DESC:Heterocyclic Compounds as Inhibitors Of IKK-2 For Hair Regeneration and Dermatological Applications

Field of invention
The present invention provides novel heterocyclic compounds of formula I or formula II, or pharmaceutically acceptable salts, a prodrugs, derivatives, solvates, or stereoisomers thereof. The novel compounds of the present invention are referred to as IAM-S021 to IAM-S037, IAM-S041 to IAM-S060. These compounds target IKK-2 (kappa-B kinase 2) a key mediator of NF-?B (nuclear factor kappa B) signalling. The compounds of the present invention have been designed and tested with aim of augmenting SOX2 expression to help regenerate hair follicles and or reduce, prevent hair fall. These compounds are useful for treatment of hair related dermatological conditions such as Androgenetic alopecia (AGA) or pattern hair loss or Alopecia areata (AA). The present invention also provides process of preparing these compounds and pharmaceutical compositions containing these compounds.

Background of the present invention
Hair fall-related dermatological issues, such as Androgenetic alopecia (AGA) or pattern hair loss, affect more than half of the adult male population globally, along with around 40 percent of adult females, with a market value of 7 billion USD per annum. This condition is moderately stressful and often has implications on body image satisfaction, occasionally leading to under-confidence and even depression in affected individuals. Dihydrotestosterone (DHT), produced from the conversion of Testosterone by 5-alpha-reductase, plays a key role in the pathophysiology of AGA. Medical treatments range from only two FDA-approved drugs, including Minoxidil (topical application) and Finasteride (oral intake), to hair transplant surgery. Unfortunately, both of the approved drugs have side effects such as facial hypertrichosis, contact dermatitis, and sexual dysfunction (Minoxidil) and depression (Finasteride). Meanwhile, hair transplant surgery is expensive, invasive, and shows varying degrees of success. AGA thus remains an unmet medical need that requires a safe and efficacious therapeutic approach.
Alopecia areata (AA) is an autoimmune hair loss condition involving hair loss in patches or total hair loss on the scalp and other body parts. AA affects about 1.7 percent of individuals and results in depression and body image issues. Present treatments include steroid administration, which is not effective. We have developed small molecules that trigger hair regeneration, as studied in human 2D and 3D in vitro models. Minoxidil treatment was used as a positive control in these experiments.
It has been shown that dermal papilla cells have an origin from neural crest cells that express SOX2, a stem cell factor involved in the maintenance of stem cells. These SOX2-positive stem cells are key cellular constituents of the dermal papilla niche (Clavel, Carlos et al., 2012) and maintain the dermal papilla cell source in the human hair follicle, which plays a key role in hair cycle maintenance. SOX2 is the key marker of dermal papilla cells, which also express certain mesenchymal stem cell markers.
Androgenetic alopecia is associated with inflammation (Rahmani et al., 2020) and the downregulation or lack of progenitor or stem cells that aid in the repopulation of the dermal niche and maintenance of dermal papillae. A key pathway associated with inflammation that is well-established is NF-?B (nuclear factor kappa B). NF-?B represents a family of transcription factors that are normally repressed in the cytoplasm by the inhibitory action of the I?B family proteins. In response to stimuli, phosphorylation of I?B family proteins is carried out by IKK-2, a kinase involved in the activation of this pathway, thus relieving the suppression and subsequently leading to the nuclear translocation of NF-?B. NF-?B acts as a transcriptional factor for genes involved in many cellular activities based on the niche and context of cells (Israël A., 2010).
Many pharmacological inhibitors have been developed to target IKK-2 and other proteins involved in this signaling pathway. Diseases such as inflammation and many cancers are associated with the hyperactivation of this pathway.

Rationale of Targeting IKK-2
IKK-2 is a kinase involved in the activation of the NF-?B signaling and has been selected as the target protein to treat dermatological issues such as Androgenetic Alopecia, but not limited to alopecia areata, psoriasis, and inflammatory dermatological diseases like atopic dermatitis. This selection is based on the following data that has been mined and connected to establish the importance of the NF-?B signaling pathway in the disease pathology. IKK2 has been used as a drug target, and previously, several small molecules were designed for this purpose (Christopher E Neipp et al., Application TW097109962A).
NPCs with high levels of NF-?B expression have been shown to downregulate SOX2 expression, while NPCs subjected to transgene IKK-2 expression treatment significantly decreased SOX2 expression (FitzPatrick, Lorna M et al., 2018). This prompted the inventors to investigate the inverse relationship between SOX2 levels and active NF-?B signaling.
The inventors of the present invention hypothesized that pharmacological inhibition of NF-?B signaling by specifically targeting IKK-2 would lead to an upregulation of SOX2 expression in dermal papilla cells, which have neural progenitor origins. This, in turn, could result in SOX2-mediated maintenance of stemness in dermal papilla cells. The application of pharmacological inhibition of IKK-2 and consequently NF-?B signaling aims to enhance SOX2 expression for the treatment of androgenetic alopecia. This treatment approach holds therapeutic importance due to the role of SOX2 expression, and incidentally, it also downregulates the inflammation commonly observed in the hair follicle niche of androgenetic alopecia (Rahmani et al., 2020). Importantly, the therapeutic application is not limited to alopecia areata, psoriasis, or inflammatory dermatological diseases such as atopic dermatitis.

Brief description of drawings
Figure I: Effect of small molecule treatment ATP levels quantified by cell Titre-Glo assay, and the MTT assay to observe cell visibility, the results indicate that the IAM 5021 treatment to HDPs leads higher ATP levels and non-toxic at 5 uM concentration.
Figure 2: Effect of small molecule treatment on Transcriptional Modulation quantified by qPCR; the results indicate that the IAM-5021 treatment to HDPs leads to upregulated expression of SOX2 and other Pro-hair regeneration factors.
Figure 3: immunofluorescence on Human Dermal Papillae Cells probing SOX2 expression; the results indicate that the SOX2 protein expression.
Figure 4: Depiction of the pathway involved in hair regeneration. The depiction is adapted from the study by FlitzPatrick, Lorna M et al. 2018.

Summary of the present invention
In an embodiment the present invention provides compounds of formula I or II, or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:

or
Formula I Formula II

wherein,
W is S or N,
X is NH or N,
Y is N,
Z is N or NH,
R1, R2 and R3 are independently selected from H, optionally substituted halogen (X), OH, SH, alkoxy (OR), alkyl amine (NHR), NO2, amine (NH2), acyl (COR), amide (CONH2), nitrile (CN), ester (COOR).
In another embodiment the compounds of formula I, are wherein when W is S, X is NH and Z is N,R1 is independently selected from H, OH, CH(OH)CH3, NH2, CONH2, CH(OH)CH3 or SH; R2 is independently selected from CN or COCH3; and R3 is independently selected from H, OH or NH2.
In still another embodiment the compounds of formula II, are wherein when each of W, X, and Y are N and Z is NH, R1 is independently selected from OH, COCH3, OCH3, NHCH3,NH2, SH, F or CN; and R2 is independently selected from H, COOH, CONH2, NO2, CN, CH3, or CF3.
In yet another embodiment the compounds of formula 1, or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof are of formula I or II which are listed in Tables 1 to 4 hereinafter.
In another embodiment the present invention provides process of preparing compound of formula 1 or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:
Formula I
comprising the steps of:
(A) synthesis of substituted 3-phenyl-1H-pyrazole-4-carbaldehyde comprising:

i. preparing substituted 2-(1-phenylethylidene)hydrazine-1-carboxamide (compound 2) by reacting compound 1 and hydrazinecarboxamide in a suitable solvent and suitable conditions to obtain compound 2;

ii. preparing 3-phenyl-1H-pyrazole-4-carbaldehyde (3) by adding POCl3 in DMF and refluxeing at 80 oC for 1h to obtain substituted 3-phenyl-1H-pyrazole-4-carbaldehyde (compound 3);
(B) synthesis of 5,6-dihydro-4H-cyclopenta[b]thiophen-2-amine derivatives comprising reacting compound 4 and active methylene coupling partner in 1,4-dioxane containing triethylamine and elemental sulphur to obtain compound 5;

(C) reacting compound 5 and compound 3 in 1:1 mole ratio in presence of ethanol at room temperature and suitable conditions to obtain compound of formula 1.
In still another embodiment of the present invention in the process provided hereinabove the suitable solvent in step (A)(i) is ethanol and the suitable conditions are stirring at room temperature for 2h.
In yet another embodiment of the present invention in the process provided hereinabove the suitable conditions in step (C) are stirring at room temperature for 2h.
In another embodiment the present invention provides process of preparing compound of formula II or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:
Formula II
comprising the steps of:
(A) synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone derivatives comprising :

i. Synthesis of 4-chloro-3-nitroquinoline derivatives (compound 7) comprising mixing compound 6, POCl3 and catalytic amount of N,N-Dimethyl amine, to obtain a homogeneous mixture; refluxing the obtained homogeneous mixture at suitable temperature and for suitable time; diluting with NaHCO3 under suitable conditions to obtain compound 7;
ii. Synthesis of 3-nitroquinolin-4-amine derivatives (compound 8) comprising mixing compound 7 with NH3 in tetrahydrofuran to obtain a reaction mixture; sealing the reaction mixture was and stirring at 80 oC for 12 h to obtain compound 8;
iii. Synthesis of quinoline-3,4-diamine (compound 9) comprising mixing compound 8 and iron powder, to obtain a solution; adding the solution in tetrahydrofuran, NH4Cl; diluting with brine solution and extracting with ethyl acetate to obtain compound 9;
iv. Synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone (compound 10) comprising mixing compound 9, corresponding aldehyde in toluene to obtain reaction mixture; refluxing the reaction mixture; diluting with brine solution and extracting with ethyl acetate to obtain compound 10;
(B) reacting compound 10 and, 4-formylpicolinic acid or isonicotinaldehyde or 2-nitroisonicotinaldehyde or 4-formylpicolinonitrile or 2-nitroisonicotinaldehyde or 2-(trifluoromethyl)isonicotinaldehyde or 4-formylpicolinamide or 4-formylpicolinonitrile acid, in a molar ratio of 1:1.1 in presence of dimethylformamide to obtain compound of formula II.
In still another embodiment of the present invention in the process provided hereinabove for preparing compound of formula II the suitable temperature in step (A)(i) is 100oC, the suitable time is 6h and the suitable conditions are diluting with NaHCO3 solution at 0oC and extracting with ethyl acetate.
In yet another embodiment the present invention provides that the compounds pf formula I or formula II or the compounds prepared by the process described hereinabove and also in details hereinafter are in the form of a pharmaceutical compositions or medicaments as inhibitors of IKK-2 (kappa-B kinase 2) for treatment of hair related dermatological conditions such as Androgenetic alopecia (AGA) or pattern hair loss or Alopecia areata (AA).

Detailed Description of the present invention
Based on available information about the protein structure and the abundance of chemical space, a strategy was devised to identify novel inhibitors against IKK-2. Utilizing the ATP binding pocket, a virtual screening was conducted to screen the in-house library of 10 million compounds. After comprehensive studies, the inventors finalized molecules for the initial screening based on binding patterns, novelty, and synthetic feasibility.
Out of the 37 molecules tested, 7 exhibited inhibitory activity in the micromolar range, while the remaining molecules demonstrated activity above the micromolar range. The compounds IAM-S021 and IAM-S041 were identified as hit molecules and were subsequently selected for further studies. In an effort to transition these hits into lead compounds, an extensive investigation was conducted on the interactive hotspots of the target protein, IKK-2.
Based on the analysis, the binding pocket was divided into four distinct parts. The first and foremost of these was the hinge region, and special attention was paid to maintain the interaction of the scaffold with the crucial amino acids within this hinge region. The other parts of the pocket encompassed a hydrogen bond acceptor region as well as two hydrogen bond donor regions.
The IUPAC name of the hit molecule IAM-S021 selected is (E)-1-(2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one. Further derivatives of the IAM-S021 have been depicted in the table and have been selected for further studies.
The rationale behind the design of these molecules is derived from their pharmacological features. An important part of the molecule is the pyrazole, which establishes significant interactions with the hinge region amino acids Glu97 and Cys99 of the target IKK-2. The phenyl ring linked to the pyrazole ring enters the hydrogen bond donor region, presenting ample opportunity for expanding the molecule to enhance activity. Various functional groups with hydrogen bond donor capacity were employed to modify the molecule.
An essential fused component is the cyclopenta[b]thiophene ring, which infiltrates the other hydrogen bond donor region located opposite to the hinge region. This region contains the amino acid Asn150 of the target IKK-2, which is polar and features an amide group. This amino acid was specifically targeted to enhance the interaction strength of the protein complex. The nitrile group attached to the cyclopenta[b]thiophene ring is positioned within the hydrogen bond acceptor region. This group was also subject to functionalization to augment the interaction pattern.
IUPAC name of IAM-S041 is 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid. The selection of this compound as hit for two important reasons. Only a few companies, such as Bristol-Myers Squibb and Kyorin, have utilized tricyclic compounds to inhibit this target. Another advantage lies in the potential development of these compound types into macrocycles, which would prove highly beneficial during the lead optimization stage, enhancing ADME (absorption, distribution, metabolism, excretion) and selectivity parameters.
The presence of nitrogen in the triazolo[1,5-c]quinazolin ring establishes a hydrogen bond interaction with hinge region amino acids, thereby satisfying the crucial kinase binding criteria discussed previously. The pyridine ring attached to it enters the hydrogen bond acceptor region, offering opportunities for derivatization. Fluorine, attached to the phenyl ring in the tricyclic structure, interacts with the hydrogen bond donor region.
Through further derivatization and activity studies, the compounds IAM-S021, IAM-S026, IAM-S035, IAM-S041, IAM-S049, IAM-S053, and IAM-S057 were identified as lead molecules with the potential to proceed to the lead optimization stage.
Accordingly, the present invention provides novel molecules of compound-1 and compound-2 of formulas that are mentioned in the tables (Table 1 , 2,3, 4).
In these molecules, W, X, Y, Z, R1, R2 and R3 each independently represent S, N, CN, OMe, OH, -COCH3, O, SH, NH2, -CONH2, COOCH3, -CH2OCH3, -CHO, -NO2, -COOH and -CH(OH)CH3 and the ring size vary from five membered ring to eight membered ring in Compound-1, while the Compound-2 has a fixed six membered size ring.
The present invention also relates to the biological evaluation of the synthesized molecules for the treating or preventing diseases for therapeutic applications such as but not limited to alopecia areata, psoriasis and inflammatory dermatological diseases such as atopic dermatitis.
In the compound 1 (Formula I) and in the compound 2 (Formula II), W, X, Y, Z at each occurrence, independently represent Nitrogen (N) and Sulphur (S).
W is independently represented as sulphur (S) in compound-1 and as Nitrogen (N) in the compound 2. While X, Y and Z independently represent nitrogen (N) in both the molecular structures of the compound-1 and the compound-2.
R1, R2 and R3 are independently selected from hydrogen, optionally substituted halogen (X), hydroxyl (OH), thiol (SH) alkoxy (OR), alkyl amine (NHR), nitro (NO2), amine (NH2), acyl (COR), amide (CONH2), nitrile (CN), ester (COOR) in the compound-1 and the compound-2.
Accordingly provided are compounds of formula 1 or II, or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:

or
Formula I Formula II

wherein,
W is S or N,
X is NH or N,
Y is N,
Z is N or NH,
R1, R2 and R3 are independently selected from H, optionally substituted halogen (X), OH, SH, alkoxy (OR), alkyl amine (NHR), NO2, amine (NH2), acyl (COR), amide (CONH2), nitrile (CN), ester (COOR).
The compounds of formula I, wherein when W is S, X is NH and Z is N, R1 is independently selected from H, OH, CH(OH)CH3, NH2, CONH2, CH(OH)CH3 or SH; R2 is independently selected from CN or COCH3; and R3 is independently selected from H, OH or NH2.
The compounds of formula II, wherein when each of W, X, and Y are N and Z is NH, R1 is independently selected from OH, COCH3, OCH3, NHCH3,NH2, SH, F or CN; and R2 is independently selected from H, COOH, CONH2, NO2, CN, CH3, or CF3.
The biological activity of the compounds is related to maintenance and upregulation of stem cells in dermal niche and dermal papillae cells such as but not limited to SOX2 expression augmentation or upregulation at mRNA and protein levels as measured by standard molecular biology methods such as quantitative PCR (qPCR), and Western Blot, Immunofluorescence, fluorescence activated cell sorter (FACS).
The biological activity is tested and validated in cell based two dimensional (2D) cultures or three dimensional (3D) cultures constituting cells selected from Dermal Papillae cells and Keratinocytes, fibroblasts. Minoxidil treatment was used as positive control in these experiments.
The biological activity of the lead molecules, including but not limited to IAM-S021 in a pharmaceutically acceptable salt form, has exhibited an effect on cell viability and cell proliferation. These effects were enhanced and increased when compared to controls within the concentration range of 1-50 µM. This enhancement was quantified through MTT assay and ATP level measurements using an in vitro model system selected from the previously mentioned 2D/3D culture, as depicted in Figure 1.
The biological activity of the lead molecules such as but not limited to IAM-S021 had shown modulation of gene expression when compared to controls in the concentration range of 1-50 uM as quantified by quantitative PCR specifically probed by primers for SOX2, LEF1, VEGF-A which are established biomarkers for hair regeneration, tested on an in vitro model system selected from the aforementioned 2D/3D culture as shown in Figure 2.
The biological activity of the lead molecules such as but not limited to IAM-S021 had shown modulation of SOX2 protein expression when compared to controls in the concentration range of 1-50 uM, tested on an in vitro model system selected from the aforementioned 2D/3D culture as shown in Figure 3. Minoxidil treatment was used as positive control in these experiments.
The biological activity of the lead molecules such as but not limited to IAM-S021 will have a determined binding activity to IKK-2 protein with inhibitory activity in the range of 100-5000 nM concentration, and further qualifies for testing on an in vitro model system selected from the aforementioned 2D/3D culture.
Although the subject matter has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. However, those skilled in the art would appreciate that scope of the disclosure extends to compounds, compositions medicaments and formulations comprising these compounds.

Table 1: Compound 1 (Formula I) and Its derivatives as NCEs with their IUPAC names
Formula I
Comp. name Functional groups IUPAC Name
W X Y Z R1 R2 R3 n
IAM-S021 S NH N N CH(OH)CH3 COCH3 H 1 (E)-1-(2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S022 S NH N N NH2 CN H 1 (E)-2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S023 S NH N N CONH2 CN H 1 (E)-4-(4-(((3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide
IAM-S024 S NH N N CH(OH)CH3 CN H 1 (E)-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S025 S NH N N SH CN H 1 (E)-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S026 S NH N N H CN OH 1 (E)-5-hydroxy-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S027 S NH N N OH COCH3 H 1 (E)-1-(2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S028 S NH N N H COCH3 H 1 (E)-1-(2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S029 S NH N N NH2 COCH3 H 1 (E)-1-(2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S030 S NH N N H CN NH2 1 (E)-5-amino-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S031 S NH N N CH(OH)CH3 COCH3 NH2 1 (E)-1-(5-amino-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S032 S NH N N OH CN H 1 (E)-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S033 S NH N N SH COCH3 H 1 (E)-1-(2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S034 S NH N N SH CN OH 1 (E)-5-hydroxy-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S035 S NH N N CONH2 CN OH 1 (E)-4-(4-(((3-cyano-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide
IAM-S036 S NH N N SH CN NH2 1 (E)-5-amino-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S037 S NH N N OH COCH3 NH2 1 (E)-1-(5-amino-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one

Table 2: Compound 1 (Formula I) and Its derivatives as NCEs with their Structural Depictions
Name Structure Name Structure

IAM-S021
IAM-S031

IAM-S022
IAM-S032

IAM-S023
IAM-S033

IAM-S024
IAM-S034

IAM-S025
IAM-S035

IAM-S026
IAM-S036

IAM-S027
IAM-S037

IAM-S028

IAM-S029

IAM-S030

…………………………………………………………………………………………………..
Table 3: Compound 2 (Formula II) and Its derivatives as NCEs with their IUPAC names

Formula II
Compound name Functional groups IUPAC Name
W X Y Z R1 R2
IAM-S041 N N N NH COCH3 COOH 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S042 N N N NH OH H 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-ol
IAM-S043 N N N NH OCH3 H 8-methoxy-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S044 N N N NH NH2 H 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine
IAM-S045 N N N NH SH H 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-thiol
IAM-S046 N N N NH COCH3 H 1-(2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S047 N N N NH NHCH3 H N-methyl-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine
IAM-S048 N N N NH F CONH2 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide
IAM-S049 N N N NH F NO2 8-fluoro-2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S050 N N N NH F CN 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S051 N N N NH F COOH 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S052 N N N NH F CH3 8-fluoro-2-(2-methylpyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S053 N N N NH COCH3 NO2 1-(2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S054 N N N NH COCH3 CF3 1-(2-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S055 N N N NH COCH3 CONH2 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide
IAM-S056 N N N NH CN H 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile
IAM-S057 N N N NH OH CN 4-(8-hydroxy-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S058 N N N NH NH2 COOH 4-(8-amino-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S059 N N N NH SH CN 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S060 N N N NH SH CONH2 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide

Table 4: Compound 2 (Formula II) and Its derivatives as NCEs with their Structural Depictions

S. No Structure S. No Structure
IAM-S041
IAM-S051

IAM-S042
IAM-S052

IAM-S043
IAM-S053

IAM-S044
IAM-S054

IAM-S045
IAM-S055

IAM-S046
IAM-S056

IAM-S047
IAM-S057

IAM-S048
IAM-S058

IAM-S049
IAM-S059

IAM-S050
IAM-S060

The process of preparing the compounds of formula I and II of the present invention is described hereinbelow:
Synthesis of substituted 3-phenyl-1H-pyrazole-4-carbaldehyde:

Scheme 1: Synthesis of substituted 3-phenyl-1H-pyrazole-4-carbaldehyde
Synthesis of substituted 2-(1-phenylethylidene)hydrazine-1-carboxamide (2) (Nicoletta Desideri et. al., 2019): In a well dried round bottom flask was charged with compound 1 and hydrazinecarboxamide in ethanol as a solvent and allowed to stir at room temperature for 2 h, after completion of the reaction the compound was filtered and well dried for further reaction.
Synthesis of 3-phenyl-1H-pyrazole-4-carbaldehyde (3): To the prepared compound 2 in a round bottom flask was added POCl3 in DMF and refluxed at 80 oC for 1h, progress of the reaction was monitored by TLC. After completion of the reaction excess POCl3 was quenched by ice-cold water and NaHCO3 solution, the formed solid residue was filtered, dried and utilized for further reactions without any further purifications.

Scheme 2: Synthesis of 5,6-dihydro-4H-cyclopenta[b]thiophen-2-amine derivatives
Synthesis of 5,6-dihydro-4H-cyclopenta[b]thiophen-2-amine derivatives (5) (W. W. Wardakhan et. al., 2013): In a well dried round bottom flask was charged with compound 4 (0.01mol) and active methylene coupling partner (0.01 mol) in 1,4-dioxane (20 mL) containing triethylamin (0.5 mL, 0.01 mol) and elemental sulphur (0.32 g, 0.01 mol). The homogeneous reaction mixture was refluxed for 1 h. The progress of the reaction was monitored by TLC, after completion of the reaction the RM was allowed to cool and the separated solid was filtered off to afford compound 5.

Synthesis of (E)-1-(2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S021): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazole-4-carbaldehyde and 1-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.15 (s, 1H), 9.25 (s, 1H), 8.18 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H ), 4.42 (brs, 1H, OH), 4.62 (q, 1H), 3.10-2.95 (m, 4H), 2.48 (s, 3H), 2.34 (m, 2H) 1.41 (d, J = 5.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 195.4, 160.2, 151.4, 146.6, 140.1, 139.3, 136.2, 131.5, 127.5, 126.3, 126.2, 109.5, 67.8, 33.1, 28.2, 26.2. 25.3, 22.4.

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Synthesis of (E)-2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S022): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-aminophenyl)-1H-pyrazole-4-carbaldehyde and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 11.85 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 6.57 (d, J = 8.37 Hz, 2H), 5.1 (brs, 2H, NH2), 2.95 (t, J = 5.25 Hz, 2H), 2.85 (t, J = 5.12 Hz, 2H), 2.32 (q, J = 4.47 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 161.2, 158.4, 145.7, 140.6, 140.0, 134.1, 128.4, 126.3, 122.9, 115.7, 109.2, 101.3, 31.8, 25.2, 24.7.
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Synthesis of (E)-4-(4-(((3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide (IAM-S023): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 4-(4-formyl-1H-pyrazol-3-yl)benzamide and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.05 (s, 1H), 9.32 (s, 1H), 8.17 (s, 1H), 7.98-8.07 (m = 4H), 5.4 (brs, 2H, NH2), 2.97 (t, J = 5.10 Hz, 2H), 2.83 (t, J = 4.93 Hz, 2H), 2.35 (q, J = 4.47 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 168.5, 160.3, 158.3, 140.7, 140.0, 136.2, 134.2, 130.3, 127.2, 115.2, 109.2, 101.2, 31.4, 25.3, 24.5.
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Synthesis of (E)-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S024): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazole-4-carbaldehyde and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.31 (s, 1H), 9.28 (s, 1H), 8.19 (s, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 4.54 (s, 1H, OH), 4.67 (q, J = 4.3, 1H), 2.93 (t, 4.2 Hz, 2H), 2.78 (t, J = 4.1 Hz, 2H), 2.34 (q, 4.42 Hz, 2H), 1.43 (d, 4.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 160.0, 157.6, 145.8, 140.7, 140.0, 134.2, 131.7, 127.2, 126.4, 125.8, 115.1, 109.2, 101.2, 69.7, 31.6, 25.2, 24.4, 22.5.
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Synthesis of (E)-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S025): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-mercaptophenyl)-1H-pyrazole-4-carbaldehyde and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.41 (s, 1H), 9.22 (s, 1H), 8.17 (s, 1H), 7.55-7.60 (m, 4H), 3.37 (s, 1H, SH), 2.93 (t, 4.0 Hz, 2H), 2.83 (t, J = 4.1 Hz, 2H), 2.33 (q, 4.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 160.7, 158.5, 140.8, 140.1, 135.2, 130.2, 129.6, 127.6, 126.2, 115.3, 109.2, 101.3, 69.7, 30.8, 24.8, 24.2.
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Synthesis of (E)-5-hydroxy-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S026): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-phenyl-1H-pyrazole-4-carbaldehyde and 2-amino-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.31 (s, 1H), 9.28 (s, 1H), 8.19 (s, 1H), 7.50-7.65 (m, 5H), 4.6 (s, 1H, OH), 4.32 (m, 1H), 3.06-2.84 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 160.2, 158.4, 140.6, 140.1, 133.5, 133.0, 129.2, 128.5, 127.4, 126.8, 115.3, 109.4, 101.3, 68.4, 39.7, 34.2.
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Synthesis of (E)-1-(2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S027): : To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-hydroxyphenyl)-1H-pyrazole-4-carbaldehyde and 1-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.21 (s, 1H), 9.30 (s, 1H), 8.18 (s, 1H), 7.31 (d, J = 7.6 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 4.3 (s, 1H, OH),2.90-2.85 (m, 4H), 2.45 (s, 3H), 2.35 (m, 2H): 13C NMR (100 MHz, CDCl3): d = 195.4, 160.0, 158.7, 149.7, 140.1, 139.6, 136.4, 128.7, 127.4, 126.3, 126.4, 116.2, 109.5, 32.4, 28.3, 26.4, 25.2.
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Synthesis of (E)-1-(2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S028): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-phenyl-1H-pyrazole-4-carbaldehyde and 1-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.31 (s, 1H), 9.28 (s, 1H), 8.19 (s, 1H), 7.62 (d, J = 7.5 Hz, 2H), 7.48-7.52 (m, 3H), 2.87-2.83 (m, 4H), 2.43 (s, 3H), 2.33 (m, 2H): 13C NMR (100 MHz, CDCl3): d = 195.3, 159.8, 151.4, 140.1, 139.7, 136.3, 130.4, 128.7, 128.4, 126.8, 126,5, 109.3, 32.3, 28.5, 25.8, 25.4.
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Synthesis of (E)-1-(2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S029): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-aminophenyl)-1H-pyrazole-4-carbaldehyde and 1-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.26 (s, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.58 (d, J = 7.7 Hz, 2H), 6.54 (d, J = 7.5 Hz, 2H), 4.6 (brs, 2H, NH2), 2.85-2.81 (m, 4H), 2.39 (s, 3H), 2.33-2.30 (m, 2H): 13C NMR (100 MHz, CDCl3): d = 193.4, 160.4, 151.8, 145.4, 140.1, 139.2, 136.0, 128.3 127.5, 126.2, 123.1, 115.3, 109.2, 32.0, 28.4, 25.6, 25.2.
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Synthesis of (E)-5-amino-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S030): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-phenyl-1H-pyrazole-4-carbaldehyde and 2,5-diamino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.31 (s, 1H), 9.33 (s, 1H), 8.18 (s, 1H), 7.58-7.62 (m, 5H), 3.8 (brs, 2H, NH2), 3.37 (m, 1H), 3.15-2.90 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 160.2, 158.4, 140.4, 140.0, 134.3, 130.2, 129.3 128.5, 127.2, 126.5, 114.7, 109.1, 101.6, 48.4, 39.6, 33.3.
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Synthesis of (E)-1-(5-amino-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S031): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazole-4-carbaldehyde and 1-(2,5-diamino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.11 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H ), 4.45 (brs, 1H, OH), 4.56 (q, 1H), 3.67 (brs, 2H, NH2), 3.34 (m, 1H) 3.12-2.97 (m, 4H), 2.47 (s, 3H), 1.43 (d, J = 5.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 194.7, 160.4, 151.6, 146.2, 140.3, 138.8, 136.5, 131.4, 127.3, 126.4, 125.8, 109.2, 68.4, 49.4, 41.2, 34.2, 28.6, 22.4.

Synthesis of (E)-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S032): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-hydroxyphenyl)-1H-pyrazole-4-carbaldehyde and 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 11.9 (s, 1H), 9.32 (s, 1H), 8.17 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 8.37 Hz, 2H), 4.3 (brs, 1H, OH), 2.90 (t, J = 5.25 Hz, 2H), 2.87 (t, J = 5.12 Hz, 2H), 2.37 (q, J = 4.47 Hz, 2H); 13C NMR (100 MHz, CDCl3): d = 162, 158.2, 140.9, 140.0, 134.5, 128.5, 126.4, 125.3, 116.1, 115.2, 108.9, 101.2, 31.2, 25.6, 24.2.
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Synthesis of (E)-1-(2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S033): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-mercaptophenyl)-1H-pyrazole-4-carbaldehyde and 1-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2 h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.31 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.60-7.55 (m, 4H), 3.4 (brs, 1H, SH), 2.92-2.85 (m, 4H), 2.47 (s, 3H), 2.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 193.6, 159.6, 151.2, 140.6, 139.4, 136.4, 130.5, 129.5, 127.3, 126.7, 109.5, 32.5, 28.6, 26.6. 25.3.
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Synthesis of (E)-5-hydroxy-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-l)methylene)amino) -5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S034): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-mercaptophenyl)-1H-pyrazole-4-carbaldehyde and 2-amino-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophene -3-carbonitrile at room temperature and allowed stir for 2 h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.35 (s, 1H), 9.29 (s, 1H), 8.18 (s, 1H), 7.62-7.57 (m, 4H), 4.53 (brs, 1H, OH), 4.26 (m, 1H), 3.36 (brs, 1H, SH), 3.16-2.87 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 161.3, 158.7, 140.4, 140.1, 134.5, 130.4, 129.3, 127.3, 126.3, 115.3, 109.2, 102.2, 68.4, 38.4, 34.7.
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Synthesis of (E)-4-(4-(((3-cyano-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide (IAM-S035): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 4-(4-formyl-1H-pyrazol-3-yl)benzamide and 2-amino-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2 h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.32 (s, 1H), 9.33 (s, 1H), 8.17 (s, 1H), 8.05-7.83 (m, 4H), 4.43 (brs, 2H, NH2), 4.06 (s, 1H, OH), 3.98 (m, 1H), 3.16-2.87 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 168.3, 160.7, 158.4, 140.9, 140.2, 136.5, 134.2, 130.2, 127.3, 126.2, 115.1, 109.3, 101.2, 69.4, 38.4, 34.2.
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Synthesis of (E)-5-amino-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile (IAM-S036): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-mercaptophenyl)-1H-pyrazole-4-carbaldehyde and 2,5-diamino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile at room temperature and allowed stir for 2 h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.25 (s, 1H), 9.24 (s, 1H), 8.21 (s, 1H), 7.63-7.53 (m, 4H), 3.64 (brs, 1H, SH), 3.37 (m, 1H), 4.43 (brs, 2H, NH2), 4.06 (s, 1H, OH), 3.98 (m, 1H), 3.72 (brs, 2H, NH2), 3.11-2.89 (m, 4H); 13C NMR (100 MHz, CDCl3): d = 168.3, 160.7, 158.4, 140.9, 140.2, 136.5, 134.2, 130.2, 127.3, 126.2, 115.1, 109.3, 101.2, 69.4, 38.4, 34.2.
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Synthesis of (E)-1-(5-amino-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-l)methylene)amino) -5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one (IAM-S037): To a well dried round bottom flask in ethanol was charged with 1:1 mole ratio of 3-(4-hydroxyphenyl)-1H-pyrazole-4-carbaldehyde and 1-(2,5-diamino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one at room temperature and allowed stir for 2 h, after completion of the reaction the precipitate was filtered and purified by recrystallization process. 1H NMR (400 MHz, CDCl3): d = 12.32 (s, 1H), 9.23 (s, 1H), 8.18 (s, 1H), 7.35 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 4.2 (brs, 1H, OH), 3.85 (brs, 2H, NH2), 3.37 (m, 1H), 3.10-2.90 (m, 4H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 195.6, 160.4, 156.8, 151.2, 140.2, 139.2, 136.4, 128.4, 127.3, 126.7, 125.3, 116.5, 109.4, 50.5, 41.3, 34.5, 28.8.
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Synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone derivatives:

Scheme 3: Synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone derivatives.
Synthesis of 4-chloro-3-nitroquinoline derivatives (7) (C. T. Allen et. al.,): In a well dried round bottom flask was charged with compound 6 (0.01mol), POCl3 (Solvent) and catalytic amount of N,N-Dimethyl amine, then the formed homogeneous mixture ewas allowed to reflux at 100 oC for 6 h. The progress of the reaction was monitored by TLC, after completion of the reaction the RM was allowed to cool and diluted with NaHCO3 solution at 0 oC and extracted with EtOAc to get the desired compound 7.
Synthesis of 3-nitroquinolin-4-amine derivatives (8): In a well dried seal tube was charged with compound 7 (0.01mol), NH3 in THF, the reaction mixture was sealed carefully and allowed to stir at 80 oC for 12 h to get the desired compound 8.
Synthesis of quinoline-3,4-diamine (9): In a well dried round bottom flask was charged with compound 8 (0.01mol) and Fe-powder (0.05 mol), to the prepared solution in THF, NH4Cl (0.05 mol) was added portion wise for 30 min. The progress of the reaction was monitored by TLC, after completion of the reaction the RM was allowed to cool and diluted with brine solution and extracted with EtOAc to get the desired compound 9.
Synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone (10): In a well dried round bottom flask was charged with compound 9 (0.01mol), corresponding aldehyde (0.01 mol) in toluene, the reaction mixture was refluxed at 110 oC for 12 h. The progress of the reaction was monitored by TLC, after completion of the reaction the RM was allowed to cool and diluted with brine solution and extracted with EtOAc to get the desired compound 10.
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Synthesis of 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid (IAM-S041): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 1-(3,4-diaminoquinolin-6-yl)ethan-1-one and 4-formylpicolinic acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.34 (s, 1H), 11.96 (s, 1H, OH), 9.01 (d, J = 7.6 Hz, 1H), 8.75-8.92 (m, 4H), 8.37 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 2.52 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 197.6, 177.4, 166.3, 156.2, 155.8, 149.1, 146.7, 145.2, 135.1, 133.4, 129.6, 127.7, 121.4, 118.9, 116.8, 25.9.
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Synthesis of 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-ol (IAM-S042): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinolin-6-ol and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.46 (s, 1H), 8.82 (d, J = 8.3 Hz, 2H), 8.74 (s, 1H), 8.26 (d, J = 8.3 Hz, 2H), 7.86 (s, 1H),7.38-7.31 (m, 2H), 4.24 (brs, 1H, OH); 13C NMR (100 MHz, CDCl3): d = 176.9, 155.4, 152.4, 151.4 149.8, 144.6, 130.5, 126.124.9, 121.1, 109.2.
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Synthesis of 8-methoxy-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolone (IAM-S043): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6-methoxyquinoline-3,4-diamine and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.31 (s, 1H), 8.78 (d, J = 8.4 Hz, 2H), 8.72 (s, 1H), 8.29 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.24 (s, 1H); 13C NMR (100 MHz, CDCl3): d = 176.9, 157.1, 152.9, 152.2, 149.4, 144.3, 131.2, 130.1, 127.1, 122.3, 121.4, 105.5, 55.6.
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Synthesis of 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine (IAM-S044): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of quinoline-3,4,6-triamine and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.29 (s, 1H), 8.82 (d, J = 8.2 Hz, 2H), 8.61 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.27 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1H), 6.82 (s, 1H), 4.62 (brs, 2H, NH2); 13C NMR (100 MHz, CDCl3): d = 177.3, 152.1, 149.2, 144.2, 142.3, 131.6, 128.1, 125.4, 121.8, 121.3, 119.4.
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Synthesis of 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-thiol (IAM-S045): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinoline-6-thiol and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.22 (s, 1H), 8.74 (d, J = 8.4 Hz, 2H), 8.68 (s, 1H), 8.27 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.2 Hz, 1H), 6.61-7.54 (m, 1H), 3.62 (brs, 1H, SH); 13C NMR (100 MHz, CDCl3): d = 177.3, 152.1, 149.2, 144.2, 142.3, 131.6, 128.1, 125.4, 121.8, 121.3, 119.4.
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Synthesis of 1-(2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one (IAM-S046): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 1-(3,4-diaminoquinolin-6-yl)ethan-1-one and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.11 (s, 1H), 8.83 (d, J = 8.6 Hz, 2H), 8.81 (s, 1H), 8.38 (d, J = 8.2 Hz, 2H), 8.26-8.21 (m, 3H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 196.4, 177.8, 156.2, 155.6, 148.7, 144.6, 134.6, 133.6, 129.1, 128.1, 124.4, 121.3, 28.5.
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Synthesis of N-methyl-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine (IAM-S047): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of N6-methylquinoline-3,4,6-triamine and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.16 (s, 1H), 8.78 (d, J = 8.4 Hz, 2H), 8.75 (s, 1H), 8.53 (d, J = 8.2 Hz, 1H), 8.21 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 3.7 (brs, 1H, NH), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 176.8, 150.2, 149.5, 144.3, 143.2, 128.6, 126.4, 125.8, 121.9, 121.0, 121.5, 121.1, 119.7, 29.7.
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Synthesis of 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide (IAM-S048): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6-fluoroquinoline-3,4-diamine and 4-formylpicolinamide at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.46 (s, 1H), 8.89-8.73 (m, 4H), 8.06 (d, J = 8.2 Hz, 1H), 7.39-7.32 (m, 2H), 5.3 (brs, 2H, NH2); 13C NMR (100 MHz, CDCl3): d = 177.6, 164.8, 160.6, 154.6, 131.2, 128.9, 125.4, 121.8, 118.5, 117.3, 109.5.
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Synthesis of 8-fluoro-2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinolone (IAM-S049): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6-fluoroquinoline-3,4-diamine and 2-nitroisonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.42 (s, 1H), 9.08 (d, J = 8.2, 1H), 8.85-8.78 (m, 3H), 8.12 (d, J = 8.2 Hz, 1H), 7.39-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 177.2, 160.6, 154.3, 150.4, 151.7, 146.4, 144.5, 131.7, 129.4, 125.7, 121.6, 118.5, 114.7, 109.3.
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Synthesis of 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile (IAM-S050): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6-fluoroquinoline-3,4-diamine and 4-formylpicolinonitrile at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.32 (s, 1H), 8.98-8.92 (m, 2H), 8.85 (s, 1H), 8.56 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.37-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 177.6, 160.7, 154.7, 153.7, 150.7, 146.7, 134.5, 131.6, 128.8, 127.6, 121.6, 118.5, 114.7, 109.3.
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Synthesis of 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid (): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6 IAM-S051-fluoroquinoline-3,4-diamine and 4-formylpicolinic acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.28 (s, 1H), 11.97 (s, 1H), 9.05 (d, J = 8.2 Hz, 1H), 8.89-8.92 (m, 2H), 8.85 (s, 1H), 8.56 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.37-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 177.4, 168.7, 160.7, 153.5, 148.7, 146.6, 131.5, 129.6, 125.7, 121.6, 118.9, 117.5, 109.7.
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Synthesis of 8-fluoro-2-(2-methylpyridin-4-yl)-1H-imidazo[4,5-c]quinolone (IAM-S052): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 6-fluoroquinoline-3,4-diamine and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.38 (s, 1H), 8.89-8.81 (m, 2H), 8.26 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.39-7.32 (m, 2H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 177.6, 160.5, 158.4, 154.5, 146.7, 138.5, 131.6, 129.7, 125.6, 121.6, 112.5, 109.7, 25.7.
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Synthesis of 1-(2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one (IAM-S053): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 1-(3,4-diaminoquinolin-6-yl)ethan-1-one and 2-nitroisonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.38 (s, 1H), 8.89-8.81 (m, 2H), 8.26 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.39-7.32 (m, 2H), 2.73 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 177.6, 160.5, 158.4, 154.5, 146.7, 138.5, 131.6, 129.7, 125.6, 121.6, 112.5, 109.7, 25.7.
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Synthesis of 1-(2-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one (IAM-S054): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 1-(3,4-diaminoquinolin-6-yl)ethan-1-one and 2-(trifluoromethyl)isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.42 (s, 1H), 9.08 (d, J = 8.3 Hz, 1H), 8.89-8.74 (m, 4H), 8.36 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 2.53 (s, 3H); 13C NMR (100 MHz, CDCl3): d = 197.5, 177.6, 159.5, 158.7, 154.5, 149.7, 135.5, 133.6, 129.6, 127.4, 122.6, 117.5, 27.3.
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Synthesis of 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide (IAM-S055): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 1-(3,4-diaminoquinolin-6-yl)ethan-1-one and 4-formylpicolinamide at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.38 (s, 1H), 8.75-8.92 (m, 5H), 8.37 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 8.2 Hz, 1H), 5.3 (brs, 2H, NH2); 13C NMR (100 MHz, CDCl3): d = 197.4, 177.1, 165.3, 156.7, 155.5, 151.3, 146.4, 144.3, 135.1, 129.6, 127.3, 127.0, 122.1, 117.9, 114.6, 26.7.

Synthesis of 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile (IAM-S056): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinoline-6-carbonitrile and isonicotinaldehyde at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.36 (s, 1H), 9.12 (s, 1H), 8.87-8.81 (m, 3H), 8.25-8.21 (m, 3H), 7.58 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 176.5, 157.4, 157.2, 149.4, 144.1, 133.4, 132.4, 129.4, 129.1, 123.4, 122.4, 121.4, 118.4, 109.7.
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Synthesis of 4-(8-hydroxy-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile (IAM-S057): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinolin-6-ol and 4-formylpicolinonitrile acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitered by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 13.28 (s, 1H), 8.98-8.91 (m, 2H), 8.73 (s, 1H), 8.62 (s, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.38-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): d = 178.2, 155.2, 152.6, 150.3, 146.5, 134.2, 130.7, 130.1, 126.8, 126.1, 125.2, 121.3, 118.9, 117.4, 109.4
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Synthesis of 4-(8-amino-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid (IAM-S058): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of quinoline-3,4,6-triamine and 4-formylpicolinic acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 12.92 (s, 1H), 11.87 (s, 1H), 9.03 (d, J = 8.2 Hz, 1H), 8.78 (d, J = 8.2 Hz, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 6.73 (s, 1H), 4.32 (s, 2H, NH2); 13C NMR (100 MHz, CDCl3): d = 177.1, 167.3, 149.4, 148.8, 146.2, 145.4, 141.1, 139.1, 128.5, 124.9, 121.5, 120.8, 119.6, 119.1, 117.2.
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Synthesis of 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile (IAM-S059): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinoline-6-thiol and 4-formylpicolinonitrile acid acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 12.79 (s, 1H), 8.95-8.88 (m, 2H), 8.73 (s, 1H), 8.57 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.60-7.54 (m, 2H), 3.5 (brs, 1H); 13C NMR (100 MHz, CDCl3): d = 176.8, 154.5, 150.9, 146.8, 134.6, 132.2, 130.6, 129.4, 128.5, 127.1, 125.3, 120.6, 119.6, 117.6.
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Synthesis of 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide (IAM-S060): To a well dried round bottom flask in DMF was charged with 1:1.1 mole ratio of 3,4-diaminoquinoline-6-thiol and 4-formylpicolinamide acid acid at room temperature and allowed stir at 110 oC, the progress of the reaction was monitored by TLC. After completion of the reaction the RM was quenched with water and extracted with EtOAc, dried on anhydrous Na2SO4 and purified by column chromatography. 1H NMR (400 MHz, CDCl3): d = 12.87 (s, 1H), 8.89-8.70 (m, 4H), 7.89 (d, J = 8.2 Hz, 1H), 7.61-7.56 (m, 2H), 5.2 (brs, 2H, NH2), 3.5 (brs, 1H); 13C NMR (100 MHz, CDCl3): d = 177.4, 165.4, 154.2, 151.6, 146.4, 144.2, 132.4, 130.6, 129.1, 128.1, 125.3, 117.8, 115.1.
References:
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FitzPatrick, Lorna M et al. “NF-?B Activity Initiates Human ESC-Derived Neural Progenitor Cell Differentiation by Inducing a Metabolic Maturation Program.” Stem cell reports vol. 10,6 (2018): 1766-1781.
Nicoletta Desideri et. al., “Design, Synthesis, Antiviral Evaluation, and SAR Studies of New 1-(Phenylsulfonyl)-1H-Pyrazol-4-yl-Methylaniline Derivatives” Front Chem., 2019, 7, 214.
W. W. Wardakhan et. al. “The Reaction of Cyclopentanone with Cyanomethylene Reagents: Novel Synthesis of Pyrazole, Thiophene, and Pyridazine Derivatives” Journal of chemistry, 2013, ID 427158.
C. T. Allen et. al., “Cyclic substituted imidazo[4,5-c]quinoline derivatives” WO 2018/163030 Al .
Christopher E Neipp et al., Application TW097109962A, Indole carboxamides as IKK2 inhibitors

,CLAIMS:We claim:
1. Compound of formula 1 or 2, or a pharmaceutically acceptable salt, a prodrug, a derivative, solvate, or a stereoisomer thereof:

or
Formula I Formula II

wherein,
W is S or N,
X is NH or N,
Y is N,
Z is N or NH,
R1, R2 and R3 are independently selected from H, optionally substituted halogen (X), OH, SH, alkoxy (OR), alkyl amine (NHR), NO2, amine (NH2), acyl (COR), amide (CONH2), nitrile (CN), ester (COOR).

2. The compounds of formula I, as claimed in claim 1:
wherein when W is S, X is NH and Z is N,
R1 is independently selected from H, OH, CH(OH)CH3, NH2, CONH2, CH(OH)CH3 or SH,
R2 is independently selected from CN or COCH3, and
R3 is independently selected from H, OH or NH2.

3. The compounds of formula II, as claimed in claim 1:
wherein when each of W, X, and Y are N and Z is NH,
R1 is independently selected from OH, COCH3, OCH3, NHCH3,NH2, SH, F or CN, and
R2 is independently selected from H, COOH, CONH2, NO2, CN, CH3, or CF3.

4. The compounds of formula I, or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof as claimed in claim 1 or 2, which is selected from the group consisting of:

Comp. name IUPAC Name

IAM-S021 (E)-1-(2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S022 (E)-2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S023 (E)-4-(4-(((3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide
IAM-S024 (E)-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S025 (E)-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S026 (E)-5-hydroxy-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S027 (E)-1-(2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S028 (E)-1-(2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S029 (E)-1-(2-(((3-(4-aminophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S030 (E)-5-amino-2-(((3-phenyl-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S031 (E)-1-(5-amino-2-(((3-(4-(1-hydroxyethyl)phenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S032 (E)-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S033 (E)-1-(2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one
IAM-S034 (E)-5-hydroxy-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S035 (E)-4-(4-(((3-cyano-5-hydroxy-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)imino)methyl)-1H-pyrazol-3-yl)benzamide
IAM-S036 (E)-5-amino-2-(((3-(4-mercaptophenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonitrile
IAM-S037 (E)-1-(5-amino-2-(((3-(4-hydroxyphenyl)-1H-pyrazol-4-yl)methylene)amino)-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)ethan-1-one

5. The compounds of formula II, or pharmaceutically acceptable salts, prodrugs, derivative, solvates, or stereoisomers thereof as claimed in claim 1 or 3, which is selected from the group consisting of:
Compound name IUPAC Name

IAM-S041 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S042 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-ol
IAM-S043 8-methoxy-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S044 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine
IAM-S045 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-thiol
IAM-S046 1-(2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S047 N-methyl-2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-amine
IAM-S048 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide
IAM-S049 8-fluoro-2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S050 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S051 4-(8-fluoro-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S052 8-fluoro-2-(2-methylpyridin-4-yl)-1H-imidazo[4,5-c]quinoline
IAM-S053 1-(2-(2-nitropyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S054 1-(2-(2-(trifluoromethyl)pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-8-yl)ethan-1-one
IAM-S055 4-(8-acetyl-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide
IAM-S056 2-(pyridin-4-yl)-1H-imidazo[4,5-c]quinoline-8-carbonitrile
IAM-S057 4-(8-hydroxy-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S058 4-(8-amino-1H-imidazo[4,5-c]quinolin-2-yl)picolinic acid
IAM-S059 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinonitrile
IAM-S060 4-(8-mercapto-1H-imidazo[4,5-c]quinolin-2-yl)picolinamide

6. Process of preparing compounds of formula I or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:

Formula I
comprising the steps of:
(A) synthesis of substituted 3-phenyl-1H-pyrazole-4-carbaldehyde comprising:

iii. preparing substituted 2-(1-phenylethylidene)hydrazine-1-carboxamide (compound 2) by reacting compound 1 and hydrazinecarboxamide in a suitable solvent and suitable conditions to obtain compound 2;

iv. preparing 3-phenyl-1H-pyrazole-4-carbaldehyde (3) by adding POCl3 in DMF and refluxeing at 80 oC for 1h to obtain substituted 3-phenyl-1H-pyrazole-4-carbaldehyde (compound 3);
(B) synthesis of 5,6-dihydro-4H-cyclopenta[b]thiophen-2-amine derivatives comprising reacting compound 4 and active methylene coupling partner in 1,4-dioxane containing triethylamine and elemental sulphur to obtain compound 5;

(C) reacting compound 5 and compound 3 in 1:1 mole ratio in presence of ethanol at room temperature and suitable conditions to obtain compound of formula 1.

7. The process as claimed in claim 6 wherein the suitable solvent in step (A)(i) is ethanol and the suitable conditions are stirring at room temperature for 2h.

8. The process as claimed in claim 6 or claim 7 wherein the suitable conditions in step (C) are stirring at room temperature for 2h.

9. Process of preparing compounds of formula II or pharmaceutically acceptable salts, prodrugs, derivatives, solvates, or stereoisomers thereof:
Formula II
comprising the steps of:
(A) synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone derivatives comprising :

v. Synthesis of 4-chloro-3-nitroquinoline derivatives (compound 7) comprising mixing compound 6, POCl3 and catalytic amount of N,N-Dimethyl amine, to obtain a homogeneous mixture; refluxing the obtained homogeneous mixture at suitable temperature and for suitable time; diluting with NaHCO3 under suitable conditions to obtain compound 7;
vi. Synthesis of 3-nitroquinolin-4-amine derivatives (compound 8) comprising mixing compound 7 with NH3 in tetrahydrofuran to obtain a reaction mixture; sealing the reaction mixture was and stirring at 80 oC for 12 h to obtain compound 8;
vii. Synthesis of quinoline-3,4-diamine (compound 9) comprising mixing compound 8 and iron powder, to obtain a solution; adding the solution in tetrahydrofuran, NH4Cl; diluting with brine solution and extracting with ethyl acetate to obtain compound 9;
viii. Synthesis of 2-(pyridin-4-yl)-3H-imidazo[4,5-c]quinolone (compound 10) comprising mixing compound 9, corresponding aldehyde in toluene to obtain reaction mixture; refluxing the reaction mixture; diluting with brine solution and extracting with ethyl acetate to obtain compound 10;
(D) reacting compound 10 and, 4-formylpicolinic acid or isonicotinaldehyde or 2-nitroisonicotinaldehyde or 4-formylpicolinonitrile or 2-nitroisonicotinaldehyde or 2-(trifluoromethyl)isonicotinaldehyde or 4-formylpicolinamide or 4-formylpicolinonitrile acid, in a molar ratio of 1:1.1 in presence of dimethylformamide to obtain compound of formula II.

10. The process as claimed in claim 9 wherein the suitable temperature in step (A)(i) is 100oC, the suitable time is 6h and the suitable conditions are diluting with NaHCO3 solution at 0oC and extracting with ethyl acetate.

11. The compounds as claimed in claims 1 to 5 or the compounds prepared by the process as claimed in claims 6 to 10 in the form of a pharmaceutical compositions or medicamenst as inhibitors of IKK-2 (kappa-B kinase 2) for treatment of hair related dermatological conditions such as Androgenetic alopecia (AGA) or pattern hair loss or Alopecia areata (AA).

Dated this 12th day of August 2023.
(GAYATRI BHASIN)
IN/PA-1246
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS