WO2023194842A1

WO2023194842A1 - Substituted tricyclic compounds and their use in rheumatoid arthritis

Info

Publication number: WO2023194842A1
Application number: PCT/IB2023/052976
Authority: WO
Inventors: Dhananjay Sathe; Dnyaneshwar Gawas; Saravanakumar IYAPPAN
Original assignee: Unichem Laboratories Limited
Priority date: 2022-04-05
Filing date: 2023-03-25
Publication date: 2023-10-12

Abstract

Present invention provides a means to prevent, cure, treat and/or to ameliorate the diseased condition in a subject suffering from Rheumatoid Arthritis. The said invention further provides a means for treatment of diseased condition in a subject suffering from Rheumatoid Arthritis using a compound of Formula (I) or a pharmaceutically acceptable salt thereof; wherein the compound of Formula (I) is wherein Q is a group of formula Q1 or Q2; (a) (wavy bond) represents the points of attachment; wherein R1 is -NRaRb; R2 is hydrogen or a C1-C10 alkyl group; Ra and Rb independently represent hydrogen or a C1-C10 alkyl group.

Description

SUBSTITUTED TRICYCLIC COMPOUNDS AND THEIR USE IN RHEUMATOID ARTHRITIS

FIELD OF INVENTION

The present invention relates to compounds of Formula I and/or its pharmaceutically acceptable salts thereof for use in prevention, treatment and/or cure of a diseased condition in a subject suffering from Rheumatoid Arthritis.

BACKGROUND OF INVENTION

Rheumatoid Arthritis (RA) is a chronic, destructive, inflammatory disease characterized by autoimmunity that induces joint inflammation and tissue destruction affecting about 1% population of the world. The age-standardized prevalence and incidence rates of RA are increasing, especially in countries such as Canada, Paraguay and Guatemala.

Rheumatoid Arthritis (RA) is associated with pain, joint swelling, progressive disability and comorbidity. Autoimmunity plays a dominant role in pathogenesis of Rheumatoid Arthritis (RA) as it induces joint inflammation and tissue destruction leading to pain, joint swelling, progressive disability, and comorbidity. Proinflammatory cytokines including IL-6, IL-1β , and TNF-α are overproduced in the rheumatoid joints and are critical mediators in the pathogenesis of rheumatoid arthritis (RA). Inhibiting of proinflammatory cytokines has been shown to improve disease symptomatology and outcome in rodent arthritis models and human clinical trials (Lijun Mei et al., 2018).

Rheumatoid Arthritis (RA) pathogenesis is also linked with inflammation. One of the major consequences of RA is the bone destruction, degradation of cartilage and bone tissue resulting in joint destruction, which if left untreated leads to functional disability, pain, reduced health-related quality of life and premature mortality. RA leads to damage of bone in inflamed joints due to overactive bone resorption by osteoclasts or dysfunction of bone formation in osteoblasts, thus damaging the structural integrity of the bone. Osteoblasts play a key role in the regulation of bone metabolism. In fact, they are involved in the production of bone matrix constituents, such as type I collagen. Subsequently, osteoblasts influence calcium and phosphate local concentrations and induce the following bone matrix mineralization. Alkaline Phosphatase (ALP) is a phenotypic marker for the early differentiation and maturation of osteoblasts. Hence, increase in ALP activity and Collagen synthesis is considered as a substantiating end point towards bone strengthening and hence, ameliorating the RA symptoms. Therefore, the other targets of RA treatment are restoration of the balance by preventing bone destruction by osteoclasts or inducing bone formation by osteoblasts.

Janus Kinase are cytoplasmic tyrosine kinases that play a major role in inflammatory responses. Their dysregulation can cause abnormal immune responses that ultimately leads to damage of tissues and other organs. At present, the medications used to treat some of the inflammatory diseases vary depending on the type of disease.

At present the medications used to treat some of the inflammatory diseases include: Analgesics help reduce pain but have no effect on inflammation. Examples of analgesics include acetaminophen (Tylenol, others), tramadol (Ultram, Ultracet, others) and narcotics containing oxycodone (Percocet, Oxycontin, others) or hydrocodone (Norco, Vicoprofen, others). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce both pain and inflammation. NSAIDs include ibuprofen (Advil, Motrin IB, others) and naproxen sodium (Aleve). Some counterirritant varieties of creams and ointments contain menthol or capsaicin. Disease- modifying antirheumatic drugs (DMARDs) are often used to treat rheumatoid arthritis. DMARDs slow or stop the immune system from attacking joints. Examples include methotrexate (Trexall) and hydroxychloroquine (Plaquenil). A new subcategory of DMARDs known as “JAK inhibitors” block the Janus kinase, or JAK, pathways, which are involved in the body’s immune response. Tofacitinib belongs to class of JAK inhibitors. Biologic response modifiers are genetically engineered drugs that target various protein molecules that are involved in the immune response. They are B/T-cells inhibitors, selective co-stimulation modulators. Examples include etanercept (Enbrel), certolizumab (Cimzia), Rituximab (Rituxan) and infliximab (Remicade).

Tricyclic and triazolopyridine compounds are disclosed in US Patents 8962629 and 8088764, which are specific JAK1 inhibitors whereas azetidine derivatives disclosed in US8158616 are mixed JAK1 and JAK2 inhibitors. While these JAK have been shown to be satisfactory, more effective and potent treatment inhibitors is required for JAK related diseases.

Further, the high direct and indirect costs associated with RA, together with the substantial morbidity and mortality affecting millions of people worldwide, underline the potential benefits of improved treatments for this chronic disease to patients, their families and society. There is vital need for early identification and potential therapies, as to reduce the ongoing burden of Rheumatoid Arthritis. OBJECT OF THE INVENTION

An object of the present invention is to provide a means to prevent, cure, and treat and/or to ameliorate the diseased condition in a subject suffering from Rheumatoid Arthritis.

An object of the present invention is to provide a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in prophylactic and/or therapeutic treatment of diseased condition in a subject suffering from Rheumatoid Arthritis.

An object of the present invention is to provide a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacturing of medicament for prophylactic and/or therapeutic treatment of diseased condition in a subject suffering from Rheumatoid Arthritis.

An object of the present invention is to provide a composition comprising of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in prophylactic and/or therapeutic treatment of Rheumatoid Arthritis.

An object of the present invention is to provide a means for treatment of Rheumatoid Arthritis, by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

Present disclosure provides a means to prevent, cure, and treat and/or to ameliorate the diseased condition in a subject suffering from Rheumatoid Arthritis. More specifically, the said invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacturing of medicament for treatment of Rheumatoid Arthritis. The said invention also provides a means for treatment of Rheumatoid Arthritis by administering to the subject a therapeutically effective amount of compound of Formula (I) or a pharmaceutically acceptable salt thereof.

Other and further aspects, features, benefits, and advantages of the present disclosure will be apparent from the following description of the presently preferred embodiments of the invention given for the purpose of disclosure. List of Tables

Table 1: List of compounds derived from Formula I

Table 2: % Inhibition by Test Compound (wrt IL-1B stimulation) on cytokine and metalloproteinases

Table 3: Inhibitory effect of Test Compound on secretion of inflammatory cytokines in Human Synovial cells (MH7A) against Hu-IL-1β induced levels

Table 4: Apoptotic effect of Test Compound by cell cycle analysis in MH7A cell line

Table 5: Apoptotic effect of Test Compound by Annexin-V staining in MH7A cell

Table 6: Apoptotic effect of Test Compound via mitochondrial membrane depolarization by JC-1 staining in MH7Acell line

Table 7: Effect of Test Compound on proliferation of MG-63 cells after 48 h.

Table 8: Anti-proliferative effect of Test Compound on Synovial Cells (MH7A) after 48h of treatment

Table 9: Effect of Test Compound on Arthritis Score

Table 10: Effect of Test Compound on Paw thickness

Table 11 : Effect of Test Compound on IL-6 in Serum

Table 12: Effect of Test Compound on IL-1β in Serum

Table 13: Effect of Test Compound on TNF-α in Serum

Table 14: Histopathology score of hind leg

Table 15: Effect of Test Compound on Paw thickness (mm) of the Groups

Table 16: Effect of Test Compound on Paw volume (ml) of the Groups

Table 17: Effect of Test Compound on Uric Acid Levels

Table 18: Effect of Test Compound on Serum IL6 levels

Table 19: Relative organ weights of groups List of Figures

Figure 1: Inhibitory effect of Test Compound on secretion of IL-8 in Human Synovial cells (MH7A) against Hu-IL-1β induced levels

Figure 2: Apoptotic effect of Test Compound by cell cycle analysis in MH7A cell line

Figure 3: Apoptotic effect of Test Compound by Annexin-V staining in MH7Acell line

Figure 4: Apoptotic effect of Test Compound via mitochondrial membrane depolarization by JC-1 staining in MH7A cell line

Figure 5: Effect of Test Compound on proliferation of MG-63 cells after 48 h

Figure 6: Anti-proliferative effect of Test Compound on synovial cells (MH7A) after 48h of treatment

Figure 7: Mean Arthritis Score

Figure 8: Mean Paw Thickness

Figure 9: Effect of Test Compound on IL-6 in Serum

Figure 10: Effect of Test Compound on IL-1β in Serum

Figure 11: Effect of Test Compound on TNF-α in Serum

Figure 12: Histopathology score of hind leg

Figure 13: Paw thickness of the group

Figure 14: Paw volume (ml) of the Groups

Figure 15: Uric acid levels of the Groups

Figure 16: Effect of Test Compound on serum IL6 levels

Figure 17a: % Relative spleen weight of groups

Figure 17b: % Relative thymus weights of groups DESCRIPTION

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

The term, "a compound for use" or "a compound as described herein" means the compound or a pharmaceutically acceptable salt, thereof. Similarly, the phrase "a compound of Formula I" means a compound of that formula and/or a pharmaceutically acceptable salt thereof.

The term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound i.e., compound of Formula I is modified by making acid or base salts thereof. The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be formed as known to those skilled in the art.

The term ‘composition’ as used herein in the present disclosure may comprise a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The term ‘excipient’ or ‘excipients’ as used herein refers to inactive or usually inert substances that are added to the formulation which do not affect the therapeutic action of the active ingredient but serve as a vehicle or medium for the active ingredient. It may be used to provide a desired consistency, to improve stability, and/or to adjust osmolality of the composition or adjust permeability. The excipients may be selected from the substances that are known to the skilled person for use in the form of compositions that are dependent on the route of administration. Exemplary excipients include diluents, carriers, binding agents, fillers lubricants, disintegrants, wetting agents, suitable coatings, stabilizers, sterilized water, physiological saline, suitable propellant cocoa butter, glycerides, suspending agents, emulsifying agents, preservatives polymers, solubilizers, cryoprotectants, lyoprotectants, bulking agent/s and/or pharmaceutically acceptable buffers or a mixture thereof. The selection of excipients for preparation of a composition of the present invention is well within the scope and understanding of the skilled person, and suitable excipients are listed in standard references such as Handbook of Pharmaceutical Excipients (Rowe RC, Sheskey P, Quinn M. Pharmaceutical Press; 2009); The Theory And Practice Of Industrial Pharmacy (Lachman, L., Lieberman, H. A., & Kanig, J. L. 1976). The Science and Practice of Pharmacy (Remington JP 2006) and Pharmaceutical Dosage Forms and Drug Delivery Systems (Allen L, Ansel HC 2013 Dec 23). The terms ‘formulation’, ‘composition’, ‘medicament’, ‘pharmaceutical formulation’ and ‘pharmaceutical composition’ are used interchangeably and refer to preparations which are in such a form as to permit the biological activity of the active ingredients to be effective, and therefore may be administered to a subject for therapeutic use, wherein the subject is a mammal, selected from the group comprising of human, cows, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird; preferably human.

The terms “administer,” “administering,” or “administration,” herein are used interchangeably and refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing an active compound, or a pharmaceutical composition thereof.

An effective amount” or “therapeutically effective amount” of a compound or any active ingredient as described herein are used interchangeably and refers to an amount sufficient to elicit a desired biological response, i.e., treating the condition. As will be appreciated by those of ordinary skill in art, the effective amount of a compound may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

The term “treatment” comprises substantially curing (i.e. eliminating) the inflammation or an underlying chronic inflammatory disease, or reducing (either permanently or temporarily) the symptoms associated with the inflammation. Such symptoms may include swelling, pain, itching, heat, redness (e.g. of the skin), loss of function (e.g. of joints or limbs), etc.

The terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skilled in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The terms “upregulation” or “upregulated” with respect to the present invention refers to the increased expression or levels of biomarkers in the body.

The term “apoptosis” is defined as a biological process of programmed cell death in which the cells destroy themselves. Induction or inducing apoptosis as disclosed herein is the use of the compound of the present invention in inducing the programmed cell death or apoptosis. In an aspect of the present disclosure, there is provided a means to prevent, cure, and treat and/or to ameliorate the diseased condition in a subject suffering from inflammatory disease. In an embodiment of the present disclosure, there is further provided a means to prevent, cure, treat and/or to ameliorate the diseased condition in a subject suffering from Rheumatoid Arthritis.

In an embodiment of the present disclosure, the compound of Formula I is

wherein Q is a group of formula Q1 or Q2;

(wavy bond) represents the points of attachment;

wherein R₁ is -NR^aR^b;

R₂ is hydrogen or a C₁-C₁₀ alkyl group; and

R^a and R^b independently represent hydrogen or a C₁-C₁₀ alkyl group.

As used herein, the term "alkyl" is intended to include branched and straight-chain saturated aliphatic hydrocarbon groups and cycloalkyl group having the specified number of carbon atoms. For example, "C₁-₁₀alkyl” is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and Cio alkyl groups. Preferred alkyl groups have from 1-6, especially 1-4, carbon atoms.

Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n- propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl). The said alkyl may be further substituted by alkyl, halogen, amides, esters, acids, cyanide, amines.

The term "cycloalkyl" refers to cyclized alkyl groups, including monocyclic ring systems. C3-13cycloalkyl is intended to include C3, C4, C5, C6, and C7cycloalkyl groups. Preferred cycloalkyl groups have from 3-8, especially 3-6, carbon atoms. Example of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The compounds of formula I may form salts with alkali metals such as sodium, potassium and lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be formed as known to those skilled in the art.

The compounds of formula I may form salts with a variety of organic and inorganic acids. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, borates and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic , toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. In addition, zwitterions ("inner salts") may be formed.

The skilled person would appreciate that since the compounds of present invention have more than one basic site, they have the capacity to form a salt with more than one molecule of acid. The present disclosure embodies mono di or tri salts of the compounds of this disclosure.

In another embodiment of the present disclosure, it is envisaged that the compound derived from Formula I includes but are not limited to one or more compounds selected from Table I

In an embodiment of the present disclosure, it is envisaged to prepare the compound of Formula I including compounds given in Table I. The skilled person in the art may prepare the said compounds by using any of the known methods in chemistry. The said compounds may be prepared using the process as described in below scheme.

Scheme I:

Scheme I illustrates the preparation of a compound of formula (I) wherein Q, R1 and R2 are defined as above and L1 and L2 represent X or leaving groups. X may be a leaving group which is either the same as that of L1 or L2 or other than that of L1 and L2. X may also be a group that can be easily substituted by or converted to -COR1.

In the present embodiment, the leaving group L1, L2 or X is one which can be easily replaced by the desired group or atom. The leaving group may be selected from halogen atoms, alkoxy and sulfonyloxy groups. Examples of sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (tritiate group)) and arylsulfonyloxy groups (for example /- toluenesulfonyloxy (tosylate group) and /-nitrosulfonyloxy (nosylate group)). For the purpose of the present invention L2 and X may be particularly selected from halogens such as bromo, chloro or iodo and a tritiate group. The selection of X is well within the understanding and knowledge of the skilled person.

In the above reactions of Scheme I,a compound of formula 1-1 is converted into a compound of formula 1-2 by a displacement reaction of a compound of formula 1-1 with ammonia solution in a suitable solvent, such as water, THF, 1,4-Dioxane, Dimethyl formamide (DMF), Dimethyl sulfoxide (DMSO) or Acetonitrile (ACN), or mixture(s) therefore at a temperature ranging from 45°C to 120°C for 0.5 hours to 20 hours to form a compound of formula 1-2.

A compound of formula 1-2 is converted to a compound of formula 1-3 by reacting a compound of formula 1-2 with a triflating agent such as trifluoromethanesulfonic anhydride or a halogenating agent in a suitable solvent such as acetonitrile, chloroform or tetrahydrofuran at a temperature ranging from -20° C to the refluxing temperature for a time period between about 1 hour to about 10 hours.

A halogenating agent according to the present invention is a reagent that is a source of halogen. For example, the agent may be a chlorinating agent such as chlorine, thionyl chloride, N-Chlorosuccinimide, Oxalyl Chloride or a brominating agent such as bromine, N- Bromosuccinimide, Carbon Tetrabromide or an iodinating agent such as Iodine, Hydriodic acid or N-Iodosuccinimide. The halogenating agent may be selected according to the knowledge and understanding of skilled person.

A Sonogashira reaction with a compound of formula 1-3 and an acetylene derivative using a suitable catalyst provides a compound of formula 1-4. The reaction conditions for a Sonogashira reaction vary depending on the starting material, the solvent and the transition metal catalyst. The reaction conditions are not limited in particular as long as they are similar to the conditions of the present reactions, and the methods well known to those skilled in the art can be used. Examples of preferred solvents include acetonitrile, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxy ethane, benzene, toluene, xylene, 1 -methyl -2-pyrrolidone, N,Ndimethylformamide and dimethylsulfoxide, dichloromethane or mixture thereof. The reaction temperature should be a temperature that is sufficient to complete the coupling reaction, and is preferably from room temperature to 100°C. The present reaction can be carried out under an inert gas atmosphere, and also under a nitrogen or an argon gas atmosphere. Under the preferred reaction conditions, this reaction is completed in 1 hour to 24 hours. The transition metal catalyst is preferably a palladium complex. Examples of palladium complexes include, but not limited to palladium (II) acetate, dichlorobis(triphenylphosphine) palladium(II), tris (dibenzylideneacetone) dipalladium (0) and tetrakis (triphenylphosphine) palladium (0). Furthermore, in the present reaction, a phosphorous chelating agent such as triphenylphosphine, tri-o-tolylphosphine or tri-tert- butylphosphine may be added in order to obtain satisfactory results. Further the reaction may be accelerated using a metal halide or a quaternary ammonium salt or other such salts, preferably copper(I) iodide, lithium chloride, tetrabutylammoniumfluoride or silver (I) oxide. Preferred results can also be obtained in the presence of a base; the base used is not limited in particular as long as it is used in a coupling reaction similar to the present reaction Examples of such bases include, but not limited to diethylamine, triethylamine, N,N- diisopropylethylamine, piperidine and pyridine.

A compound of formula 1-4 can readily undergo 5-endo-dig cyclization in the presence of a base or transition metal catalyst in the presence of a suitable solvent such as alcoholic solvents or THF or DMA to provide a compound of formula 1-5. Exemplarily the base may be selected from Potassium tert-butoxide, Lithium hydride, Lithium Aluminium hydride and n-butyl lithium and the transition metal catalyst may be selected from Palladium and a copper catalyst. A compound of formula 1-5 can be optionally protected by treating it with a protecting group to provide a compound of formula 1-6.

Exemplarily a compound of formula 1-5 is converted to the corresponding compound of formulaI-6, wherein R3 is benzenesulfonyl or benzyl, by treating the compound of formula I- 5 with benzenesulfonyl chloride, benzyl chloride or benzylbromide in the presence of a base, such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran. The reaction mixture is stirred at a temperature between about 0°C. to about 70°C, preferably about 30°C, for a time period between about 1 hour to about 3 hours, preferably about 2 hours.

R3 is a protecting group such as benzenesulfonyl, substituted benzenesulfonyl, methylsulfonyl, benzyl or carbamate protecting groups such as Boc (t-Butyloxycarbonyl) and CBz (carboxybenzyl) or other groups such as benzoyl, iso-butanoyl, acetyl, phenoxyacetyl, 4- (t-butyl)benzoyl, 4-(t-butyl)phenoxyacetyl, 4-(methoxy)benzoyl, 2-(4-nitrophenyl) ethyloxycarbonyl, 2-(2,4-dinitrophenyl)ethyloxy-carbonyl, 9 fluorenylmethoxycarbonyldiphenylcarbamoyl or formamidine groups. Particularly preferred are the benzoyl, isobutanoyl, 4-(t-butyl)benzoyl, 2-(4-nitro-i5 phenyl)ethyloxycarbonyl, 2- (2,4-dinitrophenyl)ethyl-oxycarbonyl, 9-fluorenylmethoxycarbonyl, 4-(methoxy)-benzoyl or para-(t-butyl)phenoxyacetyl, para-nitrophenyl-2-ethyloxycarbonyl group or 2-N-acetyl with the 6-0-diphenylcarbamoyl group.

Compounds of formula 1-5 and 1-6 can be converted to a compound of formula 1-8 and 1-7, respectively in a similar way as the process described for the preparation of a compound of formula 1-3.

Compounds of formula 1-8 can be converted into compounds of formula (I) by a process known to the person skilled in the art. Such process may include converting X of formula 1-8 directly to an amide group or via formation of ester, anhydride, aldehyde, ketone, cyanide, acid or any such group which can be converted to an amide group which is well within the understanding and knowledge of the skilled person.

For example, when X is converted to an ester group and successively converted to an amide, compounds of formula 1-8 can be treated with an esterifying agent in the presence of a base in a polar aprotic solvent like THF, 1,4-Dioxane, DMF, DMSO and ACN at -75°C to 100°C temperature for 0.5 hours to 20 hours which leads to formation of ester derivative. The ester derivative on reaction with a trialkylaluminium (like, trimethylaluminium) and required amine derivatives or ammonia solution in the presence of solvents like Toluene, chloroform, methanol, ethanol, THF, 1,4-Dioxane, DMF, DMSO and ACN at -10°C to 100°C temperature for 0.5 hours to 20 hours gives an amide having formula I.

A compound of formula 1-7 can be converted to a compound of formula I-9using a similar process that may be used for conversion of a compound of formula 1-8 to a compound of formula I.

A compound of formula 1-9 can be converted into a compound of formula I by cleaving the protecting group R3. Protecting groups of a compound of formula 1-9 can be cleaved by deprotecting agents as understood by the skilled person to obtain a compound of formula I. Examples of deprotecting agents for an amino protective group are acids such as trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid p-toluenesulfonic acid or bases such as alkali or alkaline bases. For example, fora compound of formula 1-9 wherein R3 is benzenesulfonyl, the deprotection is carried out by treating 1-9 with an alkali base, such as sodium hydroxide or potassium hydroxide, sodium carbonate, potassium carbonate, potassium tert-butoxide, sodiumtert-butoxide in an alcohol solvent, such as methanol or ethanol, or mixed solvents, such as alcohol/tetrahydrofuran or alcohol/water. The reaction is carried out at room temperature or to reflux temperature for a time period between about 15 minutes to about 1 hour, preferably 30 minutes. When R3 is benzyl, deprotection is either conducted by treating 1-9 with sodium in ammonia at a temperature of about -78° C for a time period between about 15 minutes to about 1 hour or by using hydrogen and a catalyst, such as palladium hydroxide on carbon, Pd/C, Raney Nickel, Raney Nickel in combination with NH2-NH2 or Hydrogen. Other suitable deprotecting agents are Lewis acids, such as, for example boron trifluorideetherate or zinc bromide in dichloromethane/isopropanol, aq. HCl, aq. HBr, HBr in acetic acid, sulfuric acid.

In another embodiment of the present disclosure, it is envisaged to prepare the compound of Formula I including compounds given in Table I. The skilled person in the art may prepare the said compound by using any of the known methods in chemistry. The said compounds may be prepared using the process as described in below scheme.

Scheme II:

Scheme II illustrates the preparation of a compound of formula (I) wherein Q, R1 R2, R3 and X as defined in aforementioned embodiment. R represents alkoxy (-OR) or CX3, Z is NO2.

In the above reactions of Scheme II, a compound of formula I- 10 can be converted to the corresponding compound of formula 1-11, by treating the compound of formula 1-10 with protecting group R3 such as benzenesulfonyl chloride, benzyl chloride or benzylbromide in the presence of a base, such as sodium hydride, potassium carbonate, sodium hydroxide, potassium hydroxide or cesium carbonate or alkyl lithium such as n-butyl lithium, secondary butyl lithium, tertiary butyl lithium or lithium diisopropyl amide. Such reaction may be carried out in solvent such as dimethylformamide, dimethylacetamide, tetrahydrofuran, hexamethyl phosphoramide, dimethyl sulfoxide, 1,4-Dioxane, acetonitrile, water, dichloromethane, Toluene, DMSO or mixture(s) therefore. The reaction mixture is stirred at a temperature between about 0°C. to about 70°C., preferably about 10°C, for a time period between about 1 hour to about 10 hours, preferably about 4 hours. R3 is a protecting group defined as above.

Compounds of formula I-11 can be converted to a compound of formula 1-12 by reacting a compound of formula I-11 with an acylating agent such as trifluoroacetic anhydride, tri chloroacetyl chloride, acid halides, acid anhydrides in a suitable solvent such as acetonitrile, chloroform, n-methyl pyrrolidone, toluene, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylacetamide 1,4-Dioxane chlorinated alkyl or aryl solvents such as dichloromethane or chlorobenzene, di chlorobenzene or di chloroethane or mixture(s) therefore at a temperature ranging from -20°C to the refluxing temperature for a time period between about 1 hour to about 15 hours preferably at 65-75°C for 4-5 hours. A compound of formula 1-12 can be converted to a compound of formula 1-13 by treating compound of formula 1-12 with nitrating agents such as alkyl ammonium nitrate for example, tetrabutyl ammonium nitrate or tetramethyl ammonium nitrate and using trifluoroacetic anhydride in solvents such as dichloromethane, toluene, acetonitrile, tetrahydrofuran, chlorobenzene, nitrobenzene, di chloroethane 1,4-Dioxane, acetonitrile, water, dimethylsulfoxide or mixture(s) therefore, at a temperature ranging from -10°C to 100°C for a time period between about 1 hour to about 30 hours preferably for 5 hours. A compound of formula I-13 can be converted to a compound of formula 1-14 by reaction with ammonia or with primary amines such as methyl amine, ethyl amine, isopropyl amine, n-propyl amine, isobutylamine or n-butylamine in suitable solvents such as tetrahydrofuran, dichloromethane, 1,4 dioxane, toluene, dimethylformamide, water, alcoholic solvents, DMSO, acetonitrile or mixture(s) thereof at a temperature ranging from -10°C to the refluxing temperature for a time period between about 1 hour to about 25 hours, preferably for 8-10 hours.

A compound of formula I-14 can be converted to compound of formula 1-15 by reduction of nitro group using metal catalyst such as palladium on carbon, Raney nickel in combination with NH2-NH2 or Hydrogen, iron/ammonium chloride, platinum on carbon, zinc/ammonium chloride, Fe/AcOH or sodium dithionite in suitable alcoholic solvents such as methanol, ethanol or water or cyclic/acyclic ethers such as tetrahydrofuran or 1,4-dioxane or acetonitrile and water or in mixture of suitable alcoholic solvents such as methanol, ethanol, or cyclic/acyclic ethers such as tetrahydrofuran or 1,4-dioxane or acetonitrile and water at temperature ranging from -10°C to reflux temperature, preferably at room temperature for time period of 1 to 10 hours.

A compound of formula 1-15 is optionally converted to compound of formula I- 15a by treating compound of formula 1-15 with alkylating agents or treating with aldehydes, ketones followed by reduction by the methods known to person skilled in the art.

A compound of formula 1-15 or I-15a can be converted to compound of formula 1-16 by cyclization methods using reagents such as triethylorthoformate and acid catalyst viz para toluene sulphonic acid or dimethylformamide or formic acid and metal catalyst such as zinc acetate, using solvents such as toluene, halobenzene such as chlorobenzene, 1,2 di chlorobenzene, dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, 1,4- dioxane, water, acetic acid, formic acid, formamide or mixture(s) thereof at a temperature ranging from room temperature to reflux temperature preferably at 0°C-100°C for period of 1 to 10 hours preferably for 5 hours. A compound of formula I-16 can be converted to compound of formula 1-17 by hydrolysis using alkali hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide or aqueous solution thereof or any other reagents as understood by the skilled person in suitable alcoholic solvents such as methanol or ethanol or water or in mixture of suitable alcoholic solvents such as methanol, ethanol, propanol, butanol, iso-butanol or cyclic/acyclic ethers such as tetrahydrofuran or 1,4-Dioxane or acetonitrile and water to obtain a compound of formula 1-17, at a temperature ranging from room temperature to reflux temperature preferably at a temperature 80°C for time period of 30 minutes to 10 hours.

A compound of formula 1-17 can be converted into a compound of formula 1-18 by cleaving the protecting group R3. Protecting groups of a compound of formula 1-17 can be cleaved by deprotecting agents as understood by the skilled person to obtain a compound of formula I. Examples of deprotecting agents for an amino protective group are acids such as trifluoroacetic acid, trichloroacetic acid, di chloroacetic acid p-toluenesulfonic acid, HCl, HBr, H2SO4 or bases such as alkali or alkaline bases. For example, for a compound of formula I-17 wherein R3 is benzenesulfonyl, the deprotection is carried out by treating 1-17 with an alkali base, such as sodium hydroxide or potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate in an alcohol solvent, such as methanol or ethanol, or mixed solvents, such as alcohol/tetrahydrofuran or alcohol/water, MDC, THF, toluene, CAN, water or mixture(s) thereof. The reaction is carried out at room temperature to reflux temperature for a time period between about 15 minutes to about 1 hour, preferably 30 minutes. When R3 is benzyl, deprotection is either conducted by treating 1-17 with sodium in ammonia at a temperature of about -78° C for a time period between about 15 minutes to about 10 hour or by using hydrogen and a catalyst, such as palladium hydroxide on carbon, Pd/C in ether solvents such as tetrahydrofuran and alcohol such as tert-butanol, MDC, THF, toluene, CAN, water or mixture(s) thereof. Other suitable deprotecting agents are Lewis acids such as boron trifluorideetherate or zinc bromide in dichloromethane/isopropanol, HCl, HBr, H2SO4.

A compound of formula 1-18 can be converted to compound of formula I by reaction of acid derivative ( Formula 1-18) with chlorinating agent such as thionyl chloride, Oxalylchloride using mixture of solvents such as dimethylformamide, dimethyl acetamide, dichloromethane, di chloroethane, tetrahydrofuran, benzene, toluene, halobenzene viz. 1,2 di chlorobenzene or acetonitrile, at a temperature ranging from 0°C to reflux temperature preferably at 70-80°C for a time period of 0.5 hours to 15 hours, preferably for 5.0 hours to form acid chloride derivative. This acid chloride derivative can be converted to desired amide compound of formula -I by reaction with ammonia or suitable primary, secondary amine such as methylamine, ethylamine, n-propylamine, isopropylamine, isobutylamine, n-butylamine, Cyclopropyl amine, cyclopentyl amine, cyclohexyl amine. Amine can be any primary or secondary alkyl amines for example, "C1-10 alkyl” is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups, in solvents such as di chloromethane, di chloroethane, tetrahydrofuran, acetonitrile, 1,4-Dioxane, dimethylformamide, dimethylacetamide or mixture(s) thereof at temperature ranging from 0°C to reflux temperature preferably at room temperature for a time period of 0.5 hours to 10 hours preferably for 5.0 hours.

A compound of formula 1-18 can be converted to a compound of formula I by treating compound of formula 1-18 with ammonia or suitable primary, secondary amine such as methylamine, ethylamine, n-propylamine, isopropylamine, isobutylamine, n-butylamine, Cyclopropyl, cyclopentyl, cyclohexyl, using coupling agents such as PyBOP, EDC. HCl,DCC, HoBt or coupling agents known to person skilled in the art. Amine can be primary or secondary alkylalkyl amines for example , "C1-10 alkyl” is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups, in solvents such as dichloromethane, di chloroethane, tetrahydrofuran, acetonitrile, 1,4-Dioxane, dimethylformamide, dimethylacetamide or mixture(s) thereof at temperature ranging from 0 °C to reflux temperature preferably at room temperature for a time period of 0.5 hours to 15 hours, preferably for 10.0 hours.

A compound of formula (I) or its pharmaceutically acceptable salts can be prepared with or without isolation of intermediates. Isolation of a compound of formula (I) or its pharmaceutically acceptable salts and its intermediates may be carried out by any method known in the art such as cooling, filtration, centrifugation, washing, drying and combination thereof.

Tyrosine kinases are important mediators of the signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and programmed cell death. They are implicated in several steps of neoplastic development and progression. Tyrosine kinase signaling pathways normally prevent deregulated proliferation or contribute to sensitivity towards apoptotic stimuli. Cytokines play key roles in controlling cell growth and the immune response. Janus kinases (referred to as JAK) are tyrosine kinases that are involved in transduction of cytokine signalling from membrane receptors to signal transducer and activator of transcription (STAT) factors. Many cytokines function by binding to and activating type I and type II cytokine receptors. These receptors in turn rely on the Janus kinase (JAK) family of enzymes for signal transduction. Currently, there are four known mammalian JAK family members: JAK1 (Janus kinase-1), JAK2 (Janus kinase-2), JAK3 (also known as Janus kinase leukocyte; JAKL; L-JAK and Janus kinase-3)and TYK-2 (also known as protein tyrosine kinase 2). Mutation or abnormal functioning of JAK may lead to signaling pathways that are genetically or epigenetically altered leading to abnormalities. Such abnormalities may also cause diseases resulting from inappropriate activation of the immune and nervous systems such as inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6.

Kinase mediated diseases are prevented or treated by inhibiting their activities. JAK inhibitors interfere with the JAK-STAT signaling pathway. Hence drugs that inhibit the activity of these Janus kinases block cytokine signaling that are effective against immune response (Current Opinion in Pharmacology. 12 (4): 464-70).

In an embodiment of the present disclosure, it is envisaged that the compound of Formula (I) or it's pharmaceutically acceptable salt, or its pharmaceutical composition thereof is use in the treatment of a disease or condition that is caused by an abnormal functioning of a kinase, especially a Janus kinase. The said compound is envisaged to significantly inhibit the upregulated levels of inflammatory cytokines; IL-8, TNF-α and VEGF as well as IL-6, MMP- 9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GRO alpha/KC/CINC-1.

In an embodiment of the present disclosure, the diseased condition in a subject is an inflammatory disease, particularly Rheumatoid Arthritis. Rheumatoid arthritis may be selected from group comprising of Seropositive RA (Rheumatoid factor positive RA), Seronegative RA (Rheumatoid factor negative RA), and Juvenile idiopathic arthritis.

In an embodiment of the present disclosure, there is provided a method of treatment of Rheumatoid Arthritis by inhibition of Janus kinases in a subject. The method comprises use of compound of Formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In an embodiment of the present invention, it is envisaged that the compound of Formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof shows pro- apoptopic potential via increase in annexin-v staining, mitochondrial membrane depolarization and cell cycle distribution. It is further envisaged that the said compound provides beneficial effect in Rheumatoid Arthritis by inhibiting serum induced proliferation of human rheumatoid like synovial cells. It is also envisaged that the said compound demonstrates significant inhibition of inflammatory cytokines and chemokines; IL-8, VEGF & TNFα as compared to Hu-IL-1β induced stimulated levels, thereby provides beneficial effect in Rheumatoid Arthritis. The said compound is also envisaged to effectively increase proliferation of osteoblasts, thereby supporting anti-RA therapy.

According to another embodiment, it is envisaged to administer a therapeutically effective amount of a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof to the subject.

In an embodiment of the present disclosure, the subject with Rheumatoid Arthritis may have rheumatoid factor level above 20 lU/ml. In other embodiment, the subject may show presence of anti-citrullinated protein antibodies (ACPA) or Anti-cyclic citrullinated peptide (ant-CCP). In another embodiment, a subject may be regarded as having rheumatoid arthritis if the subject has higher than 20 units per milliliter (u/ml) detectable levels of anti- citrullinated protein antibodies. The subject may be regarded as having rheumatoid arthritis if the subject has uric acid levels of at least 6.0 mg/dL. In another embodiment, a subject may be regarded as having rheumatoid arthritis if the subject shows presence of genetic marker HLA-B27. In another embodiment, a subject may be regarded as having rheumatoid arthritis if the subject has an erythrocyte sedimentation rate of at least 20 mm/hour.

In an embodiment of the present disclosure, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseased condition in a subject suffering from Rheumatoid Arthritis.

In an embodiment of the present disclosure, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt or a pharmaceutical composition thereof for use in the prophylactic and/or therapeutic treatment of diseased condition in a subject suffering from Rheumatoid Arthritis. The compound of Formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is envisaged to provide a subject (suffering from Rheumatoid Arthritis) with significant protection in % body weight loss, Arthritis score, Paw thickness, serum Uric acid level, histopathology scoring and non-significant decrease in paw volume, serum IL levels compared to Arthritis group.

In an embodiment of the present disclosure, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the manufacture of medicament for prophylactic and/or therapeutic treatment of diseased condition in a subject suffering from Rheumatoid Arthritis. The medicament having compound of Formula (I) or a pharmaceutically acceptable salt thereof may be administered in a subject for prophylactic and/or therapeutic treatment of diseased condition in a subject suffering from Rheumatoid Arthritis.

In an embodiment of the present disclosure, the compound of Formula I and its pharmaceutically acceptable salts may be formulated with pharmaceutically acceptable stabilizers, diluents and other excipients. As understood by the skilled person in art the suitable form of the composition may be determined by the route of administration of the composition. Therefore the suitable form of the composition may include but is not limited to, injection for intravenous (bolus or infusion), intra-arterial, intraperitoneal, subcutaneous(bolusorinfusion), intraventricular, intramuscular, or subarachnoidal route; tablet, capsule, gel, lozenge or liquid for oral ingestion; a solution, suspension or aerosol as sprays for inhalation; gel, spray or cream for topical application; transmucosal composition for administration via oral, nasal or rectal mucosa; by delivery in the form of a transdermal patch, subcutaneous implant, or in the form of a suppository. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The composition may be a vesicular drug delivery system such as, but not limited to bilosomes, liposomes, niosomes, transferosome, ethosomes, sphingosomes, pharmacosomes, multilamellar vesicles, microspheres and the like.

In an embodiment of the present disclosure, the compounds of Formula I, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof may be administered in a subject via any of the known suitable routes of drug administration. It is further envisaged that the administration of said compounds may provide a means to prevent, treat, cure or reduce the effect of diseased condition in a subject suffering from Rheumatoid Arthritis. The routes of drug administration include but not limited to intravenous injection (bolus or infusion), intra-arterial, intra-peritoneal, subcutaneous, intraventricular, intramuscular, subarachnoidal, surgical implants, oral ingestion, inhalation, topical, and mucosal (oral, nasal and/or rectal), etc. In a preferred embodiment of the present disclosure, drug may be administered enterally, parenterally and/or topically. Liquid dosage forms for oral administration may include but not limited to pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art. Injectable preparations such as aqueous or oleaginous sterile injectable suspensions may be formulated according to known techniques by suitable dispersing or wetting agents and suspending agents commonly used in the art.

In an embodiment of the present disclosure, subject may be an animal. In preferred embodiment, the subject is mammalian subject. In particular, the mammalian subject may be a human subject suffering from Rheumatoid Arthritis. The human subject may be male or female coming from different ethnic groups or race, geographical regions, countries, continents and races. For example, the human subject may be selected from a group comprising of an Asian (e.g., far-east Asian, middle-east Asian, south-east Asian, north-east Asian, or Asian Indian), a Caucasian (Canadian, American, European, or Mediterranean), an African, a pacific islander, a Hispanic, etc or a general mixed population. The said subject may be of any age, including newborn, neonate, infant, child, adolescent, adult, and geriatric, etc.

In an embodiment of the present disclosure, the compound for use is envisaged to be administered in a subject may comprise of compound of Formula I or combination of one or more salts as disclosed in Table I.

In an embodiment of the present disclosure, the compound for use is envisaged to be compound of Formula I selected from the group consisting of:

‘N-(propan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride’ and

‘N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-10 carboxamide hydrochloride’; or combination thereof. In an embodiment of the present disclosure, the compounds envisaged by the present disclosure may be given in form of a prodrug. “Prodrugs” may include any covalently bonded carriers that release an active compound of the present disclosure in vivo when such prodrug is administered to mammalian subject. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to give the parent compound. The skilled person in the art is well aware that the prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g. solubility, bioavailability, manufacturing, etc.) and the compounds of the present disclosure may be delivered in prodrug form.

In an embodiment of the present disclosure, the compounds envisaged by the present disclosure may be given at a concentration sufficient to elicit a desired biological response. As understood by the skilled person in art, the concentration of the compound envisaged by the present disclosure may vary depending upon such factors as desired biological endpoint; the pharmacokinetics of the compound, the condition being treated, the mode of administration, age, bodyweight and health of the subject.

In an embodiment of the present disclosure, prophylactic and/or therapeutic treatment of a subject may include administration of an effective concentration of compound of Formula I or a pharmaceutically acceptable salt thereof. As understood by the skilled person in art, the effective concentration of the compound of Formula I or a pharmaceutically acceptable salt thereof may be determined using pharmacokinetics and pharmacodynamic studies. Particularly, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered at a concentration in the range of 0.01 to 1000 milligram per kilogram of subject’s body weight. In certain ways of embodiment, the compounds of the disclosure may be administered as such or in a pharmaceutically acceptable form orally or parenterally at dosage levels of about 0.01 to 1000 milligram per kilogram, from 0.1 to 100 milligram per kilogram, from 0.5 to 100 milligram per kilogram or from 1 to 50 milligram per kilogram of the subject's body weight per day, once or several times per day, to obtain the desired therapeutic effect.

EXAMPLES

The following examples are provided to illustrate the invention. Examples provided herein are exemplary in nature and do not limit the scope of invention in any manner. Example 1: Preparation of N-(propan-2-yl)-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b] pyridine-8-carboxamide hydrochloride

Ethanolic hydrochloride solution was added to the solution of N-(propan-2-yl)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide (10 mmol) in 50 mL ethanol.

The reaction was stirred for 3-4 hours at ambient temperature. Reaction mass was concentrated under reduced pressure. 10 ml ethanol was added to the residue, stirred and reaction mass was concentrated under reduced pressure. Obtained solid was dried under vacuum to afford white to off while solid of the title compound (Yield = 95%). 15 1H NMR (400 MHz, DMSO-D6) δ: 1.25 (d, 6 H), 4.23 (m, 1 H), 7.99 (s, 1 H), 8.34 (s,

1H), 8.57 (s, 1H),δ 8.7 (bs1H), 11.2 (br. S, 1H), 12.9 (br. S, 2H).

PreparationofanIntermediate:6-benzyl-N, 1 -dimethyl-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridine-8-carboxamide

Step A: 6-benzyl-l-methyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

In a round bottom flask, sodium hydride (0.3 mole) was added in a DMF (5 vol) solvent, 1- methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (0.1 mole) was slowly added at 5- 15°C to a flask, the resulting suspension was stirred at room temperature for 1 hour, then benzyl bromide (0.12 mole) was slowly added at 5-15°C. The reaction mass was warmed to room temperature and stirred for 1-3 hours. The reaction was monitored on TLC. The reaction mass was cooled after completion of the reaction, methanol (1 volume) was added in the reaction mass at 5-15°C and stirred for 10 minutes. Ammonium chloride (25 vol) solution was added in the reaction mass and stirred for 30 minutes. The reaction mass was extracted with ethyl acetate (3* 5 volume). Combined organic layers were washed with water (3* 5 vol) and brine (Ivolume), then dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound (86%).

Step B: 6-benzyl-8-bromo-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine

6-benzyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (Immol) was dissolved in THF (25 mL) at room temperature and to the resulting solution was added Nbromosuccinimide (1.2 mmol). The resulting suspension was stirred at room temperature for 14 hours, then quenched with aqueous saturated sodium thiosulfate solution (20 mL). The reaction was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate (75 mL). The aqueous layer was extracted with ethyl acetate (2*100 mL) and the combined organic layers were washed with aqueous 1N sodium bicarbonate solution (50 mL) and brine (50 mL), then dried over magnesium sulfate, filtered and concentrated in vacuo to provide title compound (87%), which was used further with or without purification.

Step C: ethyl 6-benzyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxylate

6-benzyl-8-bromo-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine (173 mmol) was added in dry tetrahydrofuran (500 mL) at -78 °C and n-butyl lithium (2.5 M solution in hexane, 487 mmol) was added over a period of 2 hours. The reaction mixture was stirred for another 30 minutes at -78 °C. Ethyl chloroformate (186 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at -60 °C. The temperature was slowly increased to 30 °C and mixture was allowed to stir for 12 hours at 30 °C. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched with saturated solution of ammonium chloride (150 mL) at 0 °C and the reaction mixture was extracted with ethyl acetate (3X300 mL). The combined organic layers were washed with water, dried over anhydrous sodium sulfate (50 g), filtered and concentrated under reduced pressure to afford a crude reaction mixture. The residue was purified by chromatography to provide the title compound (50%).

Step D: 6-benzyl-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxamide

A solution of trimethylaluminium (2 M in toluene, 1.2 mmol) was added dropwise (exothermic) to a solution of methylamine (2 M in toluene, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 hour. Then a solution of ethyl 6-benzyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxylate (0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. for 3 hour and then cooled to room temperature and then poured into water and extracted with MDC which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, MDC:MeOH=90: 10) afforded the title compound as a white solid. (70%).

Example 2:Preparation of N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-8-carboxamide hydrochloride

Step A: 1-(1-benzyl-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethanone

To a stirred suspension of sodium hydride (39.3 g, 1638.5 mmol, 60%) in dimethylacetamide (500mL) was added a solution of 4-chloro-7-aza indole (100g, 655.4 mmol) in dimethylacetamide (150 mL) at 0-5°C followed by benzyl bromide (134.5 gm, 786.5mmol). The resultant reaction mixture was stirred for 4.0 hours and then quenched with 100 ml of methanol followed by saturated ammonium chloride (500mL) and extracted with ethylacetate. The organic layer was evaporated under reduced pressure to afford brown to yellow color liquid, 1-benzyl-4-chloro-1H-pyrrolo [2,3 -b]pyridine (180 gm). The above compound was dissolved in in dimethylformamide (700 mL) and then was added trifluoroacetic anhydride (129.8 g, 618.0 mmol). The resulting reaction mixture was heated at 70-75°C for 3.0 hours. Reaction mixture was cooled to 10-15°C and was added ice cold water (500 mL) followed by saturated aqueous sodium bicarbonate. Reaction mixture was filtered and purified by using Isopropanol to obtain beige to light yellow color solid 1-(1 -benzyl -4- chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethanone, (125.0 g 89.6%).

1HNMR (400 MHz, DMSO-d6): δ 9.03 (S,1H), δ 8.38 (m 1H), 8 7.46 (m, 1H), δ 7.34(m,5H), 8 5.66 (S,2H).

Step B: 1-(4-amino-1-benzyl-5-nitro-lH-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2- tri fluoroethanone

To a stirred solution of 1-(1-benzyl-4-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2- trifluoroethanone (100 g, 295.2 mmol) in dichloromethane (2500mL) was added tetrabutylammonium nitrate ( 224.7 g, 738.0 mmol) in portions followed by dropwise addition of trifluoroacetic anhydride (155 g, 738.0 mmol) at 0°C. The reaction mixture was stirred for 5.0 hours at room temperature. Organic layer was washed with water and concentrated under reduced pressure to afford yellowsolid, 1-(1-benzyl-4-chloro-5-nitro- 1Hpyrrolo[2,3-b]pyridin-3-yl)-2,2,2 trifluoroethan onene (100 gm 88.5%).

To a stirred solution of 1-(1-benzyl-4-chloro-5-nitro-1H-pyrrolo [2,3 -b]pyridin-3-yl)-2,2,2- trifluoroethanone (100 g, 260.6mmol) in dichloromethane (500 mL) was purged ammonia gas till completion of reaction on TLC. Solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (300 ml) , cooled to 5-10°C and filtered. The obtained wet solid was dried under vacuum to afford yellow solid, 1-(4-amino-1-benzyl-5- nitro-1Hpyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethanone (85gm ,89.5%) 1HNMR (400 MHz, DMSO-d6): δ 9.04 (S,1H), δ 8.94(m 1H), δ 8.73 (S, 1H), δ 7.30 (m,6H), δ 5.57 (S,2H). StepC: 1-(4, 5-diamino-1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethanone

To a stirred solution of 1-(4-amino-1-benzyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2- trifluoroethanone (85 g, 233.3 mmol) in mixture of methanol: tetrahydrofuran (1500 mL, 1 :0.5) was added Raney Nickel (21.2 g 25.0 % w/w) followed by dropwise addition of hydrazine hydrate ( 59.5 ml, 0.70 w/v) and reaction mixture was stirred for 1 hour at room temperature. After completion, reaction mixture was filtered through hyflo bed and washed with methanol (400 mL). The filtrate was concentrated under reduced pressure and obtained was purified by water (500 mL), filtered and dried under reduced pressure to afford brown color solid 1 -(4, 5-diamino-1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2-trifluoroethanone (71.0gm 90.8%) 1HNMR (400 MHz, DMSO-d6): δ 8.59 (d,lH), δ 7.66 (s 1H), δ 7.33 (m, 4H), δ 7.26 (m,lH), δ 6.56 (s,2H), 8 5.45 (s,2H), δ 4.47 (s,2H).

Step D: 1-(6-benzyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)-2,2,2- trifluoroethanone

To stirred suspension of 1-(4,5-diamino-1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2,2- trifluoroethanone (70g, 209.4 mmol) in toluene (700 mL) was added triethylorthoformate (96.7 mL, 418.8 mmol) and para-toulenesulfonic acid monohydrate (8.0 g 41.88 mmol). The resulting reaction mixture was heated at 80-85°C for 5 hours. After completion, reaction mixture was concentrated under reduced pressure. To the obtained residue was added water (700 mL), stirred at room temperature and filtered an dried to afford 1-(6-benzyl-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)-2,2,2-trifluoroethanone (65gm, 90.1%).

1HNMR (400 MHz, DMSO-d6): δ 12.51(bs,lH), δ 8.89 (m 2H), δ 8.29 (t, 1H), 8 7.31 (m,5H), δ 5.72(s,2H).

Step E: 6-benzyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxylic acid

To the solution of sodium hydroxide (151gm, 3775 mmol) in water (945 mL) was added 1- (6-benzyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-8-yl)-2,2,2 trifluoroethanone (65 gm, 188.8 mmol), reaction mass was heated at 80-85°C for 5 hours. After completion, reaction mixture was diluted with water followed by dilute HC1 and filtered. The obtained wet cake was dried under vacuum to afford beige to light brown color solid 6-benzyl-3,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxylic acid, (50gm,90.5% ) 1HNMR (400 MHz, DMSO-d6): δ 12.2(s,lH), , δ 8.75(s, 1H), δ 8.22(s,1H),δ 8.17 (s, 1H) δ 7.27(m,5H), δ 5.61(s,2H)

Step F: 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxylic acid

To the solution of liquid ammonia (750 mL) was added sodium metal (32.8 g, 1368.5mmol) lot wise. To the resulting reaction mixture, was added tertiary butanol (50 mL), Tetrahydrofuran (500 mL) followed by 6-benzyl-3,6-dihydroimidazo[4,5-d] pyrrolo [2,3- b]pyridine-8-carboxylic acid (50 g, 171.1 mmol). Then reaction mixture was stirred at -60°C to -30°C for 4.0 hours and quenched with methanol (50 mL) and water (50 mL). Solvent was evaporated under reduced pressure. Then was added water (100 ml) to the residue followed by HCl and stirred. The reaction mixture was filtered and wet solid was dried under reduced pressure to afford beige color solid 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxylic acid, (32gm,91.4%).

1HNMR (400 MHz, DMSO-d6): δ 12.39 (bs,1H), δ 12.07 (bs 1H), δ 8.66(s, 1H), δ 8.14(d,1H), δ 7.94 (s,lH).

Step G: N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxamide

To a solution of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxylic acid (30.0 g, 148.4 mmol) in dimethylformamide (15 mL) was dded thionyl chloride (300 mL) and reaction mixture was heated to 65-70°C and stirred for 4.0 hours. After completion, reaction mixture was concentrated under reduced pressure to obtain acid chloride (30 g) which was used as such for further reaction. Above acid chloride derivative (30 g) was taken into dichloromethane (300 mL), cooled to 5-10°C and added isopropyl amine (300 mL). The resulting reaction mixture was stirred for 5 hours at room temperature. After completion, reaction mass was concentrated under reduced pressure, added water (150 mL) and filtered. The obtained wet solid was dried under vacuum to afford beige to off white color solid N- (propan-2 -yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide

(29.0gm,80.3%) 1HNMR (400 MHz, DMSO-d6): δ 13.04 (bs,1H), δ 12.19 (t, 1H), 8 10.03(d,1H), δ 8.59(d,2H), δ 8.07(m,1H), δ 4.19(m,1H), δ 1.22(td,6H).

Step H: N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxamide hydrochloride

To a solution of N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8- carboxamide ( 25.0 g, 102.8 mmol) in isopropanol( 175 mL) was added solution of HCl in isopropanol at 10-15°C. The resultant reaction mixture was stirred at 50-55°C 2 hours. After completion, reaction mixture was concentrated under reduced pressure. To the residue obtained was added water (250 mL) and stirred for 1 hour at room temperature, filtered and dried under vacuumto afford beige color solid N-(propan-2-yl)-3,6-dihydroimidazo[4,5- d]pyrrolo[2,3- b]pyridine-8-carboxamide hydrochloride, (25 gm, 87.0%)

1HNMR (400 MHz, DMSO-d6): δ 13.66 (bs,1H), δ 12.87(bs, 1H), δ 9.26(s,1H), δ 8.86(s,1H), δ 8.57(d,2H),δ 4.81 (bs 1H), δ 4.22(qd,1H), δ 1.25(d,6H).

Example 3: Evaluation of mechanism of action of Test Compound in Rheumatoid Arthritis by multiplex analysis.

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3- b]pyridine-8-carboxamide hydrochloride was used as a test compound for evaluation. Hyperinflammation and overproduction of inflammatory cytokines in synovial membrane (a thin membrane present in the healthy joints) is a hallmark feature of Rheumatoid Arthritis. The present study was conducted to evaluate the mechanism of action of test compound in Rheumatoid Arthritis by multiplex analysis. In the present study, inhibitory effect of test compound was studied on IL- 1β stimulated levels of multiple inflammatory markers in Human Rheumatoid Fibroblast Like Synoviocytes (MH7A) cells for beneficial effects in Rheumatoid arthritis. Human Rheumatoid Fibroblast Like Synoviocytes (MH7A) cells were treated with test compound at various non-cytotoxic concentrations and then stimulated with IL-1β for 24 h. Inhibitory effect on the secretion of inflammatory markers was determined by multiplex analysis. Results showed that test compound demonstrated significant (p50%) inhibition of IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCLl/GROalpha/KC/CINC-1 as compared to control (IL-1β stimulated cells). The anti- inflammatory potential and beneficial effect in Rheumatoid Arthritis was confirmed by the inhibition of inflammatory markers in IL-1β stimulated MH7A cells by test compound.

Table 2:% Inhibition by Test Compound (wrt IL-1β stimulation) on cytokines and metalloproteinases

Example 4: Evaluation of inhibitory effect of test compound on secretionof inflammatory cytokines

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride was used as a test compound for evaluation.

In the present study, the inhibitory effect of test compound on secretion of inflammatory cytokines in immune cells (MH7A) against Hu-IL-1β induced stimulation. Increased secretion of inflammatory marker; IL-8, TNF-α and VEGF was observed in MH7A cells upon stimulation with Hu-IL-1β, that mimics the hyperinflammatory state prevailing in RA. Inflamed synovial cells were pre-treated with test compound and then stimulated with Hu-IL- 1β, the resultant inhibition of cytokines was measured by ELISA.

Results demonstrated that test compound was able to significantly (p<0.0001)inhibit the upregulated levels of inflammatory cytokines IL-8, TNF-α and VEGF in human synovial cells (MH7A) against Hu-IL-1β induced levels. The anti-inflammatory effect and suppression of IL-8, TNF-α and VEGF by the test compound was confirmed in human synovial cells.

Example5: Evaluation of pro-apoptotic effect of test compound in synovial cells

The present study was conducted to evaluate the pro-apoptotic effect of test compound via determining induction of apoptosis in MH7A cell line (Rheumatoid fibroblast-like synoviocytes). The cells were treated with test compound at various anti-proliferative concentrations. Resultant effect of test compound on apoptosis was determined via extemalization of Phosphatidyl Serine (PS) on cell membrane by Annexin-V staining, mitochondrial membrane depolarization by JC-1 staining and cell cycle distribution analysis by Propidium Iodide (PI) staining. Results demonstrated that test compound resulted in significant (p<0.001) pro-apoptotic potential in MH7A cells via increase in annexin-v staining, mitochondrial membrane depolarization and cell cycle distribution as compared to Tofacitinib. Induction of apoptosis by test compound was confirmed in Rheumatoid fibroblast-like synoviocytes (MH7A) by cell cycle analysis. Table 4: Apoptotic effect of Test Compound by cell cycle analysis in MH7A cell line

Table 5: Apoptotic effect of Test Compound by Annexin-V staining in MH7A cell

Example6: Evaluation of proliferation of osteoblasts by test compound

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride was used as a test compound for evaluation. The present study was conducted to investigate the effect of test compound on proliferation of human osteoblasts. MG-63 cells were treated with test compound and Reference Item (Tofacitinib Citrate) for 48 h and the cytotoxic effect was determined by MTT assay. Results demonstrated that test compound displayed significant (p<0.001, p<0.01) increase in proliferation by 41% as compared to control (Calcitriol). Based on results, it can be concluded that test compound showed proliferative activity as compared to control. Table 7: Effect of Test Compound on proliferation of MG-63 cells after 48 h.

Example7: Evaluation of inhibitory effect of test compound on proliferation of synovial cells N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride was used as a test compound for evaluation.

In the present study, the inhibitory effect of test compound on the serum induced proliferation of rheumatoid like synovial cells (MH7A) was studied. Rheumatoid like synovial cells (MH7A) were serum starved for 24 h to synchronize all the cells in similar resting phase. After 24 hours, proliferation was induced with 10% FBS and then cells treated with test compound in 10% FBS conditions for 48 hours. The resultant effect on proliferation was determined as compared to untreated cells induced with 10% FBS by MTT assay. Results demonstrated that test compound and Tofacitinib citrate led to inhibition of serum induced proliferation of MH7A cells as compared to control. The results from the study confirm that test compound have beneficial effect in RA via inhibition of synovial cells. Table 8: Anti-proliferative effect of Test Compound on Synovial Cells (MH7A) after 48h of treatment

Example8: Evaluation of anti-arthritic activity of test compound in collagen antibody induced arthritis (caia) model

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride was used as a test compound for evaluation. Evaluation of anti-arthritic activity of test compound on collagen antibody induced arthritis model in BALB/c mice was done by measuring paw thickness, arthritis score, serum cytokines (IL-6, IL-1β and TNF-α) estimation and histopathology of ankle joints.

Test compound administered for 10 days showed protection against collagen antibody induced arthritis model in BALB/c mice by significantly reducing serum IL-6, IL 1 -beta & TNF-alpha level and arthritic score, paw thickness and improved histopathology as compared to disease control group. Histopathological observation of test compound was equally comparable to reference standard (Dexamethasone) in collagen antibody induced arthritis model. Hence, test compound was found to be effective molecule against treatment and management of rheumatoid arthritis.

Table 9: Effect of Test Compound on Arthritis Score

Table 10: Effect of Test Compound on Paw thickness

Conclusion: Test compound administered for 10 days showed protection against collagen

Table 11: Effect of Test Compound on IL-6 in Serum

Table 12: Effect of Test Compound on IL-1β in Serum

Table 13: Effect of Test Compound on TNF-α in Serum

Table 14: Histopathology score of hind leg

Example9 : Evaluation of effect of test compound on collagen-induced arthritis model in rats

Evaluation of anti-arthritic activity of test compound on collagen antibody induced arthritis model in Sprague Dawley Female (SPF) rats was done by measuring% change in Arthritis score, Paw thickness, serum Uric acid level, Histopathology scoring and paw volume.

The test compound treated rats group significantly reduced % change in Arthritis score, Paw thickness, serum Uric acid level, Histopathology scoring and non-significant decrease in paw volume, serum IL levels compared to Arthritis group. The evidence also supported by Radiograph of Hind paw inhibited the soft tissue swelling, narrowing of joint space and bone destruction.

Oral administration of test compound showed significant protection against Collagen induced arthritis in rat model. (Refer Figure 13, 14, 15, 16, 17, 18a, 18b)

Table 15: Effect of Test Compound on Paw thickness (mm) of the Groups

#p<0.05, ###p<0.001 G2-Arthritis group compared to G1 -Normal control group and

* p<0.05, p<0.01 & p<0.001 Treatment groups compared to G2 Arthritis group

Table 16: Effect of Test Compound on Paw volume (ml) of the Groups

Table 17: Effect of Test Compound on Uric Acid Levels

Table 18: Effect of Test Compound on Serum IL6 levels

Table 19: Relative organ weights of groups

Claims

We Claim:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof; wherein Q is a group of formula Q1 or Q2;

(wavy bond) represents the points of attachment;

wherein R₁ is -NR^aR^b;

R₂ is hydrogen or a C₁-C₁₀ alkyl group; and R^a and R^b independently represent hydrogen or a C₁-C₁₀ alkyl group; for use in the treatment or prevention of Rheumatoid Arthritis.

2. The compound for use according to claim 1, wherein Q is Q1 and R₂ represents hydrogen or a C₁-C₁₀ alkyl group.

3. The compound for use according to claim 1, wherein Q is Q2 and R₂ represents hydrogen or a C₁-C₁₀ alkyl group.

4. The compound for use according to claim 1, wherein R₁ is -NHR^a.

5. The compound for use according to claim 1, wherein R₁ is -NHR^b.

6. The compound for use according to any one of claims 1 to 3, wherein R₂is methyl.

7. The compound for use according to any one of claims 1 to 3, wherein R₂is hydrogen.

8. The compound for use according to any one of claims 1 to 5, wherein R^a is methyl, R^b is hydrogen and R₂ methyl.

9. The compound for use according to any one of claims 1 to 5, wherein R^a is ethyl, R^b is hydrogen and R₂ methyl.

10. The compound for use according to any one of claims 1 to 5, wherein R^ais propyl, R^b is hydrogen and R₂ methyl.

11. The compound for use according to any one of claims 1 to 5, wherein R^ais isopropyl, R^b is hydrogen and R₂ methyl.

12. The compound for use according to any one of claims 1 to 5, wherein R^ais methyl, R^b and R₂ are hydrogen.

13. The compound for use according to any one of claims 1 to 5, wherein R^ais ethyl, R^b and R₂ are hydrogen.

14. The compound for use according to any one of claims 1 to 5, wherein R^ais propyl, R^b and R₂ are hydrogen.

15. The compound for use according to any one of claims 1 to 5, wherein R^ais isopropyl, R^b and R₂ are hydrogen.

16. The compound for use according to claim 1 wherein the compound of Formula (I) is selected from the group consisting of:

N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

1-methyl-N-propyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

1-methyl-N-(propan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-methyl-l,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-ethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-(propan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N,3-dimethyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-ethyl-3-methyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide; 3-methyl-N-propyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

3-methyl-N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-methyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide;

N-ethyl-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide; and

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide; or a pharmaceutically acceptable salt thereof.

17. The compound for use according to claim 1 wherein the compound of Formula (I) is selected from the group consisting of:

N-(propan-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride; and

N-(propan-2-yl)-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxamide hydrochloride.

18. A pharmaceutical composition comprising a compound of Formula (I) as defined in any one of the preceding claims or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of Rheumatoid Arthritis.

19. The compound for use according to any one of claims 1 to 17 or a composition for use according to claim 18, wherein the Rheumatoid arthritis is caused due to the upregulation of one or more biomarkers selected from IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GR0 alpha/KC/CINC- 1.

20. The compound for use according to any one of claims 1 to 17 or a composition for use according to claim 18, wherein the said compound inhibits one or more biomarkers selected from IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GRO alpha/KC/CINC-1, or induces apoptosis.

21. A method of treating or preventing Rheumatoid Arthritis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound as defined in any one of claims 1 to 17 or a composition as defined in claim 18.

22. The method according to claim 21, wherein the Rheumatoid arthritis is caused due to the upregulation of one or more of IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GRO alpha/KC/CINC-1.

23. The method according to claim 21, wherein the said compound inhibits one or more of IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES,

TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GRO alpha/KC/CINC-1, or induces apoptosis.

24. Use of a compound as defined in any one of claims 1 to 17 or a composition as defined in claim 18 for the manufacture of a medicament for use in the treatment or prevention of Rheumatoid Arthritis.

25. Use according to claim 24, wherein the Rheumatoid arthritis is caused due to the upregulation of one or more of IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL, BMP-2, and CXCL1/GRO alpha/KC/CINC-1.

26. Use according to claim 24, wherein the said compound inhibits one or more of IL-8, TNF-α, VEGF, IL-6, MMP-9, MMP-3, CCL5/RANTES, TRANCE/TNFSF11/RANKL,

BMP-2, and CXCL1/GRO alpha/KC/CINC-1; or induces apoptosis.

27. The compound for use according to any one of claims 1 to 17 or a composition for use according to claim 18, wherein the concentration of said compound is between 0.01mg/kg to 1000 mg/kg of subject’s body weight.