Succinate, Gluconate, Benzoate, etc.
  • the base addition salts of formula (I) prepared by using the pharmaceutically acceptable chemical bases.
  • the compounds of this invention formula (I) includes all conformational isomers (e,g. cis and trans isomers or E and Z isomers) and also exist as tautomers. Due to presence of double bond in the present invention compounds of formula (I), the compounds exists as a pure form of E isomer or pure form of Z isomer or mixture of any ratio of E and Z isomers.
  • the compounds of formula (I) may exist as any combination of E and Z isomers, such as 0%-100% of E isomer or 0%-100% of Z isomers. If one isomer exists 10% and other is 90% means it is a mixture of 1:9 ratio of E and Z isomers.
  • the present invented compounds of formula (1) may consistany ratio of E and Z isomers.
  • the compounds of present invention may exist in more than one from of crystal structure is called polymorph. The compounds may be existing as crystalline or amorphous form.
  • the present invention also discloses a process of preparing the compounds of the present invention.
  • the compounds of the present invention can be prepared by the general synthetic schemes 1, presented here below
  • This sulfonyl chloride intermediate 2 was coupled with 4-aminobenzoic acid 7 in presence of pyridine as a base to neutralized the liberated hydrochloric acid resulted the 4-(2-oxoindoline-5-sulfonamido)benzoic acid 8, which may be subjected to Knoevenagel condensation with thiazole-2-carbaldehyde 6 by usingpyrrolidineas base in ethanol resulted thecarboxylic acid intermediatel002, using this acid different analogs 1003 to 1013 were synthesized by amide coupling with different primary and secondary amine 9a-l using the amide coupling reagent HATU, DIPEA as base in DMF.
  • 2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido compounds of the present invention being 1001, 1014 to 1037 and may be synthesized by treating 2-oxoindoline-5- sulfonyl chloride 2 with different aromatic and aliphatic amine to give sulfonamides 5, 10- 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 & 50 those undergoes Knoevenagel condensation with thioazole-2-carbaldehyde 6 by using pyrrolidine as base in ethanol resulted final analogs 1001, 1014 to 1037, among those two analogues 1015 and 1037 converted to corresponding alkylated targets 1038, 1040 to 1105 and 1106 , 1107- 1181 respectively by treating with alkylhalide in presence of K 2 CO 3 in DMF at room temperature.
  • the process to arrive at the compounds of the present invention may comprise the steps of: i. Treating indolin-2-one (1) with chlorosulfonic acid to result in 2- oxoindoline-5-sulfonyl chloride (2), ii. Optionally treating in 2-oxoindoline-5-sulfonyl chloride (2), different aromatic and aliphatic amine to give sulfonamides (10-16), iii.
  • indolin-2-one (1) may be treated with chlorosulfonic acid or other suitable acids in a temperature of 50 to 80 for 1 to 3 h to result in 2-oxoindoline-5-sulfonyl chloride (2).
  • the 2-oxoindoline-5-sulfonyl chloride (2) may be treated with different aromatic and aliphatic amine to give sulfonamides (10-16) in presence of pyridine and 1.4- dioxane or other suitable solvent mixtures for a period of 1-3 h at room temperature.
  • the Coupling 2-oxoindoline-5-sulfonyl chloride (2) with 4-aminobenzoic acid (7) may be in the presence of pyridine as a base to neutralize the liberated hydrochloric acid, or any suitable base to neutralize the acid generated, in presence of pyrroline or ethanol at room temperature for 2-8 h to obtain 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8), Subjecting 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8) or sulfonamides (10-16), to Knoevenagel condensation with thiazole-2-carbaldehyde (6) by using pyrrolidine as base or any other base in suitable solvent ethanol resulted the carboxylic acid intermediate, or final compounds 1014 tol037. Coupling carboxylic acid intermediate with different primary and secondary amines using the amide coupling reagent such as HATU, DIPEA as base in DMF or
  • the present invention discloses a composition
  • a composition comprising the compound of the present invention along with a pharmaceutically acceptable diluent, excipient, and/or carrier.
  • the compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition may be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers. They are also be parenteral and administered as sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure. Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
  • compounds or compositions comprising the compound may be administered at a dose of from 0.1 to 500 mg/kg per day.
  • the dose range for adult humans is generally from 5 mg to 2 g/day.
  • Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the compounds of the present invention may be utilized for intervention into disorders pertaining to or related to inhibition of DENV RNA-dependent RNA polymerase. It is envisaged that the compounds of the present invention have utility in all conditions and disorders stemming or related to inhibition of DENV RNA-dependent RNA polymerase. In other words, the compounds and compositions are used to treat, prevent or delay either the onset/progress of DENV infection or onset/progress of any physiological condition that is associated with DENV infection. All compounds of the present invention were tested and found to be active in a clinically significant manner. The compounds of present invention are inhibitors of DENV RNA-dependent RNA polymerase and possess utility in all instances where inhibition of DENV RNA-dependent RNA polymerase is indicated.
  • the compounds according to the present invention is envisaged to treat, prevent or delay either the onset/progress of infection by other members of the group Flaviviridae or onset/progress of any physiological condition that is associated with infection by other members of the group Flaviviridae.
  • the compounds according to the present invention is also envisaged to treat onset/progress either the infection by Chikungunya virus (CHIKV) or any physiological condition that is associated with CHIKV infection.
  • CHIKV Chikungunya virus
  • Example-3 (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1003)
  • Example-6 (E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline- 5sulfonamido)benzamide (1006) Synthesis of (E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1006): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), butan-1- amine 9d (25.6 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h.
  • HATU 133 mg, 0.35
  • Example-7 (E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1007)
  • Example-8 (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1008)
  • Example-13 (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- Synthesis of (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1013): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), N,O- dimethylhydroxylamine .HC1 9k (34.1 mg, 0.35 mmol) in DMF (3.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h.
  • Example-16 (E/Z)-N-(2,5-difluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1016)
  • Example-26 (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1026) Synthesis of N-(4-methylbenzyl)-2-oxoindoline-5-sulfonamide (28): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 4-methybenzyl amine 27 (156.9 mg, 1.297 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h.
  • Example-35 (E/Z)-N-(3-(difluoromethoxy)benzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1035)
  • Example-36 (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5- su
  • reaction mixture was added water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic layer washed with cold water (3 ⁇ 10 mL), brine solution (10 mL), separated organic layer dried over INfeSCL and concentrated under reduced pressure.
  • Example 40 Synthesis of compounds (1038-49, 1038-52, 1038-54, 1038-55 and 1039-49, 1039-52, 1039-54): A solution of compound (10m or 13q) (1.0 equiv.), in DMF (3.0 mL) was charged with K 2 CO 3 (5.0 equiv.), followed by R-I or Br (5.0 equiv.) at room temperature and stirred for 16 h. The reaction mixture was added to water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic EtOAc layer washed with cold water (3 x 10 mL), followed by brine (10 mL), separated organic layer dried over Na 2 S0 4 and concentrated to remove solvent under reduced pressure.
  • Example 41 Synthesis of compound (1038-65, 1039-1’ & 1039-4’: A solution of compound (10m or 13q) (1.01 equiv.), in DMF (3.0 mL) was added with dried K2CO3 (1.01 equiv.), followed by alkyl iodide or alkyl bromide (1.0 equiv.) at ambient temperature and stirred for 6 h. The reaction mixture was added to water (20 mL) and extracted with EtOAc (2 x 20 mL), organic layer combined and washed with cold water (3.0 x 10 mL), later with brine (10 mL), separated organic layer dried over NaiSCL to remove moisture and solvent evaporated under reduced pressure.
  • the parameter files for protein and complexes were prepared using the leap module of AMBER suite.
  • the systems were minimized in three stages for the relaxation and removal of bad contacts in the system.
  • Steepest descent of 1000 steps followed by 1000 steps of conjugate gradient was carried out.
  • the positional restraints of 10 and 2 kcal mol 1 A '2 were applied in the first and second stages of minimization, respectively.
  • the third step minimization was carried out unrestrained.
  • the system is gradually heated for 20pico-seconds (ps) upto 300K.
  • the systems were equilibrated for lOOps at 300K and 1 atm pressure.
  • the production was run for 300ns with a time step of 2.0 ps and recording the coordinates at every lOps.
  • the analysis of the MD simulated systems was further carried out in CPPTRAJ module of AMBER16.
  • the residues interacting with 1038 and 1039 include Ser796, His711, Cys709, His798, Met761, Trp803, Leu511, Met765, Thr794, Trp795, and Thr793 as hydrophobic contacts and VdW interactions, and residues Arg729, Arg737 in hydrogen bonding ( Figure 1, panel C, section 1 & 2).
  • 1038 and 1039 dock on to the RdRp in manner which will occlude the bottom of the RNA template entrances site, possibly hindering interactions between amino acid residues crucial for the catalytic activity of RdRp and, by doing so block the RNA polymerization.
  • the docking energy of four compounds, 1015, 1037, 1038 and 1039 is given in table 2.
  • Table 3 The docking energy of indicated compounds on RdRp from viruses related to Dengue virus
  • B.3. Antiviral activity ofthe compounds of the invention B.3.1 Materials and protocols B.3.1.1 Cells and virus: K562 cells were procured from the American Type Culture Collection (ATCC) and cultured at 37°C, 5% CO2 in Iscove’s-modified Dulbecco’s media (IMDM) supplemented with Penicillin (100 U/ml), Streptomycin (0.1 mg/ml) and 10% Fetal Bovine Serum (FBS). Vero and C6/36 cells were procured from the cell line repository of the National Centre for Cell Sciences (NCCS), India and cultured respectively in Minimum Essential Medium (MEM) and L15 cell culture medium. C6/36 cells in L15 culture media were grown at 28 °C and atmospheric CO2 conditions.
  • IMDM Iscove’s-modified Dulbecco’s media
  • FBS Fetal Bovine Serum
  • Vero and C6/36 cells were procured from the cell line repository of the National Centre for Cell Sciences (NCCS), India and cultured respectively in Minimum
  • Dengue virus serotype 2 (strain NGC) was grown in C6/36 cells incubated in 28°C and at atmospheric CO2 conditions.
  • the infectious titer of the virus was determined by Focus-forming unit (FFU) assay as described below.
  • FFU Focus-forming unit
  • the inoculum was diluted in respective culture media supplemented with 2% FBS and incubated with cells for 2 hours on a rocker inside the incubator
  • B.3.1.2 Immunostaining and flow cytometry Cells were washed using ice-cold PBS before fixation with 2% PFA and permeabilization with 0.1% Triton-X-100. These were sequentially incubated with 4G2 (anti-Flavivirus group antigen) primary antibody and anti mouse Alexa-488 conjugated secondary antibody. The fluorescence was analyzed using BD-FACS Canto II flow cytometer under standard conditions, using mock-infected cells as control. The raw data was analyzed using Flow- Jo software.
  • RNA isolation, Reverse-transcription and Real-time PCR 500 ng of total RNA extracted using Trizol and purified using RNA isolation kit (Qiagen), was reverse- transcribed by random hexamers and ImProm-II Reverse-transcriptase (Promega) according to manufacturer’s instructions.
  • the complementary DNA (cDNA) was used for Real-time PCR using gene-specific primers in an ABI7500 Fast Real-time PCR system.
  • Viral RNA from culture supernatant was isolated from culture supernatant using Viral RNA isolation kit (Qiagen) according to manufacturer’s instructions and reverse-transcribed using anti- sense DNA oligo (5 ’ -ACC ATTCC ATTTTCTGGCGTT -3 ’ ).
  • Real time PCR for Dengue virus genomic RNA was performed using Taqman probe (FAM- AGCATC ATTCC AGGCAC-NFQ-MGB), forward primer: 5’-
  • FFU Focus-forming unit
  • PBMC peripheral blood mononuclear cells
  • Total cellular ATP content was estimated using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), according to the instructions of the manufacturer. After incubation the luciferase activity was measured using a Luminometer with standard protocol (Berthold).
  • the ex v/voefficacy of the synthesized compounds was evaluated by their capacity to inhibit the replication of Dengue virus serotype 2 (strain NGC) in infected cells of the human K562 cell line.
  • strain NGC Dengue virus serotype 2
  • exponentially growing K562 cells were infected with the virus at a multiplicity-of-infection (MOI) of 10 and subsequently incubated in culture media supplemented with either vehicle (Dimethyl Sulphoxide or DMSO) or different compounds, at 37 °C under 5% CO2 for 2 days. The cells were then harvested by centrifugation and either used for immunofluorescence for estimation of viral protein accumulation or extraction of total RNA for estimation of viral genomic RNA accumulation.
  • MOI multiplicity-of-infection
  • the culture supernatant was aspirated, stored in -80 ° C and later used for quantification of the infectious titer by Focus-forming unit (FFU) assay ( Figure 3, panel A).
  • the percentage of cells positive for viral antigen was quantified by immunostaining followed by analysisin a flow cytometer, using mock-infected and similarly stained cells as negative control. As shown, about 50% of the cells infected at 10 MOI, were positive for viral antigen, at 2 days post-infection ( Figure 3, panel B).
  • the Taqman probe and primersused for real-time comparison of viral genomic RNA was tested using different dilutions of a plasmid which is recombinant for the 3’ Untranslated region of the viral RNA.
  • Table 4 Inhibition of viral antigen accumulation by 20Dg/ml of each compound in K562 cells infected with Dengue virus serotype 2 (strain NGC) at 48 hours post-infection
  • Table 5 Inhibition of viral antigen accumulation by 20Dg/ml of each compound in K562 cells infected with Dengue virus serotype 2 (strain NGC) at 48 hours post-infection
  • compound 1037 showed the highest efficacy among all variants in inhibiting virus replication.
  • 1015 and 1037 were modified to generate 1038 and 1039 respectively.
  • the efficacy of 1038 and 1039 were ascertained by quantification of the infectious titer of virus produced by infected cells, which have been treated with these compounds. The result showed both 1038 and 1039 to be efficacious in decreasing secretion of infectious virus, by a direct effect on genome replication by the viral RdRp enzyme ( Figure 5, panel A).Further a dose-response efficacy using a range of 1039 concentrations showed the EC50 of the compound to be 10 Dg/ml ( Figure 5, panel B).
  • Etoposide a known cytotoxic drug was used as a positive control in these experiments.
  • the highest concentration of 1039 used here 160 Dg/ml
  • the highest concentration of 1039 used here 160 Dg/ml
  • Incubation of PBMC with a highest concentration of 160 Dg/ml of 1039 reduced the ATP content to cells similar to that of equivalent concentration of vehicle (1.6% DMSO), suggesting 1039 to be non-toxic for PBMCs as well even at this concentration (Figure 6, panel D).
  • the efficacy of the compounds of present invention were found to be active against DENV2.
  • the activity of these compounds was tested against virus belonging to the other 3 serotypes, namely DENV1, DENV3 and DENV4.
  • the infectious titre of virus produced from K562 infected with either of the four serotypes was compared to that of NITD08, a nucleoside inhibitor of DENV2.
  • the result showed 1038 to have the highest efficacy against DENV2 and to cause lowest inhibition of DENV4 replication (Figure 7).
  • 1039 was most inhibitory for DENV2 and had higher efficacy against DENV1 when compared to 1038 ( Figure 7).

Abstract

The present invention is drawn to novel compounds of formula I, II and III, including any conformational isomeric form, salts and solvates for inhibition of DENV RNA dependent and RNA polymerase. The present invention also discloses a process of synthesis of the compounds, compositions comprising the said compounds and use of the compounds and treatment comprising the compounds of the present invention.

Description

DESIGN, SYNTHESIS OF NOVEL OXYINDOLE INHIBITORS OF DENV RNA
DEPENDENT RNA POLYMERASE
FIELD OF THE INVENTION
The present invention pertains to the field of pharmaceuticals, particularly to novel Oxyindole compounds, their process of synthesis, compositions comprising the said compounds and use of the compounds for inhibition of DENV RNA-dependent RNA polymerase (RdRp).
BACKGROUND OF THE INVENTION OF DENGUE VIRUS INHIBITORS
In multiple tropical and sub-tropical regions of the world, climatic conditions of high temperature and humidity is conducive and, leads to rapid growth of two species of mosquito, Aedes aegypti and A. albopictus , carrying infectious Dengue virus (DENV) particles in the salivary gland. Female mosquitoes of both species feed on human blood and in the process inject their saliva carrying the live virus. In addition to DENV, these species are capable of transmitting other viruses like Chikungunya, Yellow fever and Zika virus in a similar manner. Most of the humans thus infected with DENV, do not develop symptoms while the rest develop a febrile illness called Dengue fever (DF), which many people especially in developing countries can ill afford to be treated and may also be fatal, DF is characterized by retro-orbital pain, pain in muscles and bone, rashes, drop in platelet level etc. The fever subsides after a few days and most patients recover without any long-term sequelae. However, in a segment of infected patients’ severe symptoms of acute reduction of blood platelet resulting in internal bleeding, leakage of plasma from blood vessels causing a drop in blood pressure, and can result in death due to hypovolemic shock. The severe form of the disease is called Dengue hemorrhagic fever (DHF), which has been graded into four increasingly hazardous grades (I, II, III and IV) among which the last two are associated with poor prognosis and marked as Dengue shock syndrome (DSS). During the acute febrile phase, peripheral blood contains moderate to high level of infectious DENV, and a greater probability of developing DHF and DSS is associated with higher virus titer at this stage. Also, when naive mosquitoes feed on the blood of individuals with high viral load, these get infected leading to further spread of the virus. DENV is endemic to more than 100 countries and is estimated to cause close to 400 million infections each year, causing widespread hospitalization and death among children and the elderly in Latin as well as Asian countries. Every year an estimated 500,000 cases of DHF occur globally causing close to 22,000 deaths. In India, dengue is endemic in almost all states and is the leading cause of hospitalization. In 2015, the Indian capital city of Delhi recorded close to 15,000 cases in one of the worst outbreaks in its history. Such fatalities and hospitalization produce massive burden on the economy of developing countries, by increasing the load on health-care facilities that might be saturated and loss of man-hours. Infection of naive mosquitoes and propagation of DENV into their progeny through hibernation in eggs is increasing the environmental load of DENV-harboring vectors and thereby leading to increase in infections. Therefore, a regulation or inhibition of DENV replication can; a) prevent severe dengue and its associated fatality b) reduce the period of hospitalization and the burden on health-care facilities, and c) inhibiting the spread of the disease into new vector mosquitoes
DENV belongs to the group of Flaviviruses and the global DENV population can be grouped into either of four distinct serological groups (termed serotype DEN-1, DEN-2, DEN-3 and DEN-4) all of which are capable of causing severe illness. Therefore, an effective drug should be equally capable of inhibiting all four serotypes. After infection of a host cell, the viral genome is translated to produce structural and non- structural proteins. The viral non-structural protein 5 (NS5) is catalyzes replication of the RNA genome and is a suitable target for anti-viral drug design. However, like other RNA-dependent RNA polymerases, polymerization by Dengue virus RdRp is prone to high rate of error in incorporation of nucleotides, which generates diversity in the progeny viruses. A random error can be positively selected for subsequent propagation if it provides resistance to a drug that is being used to inhibit the viral multiplication. Once the drug develops resistance, it is not possible to use this drug for resistance.
The RdRp domain of dengue virus is similar to that found in other such enzymes, containing 3 major sub-domains namely, thumb, palm and fingers. The palm sub-domain houses the active site. RdRp inhibition can be achieved using either nucleoside/nucleotide inhibitor (NI) drugs which mimic ribonucleotide monomers and target the active site or non- nucleoside inhibitors (NNI) drugs which bind to allosteric sites on the protein and prohibit enzyme function. An NI hinders polymerization through either chain termination or by steric hindrance to incorporation of endogenous ribonucleotides. NNIs on the other hand are designed to interact with allosteric sites on the enzyme and prevent enzyme activity by steric interference in structural movements.
DENV RNA-dependent RNA polymerase is an enzyme that utilizes RNA as a template to polymerize a complementary RNA. This polymerase is different from other types of polymerases like DNA-dependent RNA polymerases, DNA-dependent DNA polymerases and RNA-dependent DNA polymerases and can be a suitable target for inhibition of DENV.. However, there are no effective inhibitors of DENV RNA-dependent RNA polymerase.
There are no effective small molecule inhibitors that can inhibit DENV and therefore, there is a need for small molecule inhibitors which can effectively inhibit DENV.
OBJECT OF THE INVENTION
An object of the invention is to provide compounds for inhibition of DENV RNA dependent and RNA polymerase, process of synthesis of the compounds, compositions comprising the said compounds and use of the compounds and treatment of dengue comprising administration of the compounds of the present invention.
BRIEF DESCRIPTION OF FIGURES
Figure 1 depicts the structural architecture of Dengue RdRp and its Binding site: Panel A. Schematic Ribbon diagram of Dengue virus (serotype 3, PDB-ID 5F3T) RNA-dependent RNA polymerase (RdRp) showing different domains (thumb, finger, palm, active site etc.) that are important for catalysis. Panel B. Ribbon diagram of RdRp showing the possible binding site of compound 1015. Panel C. Schematic interaction diagram of ligands into the binding site indicating the amino acids potentially interacting with functional groups on 1038 (1), 1039 (2) and UNK-586 (3) from the most stable molecular dynamics simulation pose. Figure 2 depicts the stability of the complex of Compound 1039 of the present invention throughout 300ns through molecular dynamics simulations confirming the identified I- pocket through root mean square deviation (RMSD) analysis (left panel) and covariance analysis (right panel).
Figure 3 depicts the method for ex vivo screening of inhibitors of Dengue virus replication in K562 cells. Panel A: Schematic representation of experiments to screen for experimental compounds that can inhibit virus replication Panel B: Detection of intracellular Dengue virus antigen by immunofluorescence. K562 cells either mock infected or Dengue virus infected were fixed, permeabilized and immune stained using anti-Dengue primary antibody and Alexa-488 conjugated secondary antibody. The number of Dengue antigen positive cells was quantified by flow cytometry Panel C: Dynamic range of template detection in real time PCR. DNA corresponding to the 3’ untranslated region of Dengue virus genome was cloned in plasmid and different dilutions of the plasmid DNA used as template in real-time PCR using specific Taqman probe and primers. The observed threshold of detection (CT) was plotted against the final plasmid concentration in real-time PCR reaction Panel D: Schematic representation of focus-forming unit assay performed in Vero cells Panel E: Fluorescent foci of infected cells. Image of fluorescent foci, each composed of groups of adjoining cells infected with Dengue virus, as observed under fluorescence microscope. Each isolated foci of cells is counted as single infectious unit
Figure 4 depicts the efficacy of active molecules in inhibition of DENV2 growth. Panel A. K562 cells either mock-infected of DENV2-infected were incubated in growth media supplemented with either 0.1% DMSO (vehicle) or 20mg/ml of the indicated compounds for 48 hours post-infection. At the end of incubation, the cells were fixed using paraformaldehyde, permeabilized and immune-stained using anti-Flavivirus primary antibody (4G2) followed by anti-mouse Alexa-488 conjugated secondary antibody. The percentage of cells positive for viral antigen was quantified in a flow cytometer and plotted. The error bars represent standard deviation. Panel B. The total RNA from virus infected cells treated with indicated compounds, similarly as in panel A, was extracted and reverse transcribed. The cDNA was used for estimation of viral genomic RNA accumulation by real-time PCR, normalized to GAPDH mRNA. The fold enrichment of viral genomic RNA was plotted. The error bars represent standard deviation. Figure 5 depicts the inhibition of Dengue vims production from infected cells by. Panel A. K562 cells infected with Dengue vims 2 were incubated in growth media supplemented with either appropriate concentration of DMSO or 10 ug/ml of either 1038 or compound 1039. Panel B. K562 cells infected with Dengue vims 2 were incubated in growth media supplemented with either appropriate concentration of DMSO or decreasing concentration of 1039. For both panel A and B, at 48 hours post-infection the cell-free culture supernatant was collected, and the infectious titer of produced vims quantified by focus-forming unit (FFU) assay. The logarithmic values of the calculated FFU/ml to base 10 were plotted. The error bars represent standard deviation.
Figure 6 depicts the toxicity of compound 1039 in K562 and primary cells. Panel A. The total ATP content as a direct correlate of relative luciferase activity was quantified in increasing number of exponentially growing K562 cells. The coefficient of correlation is shown as R2. Panel B. Peripheral blood mononuclear cells were isolated and incubated in growth media. At 24 or 72 hours post isolation the total ATP content in increasing number of PBMCs was quantified. The coefficient of correlation is shown as R2. Panel C. K562 cells were incubated at a density of 0.3xl06cells/ml in growth media supplemented with either increasing quantity of DMSO (in % corresponding to compound 1039 solution in DMSO) or compoundl039 or 200mg/ml of Etoposide. After 48 hours of incubation 5x 103 cells from the culture was used for analysis of ATP content. A known cytotoxic agent, Etoposide was used as positive control. Panel D. PBMCs were incubated in growth media either un-supplemented or supplemented with indicated concentration of DMSO (in % corresponding to compound 1039 solution in DMSO) or compound 1039 or Etoposide. After 24 or 48 hours of incubation the total ATP content was estimated as direct correlate of relative luciferase activity.
Figure 7 depicts the pan-serotype efficacy of 1038 or 1039 compared to NITD. K562 cells infected with either DENV 1 or DENV2 or DENV3 or DENV4 was incubated for 48 hours in growth media supplemented with either DMSO or NITD (10 uM) or 1038 (20 ug/ml) or 1039 (20 ug/ml). The culture supernatant was collected, serially diluted by 10-folds and the dilutions used for Focus-forming unit (Ffu) assay using Indirect Immunofluorescence (IF). The Ffu/ml for each culture supernatant was calculated, transformed to logarithmic value to the base of 10 and plotted. The error bars represent standard deviation.
Figure 8 depicts the inhibition of DENV replication by 1038 or 1039 and 1040-1181. Panel A and Panel B. K562 cells were infected with DENV2 and incubated for 48 hours in growth media supplemented with either DMSO (0.2%) of NITD8 (lOuM) or 20ug/ml of the indicated compounds. The culture supernatant was collected, serially diluted by 10-folds and the dilutions used for Focus-forming unit (Ffu) assay using Indirect Immunofluorescence (IF). The Ffu/ml for each culture supernatant was calculated, transformed to logarithmic value to the base of 10 and plotted. The error bars represent standard deviation.
SUMMARY OF THE INVENTION
Figure imgf000008_0001
Formula I
Wherein
R1 is H, Ci-Ce straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which is optionally substituted with R6, carbocyclyl which is optionally substituted with R6, (CH2)n(heterocyclyl)n, which is optionally substituted with R6; (CH2)n(carbocyclyl)nwhich is optionally substituted with R6;
R2 is H, Ci-C6alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6
R4, R5 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6or R5 can be C1-C6 alkyl which is substituted with one or more 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S, wherein the ring system is optionally substituted with R6; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S;
R6 is H, halo, CN, CF3,OCHF2, hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CFh)n(OCFl2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
The present invention includes compounds of Formula II and Formula III and illustrative compounds of the present invention.
The present invention also discloses a process for preparing the compounds as set out herein and use of these compounds in inhibition of DENV RNA dependent RNA polymerase.
DETAILED DESCRIPTION OF THE INVENTION
The present invention discloses compounds of formula (I), including any conformational isomeric form, salts and solvates thereof:
Figure imgf000010_0001
Formula I
Wherein
R1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which is optionally substituted with R6, carbocyclyl which is optionally substituted with R6, (CH2)n(heterocyclyl)n, which is optionally substituted with R6; (CH2)n(carbocyclyl)nwhich is optionally substituted with R6;
R2 is H, Ci-C6alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6
R4, R5 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6or R5 can be C1-C6 alkyl which is substituted with one or more 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S, wherein the ring system is optionally substituted with R6; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; R6 is H, halo, CN, CF3,OCHF2, hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CH2)n(OCH2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
The compounds of the present application may be represented by the Formula II, for inhibition of DENV RNA-dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof:
Figure imgf000011_0001
Formula II
Wherein
R1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-Cr, straight chain or branched chain alkynyl; C2-Cr, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)nwhich may be optionally substituted with R6 R2 is H, Ci-C6alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R4 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6, 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R6;
R6 is H, halo, CN, CF3,OCHF2, hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CFh)n(OCF[2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
The compounds of the present invention may be represented by Formula III, for inhibition of DENV RNA-dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof:
Figure imgf000013_0001
Formula III
Wherein
R1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-CV, straight chain or branched chain alkynyl; C2-CV, alkyl-alkenyl, C2-Cr, alkyl- alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)nwhich may be optionally substituted with R6 R2 is H, Ci-C6alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
R4, is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6, 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R6;;
R6 is H, halo, CN, CF3,OCHF2, hydroxyl, Amino, C1-C6 straight or branched or C3-C6 cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo- Ci-Ce alkyl, Ci-C6 alkyloxy; Ci-Ce alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-C6 cyclic alkyl)n, CON(CH2)n(OCH2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
Certain illustrative compounds of the present invention are exemplified at Table 1, as set out in Formulas 1 to 3.
Tablel: Illustrative compounds of the present invention
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
The compounds of the present invention include: i. (E/Z)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; ii. (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)benzoic acid; iii. (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; iv. (E/Z)-2-oxo-N-(4-(piperidine-l-carbonyl)phenyl)-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; v. (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)-N-(pentan-3- yl)benzamide; vi. (E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; vii. (E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; viii. (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; ix. (E/Z)-N-(4-(morpholine-4-carbonyl)phenyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; x. (E/Z)-N-isobutyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; xi. (E/Z)-N,N-diethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; xii. (E/Z)-N,N-dimethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; xiii. (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide; xiv. (E/Z)-N-(5-chloro-2-fluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xv. (E/Z)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xvi. (E/Z)-N-(2,5-difluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xvii. (E/Z)-2-oxo-N-(pentan-3-yl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xviii. (E/Z)-5-(morpholinosulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one; xix. (E/Z)-5-(pyrrolidin-l-ylsulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one; xx. (E/Z)-N-cyclohexyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxi. (E/Z)-N-benzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxii. (E/Z)-N-(3-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxiii. (E/Z)-N-(4-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxiv. (E/Z)-N-(2-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxv. (E/Z)-N-(3-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxvi. (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxvii. (E/Z)-N-(4-isopropylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxviii. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(4-(trifluoromethyl)benzyl)indoline-5- sulfonamide; xxix. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3-(trifluoromethyl)benzyl)indoline-5- sulfonamide; xxx. (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxi. (E/Z)-N-(4-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxii. (E/Z)-N-(2,3-dimethoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxiii. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3,4,5-trimethoxybenzyl)indoline-5- sulfonamide; xxxiv. (E/Z)-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxv. (E/Z)-N-(2-(difluoromethoxy)benzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxvi. (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxxvii. (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxxviii. (E/Z)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xxxix. (E/Z)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xl. (E)-N-(2,4-difluorobenzyl)-l-ethyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xli. (E)-N-(2,4-difluorobenzyl)-l-isopropyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlii. (E)-l-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xliii . (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo- 1 -(prop-2 -yn- 1 -yl)-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; xliv. (E)-N-(2,4-difluorobenzyl)-l-isobutyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlv. (E)-l -benzyl -N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlvi. (E)-l-allyl-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlvii. (E)-l-butyl-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlviii. (E)-N-(2,4-difluorobenzyl)-l-(2-methoxyethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xlix. (E)-l-(cyclobutylmethyl)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide;
1. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; li. (E)-N-(2,4-difluorobenzyl)-l-(4-fluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lii. (E)-N-(2,4-difluorobenzyl)-N-methyl-l-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; liii. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; liv. (E)-N-(2,4-difluorobenzyl)-N-methyl-l-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lv. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lvi. (E)-N-(2,4-difluorobenzyl)-N-ethyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lvii. (E)-N-(2,4-difluorobenzyl)-N-isopropyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lviii. (E)-N-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lix. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lx. (E)-N-allyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxi. (E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxii. (E)-N-allyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxiii. (E)-N-butyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxiv. (E)-N-(2, 4-difluorobenzyl)-N-(2-methoxy ethyl)- l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxv. (E)-N-(cyclobutylmethyl)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxvi. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxvii. (E)-N-(2,4-difluorobenzyl)-N-(4-fluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxviii. (E)-N-(2,4-difluorobenzyl)-l-methyl-N-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxix. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxx. (E)-N-(2,4-difluorobenzyl)-l-methyl-N-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxxi. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; lxxii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-5-ylmethylene)indoline- 5-sulfonamide; lxxiii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(pyridin-3-ylmethylene)indoline- 5-sulfonamide; lxxiv. (E)-N-(2,4-difluorobenzyl)-3-(3,4-dimethoxybenzylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxv. (E)-3-(4-chlorobenzylidene)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxvi. (E)-N-(2,4-difluorobenzyl)-3-(4-fluorobenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxvii. (E)-3-(3-bromobenzylidene)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxviii. (E)-3-benzylidene-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxix. (E)-N-(2,4-difluorobenzyl)-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2-oxoindoline- 5-sulfonamide; lxxx. (E)-N-(2,4-difluorobenzyl)-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2-oxoindoline- 5-sulfonamide; lxxxi. (Z)-N-(2,4-difluorobenzyl)-3-(2,3-dihydro-lH-inden-l-ylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxxii. N-(2,4-difluorobenzyl)-3-(dihydro-2H-pyran-4(3H)-ylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxxiii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-3-(oxazol-5-ylmethylene)-2-oxoindoline- 5-sulfonamide; lxxxiv. (E)-N-(2,4-difluorobenzyl)-N,l -dimethyl-3-((l -methyl- lH-pyrrol-2-yl)methylene)-
2-oxoindoline-5-sulfonamide; lxxxv. (E)-N-(2,4-difluorobenzyl)-3-(furan-2-ylmethylene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxxvi. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiophen-2- ylmethylene)indoline-5-sulfonamide; lxxxvii. (E)-N-(2,4-difluorobenzyl)-N,l -dimethyl-3-((l -methyl- lH-pyrazol-4-yl)methylene)-
2-oxoindoline-5-sulfonamide; lxxxviii. N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethyl)indoline-5- sulfonamide; lxxxix. (E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xc. (E)-N-(2,4-difluorobenzyl)-N,l-diisopropyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xci. (E)-N, 1 -bis(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xcii. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xciii. (E)-N-(2,4-difluorobenzyl)-N,l-diisobutyl-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; xciv. (E)-N, 1 -dibenzyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; xcv. (E)-N,l-diallyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xcvi. (E)-N, 1 -dibutyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xcvii. (E)-N-(2,4-difluorobenzyl)-N,l-bis(2-methoxyethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xcviii. (E)-N, 1 -bis(cyclobutylmethyl)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xcix. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; c. (E)-N-(2,4-difluorobenzyl)-N,l-bis(4-fluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; ci. (E)-N-(2,4-difluorobenzyl)-N,l-bis(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cii. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; ciii. (E)-N-(2,4-difluorobenzyl)-N,l-bis(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; civ. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cv. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cvi. (E)-N-benzhydryl-l-ethyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cvii. (E)-N-benzhydryl-l-isopropyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cviii. (E)-N-benzhydryl-l-(cyclopropylmethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cix. (E)-N-benzhydryl-N-methyl-2-oxo-l-(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cx. (E)-N-benzhydryl-l-isobutyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxi. (E)-N-benzhydryl-l-benzyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxii. (E)-l-allyl-N-benzhydryl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxiii. (E)-N-benzhydryl-l-butyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxiv. (E)-N-benzhydryl-l-(2-methoxyethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxv. (E)-N-benzhydryl-l-(cyclobutylmethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxvi. (E)-N-benzhydryl-N-methyl-2-oxo- l-(pyri din-3 -ylmethyl)-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxvii. (E)-N-benzhydryl-l-(4-fluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxviii. (E)-N-benzhydryl-N-methyl-l-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxix. (E)-N-benzhydryl-N-methyl-2-oxo-l-(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxx. (E)-N-benzhydryl-N-methyl-l-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxi. (E)-N-benzhydryl-N-methyl-2-oxo-l-(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxii. (E)-N-benzhydryl-N-ethyl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxiii. (E)-N-benzhydryl-N-isopropyl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxiv. (E)-N-benzhydryl-N-(cyclopropylmethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxv. (E)-N-benzhydryl- 1 -methyl-2-oxo-N-(prop-2-yn- 1 -yl)-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxvi. (E)-N-benzhydryl-N-isobutyl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxvii. (E)-N-benzhydryl-N-benzyl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxviii. (E)-N-allyl-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxix. (E)-N-benzhydryl-N-butyl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; cxxx. (E)-N-benzhydryl-N-(2-methoxyethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxi. (E)-N-benzhydryl-N-(cyclobutylmethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxii. (E)-N-benzhydryl- l-methyl-2-oxo-N-(pyri din-3 -ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxiii. (E)-N-benzhydryl-N-(4-fluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxiv. (E)-N-benzhydryl-l-methyl-N-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxv. (E)-N-benzhydryl-l-methyl-2-oxo-N-(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxvi. (E)-N-benzhydryl-l-methyl-N-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxvii. (E)-N-benzhydryl-l-methyl-2-oxo-N-(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxxviii. (E)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-5-ylmethylene)indoline-5- sulfonamide; cxxxix. (E)-N-benzhydryl-N, l-dimethyl-2-oxo-3-(pyri din-3 -ylmethylene)indoline-5- sulfonamide; cxl. (E)-N-benzhydryl-3-(3,4-dimethoxybenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxli. (E)-N-benzhydryl-3-(4-chlorobenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxlii. (E)-N-benzhydryl-3-(4-fluorobenzylidene)-N, 1 -dimethyl-2-oxoindoline-5- sulfonamide; cxliii. (E)-N-benzhydryl-3-(3-bromobenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxliv. (E)-N-benzhydryl-3-benzylidene-N,l-dimethyl-2-oxoindoline-5-sulfonamide; cxlv. (E)-N-benzhydryl-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxlvi . (Z)-N-benzhydryl-3 -(2,3 -dihydro- lH-inden- 1 -ylidene)-N, 1 -dimethyl-2-oxoindoline-
5-sulfonamide; cxlvii. N-benzhydryl-3-(dihydro-2H-pyran-4(3H)-ylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxlviii. (E)-N-benzhydryl-N,l-dimethyl-3-(oxazol-5-ylmethylene)-2-oxoindoline-5- sulfonamide; cxlix. (E)-N-benzhydryl-N,l-dimethyl-3-((l-methyl-lH-pyrrol-2-yl)methylene)-2- oxoindoline-5-sulfonamide; cl. (E)-N-benzhydryl-3-(furan-2-ylmethylene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cli. (E)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiophen-2-ylmethylene)indoline-5- sulfonamide; clii. (E)-N-benzhydryl-N,l-dimethyl-3-((l-methyl-lH-pyrazol-4-yl)methylene)-2- oxoindoline-5-sulfonamide; cliii. N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethyl)indoline-5-sulfonamide; cliv. (E)-N-benzhydryl-N,l-diethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; civ. (E)-N-benzhydryl-N,l-diisopropyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clvi. (E)-N-benzhydryl-N,l-bis(cyclopropylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clvii. (E)-N-benzhydryl-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; clviii. (E)-N-benzhydryl-N,l-diisobutyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clix. (E)-N-benzhydryl-N,l-dibenzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clx. (E)-N, 1 -diallyl-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxi. (E)-N-benzhydryl-N,l-dibutyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxii. (E)-N-benzhydryl-N,l-bis(2-methoxyethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxiii. (E)-N-benzhydryl-N,l-bis(cyclobutylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxiv. (E)-N-benzhydryl-2-oxo-N,l-bis(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxv. (E)-N-benzhydryl-N,l-bis(4-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; clxvi. (E)-N-benzhydryl-N,l-bis(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxvii. (E)-N-benzhydryl-2-oxo-N,l-bis(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxviii. (E)-N-benzhydryl-N,l-bis(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxix. (E)-N-benzhydryl-2-oxo-N,l-bis(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxx. (E)-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; clxxi. (E)-N-(3-fluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxxii. (E)-N-(2-(difluoromethoxy)benzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxiii. (E)-N,l-dimethyl-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxxiv. (E)-N-(cyclopentyl(2,4-difluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxv. (E)-N-(l-(2,4-difluorophenyl)propyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxvi. (E)-N-(cyclohexyl(2,4-difluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxvii. (E)-N-((2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-N,l-dimethyl-2-oxo- 3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; clxxviii. (E)-N-(bis(2,4-difluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxix. (E)-N-(bis(4-fluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxx. (E)-N-(bis(4-chlorophenyl)methyl)-N, 1 -dimethyl -2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; clxxxi. (E)-N-(bis(3-fluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide.
Preferably, the compounds of the present invention may be i. 1061- (E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; ii. 1089 - (E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; iii. 1092- (E)-N-(2,4-difluorobenzyl)-2-oxo-N, 1 -di(prop-2-yn- 1 -yl)-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; iv. 1094- (E)-N, l-dibenzyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; v. 1095- E)-N, 1 -diallyl-N-(2,4-difluorobenzyl)-2-oxo-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; vi. 1105-(E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; vii. 1106-(E)-N-benzhydryl-l-ethyl-N-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide; viii. 1109-(E)-N-benzhydryl-N-methyl-2-oxo- 1 -(prop-2-yn- 1 -yl)-3 -(thiazol-2- ylmethylene)indoline-5-sulfonamide; ix. 1127-(E)-N-benzhydryl-N-benzyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; x. 1154-(E)-N-benzhydryl-N,l-diethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xi. 1157-(E)-N-benzhydryl-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; xii. 1159- (E)-N-benzhydryl-N,l-dibenzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xiii. 1170-(E)-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide.
The present invention provides for pharmaceutically acceptable acid addition salts of compounds of formula (I) as well as pharmaceutically acceptable bass addition salts. The non- toxic acids which are used to prepare the pharmaceutically acceptable acid addition salts of above-mentioned base compounds of this invention. Appropriate acids comprise, for example, the inorganic acids such as theHydrochloride, Hydrobromide, Hydroiodide, Phosphorates, Nitric acid and Sulfuric acid; or organic acids such as Methanesulfonate, Acetate, Fumarate, Saccharate, p-toluenesulfonate, Benzenesulfonate, Lactate, Succinate, Citrate, Tartrate, Succinate, Gluconate, Benzoate, etc.
The base addition salts of formula (I) prepared by using the pharmaceutically acceptable chemical bases. The pharmaceutically acceptable bass addition salts of those compounds of formula (I) that are acidic in nature and can form non-toxic base salts, such as pharmaceutically acceptable alkali metal cations, like potassium, sodium, and alkali earth metal cations, (e.g., calcium, magnesium), ammonium or water soluble amine addition salts, like n-methylglucamine, and lower alkanolammonium and other pharmaceutically acceptable organic amine salts.
The compounds of this invention formula (I) includes all conformational isomers (e,g. cis and trans isomers or E and Z isomers) and also exist as tautomers. Due to presence of double bond in the present invention compounds of formula (I), the compounds exists as a pure form of E isomer or pure form of Z isomer or mixture of any ratio of E and Z isomers. The compounds of formula (I) may exist as any combination of E and Z isomers, such as 0%-100% of E isomer or 0%-100% of Z isomers. If one isomer exists 10% and other is 90% means it is a mixture of 1:9 ratio of E and Z isomers. Similarly, the present invented compounds of formula (1) may consistany ratio of E and Z isomers. The compounds of present invention may exist in more than one from of crystal structure is called polymorph. The compounds may be existing as crystalline or amorphous form.
In another aspect, the present invention also discloses a process of preparing the compounds of the present invention. The compounds of the present invention can be prepared by the general synthetic schemes 1, presented here below
Synthesis of 2-oxo-N-(4-(-l-carbonyl)phenyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide target may be initiated with commercially available indolin-2-one 1, which may be treated with chlorosulfonic acid to afford key intermediate 2-oxoindoline-5-sulfonyl chloride 2. This sulfonyl chloride intermediate 2 was coupled with 4-aminobenzoic acid 7 in presence of pyridine as a base to neutralized the liberated hydrochloric acid resulted the 4-(2-oxoindoline-5-sulfonamido)benzoic acid 8, which may be subjected to Knoevenagel condensation with thiazole-2-carbaldehyde 6 by usingpyrrolidineas base in ethanol resulted thecarboxylic acid intermediatel002, using this acid different analogs 1003 to 1013 were synthesized by amide coupling with different primary and secondary amine 9a-l using the amide coupling reagent HATU, DIPEA as base in DMF.
Similarly 2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido compounds of the present invention being 1001, 1014 to 1037 and may be synthesized by treating 2-oxoindoline-5- sulfonyl chloride 2 with different aromatic and aliphatic amine to give sulfonamides 5, 10- 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 & 50 those undergoes Knoevenagel condensation with thioazole-2-carbaldehyde 6 by using pyrrolidine as base in ethanol resulted final analogs 1001, 1014 to 1037, among those two analogues 1015 and 1037 converted to corresponding alkylated targets 1038, 1040 to 1105 and 1106 , 1107- 1181 respectively by treating with alkylhalide in presence of K2CO3 in DMF at room temperature.
Figure imgf000060_0001
Scheme 1: General scheme for the Synthesis of Oxyindole sulfonamide compounds of the present invention (1001 to 1039 and 1040 to 1105 and 1106 to 1181)
The process to arrive at the compounds of the present invention may comprise the steps of: i. Treating indolin-2-one (1) with chlorosulfonic acid to result in 2- oxoindoline-5-sulfonyl chloride (2), ii. Optionally treating in 2-oxoindoline-5-sulfonyl chloride (2), different aromatic and aliphatic amine to give sulfonamides (10-16), iii. Coupling 2-oxoindoline-5-sulfonyl chloride (2) with 4-aminobenzoic acid (7) in presence of pyridine as a base to neutralize the liberated hydrochloric acid to obtain 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8), iv. Subjecting 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8) or sulfonamides (10-16), to Knoevenagel condensation with thiazole-2- carbaldehyde (6) by using pyrrolidine as base in ethanol resulted the carboxylic acid intermediate, or final compounds 1014 tol 037 v. Coupling carboxylic acid intermediate with different primary and secondary amines using the amide coupling reagent HATU, DIPEA as base in DMF to arrive at the compounds. In the present invention, indolin-2-one (1) may be treated with chlorosulfonic acid or other suitable acids in a temperature of 50 to 80 for 1 to 3 h to result in 2-oxoindoline-5-sulfonyl chloride (2). The 2-oxoindoline-5-sulfonyl chloride (2) may be treated with different aromatic and aliphatic amine to give sulfonamides (10-16) in presence of pyridine and 1.4- dioxane or other suitable solvent mixtures for a period of 1-3 h at room temperature. The Coupling 2-oxoindoline-5-sulfonyl chloride (2) with 4-aminobenzoic acid (7) may be in the presence of pyridine as a base to neutralize the liberated hydrochloric acid, or any suitable base to neutralize the acid generated, in presence of pyrroline or ethanol at room temperature for 2-8 h to obtain 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8), Subjecting 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8) or sulfonamides (10-16), to Knoevenagel condensation with thiazole-2-carbaldehyde (6) by using pyrrolidine as base or any other base in suitable solvent ethanol resulted the carboxylic acid intermediate, or final compounds 1014 tol037. Coupling carboxylic acid intermediate with different primary and secondary amines using the amide coupling reagent such as HATU, DIPEA as base in DMF or other suitable solvents to arrive at the compounds 1038 to 1181.
In another embodiment, the present invention discloses a composition comprising the compound of the present invention along with a pharmaceutically acceptable diluent, excipient, and/or carrier. The compositions will include a conventional pharmaceutical carrier, excipient, and/or diluent and a compound of this disclosure as the/an active agent, and, in addition, can include carriers and adjuvants, etc. The pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of this disclosure, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
Administration of the compounds of this disclosure, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, may be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. Solid dosage forms, as described above, can be prepared with coatings and shells, such as enteric coatings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of this disclosure with, for example, suitable non-irritating excipients or carriers. They are also be parenteral and administered as sterile powders for reconstitution into sterile injectable solutions or dispersions. Dosage forms for topical administration of a compound of this disclosure include ointments, powders, sprays, and inhalants. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated for the compounds in this disclosure. Compressed gases can be used to disperse a compound of this disclosure in aerosol form.
In another embodiment, compounds or compositions comprising the compound may be administered at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of one or more compounds which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
In another embodiment, the compounds of the present invention may be utilized for intervention into disorders pertaining to or related to inhibition of DENV RNA-dependent RNA polymerase. It is envisaged that the compounds of the present invention have utility in all conditions and disorders stemming or related to inhibition of DENV RNA-dependent RNA polymerase. In other words, the compounds and compositions are used to treat, prevent or delay either the onset/progress of DENV infection or onset/progress of any physiological condition that is associated with DENV infection. All compounds of the present invention were tested and found to be active in a clinically significant manner. The compounds of present invention are inhibitors of DENV RNA-dependent RNA polymerase and possess utility in all instances where inhibition of DENV RNA-dependent RNA polymerase is indicated. The compounds according to the present invention is envisaged to treat, prevent or delay either the onset/progress of infection by other members of the group Flaviviridae or onset/progress of any physiological condition that is associated with infection by other members of the group Flaviviridae. The compounds according to the present invention is also envisaged to treat onset/progress either the infection by Chikungunya virus (CHIKV) or any physiological condition that is associated with CHIKV infection.
The examples and scheme below depict the general synthetic procedure for the compounds disclosed herein. Synthesis of the compounds of Formulae I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, and that the procedures described in the examples and schemes is only one such procedure. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no description of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
The present invention is illustrated by means of examples. The examples are meant only for illustrative purposes and cannot be construed as limiting.
A. Examples illustrating synthesis of the compounds of present invention
EXPERIMENTAL SECTION:
Abbreviations used in the experimental section:
Figure imgf000063_0001
Figure imgf000064_0001
Example-l:(E/Z)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide
Synthesis of 2-oxoindoline-5-sulfonyl chloride (2):
An ice cooled CISO3H (20 mL), was charged with indolin-2-one 1 (5.0 g, 37.5 mmol) portion wise at 0 °C, after complete addition reaction mixture stirred at room temperature for 30 min and heated at 70 °C for 1 h. The reaction mixture was cooled to room temperature then poured into crushed ice and filter the precipitated solid and washed with water. Obtained solid dried under reduced pressure to afford 2-oxoindoline-5-sulfonyl chloride 2 (6.5 g, 74%): ESI [C8H6C1N03S+H]+231
Synthesis of 4-amino-N-hydroxybenzamide (4): The solution of NH2OH.HCI (4.13 g, 59.5 mmol), in MeOH (20 mL), at room temperature was charged with 6N NaOH (11 mL, 66.1 mmol), stirred for 10 min then charged with methyl 4-aminobenzoate 3 (1.0 g, 6.615 mmol), and reaction mixture stirred at room temperature for 48 h. The reaction mixture diluted with water (50 mL), acidified to pH = 6 by addition of 2N HC1 solution then extracted with EtOAc (3 x 100 mL), combined organic layer dried over anhydrous NaiSCri and concentrated under reduced pressure. Obtained solid washed with dichloromethane(20 mL) and dried under vacuum to afford 4-amino-N-hydroxybenzamide 4 (0.8 g, 79%) : ESI [CVH8N202+H]+153
Synthesis of N-hydroxy-4-(2-oxoindoline-5-sulfonamido)benzamide (5): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (500 mg, 2.15 mmol) and 4-amino-N-hydroxybenzamide 4 (492 mg, 3.23 mmol), in 1, 4-dioxane was charged with pyridine (509 mg, 6.45 mmol), resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture cooled to room temperature diluted with water (20 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 100 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with CH2CI2 and dried under vacuum to afford N-hydroxy-4-(2-oxoindoline-5- sulfonamido)benzamide 5 (300 mg, 40%) : ESI [C15H13N3O5S +H]+348
Synthesis of (E/Z)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1001): A solution of N-hydroxy-4-(2-oxoindoline-5- sulfonamido)benzamide 5 (300 mg, 0.863mmol), thiazole-2-carbaldehyde 6 (146 mg, 1.295 mmol), in EtOH (10 mL) was charged with pyrrolidine (183 mg, 2.59 mmol), resultant reaction mixture stirred at 50 °C for 1 h. The reaction mixture cooled to room temperature diluted with water acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 100 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE (2 x 5 mL) and dried under vacuum to afford (E)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1001) (120 mg, 31%): Yield: 60%; IR (KBr): u (cm 1) 2989, 2861, 1702, 1608, 1510, 1435, 1017, 891; ¾ NMR (300 MHz, DMSO- e): d 12.5 (bs, 1H), 11.2 (s, 1H), 10.83 (s, 1H), 9.74 (d, J= 1.5 Hz, 1H), 8.35 (d, J= 3.0 Hz, 1H), 8.25 (d, J= 3.0 Hz, 1H), 7.83 (dd, J = 1.8, 8.4 Hz, 1H), 7.80 - 7.75 (m, 3H), 7.27 (d, J= 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO- e): d 170, 165.2, 161.5, 147.1, 145.9, 140.5, 132.2, 130.3, 129.4, 128.2, 126.7, 126.3, 125.6, 125.4, 121.1, 117.8, 110.3; ESI [C19H14N4O5S2 +H]+ 443 Example-2: (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)benzoic acid (1002)
Figure imgf000066_0001
Synthesis of 4-(2-oxoindoline-5-sulfonamido)benzoic acid (8): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (1.00 g, 4.32 mmol), and 4-aminobenzoic acid 7 (593 mg, 4.32 mmol), in 1, 4-dioxane (20 mL), was charged with pyridine (1.02 g, 12.9 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 50 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (2 c 20 mL) and dried under vacuum to afford 4-(2-oxoindoline-5-sulfonamido)benzoic acid 8 (1.20 g, 83%) as brown solid; ESI [C15H12N2O5S + H]+333.
Synthesis of (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)benzoic acid (1002): A solution of 4-(2-oxoindoline-5-sulfonamido)benzoic acid 8 (1.20 g, 3.61 mmol), thiazole-2-carbaldehyde 6 (614 mg, 5.40 mmol), in EtOH (20 mL) was charged with pyrrolidine (768 mg, 10.8 mmol), resultant reaction mixture stirred at room temperature for 1 h then heated at 50 °C for 2 h. The reaction mixture cooled to room temperature diluted with water acidified to pH = 2 by 2N HC1 solution then filtered the solid and washed with hexanes (50 mL), dried under reduced pressure. Obtained solid washed with MTBE (2 x 10 mL) and dried under vacuum to afford (E)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzoic acid (1002) (1.10 g, 71%) as a brown solid; ¾ NMR (300 MHz, DMSO- e): d 11.17 (s, 1H), 10.83 (s, 1H), 9.75 (d, J = 1.5 Hz, 1H), 8.36 (d, J = 3.0 Hz, 1H), 8.22 (d, J= 3.0 Hz, 1H), 7.83 (dd, J= 1.8, 8.4 Hz, 1H), 7.78 - 7.75 (m, 3H), 7.27 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO- e): d 170, 165.2, 161.5, 147.1, 145.9, 140.5, 132.2, 130.3, 129.4, 128.2, 126.7, 126.3, 125.6, 125.4, 121.1, 117.9, 110; IR (KBr): u (cm 1) 3430, 2762, 1705, 1630, 1608, 1339, 1168, 917, 847, 767;ESI [C19H13N3O5S2 + H]+428
Example-3: (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1003)
Figure imgf000067_0001
Synthesis of (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1003): A solution of (E)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), pyrrolidine 9a (24.9 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water acidified to pH = 2 by 2N HC1 then solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75-150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E)-2-oxo-N-(4-(pyrrolidine-l- carbonyl)phenyl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1003) (65 mg, 58%) as a yellow solid: ¾ NMR (300 MHz, DMSO- e): d 11.15 (s, 1H), 10.53 (s, 1H), 9.69 (s, 1H), 8.34 (d, J = 3.3 Hz, 1H), 8.22 (d, J = 3.3 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.37 (d, J= 8.4 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 8.1 Hz, 1H), 3.38-3.34 (m, 2H), 3.19-3.17 (m, 2H), 1.81-1.69 (m, 4H); 13C NMR (100 MHz, DMSO- e): d 168.9, 168.5, 161.6, 147.0, 145.9, 139.3, 132.3, 130.2, 130.0, 128.4, 126.7, 126.3, 125.6, 125.3, 121.1, 118.5, 110.1, 45.1, 22.9; IR (KBr): u (cm 1) 3430, 2965, 1718, 1634, 1608, 1467, 1339, 1167, 811, 761; ESI [C23H20N4O4S2 + H]+481 Example-4: (E/Z)-2-oxo-N-(4-(piperidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1004)
Figure imgf000068_0001
1002 1004
Synthesis of (E/Z)-2-oxo-N-(4-(piperidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1004): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), piperidine 9b (29.8 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by addition of 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75- 150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-2-oxo-N-(4- (piperidine-l-carbonyl)phenyl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1004) (58 mg, 50%) as a pink solid: ¾ MR (400 MHz, DMSO- e): d 11.16 (s, 1H), 10.53 (s, 1H), 9.70 (d, 7= 1.6 Hz, 1H), 8.35 (d, J= 3.2 Hz, 1H), 8.22 (d, 7= 3.2 Hz, 1H), 7.80 (dd, J= 8.4, 2.0 Hz, 1H), 7.75 (s, 1H), 7.29-7.19 (m, 4H), 7.04 (d, J = 8.4 Hz, 1H), 3.56-3.35 (m, 4H), 1.55-1.44 (m, 6H); 13C NMR (100 MHz, DMSO-76): d 168.4, 168.9, 161.5, 146.9, 145.9, 139.3, 132.2,132.1, 130.2, 127.3, 126.6, 126.4, 125.7, 125.3, 121.1, 118.7, 110.0, 42.5, 26.6, 23.1; JR (KBr): u (cm 1) 3262, 2929, 1716, 1636, 1606, 1404, 1163, 1096, 926; ESI [C24H22N4O4S2 + H]+ 495
Example-5: (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)-N-
(pentan-3-yl)benzamide (1005)
Figure imgf000069_0001
H H
1002 1005
Synthesis of (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)-N- (pentan-3-yl)benzamide (1005): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), pentan-3- amine 9c (30.4 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75-150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)-N-(pentan-3-yl)benzamide (1005) (50 mg, 43%) as a yellow solid: ¾ NMR (400 MHz, DMSO- e): d 11.15 (s, 1H), 10.66 (s, 1H), 9.74 (d, J = 1.60 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.22 (d, J= 3.2 Hz, 1H), 7.81 (dd, J= 8.2, 1.2 Hz, 2H), 7.76 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 3.72-3.67 (m, 1H), 1.48-1.34 (m, 4H), 0.80-0.77 (m, 6H); 13C NMR (100 MHz, DMSO- e): d 168.9, 165.3, 161.5, 157.2, 147.0, 145.9, 132.2, 130.3, 129.7, 128.4, 126.7, 126.3, 125.6, 125.4, 121.2, 117.9, 110.0, 51.9, 26.8, 10.6; IR (KBr): u (cm 1) 2925, 1715, 1630, 1608, 1504, 1464, 1128, 1166, 915, 766; ESI [C24H24N4O4S2 + H]+497
Example-6:(E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline- 5sulfonamido)benzamide (1006)
Figure imgf000069_0002
Synthesis of (E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1006): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), butan-1- amine 9d (25.6 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by addition of 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75- 150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-N-butyl-4-(2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamido)benzamide (1006) (48 mg, 42%) as a yellow solid: ¾ NMR (400 MHz, DMSO^/e): d 11.16 (s, 1H), 10.67 (s, 1H), 9.73 (d, J= 2.0 Hz, 1H), 8.34 (d, J = 3.2 Hz, 1H), 8.23-8.22 (m, 2H), 7.80 (dd, J = 8.2, 1.6 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 8.8 Hz, 2H), 7.04 (d, J= 8.4 Hz, 1H), 3.17 (q, J = 6.8 Hz, 2H), 1.45-1.41 (m, 2H), 1.29-1.23 (m, 2H), 0.85 (t, J= 7.2 Hz, 3H); 13C NMR (400 MHz, DMSO- e): d 168.9, 165.2, 161.5, 147, 145.9, 140.5, 132.2, 130.3, 129.4, 128.3, 126.7, 126.3, 125.06, 125.4, 121.7, 117.9, 110, 41.2, 31.2, 19.6, 13.6; IR (KBr): u (cm 1) 3112, 1702, 1608, 1435, 1278, 1114, 1017, 921; ESI [C23H22N4O4S2 + H]+ 483.1.
Example-7:(E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1007)
Figure imgf000070_0001
1002
Synthesis of (E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1007): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), 2- methoxyethanamine 9e (26.3 mg, 0.35 mmol) in DMF (3.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 50 mL), combined organic layer washed with cold water (3 x 10 mL), dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75-150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1007) (49.0 mg, 43%) as a yellow solid: ¾ NMR (400 MHz, DMSO- e): d 11.17 (s, 1H), 10.7 (s, 1H), 9.73 (d, J= 2.0 Hz, 1H), 8.34-8.33 (m, 2H), 8.22 (d, J = 2.8 Hz, 1H), 7.80 (dd, J = 1.6, 8.2 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J= 8.8 Hz, 2H), 7.21 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 8.4 Hz, 1H), 3.38-3.35 (m, 4H), 3.15 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 168.9, 165.4, 161.5, 147.0, 145.9, 140.6, 132.2, 130.3, 128.8, 128.4, 126.6, 126.3, 125.6, 125.4, 121.2, 117.9, 110.0, 70.4, 57.8, 36.3; IR (KBr): u (cm 1) 3263, 1714, 1607, 1507, 1313, 1116, 920; ESI [C22H20N4O5S2 + H]+485.
Example-8: (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1008)
Figure imgf000071_0001
1002
Synthesis of (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1008): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), cyclopropanamine9f (19.9 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water acidified to pH = 2 by addition of 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE (2 x 10 mL) and died to afford (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1008) (58 mg, 54%) as a yellow solid: ¾ NMR (300 MHz, DMSO- e): d 11.14 (s, 1H), 10.67 (s, 1H), 9.73 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 3.0 Hz, 1H), 8.21-8.22 (m, 2H), 7.79 (dd, J = 1.8, 8.4 Hz, 1H), 7.75 (s, 1H), 7.67 (d, J = 6.6 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.03 (d, J= 8.4 Hz, 1H), 2.77-2.69 (m, 1H), 0.66-0.60 (m, 2H), 0.50-0.48 (m, 2H); 13C NMR (100 MHz, DMSO- e): d 168.9, 166.7, 161.5, 147.0,
145.9, 140.6, 132.2, 130.3, 129.1, 128.3, 126.6, 126.3, 125.6, 125.4, 121.2, 117.9, 110.0,
22.9, 5.7; IR (KBr): u (cm 1) 2914, 1703, 1609, 1463, 1435, 1304, 1140, 890; ESI [C22H18N4O4S2 + H]+467.
Example-9: (E/Z)-
N-(4— (morpholine-4-carbonyl)phenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-s ulfonamide (1009)
Figure imgf000072_0001
1002
Synthesis of (E/Z)-
N-(4— (morpholine-4-carbonyl)phenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-s ulfonamide (1009): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), morpholine 9g (30.5 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried to afford (E/Z)-(4-(morpholine-4-carbonyl)phenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-s ulfonamide (1009) (58 mg, 50%) as a yellow solid: ¾ NMR (400 MHz, DMSO- is): d 11.15 (s, 1H), 10.57 (s, 1H), 9.71 (d, J = 1.2 Hz, 1H), 8.35 (d, 7= 3.2 Hz, 1H), 8.22 (d, J = 3.2 Hz, 1H), 7.81 (dd, J= 1.2, 6.4 Hz, 1H), 7.75 (s, 1H), 7.28-7.21 (m, 4H), 7.04 (d, J= 6.4 Hz, 1H), 3.49-3.46 (m, 8H); 13C NMR (100 MHz, DMSO- e): d 168.9, 168.5, 161.5, 147.0,
145.9, 139.3, 132.3, 130.2, 130.1, 128.4, 126.7, 126.3, 125.6, 125.3, 121.1, 118.5, 110.0,
65.9, 43.8; IR (KBr): u (cm 1) 2989, 1702, 1608, 1435, 1221, 1164, 1017, 921; ESI [C23H20N4O5S2 + H]+497.
Example-10: (E/Z)-N-isobutyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1010)
Figure imgf000073_0001
1002
Synthesis of (E/Z)-N-isobutyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1010): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), 2- methylpropan-1 -amine 9h (25.6 mg, 0.35 mmol) in DMF (5.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then filtered the solid washed with water (20 mL). Obtained solid dissolved in EtOAc (50 mL) dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried to afford (E/Z)-N-isobutyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1010) (48 mg, 42%) as a light yellow solid; ¾ NMR (400 MHz, DMSO- e): d 11.15 (s, 1H), 10.67 (s, 1H), 9.74 (d, J = 2.0 Hz, 1H), 8.34 (d, J = 3.2 Hz, 1H), 8.25-8.21 (m, 2H), 7.81 (dd, 7 = 1.6, 8.2 Hz, 1H), 7.76 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 7.03 (d, J= 8.0 Hz, 1H), 2.99 (t, J= 6.4 Hz, 2H), 1.81-1.71 (m, 1H), 0.83 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, DMSO-76): d 168.9, 165.4, 161.5, 147.0, 145.9, 140.5, 132.2, 130.3, 129.4, 128.3, 126.6, 126.3, 125.6, 125.4, 121.2, 117.9, 110.0, 46.5, 28.0, 20.1; JR (KBr): u (cm 1) 2923, 1712, 1623, 1403, 1166, 921, 724;ESI [C23H22N4O4S2 + H]+483.
Example-11: (E/Z)-N,N-diethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1011)
Figure imgf000074_0001
1002
Synthesis of (E/Z)-N,N-diethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1011): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), diethylamine9i (25.6 mg, 0.35 mmol) in DMF (3.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 50 mL), combined organic layer dried over anhydrous NaiSCE and concentrated under reduced pressure. Obtained solid purified by column chromatography eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-N,N-diethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1011) (52 mg, 46%) as yellow solid; ¾ NMR (400 MHz, DMSO- e): d 11.14 (s, 1H), 10.5 (s, 1H), 9.70 (s, 1H), 8.34 (d, J= 2.8 Hz, 1H), 8.21 (d, 7 = 2.8 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.74 (s, 1H), 7.26 (d, J= 8.4 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 7.04 (d, J = 8.4 Hz, 1H), 3.18-3.16 (m, 4H), 1.03 (t, J = 6.2 Hz, 6H) ; 13C NMR (100 MHz, DMSO-de): d 169.4, 168.9, 161.5, 146.9, 146.0, 138.7, 132.2, 132.0, 130.2, 127.3, 126.6, 126.3, 125.7, 125.3, 121.1, 118.7, 109.9, 42.5, 13.1; IR (KBr): u (cm 1) 3155, 1695, 1607, 1443, 1305, 1166, 920, 732; ESI [C23H22N4O4S2 + H]+483.
Example-12:(E/Z)-N,N-dimethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1012)
Figure imgf000075_0001
Synthesis of (E/Z)-N,N-dimethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1012): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), dimethyl amine 2M in THF 9j (0.175 mL, 0.35 mmol) in DMF (3.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 50 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid purified by column chromatography on silicagel (75-150 pm) eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-N,N-dimethyl-4-(2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamido)benzamide (1012) (59 mg, 45%) as yellow solid; 1H NMR (400 MHz, DMSO^/e): d 11.14 (s, 1H), 10.5 (s, 1H), 9.70 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.21 (d, J= 2.8 Hz, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.74 (s, 1H), 7.28-7.20 (m, 4H), 7.04 (d, J = 8.4 Hz, 1H), 2.08 (bs, 3H), 2.74 (bs, 3H); 13C NMR (100 MHz, DMSO- e): d 169.5, 168.9, 161.5, 146.9, 145.9, 139.0, 132.3, 131.1, 130.2, 128.3, 126.6, 126.4, 125.6, 125.3, 121.1, 118.4, 109.9, 37.8; IR (KBr): u (cm 1) 3129, 2925, 1695, 1609, 1306, 1141, 925, 762; ESI [C21H18N4O4S2 + H]+ 455.2
Example-13: (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-
Figure imgf000075_0002
Synthesis of (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide (1013): A solution of (E/Z)-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzoic acid (1002) (100 mg, 0.23 mmol), N,O- dimethylhydroxylamine .HC1 9k (34.1 mg, 0.35 mmol) in DMF (3.0 mL), were charged with HATU (133 mg, 0.35 mmol), followed by DIPEA (0.115 mL, 0.701 mmol) resultant reaction mixture stirred at room temperature for 3 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 50 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid purified by column chromatography eluted with 1-10% CH3OH in dichloromethane to afford (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamido)benzamide (1013) (59 mg, 54%) as light yellow solid; ¾ NMR (400 MHz, DMSO- e): d 11.15 (s, 1H), 10.66 (s, 1H), 9.75 (d, J = 2.0 Hz, 1H), 8.35 (d, J= 3.2 Hz, 1H), 8.22 (d, J= 2.8 Hz, 1H), 7.82 (dd, J= 2.0, 8.0 Hz, 1H), 7.75 (s, 1H), 7.47 (d, J= 8.8 Hz, 2H), 7.22 (d, J= 8.8 Hz, 2H), 7.04 (d, J= 8.4 Hz, 1H), 3.41 (s, 3H), 3.15 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 168.9, 165.4, 161.5, 147.0, 145.9, 140.6, 132.2, 130.3, 129.0, 128.3, 126.6, 126.3, 125.6, 125.4, 120.6, 117.9, 110.0, 70.4, 57.8; IR (KBr): u (cm 1) 3183, 2935, 1691, 1605, 1464, 1169, 912, 754; ESI [C21H18N4O5S2
+ H]+471
Example-14: (E/Z)-N-(5-chloro-2-fluorophenyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1014)
Figure imgf000076_0001
Figure imgf000076_0002
1014 H Synthesis of N-(5-chloro-2-fluorophenyl)-2-oxoindoline-5-sulfonamide (10): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.86 mmol), and 5-chloro-2-fluoroaniline 91 (188 mg, 1.29 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (205 mg, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(5-chloro-2-fluorophenyl)-2-oxoindoline-5-sulfonamide 10 (160 mg, 54%) as a yellow solid;ESI[Ci4HioClFN203S + H]+341
Synthesis of (E/Z)-N-(5-chloro-2-fluorophenyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1014): A solution of N-(5-chloro-2-fluorophenyl)-2- oxoindoline-5-sulfonamide 10 (160 mg, 0.47 mmol), thiazole-2-carbaldehyde 6 (79.9 mg, 0.705 mmol), in EtOH (1.0 mL) was charged with pyrrolidine (100.1 mg, 1.41 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature and filtered the precipitated solid, washed with EtOH (5 mL) and with MTBE (15 mL). Obtained solid dried under reduced pressure to afford (E/Z)-N-(5-chloro- 2-fluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1014) (68 mg, 33%) as yellow solid: ¾ NMR (400 MHz, DMSO- e): 5 11.18 (s, 1H), 10.39 (s, 1H), 9.61 (s, 1H), 8.17-8.20 (m, 2H), 7.74-7.77 (m, 2H), 7.39-7.41 (m, 1H), 7.20-7.26 (m, 2H), 7.05 (d, J= 4.0 Hz, 1H); 13C NMR (100 MHz, DMSO- e): 5 168.9, 161.4, 154.9, 152.5, 147.0, 145.7, 132.3, 130.2, 128.0, 126.5, 126.2, 125.5, 125.4, 124.8, 121.1, 117.7, 117.5, 109.9; IR (KBr): u (cm 1 3254, 1717, 1611, 1495, 1306, 1170, 934, 733; ESI [C14H10CIFN2O3S + H]+ 435.
Example-15: (E/Z)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1015)
Figure imgf000078_0001
Synthesis of N-(2,4-difluorobenzyl)-2-oxoindoline-5-sulfonamide (11): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 5(2,4- difluorophenyl)methanamine9m (185 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (205 mg, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-(2,4-difluorobenzyl)-2-oxoindoline-5- sulfonamide 11 (180 mg, 61%); ESI [C15H12F2N2O3S + H]+339.
Synthesis of (E/Z)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1015): A solution of N-(2,4-difluorobenzyl)-2-oxoindoline-5-sulfonamide 11(180 mg, 0.532 mmol), thiazole-2-carbaldehyde 6 (90.5 mg, 0.798 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (113.3 mg, 1.59 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature and filtered the precipitated solid, washed with EtOH (5 mL) and with MTBE (15 mL). Obtained solid dried under reduced pressure to afford (E/Z)-N-(2,4- difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1015) (120 mg, 52%) as yellow solid; ¾ NMR (400 MHz, DMSO- e): d 11.12 (s, 1H), 9.61 (d, J= 2.0 Hz, 1H), 8.29 (d, J= 3.2 Hz, 1H), 8.21 (d, J= 3.2 Hz, 1H), 8.14 (t, J= 6.4 Hz, 1H), 7.78 (s, 1H), 7.75 (dd, J= 2.0, 8.0 Hz, 1H), 7.34-7.32 (m, 1H), 7.06-6.91 (m, 2H), 6.88 (dt, J= 1.6, 4.6 Hz, 1H), 4.08 (d, J= 6.40 Hz, 2H); 13C NMR (100 MHz, DMSO- e): d 169.0, 162.7, 161.5, 160.9, 160.3, 160.1, 158.6, 146.4, 133.6, 131.3, 130.0, 126.5, 125.4, 121.0, 120.8, 111.1, 110.9, 109.7, 103.3; IR (KBr):u (cm 1) 3225, 2871, 1696, 1605, 1466, 1169, 852, 732;ESI
[C19H13F2N3O3S2+ H]+ .
Example-16: (E/Z)-N-(2,5-difluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1016)
Figure imgf000079_0001
Synthesis of N-(2,5-difluorophenyl)-2-oxoindoline-5-sulfonamide (12): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 5(2,4- difluorophenyl)methanamine9n (167 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (205 mg, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Obtained solid washed with MTBE and dried under vacuum to afford N-(2,5-difluorophenyl)-2-oxoindoline-5- sulfonamide 12 (160 mg, 57%) as yellow solid; ESI [C14H10F2N2O3S + H]+ 325.
Synthesis of (E/Z)-N-(2,5-difluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1016): A solution of N -(2,5-difluorophenyl)-2-oxoindoline-5-sulfonamide 12 (160 mg, 0.493 mmol), thiazole-2-carbaldehyde 6 (83.9 mg, 0.74 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (105 mg, 1.479 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature and filtered the precipitated solid, washed with EtOH (5 mL) and with MTBE (15 mL). Obtained solid dried under reduced pressure to afford (E/Z)-N -(2,5- difluorophenyl)-2-oxoindoline-5-sulfonamide (1016) (120 mg, 58%) as yellow solid; 1H-NMR (300 MHz, DMSO- e): d 11.18 (s, 1H), 10.40 (s, 1H), 9.63 (d, J= 1.5 Hz, 1H), 8.19 (s, 2H), 7.77-7.76 (m, 2H), 7.27-7.14 (m, 2H), 7.05 (d, J= 8.4 Hz, 1H), 6.98-6.91 (m, 1H); 13C NMR (100 MHz, DMSO-de): d 168.9, 161.4, 147.0, 145.7, 132.3, 130.2, 126.5,
126.3, 126.1, 125.5, 125.3, 121.1, 117.1, 117.0, 116.9, 116.8, 112.6, 112.5, 112.4, 112.3,
111.4, 111.1, 109.9; IR (KBr):u (cm 1) 2345, 1716, 1611, 1496, 1255, 1171, 932, 823; ESI [C18H11F2N3O3S2+ H]+ 420.
Example-17:(E/Z)-2-oxo-N-(pentan-3-yl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1017)
Figure imgf000080_0001
Synthesis of 2-oxo-N-(pentan-3-yl)indoline-5-sulfonamide (13): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and pentan-3 -amine 9c (112 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (205 mg, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 6 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCri and concentrated under reduced pressure. Obtained solid washed with MTBE and dried under vacuum to afford 2- oxo-N-(pentan-3-yl)indoline-5-sulfonamide 13 (130 mg, 53%); ESI [C13H18N2O3S + H]+ 283.
Synthesis of (E/Z)-2-oxo-N-(pentan-3-yl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1017): A solution of 2-oxo-N-(pentan-3-yl)indoline-5-sulfonamide 13 (130 mg, 0.46 mmol), thiazole-2-carbaldehyde 6 (72 mg, 0.63 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (98 mg, 1.38 mmol), resultant reaction mixture stirred room temperature for 2h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature diluted with water acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 100 mL), combined organic layer dried over anhydrous NaiSCri and concentrated under reduced pressure. Obtained crude compound purified by column chromatography on silicagel (75-150 pm) eluted with 1-10% MeOH in dichloromethane to afford (E)-2-oxo-N-(pentan-3-yl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1017) (80 mg, 46%); 1H-NMR (400 MHz, DMSO-76): d 11.10 (s, 1H), 9.69 (d, 7= 1.6 Hz, 1H), 8.30 (d, J= 3.6 Hz, 1H), 8.20 (d, J= 3.2 Hz, 1H), 7.80-7.77 (m, 2H), 7.59 (d, J= 7.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.03-2.98 (m, 1H), 1.37-1.23 (m, 4H), 0.78-0.62 (m, 6H); 13C NMR (100 MHz, DMSO-76): d 169.1, 161.6, 146.1, 145.8, 135.5, 129.9, 126.8, 126.4, 125.4, 124.9, 120.9, 109.6, 56.1, 26.7, 9.8; IR (KBr):u (cm 1) 2855, 1709, 1610, 1465, 1306, 1165, 1113, 794; ESI [C17H19N3O3S2+ H]+ 378.
Example-18: (E/Z)-5-(morpholinosulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one
(1018)
Figure imgf000081_0001
1018
Synthesis of 5-(morpholinosulfonyl)indolin-2-one (14): A solution of 2-oxoindoline-5- sulfonyl chloride 2 (200 mg, 0.86 mmol), and morpholine 9g (112 mg, 1.29 mmol), in 1, 4- dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained solid washed with MTBE and dried under vacuum to afford 5- (morpholinosulfonyl)indolin-2-one 14 (150 mg, 61%); ESI [C12H14N2O4S + H]+ 283. Synthesis of (E/Z)-5-(morpholinosulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one (1018): A solution of 5-(morpholinosulfonyl)indolin-2-one 14 (140 mg, 0.526 mmol), thiazole-2-carbaldehyde 6 (90.4 mg, 0.79 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (113 mg, 1.58 mmol), resultant reaction mixture stirred room temperature for 2h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature diluted with water acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained crude compound was purified by column chromatography on silicagel (75-150 pm), eluted with 1-10% MeOH in dichloromethane to afford (E/Z)-5- (morpholinosulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one (1018) (95 mg, 42%) as yellow solid; 1H-NMR (300 MHz, DMSO- e): d 11.21 (s, 1H), 9.67 (d, J = 1.2 Hz, 1H), 8.32 (d, J = 3.0 Hz, 1H), 8.21 (d, J = 3.0 Hz, 1H), 7.82 (s, 1H), 7.72 (dd, J = 1.5, 8.2 Hz, 1H), 7.11 (d, J= 8.1 Hz, 1H), 3.66-3.64 (m, 4H), 2.96-2.94 (m, 4H); 13C NMR (100 MHz, DMSO-de): d 169.0, 161.6, 147.2, 145.9, 131.2, 127.2, 126.7, 126.4, 126.3, 125.4, 121.5, 109.9, 65.3, 45.9; IR (KBr):u (cm 1) 3129, 2861, 1705, 1605, 1465, 1305, 1165, 1112, 950, 726; ESI [C16H15N3O4S2+ H]+ 378.
Example-19: (E/Z)-5-(pyrrolidin-l-ylsulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one (1019)
Figure imgf000082_0001
1019 Synthesis of 5-(pyrrolidin-l-ylsulfonyl)indolin-2-one (15): A solution of 2-oxoindoline-5- sulfonyl chloride 2 (200 mg, 0.865 mmol), and pyrrolidine 9a (97.4 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 with 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCri and concentrated under reduced pressure. Obtained solid washed with MTBE and dried under vacuum to afford 5-(pyrrolidin-l- ylsulfonyl)indolin-2-one 15 (110 mg, 47%) as a yellow solid;ESI[Ci2Hi4N203S+ H]+ 267.
Synthesis of (E/Z)-5-(pyrrolidin-l-ylsulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one (1019): A solution of 5-(pyrrolidin-l-ylsulfonyl)indolin-2-one 15 (110 mg, 0.406 mmol), thiazole-2-carbaldehyde 6 (83 mg, 0.73 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (86 mg, 1.22 mmol), The resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature diluted with water (10 mL) acidified to pH = 2 with 2N HC1 solution then extracted with EtOAc (3 x 100 mL), combined organic layer dried over anhydrous Na2S04 and concentrated under reduced pressure. Obtained crude compound purified by column chromatography on silicagel (75-150 pm), eluted with 1-10% MeOH in dichloromethane to afford (E/Z)-5- (pyrrolidin-l-ylsulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one (1019) (85 mg, 48%) as yellow solid^H-NMR (300 MHz, DMSO- e): d 11.13 (s, 1H), 9.71 (d, J = 2.0 Hz, 1H), 8.29 (d, J= 3.2 Hz, 1H), 8.21 (d, J= 3.2 Hz, 1H), 7.80 (s, 1H), 7.77 (dd, J= 2.0 , 8.0 Hz, 1H), 7.08 (d, J= 8.4 Hz, 1H), 3.22-3.18 (m, 4H), 1.69-1.65 (m, 4H); 13C NMR (100 MHz, DMSO-de): 5168.9, 161.7, 146.8, 145.7, 130.9, 129.5, 126.7, 126.6, 125.8, 125.2, 121.5, 109.7, 47.8, 24.7; IR (KBr):u (cm 1) 2917, 1704, 1606, 1466, 1306, 1145, 951, 726; ESI [C16H15N3O3S2+ H]+ 362.
Example-20: (E/Z)-N-cyclohexyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1020)
Figure imgf000084_0001
1020
Synthesis of N-cyclohexyl-2-oxoindoline-5-sulfonamide (16): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and cyclohexanamine9o (128.5 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 c 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-cyclohexyl-2-oxoindoline-5-sulfonamide 16 (170 mg, 66%); ESI [C14H18N2O3S+ H]+ 295.
Synthesis of (E/Z)-N-cyclohexyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1020): A solution of N-cyclohexyl-2-oxoindoline-5-sulfonamide 16 (170 mg, 0.578 mmol), thiazole-2-carbaldehyde 6 (98 mg, 0.86 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (123 mg, 1.73 mmol), resultant reaction mixture stirred room temperature for 2h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature diluted with water acidified to pH = 2 by 2N HC1 solution, filtered the precipitated solid, washed with water (10 mL) and with MTBE (20 mL). Obtained solid dried under vacuum to afford (E/Z)-N-cyclohexyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1020) (85 mg, 50%) as a light yellow solid; ¾-NMR (400 MHz, DMSO- e): d 11.10 (s, 1H), 9.69 (d, J = 1.6 Hz, 1H), 8.30 (d, J= 3.6 Hz, 1H), 8.20 (d, J= 3.2 Hz, 1H), 7.80-7.77 (m, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 3.01-2.98 (m, 1H), 1.68-1.57 (m, 4H), 1.44-1.41 (m, 1H), 1.21-1.06 (m, 5H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.6, 146.2, 145.9, 135.3, 129.8, 126.7, 126.5, 125.2, 125.0, 121.1, 109.8, 52.1, 33.3, 24.8, 24.4; IR (KBr):u (cm 1) 3226, 2930, 1708, 1610, 1466, 1307, 1165, 1068, 733, 528 ; ESI [C18H19N3O3S2+ H]+
390.
Example-21 :(E/Z)-N-benzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide
(1021)
Figure imgf000085_0001
Synthesis of N-benzyl-2-oxoindoline-5-sulfonamide (18): A solution of 2-oxoindoline-5- sulfonyl chloride 2 (200 mg, 0.865 mmol), and benzyl amine 17 (138 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCE and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N- benzyl-2-oxoindoline-5-sulfonamide 18 (160 mg, 61%) as a yellow solid; ESI [C15H14N2O3S+ H]+303.
Synthesis of (E/Z)-N-benzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1021): A solution of N-benzyl-2-oxoindoline-5-sulfonamide 18 (160 mg, 0.529 mmol), thiazole-2-carbaldehyde 6 (90 mg, 0.79 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (112 mg, 1.578 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N- benzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1021) (70 mg, 33%) as a yellow solid; 1H-NMR (400 MHz, DMSO- e): d 11.10 (s, 1H), 9.68 (d, J= 1.20 Hz, 1H), 8.28 (dd, J = 0.6, 8.1 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 8.18-8.17 (m, 1H), 7.80-7.77 (m, 2H), 7.28-7.19 (m, 5H), 7.03 (d, J= 6.30 Hz, 1H), 4.05 (d, J= 2.70 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d 169.0, 161.6, 146.4, 145.8, 137.7, 133.86, 130.0, 128.1, 127.6, 127.5, 126.7, 126.5, 125.5, 125.0, 121.1, 109.7, 46.2; IR (KBr): u (cm 1) 3219, 2361, 1696, 1603, 1463, 1332, 1166, 1066, 734; ESI [C19H15N3O3S2+ H]+398.
Example-22: (E/Z)-N-(3-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1022)
Figure imgf000086_0001
Synthesis of N-(3-fluorobenzyl)-2-oxoindoline-5-sulfonamide (20): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 3-fluorobenzyl amine 19 (162 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-(3-fluorobenzyl)-2-oxoindoline-5-sulfonamide 20 (150 mg, 54%) as a yellow solid; ESI [C15H13FN2O3S+ H]+321 Synthesis of (E/Z)-N-(3-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1022): A solution of N-(3-fluorobenzyl)-2-oxoindoline-5-sulfonamide 20 ( (150 mg, 0.468 mmol), thiazole-2-carbaldehyde 6 (79.7 mg, 0.703 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (99.6 mg, 1.404 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(3-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1022)(80 mg, 41%); 1H-NMR (400 MHz, DMSO- e): d 11.10 (s, 1H), 9.65 (d, J = 2.00 Hz, 1H), 8.29 (d, J = 3.20 Hz, 1H), 8.20-8.19 (m, 2H), 7.78-7.76 (m, 2H), 7.29-7.19 (m, 1H), 7.08-7.02 (m, 4H), 4.09 (d, J = 3.20 Hz, 2H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.5, 146.4, 145.8, 140.8, 133.7, 130.0, 129.9, 126.6, 126.4, 125.5, 125.0, 123.4, 121.1, 114.2, 114.0, 113.7, 113.5, 109.7, 45.6; IR (KBr): u (cm 1) 2920, 1696, 1606, 1462, 1333, 1166, 1069, 923, 788; ESI [C19H14FN3O3S2+ H]+416.
Example-23: (E/Z)-N-(4-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1023)
Figure imgf000087_0001
Synthesis of N-(4-chlorobenzyl)-2-oxoindoline-5-sulfonamide (22): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 4-chlorobenzyl amine 21 (182 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 with 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(4-chlorobenzyl)-2-oxoindoline-5-sulfonamide 22 (150 mg, 51%) as a yellow solid; ESI [C15H13CIN2O3S+ H]+337.
Synthesis of (E/Z)-N-(4-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1023): A solution of N-(4-chlorobenzyl)-2-oxoindoline-5-sulfonamide 22 (150 mg, 0.446 mmol), thiazole-2-carbaldehyde 6 (95 mg, 1.33 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (75 mg, 0.669 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature, filtered the solid, washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(4-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1023) (70 mg, 36%); 1H-NMR (400 MHz, DMSO- e): 11.08 (s, 1H), 9.60 (d, J= 2.00 Hz, 1H), 8.29 (d, J= 3.20 Hz, 1H), 8.20-8.19 (m, 1H), 8.18-8.17 (m, 1H), 7.75 (dd, J= 2.00 , 8.40 Hz, 2H), 7.28-7.22 (m, 4H), 7.02 (d, J = 8.00 Hz, 1H), 4.05 (s, 2H); 13C NMR (100 MHz, DMSO- e): d: 169.0, 161.6, 146.4, 145.8, 136.8, 133.8, 131.5, 130.0, 129.4, 128.0, 127.9, 126.6, 126.4, 125.5, 125.0, 121.1, 109.7, 45.5; IR (KBr): u (cm 1) 2870, 2360, 1694, 1605, 1465, 1336, 1167, 1066, 1014, 818, 730; ESI [C15H13CIN2O3S+ H]+432.
Example-24: (E/Z)-N-(2-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1024)
Figure imgf000088_0001
Synthesis of N-(2-chlorobenzyl)-2-oxoindoline-5-sulfonamide (24): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 2-chlorobenzyl amine 23 (182 mg, 1.298 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(2-chlorobenzyl)-2-oxoindoline-5-sulfonamide 24 (148 mg, 49%) as alight yellow solid;ESI [C15H13CIN2O3S+ H]+337.
Synthesis of (E/Z)-N-(2-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1024): A solution of N-(2-chlorobenzyl)-2-oxoindoline-5-sulfonamide 24 (148 mg, 0.440 mmol), thiazole-2-carbaldehyde 6 (74.9 mg, 0.66 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (93.7 mg, 1.32 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (3.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(2-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1024) (72 mg, 37%); ¾-NMR (400 MHz, DMSO- e): 11.1 (s, 1H), 9.65 (d, J = 1.2 Hz, 1H), 8.2 (s,lH), 8.22-8.18 (m, 2H), 7.76-7.74 (m, 2H), 7.05-6.98 (m, 5H), 4.12-4.10 (m, 2H); 13C NMR (100 MHz, DMSO^/e): d 169.0, 161.5, 146.3, 145.8, 137.5, 137.1, 133.9, 130.0, 128.2, 127.5, 126.7, 125.5, 124.9, 121.0, 109.6, 46.4; IR (KBr): u (cm 1) 3372, 3113, 1708, 1612, 1320, 1160, 822, 622; ESI [C19H14CIN3O3S2+ H]+432.
Example-25: (E/Z)-N-(2-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1025)
Figure imgf000089_0001
Synthesis of N-(3-methylbenzyl)-2-oxoindoline-5-sulfonamide (26): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 3-methybenzyl amine 25 (156.9 mg, 1.297 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCri and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-(3-methylbenzyl)-2-oxoindoline-5-sulfonamide (26) (160 mg, 58%) as a yellow solid; ESI [Ci6Hi6N203S+ H]+317.
Synthesis of (E/Z)-N-(2-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1025): A solution of N-(3-methylbenzyl)-2-oxoindoline-5-sulfonamide (26) (160 mg, 0.506 mmol), thiazole-2-carbaldehyde 6 (80.0 mg, 0.759 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (107 mg, 1.52 mmol), resultant reaction mixture heated at 50 °C for 2 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (2.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(2-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1025) (78 mg, 37%) as light yellow solid; ¾-NMR (400 MHz, DMSO- e): 11.10 (s, 1H), 9.65 (d, J = 1.20 Hz, 1H), 8.28 (d, J = 3.2 Hz, 1H), 8.20 (dd, J = 3.2, 10.4 Hz, 1H), 8.07-8.04 (m, 1H), 7.77-7.75 (m, 2H), 7.07-6.99 (m, 5H), 4.01 (d, J= 5.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6): d: 169.0, 161.5, 146.3, 145.8, 137.5, 137.1, 133.9, 130.0, 127.1, 127.9, 127.5, 126.7, 126.4, 125.5, 124.9, 124.6, 121.0, 109.7, 46.2, 20.7; IR (KBr): u (cm 1) 2918, 2851, 1695, 1605, 1464, 1332, 1165, 1068, 814, 731; ESI [C20H17N3O3S2+ H]+412.
Example-26: (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1026)
Figure imgf000090_0001
Synthesis of N-(4-methylbenzyl)-2-oxoindoline-5-sulfonamide (28): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 4-methybenzyl amine 27 (156.9 mg, 1.297 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-(4-methylbenzyl)-2-oxoindoline-5-sulfonamide (28) (170 mg, 62%) as light yellow solid; ESI [Ci6Hi6N203S+ H]+317.
Synthesis of (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1026): A solution of N-(4-methylbenzyl)-2-oxoindoline-5-sulfonamide (28) (170 mg, 0.536 mmol), thiazole-2-carbaldehyde 6 (91.5 mg, 0.806 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (114 mg, 1.62 mmol), resultant reaction mixture heated at 50 °C and stirred for 2 h. The reaction mixture cooled to room temperature filtered the solid, washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1026) (78 mg, 37%); ¾-NMR (400 MHz, DMSO- e): 11.09 (s, 1H), 9.62 (d, J= 2.00 Hz, 1H), 8.28 (d, J= 3.20 Hz, 1H), 8.19 (d, J= 2.80 Hz, 1H), 8.07-8.01 (m, 1H), 7.79-7.77 (m, 2H), 7.09 (d, J= 8.00 Hz, 2H), 7.04-6.97 (m, 3H), 4.00 (d, J= 6.00 Hz, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d: 169.1, 161.6, 146.3, 145.8, 136.0, 134.6, 133.9, 130.0, 128.6, 127.5, 126.7, 126.4, 125.5, 125.0, 121.1, 109.7, 46.0, 20.6; IR (KBr): u (cm 1) 2850, 1872, 1695, 1604, 1462, 1332, 1225, 1165, 1067, 815, 731; ESI [C20H17N3O3S2+ H]+412.
Example-27:(E/Z)-N-(4-isopropylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1027)
Figure imgf000092_0001
Synthesis of N-(4-isopropylbenzyl)-2-oxoindoline-5-sulfonamide (30): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (4- isopropylphenyl)methanamine29 (193.2 mg, 1.297 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(4-isopropylbenzyl)-2-oxoindoline-5- sulfonamide (30) (155 mg, 52%); ESI [C18H20N2O3S+ H]+ 345.
Synthesis of (E/Z)-N-(4-isopropylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1027): A solution of N-(4-isopropylbenzyl)-2-oxoindoline-5-sulfonamide (30) (155 mg, 0.45 mmol), thiazole-2-carbaldehyde 6 (76.6 mg, 0.675 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (95.8 mg, 1.35 mmol), resultant reaction mixture heated at 50 °C for 2 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E)-N-(4-isopropylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1027) (78 mg, 39%) as a yellow solid; 1H-NMR (300 MHz, DMSO- e): 11.07 (s, 1H), 9.63 (s, 1H), 8.30 (d, J= 3.00 Hz, 1H), 8.20 (d, J= 3.00 Hz, 1H), 8.12-8.05 (m, 1H), 7.76-7.73 (m, 2H), 7.13-7.11 (m, 2H), 7.04-6.99 (m, 2H), 4.02 (s, 2H), 2.82-2.73 (m, 1H), 1.12 (d, J = 6.90 Hz, 6H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.5, 147.1, 146.2, 145.8, 134.9, 133.9, 130.0, 127.7, 127.6, 126.7, 126.4, 125.9, 125.6, 124.9, 121.0, 109.6, 46.0, 33.0, 23.8; IR (KBr): u (cm 1) 2960, 2920, 1695, 1604, 1464, 1332, 1165, 1066, 818, 709; ESI [C22H21N3O3S2+ H]+ 440.
Example-28: (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(4-
(trifluoromethyl)benzyl)indoline-5-sulfonamide (1028)
Figure imgf000093_0001
Synthesis of 2-oxo-N-(4-(trifluoromethyl)benzyl)indoline- 5-sulfonamide (32): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (4- (trifluoromethyl)phenyl)methanamine31 (181.6 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford 2-oxo-N-(4- (trifluoromethyl)benzyl)indoline-5-sulfonamide (32) (180 mg, 56%) as a yellow solid; ESI [C16H13F3N2O3S+ H]+ 371.
Synthesis of (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(4-
(trifluoromethyl)benzyl)indoline-5-sulfonamide (1028): A solution of 2-oxo-N-(4- (trifluoromethyl)benzyl)indoline-5-sulfonamide (32) (180 mg, 0.486 mmol), thiazole-2- carbaldehyde 6 (66.2 mg, 0.583 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (87.2 mg, 1.21 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(4-(trifluoromethyl)benzyl)indoline-5- sulfonamide (1028) (80 mg, 40%) as a yellow solid^H-NMR (400 MHz, DMSO- is): 11.09 (s, 1H), 9.58 (d, 7= 1.60 Hz, 1H), 8.30 (d, J= 3.20 Hz, 1H), 8.23-8.18 (m, 2H), 7.75 (dd, J = 1.60, 7.20 Hz, 2H), 7.49 (d, J= 8.40 Hz, 2H), 7.42 (d, J= 8.00 Hz, 2H), 7.00 (d, J= 8.40 Hz, 1H), 4.16 (d, J = 4.80 Hz, 2H); 13C NMR (100 MHz, DMSO-76): d: 169.0, 161.5, 146.4, 145.8, 142.6, 133.7, 130.0, 128.3, 128.2, 126.6, 126.4, 125.5, 124.9, 124.8, 124.7, 121.0, 109.7, 45.7; IR (KBr): u (cm 1) 2849, 1695, 1605, 1466, 1420, 1324, 1170, 1064, 818; ESI [C20H14F3N3O3S2+ H]+ 466.
Example-29: (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3-
(trifluoromethyl)benzyl)indoline-5-sulfonamide (1029)
Figure imgf000094_0001
1029
Synthesis of 2-oxo-N-(3-(trifluoromethyl)benzyl)indoline- 5-sulfonamide (34): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (3- (trifluoromethyl)phenyl)methanamine33 (156.9 mg, 1.297 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (209 mL, 2.59 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford 2-oxo-N-(3- (trifluoromethyl)benzyl)indoline-5-sulfonamide (34) (155 mg, 52%) as a yellow solid; ESI [C16H13F3N2O3S+ H]+ 371. Synthesis of (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3-
(trifluoromethyl)benzyl)indoline-5-sulfonamide (1029): A solution of 2-oxo-N-(4- (trifluoromethyl)benzyl)indoline-5-sulfonamide (34) (155 mg, 0.45 mmol), thiazole-2- carbaldehyde 6 (76.6 mg, 0.675 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (95.8 mg, 1.35 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3-(trifluoromethyl)benzyl)indoline-5- sulfonamide (1029) (78 mg, 39%) as a yellow solid; 1H-NMR (400 MHz, DMSO- is): 11.07 (s, 1H), 9.61 (d, J = 1.60 Hz, 1H), 8.29 (d, J = 3.20 Hz, 1H), 8.24-8.18 (m, 2H), 7.75-7.73 (m, 2H), 7.53-7.49 (m, 3H), 7.40-7.38 (m, 1H), 6.99 (d, J = 8.00 Hz, 1H), 4.19 (s, 2H); 13C NMR (100 MHZ, DMSO- e): d 169.0, 161.5, 146.4, 145.8, 139.2, 133.8, 131.6, 129.9, 129.0, 126.6, 126.4, 125.5, 125.0, 123.88, 123.84, 123.6, 123.5, 121.1, 109.7, 45.6; IR (KBr): u (cm 1) 2921, 1694, 1603, 1463, 1328, 1166, 1138, 1069, 813, 732; ESI [C20H14F3N3O3S2+ H]+ 466.
Example-30: (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-
Figure imgf000095_0001
1030 Synthesis of N-(3-methoxybenzyl)-2-oxoindoline-5-sulfonamide (36): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (3- methoxyphenyl)methanamine35 (142 mg, 1.03 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (102.5 mg, 1.29 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-(3-methoxybenzyl)-2-oxoindoline-5- sulfonamide (36) (180 mg, 62%) as a yellow solid; ESI [C16H16N2O4S+ H]+ 333.
Synthesis of (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1030): A solution of N-(3-methoxybenzyl)-2-oxoindoline-5-sulfonamide (36) (180 mg, 0.542 mmol), thiazole-2-carbaldehyde 6 (92.2 mg, 0.815 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (115 mg, 1.626 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(3-methoxybenzyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1030) (80 mg, 40%) as a yellow solid; 1H-NMR (300 MHz, DMSO^/e): 11.08 (s, 1H), 9.66 (d, J= 1.50 Hz, 1H), 8.29 (d, J= 3.00 Hz, 1H), 8.22-8.12 (m, 2H), 7.77-7.75 (m, 2H), 7.13-7.00 (m, 2H), 6.81-6.71 (m, 3H), 4.04 (s, 2H), 3.63 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.5, 159.0, 146.3, 145.8, 139.2, 133.9, 130.0, 129.14, 129.1, 126.7, 126.4, 125.5, 125.0, 119.7, 119.7, 112.94, 112.5, 109.7, 54.8, 46.1; IR (KBr): u (cm 1) 2919, 2728, 1712, 1695, 1604, 1464, 1333, 1314, 1164, 1066, 788, 733; ESI [C20H17N3O4S2+ H]+ 428.
Example-31: (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1031)
Figure imgf000097_0001
2 38
Figure imgf000097_0002
1031
Synthesis of N-(4-methoxybenzyl)-2-oxoindoline-5-sulfonamide (38): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (4- methoxyphenyl)methanamine37 (142 mg, 1.03 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (102 mL, 1.29 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 20 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(4-methoxybenzyl)-2- oxoindoline-5-sulfonamide (38) (178 mg, 61%) as a yellow solid; ESI [C16H16N2O4S+ H]+ 333.
Synthesis of (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1031): A solution of N-(4-methoxybenzyl)-2-oxoindoline-5-sulfonamide (38) (178 mg, 0.536 mmol), thiazole-2-carbaldehyde 6 (91.2 mg, 0.804 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (114 mg, 1.6 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (15 mL) and dried under reduced pressure to afford (E/Z)-N-(4-methoxybenzyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1031) (90 mg, 48%) as a yellow solid; 1H-NMR (400 MHz, DMSO^/e): 11.10 (s, 1H), 9.63 (d, J= 2.00 Hz, 1H), 8.29 (d, J= 3.20 Hz, 1H), 8.20 (d, J= 3.20 Hz, 1H), 8.01 (t, J= 6.00 Hz, 1H), 7.77-7.74 (m, 2H), 7.12 (d, J = 8.40 Hz, 2H), 7.02 (d, J= -8.00 Hz, 1H), 6.74 (d, J= 8.80 Hz, 2H), 3.97 (d, J= 5.60 Hz, 2H), 3.67 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 169.0, 161.5, 158.3, 146.3, 145.8, 133.9, 130.0, 129.5, 128.97, 128.91, 126.7, 126.4, 125.5, 124.9, 113.4, 109.7, 54.9, 45.7; IR (KBr): u (cm 1) 2847, 1694, 1605, 1512, 1464, 1331, 1240, 1166, 1063, 815, 732; ESI [C20H17N3O4S2+ H]+ 428.
Example-32: (E/Z)-N-(2,3-dimethoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5-sulfonamide (1032)
Figure imgf000098_0001
Synthesis of N-(2,3-dimethoxybenzyl)-2-oxoindoline- 5-sulfonamide (40): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (2,3- dimethoxyphenyl)methanamine39 (173 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL) acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(2,3-dimethoxybenzyl)-2- oxoindoline-5-sulfonamide (40) (190 mg, 62%) as a yellow solid; ESI [C17H18N2O5S+ H]+ 363.
Synthesis of (E/Z)-N-(2,3-dimethoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1032): A solution of N-(2,3-dimethoxybenzyl)-2-oxoindoline-5-sulfonamide (40) (190 mg, 0.524 mmol), thiazole-2-carbaldehyde 6 (71.4 mg, 0.629 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (115 mg, 1.62 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (2.0 mL) followed by MTBE (10 mL) and dried under reduced pressure to afford (E/Z)-N-(2,3-dimethoxybenzyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1032) (78 mg, 39%) as a yellow solid^H-NMR (400 MHz, DMSO- e): 11.0 (bs, 1H), 9.65 (d, J= 2.0 Hz, 1H), 8.29 (s, 1H), 8.28-8.11 (m, 2H), 7.77-7.75 (m, 2H), 7.12-7.00 (m, 2H), 6.81-6.71 (m, 2H), 4.03 (s, 2H), 3.63 (s, 3H), 3.41 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.5, 159.1, 146.3, 145.8, 139.2, 133.9, 130.0, 129.1, 126.7, 126.4, 125.5, 125.0, 121.0, 119.7, 112.9, 112.5, 109.7; ffi. (KBr): u (cm 1) 3104, 1711, 1605, 1462, 1335, 1165, 793, 624; ESI [C21H19N3O5S2+ H]+ 458.
Example-33: (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3,4,5- trimethoxybenzyl)indoline-5-sulfonamide (1033)
Figure imgf000099_0001
Synthesis of 2-oxo-N-(3,4,5-trimethoxybenzyl)indoline-5-sulfonamide (42): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (3,4,5- trimethoxyphenyl)methanamine41 (204 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford 2-oxo-N-(3,4,5- trimethoxybenzyl)indoline-5-sulfonamide (42) (175 mg, 51%) as a yellow solid; ESI [C18H20N2O6S+ H]+ 393.
Synthesis of (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3,4,5-trimethoxybenzyl)indoline- 5-sulfonamide (1033): A solution of 2-oxo-N-(3,4,5-trimethoxybenzyl)indoline-5- sulfonamide (41) (175 mg, 0.446 mmol), thiazole-2-carbaldehyde 6 (60.7 mg, 0.535 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (115 mg, 1.62 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (10 mL) and dried under reduced pressure to afford (E/Z)-2-oxo-3-(thiazol-2- ylmethylene)-N-(3,4,5-trimethoxybenzyl)indoline-5-sulfonamide (1033) (80 mg, 36%) as yellow solid; 1H-NMR (400 MHz, DMSO- e): 11.00 (s, 1H), 9.59 (d, J = 1.60 Hz, 1H), 8.29 (d, J= 3.20 Hz, 1H), 8.19 (d, J= 3.20 Hz, 1H), 8.12-8.07 (m, 1H), 7.74-7.69 (m, 2H), 6.95 (d, J = 8.00 Hz, 1H), 6.42 (s, 2H), 4.04 (s, 2H), 3.55 (s, 6H), 3.51 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 169.0, 161.5, 152.4, 146.2, 145.8, 136.1, 134.1, 132.8, 127.0, 126.4, 125.7, 124.8, 119.5, 109.5, 104.7, 59.7, 55.5, 46.5; IR (KBr): u (cm 1) 3215, 2922, 1710, 1602, 1460, 1325, 1230, 1165, 1067; ESI [C22H21N3O6S2+ H]+ 488.
Example-34: (E/Z)-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1034)
Figure imgf000101_0001
Synthesis of 2-oxo-N-(pyridin-3-ylmethyl)indoline-5-sulfonamide (44): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and pyri din-3 -ylmethanamine 43 (112 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (20 mL), neutralized to pH = 7 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford 2-oxo-N-(pyridin-3-ylmethyl)indoline-5-sulfonamide (44) (170 mg, 64%); ESI [C14H13N3O3S+ H]+ 304.
Synthesis of (E/Z)-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1034): A solution of 2-oxo-N-(pyridin-3-ylmethyl)indoline-5-sulfonamide (42) (170 mg, 0.561 mmol), thiazole-2-carbaldehyde 6 (76.3 mg, 0.673 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (115 mg, 1.62 mmol), resultant reaction mixture stirred at room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature filtered the solid washed with EtOH (1.0 mL) followed by MTBE (5 mL) and dried under reduced pressure to afford (E/Z)-2-oxo-N-(pyridin-3-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1034) (50 mg, 22%) as a yellow solid; 1H-NMR (300 MHz, DMSO- e): 11.12 (s, 1H), 9.67 (s, 1H), 8.41-8.38 (m, 2H), 8.30-8.20 (m, 3H), 7.77 (d, J = 4.80 Hz, 2H), 7.66-7.64 (m, 1H), 7.24 (dd, J = 4.50 , 7.35 Hz, 1H), 7.04-7.02 (m, 1H), 4.09 (s, 2H), 13C NMR (100 MHz, DMSO- e): 5169, 161.6, 148.8, 148.2, 146.4, 145.9, 135.3, 133.5, 133.3, 130.0, 126.6, 126.5, 125.5, 125.1, 123.1, 121.1, 109.8, 43.7; IR (KBr): u (cm 1) 2849, 1710, 1604, 1461, 1328, 1165, 1068, 811, 625; ESI [C18H14N4O3S2+ H]+ 399.
Example-35: (E/Z)-N-(3-(difluoromethoxy)benzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1035)
Figure imgf000102_0001
Synthesis of N-(3-(difluoromethoxy)benzyl)-2-oxoindoline-5-sulfonamide (46): A solution of 2-oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and (3- (difluoromethoxy)phenyl)methanamine45 (179 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (10 mL) and dried under vacuum to afford N-(3-(difluorom ethoxy )benzyl)-2- oxoindoline-5-sulfonamide (46) (180 mg, 56%) as a yellow solid; ESI [C16H14F2N2O4S+ H]+ 369.
Synthesis of (E/Z)-N-(3-(difluoromethoxy)benzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1035): A solution of N-(3-
(difluoromethoxy)benzyl)-2-oxoindoline-5-sulfonamide (46) (180 mg, 0.489 mmol), thiazole-2-carbaldehyde 6 (66.5 mg, 0.586 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (52 mg, 0.733 mmol), resultant reaction mixture stirred at room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature. The reaction mass concentrated under reduced pressure and crude compound was purified by column chromatography on silicagel (75-150 pm) eluted with 1%-10% MeOH in di chi orom ethane to afford (E)-N-(3-(difluorom ethoxy )benzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1035) (80 mg, 35%) as a yellow solid; 1H-NMR (400 MHz, DMSO- e): 11.13 (s, 1H), 9.69 (d, J= 1.6 Hz, 1H), 8.31 (d, J= 3.2 Hz, 1H), 8.27 (d, J= 3.2 Hz, 1H), 8.19 (d, J= 2.8 Hz, 1H), 8.19-8.10 (m, 1H), 7.79-7.77 (m, 2H), 7.44 (dd, J = 1.2, 7.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.16-6.90 (m, 3H), 4.10 (d, J = 6.4 Hz, 2H); 13C NMR (100 MHz, DMSO- e): d 169.0, 161.5, 148.3, 146.4, 145.8, 133.6, 130.0, 129.5, 128.7, 128.6, 126.6, 126.4, 125.4, 125.0, 121.1, 117.9, 116.4, 109.7, 40.5; IR (KBr): u (cm l) 3245, 2870, 1698, 1605, 1464, 1332, 1314, 1144, 1116, 885, 762; ESI [C20H15F2N3O4S2+ H]+ 464.
Example-36: (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5- su
Figure imgf000103_0001
Figure imgf000103_0002
1036
Synthesis of 2-oxo-N-(l-phenylethyl)indoline- 5-sulfonamide (48): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and 1-phenylethanamine 47 (125.6 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL) acidified to pH = 2 by addition of 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous INfeSCL and concentrated under reduced pressure. Obtained solid washed with MTBE and dried under vacuum to afford 2-oxo-N-(l-phenylethyl)indoline-5-sulfonamide (48) (165 mg, 60%) as a yellow solid; ESI [C16H16N2O3S+ H]+ 317.
Synthesis of (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1036): A solution of 2-oxo-N-(l-phenylethyl)indoline-5 -sulfonamide (48) (165 mg, 0.522 mmol), thiazole-2-carbaldehyde 6 (70.8 mg, 0.626 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (112 mg, 1.58 mmol), resultant reaction mixture stirred room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature reaction mass concentrated under reduced pressure and crude compound was purified by column chromatography eluted with 1-10% MeOH in dichloromethane to afford (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide (1036) (80 mg, 37%) as a yellow solid; 1H-NMR (400 MHz, DMSO-76): 11.02 (s, 1H), 9.51 (d, 7= 1.6 Hz, 1H), 8.31 (d, J= 3.2 Hz, 1H), 8.20 (d, J= 3.2 Hz, 1H), 8.15-8.10 (m, 1H), 7.72 (s, 1H), 7.65 (dd, J= 1.6, 8.0 Hz, 1H), 7.20-7.14 (m, 2H), 7.06-7.04 (m, 3H), 6.91 (d, J= 8.0 Hz, 1H), 4.38 (q, J = 7.2, 15.2 Hz, 1H), 1.26 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-d6): d 169.0, 161.5, 146.3, 145.8, 137.7, 133.8, 130.0, 128.1, 128.0, 127.6, 127.5, 126.9, 126.7, 125.5, 125.0, 121.1, 109.8, 49.2, 21.2; IR (KBr): u (cm 1) 3294, 2850, 1720, 1618, 1479, 1430, 1328, 1237, 1147, 1069, 824; ESI [C20H17N3O3S2+ H]+412.
Example-37:(E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1037)
Synthesis of N-benzhydryl-2-oxoindoline-5-sulfonamide (50): A solution of 2- oxoindoline-5-sulfonyl chloride 2 (200 mg, 0.865 mmol), and diphenylmethanamine49 (189.9 mg, 1.038 mmol), in 1, 4-dioxane (5.0 mL), was charged with pyridine (103 mL, 1.298 mmol) resultant reaction mixture stirred at room temperature for 2 h. The reaction mixture diluted with water (10 mL), acidified to pH = 2 by 2N HC1 solution then extracted with EtOAc (3 x 30 mL), combined organic layer dried over anhydrous NaiSCL and concentrated under reduced pressure. Obtained solid washed with MTBE (20 mL) and dried under vacuum to afford N-benzhydryl-2-oxoindoline-5-sulfonamide (50) (188 mg, 57%) as a yellow solid; ESI [C21H18N2O3S + H]+379.
Synthesis of (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1037): A solution of N-benzhydryl-2-oxoindoline-5-sulfonamide (50) (188 mg, 0.497 mmol), thiazole-2-carbaldehyde 6 (67.6 mg, 0.596 mmol), in EtOH (5.0 mL) was charged with pyrrolidine (105 mg, 1.48 mmol), resultant reaction mixture stirred at room temperature for 2 h and heated at 50 °C for 1 h. The reaction mixture cooled to room temperature reaction mass concentrated under reduced pressure and crude compound was purified by column chromatography on silicagel (75-150 pm), eluted with 1-10% MeOH in dichloromethane to afford (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1037) (110 mg, 46%) as a yellow solid; 1H-NMR (400 MHz, DMSO- is): 10.96 (bs, 1H), 9.43 (d, J= 2.0 Hz, 1H), 8.71-8.73 (m,lH), 8.33 (d, J= 3.2 Hz, 1H), 8.19
103 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.61 (dd, J = 2.0, 8.0 Hz, 1H), 7.23-7.20 (m, 1H), 7.18-7.15 (m, 4H), 7.08-7.05 (m, 5H), 6.91 (d, J = 8.0 Hz, 1H), 5.15-5.18 (m, 1H); 13C NMR (100 MHz, DMSO-d6): d 169.0, 161.4, 146.0, 145.9, 141.6, 141.5, 134.2, 130.0, 128.0, 127.9, 127.0, 126.7, 126.6, 126.2, 125.7, 124.8, 120.6, 109.1, 60.7; IR (KBr): u 3224, 1704, 1599, 1462, 1302, 1164, 1066, 957 (cm 1) ; ESI [C25H19N3O3S2 + H]+474.
Example-38:(E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1038)
Figure imgf000106_0001
1015 1038
Synthesis of (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1038): A solution of (E)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1015) (50 mg, 0.115 mmol), in DMF (3.0 mL) was charged with K2CO3 (47.8 mg, 0.346 mmol), followed by CH3I (0.029 mL, 0.46 mmol) at room temperature and stirred for 6 h. The reaction mixture was added water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic layer washed with cold water (3 ^ 10 mL), brine solution (10 mL), separated organic layer dried over INfeSCL and concentrated under reduced pressure. Crude compound was purified by column chromatography on silicagel (75-150 pm), eluted with 10-100% EtOAc in hexanes, compound isolated at 50% of EtOAc to afford (E/Z)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1038) (43 mg, 81%) as a yellow solid; IR (KBr): u (cm 1) ; ¾-NMR (400 MHz, DMSO- e): 9.91 (d, J= 1.6 Hz, 1H), 8.17 (d, J= 3.2 Hz, 1H), 7.91 (dd, J = 1.6, 8.0 Hz, 1H), 7.85 (s, 1H), 7.68 (d, J = 3.2 Hz, 1H), 7.55-7.50 (m, 1H), 6.97 (d, J= 8.0 Hz, 1H), 6.92-6.90 (m, 1H), 6.81-6.75 (m, 1H), 4.34 (s, 2H), 3.36 (s, 3H), 2.74 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 168.7, 162.0, 147.8, 145.9, 131.6, 131.3,
130.9, 126.4, 126.3, 126.1, 124.5, 123.2, 121.9, 111.9, 111.7, 107.6, 103.7, 130.2, 46.9,
34.9, 26.6; ESI [C21H17F2N3O3S2 + H]+462. Example-39: (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1039)
Figure imgf000107_0001
Synthesis of (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1039): A solution of (E)-N-benzhydryl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1037) (50 mg, 0.105mmol), in DMF (3.0 mL) was charged with K2CO3 (58.3 mg, 0.422 mmol), followed by CH3I (0.027 mL, 0.422 mmol) at room temperature and stirred for 6 h. The reaction mixture water (20 mL) was added and extracted with EtOAc (2 c 20 mL), combined organic layer washed with cold water (3 ^ 10 mL), brine solution (10 mL), separated organic layer dried over NaiSCL and concentrated under reduced pressure. Crude compound was purified by column chromatography on silicagel (75-150 pm), eluted with 10-100% EtOAc in hexanes, compound isolated at 55% of EtOAc. Obtained solid recrystallized in MTBE (2 mL) and dichloromethane (0.5 mL)to afford (E/Z)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1039) (45 mg, 86%) as a yellow solid; 1H-NMR (400 MHz, DMSO- is): 9.7 (d, J = 2.0 Hz, 1H), 8.25 (d, J= 3.6 Hz, 1H), 8.20 (d, J= 3.2 Hz, 1H), 7.87-7.85 (m, 2H), 7.21-7.19 (m, 7H), 7.06-7.04 (m, 4H), 6.35 (s, 1H), 3.28 (s, 3H), 2.68 (s, 3H); 13C NMR (100 MHz, DMSO- e): d 168.8, 161.7, 147.4, 146.0, 144.4, 138.3, 138.2, 133.7, 130.6, 128.8, 128.5, 127.8, 127.5, 126.8, 126.3, 125.8, 124.2, 121.4, 107.1, 64.3, 31.2, 26.5; IR (KBr): u (cm 1) 3082, 2937, 1716, 1600, 1323, 1166, 732; ESI [C27H23N3O3S2+ H]+ 502.
Example 40: Synthesis of compounds (1038-49, 1038-52, 1038-54, 1038-55 and 1039-49, 1039-52, 1039-54): A solution of compound (10m or 13q) (1.0 equiv.), in DMF (3.0 mL) was charged with K2CO3 (5.0 equiv.), followed by R-I or Br (5.0 equiv.) at room temperature and stirred for 16 h. The reaction mixture was added to water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic EtOAc layer washed with cold water (3 x 10 mL), followed by brine (10 mL), separated organic layer dried over Na2S04 and concentrated to remove solvent under reduced pressure. Crude compound was purified by combi-flash chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound isolated at 40% of EtOAc to afford compounds (1038-49, 1038-52, 1038-54, 1038-55 and 1039-49, 1039-52, 1039-54).
Example 40.1: Synthesis of (E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-
(thiazol-2-ylmethylene)indoline-5-sulfonamide (1038-49)
Figure imgf000108_0001
Yield: 65%; as a yellow solid; mp: 119-123 °C; ¾ NMR (400 MHz, DMSO-d6): 9.79 (d, J = 1.60 Hz, 1H), 8.276 (d, J= 3.20 Hz, 1H), 8.23 (d, J= 3.20 Hz, 1H), 7.90 (s, 1H), 7.88 (dd, J= 2.00 , 8.40 Hz, 1H), 7.53-7.49 (m, 1H), 7.32 (d, J = 8.40 Hz, 1H), 7.19-7.22 (m, 1H), 7.06-7.05 (m, 1H), 4.42 (s, 2H), 3.87 (q, J= 7.20 Hz, 2H), 3.23 (q, J= 7.20 Hz, 2H), 1.22 (t, J= 7.20 Hz, 3H), 0.96 (t, J= 7.20 Hz, 3H); MS (ESI+APCI): m/z = 490 [M + H]+.
Example 40.2: Synthesis of (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-di(prop-2-yn-l-yl)-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1038-52)
Figure imgf000108_0002
Yield: 60%; as a yellow solid; mp: 123-125 °C; ¾ NMR (400 MHz, DMSO-d6): 9.89 (s, 1H), 8.32 (d, J= 3.20 Hz, 1H), 8.25 (d, J= 3.20 Hz, 1H), 8.02-7.98 (m, 2H), 7.50-7.38 (m, 2H), 7.27-7.22 (m, 1H), 7.11-7.07 (m, 1H), 4.73 (s, 2H), 4.72 (s, 2H), 4.00 (s, 2H), 3.30 (s, 1H), 3.02 (s, 1H); MS (ESI+APCI): m/z = 510 [M + H]+.
Example 40.3: Synthesis of ((E)-N,l-dibenzyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide (1038-54)
Figure imgf000109_0002
Yield: 68%; as a yellow solid; mp: 126-129 °C; ¾ NMR (400 MHz, DMSO-d6): 9.81 (d, J = 2.00 Hz, 1H), 8.25 (d, J= -9.20 Hz, 1H), 8.01 (s, 1H), 7.86 (dd, J= 2.00 , 8.40 Hz, 1H), 7.39-7.36 (m, 4H), 7.33-7.31 (m, 1H), 7.22-7.20 (m, 2H), 7.19-7.12 (m, 6H), 6.92-6.92 (m, 1H), 6.80-6.73 (m, 1H), 5.10 (s, 2H), 4.38 (s, 4H); MS (ESI+APCI): m/z = 614 [M + H]+.
Example 40.4: Synthesis of (E)-N,l-diallyl-N-(2,4-difluorobenzyl)-2-oxo-3-
(thiazol-2-ylmethylene)indoline-5-sulfonamide (1038-55)
Figure imgf000109_0001
Yield: 45%; as a yellow solid; mp: 118-123 °C; ¾ NMR (400 MHz, DMSO-de): 9.80 (d, J = 2.00 Hz, 1H), 8.23 (d, J= 3.20 Hz, 1H), 8.22 (d, J= 3.20 Hz, 1H), 7.94 (s, 1H), 7.88 (dd, J= 2.00 , 8.40 Hz, 1H), 7.48-7.44 (m, 1H), 7.21-7.11 (m, 1H), 7.04-7.01 (m, 2H), 5.95-5.88 (m, 1H), 5.57-5.55 (m, 1H), 5.23-5.20 (m, 2H), 5.07-5.00 (m, 2H), 4.48 (d, J = 4.80 Hz,
1H), 4.38 (s, 2H), 3.83 (d, J= 6.40 Hz, 1H); MS (ESI+APCI): mlz = 514 [M + H]+.
Example 40.5: Synthesis of (E)-N-benzhydryl-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1039-49)
Figure imgf000110_0002
Yield: 52%; as a yellow solid; mp: 139-143 °C;1H NMR (400 MHz, DMSO-d6): 9.83 (d, J = 1.60 Hz, 1H), 8.09 (d, J = 3.20 Hz, 1H), 7.78-7.72 (m, 3H), 7.62 (d, J = 3.20 Hz, 1H), 7.17-7.08 (m, 9H), 6.77 (d, J= 8.40 Hz, 1H), 6.47 (s, 1H), 3.87 (q, J= 7.20 Hz, 2H), 3.41 (q, J= 6.80 Hz, 2H), 1.33 (t, J= 7.20 Hz, 3H), 0.84 (t, J= 5.60 Hz, 3H); MS (ESI+APCI): mlz = 530 [M + H]+.
Example 40.6: Synthesis of (E)-N-benzhydryl-2-oxo-N,l-di(prop-2-yn-l-yl)-3-
(thiazol-2-ylmethylene)indoline-5-sulfonamide (1039-52)
Figure imgf000110_0001
Yield: 55%; as a yellow solid; mp: 140-143 ^H NMR (400 MHz, CDCh): 9.91 (d, J = 2.00 Hz, 1H), 8.13 (dd, J= 1.20 , 3.00 Hz, 1H), 7.85 (dd, J= 2.00 , 8.40 Hz, 2H), 7.82 (s, 1H), 7.27-7.18 (m, 10H), 7.03 (d, J= 8.40 Hz, 1H), 6.38 (s, 1H), 4.63 (d, J= 2.40 Hz, 2H), 4.10 (d, J = 2.40 Hz, 2H), 2.30 (t, J = 2.80 Hz, 1H), 1.90 (t, J = 2.40 Hz, 1H); MS (ESI+APCI): mlz = 550 [M + H]+.
Example 40.7: Synthesis of (E)-N-benzhydryl-N,l-dibenzyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (14q-5)
Figure imgf000111_0001
_
Yield: 55%; as a yellow solid;mp: 151-154 °C; ¾ NMR (400 MHz, CDCb): 9.82 (s, 1H), 8.13 (d, J= 3.20 Hz, 1H), 7.87 (s, 1H), 7.65 (d, J= 3.20 Hz, 1H), 7.38-7.31 (m, 7H), 7.09- 7.03 (m, 11H), 6.93-6.92 (m, 3H), 6.82-6.79 (m, 1H), 5.00 (s, 2H), 4.58 (s, 2H); MS (ESI+APCI): m/z = 554 [M + H]+.
Example 41: Synthesis of compound (1038-65, 1039-1’ & 1039-4’): A solution of compound (10m or 13q) (1.01 equiv.), in DMF (3.0 mL) was added with dried K2CO3 (1.01 equiv.), followed by alkyl iodide or alkyl bromide (1.0 equiv.) at ambient temperature and stirred for 6 h. The reaction mixture was added to water (20 mL) and extracted with EtOAc (2 x 20 mL), organic layer combined and washed with cold water (3.0 x 10 mL), later with brine (10 mL), separated organic layer dried over NaiSCL to remove moisture and solvent evaporated under reduced pressure. Crude compound was purified by combi-flash instrument column chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound separated at 60% of EtOAc to afford compounds (1038-65, 1039-1’ & 1039-4’).
Example 41.1: (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1038-65)
Figure imgf000112_0001
Yield: 30%; as a yellow solid; mp: 196-201 °C; ¾ NMR (400 MHz, DMSO-de): 9.65 (s, 1H), 8.30 (d, J = 3.20 Hz, 1H), 8.29 (s, 1H), 8.23-8.17 (m, 1H), 7.87-7.83 (m, 2H), 7.38- 7.32 (m, 1H), 7.23-7.20 (m, 2H), 7.06-7.01 (m, 1H), 6.92-6.87 (m, 1H), 4.07 (d, J= 0.2 Hz, 2H), 3.28 (s, 3H); MS (ESI+APCI): m/z = 448 [M + H]+.
1.9 (E)-N-benzhydryl-2-oxo-l-(prop-2-yn-l-yl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide (1039-1’)
Figure imgf000112_0002
Yield: 53%; as a yellow solid;1H NMR (400 MHz, DMSO-de): 9.49 (d, J =2.00 Hz, 1H), 8.77 (d, J= 9.60 Hz, 2H), 8.36 (d, J= 3.20 Hz, 1H), 8.24 (d, J= 3.20 Hz, 1H), 7.84 (s, 1H), 7.73 (dd, J= 1.60 , 8.40 Hz, 1H), 7.22-7.04 (m, 10H), 5.55 (d, J= 10.0 Hz, 1H), 4.63 (d, J = 2.0 Hz, 2H), 3.36 (t, J= 2.40 Hz, 1H); MS (ESI+APCI): m/z = 512 [M + H]+.
Example 41.2: (E)-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1039-65)
Figure imgf000113_0001
Yield: 53%; as a yellow solid; ¾ NMR (400 MHz, DMSO- e): 9.50 (d, J=2.00 Hz, 1H), 8.75 (d, J= 9.60 Hz, 2H), 8.38 (d, J= 3.20 Hz, 1H), 8.24 (d, J= 3.20 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J = 1.60 , 8.40 Hz, 1H), 7.22-7.04 (m, 10H), 5.55 (d, J = 10.0 Hz, 1H), 3.36 (s, 3H); MS (ESI+APCI): m/z = 488 [M + H]+.
Example 41.3: (E)-N-benzhydryl-l-ethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (14q-l’)
Figure imgf000113_0002
Yield: 62%; as a yellow solid; ¾ NMR (400 MHz, CDCh): 9.71 (d , J= 1.60 Hz, 1H), 8.18 (d, J= 3.20 Hz, 1H), 7.78-7.65 (m, 3H), 7.16-7.05 (m, 10H), 6.73 (d, J= 8.00 Hz, 1H), 5.65 (d, J= 7.20 Hz, 1H), 5.21 (d, J= 7.20 Hz, 1H), 3.85 (q, J= 8.00 Hz, 2H), 1.30 (t, J= 7.20 Hz, 3H); MS (ESI+APCI): m/z = 502 [M + H]+.
Example 41.4: Synthesis of (E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1038-22)
Figure imgf000114_0002
A solution of compound (1038-65) (50 mg, 0.11 mmol), in DMF (3.0 mL) was charged with K2CO3 (46.3 mg, 0.335 mmol), followed by benzylbromide (38.3 mg, 0.223 mmol) at room temperature and stirred slowly for 6 h. The reaction mixture was added to water (20 mL) and extracted with ethylacetate (2 c 20 mL), combined organic layer well washed with cold water (3 c 10 mL), brine (10 mL), separated organic layer dried using Na2SC>4 and concentrated to remove solvent under reduced pressure. Crude compound was purified by ISCO combi-flash chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound isolated at 40% of EtOAc to afford compound 1038-22 (45 mg, 75%)as a yellow solid; MS (ESI+APCI): m/z = 538 [M + H]+.
Example 41.5: Synthesis of (E)-N-benzhydryl-N-methyl-2-oxo-l-(prop-2-yn-l-yl)-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide (1039-4)
Figure imgf000114_0001
A solution of compound (1039-4’) (50 mg, 0.097 mmol), in DMF (3.0 mL) was added K2CO3 (40.2 mg, 0.293 mmol), followed by added CH3I (27.5 mg, 0.195 mmol) at room temperature and stirred for 6 h. The reaction mass was added to di-water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic layer was washed with cold water (3 x 10 mL), brine (10 mL), separated organic layer dried over NaiSCL and evaporated under vacuum. Crude compound was purified by Teledyne ISCO combi-flash column chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound isolated at 40% of EtOAc to afford compound 1039-4 (35 mg, 68%)as a yellow solid1H NMR (400 MHz, DMSO-d6): 9.86 (d, J= 2.00 Hz, 1H), 8.08 (d, J= 3.20 Hz, 1H), 7.82-7.79 (m, 2H), 7.64 (d, J= 3.20 Hz, 1H), 7.19-7.12 (m, 10H), 7.04 (d, J= 8.40 Hz, 1H), 6.53 (s, 1H), 4.63 (d, J= 2.80 Hz, 2H), 2.79 (s, 3H), 2.31 (s, 1H); MS (ESI+APCI): mlz = 526 [M + H]+.
Example 41.6: Synthesis of (E)-N-benzhydryl-N-benzyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1039-22)
Figure imgf000115_0001
A solution of compound (1039-65) (50 mg, 0.102 mmol), in DMF (3.0 mL) was charged with K2CO3 (42.2 mg, 0.306 mmol), followed by added benzylbromide (34.8 mg, 0.204 mmol) at 25 to 30 °C temperature and stirred for 6.0 h. The reaction mixture was added to cold water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic layer washed with cold water (3 c 10 mL), later with brine (10 mL), separated organic layer combined and dried over NaiSCL and concentrated under reduced pressure. Crude compound was purified by combi-flash chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound isolated at 40% of EtOAc to afford compound 1039-22 (50 mg, 86%)as a yellow solid; MS (ESI+APCI): mlz = 578 [M + H]+.
Example 41.7: Synthesis of (E)-N-benzhydryl-l-ethyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide (1039-1)
Figure imgf000116_0001
A solution of compound (1039-1’) (50 mg, 0.099 mmol), in DMF (3.0 mL) was charged with K2CO3 (41.3 mg, 0.299 mmol), followed by added CH3I (27.9 mg, 0.198 mmol) at room temperature and stirred for 6.0 h. The reaction mixture poured in water (20 mL) and extracted with EtOAc (2 c 20 mL), combined organic layer washed with cold water (3 ^ 10 mL), brine (10 mL), separated organic layer dried over NaiSCL and volatiles removed under reduced pressure. Crude compound was purified by combi-flash chromatography on silicagel eluted with 10-100% EtOAc in hexanes, compound separated at 40% of ethylacetate to afford compound 1039-1 (42 mg, 80%)as a yellow solid; 'H NMR (400 MHz, DMSO-d6): 9.83 (d, J= 2.00 Hz, 1H), 8.07 (d, J= 3.20 Hz, 1H), 7.79 (s, 1H), 7.76 (dd, J = 2.00 , 8.40 Hz, 1H), 7.62 (d, J = 3.20 Hz, 1H), 7.29-7.27 (m, 1H), 7.19-7.12 (m, 9H), 6.82 (d, J= 8.40 Hz, 1H), 6.53 (s, 1H), 3.87 (q, J= 6.80 Hz, 2H), 2.79 (s, 3H), 1.32 (t, J= 7.20 Hz, 3H); MS (ESI+APCI): m/z = 516 [M + H]+.
B. Examples illustrating the BiologicalActivity of the compounds of the present invention
B. 1. Computational protocols:
B. 1.1 Docking study: The crystal structure of dengue RdRp (DENV RdRp) in complex with an inhibitor (PDB-ID: 5F3T) was obtained from Protein data bank. This co-crystal inhibitor is present at the interface between thumb and palm domains (hereafter I-site). The blind and focused docking was performed with Autodock Vina and Autodock 4.2.6 for screening of compounds 1001-1039 and re-docking of the best hits, respectively. The blind docking of these compounds were carried out by taking grid on the whole protein, while focused docking was formed on the center of the co-crystal ligand in the protein structure. The Lamarckian genetic algorithm was used for conformational sampling of the compounds. For each docking simulation, 200 runs were carried out with 150 population size and 2.5xl06 energy evaluations. The poses were ranked and clustered based on Autodock energy scores and populations.
B.1.2 System preparations and molecular dynamics simulations: The best protein- ligand complex structure was prepared using protein preparation wizard of maestro by adding the missing hydrogens, assignment of bond orders and filling missing sidechains. The protein structure optimization and minimization was carried out using OPLS2 forcefield. To study the molecular interactions of best ligands with its protein, the systems were subjected to molecular dynamics simulations with amber 16 using amber ffl4sb force field. The GAFF force field was used to describe the ligand structure, with charges calculated following the standard AMBER protocol: from the electrostatic potential map generated by the molecule (calculated with Gaussian03), RESP charges were derived using the ANTECHAMBER module of AMBER. The parameter files for protein and complexes were prepared using the leap module of AMBER suite. The systems were minimized in three stages for the relaxation and removal of bad contacts in the system. Steepest descent of 1000 steps followed by 1000 steps of conjugate gradient was carried out. The positional restraints of 10 and 2 kcal mol 1 A'2 were applied in the first and second stages of minimization, respectively. The third step minimization was carried out unrestrained. The system is gradually heated for 20pico-seconds (ps) upto 300K. The systems were equilibrated for lOOps at 300K and 1 atm pressure. The production was run for 300ns with a time step of 2.0 ps and recording the coordinates at every lOps. The analysis of the MD simulated systems was further carried out in CPPTRAJ module of AMBER16.
B.1.3 MM/GBSA and alanine scanning: The binding free energy calculations were determined using MM-GBSA/PBSA approaches in amberl6. We extracted 1000 snapshots from last 50ns of the equilibrated MD trajectory for the calculation of the average binding free energy. The residue wise free energy calculation and alanine scanning was also carried out on the same snapshots. The alanine scanning was implemented for the residues having contribution more than 1 kcal/mol by mutating them to alanine. The negative values mean or suggestfavorable contribution of the residue in the complex.
B. 2.1 Docking studies An extensive multi-step molecular docking was carried out on modeled RdRp of Dengue serotype 3 (PDB database ID: 5I3P). The crystal structure lacks the loop region of the RNA template entrance site, which in case of Dengue as well as a few other RNA viruses has been well documented as a favorable target site for non-nucleoside allosteric inhibitor molecules. Therefore, modelling was carried out for loop building and its optimization through Molecular Dynamics Simulation (Figure 3, panel A and B). The optimized RdRp was then used for blind docking studies, which works without any prior knowledge of existing binding that can impose a bias. Subsequently focused docking was performed by taking the top three cluster representatives. Finally, based on number of possible conformations and lowest docking energy at the I-site, which is at the bottom of the RNA template entrance site, appeared as the most likely binding site of compounds 1001-1039. Among all, four compounds i.e.1015, 1037, 1038, and 1039 were taken for further analysis. Initiating with 1015 and culminating in 1039, the compounds exhibited increasing number of possible conform ers (number of conform ers in 1015 and 1039 in table X) coupled with significant reduction of docking energy (docking energy of 1015 and 1039 in table X). The docking of 1038 and 1039 was compared to that of UNK-586, a co-crystal of which with the RdRp is available (Figure 3, panel C, section 3). Interestingly, this series reciprocate the same key residues, though some more residues are involved here, indicating the more compactness of the binding site. In our docking studies, 1038 and 1039 fit onto residues of the RdRp that are near to the ones responsible for interaction with UNK-586, in addition to a few exclusive residues indicating a more compact biding. The amino acids involved in good binding affinity of UNK compounds are Ser710, Leu511, His798, Trp803, Ala799 and Thr794 as hydrophobic contacts and VdW interactions. The residues interacting with 1038 and 1039 include Ser796, His711, Cys709, His798, Met761, Trp803, Leu511, Met765, Thr794, Trp795, and Thr793 as hydrophobic contacts and VdW interactions, and residues Arg729, Arg737 in hydrogen bonding (Figure 1, panel C, section 1 & 2). Overall, 1038 and 1039 dock on to the RdRp in manner which will occlude the bottom of the RNA template entrances site, possibly hindering interactions between amino acid residues crucial for the catalytic activity of RdRp and, by doing so block the RNA polymerization. The docking energy of four compounds, 1015, 1037, 1038 and 1039 is given in table 2.
Interestingly, when compared with known structures of the RdRp from two other viruses, namely Japanese encephalitis virus and Chikungunya virus, compound 1039 showed docking energy comparable with that with Dengue RdRp, suggesting it tohave equal or higher efficacy in inhibiting the RdRp enzyme coded by the genome of these two viruses (Table 3)
Table 2: The docking energy of indicated compounds on Dengue virus RdRp:
Figure imgf000119_0001
Table 3: The docking energy of indicated compounds on RdRp from viruses related to Dengue virus
Figure imgf000119_0002
B. 2.2 Result of Molecular dynamics simulations
To confirm the binding site of compound 1039, a 300 ns long MD simulation was carried out with the protein, ligand and the complex in their solvation states. Since water plays a crucial role in change of protein conformations and in molecular recognition process, the MD data confirms and corroborates the findings of docking outcomes very well. The root- mean square deviation shows the least transition for protein structure and the complex, indicating the stability of the trajectory in the presence of the compound (Figure 2).
B.3. Antiviral activity ofthe compounds of the invention B.3.1 Materials and protocols B.3.1.1 Cells and virus: K562 cells were procured from the American Type Culture Collection (ATCC) and cultured at 37°C, 5% CO2 in Iscove’s-modified Dulbecco’s media (IMDM) supplemented with Penicillin (100 U/ml), Streptomycin (0.1 mg/ml) and 10% Fetal Bovine Serum (FBS). Vero and C6/36 cells were procured from the cell line repository of the National Centre for Cell Sciences (NCCS), India and cultured respectively in Minimum Essential Medium (MEM) and L15 cell culture medium. C6/36 cells in L15 culture media were grown at 28 °C and atmospheric CO2 conditions. Dengue virus serotype 2 (strain NGC) was grown in C6/36 cells incubated in 28°C and at atmospheric CO2 conditions. The infectious titer of the virus was determined by Focus-forming unit (FFU) assay as described below. For all infections the inoculum was diluted in respective culture media supplemented with 2% FBS and incubated with cells for 2 hours on a rocker inside the incubator
B.3.1.2 Immunostaining and flow cytometry: Cells were washed using ice-cold PBS before fixation with 2% PFA and permeabilization with 0.1% Triton-X-100. These were sequentially incubated with 4G2 (anti-Flavivirus group antigen) primary antibody and anti mouse Alexa-488 conjugated secondary antibody. The fluorescence was analyzed using BD-FACS Canto II flow cytometer under standard conditions, using mock-infected cells as control. The raw data was analyzed using Flow- Jo software.
B.3.1.3 Total RNA isolation, Reverse-transcription and Real-time PCR: 500 ng of total RNA extracted using Trizol and purified using RNA isolation kit (Qiagen), was reverse- transcribed by random hexamers and ImProm-II Reverse-transcriptase (Promega) according to manufacturer’s instructions. The complementary DNA (cDNA) was used for Real-time PCR using gene-specific primers in an ABI7500 Fast Real-time PCR system. Viral RNA from culture supernatant was isolated from culture supernatant using Viral RNA isolation kit (Qiagen) according to manufacturer’s instructions and reverse-transcribed using anti- sense DNA oligo (5 ’ -ACC ATTCC ATTTTCTGGCGTT -3 ’ ). Real time PCR for Dengue virus genomic RNA was performed using Taqman probe (FAM- AGCATC ATTCC AGGCAC-NFQ-MGB), forward primer: 5’-
GARAGACCAGAGATCCTGCTGTCT-3’and reverse primer: 5’-
ACC ATTCC ATTTTCTGGCGTT-3 ’ . B.3.1.4 Focus-forming unit (FFU) assay: Vero cell monolayers in 24-well plate were infected using different dilutions of virus in MEM supplemented with 2% FBS. The inoculum was incubated with cells for 2 hours at 37 °C, 5% CO2 with rocking. The inoculum was discarded and MEM-supplemented with 10% FBS was overlaid on the cells, which were then incubated for 48 hours. Cells were then fixed with 2% para-formaldehyde (PFA), permeabilized with buffer supplemented with 0.1 % Triton-X-100 and sequentially stained using anti-DENV primary antibody (dilution 1:400 of Mab8705, Millipore) and anti- Mouse Alexa-488 conjugated secondary antibody (dilution 1:500; ThermoFisher Scientific). The number of fluorescent foci corresponding to each dilution was counted in a fluorescent microscope and the titer calculated as FFU/ml.
B.3.1.5 Isolation of peripheral blood mononuclear cells (PBMC) from blood:5 ml of venous blood was collected in EDTA-treated vacutainer tubes, from healthy volunteers by a trained phlebotomist. The blood was mixed with and equal amount of sterile phosphate- buffered saline (PBS) and carefully overlaid on 5 ml of Histopaque solution (Sigma). The tubes were centrifuged at 1600 rpm for 30 minutes. The PBMC in the interphase were carefully aspirated, washed with sterile PBS and cultured in RPMI-1640 supplemented with 10% FBS, Glutamine and Penicillin-Streptomycin mix, at 37 °C, 5% CO? for different time points. Ethical approval for using blood from healthy volunteers was granted by the Institutional human ethics committee.
B. 3.1.6 Measurement of total cellular ATP content: Total cellular ATP content was estimated using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega), according to the instructions of the manufacturer. After incubation the luciferase activity was measured using a Luminometer with standard protocol (Berthold).
B. 3.2 Experimental results of antiviral activity
The ex v/voefficacy of the synthesized compounds was evaluated by their capacity to inhibit the replication of Dengue virus serotype 2 (strain NGC) in infected cells of the human K562 cell line. For this purpose, exponentially growing K562 cells were infected with the virus at a multiplicity-of-infection (MOI) of 10 and subsequently incubated in culture media supplemented with either vehicle (Dimethyl Sulphoxide or DMSO) or different compounds, at 37 °C under 5% CO2 for 2 days. The cells were then harvested by centrifugation and either used for immunofluorescence for estimation of viral protein accumulation or extraction of total RNA for estimation of viral genomic RNA accumulation. The culture supernatant was aspirated, stored in -80 °C and later used for quantification of the infectious titer by Focus-forming unit (FFU) assay (Figure 3, panel A). The percentage of cells positive for viral antigenwas quantified by immunostaining followed by analysisin a flow cytometer, using mock-infected and similarly stained cells as negative control. As shown, about 50% of the cells infected at 10 MOI, were positive for viral antigen, at 2 days post-infection (Figure 3, panel B). The Taqman probe and primersused for real-time comparison of viral genomic RNA was tested using different dilutions of a plasmid which is recombinant for the 3’ Untranslated region of the viral RNA. As shown serial logarithmic dilution of the plasmid DNA to the base of 10, led to a linear increase in the threshold of detection in real-time PCR analysis (Figure 3, panel C). The culture supernatant was used for quantification of infectious titer, as explained in materials and methods and schematically shown in Figure 3, panel D. After immunostaining only the wells that showed distinctly isolated foci were used for counting of the total foci and calculation of FFU/ml of supernatant (Figure 3, panel E).
The efficacy of compounds 1002-1020 was evaluated through immunofluorescence assay as described in figure 3, panel B. The results for a few of the compounds is depicted in Figure 4, panel A and the efficacy for all is provided in Table 3. As suggested by our docking study no inhibition was for 1012 while 1015 significantly reduced accumulation of Dengue viral protein (Figure 4, panel Aand Table 3). In corroboration of the result using immunofluorescence, 1015 but not 1006 dramatically inhibited the accumulation of viral genomic RNA under similar condition of infection in K562 cells (Figure 4, panel B).
Table 4: Inhibition of viral antigen accumulation by 20Dg/ml of each compound in K562 cells infected with Dengue virus serotype 2 (strain NGC) at 48 hours post-infection
Figure imgf000122_0001
Figure imgf000123_0001
Based on structure guided approach, further variants of 1015 were designed and the synthesized compounds evaluated for their efficacy in inhibition accumulation of Dengue virus antigen. The results are shown in table 5:
Table 5:Inhibition of viral antigen accumulation by 20Dg/ml of each compound in K562 cells infected with Dengue virus serotype 2 (strain NGC) at 48 hours post-infection
Figure imgf000123_0002
Figure imgf000124_0001
As shown in table 5, compound 1037 showed the highest efficacy among all variants in inhibiting virus replication. To further enhance the efficacy and reduce toxicity 1015 and 1037 were modified to generate 1038 and 1039 respectively. The efficacy of 1038 and 1039 were ascertained by quantification of the infectious titer of virus produced by infected cells, which have been treated with these compounds. The result showed both 1038 and 1039 to be efficacious in decreasing secretion of infectious virus, by a direct effect on genome replication by the viral RdRp enzyme (Figure 5, panel A).Further a dose-response efficacy using a range of 1039 concentrations showed the EC50 of the compound to be 10 Dg/ml (Figure 5, panel B).
Subsequent to establishment of efficacy, the toxicity of 1039 was ascertained both in the cell line used for efficacy study and peripheral blood mononuclear cells (PBMCs) purified from the blood of healthy human volunteers. A comparison of the total intracellular Adenosine triphosphate (ATP) content was taken as the index of cytotoxicity. As expected, for both types of cells a linear increase in the number of cells showed a concomitant increase in the estimation of total ATP (Figure 6, panel A and B). An intermediate value with respect to the number of cells from this linear range was used for evaluating the toxicity of an increasing concentration of 1039, compared to equivalent concentration of the solvent used for compound solubilization (DMSO). Etoposide, a known cytotoxic drug was used as a positive control in these experiments. As shown, in contrast to Etoposide which induced significant cell death, the highest concentration of 1039 used here (160 Dg/ml) did not induce any cell death as evidenced by maintenance of ATP levels similar to that of controls, namely no drug and 1.6% DMSO (Figure 6, panel C). Incubation of PBMC with a highest concentration of 160 Dg/ml of 1039, reduced the ATP content to cells similar to that of equivalent concentration of vehicle (1.6% DMSO), suggesting 1039 to be non-toxic for PBMCs as well even at this concentration (Figure 6, panel D).
The efficacy of the compounds of present invention were found to be active against DENV2. The activity of these compounds was tested against virus belonging to the other 3 serotypes, namely DENV1, DENV3 and DENV4. The infectious titre of virus produced from K562 infected with either of the four serotypes was compared to that of NITD08, a nucleoside inhibitor of DENV2. The result showed 1038 to have the highest efficacy against DENV2 and to cause lowest inhibition of DENV4 replication (Figure 7). Similarly 1039 was most inhibitory for DENV2 and had higher efficacy against DENV1 when compared to 1038 (Figure 7).
Compounds 1040-1081 were designed, synthesized as per examples above and their efficacy tested against replication of DENV2 by FFU assay. The result showed that compounds 1061, 1089, 1095 and 1105 to show equal efficacy as the parent compound. In addition, compoundsll06 and 1154 to have equal efficiency. Based on toxicity and the similarity of structure between 1089 and 1154, these two compounds show the highest selectivity index in inhibiting Dengue virus replication. In particular, the illustrative compounds of the present invention that were active include compounds 1061, 1089,1092,1094.1095, 1105,1106,1109,1127.1154,1157, 1159,1170

Claims

We Claim:
1. Compounds of formula (I), for inhibition of DENV RNA-dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof:
Figure imgf000126_0001
Formula I
Wherein
R1 is H, Ci-Ce straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-C6 straight chain or branched chain alkynyl; C2-C6 alkyl- alkenyl, C2-C6 alkyl-alkynyl, -CH2(CH2)nOMe, heterocyclyl which is optionally substituted with R6, carbocyclyl which is optionally substituted with R6, (CH2)n(heterocyclyl)n, which is optionally substituted with R6; (CH2)n(carbocyclyl)n which is optionally substituted with R6;
R2 is H, C1-C6 alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that is optionally aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6 R4, R5 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6 or
R5 can be C1-C6 alkyl which is substituted with one or more 3-8 membered carbocyclyl or 3-8 membered heterocyclyl ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S, wherein the ring system is optionally substituted with R6; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S; or R4 and R5 may form a ring with the N to which it is attached, which ring may contain additional heteroatom selected from the group comprising O, N, S;
R6 is H, halo, CN, CF3,OCHF2, hydroxyl, Amino, C1-C6 straight or branched or C3- Ce cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo-Ci-C6 alkyl, C1-C6 alkyloxy; C1-C6 alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-Ce cyclic alkyl)n, CON(CH2)n(OCH2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
2. The compounds as claimed in claim 1, of Formula II, for inhibition of DENV RNA- dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof
Figure imgf000127_0001
Formula II
Wherein
R1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-C6 straight chain or branched chain alkynyl; C2-C6 alkyl- alkenyl, C2-Ce alkyl-alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)n which may be optionally substituted with R6 R2 is H, C1-C6 alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6;
R4 is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2- C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6 , 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R6;
R6 is H, halo, CN, CF3,OCHF¾ hydroxyl, Amino, C1-C6 straight or branched or C3- Ce cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo-Ci-C6 alkyl, C1-C6 alkyloxy; C1-C6 alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-Ce cyclic alkyl)n, CON(CH2)n(OCH2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic rings containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
3. The compounds of Formula III, as claimed in claim 1, for inhibition of DENV RNA- dependent RNA polymerase, including any conformational isomeric form, salts and solvates thereof
Figure imgf000129_0001
Formula III
Wherein
R1 is H, C1-C6 straight chain or branched chain alkyl; C2-C6 straight chain or branched chain alkenyl; C2-G straight chain or branched chain alkynyl; C2-G alkyl- alkenyl, C2-G alkyl-alkynyl, -CH2(CH2)nOMe, heterocyclyl which may be substituted with R6, carbocyclyl which may be substituted with R6, (CH2)n(heterocyclyl)n, which may be optionally substituted with R6; (CH2)n(carbocyclyl)n which may be optionally substituted with R6 R2 is H, C1-C6 alkyl;
R3 is H, 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
R2 and R3 is combined to form 5 membered or a 6 membered carbocycle or heterocycle that may be aromatic or aliphatic, which may contain single ring or fused ring and the ring may comprise 1 to 3 heteroatoms selected from the group comprising O, N, S, which may optionally be further substituted with R6.
R4, is independently H, C1-C6 straight or branched or cyclic alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(CH2)nOMe, -(CH2)n(3 to 8 membered carbocyclic) optionally substituted with one or more R6, (CH2)n(3 to 8 membered heterocyclic ring) containing 1 to 3 heteroatoms selected from the group comprising O, N, S) optionally substituted with R6 , 3 to 8 membered carbocyclic ring, optionally substituted with one or more R6, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S which may be optionally substituted by one or more R6;;
R6 is H, halo, CN, CF3,OCHF¾ hydroxyl, Amino, C1-C6 straight or branched or C3- Ce cyclic alkyl, C1-C6 straight or branched alkenyl, C1-C6 straight or branched alkynyl, halo-Ci-C6 alkyl, C1-C6 alkyloxy; C1-C6 alkylamino, NHOH, COOH, CONR7, CONHOH, CON(CI-C6 alkyl)n, CON(CI-C6 branched chain alkyl)n, CON(C3-Ce cyclic alkyl)n, CON(CH2)n(OCH2)n, CON(heteroalkyl), CON(carbocyclyl), CON (heterocyclyl); CO(heterocyclyl), wherein the heterocyclyl is 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S;
R7 is H, OH, 3 to 8 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising O, N, S; n is 0 to 3;
It is understood by a person skilled in the art that wherever the valences are not fulfilled, the same can be completed by substitution of H.
4. The compounds as claimed in claim 1, wherein the compounds are selected from the group comprising; i. (E/Z)-N-hydroxy-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; ii. (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)benzoic acid; iii. (E/Z)-2-oxo-N-(4-(pyrrolidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; iv. (E/Z)-2-oxo-N-(4-(piperidine-l-carbonyl)phenyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; v. (E/Z)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamido)-N- (pentan-3 -yl)benzamide ; vi. (E/Z)-N-butyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; vii. (E/Z)-N-(2-methoxyethyl)-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; viii. (E/Z)-N-cyclopropyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; ix. (E/Z)-N-(4-(morpholine-4-carbonyl)phenyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; x. (E/Z)-N-isobutyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; xi. (E/Z)-N,N-diethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; xii. (E/Z)-N,N-dimethyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; xiii. (E/Z)-N-methoxy-N-methyl-4-(2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamido)benzamide ; xiv. (E/Z)-N-(5-chloro-2-fluorophenyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xv. (E/Z)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xvi. (E/Z)-N-(2,5-difluorophenyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xvii . (E/Z)-2-oxo-N-(pentan-3 -yl)-3 -(thiazol-2-ylmethylene)indoline-5 - sulfonamide; xviii. (E/Z)-5-(morpholinosulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one; xix. (E/Z)-5-(pyrrolidin-l-ylsulfonyl)-3-(thiazol-2-ylmethylene)indolin-2-one; xx. (E/Z)-N-cyclohexyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxi. (E/Z)-N-benzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; xxii. (E/Z)-N-(3-fluorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxiii. (E/Z)-N-(4-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxiv. (E/Z)-N-(2-chlorobenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxv. (E/Z)-N-(3-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxvi. (E/Z)-N-(4-methylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indobne-5- sulfonamide; xxvii. (E/Z)-N-(4-isopropylbenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxviii. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(4-
(trifluoromethyl)benzyl)indoline -5 -sulfonamide ; xxix. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3- (trifluoromethyl)benzyl)indoline -5 -sulfonamide ; xxx. (E/Z)-N-(3-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxi. (E/Z)-N-(4-methoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxii. (E/Z)-N-(2,3-dimethoxybenzyl)-2-oxo-3-(thiazol-2-ylmethylene)indobne-5- sulfonamide; xxxiii. (E/Z)-2-oxo-3-(thiazol-2-ylmethylene)-N-(3,4,5-trimethoxybenzyl)indobne- 5 -sulfonamide; xxxiv. (E/Z)-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxv. (E/Z)-N-(2-(difluoromethoxy)benzyl)-2-oxo-3-(thiazol-2- ylmethylene)indobne-5 -sulfonamide ; xxxvi. (E/Z)-2-oxo-N-(l-phenylethyl)-3-(thiazol-2-ylmethylene)indobne-5- sulfonamide; xxxvii. (E/Z)-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; xxxviii. (E/Z)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indobne-5 -sulfonamide ; xxxix. (E/Z)-N-benzhydryl-N, l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indobne-5 -sulfonamide ; xl. (E)-N-(2,4-difluorobenzyl)-l-ethyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indobne-5 -sulfonamide ; xb. (E)-N-(2,4-difluorobenzyl)-l-isopropyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indobne-5 -sulfonamide ; xlii. (E)- l-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-N-methyl-2 -oxo-3- (thiazol-2-ylmethylene)indobne-5 -sulfonamide ; xliii. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(prop-2-yn-l-yl)-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; xliv. (E)-N-(2,4-difluorobenzyl)-l-isobutyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xlv. (E)-l-benzyl-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xlvi. (E)-l-allyl-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xlvii. (E)-l-butyl-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xlviii. (E)-N-(2,4-difluorobenzyl)-l-(2-methoxyethyl)-N-methyl-2-oxo-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; xlix. (E)-l-(cyclobutylmethyl)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ;
1. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(pyridin-3-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; li. (E)-N-(2,4-difluorobenzyl)-l-(4-fluorobenzyl)-N-methyl-2-oxo-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; lii. (E)-N-(2,4-difluorobenzyl)-N-methyl-l-(oxetan-3-ylmethyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; liii. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(thiazol-2-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; liv. (E)-N-(2,4-difluorobenzyl)-N-methyl-l-(oxazol-2-ylmethyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; lv. (E)-N-(2,4-difluorobenzyl)-N-methyl-2-oxo-l-(pyrazin-2-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; lvi. (E)-N-(2,4-difluorobenzyl)-N-ethyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lvii. (E)-N-(2,4-difluorobenzyl)-N-isopropyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lviii. (E)-N-(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-l-metliyl-2-oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; lix. (E)-N-(2,4-difluorobenzyl)- 1 -methyl -2-oxo-N-(prop-2-yn- 1 -yl)-3-(thiazol-
2-ylmethylene)indoline-5-sulfonamide; lx. (E)-N-allyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lxi. (E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lxii. (E)-N-allyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lxiii. (E)-N-butyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; lxiv. (E)-N-(2,4-difluorobenzyl)-N-(2-methoxyethyl)-l-methyl-2-oxo-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; lxv. (E)-N-(cyclobutylmethyl)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxvi. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(pyridin-3-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxvii. (E)-N-(2,4-difluorobenzyl)-N-(4-fluorobenzyl)-l-methyl-2-oxo-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; lxviii. (E)-N-(2,4-difluorobenzyl)-l-methyl-N-(oxetan-3-ylmethyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxix. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(thiazol-2-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxx. (E)-N-(2,4-difluorobenzyl)-l-methyl-N-(oxazol-2-ylmethyl)-2-oxo-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxxi. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-N-(pyrazin-2-ylmethyl)-3- (thiazol-2-ylmethylene)indoline-5 -sulfonamide ; lxxii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-5- ylmethylene)indoline-5 -sulfonamide ; lxxiii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(pyridin-3- ylmethylene)indoline-5 -sulfonamide ; lxxiv. (E)-N-(2,4-difluorobenzyl)-3-(3,4-dimethoxybenzylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxv. (E)-3-(4-chlorobenzylidene)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2- oxoindoline-5 -sulfonamide ; lxxvi. (E)-N-(2,4-difluorobenzyl)-3-(4-fluorobenzylidene)-N,l-dimethyl-2- oxoindoline-5 -sulfonamide ; lxxvii. (E)-3-(3-bromobenzylidene)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxviii. (E)-3-benzylidene-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; lxxix. (E)-N-(2,4-difluorobenzyl)-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2- oxoindoline-5 -sulfonamide ; lxxx. (E)-N-(2,4-difluorobenzyl)-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2- oxoindoline-5 -sulfonamide ; lxxxi . (Z)-N-(2,4-difluorobenzyl)-3 -(2,3 -dihydro- lH-inden- 1 -ylidene)-N, 1 - dimethyl-2-oxoindoline-5 -sulfonamide ; lxxxii. N-(2,4-difluorobenzyl)-3-(dihydro-2H-pyran-4(3H)-ylidene)-N,l-dimethyl- 2-oxoindoline -5 -sulfonamide ; lxxxiii. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-3-(oxazol-5-ylmethylene)-2- oxoindoline-5-sulfonamide; lxxxiv. (E)-N-(2,4-difluorobenzyl)-N, 1 -dimethyl-3-(( 1 -methyl- lH-pyrrol-2- yl)methylene)-2-oxoindoline-5-sulfonamide; lxxxv. (E)-N-(2,4-difluorobenzyl)-3-(furan-2-ylmethylene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; lxxxvi. (E)-N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiophen-2- ylmethylene)indohne-5 -sulfonamide ; lxxxvii . (E)-N-(2,4-difluorobenzyl)-N, 1 -dimethyl-3 -(( 1 -methyl- lH-pyrazol-4- yl)methylene)-2-oxoindoline-5-sulfonamide; lxxxviii. N-(2,4-difluorobenzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethyl)indoline- 5 -sulfonamide; lxxxix. (E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indohne-5 -sulfonamide ; xc. (E)-N-(2,4-difluorobenzyl)-N,l-diisopropyl-2-oxo-3-(thiazol-2- ylmethylene)indohne-5 -sulfonamide ; xci. (E)-N,l-bis(cyclopropylmethyl)-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indohne-5 -sulfonamide ; xcii. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indohne-5 -sulfonamide ; xciii. (E)-N-(2,4-difluorobenzyl)-N,l-diisobutyl-2-oxo-3-(thiazol-2- ylmethylene)indohne-5 -sulfonamide ; xciv. (E)-N,l-dibenzyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xcv. (E)-N,l-diallyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xcvi. (E)-N,l-dibutyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xcvii. (E)-N-(2,4-difluorobenzyl)-N,l-bis(2-methoxyethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xcviii. (E)-N, l-bis(cy clobutylmethyl)-N-(2,4-difluorobenzyl)-2 -oxo-3 -(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xcix. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; c. (E)-N-(2,4-difluorobenzyl)-N,l-bis(4-fluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; ci. (E)-N-(2,4-difluorobenzyl)-N,l-bis(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cii. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; ciii. (E)-N-(2,4-difluorobenzyl)-N,l-bis(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; civ. (E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-bis(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cv. (E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cvi. (E)-N-benzhydryl-l -ethyl -N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cvii. (E)-N-benzhydryl- l-isopropyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cviii. (E)-N-benzhydryl-l-(cyclopropylmethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cix. (E)-N-benzhydryl-N-methyl-2-oxo- 1 -(prop-2 -yn- 1 -yl)-3 -(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; ex. (E)-N-benzhydryl- l-isobutyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxi. (E)-N-benzhydryl-l-benzyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxii. (E)-l-allyl-N-benzhydryl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxiii. (E)-N-benzhydryl-l-butyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxiv. (E)-N-benzhydryl-l-(2-methoxyethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxv. (E)-N-benzhydryl-l-(cyclobutylmethyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxvi. (E)-N-benzhydryl-N-methyl-2-oxo-l-(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxvii. (E)-N-benzhydryl-l-(4-fluorobenzyl)-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxviii. (E)-N-benzhydryl-N-methyl-l-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxix. (E)-N-benzhydryl-N-methyl-2-oxo- 1 -(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxx. (E)-N-benzhydryl-N-methyl-l-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxi. (E)-N-benzhydryl-N-methyl-2-oxo-l-(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxii . (E)-N -benzhydryl-N-ethyl- 1 -methyl -2 -oxo-3 -(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxiii. (E)-N-benzhydryl-N-isopropyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxiv. (E)-N-benzhydryl-N-(cyclopropylmethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide; cxxv. (E)-N-benzhydryl- 1 -methyl -2 -oxo-N-(prop-2-yn- 1 -yl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxvi. (E)-N-benzhydryl-N-isobutyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxvii. (E)-N-benzhydryl-N-benzyl- l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxviii. (E)-N-allyl-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxix. (E)-N-benzhydryl-N-butyl- 1 -methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxx. (E)-N-benzhydryl-N-(2-methoxyethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxi. (E)-N-benzhydryl-N-(cyclobutylmethyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxii. (E)-N-benzhydryl-l-methyl-2-oxo-N-(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxiii. (E)-N-benzhydryl-N-(4-fluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxiv. (E)-N-benzhydryl-l-methyl-N-(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxv. (E)-N-benzhydryl-l-methyl-2-oxo-N-(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxvi. (E)-N-benzhydryl-l-methyl-N-(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxvii. (E)-N-benzhydryl- 1 -methyl-2-oxo-N-(pyrazin-2-ylmethyl)-3 -(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; cxxxviii. (E)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-5-ylmethylene)indoline- 5 -sulfonamide; cxxxix. (E)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(pyridin-3-ylmethylene)indoline- 5 -sulfonamide; cxl. (E)-N-benzhydryl-3-(3,4-dimethoxybenzylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; cxli . (E)-N-benzhydryl-3 -(4-chlorobenzylidene)-N, 1 -dimethyl-2-oxoindoline-5 - sulfonamide; cxlii. (E)-N-benzhydryl-3-(4-fluorobenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxliii. (E)-N-benzhydryl-3-(3-bromobenzylidene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxliv. (E)-N-benzhydryl-3-benzylidene-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cxlv. (E)-N-benzhydryl-3-(isoxazol-4-ylmethylene)-N,l-dimethyl-2-oxoindoline- 5 -sulfonamide; cxlvi. (Z)-N-benzhydryl-3-(2,3-dihydro-lH-inden-l-ylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; cxlvii. N-benzhydryl-3-(dihydro-2H-pyran-4(3H)-ylidene)-N,l-dimethyl-2- oxoindoline-5-sulfonamide; cxlviii. (E)-N-benzhydryl-N,l-dimethyl-3-(oxazol-5-ylmethylene)-2-oxoindoline-5- sulfonamide; cxlix. (E)-N-benzhydryl-N, 1 -dimethyl-3-(( 1 -methyl- lH-pyrrol-2-yl)methylene)-2- oxoindoline-5-sulfonamide; cl. (E)-N-benzhydryl-3-(furan-2-ylmethylene)-N,l-dimethyl-2-oxoindoline-5- sulfonamide; cli. (E)-N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiophen-2-ylmethylene)indoline- 5 -sulfonamide; clii . (E)-N-benzhydryl-N, 1 -dimethyl-3 -((1 -methyl- lH-pyrazol-4-yl)methylene)-
2-oxoindoline -5 -sulfonamide ; cliii. N-benzhydryl-N,l-dimethyl-2-oxo-3-(thiazol-2-ylmethyl)indoline-5- sulfonamide; cliv. (E)-N-benzhydryl-N,l-diethyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; civ. (E)-N-benzhydryl-N, 1 -diisopropyl -2 -oxo-3-(thiazol-2 - ylmethylene)indoline-5 -sulfonamide ; clvi. (E)-N-benzhydryl-N,l-bis(cyclopropylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clvii. (E)-N-benzhydryl-2-oxo-N, 1 -di(prop-2-yn- 1 -yl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clviii. (E)-N-benzhydryl-N,l-diisobutyl-2-oxo-3-(thiazol-2-ylmethylene)indoline- 5 -sulfonamide; clix. (E)-N-benzhydryl-N,l-dibenzyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clx. (E)-N,l-diallyl-N-benzhydryl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxi. (E)-N-benzhydryl-N,l-dibutyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxii. (E)-N-benzhydryl-N,l-bis(2-methoxyethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxiii. (E)-N-benzhydryl-N,l-bis(cyclobutylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxiv. (E)-N-benzhydryl-2-oxo-N,l-bis(pyridin-3-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxv. (E)-N-benzhydryl-N,l-bis(4-fluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxvi. (E)-N-benzhydryl-N,l-bis(oxetan-3-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxvii. (E)-N-benzhydryl-2-oxo-N,l-bis(thiazol-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxviii. (E)-N-benzhydryl-N,l-bis(oxazol-2-ylmethyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxix. (E)-N-benzhydryl-2-oxo-N,l-bis(pyrazin-2-ylmethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxx. (E)-N-benzhydryl-l-methyl-2-oxo-3-(thiazol-2-ylmethylene)indoline-5- sulfonamide; clxxi. (E)-N-(3-fluorobenzyl)-N, l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxii. (E)-N-(2-(difluoromethoxy)benzyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxiii. (E)-N,l-dimethyl-2-oxo-N-(l-phenylethyl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxiv. (E)-N-(cyclopentyl(2,4-difluorophenyl)methyl)-N, l-dimethyl-2 -oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; clxxv. (E)-N-(l-(2,4-difluorophenyl)propyl)-N, l-dimethyl-2 -oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxvi. (E)-N-(cyclohexyl(2,4-difluorophenyl)methyl)-N, l-dimethyl-2 -oxo-3- (thiazol-2-ylmethylene)indoline-5-sulfonamide; clxxvii. (E)-N-((2,4-difluorophenyl)(tetrahydro-2H-pyran-4-yl)methyl)-N, 1 - dimethyl-2 -oxo-3-(thiazol-2-ylmethylene)indoline-5-sulfonamide; clxxviii. (E)-N-(bis(2,4-difluorophenyl)methyl)-N, l-dimethyl-2 -oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxix. (E)-N-(bis(4-fluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxx. (E)-N-(bis(4-chlorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; clxxxi. (E)-N-(bis(3-fluorophenyl)methyl)-N,l-dimethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5-sulfonamide.
5. The compounds of the present invention, as claimed in claim 1, i. 1061-(E)-N-benzyl-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; ii. 1089-(E)-N-(2,4-difluorobenzyl)-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; iii. 1092-(E)-N-(2,4-difluorobenzyl)-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol- 2-ylmethylene)indoline-5-sulfonamide; iv. 1094-(E)-N,l-dibenzyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; v. 1095-E)-N, l-diallyl-N-(2,4-difluorobenzyl)-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; vi. 1105-(E)-N-(2,4-difluorobenzyl)-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; vii. 1106-(E)-N-benzhydryl-l-ethyl-N-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; viii. 1109-(E)-N-benzhydryl-N-methyl-2-oxo-l-(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; ix. 1127-(E)-N-benzhydryl-N-benzyl-l-methyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; x. 1154-(E)-N-benzhydryl-N,l-diethyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xi. 1157-(E)-N-benzhydryl-2-oxo-N,l-di(prop-2-yn-l-yl)-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xii. 1159- (E)-N-benzhydryl-N,l-dibenzyl-2-oxo-3-(thiazol-2- ylmethylene)indoline-5 -sulfonamide ; xiii . 1170-(E)-N-benzhydryl- 1 -methyl -2 -oxo-3 -(thiazol-2-ylmethylene)indoline- 5 -sulfonamide.
6. A process of synthesis of the compounds as claimed in claim 1, comprising the steps of i. Treating indolin-2-one (1) with chlorosulfonic acid to result in 2- oxoindoline-5-sulfonyl chloride (2), ii. Optionally treating in 2-oxoindoline-5-sulfonyl chloride (2), different aromatic and aliphatic amine to give sulfonamides (10-16), iii . Coupling 2-oxoindoline-5 -sulfonyl chloride (2) with 4-aminobenzoic acid (7) in presence of pyridine as a base to neutralize the liberated hydrochloric acid to obtain 4-(2-oxoindoline-5-sulfonamido) benzoic acid (8), iv. Subjecting 4-(2-oxoindoline-5-sulfonamido) benzoic acid (8) or sulfonamides (10-16), to Knoevenagel condensation with thiazole-2- carbaldehyde (6) by using pyrrolidine as base in ethanol resulted the carboxylic acid intermediate, or final compounds 1014 to 1037, v. Coupling carboxylic acid intermediate with different primary and secondary amines using the amide coupling reagent HATU, DIPEA as base in DMF to arrive at the compounds.
7. The process of synthesis as claimed in claim 6 of the compounds as claimed in claim 1, wherein i. Indolin-2-one (1) is treated with chlorosulfonic acid or other suitable acids at a temperature of 50 to 80 for 1 to 3 h to result in 2-oxoindoline-5 -sulfonyl chloride (2), ii. The 2-oxoindoline-5-sulfonyl chloride (2) is treated with different aromatic and aliphatic amine to give sulfonamides (10-16) in presence of pyridine and 1.4-dioxane or other suitable solvent mixtures for a period of 1-3 h at room temperature, iii . Coupling 2-oxoindoline-5 -sulfonyl chloride (2) with 4-aminobenzoic acid (7) is in the presence of pyridine as a base to neutralize the liberated hydrochloric acid, or any suitable base to neutralize the acid generated, in presence of pyrroline or ethanol at room temperature for 2-8 h to obtain 4-(2-oxoindoline- 5-sulfonamido) benzoic acid (8), iv. Subjecting 4-(2-oxoindoline-5-sulfonamido) benzoic acid (8) or sulfonamides (10-16), to Knoevenagel condensation with thiazole-2- carbaldehyde (6) by using pyrrolidine as base or other suitable bases in ethanol resulted the carboxylic acid intermediate, or final compounds 1014 tol037. v. Coupling carboxylic acid intermediate with different primary and secondary amines using the amide coupling reagent such as HATU, DIPEA as base in DMF to arrive at the compounds 1038 to 1181.
8. A pharmaceutical composition comprising any of the compound as claimed in claim 1 along with pharmaceutically acceptable diluent, excipient, or carrier.
9. The composition as claimed in claim 7, when administered orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi solid, lyophilized powder, or liquid dosage forms.
10. The compounds as claimed in claim 1, when administered at a dose of from 0.1 to 500 mg/kg per day.
11. The compounds as claimed in claim 1, for their use or intervention into disorders pertaining to or related to inhibition of DENY R A-dependent R A polymerase.
PCT/IN2021/050596 2020-06-21 2021-06-21 Design, synthesis of novel oxyindole inhibitors of denv rna dependent rna polymerase WO2021260722A1 (en)

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