HETEROBIC YCLIC COMPOUNDS AS ORAL GLP1R AGONISTS

FIELD OF INVENTION

The present invention provides novel heterobicyclic compounds of general formula (I) and their salts that are useful for the treatment of diabetes mellitus, obesity and other metabolic disorders especially involving the agonism of the GLP1 receptor. Further, the present invention relates to processes of preparing such compounds, their novel intermediates involved in their synthesis, their pharmaceutically acceptable salts, methods for using such compounds and pharmaceutical compositions containing them.

Formula I

BACKGROUND OF THE INVENTION

Glucagon Like Peptide 1 (GLP1) (7-36) is an endocrine hormone secreted by L cells of pancreas by the stimulation of food intake and other conditions. GLP1 peptide acts as an agonist to stimulate its receptor, GLP1R, to produce insulin and to inhibit glucagon production in a glucose dependent manner.

GLP1R agonism has multiple physiological effects including gastric emptying, satiety, food intake, body weight loss etc. Because of these properties, GLP1R agonists like Exenatide, Liraglutide, and Semaglutide etc. are extensively used for the treatment of diabetes and obesity.

Diabetes and Obesity are the two most common metabolic disorder diseases prevalent in modern lifestyle which are rapidly growing in all parts of the world. Diabetes is associated with hyperglycemia which further causes and becomes responsible for multiple diseases like diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, diabetic wound, hypertension, dyslipidemia, hyperinsulinemia etc. Obesity on the other hand is associated with insulin resistance, liver diseases (NAFLD, NASH) etc. Many GLP1R agonists have been disclosed in the literature - J. Med. Chem. 2022, Nature Medicine 2021, W02020103815, W02022031994, WO2021191812, WO2021118906, WO2021116874 and WO2020234726.

We herein disclose novel compounds of general formula (I) which are oral GLP-1 agonist and are useful for the treatment of diabetes mellitus, obesity, body weight reduction, insulin resistance etc. involving the agonism of the glucagon like peptide 1 receptor.

SUMMARY OF THE INVENTION

The present invention discloses novel compounds as defined by the general formula (I) that are useful for the treatment of diabetes mellitus, obesity, body weight reduction, insulin resistance etc. involving the agonism of the glucagon like peptide 1 receptor.

EMBODIMENT(S) OF THE PRESENT INVENTION

The main objective of the invention is to provide novel compounds of formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical composition comprising them or mixture thereof.

The another embodiment of the invention is to provide a process for the preparation of compound of formula (I), process of their novel intermediates, their pharmaceutically acceptable.

The further embodiment of the present invention is to provide the pharmaceutical compositions containing compounds of the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts, in combination with suitable pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture.

The yet another embodiment is to provide the use of the novel compounds of the present invention as anti-metabolic disorder agents, by administering a therapeutically effective & non-toxic amount of the compound as defined by the general formula (I), their tautomeric forms, their stereoisomers, their pharmaceutically acceptable salts and pharmaceutical composition comprising them or mixture thereof .

In some embodiments, the compound of formula (I) can be administered in combination with other therapeutic agents. DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to compounds as defined by the general formula (I),

Formula (I)

Wherein.

X represent N, CH or -CF;

Y represents hydrogen, halogen, -CN, alkyl and haloalkyl; m represents 1 , 2, 3 and 4. In another preferred embodiment, the groups referred to above may comprise of:

"Alkyl" by itself or as part of another substituent, means, unless otherwise stated, a straight- or branched- chain, fully saturated aliphatic hydrocarbon radical having the number of carbon atoms designated. For example, "Ci-ealkyl" refers to a hydrocarbon radical, either straight- or branched-chain, that contains from 1 to 6 carbon atoms and that is derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Alkyl includes branched-chain isomers of straight- chain alkyl groups, such as isopropyl, t-butyl, isobutyl, sec-butyl, and the like.

"Halo" or "halogen" by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include an alkyl in which one or more hydrogen is replaced by halogen atoms that can be the same or different, in a number ranging from one up to the maximum number of halogens permitted e.g. for alkyl, (2m'+l), where m' is the total number of carbon atoms in the alkyl group. For example, the term "haloCi-galkyl" is meant to include difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, 4-chlorobutyl, 3 -bromopropyl, and the like. Additionally, term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms. In one group of embodiments, the haloalkyl and haloalkoxy groups have from one to five or from one to three halogen atoms. Examples of haloalkoxy groups include difluoro methoxy and trifluoro methoxy.

The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.

The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single tablet/capsule having a fixed ratio of active ingredients or in multiple, separate tablet/capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.

Compounds of formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula (I), either as single species or mixtures thereof.

Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula (I).

List of Abbreviation

ACN: acetonitrile

THF: Tetrahydro furan

PSI: pound-force per square inch

DMF: Dimethyl formamide MTBE: Methyl tert-butyl ether

DCM: Dichloromethane

DIPEA: Disopropyl ethyl amine

EtOAc: Ethyl acetate

K2CO3: Potassium Carbonate

NaHCO: Sodium bicarbonate hrs: Hour(s) rt : room temperature min: Minute(s) tRe _t : Retention time

HBr: Hydrobromic acid

RT: Room temperature [25-30 °C]

T1D: Type 1 Diabetes

T2DM: Type 2 Diabetes Mellitus

LADA: Latent Autoimmune Diabetes of Adults

EOD: Early Onset type 2 Diabetes

YOAD: Youth-Onset Atypical Diabetes

MODY: Maturity Onset Diabetes of The Young

NAFLD: Non-Alcoholic Fatty Liver Disease

NASH: Nonalcoholic Steatohepatitis

Instrument details

Mass spectrum was recorded on LC-MS 2010-A Shimadzu.

HPLC purity was determined by using Agilent 1100 instrument.

HPLC Column: YMC J Sphere Cl 8 (150X4.6 mm)4p Mobile phase: 0.05 % TFA in water: ACN gradient.

Flow rate: l.O mL/min.

Wave length: UV at 220 nm.

UPLC was determined on Acquity Ultra performance instrument.

UPLC Column: BEHC18 (2.1xl00mm)1.7 p

Mobile phase: 0.05 % TFA in water: ACN gradient.

Flow rate: 0.04 mL/min NMR spectrum: Bruker Avanc 400 MHz

Suitable groups and substituents on the groups may be selected from those described anywhere in the specification.

Preferred compounds according to the present invention include but are not limited to:

(S)-2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl )-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((3-methox yoxetan-3- yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid;

(S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4, 5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2- yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl) -3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4 ,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxy ethyl)-3H- imidazo[4,5-b]pyridine-5-carboxylic acid; (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5- yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5 -ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3 ,5-dihydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6- carboxylic acid;

(S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl )-3,5- dihydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylm ethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 5-dihydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l -((1 -ethyl- IH-imi dazol-5-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylic acid; 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5- yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5- yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid;

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2- yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2 ,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d] imidazole-6- carboxylic acid;

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo-imida zole-6- carboxylic acid;

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5 -b]pyridine-5- carboxylic acid; (2-((2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6- carboxylic acid;

(S)-2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl) -2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6- carboxylic acid;

2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6- carboxylic acid;

2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5 ,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6- carboxylic acid;

(S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6- carboxylic acid compound with 2,2,2-trifluoroacetic acid;

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6- carboxylic acid; 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dih ydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-d ihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH- benzo[d]imidazole-6-carboxylic acid;

(S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl) -2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6 -dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6- carboxylic acid;

2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6 -dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6- carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid;

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid.

Pharmaceutical composition comprising compound of general formula (I), their tautomeric forms, their pharmaceutically acceptable salts, solvates and their mixtures having pharmaceutically acceptable carriers, solvents, diluents, excipients and other media normally employed in their manufacture. Use of the general formula (I) for the treatment of diseases selected from T1D, T2DM, pre-diabetes, idiopathic T1D, LADA, EOD, YOAD, MODY, malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral adipose deposition, sleep apnea, obesity, eating disorders, weight gain from use of other agents, excessive sugar craving, dyslipidemia, hyperinsulinemia, NAFLD, NASH, fibrosis, NASH with fibrosis, cirrhosis, hepatocellular carcinoma, cardiovascular disease, atherosclerosis, coronary artery disease, peripheral vascular disease, hypertension, endothelial dysfunction, impaired vascular compliance, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, post-prandial lipemia, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson’s Disease, left ventricular hypertrophy, peripheral arterial disease, macular degeneration, cataract, glomerulosclerosis, chronic renal failure, metabolic syndrome, syndrome X, premenstrual syndrome, angina pectoris, thrombosis, atherosclerosis, transient ischemic attacks, vascular restenosis, impaired glucose metabolism, conditions of impaired fasting plasma glucose, hyperuricemia, gout, erectile dysfunction, skin and connective tissue disorders, psoriasis, foot ulcerations, ulcerative colitis, hyper apo B lipoproteinemia, Alzheimer’s Disease, schizophrenia, impaired cognition, inflammatory bowel disease, short bowel syndrome, Crohn’s disease, colitis, irritable bowel syndrome, Polycystic Ovary Syndrome, and addiction by administering a therapeutically effective & non-toxic amount of the compound of formula (I), or their pharmaceutically acceptable compositions to the mammals.

In one of the embodiments compound of formula (I) of the present invention may be used in combination with one or more suitable pharmaceutically active agents selected from following therapeutic agents in any combination. Compound of formula (I) may appropriately combined with FXR agonist and semi-synthetic bile acid analogue, ACC inhibitor, Dual CCR2 and CCR5 antagonist, Thyroid hormone receptor beta agonist, MAPK5/ ASK-1 inhibitor, SGLT-2 inhibitor, Glucagon-like peptide-1 (GLP-1) receptor agonist, Glucagon-like peptide-1 (GLP-1) mimetics, PPAR a/5 agonist, Stearoyl Coenzyme A Desaturase 1 (SCD1) inhibition-Synthetic fatty acid-bile acid conjugate, Caspase inhibitor, metformin, sulfonyl ureas, long chain fatty acid agonists (GPR40, GPR120), DPP4 inhibitors, insulin sensitizer, Bempedoic acid or pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared using the methods described below, together with conventional techniques known to those skilled in the art of organic synthesis or variation thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to those described below, where all symbols are as defined earlier.

Synthetic procedures:

General synthetic schematic route for the synthesis of final molecules.

In the general scheme of synthesis of our examples in the invention, an intermediate like amine A was synthetized by multiple steps and similarly a chloro intermediate like B was also synthetized through multiple steps from commercially available starting material. The two intermediates A and B were then coupled in presence of an inorganic base like potassium carbonate to produce precursor compound C. The ester precursor C is then hydrolyzed in the presence of mild base DBU to provide final molecule D which was then purified and tested in different biological assays.

The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with suitable acids in suitable solvents by processes known in the art.

The invention is further exemplified by the following examples below, which provides some of the several preferred embodiments of the present invention. These examples are provided merely as representative embodiments and should not be construed to limit the scope of the invention in any way.

Synthetic schemes:

Intermediate 1

Sysnthesis of methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate nzyloxy)methyl)oxetane

Trimethylsulfoxonium iodide (2.68 g, 12.18 mmol) was dissolved in n-butanol (20 ml) and potassium tert-butoxide (1.367 g, 12.18 mmol) was added to it and stirred at 60 °C for 2 hrs. Then, (S)-2-((benzyloxy)methyl)oxirane (1g, 6.09 mmol) was added slowly for a period of 2 min. and stirred at 80 °C for 4 hrs. After completion of reaction solvent was evaporated and crude material was extracted with ethyl acetate. Organic layer was dried over sodium sulfate and evaporated. Crude material was purified by combi flash to obtain ((S)-2-((benzyloxy)methyl)oxetane (0.85 g, 4.77 mmol, 78 % yield).

Step 2:

Preparation of (S)-oxetan-2-ylmethanol

Compound (S)-2-((benzyloxy)methyl)oxetane (3.9 g, 21.88 mmol) was dissolved in THF (28 ml) and catalytic amount of acetic acid (0.013 ml, 0.219 mmol) was added to it and degassed with nitrogen for 10 min. Then, palladium hydroxide on carbon (0.384 g, 0.547 mmol) was added to it and reaction was kept in autoclave at 50 °C under 80 PSI hydrogen pressure for 6 hrs and further at RT for 14 hrs. Next day reaction was continued at 70 °C for 6 hrs. After completion of reaction, reaction mass was filtered through celite and crude material (in THF solution) was directly used for next step considering 100% yield.

Step 3:

Preparation of (S)-oxetan-2-ylmethyl methanesulfonate

THF solution (20 mL) of (S)-oxetan-2-ylmethanol (0.47 g, 5.33 mmol) was cooled to 0 °C and triethylamine (1.859 ml, 13.34 mmol) was added to it and stirred for 10 min. Then, methanesulfonic anhydride (1.394 g, 8.00 mmol) was added to it maintaining temperature 0-10 °C. Further, reaction mixture was stirred for overnight. Then, ice water was added to the reaction and extracted with ethyl acetate. Organic layer was washed with water, brine and dried over sodium sulfate. Crude material was purified by combiflash to obtain (S)-oxetan-2-ylmethyl methanesulfonate (600 mg, 3.61 mmol, 67.7 % yield).

Step 4:

Preparation of (S)-2-(azidomethyl)oxetane

Compound (S)-oxetan-2-ylmethyl methanesulfonate (600 mg, 3.61 mmol) was dissolved in N,N-Dimethylformamide (12 ml) and sodium azide (352 mg, 5.42 mmol) was added to it and reaction mixture was heated to 80 °C for 3 hrs. After completion of reaction, reaction mixture was cooled and diethyl ether was added and filtered through celite. Crude material was evaporated and directly used for next step.

Step 5:

Preparation of (S)-oxetan-2-ylmethanamine

Solution of Compound (S)-2-(azidomethyl)oxetane (408 mg, 3.61 mmol) in DMF (3 mL) was dissolved in THF (8 ml) and degassed by nitrogen for 5 min. Then, palladium on charcoal (384 mg, 3.61 mmol) was added and reaction mixture was stirred under hydrogen at 55 PSI for overnight (16 hrs) at RT. After completion of reaction, reaction mixture was passed through celite and solution was directly used for next step considering 100% yield.

Step 6:

Preparation of methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate

Solution of (S)-oxetan-2-ylmethanamine (314 mg, 3.60 mmol) was dissolved in THF (20 ml) and methyl 3-fluoro-4-nitrobenzoate (718 mg, 3.60 mmol), triethylamine( 1.507 ml, 10.81 mmol) was added to it and reaction mixture was heated at 40 °C overnight. After completion of reaction, solvent was evaporated and crude material was extracted with ethyl acetate. Organic layer was washed with water, brine and dried over sodium sulphate. Crude material obtained was purified by combi flash to obtain methyl (S)-4- nitro-3-((oxetan-2-ylmethyl)amino)benzoate (250 mg, 0.939 mmol, 26.1 % yield).

Step 7:

Preparation of methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate

Solution of Compound methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (250 mg, 0.939 mmol) was dissolved in MeOH (8 ml) and degassed by nitrogen for 5 min. Then, palladium on charcoal (24.98 mg, 0.023 mmol) was added and reaction mixture was stirred under hydrogen at 55 PSI for overnight (16 hrs) at room temperature. After completion of reaction, reaction mixture was passed through celite and solution was directly used for next step.

Step 8: Preparation of methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

Methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (210 mg, 0.889 mmol) and 2- chl oro-1, 1,1 -trimethoxy ethane (151 mg, 0.978 mmol) was dissolved in Acetonitrile (5 ml) and catalytic amount of p- toluenesulfonic acid monohydrate (8.45 mg, 0.044 mmol) was added to it and reaction mixture was heated to 60 °C for 2 hrs. The reaction mixture was heated overnight. After completion of reaction, solvent was evaporated and crude material was purified by combi flash to obtain methyl (S)-2-(chloromethyl)-l-(oxetan-2- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (160 mg, 0.543 mmol, 61.1 % yield).

Example 01

(S)-2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl )-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid

Synthesis of intermediate tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)- carboxylate 4-methylbenzenesulfonate

Step 1:

Preparation of l,4-dibromo-2,3-bis(bromomethyl)but-2-ene Take the 2,3 -dimethylbutane (15.11 ml, 116 mmol) in RBF, put the flask in cooling bath by maintain temp. 0-5°C and then add bromine (46.3 ml, 899 mmol) in it and then add HBr (1.313 ml, 11.60 mmol) and reflux the reaction mixture up to 42-45°C for 20 hr. Add the aqueous solution of sodium bisulphate in reaction mix and then dilute it with ethyl acetate and spot the organic layer. Add water to the reaction mixture Ice cool water and add aqueous solution of NaHSO3 in reaction to quench excess bromine (till the colour of reaction mix. become colourless), decant the water layer from sticky yellow solid. Add MTBE in it and stir it for half an hour and then free flow yellow solid observed and filter it and dry it. Take crude bromo, and add ethyl acetate in it and reflux it for 30 min and cool it 5-10°C stir for 30 min again and filter the solution and dry it. l,4-Dibromo-2,3-bis(bromomethyl)but-2-ene was obtained. (5.66 g, 14.16 mmol, 12.20 % yield).

Preparation of 2,5-ditosyl-l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole

Take the l,4-dibromo-2,3-bis(bromomethyl)but-2-ene (1 g, 2.502 mmol) in flask and DMF (13.00 ml) in it then add K2CO3 (5.59 g, 40.4 mmol) in it at room temperature and then add /?-Toluenesulfonamide (1.000 g, 5.84 mmol) in it let it stir at room temperature for 16hr. Add ice in reaction mixture and stir it for 10 min and free flow solid precipitate out filter it and dry it. (820 mg, 78% Yield).

Step 3:

Preparation of l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide

^{HBr HN} i ^{NH HBr}

Take the 2,5-ditosyl-l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole (1.0 g, 2.389 mmol) in RBF, put the RBF in cooling bath 0°C and then HBr (5.52 ml, 47.8 mmol) was added in it and then phenol (1.010 ml, 10.08 mmol) was added(hot liquid) in it and let it stir and heat it up to 110°C for 16hrs. Let the reaction mixture cool and then add hyflow in it and hyflow filter it, wash it with hydrobromic acid and with DCM. Separate the layer and wash the aqueous layer with DCM (3 times). Add charcoal in aqueous layer and stir it for 15 min., hyflow filter it and wash with hydrobromic acid. Concentrate the hydrobromic acid layer below 60°C. Dry it completely and wash with (1 :1) ethanol:DIPE, stir it for half an hour and filter it. Wash the solid with (1 :1) ethanol:DIPE , dry the solid. (330 mg, 50.8% yield).

Step 4:

Preparation of di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)-dicarboxylate

In 25 ml RBF, charge potable water (3 ml) and sodium bicarbonate (273 mg, 3.25 mmol) at 25-35 °C, cool it to 20 °C. l,2,3,4,5,6-hexahydropyrrolo[3,4-c]pyrrole dihydrobromide (295 mg, 1.08 mmol) was added portion wise at 20-25 °C. Boc Anhydride (0.55 ml) in MeOH (0.6 ml) was added in to it at 25-30°C. Stirred it for 16 hrs. Filter the solid and wash with water to obtain di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)- dicarboxylate (274 mg, 81% yield) Step 5:

Preparation of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate 4- methylbenzenesulfonate

In 25 ml RBF, charge di-tert-butyl 4,6-dihydropyrrolo[3,4-c]pyrrole-2,5(lH,3H)- dicarboxylate (274 mg, 0.883 mmol) in isopropyl acetate (8.22 ml) p-toluenesulfonic acid (168 mg, 0.883 mmol) was added at 25°C and stirred it for 16 hrs. Filter the solid and wash with isopropyl acetate to 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate 4-methylbenzenesulfonate (212 mg, 62.8% yield).

Step 6:

Preparation of tert-butyl 5-(6-chloropyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyr role- 2(1 H)-carboxylate

To a solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate 4- methylbenzenesulfonate (4.3 g, 11.24 mmol) and 2,6-dichloro pyridine (1.66 g, 11.24 mmol) in dimethylformamide (20 ml) was placed caesium carbonate (9.16 g, 28.1 mmol). The reaction mixture was stirred at 80°C for 16 hrs, Reaction mixture was quenched by adding reaction mixture to water. Product was extracted using ethyl acetate, washed with water, brine, dried over sodium sulphate, concentrate and purified by column chromatography to obtain tert-butyl 5-(6-chloropyridin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (1.6 g, 44 % yield).

Step 7:

Preparation of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate

To a clear solution of tert-butyl 5-(6-chloropyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrole-2(lH)-carboxylate (0.3 g, 0.93 mmol) in toluene (6 ml). Degassed it with N2 balloon. 3-fluoro-4-(hydroxymethyl)benzonitrile (211 mg, 1.39 mmol), CS2CO3 (759 mg, 2.33 mmol), Johnphos (34.8 mg, 0.11 mmol) and Pd2(dba)s (53.8 mg, 0.059 mmol) was added in to it at 25°C. Again degassed it. Reaction mass was stirred at preheated 110- 120°C for 3 hrs. Product was diluted with ethyl acetate (15 ml) and fdter the solid. Evaporate the solvent under reduced pressure and product was purified by column chromatography to obtain tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)- 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (170 mg, 41.8 % yield).

Step 8

Preparation of 3-fluoro-4-(((6-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH )-yl)pyridin- 2-yl)oxy)methyl)benzonitrile 4-methylbenzenesulfonate

To a solution of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (170 mg, 0.38 mmol) in EtOAc (3.4 ml) /?-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 2 hrs, Filter the solid to obtain 3-fluoro-4-(((6- (3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin-2-y l)oxy)methyl)benzonitrile 4- methylbenzenesulfonate (179 mg, 67.5 % yield).

Step-9

Methyl(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2 -yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

3-fluoro-4-(((6-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2 (lH)-yl)pyridin-2- yl)oxy)methyl)benzonitrile 4-methylbenzenesulfonate (90 mg, 0.132 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (39mg, 0.132 mmol) was dissolved in Acetonitrile (2 ml) and potassium carbonate (91 mg, 0.66 mmol) was added to it and reaction mixture was heated to 60 °C was heated for 2hrs. After completion of reaction, After completion of reaction, Dilute RM with EtOAc and wash with water and brine, evaporate the solvent and crude material was purified by combi flash to obtain methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)- 3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (40 mg, 50.9 % yield). Mass [M+H]+ = 595.3 Step- 10

(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3 ,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid

Compound methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4, 5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (40 mg, 0.067 mmol) was dissolved in ACN (1 ml) Then l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (19.48 mg, 0.14 mmol) in water (0.2 ml) was added and reaction mixture was stirred at RT for overnight (16 h) After completion of reaction, evaporate the solvent and dilute it with water. Reaction mixture was acidify with 10% citric acid solution. Extract the product with EtOAc (10 ml), wash with H2O (5 ml), brine (5 ml), dried over Na2SO4 and concentrate. Purified the product through combiflash to obtain (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin- 2-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl )-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid ( 10 mg, 25.6% yield). Mass [M+H]+ = 581.2 'H-NMR (400 MHz, DMSO-d6) 5 12.8(bs, 1H), 8.26 (s, 1H), 7.80-7.88 (m, 2H), 7.64- 7.69 (m, 3H), 7.43-7.47 (m, 1H), 6.06 (d, J=8.0Hz, 1H), 5.96 (d, J= 8.0 Hz, 1H), 5.44 (s, 2H), 5.1 (m, 1H), 4.7-4.9 (m, 3H), 4.24-4.37 (m, 3H), 4.08 (m, 4H), 3.6 (m, 4H), 2.33- 2.43(m, 2H)

Example 02

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Step-1 methyl2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 1 using 3-fluoro-4-(((6-(3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin-2-yl)oxy)met hyl)benzonitrile 4- methylbenzenesulfonate and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)- l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate (40mg,77 % yield).

Step-2

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Procedure same as written in step 10 in Example 1 using methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)-

1-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate to obtain 2-((5-(6-((2-fluoro-4- isocyanobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrrol-2(lH)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy lic acid (10 mg, 21.34 % yield). Mass [M+H]+ = 569.1 Example 03

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)methyl)- 1 -((3 -methoxy oxetan-3 -yl)methyl)- 1 H-benzo[d] imidazole-6- carboxylic acid Step-1

Methyl 2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2( lH)-yl)methyl)- 1 -((3 -methoxy oxetan-3-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 1 using 3-fluoro-4-(((6-(3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyridin-2-yl)oxy)met hyl)benzonitrile 4- methylbenzenesulfonate and methyl 2-(chloromethyl)-l -((3 -methoxy ox etan-3 - yl)methyl)-lH-benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((2-fluoro-4- isocyanobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrrol-2(lH)- yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d]imida zole-6-carboxylate (33 mg, 29.9 % yield).

Step-2

2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)methyl)- 1 -((3 -methoxy oxetan-3 -yl)methyl)- 1 H-benzo[d] imidazole-6- carboxylic acid

Procedure same as written in step 10 in Example 1 using methyl 2-((5-(6-((2-fluoro-4- isocyanobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrrol-2(lH)- yl)methyl)- 1 -((3 -methoxyoxetan-3 -yl)methyl)- 1 H-benzo[d] imidazole-6-carboxylate to obtain2-((5-(6-((2-fluoro-4-isocyanobenzyl)oxy)pyridin-2-yl) -3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2( lH)-yl)methyl)- 1 -((3 -methoxy oxetan-3-yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylic acid(8 mg, 20.90 % yield). Mass [M+H]+ = 611.5 'H-NMR (400 MHz, DMSO-d6) 5 8.51 (s, 1H),7.9-8.O (m, 2H), 7.6-7.8 (m, 3H), 7.52(m, 1H), 6.13 (d, J=8.0Hz, 1H), 6.00 (d, J= 8.0 Hz, 1H), 5.46 (s, 2H), 5.1 (s, 2H), 4.92 (s, 2H), 4.76 (s, 3H), 4.52 (m, 4H), 4.38 (m, 4H), 4.17(m, 4H)

Example 04 (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4 ,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid Step: 1

Preparation of 2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-l , 2, 3, 4,5,6- hexahydropyrrolo[3,4-c]pyrrole bis(4-methylbenzenesulfonate)

Procedure same as written in step 8 in Example 1 using tert-butyl 5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrole-2(lH)- carboxylate to obtain 2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,4,5,6 - hexahydropyrrolo[3,4-c]pyrrole bis(4-methylbenzenesulfonate)

(150mg, 61.7 % yield). Mass [M+H]+ = 346.1

Step-2 methyl(S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-y l)-3,4,5,6- tetrahydropyrrolo[3 ,4-c]pyrrol-2(l H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1H- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 1 using 2-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,4,5,6-hexahydropyrrolo[ 3,4-c]pyrrole bis(4- methylbenzenesulfonate)and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl(S)-2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)- l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate(74 mg, 53.9 % yield). Mass [M+H]+ = 604.3

Step-3

(S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid

Procedure same as written in step 10 in Example 1 using methyl(S)-2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)- l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate to obtain (S)-2-((5-(6-((4- chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropy rrolo[3,4-c]pyrrol-2(lH)- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylicacid ( 6mg, 6.49 % yield). Mass [M+H]+ = 590.4 'H-NMR (400 MHz, DMSO-d6) 5 8.37 (s, 1H), 7.9-7.92 (m, 1H), 7.77-7.79 (m, 1H), 7.4- 7.6(m, 3H), 7.3-7.4 (m, 1H), 6.00-6.10 (m, 2H), 5.36 (s, 2H), 5.1-5.3 (m, 3H), 4.64 (m, 2H), 4.36-4.39 (m, 4H), 4.21 (m, 4H), 2.7-2.8 (m, 2H), 2.2-2.3(m, 2H)

Example 05

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4, 5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Step-1 methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6 - tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 1 using 2-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,4,5,6-hexahydropyrrolo[ 3,4-c]pyrrole bis(4- methylbenzenesulfonate)and methyl 2-(chloromethyl)-l -(2-methoxyethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)- l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate (54 mg, 40% yield). Mass [M+H]+ = 593.4

Step-2 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6 -tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6 - tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate (54 mg, 0.091 mmol) was dissolved in MeOH (1.1 ml). Then Lithium Hydroxide monohydrate (19.10 mg, 0.455 mmol) in Water (0.25 ml) was added and reaction mixture was stirred at RT for overnight (16 h) After completion of reaction, evaporate the solvent and dilute it with water. Reaction mixture was acidify with 10% citric acid soln. Filter the solid compound. Purified the Product to obtain desire product. (5 mg, 7.41 % yield). Mass [M+H]+ = 579.4

'H-NMR (400 MHz, DMSO-d6) 5 8.26-8.28 (m, 1H), 8.07-8.09 (m, 1H), 7.46-7.61 (m, 4H), 7.30-7.32(m, 1H), 6.09 (d, J=8.0Hz, 1H), 6.00 (d, J=8.0Hz, 1H), 5.36 (s, 2H), 4.57- 4.58 (m, 3H), 4.21 (m, 5H), 3.71-3.74 (m, 3H), 3.21-3.26 (m, 6H)

Example 06

(S)-2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2- yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid Step 1

Preparation of 3 -fluoro-4-(((2-(3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)- yl)pyrimidin-4-yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate) To a solution of tert-butyl 5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (155 mg, 0.35 mmol) in EtOAc (3.1 ml) para toluene sulfonic acid monohydrate (182 mg, 0.95 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 2 hrs, Filter the solid to obtain 3-fluoro-4- (((2-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyrimi din-4- yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate) (242 mg, 100 % yield).

Step-2 methyl (S)-2-((5-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 1 using 3-fluoro-4-(((2-(3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)pyrimidin-4-yl)oxy)m ethyl)benzonitrile bis(4- methylbenzenesulfonate) to obtain methyl (S)-2-((5-(4-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-2-yl)-3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylate ( 52 mg, 24.59

% yield). Mass [M+H]+ = 596.4

Step-3

(S)-2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2- yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Procedure same as written in step 10 in Example 1 using methyl (S)-2-((5-(4-((4-cyano- 2-fluorobenzyl)oxy)pyrimidin-2-yl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol-2(lH)- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylate to obtain (S)-2- ((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)-3,4,5 ,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid ( 5 mg, 8.80 % yield). Mass [M+H]+ = 582.4

'H-NMR (400 MHz, DMSO-d6) 5 12.90(bs, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.87-7.92 (m, 2H), 7.72-7.76(m, 3H), 6.22 (d, J=5.6Hz, 1H), 5.51 (s, 2H), 4.75-4.81 (m, 1H), 4.62- 4.79 (m, 3H), 4.32-4.37 (m, 2H), 4.11-4.25 (m, 7H), 2.61-2.73(m, 2H), 2.37-2.42(m, 2H)

Example 07

(S)-2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl) -3,4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid Step-1 methyl (S)-2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

To a solution 3-fluoro-4-(((4-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH )-yl)pyrimidin- 2-yl)oxy)methyl)benzonitrile 4-methylbenzenesulfonate (90 mg, 0.177 mmol) in acetonitrile (1 ml) were added potassium carbonate (122 mg, 0.833 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (90 mg, 0.177 mmol) and reaction mixture was stirred at 60-70 °C for 2 hrs. Reaction mixture was cooled to rt charged water and extracted with ethyl acetate. Adsorbed on silica and eluted with 0 to 80 % ethyl acetate in hexane to obtained methyl (S)-2-((5-(2-((4-cyano- 2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol-2(lH)- yl)methyl)-l -(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (50mg, yield 38%) Mass m/z 596.4 [M+H] ⁺ Step-2

Synthesis of (S)-2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

To a solution of methyl (S)-2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-5-carboxylate (50 mg, 0.084 mmol) in acetonitrile (1 ml) was added aqueous solution of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (24.31 mg, 0.175 mmol) and reaction mixture was stirred at RT for 20 hrs. Removed organic solvent and acidify with 10% citric acid sol. to pH 5 to 6. Precipitated solid was filtered and dried. Stirred solid in diethyl ether and filtered to obtained (S)-2-((5-(2-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylic acid (4 mg, yield 7%) Mass m/z 582.4 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 8.6O(1H, s), 8.29(1H, dd, J=10.3Hz& J=2.3Hz), 8.17(1H, dd, J=7.2&J=1.6Hz), 8.02(lH, d, J=8.2Hz), 7.99(1H, s), 7.39(1H, d, 8.2Hz), 7.31(1H, dd, J=8.2Hz& J=2.2Hz), 6.3O(1H, m), 5.31(2H, s), 4.98(2H, m), 4.57(2H,m), 4.55(2H,s), 3.81(2H, s), 3.88(4H, m), 3.11(4H, m), 2.5(1H, m)

Example 08

2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4 ,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Synthesis of methyl 2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3 ,4-c]pyrrol-2(l H)-yl)methyl)- 1 -(2-methoxy ethyl)- 1H- benzo[d]imidazole-6-carboxylate

Title compound was synthesized using methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH- benzo[d]imidazole-6-carboxylate (36.1 mg, 0.128 mmol)and potassium carbonate (88 mg, 0.638 mmol), 3-fluoro-4-(((4-(3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol-2(lH )- yl)pyrimidin-2-yl)oxy)methyl)benzonitrile 4-methylbenzenesulfonate (65 mg, 0.128 mmol) to obtained methyl 2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(2-methoxyethyl)- 1 H- benzo[d]imidazole-6-carboxylate (22 mg, yield 30 %) Mass m/z 584.4 [M+H] ⁺ Step-2

Synthesis of 2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5, 6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 Example 1 by using methyl2-((5-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate (0.022 g, 0.038 mmol)and l,3,4,6,7,8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (10.91 mg, 0.078 mmol) to obtained 2-((5-(2-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy lic acid (4 mg, yield 30%) Mass m/z 570.4[M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 8.51(1H, s), 8.31(1H, dd, J=12.4Hz& J=2.9Hz), 8.11(1H, dd, 6Hz), 7.91(1H, d, J=7.5Hz), 7.97(1H, s), 7.35(1H, d, 9Hz), 7.35(1H, dd, J=11.2Hz& J=2.2Hz), 6.3O(1H, s), 5.36(2H, s), 4.91(2H, s), 4.33(2H, t, 7.2Hz), 3.90(2H, m), 3.89(4H, m), 3.31(3H, s), 3.09(4H, m)

Example 09

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylic acid

Step- 1

Preparation of tert-butyl 5-(2-(chloropyrimidine-4-yl)-3,4,5,6-tetrahydropyrrolo-2 [3,4-c] pyrrole-2- (1H)- carboxylate

To a solution of tert-butyl 3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate 4- methylbenzenesulfonate (2.57 gm, 6.71 mmol) and 2,4-dichloro pyrimidine (1 gm, 6.71 mmol) in dimethylformamide (20 ml) was placed triethyl amine (4.68 ml). The reaction mixture was stirred at 25°C for 16 hrs, Reaction mixture was quenched by adding reaction mixture to water. Product was extracted using ethyl acetate, washed with water, brine, dried over sodium sulphate, concentrate and purified by column chromatography to obtain tert-butyl 5-(2-(chloropyrimidine-4-yl)-3,4,5,6-tetrahydropyrrolo-2 [3,4-c] pyrrole- 2- (1H)- carboxylate (850 mg, 39.2 % yield). Mass m/z [M+H] ⁺ = 323.2

Step- 2 Synthesis of tert-butyl 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate Tert-butyl 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate was synthesized using tert-butyl 5-(2- chloropyrimidin-4-yl)-3,4,5,6-tetrahydropyrrolo[3,4-c]pyrrol e-2(lH)-carboxylate (400 mg, 1.239 mmol) in toluene (4 ml). Degassed it with N2 balloon. (4-chloro-2- fluorophenyl)methanol (398 mg, 2.478 mmol), CS2CO3 (1.0 gm, 3.10 mmol), BINAP (116 mg, 0.186 mmole combiflash) and Pd2(dba)3, (68.1 mg, 0.074 mmol) was added in to it at 25 °C. Again degassed it. Reaction mass was stirred at preheated 110-120°C for 16 hrs. Product was diluted with ethyl acetate (15 ml) and filter the solid. Evaporate the solvent under reduced pressure and product was purified by column chromatography to obtain tert-butyl 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (480 mg, 87 % yield). Mass m/z [M+H] ⁺ = 447.3

Step- 3

Synthesis of 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5 ,6- hexahydropyrrolo[3,4-c]pyrrole bis(4-methylbenzenesulfonate)

Title compound was synthesized using procedure given in step 8 of previous example 1 using tert-butyl 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrole-2(lH)-carboxylate (200 mg, 0.448 mmol) to obtain 2-(2- ((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5,6-he xahydropyrrolo[3,4- c]pyrrole bis(4-methylbenzenesulfonate) (250 mg, 81%yield). Mass m/z [M+H] ⁺ = 347.2

Step- 4

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxy ethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylate

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxy ethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylate was done using procedure given in step 9 in previous examplel using 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5 ,6- hexahydropyrrolo[3,4-c]pyrrole bis(4-methylbenzenesulfonate) (50 mg, 0.096 mmol) and methyl 2-(chloromethyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridin e-5-carboxylate (27.32 mg, 0.096 mmol) with K2CO3 (66.6 mg, 0.482 mmol) methyl 2-((5-(2-((4-chloro- 2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol-2(lH)- yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-ca rboxylate (35 mg, 61%) mass m/z[M+H] ⁺ = 594.3

Step- 5

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxy ethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylic acid

To a solution of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-3-(2-methoxy ethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylate (35 mg, 0.059 mmol) in methanol (2 ml) was added aqueous solution of LiOH (10 mg, 0.236 mmol) at room temperature and stirred for 20 hrs. After completion of reaction, solvent was removed and charged 10 % citric acid solution till pH 6 to 6.5 and solid was filtered and wash with water and dry to obtain (2-((5-(2-((4-chloro- 2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol-2(lH)- yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-ca rboxylic acid (3 mg, 9 % yield). Mass m/z [M+H] ⁺ = 580.4

'H-NMR (400 MHz, DMSO-d6) 5 8.34 (d, 1H), 8.29-8.31 (d,lH), 7.81-7.83 (m, 2H), 7.15-7.17 (m, 2H), 7.35-7.37 (m,lH) , 5.16 (s, 2H), 4.65 (s, 4H), .4.48-4.51 (m, 4H), 4.43 (s, 2H,), 3.85 (s,lH), 3.35-3.37 (m, 3H), 3.23 (s, 3H), 3.03(s,lH)

Example 10

(S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl )-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Synthesis of methyl (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 by using 2-(2-((4- chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5,6-hexahy dropyrrolo[3,4-c]pyrrole (290 mg, 0.836 mmol), K2CO3 (347 mg, 2.53 mmol) and methyl (S)-2-(chloromethyl)-3- (oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (296 mg, 0.836 mmol) to methyl (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (210 mg, yield 42 %) Mass m/z 606.4 [M+H] ⁺

Step-2

Synthesis of (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 by using methyl (S)-2- ((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6 -tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylate (0.19 g, 0.314 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (87 mg, 0.628 mmol) to obtained (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylic acid (130 mg, yield 65 %) Mass m/z 592.4 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 8.4O(1H, s), 8.21(1H, dd, J=11.3Hz& J=3.3Hz), 8.12(1H, dd, J=9.2&J=3.6Hz), 7.97(1H, d, J=7.2Hz), 7.91(1H, s), 7.29(1H, d, 9.9Hz), 7.21(1H, dd, J=8.2Hz& J=2.2Hz), 6.29(1H, m), 5.29(2H, s), 4.91(2H, m), 4.55(2H,m), 4.57(2H,s), 3.87(2H, s), 3.81(4H, m), 3.09(4H, m), 2.5(1H, m)

Example 11

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l -((1 -ethyl- IH-imi dazol-5-yl)methyl)-lH-benzo[d]imi dazole- 6-carboxylic acid

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5-yl)methyl)- 1 H-benzo [d] imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 1 by using 2- (2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5,6 -hexahydropyrrolo[3,4- c]pyrrole (100 mg, 0.126 mmol), K2CO3 (133 mg, 0.631 mmol) and methyl (S)-2- (chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridi ne-5-carboxylate (60 mg, 0.126 mmol) methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylate(50 mg, yield 9 %) Mass m/z 586.3 [M+H] ⁺

Step2:

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylic acid Title compound was synthesized as per procedure given in step 2 Example 5 by using methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylate (50 mg, 0.014 mmol) and LiOH.H2O (16 mg, 0.096 mmol) to obtained 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl- lH-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid (10 mg, yield 58 %) Mass m/z 572.2 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 8.30(lH, s), 8.12(1H, dd, J=10.3Hz& J=2.3Hz), 8.01(lH, dd, 5.6Hz), 7.87(1H, d, J=7.2Hz), 7.85(1H, s), 7.31(1H, d, 10Hz), 7.24(1H, dd, J=13.2Hz& J=2.2Hz), 6.25(1H, m), 5.26(2H, s), 4.93(2H, s), 4.33(2H, s), 4.13(2H, m), 3.85(4H, m), 3.09(4H, m), 1.25(3H, t, J=5.2Hz)

Example 12

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5 -ylmethyl)-lH- Title compound was synthesized as per procedure given in step 9 Example 1 by using 2- (2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,4,5,6 -hexahydropyrrolo[3,4- c]pyrrole (100 mg, 0.126 mmol), K2CO3 (133 mg, 0.631 mmol) and methyl 2- (chloromethyl)-l -(thiazol-5-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (64 mg,

0.126 mmol) to obtained methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(thiazol- 5-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (50 mg, yield 9 %) Mass m/z 586.3 [M+H] ⁺ Step: 2

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5 -ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 5 by using methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5 -ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (40 mg, 0.014 mmol) and LiOH.H2O (16 mg, 0.096 mmol) to obtained 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(thiazol-5 -ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid (3 mg, yield 58 %) Mass m/z 572.2 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 9.2(1H, s), 8.31(1H, s), 8.10(lH, dd, J=11.3Hz& J=3.3Hz), 8.01(lH, dd, 9.6Hz&J=2.3Hz), 7.87(1H, d, J=7.2Hz), 7.81(1H, s), 7.21(1H, d, 9.0Hz), 7.24(1H, dd, J=13.2Hz& J=2.2Hz),7.01(lH, s), 6.2O(1H, m), 5.26(2H, s), 4.93(2H, s), 4.33(2H, s), 3.81(4H, m), 3.09(4H, m) Example 13

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imid azole-6-carboxylic acid

Step-1

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 1 by using methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylate (lOOmg, 0.193 mmol)and potassium carbonate (133 mg, 0.963 mmol),3-fluoro-4-(((4- (3,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)pyrimidin-2-yl)oxy)methyl)benzonitrile 4-methylbenzenesulfonate (55 mg, 0.193 mmol) to obtained methyl 2-((5-(2-((4-chloro- 2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6-tetrahydropyrrolo [3,4-c]pyrrol-2(lH)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy late (40 mg, yield 35%) Mass m/z 593.5 [M+H] ⁺

Step-2

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 5 by using methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylate(0.040g,0.067mmol) and l,3,4,6,7,8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (20 mg, 0.140 mmol) to obtained 2,2,2-trifluoroacetic acid compound with 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxy ethyl)-lH- benzo[d]imidazole-6-carboxylic acid (4 mg, yield 9%) Mass m/z 579.5[M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 12.93(lH,bs), 8.31(1H, s), 8.11(1H, dd, J=11.3Hz& J=2.3Hz), 8.02(lH, dd, 5.6Hz), 7.89(1H, d, J=7.2Hz), 7.87(1H, s), 7.3O(1H, d, 11Hz), 7.25(1H, dd, J=14.2Hz& J=4.2Hz), 6.25(1H, m), 5.26(2H, s), 4.93(2H, s), 4.33(2H, t, 6.2Hz), 3.95(2H, m), 3.86(4H, m), 3.35(3H, s), 3.09(4H, m)

Synthesis of Intermediate 02

2-trityl- 1.2.3.5-tetraliydropyrrolo|3.4-c| pyrrole

Step-1

Synthesis of dimethyl lH-pyrrole-3,4-dicarboxylate

To a cooled solution (0 to 5 °C) of potassium tert-butoxide (15.57 g, 139 mmol) in THF (200 ml) was added mixture of dimethyl fumarate (10 g, 69.4 mmol) and TOSMIC (13.55 g, 69.4 mmol) in THF (100 ml) dropwise by addition funnel in 30 to 45 min. Reaction mixture stirred at same temp for 0.5 hr. Remove ice bath and stirred at RT for 0.5 hr. Reaction mixture dumped in brine solution 20 ml. Extracted with 100 ml ethyl acetate. Combined organic layer dry on sodium sulfate and concentrated. Resulting solid was stirred in ethyl acetate and filtered to obtained dimethyl lH-pyrrole-3,4-dicarboxylate (7 g, yield 52%) Mass m/zl84.1 [M+H] ⁺ Step-2

Synthesis of dimethyl 1 -tosyl- lH-pyrrole-3,4-di carboxylate

To a solution of dimethyl lH-pyrrole-3,4-dicarboxylate (7 g, 38.2 mmol) in DMF (70 ml) was added NaH (2.293 g, 57.3 mmol) lot wise under cooling and N2 atm. Reaction mixture was stirred at RT for 15 min, then cooled and 4-methylbenzenesulfonyl chloride (8.74 g, 45.9 mmol) was added lot wise and stirred at RT for 2 hr. Charged ice water and precipitated solid was filtered dry to obtained dimethyl l-tosyl-lH-pyrrole-3,4- dicarboxylate (7 g, yield 54%). Mass m/z 338.1 [M+H] ⁺ Step-3

Synthesis of (1 -tosyl- lH-pyrrole-3,4-diyl)dimethanol To a solution of dimethyl 1 -tosyl- lH-pyrrole-3,4-dicarboxylate (3.8 g, 11.26 mmol) in THF (65.0 ml) was added lithium aluminum hydride (0.855 g, 22.53 mmol) lot wise under cooling in 30 min. Reaction mixture was stirred for 1 hr at RT. After completion of reaction, quenched with wet sodium sulfate and stirred for 0.5 hr. Filtered solid wash with ethyl acetate concentrated and purified by column with 0 to 60% ethyl acetate in hexane to obtained (l-tosyl-lH-pyrrole-3,4-diyl)dimethanol (1.5 g, yield 47%). Mass m/z 282.1 [M+H] ⁺

Step-4

Synthesis of 3,4-bis(bromomethyl)-l-tosyl-lH-pyrrole

To a solution of (1 -tosyl- lH-pyrrole-3,4-diyl)dimethanol (1.5 g, 5.33 mmol) in DCM (30 ml) was added phosphorous tribromide (1.006 ml, 10.66 mmol) dropwise under cooling (0-5 °C). After addition, temp slowly raised to 5-10 °C and stirred for 1 hr. Reaction mixture was diluted with sat. sodium bicarbonate and extracted with DCM and purified by column with 0 to 5% ethyl acetate to obtained 3,4-bis(bromomethyl)-l-tosyl-lH- pyrrole (1.0 g, yield 46%).

Step- 5

Synthesis of 5-tosyl-2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole

To a solution of 3,4-bis(bromomethyl)-l-tosyl-lH-pyrrole (700 mg, 1.719 mmol) in DMF (8 ml) were added N-ethyl-N-isopropylpropan-2-amine (0.744 ml, 4.30 mmol) and stir and added triphenylmethanamine (535 mg, 2.063 mmol) and reaction mixture stirred at 50 C for 2 hr. Charged water and precipitated solid was filtered and suck dry well and load into column and eluted with 0 to 15% ethyl acetate in hexane to obtained 5-tosyl-2- trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (0.5 g , yield 39%).

Step-6

Synthesis of 2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole

Flask covered by aluminum foil to protect from sunlight and charged 5-tosyl-2-trityl- l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (3.1 g, 6.14 mmol) in DMSO (45 ml), and cooled to 20 °C and added potassium tert-butoxide (2.068 g, 18.43 mmol) lot wise then stir reaction mixture at RT for 5 min. Charged water and precipitated solid was filtered and wash with water and dried to obtained 2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (1.3 g, yield 60%).

Synthesis of Intermediate 03

Synthesis of 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2- yl)oxy)methyl)3 -fluorobenzonitrile bis(2,2,2-trifluoroacetate)

Step-1

Synthesis of 5-(6-chloropyridin-2-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[ 3,4-c]pyrrole

To a solution of 2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole (800 mg, 2.283 mmol, in DMF (3 ml) was then added sodium hydride (183 mg, 4.57 mmol) at RT and reaction mixture was stirred for 10 min. then added 2,6-dichloropyridine (338 mg, 2.283 mmol) and reaction mixture stirred at 65 °C for 1 to 1.5 hr. Then reaction mixture was cooled to RT and ice was added, precipitated solid was filtered and suck dried to obtained 5-(6- chloropyridin-2-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c ]pyrrole (855 g, yield 81%). Step-2

Synthesis of 3-fluoro-4-(((6-(5-trityl-5,6-dihydropyrrolo[3,4-c]pyrrol-2( 4H)-yl)pyridin-2- yl)oxy)methyl)benzonitrile

To a solution of 3-fluoro-4-(hydroxymethyl)benzonitrile (147 mg, 0.974 mmol), 5-(6- chloropyridin-2-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c ]pyrrole (300 mg, 0.649 mmol) and Cs2CO3 (529 mg, 1.623 mmol) in Toluene (1.5 ml), N2 was bubbled for 10 min. Added Pd2(dba)3 (59.5 mg, 0.065 mmol) and [l,l'-bi phenyl] -2-yldi-tert- butylphosphane (38.8 mg, 0.130 mmol) and N2 bubbled for further 5 min. and flask kept under stirring on preheated oil bath at temp. 110-120 °C for 3 hrs. Reaction mixture was cooled and adsorbed on silica and eluted with 0 to 5% ethyl acetate in hexane to obtained 3-fluoro-4-(((6-(5-trityl-5,6-dihydropyrrolo[3,4-c]pyrrol-2( 4H)-yl)pyridin-2- yl)oxy)methyl)benzonitrile (200 mg, yield 53%) Step-3

Synthesis of 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2- yl)oxy)methyl)3 -fluorobenzonitrile bis(2,2,2-trifluoroacetate)

To a solution of 3-fhioro-4-(((6-(5-trityl-5,6-dihydropyrrolo[3,4-c]pyrrol-2( 4H)- yl)pyridin-2-yl)oxy)methyl)benzonitrile (200 mg, 0.347 mmol) in DCM (5 ml) were added TFA (0.401 ml, 5.20 mmol) at RT and reaction mixture was stirred for 0.5 hr at RT. Removed solvent and triturated in diethyl ether to obtained 4-(((6-(5,6- dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2-yl)oxy)methyl )-3-fluorobenzonitrile bis(2,2,2-trifluoroacetate) (150 mg, yield 77%), Mass m/z 335.2 [M+H] ⁺

Synthesis of Intermediate 04

5-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-l,2,3,5 -tetrahydropyrrolo[3,4- c]pyrrole bis(2,2,2-trifluoroacetate)

Synthesis of 5-(6-((5-chl oropyridin-2-yl)methoxy)pyridin-2-yl)-2-trityl-l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole

Title compound was synthesized as per procedure given in step 2 of intermediate 3 by using 5-(6-chloropyridin-2-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[ 3,4-c]pyrrole and (5- chloropyridin-2-yl)methanol to obtained 5-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2- yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole

Step 2: Synthesis of 5-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-l,2,3,5- tetrahydropyrrolo[3,4-c]pyrrole bis(2,2,2-trifluoroacetate)

Title compound was synthesized as per procedure given in step 3 of intermediate 3 by using 5-(6-((5-chl oropyridin-2-yl)methoxy)pyridin-2-yl)-2-trityl-l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole to obtained 5-(6-((5-chloropyridin-2-yl)methoxy)pyridin- 2-yl)-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole bis(2,2,2-trifluoroacetate) Mass m/z 327 [M+H] ⁺

Synthesis of Intermediate 05

6-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin- 2-yl)oxy)methyl)nicotinonitrile bis(2,2,2-trifluoroacetate)

Step 1:

Synthesis of 6-(((6-(5-trityl-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)py ridin-2- yl)oxy)methyl)nicotinonitrile

Title compound was synthesized as per procedure given in step 2 of intermediate 3 by using 5-(6-chloropyridin-2-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[ 3,4-c]pyrrole and 6- (hydroxymethyl)nicotinonitrile to obtained 6-(((6-(5-trityl-5,6-dihydropyrrolo[3,4- c]pyrrol-2(4H)-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile Step 2: Synthesis of 6-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2- yl)oxy)methyl)nicotinonitrile bis(2,2,2-trifluoroacetate)

Title compound was synthesized as per procedure given in step 3 of intermediate 3 by using 6-(((6-(5-trityl-5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)py ridin-2- yl)oxy)methyl)nicotinonitrile to obtained 6-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)- yl)pyridin-2-yl)oxy)methyl)nicotinonitrile bis(2,2,2-trifluoroacetate) Mass m/z 318 [M+H] ⁺

Synthesis of Intermediate 6

5-(2-((5-chloropyridin-2-yl)methoxy)pyrimidin-4-yl)-l,2,3 ,5-tetrahydropyrrolo[3,4- c]pyrrole bis(2,2,2-trifluoroacetate)

Synthesis of 5-(2-chloropyrimidin-4-yl)-2-trityl-l,2,3,5-tetrahydropyrrol o[3,4-c]pyrrole

To a solution of 2-trityl- 1,2,3, 5-tetrahydropyrrolo[3,4-c]pyrrole (600 mg, 1.712 mmol), in THF (10 ml), was added potassium tert-butoxide (288 mg, 2.57 mmol) at RT and reaction mixture stirred for 10 min. 2,4-Dichloropyrimidine (383 mg, 2.57 mmol) was then added and reaction mixture stirred at 50°C for 20 hr. After completion of reaction cooled to RT and ice water was added and extracted with ethyl acetate concentrated and purified by column chromatography using 0 to 15% ethyl acetate in hexane to obtained 5- (2-chloropyrimidin-4-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[ 3,4-c]pyrrole (160 mg, yield 19%) Mass m/z 463 [M+H] ⁺ Step 2: Synthesis of 5-(2-((5-chloropyridin-2-yl)methoxy)pyrimidin-4-yl)-2-trityl -l,2,3,5- tetrahydropyrrolo[3,4-c]pyrrole

Title compound was synthesized as per procedure given in step 2 of intermediate 3 by using 5-(2-chloropyrimidin-4-yl)-2-trityl-l,2,3,5-tetrahydropyrrol o[3,4-c]pyrrole and (5- chloropyridin-2-yl)methanol to obtained 5-(2-((5-chloropyridin-2-yl)methoxy)pyrimidin- 4-yl)-2-trityl-l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole Mass m/z 570.2 [M+H] ⁺ Step 3:

Synthesis of 5-(2-((5-chloropyridin-2-yl)methoxy)pyrimidin-4-yl)-l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole bis(2,2,2-trifluoroacetate)

Title compound was synthesized as per procedure given in step 3 of intermediate 3 by using 5-(2-((5-chloropyridin-2-yl)methoxy)pyrimidin-4-yl)-2-trityl -l,2,3,5- tetrahydropyrrolo[3,4-c]pyrrole to obtained 5-(2-((5-chloropyridin-2- yl)methoxy)pyrimidin-4-yl)-l,2,3,5-tetrahydropyrrolo[3,4-c]p yrrole bis(2,2,2- trifluoroacetate) Mass m/z 328 [M+H]

Synthesis of Intermediate 07

5 -(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 1 ,2,3,5 -tetrahydropyrrole [3 ,4- c]pyrrole bis(2,2,2-trifluoroacetate)

Synthesis of 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2-trityl- l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole

Title compound was synthesized as per procedure given in step 2 of intermediate 3 by using 5-(2-chloropyrimidin-4-yl)-2-trityl-l,2,3,5-tetrahydropyrrol o[3,4-c]pyrrole and (4- chloro-2-fluorophenyl)methanol to obtained 5-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-2-trityl-l,2,3,5-tetrahydro pyrrolo[3,4-c]pyrrole Mass m/z 587.2 [M+H] ⁺ Step 2:

Synthesis of 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole bis(2,2,2-trifluoroacetate)

Title compound was synthesized as per procedure given in step 3 of intermediate 3 by using 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2-trityl- l, 2,3,5- tetrahydropyrrolo[3,4-c]pyrrole to obtained 5-(2-((4-chloro-2-fluor obenzyl)oxy)pyrimidin-4-yl)-l,2,3,5-tetrahydropyrrolo[3,4-c] pyrrole bis(2,2,2- trifluoroacetate) Mass m/z 345.0 [M+H] ⁺

Example 14

(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3 ,5-dihydropyrrolo[3,4-c]pyrrol- 2(1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H-benzo[d] imidazole-6-carboxylic acid Step-1

Synthesis of methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate

To a solution of 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrrol-2(4H)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile bis(2,2,2-trifluoroacetate) (40 mg, 0.071 mmol) in acetonitrile (1 ml) were added potassium carbonate (39.3 mg, 0.284 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (20.96 mg, 0.071 mmol) and reaction mixture was stirred at 60-70 °C for 2 hr. Reaction mixture was cooled to RT charged water and extracted with ethyl acetate. Adsorbed on silica and eluted with 0 to 80 % ethyl acetate in hexane to obtained methyl (S)-2-((5-(6-((4-cyano- 2-fluorobenzyl)oxy)pyridin-2-yl)-3,5-dihydropyrrolo[3,4-c]py rrol-2(lH)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (15 mg, yield 36%) Mass m/z 593.3 [M+H] ⁺

Step-2

Synthesis of (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylic acid

To a solution of methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (15 mg, 0.025 mmol) in acetonitrile (1 ml) was added aqueous solution of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (8.81 mg, 0.063 mmol) and reaction mixture was stirred at RT for 20 h. Removed organic solvent and acidify with 10% citric acid sol. To pH 5 to 6. Precipitated solid was filtered and dried. Stirred solid in diethyl ether and filtered to obtained (S)-2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,5-dihydropyrrolo[3,4-c]pyrr ol-2(lH)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (8 mg, yield 55%) Mass m/z 579.3 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 8.34 (s, 1H), 8.01-8.03 (d, J= 8.4Hz, 1H), 7.71-7.77 (m, 3H), 7.57-7.63 (m, 2H), 7.35 (s, 2H), 7.06-7.12 (dd, J= 8.4 Hz & 5.6 Hz, 1H), 6.69- 6.79 (d, J= 8Hz, 1H), 5.58 (s, 2H), 4.65 (bs, 4H), .45-4.48 (m, 4H), 2.76-2.90 (m, 4H), 2.49-2.51 (m, 1H)

Example 15

(S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl )-3,5-dihydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]i midazole-6-carboxylic acid

Step 1

Synthesis of methyl (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 of Example 17 by using 5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-l,2,3,5-t etrahydropyrrolo[3,4- c]pyrrole bis(2,2,2-trifluoroacetate) (50 mg, 0.087 mmol), K2CO3 (60.3 mg, 0.436 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6- carboxylate (25.7 mg, 0.087 mmol) to obtained methyl (S)-2-((5-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3,5-dihydropyrrolo[3,4-c]py rrol-2(lH)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (40 mg, yield 75 %) Mass m/z 603.1 [M+H] ⁺ Step 2

Synthesis of (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylic acid

This compound was synthesized as per procedure given in step 2 of Example 17 by using methyl (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylate (40 mg, 0.066 mmol) and LiOH (11.12 mg, 0.464 mmol) to obtained (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-2-ylmethyl)- 1 H- benzo[d]imidazole-6-carboxylic acid (12 mg, yield 31 %). Mass m/z = 589.1 [M+H] ⁺

Example 16 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,5-d ihydropyrrolo[3,4-c]pyrrol-

2(lH)-yl)methyl)-l-((l-ethyl-lH-imidazol-5-yl)methyl)-lH- benzo[d]imidazole-6- carboxylic acid

Synthesis of methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -((1 -ethyl- 1 H-imidazol-5 -yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 of Example 17 by using 5 -(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)- 1 ,2,3,5 -tetrahydropyrrole [3 ,4- c]pyrrole (15 mg, 0.044 mmol), K2CO3 (30.1 mg, 0.218 mmol) and methyl 2- (chloromethyl)-l-((l-ethyl-lH-imidazol-5-yl)methyl)-lH-benzo [d]imidazole-6- carboxylate (14.48 mg, 0.044 mmol) to obtained methyl 2-((5-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3,5-dihydropyrrolo[3,4-c]py rrol-2(lH)-yl)methyl)-l- ((1 -ethyl- lH-imidazol-5-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (7 mg, yield 21 %) Mass m/z 641 [M+H] ⁺ Step 2

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,5- dihydropyrrolo [3 ,4-c]pyrrol-2( 1 H)-yl)methyl)- 1 -((1 -ethyl- 1 H-imidazol-5 -yl)methyl)- 1 H- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 of Example 17 by using methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,5-d ihydropyrrolo[3,4- c]pyrrol-2(lH)-yl)methyl)-l -((1 -ethyl- IH-imi dazol-5-yl)methyl)-lH-benzo[d]imi dazole- 6-carboxylate (7 mg, 10.92 pmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (6.08 mg, 0.044 mmol) to obtained 2-((5-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3,5-dihydropyrrolo[3,4-c]py rrol-2(lH)-yl)methyl)-l- ((1 -ethyl- lH-imidazol-5-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (2.5 mg, yield = 37 %) Mass m/z = 627 [M+H] ⁺ Example 17

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Synthesis of intermediate 8:

4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitril e

Step 1:

Charge 3-fluoro-4-(hydroxymethyl)benzonitrile (1.123 g, 7.43 mmol), 2,6- dichloropyridine (1.0 g, 6.76 mmol) and CESIUM CARBONATE (3.30 g, 10.14 mmol) in ACN (10 ml) at 25°C. Stirred it at 80°C for 16 h. After completion of reaction Filter the solid through Highflow and ml was evaporated under reduced pressure. Crude product was purified by column chromatography using Hexane:EtOAc (950 ml : 50 ml) as a solvent. Wt.= 1 g (Y%=56%)

Synthesis of intermediate 9: tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate Boc

Step-1 : 2,3,3a,4,7,7a-hexahydro-lH-isoindole

In a 250ml three neck RBF, THF (75ml) was charged and cooled externally with dry ice to -5 to 0°C. Lithium aluminum hydride powder (3.26 g, 86 mmol) was added portion wise, over a period of 15min, while maintaining the internal temperature below 5 °C. Tetrahydrophthalimide (1) (5 g, 33.1 mmol) was added portion wise, over a period of 10 min, maintaining an internal temperature below 5 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was then heated at 66-67 °C for 16 h. The reaction mixture was cooled to room temperature and subsequently up to -10 °C with dry ice. The reaction mixture was quenched with dropwise addition of ice water (75mL), while maintaining an internal temperature below 5 °C. Upon completion of water addition, the reaction mixture turned to a thick slurry. Additional THF (20ml) and solid sodium sulfate were added followed by dropwise addition of KOH solution (15%; 0.58g KOH in 3.8ml water), over a period of 20min, while maintaining an internal temperature below 5 °C. Additional water (10ml) and solid sodium sulfate (2 g) were added, and the reaction mixture was slowly warmed to room temperature. At room temperature it was stirred for another 30 min, and the solid inorganic material was filtered off through a HyFlo SuperCel bed. The inorganic solid impurity was washed twice with THF (2 x 15 ml), and the combined THF layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield compound 2 2,3,3a,4,7,7a-hexahydro-lH-isoindole as an oil (3.6g) (Y:86%) Mass m/z 124.2 [M+H] ⁺ which was used in the next reaction, without any further purification.

Step-2: tert-Butyl 3a,4,7,7a-Tetrahydro-lH-isoindole-2(3H)-carboxylate

250 ml three neck RBF was charged with compound 2 (3.6 g, 29.2 mmol), dissolved in THF (54ml), and cooled up to 0 to -5 °C. Boc-anhydride (8.48 ml, 36.5 mmol) was added dropwise, while maintaining an internal temperature between 0 and 5 °C, over a period of lOmin. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 h. A solution of glycine (1.755 g, 23.38 mmol) and sodium carbonate (5.27 g, 49.7 mmol) in water (12ml) was added to the reaction mixture at room temperature and stirred for an additional 20 h. The reaction mixture was concentrated under reduced pressure to remove THF and dried under vacuum. The n-Hexane (25 ml) and additional water (8 ml) were added and stirred at room temperature for 15 min. The reaction mixture was filtered through HyFlo SuperCel, and the layers were separated. The aqueous layer was extracted with n-hexane (2 x 20 ml), and the combined organic layer as washed with water (2 x 20 ml) and brine (20 ml). The hexane layer was stirred with activated charcoal (~500 mg), for 20min at room temperature, and filtered through HyFlo SuperCel. The combined hexane was dried over sodium sulfate, filtered, and concentrated in vacuo to afford compound (3) tert-Butyl 3a,4,7,7a-Tetrahydro-lH-isoindole-2(3H)- carboxylate( (5.4g, 83%) as a brown oil. Mass m/z 124.1 [M+H] ⁺

Step-3 : 2,2-(l -(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

250ml three neck RBF was charged with a solution of tert-butyl l,3,3a,4,7,7a-hexahydro- 2H-isoindole-2-carboxylate (5.4 g, 24.18 mmol), dissolved in n-pentane (27ml), and cooled externally to 0 °C. A freshly prepared solution of KMnO4 (11.46 g, 72.5 mmol) and TBAB (1.169 g, 3.63 mmol) were dissolved in Water (92 ml) added dropwise while maintaining the inner temperature 0 to -5°C in span of 30 min. The reaction mixture was further stirred at 0-5 °C for 1 h. The reaction mixture was filtered through HyFlo SuperCel, and the residual solid was slurry washed with water (2 x 8 ml). The combined filtrate was washed with ethyl acetate (12ml), and the organic layer was separated. The aqueous layer was acidified with a 1 N HC1 solution (pH ~ 3) and extracted with ethyl acetate (3 x 40 ml). The combined ethyl acetate layer was washed with brine (28 ml), treated with activated charcoal (9g), and filtered through the HyFlo SuperCel. The organic solvent was distilled under vacuum to afford the title compound (7g) as an off- white solid, which was purified by solvent treatment. Ethyl acetate (40ml) was added, and the solid was stirred for 30 min, at room temperature; afterward, n- hexane (8ml) was slowly added, followed by stirring for 90 min. The solid product was fdtered in vacuo and washed with 30% ethyl acetate in n-hexane (1 x 2.5 L). The product was dried for 2 h to yield compound 4 (5.3g, 75%) as a white solid. Mass m/z 286.2 [M-H] ⁺

Step-4: Tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclopenta[c]-pyrrole-2(lH)-carboxyl ate O=<^£^N- Boc

250 ml three neck RBF was charged with ACETIC ANHYDRIDE (26.1 ml, 277 mmol) followed by slow addition of 2,2'-(l-(tert-butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic acid (5.3 g, 18.45 mmol). The reaction mixture was heated at 135 °C for 45min. Sodium acetate (1.286g, 15.68 mmol) was added to the reaction mixture portion wise, over a period of 30 min, and additionally, the mixture was stirred at 135 °C for 30 min. The reaction mixture was cooled up to 5-10 °C, and MeOH (10 ml) was added dropwise; while the internal temperature was maintained between 10 and 15 °C, addition of methanol was completed within 2 h, and the reaction mixture was cooled up to -5 °C. The reaction mixture was poured into 10 ml ice water, and slowly solid sodium carbonate (~12 g, pH ~ 10) was added, followed by cyclohexane addition (~50 ml). The reaction mixture was stirred for 15 min and filtered through HyFlo SuperCel to remove solid inorganic waste, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with cyclohexane (2 x 40 ml). The combined organic solvent was dried over sodium sulfate and concentrated in vacuo.

To afford crude product (~1.44 g). The crude product was purified by reprecipitation from cyclohexane. The crude product was dissolved in cyclohexane (6 ml) at 60 °C. It was allowed to cool gradually to room temperature and then to 5-10 °C in an ice bath, for 1 h. The off white colored solid product was filtered and dried in vacuo to afford pure compound 1 (2.4g, 58%) as a white solid . Mass m/z 226.3 [M+H] ⁺ Step 5:

Preparation of tert-butyl 5-(((trifluoromethyl)sulfonyl)oxy)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

To a solution of tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (1 g, 4.44 mmol) in THF (20.00 ml). Cool it at 0°C. Charge N- Phenyltrifluoromethanesulfonimide (1.982 g, 5.55 mmol) and LHMDS (7.56 ml, 7.77 mmol) in to it at 0 °C. Stirred it for 1 h at 0 °C. From The reaction mixture was diluted with EtOAc (35 ml) and wash with cold water (15 ml) and brine (15 ml). Organic solvent was concentrated under reduced pressure to afford crude product. Crude product was purified by column chromatography using Hexane:EtOAc (800 ml : 200 ml) as a solvent. Wt.= 1.56 g (Y%=100%) Step 6: Preparation of tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate Boc

Tert-butyl 5-(((trifhioromethyl)sulfonyl)oxy)-3,3a,4,6a-tetrahydrocyclo penta[c]pyrrole- 2(lH)-carboxylate (1.56 g, 4.37 mmol) was dissolve in Dioxane (31.2 ml) charge bis(pinacolato)diboron (1.219 g, 4.80 mmol), potassium acetate (1.285 g, 13.10 mmol) and PdC12(dppf) (0.319 g, 0.437 mmol) in to it under nitrogen at 25 °C.

The reaction mixture was diluted with EtOAC (25 ml) and filter the solid .Organic solvent was concentrated under reduced pressure to afford crude product. Crude product was purified by column chromatography using Hexane: EtOAC (800 ml : 200 ml) as a solvent. Wt.= 1.0 g (%Y=68%)

Coupling:

Step 7:

Preparation of tert-butyl5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3, 3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate

Dissolve 4-(((6-chloropyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile (350 mg, 1.332 mmol) in H ₂ O (0.7 ml) and Dioxane (7.00 ml) at 25°C to give a colourless suspension. Charge tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (447 mg, 1.332 mmol) in to it at 25 °C.

Charge PdCl ₂ (dppf) (97 mg, 0.133 mmol) and caesium carbonate (972 mg, 2.98 mmol) in to it at 25 °C and stirred it for 16 h at 90 °C. The reaction mixture was diluted with EtOAc (25 ml) and wash with H ₂ O (15 ml) and brine (15 ml). Organic solvent was concentrated under reduced pressure to afford desired crude product. Crude product was purified by column chromatography using Hexane:EtOAc (900 ml : 100 ml) as a solvent. Wt.= 350 mg (%Y=60%) Step 8:

Preparation of 3-fluoro-4-(((6-(l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol- 5-yl)pyridin-

2-yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate)

To a solution of tert-butyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (350 mg, 0.8 mmol) in EtOAc (7 ml) para toluene sulfonic acid monohydrate (412 mg, 2.17 mmol) was added at 25°C. The reaction mixture was stirred at 60°C for 2 hrs, Filter the solid to obtain 3-fluoro-4-(((6- (l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)pyridin-2-y l)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate) (437 mg, 80 % yield).

Step 9:

Methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

3-fluoro-4-(((6-(l,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrr ol-5-yl)pyridin-2- yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate) (150 mg, 0.17 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (52 mg, 0.17 mmol) was dissolved in Acetonitrile (3 ml) and potassium carbonate (117.3 mg, 0.85 mmol) was added to it and reaction mixture was heated to 60 °C was heated for 2 hr. After completion of reaction, Dilute RM with EtOAc and wash with water and brine, evaporate the solvent and crude material was purified by combiflash to obtain methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate (120 mg, 92 % yield). Mass [M+H]+ = 594

Step- 10:

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Compound methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,3a ,4,6a- hexahydrocyclopenta[c]pyrrol-5-yl)methyl)-l-(((S)-oxetan-2-y l)methyl)-lH- benzo[d]imidazole-6-carboxylate (120 mg, 0.20 mmol) was dissolved in ACN (3.1 ml) Then l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (58.5 mg, 0.42 mmol) in Water (0.5 ml) was added and reaction mixture was stirred at RT for overnight (16 h) After completion of reaction, evaporate the solvent and dilute it with water. Reaction mixture was acidify with 10% citric acid soln. Extract the product with EtOAc (10 ml), wash with H2O (5 ml), brine (5 ml), dried over Na2SO4 and concentrate. Purified the Product through combiflash to obtain 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2- yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl) -l-(((S)-oxetan-2- yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (27 mg, 22.73% yield. Mass [M+H]+ = 580

'H-NMR (400 MHz, DMSO-d6) 5 12.73(bs, 1H), 8.21 (s, 1H), 7.89-7.91 (m, 2H), 7.72- 7.88 (m, 3H), 7.05-7.12(m, 2H), 6.76 (s, 2H), 6.41 (s, 1H), 5.46-5.50 (m, 2H), 4.95 (s, 2H), 4.45 (s, 1H), 4.22-4.24 (m, 2H), 4.04(s, 2H), 3.31-3.43(m, 4H), 2.94(s, 2H), 2.17- 2.19(d, J=6.8Hz, 1H) Example 18

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylic acid

Step 1 methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 3-fluoro-4-(((6-(l,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrol-5-yl)pyridin-2-yl)oxy)methyl)be nzonitrile bis(4- methylbenzenesulfonate) and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy late (94 mg, 68.7 % yield).

Step-2: 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylic acid Procedure same as written in step 10 in Example 20 using methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy late to obtain 2-((5-(6- ((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahy drocyclopenta[c]pyrrol- 2(lH)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylic acid (15 mg, 16.69 % yield). Mass [M+H]+ = 568.6

'H-NMR (400 MHz, DMSO-d6) 5 8.30 (s, 1H), 7.90-7.93 (m, 2H), 7.74-7.88 (m, 4H), 7.10-7.14(m, 1H), 6.83-6.85 (m, 1H), 6.49 (s, 1H), 5.51 (s, 2H), 4.84 (m, 2H), 4.55 (m, 2H), 3.5-3.9 (m, 9H), 3.24(s, 4H)

Example 19 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)- 1 H-benzo [d] imidazole-6-carboxylic acid

Step 1 Methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6 a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 3-fluoro-4-(((6-(l,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrol-5-yl)pyridin-2-yl)oxy)methyl)be nzonitrile bis(4- methylbenzenesulfonate) and methyl 2-(chloromethyl)-l-((l-ethyl-lH-imidazol-5- yl)methyl)-lH-benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-((l-ethyl-lH-imidazol-5-yl)methyl)-lH-benzo[d]i midazole-6-carboxylate (35 mg, 25.1% yield). Mass [M+H]+ = 632.5

Step-2:

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylicacid

Procedure same as written in step 10 in Example 20 using methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l -((1 -ethyl-lH-imidazol-5-yl)methyl)-lH-benzo[d]imidazole-6-carbo xylate to obtain2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3, 3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2( l H)-yl)methyl)-l -(( l -ethyl- l H-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid (15 mg, 43.8% yield). Mass [M+H]+ = 618.5 'H-NMR (400 MHz, DMSO-d6) 5 8.04 (m, 2H), 7.89-7.91 (m, 1H), 7.79 (m, 1H), 7.6- 7.72(m, 3H), 7.50 (m, 1H), 7.01-7.05 (m, 1H), 6.76-6.79 (m, 1H), 6.41 (s, 2H), 5.66 (s, 2H), 5.49 (s, 2H), 3.84(s, 2H), 3.70-3.76(m, 2H), 3.3(m, 4H), 2.9(m, 2H), 1.86-1.89(m,

2H), 0.84-0.91(m, 3H)

Example 20

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Step 1

Preparation of 5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,3a,4, 6a- hexahydrocyclopenta[c]pyrrolebis(4-methylbenzenesulfonate)

Intermediate was synthesized as per procedure given in step 8 Example 1. Step 2

Methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4, 6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,3a,4,6a hexahydrocyclopenta[c]pyrrolebis(4- methylbenzenesulfonate) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylate (100 mg, 57.1 % yield). Mass [M+H]+ = 603.3

Step-3

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Procedure same as written in step 2 in Example 5 using methyl 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylate to obtain 2- ((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a - tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid ( 85mg, 70.3 % yield. Mass [M+H]+ = 589.

'H-NMR (400 MHz, DMSO-d6) 5 8.23 (s, 1H), 7.5-7.9 (m, 5H), 7.3 (m, 1H), 7.03- 7.10(m, 1H), 6.74 (m, 1H), 6.44-6.49 (m, 1H), 5.4 (s, 2H), 4.98 (m, 1H), 4.67(m, 1H), 4.48(m, 1H), 4.24-4.26(m, 2H), 4.08(m, 1H), 3.48(m, 1H), 2.95-3.04(m, 2H), 2.51- 2.73(m, 5H), 2.33-2.49(m, 3H)

Example 21

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylic acid

Step 1

Methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4, 6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-l,2,3,3a,4,6a-hexahydrocyclop enta[c]pyrrolebis(4- methylbenzenesulfonate) and methyl 2-(chloromethyl)-l-((l-ethyl-lH-imidazol-5- yl)methyl)-lH-benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l-((l-ethyl-lH-imidazol-5-yl)methyl)-lH-benzo[d]i midazole-6-carboxylate (44 mg, 33.8% yield). Mass [M+H]+ = 641.2

Step-2:

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a ,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylic acid

Procedure same as written in step 2 in Example 5 using methyl 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopent a[c]pyrrol-2(lH)- yl)methyl)-l -((1 -ethyl-lH-imidazol-5-yl)methyl)-lH-benzo[d]imidazole-6-carbo xylate to obtain 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4, 6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid (25mg, 58.1% yield. Mass [M+H]+ = 627.2 'H-NMR (400 MHz, DMSO-d6) 5 8.06 (s, 1H), 7.82 (d, J=1.6Hz, 1H), 7.67-7.71 (m, 2H), 7.57(m, 2H), 7.45-7.48 (m, 1H), 7.3 (m, 1H), 7.02(m, 1H), 6.74(d, J=8.0Hz, 1H), 6.45(d, J=2.8Hz, 2H), 5.68 (s, 2H), 5.40 (s, 2H), 3.88(m, 2H), 3.77(m, 2H), 3.32-3.39(m, 2H), 2.90(m, 2H), 2.58-2.67(m, 4H), 0.89-0.93(t, J=7.2Hz, 3H)

Example 22

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Step 1

Preparation of 3-fluoro-4-(((2-(l ,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5- yl)pyrimidin-4-yl)oxy)methyl)benzonitrilebis(4-methylbenzene sulfonate)

Intermediate was synthesized as per procedure given in step 8 Example 1.

Step 2

Methyl 2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3 a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 3-fluoro-4-(((2-(l,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrol-5-yl)pyrimidin-4-yl)oxy)methyl) benzonitrilebis(4- methylbenzenesulfonate) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(4-((2-fluoro-4- isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2(lH)- yl)methyl)-l -(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylat e (80 mg, 61.1 % yield).

Step-3

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylicacid

Procedure same as writen in step 10 in Example 1 using methyl 2-((5-(4-((2-fluoro-4- isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2(lH)- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylate to obtain 2- ((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid (20 mg, 25% yield. Mass [M-H] = 579.4 'H-NMR (400 MHz, DMSO-d6) 5 8.53 (m, 1H), 8.16 (m, 1H), 7.91-8.0 (m, 4H), 7.73(m, 2H), 6.76 (m, 1H), 5.53 (s, 2H), 4.94-4.97(m, 1H), 4.58(m, 1H), 4.44(m, 1H), 4.25 (m, 1H), 4.07-4.10 (m, 2H), 3.49(m, 7H), 3.00(m, 2H), 2.33-2.38(m, 2H)

Example 23

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylic acid Step 1

Methyl 2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3 a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(2-methoxye thyl)-lH- benzo[d]imidazole-6-carboxylate

Procedure same as written in step 9 in Example 20 using 3-fluoro-4-(((2-(l,2,3,3a,4,6a- hexahydrocyclopenta[c]pyrrol-5-yl)pyrimidin-4-yl)oxy)methyl) benzonitrilebis(4- methylbenzenesulfonate) and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH- benzo[d]imidazole-6-carboxylate to obtain methyl 2-((5-(4-((2-fluoro-4- isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2(lH)- yl)methyl)-l -(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylat e(76 mg, 59.2 % yield).

Step-3

2-((5-(4-((2-fluoro-4-isocyanobenzyl)oxy)pyrimidin-2-yl)- 3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylicacid

Procedure same as written in step 10 in Example 20 using methyl 2-((5-(4-((2-fluoro-4- isocyanobenzyl)oxy)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclo penta[c]pyrrol-2(lH)- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylate to obtain 2- ((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-((l-ethyl-l H-imidazol-5-yl)methyl)- lH-benzo[d]imidazole-6-carboxylic acid (20 mg, 27.5 % yield. Mass [M+H]+ = 569 'H-NMR (400 MHz, DMSO-d6) 5 12.73(s, 1H), 8.49 (d, J=5.6Hz,lH), 8.12 (s, 1H), 7.74- 7.79 (m, 3H), 7.62(d, J=8.4Hz, 1H), 6.83 (d, J=5.6Hz, 1H), 6.72 (d, J=2.0Hz, 1H), 5.54(s, 2H), 4.42(m, 2H), 3.92-3.95(m, 1H), 3.81-3.85 (m, 1H), 3.33-3.48 (m, 4H), 2.96-3.00(m, 4H), 2.63-2.68(m, 4H), 1.34(s, 2H)

Example 24

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2- yl)-3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Step 1:

Synthesis of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl) -

3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)- l-(((S)-oxetan-2-yl)methyl)-

1 H-benzo [d] imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 20 by using 2- (6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tetra hydropyrrolo[3,4-c]pyrazole 4-methylbenzenesulfonate (90 mg, 0.123 mmol), K2CO3 (85 mg, 0.613 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (43.4 mg, 0.147 mmol) to obtained methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5- fluoropyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol- 2(lH)-yl)methyl)-l-(((S)- oxetan-2-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (70 mg, yield 66 %) Mass m/z 612.5 [M+H] ⁺ Step 2:

Synthesis of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl) -3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 Example 20 by using methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyridin-2-yl) -3,3a,4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate (70 mg, 0.114 mmol) and l,3,4,6,7,8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (32 mg, 0.227 mmol) to obtained 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)-5-fluoropyridin-2-yl)-3,3a,4,6a-tetrahydro cyclopenta[c]pyrrol-2(lH)- yl)methyl)-l-(((S)-oxetan-2-yl)methyl)-lH-benzo[d]imidazole- 6-carboxylic acid (20 mg, yield 29 %) Mass m/z 598.4 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 12.5(br s, 1H), 8.2(s,lH),7.93-7.90(d, J=10Hz,lH), 7.80-7.78(d, J=8.4Hz,lH), 7.73-7.62(m, 4H),7.32-7.14(d,J=5.2Hz,lH) 6.39-

6.36(d,J=13.6Hz,lH),5.5(s,2H),4.96-4.44(m, 3H),4.27-4.02(m,2H), 3.45(s,2H), 3.17 - 2.20(m,9H) 1.34(s,lH) Synthesis of intermediate 10

Benzyl 5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate bis(4- methylbenzenesulfonate) Step 1:

Preparation of 2-benzyl 5 -(tert- butyl) pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate

Cbz

To a cooled solution of sodium hydride (0.287 g, 7.17 mmol) in THF (20 ml), solution of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (1 g, 4.78 mmol) in THF was added lot wise and stir for 5 min. Then benzyl chloroformate (1.501 ml, 5.26 mmol) was added and reaction mixture stirred at room temperature for 1 hrs. Water was added and extracted with ethyl acetate and purified by column with 0 to 20% ethyl acetate in hexane to get 2-benzyl 5-(tert-butyl) pyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate (1.2 g, 73.1 % yield). Step 2:

Preparation of benzyl 5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate bis(4- methylbenzenesulfonate) To a cooled solution of 2-benzyl 5 -(tert-butyl) pyrrolo[3,4-c]pyrazole-2,5(4H,6H)- dicarboxylate (100 mg, 0.291 mmol) in ethyl acetate (2 ml), para-toluenesulfonic acid was added and reaction mixture was stirred at reflux for 3 to 4 hrs. Removed the solvent and oily residue was stirred in diethylether and solution was decanted to obtained benzyl 5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate bis(4-methylbenzenesulfonate) (120 mg, 70.1% yield).

Synthesis of Intermediate 11

4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin -2-yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate)

Step 1

Preparation of tert-butyl 2-(6-chloropyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-

5(4H)-carboxylate

To a solution of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (1.41 g, 6.76 mmol) in DMF (25 ml), 2,6-dichloropyridine (1.0 gm, 6.76 mmol) and CS2CO3 (3.26 g, 16.89 mmol) mmol were added. The reaction mixture was stirred at 85°C for 20 hrs, Reaction mixture was quenched by adding reaction mixture to water. Product was extracted with ethyl acetate. Solvent was dried over sodium sulphate and evaporated. Compound was purified by column chromatography to obtain tert-butyl 2-(6- chloropyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (900 mg, 41.5 % yield). Mass m/z 321.1 [M+H] ⁺ Step 2

Preparation of tert-butyl 2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

To a clear solution of tert-butyl 2-(6-chloropyridin-2-yl)-2,6-dihydropyrrolo[3,4- c]pyrazole-5(4H)-carboxylate (0.1 g, 0.312 mmol) in toluene (1.5 ml) . Degassed it with N2 balloon. 3-fhioro-4-(hydroxymethyl)benzonitrile (49.5 mg, 0.327 mmol), CS2CO3 (259 mg, 0.795 mmole), Johnphos (11 mg, 0.038 mmole) and Pd2(dba)s (17 mg, 0.019 mmol) was added in to it at 25°C. Again degassed it. Reaction mass was stirred at preheated 110-120°C for 16 hrs. Product was diluted with ethyl acetate (15 ml) and filter the solid. Evaporate the solvent under reduced pressure and product was purified by column chromatography to tert-butyl 2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)- 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (80 mg, 59 % yield). Mass m/z 436.1 [M+H] ⁺

Step 3

Preparation of 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile bis(4-methylbenzenesulfonate)

To a tert-butyl 2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydrop yrrolo[3,4- c]pyrazole-5(4H)-carboxylate)(195 mg, 0.448 mmol) in ethyl acetate (3.8 ml) were added 4-methylbenzenesulfonic acid hydrate (230 mg, 1.209 mmol) and reaction mixture was stirred at 60 °C for 2 hrs. After completion of reaction, solvent was removed under vaccuum to obtain 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile bis(4-methylbenzenesulfonate) (250 mg, 82% yield). Mass m/z 335 [M+H] ⁺

Synthesis of Intermediate 12 2-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,4,5,6-te trahydropyrrolo[3,4- c]pyrazole bis(2,2,2-trifluoroacetate)

Step 1

Preparation of tert-butyl 2-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using tert-butyl 2-(6-chloropyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5 (4H)- carboxylate and (5-chloropyridin-2-yl)methanol to obtained tert-butyl 2-(6-((5- chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,6-dihydropyrrolo[ 3,4-c]pyrazole-5(4H)- carboxylate Mass m/z 428.2 [M+H] ⁺

Step 2

Preparation of 2-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazole bis(2,2,2-trifluoroacetate)

To a solution of tert-butyl 2-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (60 mg, 0.140 mmol) in DCM (2.5 ml) was added TFA (0.108 ml, 1.402 mmol) and reaction mixture was stirred at RT for 6 hr. After completion of reaction, solvent was removed and stirred solid in diethyl ether and filtered and dried to obtained 2-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)-2, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazole bis(2,2,2-trifluoroacetate) (75 g, yield = 96%) Mass m/z 328.2 [M+H] ⁺

Synthesis of Intermediate 13 6-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)nicotinonitrile bis(2,2,2-trifluoroacetate)

Step 1

Preparation of tert-butyl 2-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using tert-butyl 2-(6-chloropyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5 (4H)- carboxylate and 6-(hydroxymethyl)nicotinonitrile to obtained tert-butyl 2-(6-((5- cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,6-dihydropyrrolo[3 ,4-c]pyrazole-5(4H)- carboxylate Mass m/z 419.3 [M+H] ⁺

Step 2

Preparation of 6-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)nicotinonitrile bis(2,2,2-trifluoroacetate)

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using tert-butyl 2-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate to obtained 6-(((6-(5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2-yl)oxy)methy l)nicotinonitrile bis(2,2,2- trifluoroacetate) Mass m/z 319.2 [M+H] ⁺

Synthesis of Intermediate 14

2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,4,5, 6-tetrahydropyrrolo[3,4- c]pyrazole bis(4-methylbenzenesulfonate

Step 1

Preparation of tert-butyl 2-(2-chloropyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole - 5(4H)-carboxylate Boc

Title compound was synthesized as per procedure given in step 1 of intermediate 11 by using tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate and 2,4- dichloropyrimidine to obtained tert-butyl 2-(2-chloropyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate Mass m/z 322.2 [M+H] ⁺ Step 2

Preparation of tert-butyl 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using tert-butyl 2-(2-chloropyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole -5(4H)- carboxylate and (4-chloro-2-fluorophenyl)methanol to obtained tert-butyl 2-(2-((4- chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrrolo [3,4-c]pyrazole-5(4H)- carboxylate Mass m/z 446.2 [M+H]+

Step 3

Preparation of 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazole bis(4-methylbenzenesulfonate)

Title compound was synthesized as per procedure given in step 3 of intermediate 11 by using tert-butyl 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate to obtained 2-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-2,4,5,6-tetrahydropyrrolo[3 ,4-c]pyrazole bis(4- methylbenzenesulfonate) Mass m/z 346.1 [M+H] ⁺

Synthesis of Intermediate 15

4-(((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimid in-2-yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate)

Step 1

Preparation of tert-butyl 2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using tert-butyl 2-(2-chloropyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]pyrazole -5(4H)- carboxylate and 3-fluoro-4-(hydroxymethyl)benzonitrile to obtained tert-butyl 2-(2-((4- cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrrolo[ 3,4-c]pyrazole-5(4H)- carboxylate Mass m/z 437.2 [M+H]+

Step 2

Preparation of 4-(((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimidin- 2- yl)oxy)methyl)-3-fluorobenzonitrile bis(4-methylbenzenesulfonate)

Title compound was synthesized as per procedure given in step 3 of intermediate 11 by using tert-butyl 2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate to obtained 4-(((4-(5,6- dihydropyrrolo [3, 4-c]pyrazol-2(4H)-yl)pyrimidin-2-yl)oxy)methyl)-3 -fluorobenzonitrile bis(4-methylbenzenesulfonate) Mass m/z 337.1 [M+H] ⁺

Synthesis of Intermediate 16

5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6- tetrahydropyrrolo[3,4- c]pyrazole trihydrobromide

Preparation of benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)- carboxylate

Title compound was synthesized as per procedure given in step 1 of intermediate 11 by using benzyl 5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate and 2,6- dichloropyridine to obtained benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4- c]pyrazole-2(4H)-carboxylate Mass m/z 355.2 [M+H] ⁺ Step 2

Preparation of benzyl 5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 12 by using benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)- carboxylate and (4-chloro-2-fluorophenyl)methanol to obtained benzyl 5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zole-2(4H)-carboxylate Mass m/z 479 [M+H] ⁺

Step 3

Preparation of 5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6- tetrahydropyrrolo[3,4-c]pyrazole trihydrobromide

To a cooled solution of benzyl 5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate (350 mg, 0.731 mmol) in AcOH (4 ml) was added 33% hydrobromic acid in acetic acid (0.962 ml, 5.85 mmol) and reaction mixture stirred at RT for 18 hr. After completion of reaction, acetic acid was removed solvent and solid stirred in diethyl ether filtered and dried to obtained (Yield: 300 mg, 70%). Mass m/z 345 [M+H] ⁺ Synthesis of Intermediate 17

4-(((6-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)pyridin -2-yl)oxy)methyl)-3- fluorobenzonitrile trihydrobromide

Step 1

Preparation of benzyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate

Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2 (4H)- carboxylate and 3-fluoro-4-(hydroxymethyl)benzonitrile to obtained benzyl 5-(6-((4- cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3, 4-c]pyrazole-2(4H)- carboxylate Mass m/z 470.2 [M+H] ⁺

Step 2

Preparation of 4-(((6-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile trihydrobromide

Title compound was synthesized as per procedure given in step 3 of intermediate 11 by using benzyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydrop yrrolo[3,4- c]pyrazole-2(4H)-carboxylate to obtained 4-(((6-(2,6-dihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile trihydrobromide Mass m/z 336.1 [M+H] ⁺

Synthesis of Intermediate 18

4-(((6-(4,6-dihydropyrrolo[3 ,4-c] pyrazol-5 ( 1 H)-yl)pyridin-2-yl)oxy)methyl)-3 - fluorobenzonitrile trihydrobromide

Step 1

Preparation of benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole-l (decarboxylate Cbz

Title compound was synthesized as per procedure given in step 1 of intermediate 11 by using benzyl 5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-carboxylate bis(2,2,2- trifluoroacetate) and 2,6-dichloropyridine to obtained benzyl 5-(6-chloropyridin-2-yl)- 5,6-dihydropyrrolo[3,4-c]pyrazole-l(4H)-carboxylate. Mass m/z 355.2 [M+H] ⁺ Step 2

Preparation of benzyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazole-l(4H)-carboxylate Title compound was synthesized as per procedure given in step 2 of intermediate 11 by using benzyl 5-(6-chloropyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazole- l (4H)- carboxylate

3-fluoro-4-(hydroxymethyl)benzonitrile to obtained benzyl 5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zole-l(4H)-carboxylate

Mass m/z 470.2 [M+H] ⁺

Step 3

Preparation of 4-(((6-(4,6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile trihydrobromide

Title compound was synthesized as per procedure given in step 3 of intermediate 11 by using benzyl 5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydrop yrrolo[3,4- c]pyrazole-l(4H)-carboxylate to obtained 4-(((6-(4,6-dihydropyrrolo[3,4-c]pyrazol- 5(lH)-yl)pyridin-2-yl)oxy)methyl)-3-fluorobenzonitrile trihydrobromide Mass m/z 336.1 [M+H] ⁺

Example 25

(S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2 ,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid Step 1:

Preparation of methyl (S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin -2-yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methyl benzenesulfonate) (52 mg, 0.077 mmol) and methyl (S)-2- (chloromethyl)-l -(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (25 mg, 0.085 mmol) was dissolved in acetonitrile (2 ml) and potassium carbonate (46.9 mg, 0.339 mmol) was added to it and reaction mixture was heated to 60 °C was heated overnight. After completion of reaction, solvent was evaporated and crude material was purified by combi flash to obtain methyl (S)-2-((2-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (45 mg, 0.076 mmol, 98 % yield). Mass 594 [M+H] ⁺ Step 2:

Synthesis of (S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid To a solution of methyl (S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate (45 mg, 0.076 mmol) in ACN (1 ml) aqueous solution of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (0.152 mmol) was added, at RT and stirred for 20 hrs. After completion of reaction, solvent was evaporated and charged 10% citric acid solution till pH 6 to 6.5 and solid was filtered and wash with water and dry to obtain (S)-2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid (5 mg, 12% yield). Mass 579 [M+H] ⁺

'H-NMR (400 MHz, DMSO-d6) 5 12.76.00 (s, 1H), 8.17 (s,lH), 8.37 (s, 1H), 7.89-7.92 (m,3H), 7.47-7.51 (m, 4H), 6.81-6.83 (d, 1H), 5.37 (s, 2H), 5.06-5.07 (d, 1H), 4.62-4.64 (m, 2H), 4.68-4.70 (m, 4H), 3.83-3.85 (m, 4H), 2.54-2.72 (m, 2H)

Example 26

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo-imidazole-6-car boxylic acid

Preparation of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH-benzo- imidazole-6-carboxylate

4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin -2-yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (90 mg, 0.132 mmol) and methyl 2- (chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-car boxylate (37.4 mg, 0.132 mmol) was dissolved in Acetonitrile (2 ml) and potassium carbonate (73.2 mg, 0.530 mmol) was added to it and reaction mixture was heated to 60 °C for overnight. After completion of reaction, solvent was evaporated and crude material was purified by combi flash to methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH-benzo- imidazole-6-carboxylate (68 mg, 0.117 mmol, 88 % yield). Mass 582 [M+H] ⁺ Step 2:

Synthesis of 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH-benzo- imidazole-6-carboxylic acid

To a solution of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate (43 mg, 0.074 mmol) acetonitrile (1 ml) was added in aq solution of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (0.0205 g, 0.147 mmol) at room temperature and stirred for 20 hrs. After completion of reaction, solvent was evaporated and charged 10% citric acid solution till pH 6 to 6.5 and solid was filtered and wash with water and dry to obtain 2-((2-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-l-(2- methoxyethyl)-lH-benzo-imidazole-6-carboxylic acid (6 mg, 10.57 mmol, 14% yield). Mass 568 [M+H] ⁺

'H-NMR (400 MHz, DMSO-d6) 5 12.76.00 (s, 1H), 8.17 (s,lH), 8.37 (s, 1H), 7.89-7.91 (m,3H), 7.66-7.70 (m,3H) 7.47-7.51 (m,4H), 6.81-6.83 (d, 1H), 5.37 (s, 2H), 5.06-5.07 (d, 1H), 4.62-4.64 (m, 2H), 4.29-4.31 (m, 4H),3.33 (s, 3H)

Example 27

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4-c]pyrazol-

5(4H)-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5-b]pyri dine-5-carboxylic acid

Step 1:

Synthesis methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-3-(2-methoxyet hyl)-3H-imidazo[4,5- b]pyridine-5-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 4- (((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2-yl )oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (90 mg, 0.132 mmol), K2CO3 (73.2 mg, 0.530 mmol) and methyl 2-(chloromethyl)-3-(2-methoxyethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylate (41.3 mg, 0.146 mmol) to obtained methyl 2-((2-(6-((4-cyano- 2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]py razol-5(4H)-yl)methyl)-3- (2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (25 mg, yield 32 %) Mass m/z 583.4 [M+H] ⁺

Step 2:

Synthesis of 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-3-(2-methoxyet hyl)-3H-imidazo[4,5- b]pyridine-5-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 29 by using methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihy dropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-3-(2-methoxyethyl)-3H-imidazo[4,5 -b]pyridine-5- carboxylate (20 mg, 0.034 mmol) and 1 l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (16.73 mg, 0.120 mmol) to obtained 2-((2-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-3-(2- methoxyethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (12 mg, yield = 62 %) Mass m/z = 569.4 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 13.00 (bs, 1H), 8.32 (s, 1H), 8.14-8.16 (d, J= 8.4 Hz, 1H), 7.99-8.01 (d, J= 8.4 Hz, 1H), 7.85-7.94 (m, 2H), 7.72-7.80 (m, 2H), 7.39-7.41 (d, J= 8.0 Hz, 1H), 6.78-6.80 (d, J= 8 Hz, 1H), 5.57 (s, 2H), 4.62-4.65 (t, 2H), 4.39 (s, 2H), 3.91-3.94 (m, 4H), 3.76-3.78 (t, 2H), 3.24 (s, 3H)

Example 28

(2-((2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2 ,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylic acid

Step 1: Synthesis of methyl 2-((2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,4,5,6-t etrahydropyrrolo[3,4- c]pyrazole bis(4-methylbenzenesulfonate) (100 mg, 0.145 mmol), K2CO3 (100 mg, 0.724 mmol) and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6- carboxylate (41.0 mg, 0.145 mmol) to obtained methyl 2-((2-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]py razol-5(4H)-yl)methyl)-l- (2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate (25 mg, yield 29 %) Mass m/z 592.3 [M+H] ⁺ Step 2:

Synthesis of (2-((2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid

This compound was synthesized as per procedure given in step 2 Example 29 by using methyl 2-((2-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-d ihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylate (25 mg, 0.042 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (11.75 mg, 0.084 mmol) to obtained 8 mg (yield = 33 %) Mass m/z = 578.3 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 8.61-8.62 (d, J= 5.6 Hz, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.80-7.82 (d, J= 7.6 Hz, 1H), 7.61-7.66 (m, 2H), 7.46-7.53 (m, 2H), 7.33-7.35 (d, J= 8 Hz, 1H), 5.48 (s, 2H), 4.59-4.61 (t, 2H), 4.33 (s, 2H), 3.93 (s, 2H), 3.86 (s, 2H), 3.68- 3.70 (t, 2H), 3.19 (s, 3H)

Example 29

(S)-2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl) -2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid

Synthesis of (methyl (S)-2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2, 6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 4-(((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimidin- 2-yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (100 mg, 0.147 mmol), K2CO3 (102 mg, 0.735 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (43.3 mg, 0.147 mmol) to obtained methyl (S)-2-((2-(2- ((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrr olo[3,4-c]pyrazol-5(4H)- yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylate (25 mg, yield 29 %) Mass m/z 595.4 [M+H] ⁺ Step 2:

Synthesis of (S)-2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2, 6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 29 by using methyl (S)-2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2, 6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate (25 mg, 0.042 mmol) and l,3,4,6,7,8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (17.56 mg, 0.126 mmol) to obtained (S)-2-((2-(2-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrrolo[3,4-c]py razol-5(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (8 mg, yield 33 %) Mass m/z 581.4 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 8.62-8.63 (d, J= 5.6 Hz, 1H), 8.37 (s, 1H), 8.25 (s, 1H), 7.93-7.95 (d, J= 9.6 Hz, 1H), 7.74-7.82 (m, 3H), 7.64-7.66 (d, J= 8.4 Hz, 1H), 7.47- 7.49 (d, J= 5.2 Hz, 1H), 5.58 (s, 2H), 5.06-5.07 (d, J= 4.8Hz, 1H), 4.62-4.82 (m, 2H), 4.29-4.50 (m, 4H), 3.83-3.98 (m, 4H), 2.50-2.72 (m, 2H)

Example 30

2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-d ihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d ]imidazole-6-carboxylic acid

Step 1:

Synthesis of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (90 mg, 0.132 mmol), K2CO3 (91 mg, 0.662 mmol) and methyl 2-(chloromethyl)-l -((3 -methoxy oxetan-3 -yl)methyl)-lH- benzo[d]imidazole-6-carboxylate (43.0 mg, 0.132 mmol) to obtained methyl 2-((2-(6-((4- cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3, 4-c]pyrazol-5(4H)- yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d]imida zole-6-carboxylate (55 mg, yield 66 %) Mass m/z 624.1 [M+H] ⁺ Step 2:

Synthesis of 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

This compound was synthesized as per procedure given in step 2 Example 29 by using methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihy dropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH-benzo[d]imidazole-6- carboxylate (50 mg, 0.080 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (33.5 mg, 0.241 mmol) to obtained 2-((2-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-l- ((3 -methoxy oxetan-3-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid (18 mg, yield = 37 %) Mass m/z = 610.1 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 12.80 (bs, 1H), 8.29 (s, 1H), 8.34 (s, 1H), 7.72-7.93 (m, 4H), 7.72-7.74 (d, J= 8.0 Hz, 1H), 7.66-7.68 (d, J= 8.4 Hz 1H), 7.39-7.41 (d, J= 8.0 Hz, 1H), 6.78-6.80 (d, J= 8.0 Hz, 1H), 5.56 (s, 2H), 4.95 (s, 2H), 4.69-4.71 (d, J= 7.6 Hz, 2H), 4.50-4.52 (d, J= 7.6 Hz, 2H), 4.36 (s, 2H), 3.87-3.91 (s, 4H), 3.43 (s, 3H)

Example 31

(S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid Step 1:

Synthesis of methyl (S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6 - dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 2- (6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tetra hydropyrrolo[3,4-c]pyrazole 4-methylbenzenesulfonate (150 mg, 0.290 mmol), K2CO3 (201 mg, 1.451 mmol) and methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidaz ole-6-carboxylate (86 mg, 0.290 mmol) to obtained methyl (S)-2-((2-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (84 mg, yield 48 %) Mass m/z 603.1 [M+H] ⁺ Step 2:

Synthesis of (S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6 - dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 29 by using methyl (S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6 -dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylate (84 mg, 0.139 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (40.3 mg, 0.290 mmol) to obtained (S)-2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6 - dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic (35 mg, yield 42 %) Mass m/z 589 [M+H] ⁺

'H-NMR (400 MHz, DMSO-d6) 5 12.83(bs, 1H), 8.35 (s, 1H), 8.27 (s, 1H), 7.85-7.87 (m, 2H), 7.51-7.59(m, 2H), 7.4-7.48 (m, 1H), 7.34-7.38 (m, 1H), 7.32(m, 2H), 6.74(s, 1H), 5.47-5.76(m, 3H), 4.04(m, 1H), 3.87-3.85 (m, 4H)

Example 32

2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylic acid

Step 1:

Synthesis of methyl 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 2- (6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tetra hydropyrrolo[3,4-c]pyrazole 4-methylbenzenesulfonate (150 mg, 0.290 mmol), K2CO3 (201 mg, 1.451 mmol) and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylate (82 mg, 0.290 mmol) to obtained methyl 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2- yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l -(2-methoxy ethyl)- 1H- benzo[d]imidazole-6-carboxylate (113 mg, yield 66 %) Mass m/z 591.1 [M+H] ⁺ Step 2:

Synthesis of 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 29 by using methyl 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dih ydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylate (113 mg, 0.191 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (55.4 mg, 0.398 mmol) to obtained 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid (50 mg, yield 45 %) Mass m/z 577.1 [M+H] ⁺ 'H-NMR (400 MHz, DMSO-d6) 5 12.64(bs, 1H), 8.35 (s, 1H), 8.20-8.23 (m, 2H), 7.83- 7.86(m, 2H), 7.60-7.71 (m, 4H), 6.74(d, J=8.0Hz, 1H), 5.47 (s, 2H), 4.61 (s, 2H), 4.34(s, 2H), 3.88-3.92(s, 4H), 3.69-3.71(m, 1H), 3.14-3.26(s, 3H)

Example 33

2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d ]imidazole-6-carboxylic acid Step 1:

Synthesis of methyl 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 29 by using 2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tet rahydropyrrolo[3,4- c]pyrazole 4-methylbenzenesulfonate (150 mg, 0.290 mmol), K2CO3 (201 mg, 1.451 mmol) and methyl 2-(chloromethyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate (94 mg, 0.290 mmol) to obtained methyl 2-((2-(6-((4- chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3 ,4-c]pyrazol-5(4H)- yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d]imida zole-6-carboxylate (105 mg, yield 57 %) Mass m/z 633.1 [M+H] ⁺ Step 2:

Synthesis of 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 29 by using methyl 2-((2-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dih ydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)- lH-benzo[d]imidazole-6- carboxylate (105 mg, 0.166 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (48 mg, 0.345 mmol) to obtained 2-((2-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3,4-c]pyra zol-5(4H)-yl)methyl)-l-

((3 -methoxy oxetan-3-yl)methyl)-lH-benzo[d]imidazole-6-carboxylic acid

(30 mg, yield 29 %) Mass m/z 619 [M+H] ⁺

'H-NMR (400 MHz, DMSO-d6) 5 12.83(bs, 1H), 8.34 (s, 2H), 7.84-7.86 (m, 2H), 7.48- 7.51(m, 2H), 7.38-7.40 (m, 2H), 7.31-7.34(m, 2H), 6.73-6.75(m, 1H), 5.46 (s, 2H), 4.96 (s, 1H), 4.69-4.71(m, 2H), 4.50(d, J=7.6Hz, 2H), 4.37(s, 2H), 3.88-3.92(m, 4H), 3.26- 3.43(m, 3H)

Example 34

(S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5 ,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid

Step 1:

Preparation of methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate.

To a solution of 4-(((6-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)pyridin-2- yl)oxy)methyl)-3-fluorobenzonitrile trihydrobromide (30 mg, 0.052 mmol) in acetonitrile (2 ml) were added methyl (S)-2-(chloromethyl)-l-(oxetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (15.30 mg, 0.052 mmol) and potassium carbonate (43.0 mg, 0.311 mmol) and reaction mixture was stirred at 60 ° for 3 hrs. After completion of reaction, diluted with water and extracted with ethyl acetate and purified by column with 0 to 90 % ethyl acetate in hexane to obtain methyl (S)-2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zol-2(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate ( 10 mg, 33% yield). Mass 594 [M+H] ⁺

Step 2:

Preparation of (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid

To a solution of methyl (S)-2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate (10 mg, 0.017 mmol) in acetonitrile (2 ml) was added aqueous solution of l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (4.69 mg, 0.034 mmol) at room temperature and stirred for 20 hrs. After completion of reaction, solvent was removed and charged 10 % citric acid solution till pH 6 to 6.5 and solid was filtered and wash with water and dry to obtain (S)-2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zol-2(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (4 mg, 41% yield). Mass 580 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1H), 8.24 (s, 1H), 7.72-7.93 (m, 5H), 7.66 (s, 1H), 7.39-7.41 (d, J= 8.0 Hz 1H), 6.78-6.80 (d, J= 8.0 Hz, 1H), 5.57 (s, 2H), 5.01 (s, 2H), 4.79 (s, 2H), 4.29-4.66 (m, 3H), 3.65-3.90 (m, 4H), 2.50-5.72 (m, 2H) Example 35

(S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid compound with 2,2,2-trifluoroacetic acid

Step 1:

Synthesis of methyl (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6 - dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 38 by using 5- (6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tetra hydropyrrolo[3,4-c]pyrazole trihydrobromide (100 mg, 0.170 mmol), K2CO3 (118 mg, 0.851 mmol) and methyl (S)-2- (chloromethyl)-l -(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (50.2 mg, 0.170 mmol) and to obtained methyl (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin- 2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(o xetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (25 mg, yield 24 %) Mass m/z 603 [M+H] ⁺ Step 2:

Synthesis of (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6 - dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid compound with 2,2,2-trifluoroacetic acid

Title compound was synthesized as per procedure given in step 2 Example 38 by using methyl (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6 -dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylate (20 mg, 0.033 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (13.85 mg, 0.099 mmol) to obtained (S)-2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(oxetan- 2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1.8 mg, yield 8 %) Mass m/z 589 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 13.00 (bs, 1H), 8.47 (s, 1H), 8.33-8.35 (d, J= 8.0 Hz, 1H), 7.89-7.91 (d, J= 7.6 Hz 1H), 7.87 (s, 1H), 7.75-7.77 (d, J= 8.0 Hz 1H), 7.63-7.65 (d, J= 8.4 Hz, 1H), 7.50-7.52 (d, J= 8.0 Hz, 1H), 7.42-7.44 (d, J= 8.0 Hz, 1H), 7.33-7.35 (d, J= 7.6 Hz, 1H), 6.80-6.82 (d, J= 7.6 Hz, 1H), 5.48 (s, 2H), 5.06-5.07 (d, J = 5.2Hz, 1H), 4.88-4.92 (m, 2H), 4.77-4.82 (m, 2H), 4.29-4.67 (m, 6H), 2.67-2.75 (m, 1H), 2.30-2.45 (m, 1H)

Example 36

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol- 2(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylic acid

Step 1:

Synthesis of methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 38 by using 5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tet rahydropyrrolo[3,4- c]pyrazole trihydrobromide (100 mg, 0.170 mmol), K2CO3 (118 mg, 0.851 mmol) and methyl 2-(chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-c arboxylate (57.7 mg, 0.204 mmol) to obtained methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2- yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l -(2-methoxy ethyl)- 1H- benzo[d]imidazole-6-carboxylate (25 mg, yield 25 %) Mass m/z 591 [M+H] ⁺ Step 2:

Synthesis of 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 38 by using methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dih ydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylate (20 mg, 0.034 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (14.13 mg, 0.102 mmol) to obtained 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid (4 mg, yield = 17 %) Mass m/z = 577 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 13.03 (bs, 1H), 8.57 (s, 1H), 8.42 (s, 1H), 7.90-8.05 (m, 2H), 7.7534-7.77 (m, 5H), 6.83 (s, 1H), 5.48 (s, 2H), 4.91 (s, 2H), 4.06-4.61 (m, 6H), 3.81 (s, 3H), 3.22 (s, 2H)

Ill Example 37

2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-

2(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benz o[d]imidazole-6-carboxylic acid

Step 1:

Synthesis of methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 38 by using 5- (6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-2,4,5,6-tetra hydropyrrolo[3,4-c]pyrazole trihydrobromide (40 mg, 0.068 mmol), K2CO3 (37.59 mg, 0.272 mmol) and methyl 2- (chloromethyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d]i midazole-6-carboxylate (22 mg, 0.068 mmol) to obtained methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin- 2-yl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-(( 3-methoxyoxetan-3- yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (20 mg, yield 46 %) Mass m/z 633 [M+H] ⁺ Step 2:

Synthesis of 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 38 by using methyl 2-((5-(6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dih ydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)- 1 -((3 -methoxy oxetan-3 -yl)m ethyl)- 1 H-benzo [d] imidazole-6- carboxylate (20 mg, 0.032 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (13.19 mg, 0.095 mmol) to obtained 2-((5-(6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zol-2(4H)-yl)methyl)-l- ((3 -methoxyoxetan-3-yl)methyl)-l H-benzo [d]imidazole-6-carboxylic acid (3.5 mg, yield = 15 %) Mass m/z = 619 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 5 12.92 (s, 1H), 8.61 (s, 1H), 8.58 (s, 1H), 7.90 (s, 1H), 7.86-7.88 (d, J= 8.8 Hz 1H), 7.32-7.79 (m, 5H), 6.81-6.83 (d, J= 8.8 Hz, 1H), 5.48 (s, 2H), 4.95 (s, 2H), 4.61-4.74 (m, 4H), 4.51-4.53 (d, J= 7.6 Hz, 2H), 4.15-4.29 (m, 4H), 3.45 (s, 3H)

Example 38

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-d ihydropyrrolo[3,4-c]pyrazol-

2(4H)-yl)methyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benz o[d]imidazole-6-carboxylic acid

Step 1:

Synthesis of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 Example 38 by using 4-(((6-(2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)pyridin-2- yl)oxy)methyl)-3- fluorobenzonitrile trihydrobromide (80 mg, 0.138 mmol, K2CO3 (77 mg, 0.554 mmol) and methyl 2-(chloromethyl)-l-((3-methoxyoxetan-3-yl)methyl)-lH-benzo[d ]imidazole- 6-carboxylate (49.4 mg, 0.152 mmol) to obtained methyl 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zol-2(4H)-yl)methyl)-l- ((3 -methoxy oxetan-3-yl)methyl)-lH-benzo[d]imidazole-6-carboxylate (50 mg, yield 58 %) Mass m/z 624.1 [M+H] ⁺ Step 2:

Synthesis of 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-l-((3-methoxyo xetan-3-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 Example 38 by using methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihy dropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)- 1 -((3 -methoxy oxetan-3 -yl)m ethyl)- 1 H-benzo [d] imidazole-6- carboxylate (50 mg, 0.080 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2- a]pyrimidine (22.32 mg, 0.160 mmol) to obtained 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-5,6-dihydropyrrolo[3,4-c]pyra zol-2(4H)-yl)methyl)-l- ((3 -methoxyoxetan-3-yl)methyl)-l H-benzo [d]imidazole-6-carboxylic acid (12 mg, yield = 25%) Mass m/z = 610.1 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 8.33 (s, 1H), 8.29 (s, 1H), 7.72-7.88 (m, 5H), 7.63- 7.66 (d, J= 8.8Hz, 1H), 7.39-7.41 (d, J= 7.6Hz, 1H), 6.78-6.80 (d, J= 7.6 Hz, 1H), 5.56 (s, 2H), 4.94 (s, 2H), 4.69-4.70 (d, J= 7.2 Hz, 2H), 4.63-4.65 (d, J= 6.4 Hz, 2H), 4.36 (s, 2H), 3.80-3.96 (m, 4H), 3.43 (s, 3H)

Example 39

(S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl) -2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylic acid

Step 1

Synthesis of methyl (S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2, 6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 of example 38 using 4- (((2-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimidin-4- yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (90 mg, 0.132 mmol), methyl (S)-2- (chloromethyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6- carboxylate (42.9 mg, 0.145 mmol) with K2CO3 (91 mg, 0.661 mmol) to methyl (S)-2-((2-(4-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-2-yl)-2,6-dihydropyrrolo[3,4-c]py razol-5(4H)-yl)methyl)-l- (oxetan-2-ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (26 mg, 31% yield) mass m/z [M+H] ⁺ = 595

Step- 2

Synthesis of (S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2, 6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 of example 38 methyl (S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2, 6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-2-ylmethyl)-lH-benzo[d] imidazole-6-carboxylate (20 mg, 0.034mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine

(9.36 mg, 0.067 mmol) to obtain (S)-2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin- 2-yl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(o xetan-2-ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid. (18 mg, 86% yield) mass m/z [M+H] ⁺ = 581

1H-NMR (400 MHz, DMSO-d6) 5 8.55 (s, 1H), 8.55-8.54 (d, J= 5.6 Hz, 1H), 8.27 (s, 1H), 7.93-7.95 (d, J= 9.6 Hz, 1H), 7.89-7.81 (m, 3H), 7.77-7.75 (d, J= 8 Hz, 1H), 7.68- 7.66 (d, J= 8 Hz, 1H), 5.64 (s, 2H), 5.08-5.07 (d, J= 4 Hz, 1H), 4.67-4.84 (m, 2H), 4.33- 4.50 (m, 4H), 3.97-3.94 (m, 4H), 2.50-2.72 (m, 2H)

Example 40

2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6 -dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylic acid

Step 1

Synthesis of methyl 2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 1 of example 38 using 4- (((2-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimidin-4- yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (90 mg, 0.132 mmol), methyl 2- (chloromethyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-car boxylate (41.1 mg, 0.145 mmol) with K2CO3 (91 mg, 0.661 mmol) to obtain methyl 2-((2-(4-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-2-yl)-2,6-dihydropyrrolo[3,4-c]py razol-5(4H)-yl)methyl)-l- (2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate (50 mg, 64.9 % yield) mass m/z [M+H] ⁺ = 583 Step- 2

Synthesis of 2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 2 of example 38 using methyl 2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6-di hydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylate (50 mg, 0.086 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (23. 89 mg, 0.172 mmol) to obtain 2-((2-(4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid (15 mg, 29.5 % yield) mass m/z [M+H] ⁺ = 569 1H-NMR (400 MHz, DMSO-d6) 5 8.55 (s, 1H), 8.37-8.33 (d,J=16 ,1H), 8.18 (s, 1H), 7.95-7.93 (d, J= 8 Hz, 1H), 7.89-7.85 (m, 2H), 7.82-7.80 (m, 2H), 7.77-7.75 (d, J= 8 Hz, 1H), 5.64 (s, 2H), 4.61(s, 2H), 4.33 (s, 2H), 3.91 (s, 2H), 3.86 (d, 2H), 3.71-69 (d, 2H), 329 (d, 3H)

Intermediate 19 :

Methyl 2-(chloromethyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d]imidazole- 6-carboxylate -nitro-3-((oxetan-3-ylmethyl)amino)benzoate Oxetan-3-ylmethanamine (175 mg, 2.009 mmol) was dissolved in THF (20 ml) was followed by addition of methyl 3-fluoro-4-nitrobenzoate (400 mg, 2.009 mmol). To the reaction mixture TEA (1.6 ml, 11.48 mmol) was added. The reaction mixture was kept to completion at 60-70 °C for 1.5 to 2 hours. TLC was checked for completion of reaction. During work-up water was added into it and extract it with EA. After evaporation this crude was purify by combiflash. 450 mg, yield 90%)

Step-2

Synthesis of methyl 4-amino-3-((oxetan-3-ylmethyl)amino)benzoate

To a solution of methyl 4-nitro-3-((oxetan-3-ylmethyl)amino)benzoate (450 mg, 1.690 mmol) in THF (1.5 ml) was added Pd-C (90 mg, 0.085 mmol) and RM stirred under H2 balloon pressure till disappearance of yellow color to became colorless RM, about 1 hrs. TLC-complies. Filtered through celite and concentrated under below 40 °C bath temp. To get light brown oily compound. (380 mg, yield 86%) Mass m/z 237 [M+H] ⁺

Step-3

Synthesis of methyl 2-(chloromethyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d]imidazole- 6-carboxylate

To a solution of methyl 4-amino-3-((oxetan-3-ylmethyl)amino)benzoate (380 mg, 1.608 mmol) in ACN (3.5 ml) were added pTsOH (30.6 mg, 0.161 mmol) and 2-chl oro-1, 1,1- trimethoxy ethane (373 mg, 2.412 mmol) at RT and heated to 60 °C for 5 hrs. TLC- complies. Directly adsorbed on silica and eluted with 0 to 60 % EA in hexane (253 mg, yield 52%) Mass m/z 295.1 [M+H] ⁺ Example 41

2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6 -dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylic acid

Step-1

Synthesis of methyl 2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 example- 1 by using 4- (((4-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyrimidin-2- yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) and methyl 2-(chloromethyl)-l-(2- methoxyethyl)-lH-benzo[d]imidazole-6-carboxylate to obtained methyl 2-((2-(2-((4- cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-dihydropyrrolo[ 3,4-c]pyrazol-5(4H)- yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imidazole-6-carboxy late (25 mg, yield 48 %) Mass m/z 583.4 [M+H] ⁺ Step-2

Synthesis of 2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyet hyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 example- 1 by using methyl 2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-di hydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylate to obtained 2-((2-(2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)-2,6-di hydropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(2-methoxyethyl)-lH-benzo[d]imi dazole-6-carboxylic acid (12 mg, yield 45.6%) Mass m/z 569.5 [M+H] ⁺

1H-NMR (400 MHz, DMSO-d6) 8.5 (d, J=5.6Hz,lH), 8.21 (s, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.54-7.28 (m, 3H), 5.6(s, 2H), 4.64 (t, J = 5.2 Hz, 2H), 4.28 (s, 2H), 3.98 (s, 2H), 3.93 (s, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.33 (s, 3H).

Example 42

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5 ,6-tetrahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-3 -ylmethyl)- 1 H-benzo [d] imidazole-6-carboxylic acid

Synthesis of methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 1 by using 3- fluoro-4-(((6-(3 ,4, 5,6-tetrahydropyrrolo [3 ,4-c] pyrrol-2( 1 H)-yl)pyridin-2- yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulfonate) (63 mg, 0.093 mmol), potassium carbonate (63.9 mg, 0.463 mmol) and methyl 2-(chloromethyl)-l-(oxetan-3- ylmethyl)-lH-benzo[d]imidazole-6-carboxylate (24.55 mg, 0.083 mmol), to obtained methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (24 mg, yield 44 %) Mass m/z 595.4 [M+H] ⁺ Step 2: 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-3 -ylmethyl)- 1 H-benzo [d] imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 Example 1 by using methyl 2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (24 mg, 0.040 mmol) and l,3,4,6,7,8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (11.69 mg, 0.084 mmol) to obtained 2-((5-(6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2-yl)-3,4,5,6-tetrahydropyrrolo[3,4 -c]pyrrol-2(lH)-yl)methyl)- l-(oxetan-3-ylmethyl)-lH-benzo[d]imidazole-6-carboxylic acid (5 mg, yield 18%) Mass m/z 581.4 [M+H] ⁺ 'H-NMR (400 MHz, DMSO-d6) 5 8.36 (s, 1H), 7.86-7.89 (m, 4H), 7.68-7.75(m, 3H), 7.49 (s, 1H), 6.11(d, J=8.0Hz, 2H),5.45 (s, 2H), 4.71-4.73 (m, 2H), 4.59-4.63(m, 2H), 4 45-448(m, 4H), 4.15(m, 8H)

Example 43

2-((5-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-3,3a, 4,6a- tetrahydrocyclopenta[c]pyrrol-2(lH)-yl)methyl)-l-(((S)-oxeta n-2-yl)methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Step 1:

Synthesis of methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-yl methyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 1 by using 3 4-(((6-(5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)pyridin-2- yl)oxy)methyl)-3- fluorobenzonitrile bis(4-methylbenzenesulfonate) (100 mg, 0.147 mmol), K2CO3 (102 mg, 0.736 mmol) and methyl 2-(chloromethyl)-l-(oxetan-3-ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (43.4 mg, 0.147 mmol) to obtained methyl 2-((2-(6-((4- cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihydropyrrolo[3, 4-c]pyrazol-5(4H)- yl)methyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d]imidazole-6-carb oxylate (25 mg, yield 29 %) Mass m/z 594.4 [M+H] ⁺ Step 2:

Synthesis of 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 Example 1 by using methyl 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6-dihy dropyrrolo[3,4- c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d] imidazole-6-carboxylate (20 mg, 0.034 mmol) and l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (9.38 mg, 0.067 mmol)to obtained 2-((2-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)methyl)-l-(oxetan-3-yl methyl)-lH- benzo[d]imidazole-6-carboxylic acid (8 mg, yield 41%) Mass m/z 580.4 [M+H] ⁺ 1H-NMR (400 MHz, DMSO-d6) 5 12.90 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 7.67-7.93 (m, 5H), 7.67-7.69 (d, J= 7.6Hz, 1H), 7.39-7.41 (d, J= 7.6 Hz, 1H), 6.78-6.80 (d, J= 7.6Hz, 1H), 5.57 (s, 2H), 4.75-4.77 (d, J=7.6Hz, 2H), 4.48-4.59 (m, 4H), 4.33 (s, 2H), 3.87-3.91 (m, 4H), 3.57-3.63 (m, 1H)

Example 44

2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3, 4,5,6-tetrahydropyrrolo[3,4- c]pyrrol-2( 1 H)-yl)methyl)- 1 -(oxetan-3 -ylmethyl)- 1 H-benzo [d] imidazole-6-carboxylic acid Step-1

Synthesis of methyl (S)-2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4,5,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-2- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate

Title compound was synthesized as per procedure given in step 9 Example 1 by using 3- fluoro-4-(((4-(3 ,4, 5,6-tetrahydropyrrolo [3 ,4-c] pyrrol-2( 1 H)-yl)pyrimidin-2- yl)oxy)methyl)benzonitrile bis(4-methylbenzenesulf onate) (100 mg, 0.147 mmol), K2CO3 (101 mg, 0.733 mmol) and methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)- 3H-imidazo[4,5-b]pyridine-5-carboxylate (44mg, 0.147 mmol) to obtained methyl 2-((5- (2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5,6-tet rahydropyrrolo[3,4-c]pyrrol- 2(lH)-yl)methyl)-l-(oxetan-3-ylmethyl)-lH-benzo[d]imidazole- 6-carboxylate (50 mg, yield 57%) Mass m/z 596.5 [M+H] ⁺

Step-2

Synthesis of 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylic acid

Title compound was synthesized as per procedure given in step 10 Example 1 by using methyl 2-((5-(2-((4-chloro-2-fluorobenzyl)oxy)pyrimidin-4-yl)-3,4,5 ,6- tetrahydropyrrolo[3,4-c]pyrrol-2(lH)-yl)methyl)-l-(oxetan-3- ylmethyl)-lH- benzo[d]imidazole-6-carboxylate (0.05 g, 0.083 mmol) and 1,3, 4,6,7, 8-hexahydro-2H- pyrimido[l,2-a]pyrimidine (24 mg, 0.172 mmol) to obtained 2-((5-(2-((4-chloro-2- fluorobenzyl)oxy)pyrimidin-4-yl)-3 ,4, 5 ,6-tetrahydropyrrolo [3 ,4-c]pyrrol-2( 1 H)- yl)methyl)- 1 -(oxetan-3 -ylmethyl)- 1 H-benzo [d] imidazole-6-carboxylic acid (5 mg, yield 7 %) Mass m/z 591.4 [M+H]

1H-NMR (400 MHz, DMSO-d6) 5 12.9O(1H, s), 8.3O(1H, s), 8.1O(1H, dd, J=12.3Hz& J=4.3Hz), 8.02(lH, dd, J=11.2&J=5.6Hz), 7.87(1H, d, J=7.2Hz), 7.81(1H, s), 7.3O(1H, d, 9Hz), 7.25(1H, dd, J=11.2Hz& J=2.2Hz), 6.29(1H, m), 5.29(2H, s), 4.93(2H, m), 4.55(2H,m), 4.56(2H,s), 3.86(2H, s), 3.85(4H, m), 3.09(4H, m), 2.5(1H, m)

Intermediate 20:

Synthesis of methyl 2-(chloromethyl)-l-(thiazol-5-ylmethyl)-lH-benzo[d]imidazole -6- carboxylate

Step-1

Synthesis of thiazol-5-ylmethyl methanesulfonate

To a cooled solution of thiazol-5-ylmethanol (5g, 43.4 mmol) in DCM (50 ml) at 0°C , TEA (12.10 ml, 87 mmol) was added dropwise followed by Ms-Cl (4.40 ml, 56.4 mmol) at same temp. The reaction mixture was stirred at rt for 4 hrs till SM vanished on TLC. Quenched with Water & extracted with EtOAc to get Crude, was purified by column chromatography to obtained 1.58 g liquid compound (Yield 18.8%). Mass m/z 194.235 [M+H] ⁺ Step-2

Synthesis of 5-(azidomethyl)thiazole

To a solution of thiazol-5-ylmethyl methanesulfonate (0.1 g, 0.518 mmol) in DMF (2 ml), was add SODIUM AZIDE (0.067 g, 1.035 mmol) and leave the reaction to stir at room temperature for 20 h. Dilute the reaction mixture by the addition of water and extract with EtOAc .Wash the combine organic layers with brine. Dry over Na2SO4 and filter. Remove the solvent in vacuo and purify the crude by flash column chromatography to obtained 0.065 g liquid compound (yield 90%). Mass m/z 141.164 [M+H] ⁺

Step-3

Synthesis of thiazol-5-ylmethanamine

To a solution of 5-(azidomethyl)thiazole (3.13 g, 22.33 mmol) in THF (30 ml) & Water (9.00 ml), triphenylphosphine (7.61 g, 29.0 mmol) was added at rt, reaction mixture was stirred at r.t , SM vanished in 2 hrs. Acid-Base Workup : Quenched Solvent was evaporated at high vacuum, HC1 added to remaining aqueous solution to make a salt, washed with EtOAc to remove PPh3 & PPh3O multiple time, aqueous was separated & Basify to ppt the Amine, was extracted in DCM, Combine layer was passed through hyflow to remove emulsion & aqueous Layer was saturated by adding NaCl to facilate Extraction of Amine to DCM, Solvent was evaporated to dryness, Product was stored under -20°C to obtained 0.56 g off white liquid. (Yield 21.97 %). Mass m/z 115.166 [M+H] ⁺

Step-4

Synthesis of methyl 4-nitro-3-((thiazol-5-ylmethyl)amino)benzoate To a solution of methyl 3-fluoro-4-nitrobenzoate (30 mg, 0.151 mmol) & [Reactants] in DMF (1 ml), was added TEA (0.063 ml, 0.452 mmol) at 20°C. The reaction mixture was stirred at same temp for 2 hrs. Workup: Diluted with water & extracted with EtOAc & purified by column chromatography.to obtained 42.0 mg light yellow solid compound (yield 95%). Mass m/z 294 [M+H] ⁺

Step-5

Synthesis of methyl 4-amino-3-((thiazol-5-ylmethyl)amino)benzoate

To a solution of [Products] in EtOH (10ml) & Water (4.00 ml) system solvent, IRON (0.876 g, 15.68 mmol) & ammonium chloride (0.839 g, 15.68 mmol) was added at R.T. & heated at 70°C for 3 hrs. Workup : After completion , Solution was filtered through Hyflow, rinsed with (1: 1) MeOH:DCM , Filtrate was evaporated at high vacuum, residue was dissolved in water & compound was extracted in EtOAc & purified by combiflash column to obtained 0.35 g light yellow solid compound (yield 40.7 %). Mass m/z 264 [M+H] ⁺

Step-6

Synthesis of methyl 2-(chloromethyl)-l-(thiazol-5-ylmethyl)-lH-benzo[d]imidazole -6- carboxylate

To A solution of methyl 4-amino-3-((thiazol-5-ylmethyl)amino)benzoate (350 mg, 1.329 mmol) & 2-chl oro-1, 1,1 -trimethoxyethane (370 mg, 2.393 mmol) in Acetonitrile (4 ml), /?-toluenesulfonic acid monohydrate (50.6 mg, 0.266 mmol) was added as catalyst at r.t. & RM was refluxed at 80°C for 7 hrs. Workup: Quenched with water & extracted with EtOAc quantitatively, crude was purified by column chromatography.to obtained 215 mg off white solid (yield 50.3 %). Mass m/z 322 [M+H] ⁺ . Screening small molecule GLP-1R agonist using cAMP assay

To identify GLP-1R agonist, a cell based cAMP measurement assay has been used. Briefly, CHO-hGLP-lR (stably expressing full length human GLP-1R) were routinely maintained in complete DMEM media containing 800 pg/ml Neomycin. On day 1, 50,000 cells/well were seeded in 96 well cell culture plate. Next day, seeding media was completely aspirated and cells were primed with (100 pl/well) plain media (without FBS) containing 0.1% BSA, 100 pM and 3 pM BETP (2-(Ethylsulfinyl)-4-[3- (phenylmethoxy)phenyl]-6-(trifluoromethyl)pyrimidine) for 30 mins in humidified CO2 incubator. This was followed by addition of 2X drug solution (100 pl/ well) made in the same priming media and incubated for another 30 mins in humidified CO2 incubator. After that, cells were lysed (20 pl/well) with lysis buffer (Tris-Cl, pH 8.0, 150 mM NaCl and 0.1% Triton-X 100) for 20 mins on a plate shaker at RT. To clarify, lysate was centrifuged for 10 min at 4000 rpm at RT. Finally, 10 pl of lysate was used for cAMP measurement using cAMP Gs dynamic kit (Cis Bio, cat no: 62AM4PEB) according to the manufacturer’s protocol. % cAMP stimulation was measured with respect to the vehicle containing 0.4% DMSO.

Table 1: GLPIR agonism of prepared examples

In one of the embodiments compound of formula (I) of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.

The compounds of formula (I) or pharmaceutical compositions containing them are suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration for the treatment of various disease conditions as described hereinbefore.

The pharmaceutical composition is provided by employing conventional techniques. Preferably the composition is in unit dosage form containing an effective amount of the active component, that is, the compounds of formula (I) according to this invention.

The quantity of active component, that is, the compounds of formula (I) according to this invention, in the pharmaceutical composition and unit dosage form thereof may be varied or adjusted widely depending upon the particular application method, the potency of the particular compound and the desired concentration. Generally, the quantity of active component will range between 0.5% to 90% by weight of the composition.

Thus, a pharmaceutical composition comprising the compounds of the present invention may comprise a suitable binder, suitable bulking agent &/or diluent and any other suitable agents as may be necessary. Optionally, the pharmaceutical composition may be suitably coated with suitable coating agents. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.